00 Cover 1

VOL. 58, NO. 12

THE JOURNAL OF

DECEMBER 1997

CLINICAL PSYCHIATRY A CME Certified Publication

Volume 58

December 1997

Number 12

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e at du ra ted stgprin Po be ns ay ia y m ic op ys nal c Pherso 97 ne p

THE JOURNAL OF CLINICAL PSYCHIATRY

Lamotrigine in Rapid-Cycling Bipolar Disorder

S. Hossein Fatemi, Daniel J. Rapport, Joseph R. Calabrese, and Paul Thuras

CME ARTICLE

Determinants of Pharmacologic Treatment Failure in Panic Disorder Deborah S. Cowley, Eileen H. Ha, and Peter P. Roy-Byrne

Index to Volume 58

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INDEX

Celebrating Over 50 Years of Service to Psychiatrists

PAGES 518–578

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CLINICAL PSYCHIATRY

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T he Journal of Clinical Psychiatry (ISSN 01606689) is published monthly by Physicians Postgraduate Press, Inc. Address correspondence to P.O. Box 752870, Memphis, TN 38175-2870; phone inquiries to (901) 751-3800. Subscription rates: domestic, $70.00; foreign, $120.00; student, $50.00. Single copies of the Journal or supplements are $8.50 (including postage and handling); prepayment is requested.

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a du ra ted stgprin Po be ns ay ia y m ic op ys nal c Pherso 97 ne p

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The Journal of Clinical Psychiatry is indexed in Index Medicus, Excerpta Medica, Psychological Abstracts, Current Contents, Science Citation Index, Hospital Literature Index, Biological Abstracts, Cumulative Index of Allied Health and Nursing, International Nursing, Industrial Medicine, Chemical Abstracts, Adolescent Mental Health Abstracts, and Alcohol and Alcohol Science Problems Database.

BOARD

THE JOURNAL OF

CLINICAL PSYCHIATRY BRAINSTORMS 520 Serotonin: It’s Possible to Have Too Much of a Good Thing.

Stephen M. Stahl

ORIGINAL ARTICLES 522 Lamotrigine in Rapid-Cycling Bipolar Disorder.

S. Hossein Fatemi, Daniel J. Rapport,

Joseph R. Calabrese, and Paul Thuras

528 Venlafaxine in Dysthymic Disorder.

David L. Dunner, Helen E. Hendrickson,

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Carolyn Bea, and Chris B. Budech

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532 Double-Blind Comparison of Bupropion Sustained Release and Sertraline Richard J. Kavoussi, R. Taylor Segraves, Arlene R. Hughes, in Depressed Outpatients. John A. Ascher, and J. Andrew Johnston

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538 The Effects of Risperidone on the Five Dimensions of Schizophrenia Derived by Factor Analysis: Combined Results of the North American Trials. Stephen R. Marder,

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John M. Davis, and Guy Chouinard

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CME ACTIVITY

555 Determinants of Pharmacologic Treatment Failure in Panic Disorder. Deborah S. Cowley, Eileen H. Ha, and Peter P. Roy-Byrne LETTERS TO THE EDITOR

547 Clozapine-Benzodiazepine Interactions. and Robert Cancro

548 Mania From Dexfenfluramine.

Imran Faisal, J. P. Lindenmayer, Zebulon Taintor,

Charles L. Bowden and James Dickson, Jr.

549 Effects of Olanzapine on Polydipsia and Intermittent Hyponatremia.

Kimberly H. Littrell,

Craig G. Johnson, Steven H. Littrell, and Carol D. Peabody

549 A Possible Pharmacokinetic Interaction Between Fluoxetine and Acetylsalicylic Acid. Mujeeb U. Shad, Anne T. Harvey, and James B. Lucot Raymond A. Faber

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550 Asystole in ECT.

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BOOK REVIEWS

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AUTHOR INDEX

573

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SUBJECT INDEX

see July 1997, pages 287–288

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INFORMATION FOR AUTHORS

Volume 58

December 1997

Number 12

BRAINSTORMS Clinical Neuroscience Update

Serotonin: It’s Possible to Have Too Much of a Good Thing Stephen M. Stahl, M.D., Ph.D.

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Issue: Although serotonin can mediate numerous therapeutic actions, too much serotonin can cause dangerous toxicity.

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erotonin has been at the heart of innovation in psychopharmacology for the past decade.1,2 Serotonin selective reuptake inhibitors (SSRIs) in particular have led the way, but many other agents also act on serotonin, in one fashion or another.2 These include other antidepressants, as well as novel atypical antipsychotics, various antiemetics, modern migraine therapies, and certain drugs of abuse. Also included is the appetite suppressant fenfluramine, both in its d,l form (Pondimin) and in its pure d form (Redux).2

serotonin yet simultaneously block serotonin’s actions at some of its undesired places, reducing the price of doing business in some cases.4 Under other circumstances, however, the price escalates beyond what is reasonable.

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only antidepressant action, but also therapeutic effects in a number of other conditions, including obsessivecompulsive disorder, panic attacks, bulimia, and others.3 However, the price of doing business is often higher than desired. Increasing serotonin in places where it is not welcome can produce the side effects of anxiety, insomnia, sexual dysfunction, and gastrointestinal disturbances.4 Most of these problems are more of a nuisance than a danger and commonly abate with time as tolerance to them develops. Furthermore, newer antidepressants such as nefazodone and mirtazapine enhance

Enhancing serotonin in key CNS pathways and at desired serotonin receptor subtypes hypothetically mediates therapeutic actions in depression, obsessive-compulsive disorder, panic disorder, and bulimia

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Toxic levels of serotonin can cause a life-threatening serotonin syndrome of fever, myoclonus, coma, seizures, cardiovascular collapse, and death

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Damage to cardiac valves in patients receiving Fen-phen led to withdrawal of the serotonin-releasing agent fenfluramine from the U.S. market and is provoking a search to determine whether serotonin is responsible

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BRAINSTORMS is a monthly section of The Journal of Clinical Psychiatry aimed at providing updates of novel concepts emerging from the neurosciences that have relevance to the practicing psychiatrist. From the Clinical Neuroscience Research Center in San Diego and the Department of Psychiatry at the University of California San Diego. Reprint requests to: Stephen M. Stahl, M.D., Ph.D., Editor, BRAINSTORMS, 8899 University Center Lane, Suite 130, San Diego, CA 92122.

Take-Home Points

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Does Serotonin Use Demand Too High of a Price? When the SSRIs are administered, they increase serotonin in every serotonin pathway and at every one of the dozen or more serotonin receptor subtypes. Although this is something akin to dunking the brain into a bucket of serotonin, the net consequence is not

Can You Have Too Much Serotonin? If serotonin increases too much, it can be life-threatening and occasionally lethal. Serotonin toxicity manifests itself after certain drug combinations, especially when SSRIs are combined with monoamine oxidase inhibitors.5 The consequential serotonin syndrome can mimic the

J Clin Psychiatry 58:12, December 1997

BRAINSTORMS Clinical Neuroscience Update

? Cardiac valve pathology

Too Much Serotonin

Serotonin syndrome: fever, tremor, coma, seizures, death GI disturbance Sexual dysfunction Insomnia Anxiety

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inhibitors like SSRIs, in addition to being inhibitors of serotonin synthesis and perhaps directly active at some serotonin receptor subtypes.2–4,9 So far, there is no rationale or empiric observations to create any concern that the SSRIs cause cardiac problems similar to those associated with fenfluramine. Nevertheless, vigilance for the unexpected is the duty of prescribers. In summary, there is good news and there is bad news about serotonin. The right amount in the right places is a powerful therapeutic tonic. But, too much in the wrong places can be hazardous to your health. ◆

1. Sambunaris A, Keppel Hesselink J, Pinder R, et al. Development of new antidepressants. J Clin Psychiatry 1997;58(suppl 6):40–53 2. Stahl SM. Essential Psychopharmacology. New York, NY: Cambridge University Press; 1996 3. Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors: serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. In press 4. Stahl SM. Psychopharmacology of Antidepressants. London, England: Dunitz Press; 1997 5. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705–713 6. Levine RJ. Serotonin and the carcinoid syndrome: histamine and mastocytosis. In: Bondy PK, Rosenberg LE, eds. Duncan’s Diseases of Metabolism. Philadelphia, Pa: WB Saunders; 1974:1651–1684 7. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337: 581–588 8. Redux (d-fenfluramine). Physicians’ Desk Reference. Montvale, NJ: Medical Economics; 1997:2911–2914 9. Harvey JA, McMaster SE. Fenfluramine: cumulative neurotoxicity after chronic treatment with low dosages in the rat. Communications in Psychopharmacology 1977;1:3–17

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REFERENCES

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symptoms of neuroleptic malignant syndrome but does not have muscular breakdown. The Bulimia is a chance assoserotonin syndrome is ciation or whether a combination of fever, Panic fenfluramine myoclonus, coma, seiOCD causes this damzures, cardiovascular Depression age. Whether recollapse, and death. Not Enough Serotonin lease of serotonin Treatment is with coolonto these valves ing mattresses, serotonin-2 antagonists, dopamine agonists, by fenfluramine is the mechanism of this damage is a possibility, but it is and intensive care.5 unproven. Although the side effects of SSRIs Fenfluramine is associated with alone are hypothetically due to serotoother toxicities, both cardiovascular nin as well, the term serotonin syndrome is reserved for the clinical and CNS; that is, there is an increased incidence of primary pulmonary hyconsequences of dangerous serotonin pertension not only in fenfluramine toxicity. Such toxicity is fortunately users, but also in those with obesity, rare, as the risk of certain serotonergic drug combinations is generally well i.e., those most likely to take fenfluramine in the first place.8 Long-lasting known. depletion of serotonin from the brain due to destruction of serotonergic Does Too Much Serotonin axon terminals is also observed in rats Break Your Heart? exposed to fenfluramine brain conBoth drugs and diseases can increase the release of circulating sero- centrations about 10 times higher than tonin. For example, some malignant those in man.9 Although there have carcinoid tumors secrete serotonin been no reports of long-lasting or perand can cause waves of serotonin re- manent serotonin depletion in brains lease into the systemic circulation, of human fenfluramine users, or any which in turn can make the patient proven changes in behavior, this possibility has always been a nagging flush.6 Over time, these tumors are associated with cardiac valvular dam- concern for the long-term safety of age, especially on the right side of the fenfluramine use. Since fenfluramine also causes heart, which presumably gets bombed with the serotonin before the seroto- long-term depletion of serotonin in nin moves to the lungs where meta- circulating platelets, as do the SSRIs, there is some pharmacologic overlap bolic enzymes chew it up.6 Recent reports indicate that similar between these two classes of drugs. cardiac valvular pathology is associ- Although fenfluramine and its active ated with fenfluramine administra- metabolite are predominantly serototion.7 It is not known whether this nin releasers, they are also reuptake

521


Lamotrigine in Rapid-Cycling Bipolar Disorder S. Hossein Fatemi, M.D., Ph.D., Daniel J. Rapport, M.D., Joseph R. Calabrese, M.D., and Paul Thuras, Ph.D.

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Background: We evaluated the antidepressant and mood-stabilizing effects of lamotrigine, a novel anticonvulsant, in a group of rapid-cycling bipolar patients. Most were already nonresponders or poor partial responders to other conventional mood-stabilizing agents. Method: This open, naturalistic, and prospective study was conducted with five rapid-cycling bipolar patients (DSM-IV). Each received lamotrigine titrated to a minimum dose of 150 mg/day as monotherapy or in combination with other psychotropic agents. Patients were assessed with the Global Assessment Scale (GAS), Beck Depression Inventory (BDI), and Young Mania Rating Scale (YMRS) for evidence of cycling mood. Results: Lamotrigine was used at a mean ± SD dose of 185.0 ± 33.5 mg/day for 225.8 ± 28.0 days. Random regression modeling of data showed significant dose- and time-dependent improvements in depressive symptoms and social function of patients taking lamotrigine (Dose: z = 2.17, p < .03 for BDI, z = 4.44, p < .001 for GAS; Time: z = –3.79, p < .001 for BDI, z = 2.16, p < .03 for GAS). Further random regression modeling analysis of change over time in symptoms prior to lamotrigine compared with symptoms during lamotrigine treatment showed a significant treatment by time effect for GAS (z = 2.40, p < .016) and a trend for BDI scores (z = –1.79, p < .073). No significant time or dosage effect or time by treatment effect was observed for YMRS. Finally, t statistics showed a significant reduction in mean BDI scores following treatment with lamotrigine (t = –5.26, p < .006). Lamotrigine was well tolerated by all patients; only one patient experienced several side effects, which were probably due to interaction between several psychotropic medications. Conclusion: Lamotrigine augmentation therapy and monotherapy appeared to have moodstabilizing and antidepressant efficacy in the treatment of five rapid-cycling bipolar patients. The effect persisted for an average of 7.5 months. (J Clin Psychiatry 1997;58:522–527)

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Received Feb. 26, 1997; accepted June 16, 1997. From the Department of Psychiatry (Drs. Fatemi and Thuras) and Department of Cell Biology and Neuroanatomy (Dr. Fatemi), University of Minnesota, Minneapolis, and the Department of Psychiatry, Case Western Reserve University (Drs. Rapport and Calabrese), Cleveland, Ohio. The authors gratefully acknowledge the secretarial assistance of Ms. Janet Bockenstedt. Reprint requests to: S. Hossein Fatemi, M.D., Ph.D., Departments of Psychiatry and of Cell Biology and Neuroanatomy, University of Minnesota, School of Medicine, 420 Delaware Street Southeast, Box 392, University of Minnesota Hospital and Clinic, Minneapolis, MN 554550392.

apid-cycling bipolar disorder affects 13% to 20% of all bipolar patients, and 72% to 82% of these patients are resistant to lithium therapy.1 This variant of bipolar disorder is associated with greater morbidity such as substance abuse, anxiety disorders, borderline personality disorder, and hypothyroidism.1,2 Patients also suffer a higher rate of mortality by suicide.3 Alternative therapeutic agents are needed for this population since the currently available mood stabilizers can be ineffective or inadequate at relieving the depressive component of mood cycles.4 An additional concern is that the use of antidepressants in bipolar patients has been associated with the induction of mania and the development of rapid cycling,5 which often precludes their use on a continued basis. Recently, we reported on the antidepressant effects of lamotrigine in a patient with rapid-cycling bipolar I disorder.6 In the current preliminary study, we have extended our observations to a similar group of five rapid-cycling bipolar patients. All patients exhibited greater moodstabilizing as well as significant antidepressant effect for periods of treatment ranging from 189 to 265 days. To our knowledge, this is the first report of lamotrigine’s moodstabilizing and antidepressant effects in a population of treatment-resistant rapid-cycling bipolar patients.

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METHOD All patients referred to the Mood Disorders Program at Case Western Reserve University and University Hospitals of Cleveland, Ohio, between February 1990 and February 1997 who were diagnosed with rapid-cycling bipolar I and II disorders were eligible for the study. Patients were diagnosed by one of us (D.J.R.) using a systematic 522 521

Fatemi et al.

Table 1. Demographic and Clinical Data for Patients on Lamotrigine Treatment*

Patient 1

Age (y) Sex 43 F 27

F

3

40

F

4

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5

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Diagnosis and Duration BPI, mixed RC 3 y BPII, RC 14 y BPII, depressed RC 20 y BPII, RC, depressed 20 y BPII, RC 20 y

F

Comorbid Diagnoses

Personality disorder NOS

Total Treatment Time (d) 305

Concurrent Medications Fluoxetine

Duration of Duration of Duration Treatment Monotherapy Final of Treatment With With Dose of With Other Lamotrigine Lamotrigine Lamotrigine Agents (d) (d) (d) (mg) 40 265 190 225

Divalproex

1502

1290

212

107

200

Divalproex

803

571

232

90

200

1677

1446

231

0

150

1291

1102

189

43

150

225.8 ± 28.0

86 ± 71.6

185.0 ± 33.5

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Borderline PD, Divalproex, lithium, hypothyroidism tetraiodothyronine, triiodothyronine Panic disorder, Divalproex, borderline PD, triiodothyronine, hypothyroidism fluoxetine, methylphenidate

889.8 ± 578.4

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Total 39 1115.6 (mean ± 7.8 ± 559.0 ± SD) *Abbreviations: BPI = bipolar I, BPII = bipolar II, PD = personality disorder, RC = rapid cycler.

Five women ranging in age from 27 to 48 years entered the study. Their duration of treatment before lamotrigine ranged from 40 to 1446 days, with a mean of 889.8 days (Table 1). The patients had suffered from bipolar I or II disorder with rapid cycling for a period of 3 to 20 years and were generally nonresponders or partial responders to other mood stabilizers. Three of the patients also carried other diagnoses such as borderline personality disorder (Patients 4 and 5), personality disorder NOS (Patient 3), panic disorder (Patient 5), and hypothyroidism (Patients 4 and 5) (Table 1). Duration of lamotrigine treatment ranged from 189 to 265 days with a mean of 225.8 days (Table 1). The mean dose of lamotrigine was 185 mg/day (Table 1). Four of the patients were successfully tapered off all other medications other than thyroid supplements. One patient continued to be treated with a combination of lithium, divalproex sodium, and lamotrigine (Table 1). Comparison of behavioral scores before and after treatment with lamo-

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RESULTS

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Statistical Analysis Random regression models were computed to evaluate change in BDI, GAS, and YMRS scores as a function of time and treatment dose with lamotrigine. Dose was modeled as a lagged variable, with dosage prescribed at one date predicting symptoms at the next measurement interval. Additional analyses were conducted to compare symptom change over time before and after administration of lamotrigine. In a random regression model,12,13 change over time is modeled at both the individual and population levels. Individual models of change over time are estimated and augmented using population-level trend data. This type of model offers some unique advantages over mixed-effects ANOVA models, which allow for random responses of in-

dividuals over time but are restricted to modeling time as a fixed effect. In random regression models, time can also be modeled as a random factor, and, thus, each individual can vary in both the number of measurements over time and the time course of those measurements. Furthermore, mixed-effects ANOVA models allow no missing data. Random regression models are based on an individual’s available data for each point, but augment from population data using empirical Bayes’ estimation methods when individual level data are missing. Thus, all available data can be used in the estimation of change. The MIXREG14 random regression program was used to fit the models.

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computerized checklist of the DSM-IV criteria.7 Patients with active drug or alcohol abuse or serious medical problems were excluded from this study. The method of the study was open, naturalistic, and prospective. In all cases, informed verbal and written consent was obtained after the procedure had been fully explained to each patient. Patients were monitored for symptoms of depression, mania/hypomania, and side effects every 4 to 6 weeks. Beck Depression Inventory (BDI),8 Young Mania Rating Scale (YMRS),9 and Global Assessment Scale (GAS)10 scores were obtained during all visits by one rater (D.J.R.). The dose of lamotrigine was initiated and titrated to a minimum dose of 150 mg/day according to the FDAapproved protocol11 and previously reported.6 Patients initially received lamotrigine in conjunction with other agents including fluoxetine, methylphenidate, divalproex sodium, triiodothyronine, tetraiodothyronine, and lithium.



Table 2. BDI, GAS, and YMRS Scores Before and After Treatment With Lamotrigine* BDIa

GASb

YMRSc

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Before After Before After Before After Patient Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD 1 17.33 12.1 6.17 2.9 61.67 2.9 74.50 4.6 6.67 5.7 1.17 2.0 2 13.87 14.2 4.50 3.6 66.24 13.7 81.67 7.5 0.24 1.2 1.50 3.7 3 12.11 6.6 6.00 6.4 73.89 9.3 79.00 8.2 0 0 0 0 4 11.58 8.6 8.75 6.5 64.96 7.3 52.47 9.2 0.13 0.7 0.47 0.8 5 19.57 10.6 11.25 5.0 66.63 9.8 76.00 1.7 0 0 0 0 Total mean 14.89 3.4 7.33 2.66 66.67 4.5 72.90 11.7 1.40 2.9 0.67 0.7 *Abbreviations: BDI = Beck Depression Inventory, GAS = Global Assessment Scale, YMRS = Young Mania Rating Scale. Comparison of before vs after lamotrigine treatment scores: aBDI: t = –5.260, p < .006; bGAS: t = –1.223, p < .289; c YMRS: t = –0.649, p < .552.

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Figure 1. Individual BDI and GAS Scores Versus Lamotrigine Doses and Times of Treatment* 100

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trigine (Table 2) showed improvements in all scores; however, only the mean BDI score dropped significantly after treatment with lamotrigine (t ≅ –5.260, p < .006, Table 2). Random regression models examined change in symptoms over time during treatment with lamotrigine. It was found that BDI symptoms declined significantly over time (z = –3.79, p < .001) and GAS scores increased significantly over time (z = 2.16, p < .031) (Figure 1). A second set of models were then run in which change over time competed with change as response to dose. In these models, BDI symptoms no longer showed a significant time effect but did reveal a significant dose effect (z = 2.17, p < .030). There was a decrease of 4.1 symptoms for every 100 mg of lamotrigine administered. Similarly, for GAS, time was no longer a significant predictor, but there was a significant dose response (z = 4.44, p < .001). For every 100 mg of lamotrigine administered, there was a 10.5-point increase in GAS score (Figure 1). No significant time or dosage effects were observed for symptoms on the YMRS. Further random regression models examined change over time in symptoms before lamotrigine compared with symptoms during lamotrigine treatment. Total treatment time before lamotrigine ranged from 40 to 1446 days with a mean of 889.8 days. A significant treatment by time effect was observed for GAS scores (z = 2.40, p < .016). Improvement was 0.8 points per 100 days before lamotrigine (Figure 2) and 5.59 points per 100 days during lamotrigine treatment. A trend was also found when comparing change in BDI symptoms over time before and after treatment with lamotrigine (z = –1.79, p < .073). Before lamotrigine, BDI symptoms showed essentially no change, actually increasing 0.09 points per 100 days of treatment. Under lamotrigine, BDI scores decreased 3.9 points per 100 days of treatment. There was no significant time by treatment condition interaction for YMRS scores over the course of treatment before or after lamotrigine.

80

GAS BDI

0

0

50

100 150 Lamotrigine Dose (mg)

200

250

BDI vs Dose: intercept = 13.20, slope = –0.050, r2 = .30. GAS vs Dose: intercept = 51.96, slope = 0.116, r2 = .22.

100

GAS

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Illustrative Cases The following case vignettes demonstrate the symptoms present in this patient group before and after lamotrigine treatment.

40

BDI

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60

0

0

50

100 150 Days of Treatment

200

250

300

BDI vs Days of Treatment: intercept = 10.69, slope = –0.039, r2 = .22. GAS vs Days of Treatment: intercept = 60.24, slope = 0.063, r2 = .098 *Abbreviations: BDI = Beck Depression Inventory, GAS = Global Assessment Scale. Regression lines seen here are for descriptive purposes. Moreover, slopes and intercepts reported here are based on multiple data points from the same individuals and thus are estimates. See text for slopes and intercepts derived from the mixed regression analysis.

524 523

Fatemi et al.

Figure 2. Impact of Lamotrigine on Global Assessment Scale (GAS) Scores During Days of Treatment 100 After lamotrigine

90

GAS

80 70 Before lamotrigine

60

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50

30

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200

400

600

Before lamotrigine After lamotrigine

800

1000 1200 1400 1600

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Days of Treatment

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Case 1. A 43-year-old white woman with a 3-year history of bipolar I disorder, mixed, rapid-cycling subtype, presented in a mixed state. She had been taking fluoxetine 20 mg for over 1 year and presented because of persistently dysphoric mood. She was given the option to add lamotrigine to her regimen or a conventional mood stabilizer and elected lamotrigine therapy. Lamotrigine was initiated using the standard protocol. Within 1 month, she reported that her mood was significantly less sad, less irritable, and less dysphoric on the combination of lamotrigine 150 mg and fluoxetine 20 mg per day. After another month, the fluoxetine was tapered to 10 mg. After 81/2 weeks of combination therapy, she reported episodes of irritability that were more mild and being “calmer and more relaxed,” with cessation of crying spells and racing thoughts. Two weeks later, fluoxetine therapy was discontinued, and lamotrigine was empirically increased to 225 mg/day. Her mood assessed 11 weeks after starting treatment was determined to be euthymic. Case 2. A 27-year-old white woman with a 14-year history of bipolar II disorder, rapid-cycling subtype, presented to our clinic in 1992. Treatment with divalproex sodium was instituted at therapeutic levels, but, despite treatment, she continued to suffer major mood swings. Between 1992 and the initiation of lamotrigine in mid1995, she suffered six episodes of recurrent major depression and four episodes of unequivocal hypomania; each episode occurring while she was taking therapeutic levels of divalproex sodium sometimes in combination with antidepressants. In mid-1995, she failed to respond to a combination of divalproex sodium and carbamazepine because of intolerable side effects. Following this and during a brief euthymic interval, lamotrigine was started per the standard protocol and added to divalproex sodium 1500 mg/day. At the outset, our intention was to

titrate lamotrigine empirically to a dose of 150 mg, and, once a clinical response was evident, to taper her off of the divalproex sodium. Over the next 3 months, divalproex sodium was discontinued, and lamotrigine 200 mg/day was achieved. Since the completion of lamotrigine titration, her mood has been maintained, cycle free for the period of this study. Case 3. A 40-year-old white woman with a 20-year history of bipolar II disorder, rapid-cycling subtype and personality disorder NOS presented in the depressed phase of her illness to our clinic. She was initially treated with divalproex sodium monotherapy for 4 months until, because of persistent depression, sertraline was added. She remained on the combination of sertraline 100 mg/day and divalproex sodium (low blood levels of approximately 40 ng/L) for the next 11 months. Sertraline was discontinued because of persistently lowered libido. Over the next 5 months, she remained on divalproex sodium monotherapy but failed to tolerate this because of recurrent depression. At that time, lamotrigine therapy was offered and accepted. A combination of lamotrigine and divalproex sodium were used initially per the standard protocol. Her dosage of divalproex sodium remained unchanged initially, but, within 4 months, it was tapered and discontinued. Thereafter, she has remained on lamotrigine monotherapy with good effect. At the last evaluation, she described her mood swings as significantly more mild, lasting approximately 3 days and still occurring approximately every 2 weeks. She is no longer functionally impaired by her cycling. Case 4. A 37-year-old white woman with a 20-year history of bipolar II disorder, rapid-cycling subtype, had comorbid borderline personality disorder and hypothyroidism. Despite adequate treatment at therapeutic levels of lithium and divalproex sodium for 5 years, she suffered one episode of hypomania and two distinct episodes of recurrent depression 2 years apart, just prior to the introduction of lamotrigine therapy. She was offered lamotrigine as a possible therapeutic agent to be combined with her current doses of lithium and divalproex sodium with the hope that it would reduce or eliminate her recurrent mood swings. Lamotrigine was added according to the standard protocol in September 1995 and titrated empirically to 150 mg/day. The result has been a marked diminution of her affective instability and recurrent mood swings. She feels that her mood is euthymic except during the week prior to her menstrual flow. At that time, she still becomes much more melancholic and irritable. Once her period starts, she feels euthymic again and otherwise has no complaints. She continues to tolerate the medications well with just a minor tremor. Case 5. A 48-year-old white woman with a greaterthan-20-year history of bipolar II disorder, rapid-cycling subtype had comorbid panic disorder without agoraphobia and borderline personality disorder. She also suffered J Clin Psychiatry 58:12, December 1997


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from hypothyroidism for which she was being adequately supplemented. This patient was treatment responsive to low doses of divalproex sodium at consistent blood levels of 36 ng/L, in combination with triiodothyronine, methylphenidate, and fluoxetine up to 60 mg/day. However, she was unable to tolerate this combination of medications due to excessive weight gain of greater than 40 lb (> 18.2 kg). After achieving a 16-week euthymic interval, she was offered lamotrigine, which was added to her regimen per the standard protocol. In 2 months, the dose of lamotrigine was titrated empirically to 100 mg/day, at which point divalproex was tapered and discontinued over a 4-week period. Lamotrigine was then titrated to 150 mg/day. Because her mood remained stable over the next 4 months, fluoxetine and methylphenidate were tapered and discontinued. Since then, her mood has remained clinically euthymic on lamotrigine monotherapy.

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Drug names: carbamazepine (Tegretol and others), divalproex sodium (Depakote), fluoxetine (Prozac), lamotrigine (Lamictal), methylphenidate (Ritalin), sertraline (Zoloft).

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This study provides preliminary evidence that lamotrigine may be a safe and effective treatment for patients with treatment-resistant rapid-cycling bipolar disorder. Data collected so far suggest that lamotrigine is an effective antidepressant with potential to improve social functioning. A strength of this study is the analysis of cumulative data on each patient extending from 305 to 1677 days using random regression models. These models take into account the considerable heterogeneity in the response of individuals to treatment. Moreover, random regression models allow for the presence of missing data, timevarying covariates, and subjects measured at different time points.12–14 Using random regression models, we were able to derive several important findings concerning the effect of lamotrigine in treatment of five rapid-cycling bipolar patients. Lamotrigine either alone or in combination with other agents caused significant time-dependent increases in GAS scores compared with treatment prior to lamotrigine, thus contributing to the overall improvement in social functioning of these patients. A similar time-dependent trend was also seen when BDI scores were analyzed for a lamotrigine effect, indicating improvement in depressive symptoms. When mean BDI scores before and after treatment were investigated and analyzed, a significant lamotrigine effect could also be demonstrated. Finally, random regression models showed significant dose- and time-dependent improvements in social functioning and depression scales. Another strength of this study concerns the use of lamotrigine in a population of rapid-cycling patients who generally were nonresponders or poor responders to lithium, divalproex, and carbamazepine and were considered treatment refractory. Indeed, four of five patients who participated in this study had long histories of bipolar disorder

(14–20 years) and exhibited partial response or no response to various mood stabilizers and other agents. Addition of lamotrigine to their regimens decreased the frequency of cycling and improved their mood and social functioning. The limitations of our study included the open nature of this trial, i.e., no control group, and the small number of subjects. Furthermore, all subjects in this study consisted of female patients, and thus our data may not be extrapolated to male patients with bipolar disorder. Additionally, we cannot rule out the potential synergistic and mood-stabilizing effects of other agents taken by patients during this trial. Another limitation of this study relates to the ascertainment of diagnoses based on clinical interview and use of a systematic computerized checklist of DSM-IV criteria and not a structured diagnostic instrument. The current preliminary report extends our previous case report6 demonstrating the potential antidepressant effects of lamotrigine in a rapid-cycling bipolar patient. This report is the first report of a group of bipolar patients with rapid cycling who have responded favorably to the addition of lamotrigine for an average of 7.5 months. All patients tolerated the addition of lamotrigine. Only one patient while taking lithium and divalproex sodium concurrently experienced side effects including nausea, headache, dizziness, dry mouth, constipation, loose stools, rash, and tremor. Despite potential benefits of lamotrigine, the results of this study should be interpreted cautiously due to the open design of the study, small sample size, and use of concurrent psychotropic medications early during the initiation of the trial with lamotrigine. The study does show, however, the promise of a new mood-stabilizing agent that works through a novel mechanism of action by stabilizing presynaptic neural membranes, thereby modulating release of excitatory amino acids. Currently, a multicenter, placebo-controlled, fixed-dose study of the safety and efficacy of lamotrigine in the treatment of bipolar disorder is ongoing.15

REFERENCES

1. Calabrese JR, Fatemi SH, Kujawa MJ, et al. Predictors of response to mood stabilizers. J Clin Psychopharmacol 1996;16:24S–31S 2. Bauer MS, Calabrese JR, Dunner DL, et al. Multi-site data reanalysis: validity of rapid cycling as a course modifier for bipolar disorder in DSMIV. Am J Psychiatry 1994;151:506–515 3. Fawcett J, Scheftner W, Fogg L, et al. Time-related predictors of suicide in major affective disorder. Am J Psychiatry 1990;147:1189–1194 4. Okuma T. Effects of carbamazepine and lithium on affective disorders. Neuropsychobiology 1993;27:138–145 5. Altshuler LL, Post RM, Leverich GS, et al. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995; 152:1130–1138 6. Calabrese JR, Fatemi SH, Woyshville MJ. Antidepressant effects of la-

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motrigine in rapid cycling bipolar disorder [letter]. Am J Psychiatry 1996; 153:1236 7 . American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994:317–391 8. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–571 9. Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;133:429–435 10. Endicott J, Spitzer RL, Fleiss JL, et al. The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 1976;33:766–771 11. Lamictal (lamotrigine). Physicians’ Desk Reference. Montvale, NJ: Medical Economics; 1997:1105–1110

12. Gibbons RD, Hedeker D, Watermaux C, et al. Random regression models: a comprehensive approach to the analysis of longitudinal psychiatric data. Psychopharmacol Bull 1988;24:438–443 13. Gibbons RD, Hedeker D, Elkin I, et al. Some conceptual and statistical issues in analysis of longitudinal psychiatric data. Arch Gen Psychiatry 1993;50:739–750 14. Hedeker D. MIXREG: a FORTRAN Program for Mixed-Effects Linear Regression Models. Chicago, Ill: Prevention Research Center, University of Illinois; 1993 15. Calabrese JR, Bowden CL, McElroy S, et al. Efficacy of lamotrigine in bipolar disorders: preliminary data on affective disorders. In: Manji HK, Bowden C, Belmaker R, eds. Mechanisms of Antibipolar Disorder Treatments: Focus on Lithium, Valproate, and Carbamazepine. Washington, DC: American Psychiatric Press; 1997

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Venlafaxine in Dysthymic Disorder

Venlafaxine in Dysthymic Disorder David L. Dunner, M.D., Helen E. Hendrickson, M.D., Carolyn Bea, and Chris B. Budech

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Background: Dysthymic disorder is a chronic depression that is usually characterized by depression rating scale scores that are lower than those for major depressive disorder. Recent studies suggest that pharmacotherapy is quite effective in the treatment of patients with this condition and, in particular, that the newer antidepressants may be better tolerated than older tricyclic antidepressants. The purpose of this study was to investigate the use of a structurally novel antidepressant, venlafaxine, in the treatment of dysthymic disorder. Method: Seventeen patients with dysthymic disorder were entered into the study, and 14 completed it. A psychiatric interview was used to establish diagnosis, and behavior was assessed by using the Hamilton Rating Scale for Depression (HAM-D) and the Beck Depression Inventory (BDI). Patients were seen over a 9-week period, and venlafaxine treatment proceeded on an openlabel basis, from a starting dose of 18.75 mg b.i.d. to a maximum dose of 225 mg/day. Results: Two patients discontinued early because of side effects, and 1 patient took a single dose, felt better, and did not complete the trial. Analyses of all 17 patients showed significant improvement in HAM-D and BDI scores at the end of the study. Among the completers, there were two response patterns: one group of 7 patients responded quickly to low-dose (75 mg) venlafaxine, and a second group of 7 required the maximum dose. Three of the 7 high-dose patients showed considerable improvement. Side effects in this study were generally in keeping with what has been reported using venlafaxine in treatment of major depressive disorder. No patients evidenced increased blood pressure. Conclusion: Our study supports the treatment of dysthymic patients with venlafaxine, which has equal efficacy and greater tolerability than tricyclic antidepressants. (J Clin Psychiatry 1997;58:528–531)

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Received Feb. 26, 1997; accepted Aug. 7, 1997. From the Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle. Supported by a research grant from Wyeth-Ayerst Laboratories. Reprint requests to: David L. Dunner, M.D., Department of Psychiatry and Behavioral Sciences, University of Washington, 4225 Roosevelt Way NE, Suite 306, Seattle, WA 98105.

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he purpose of this paper is to discuss the use of venlafaxine in the treatment of dysthymic disorder. Dysthymic disorder is a chronic depressive condition. Generally, depression ratings for patients with dysthymic disorder are lower than for patients with major depressive disorder, and dysthymic disorder is often viewed as a mild depressive state. However, dysthymic disorder is associated with considerable psychosocial disabilities.1,2 The description of dysthymic disorder in DSM-III3 included its classification as a neurotic depression, and there was a prevailing notion that this mood disorder might be best treated with psychotherapy rather than pharmacotherapy. However, a review of recent studies clearly shows that patients with dysthymic disorder respond to antidepressant pharmacotherapy.4 Previous studies have suggested that the tricyclic antidepressants may be poorly tolerated in patients with major depression of mild severity as compared to patients with major depression of moderate or greater severity.5 Serotonin selective reuptake inhibitors (SSRIs) have been shown to be better tolerated than tricyclic antidepressants in the treatment of major depression, and therefore, SSRIs may be preferable for the treatment of depressed patients with dysthymic disorder.6 Venlafaxine is a structurally novel antidepressant that blocks the reuptake of serotonin and norepinephrine. The efficacy and safety of venlafaxine have been demonstrated in patients with major depressive disorder.7–9 The present study was an initial evaluation of venlafaxine in outpatients with dysthymic disorder.

This was a 9-week, seven-visit, open-label treatment study for patients who met DSM-IV10 criteria for dysthymic disorder during 2 or more years prior to entry. All participating subjects gave written informed consent. Subjects were evaluated and then treated with venlafaxine on an open-label basis for 9 weeks. The initial evaluation consisted of a semistructured diagnostic interview to establish diagnosis, a physical examination, and routine laboratory testing. After the evaluation, patients were followed on a weekly basis for the first 3 weeks, and then every other week through Week 9. Doses of venlafaxine began at 37.5 mg/day (18.75 mg b.i.d.) and were titrated according to patient tolerability by 37.5 mg every 2 to 3 528 527

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days to a target dose of 225 mg/day. For patients who could not tolerate the initial dose of 37.5 mg/day, the dose could be reduced by half and titration could occur more slowly. A minimal dose of 75 mg/day for continuation in the study was required. Subjects were required to have an entry score of at least 12 points on the 17-item Hamilton Rating Scale for Depression (HAM-D-17).11 All subjects were 18 years of age or older. Patients could have had a history of other psychiatric conditions such as major depressive disorder 2 years or more prior to study entry. Alcohol or other substance abuse could not have been present for at least 6 months prior to study entry, but in fact no subjects had alcohol or substance abuse for at least 2 years prior to entry. Exclusion criteria included use of other psychotropic medications within 2 weeks prior to study entry (4 weeks for fluoxetine), use of investigational medications within 30 days prior to study entry, presence of an uncontrolled medical disorder or a history of hypertension, and suicidal ideation judged by the clinician to be incompatible with safe study participation. Assessments included the HAM-D-17 and the Beck Depression Inventory (BDI).12 Vital signs were assessed at each visit. No other psychoactive medications were permitted nor was psychotherapy allowed during the study period. Medication compliance was assessed by pill counts. At follow-up visits, patients were evaluated by a study psychiatrist (D.L.D. or H.E.H.). Visits were no longer than 15 minutes and were generally according to the format of medication management.13 Side effects were assessed by the treating psychiatrist by asking the patient about changes in symptoms, medical problems, and use of concomitant medication.

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patients had a mean of 13.9 years of dysthymia. The mean time depressed was 62.6%. Eleven of the patients were men, and 5 of the patients had never married. Six of the 17 patients were diagnosed as having primary and uncomplicated (having a history of no other Axis I disorder) dysthymia. Thirteen patients had never had a major depressive episode. Three of the patients had dysthymic disorder occurring after a period of marijuana abuse, a major depressive episode, or recurrent major depression (one patient each). One patient had dysthymia complicated by isolated and infrequent panic attacks, 1 by a history of anorexia nervosa, 1 by alcoholism and trichotillomania, 1 by recurrent depression, 2 by marijuana abuse, 1 by marijuana and alcohol abuse, and 1 by alcohol abuse alone. Nine of the patients had had previous psychotherapy. Of 11 patients who had had antidepressant pharmacotherapy, 1 patient did not benefit from an adequate trial (dose and duration) of an antidepressant, 3 had improvement, and 2 showed partial improvement. The trials were limited by early side effects in 2 patients and by inadequate duration in 3 patients. Of the fourteen patients who completed treatment, all improved over baseline. A group of 7 patients required the maximum dose of 225 mg/day, and 7 patients responded at 75 mg/day and continued at that dose. Of the 7 patients who required only the minimum dose, all met criteria for recovery of major depressive disorder proposed by Frank et al.14: a HAM-D-17 score of 7 or less and a BDI score of 8 or less at endpoint. Six patients had a HAM-D-17 of 4 or less at endpoint and met remission criteria proposed for dysthymic disorder by Thase et al.15 Of the patients who required 225 mg/day, 3 had a HAM-D-17 of 7 or less and a BDI of 8 or less (2 of these patients had a final HAM-D17 score of 4 or less), and the other 4 modestly improved over their baseline condition. The mean dose of venlafaxine was 162.5 mg/day, but there was a bimodal distribu-

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Seventeen patients were entered into this study. Three patients dropped out early, and the results of these patients were available for only baseline and limited follow-up assessment. One patient who dropped out early took one dose of medication, felt better, and returned only once for follow-up a month after the single dose. She had remained euthymic in that interval. A second patient was discontinued because of treatment-emergent side effects involving nausea, panic attacks, anxiety, and insomnia and an inability to increase the dose beyond 18.75 mg/day. This patient discontinued the study at the second visit. A third patient took one dose and discontinued the study because of insomnia. The remaining 14 patients were followed for 9 weeks. The demographics of the patient sample are presented in Table 1. The patients had a mean age of 40 years and were mildly depressed as evidenced by a mean baseline HAM-D-17 of 17.4 and baseline BDI of 19.8. The duration of the current dysthymic condition was 8.2 years, and 528 529

Variable Result Sex Men (N) 11 Women (N) 6 Age (y), mean ± SD 40.0 ± 9.0 Duration current dysthymia (y), mean ± SD 8.2 ± 8.3 Percentage of time depressed, mean ± SD 62.6 ± 11.6 Prior psychotherapy (N) 15 Prior pharmacotherapy (N) 10 Prior history of major depressive episode (N) 3 Primary uncomplicated dysthymia (N) 7 Baseline HAM-D, mean ± SD 17.4 ± 3.9 Baseline BDI, mean ± SD 19.8 ± 7.7 Final HAM-D, mean ± SD 7.0 ± 6.1a Final BDI, mean ± SD 7.1 ± 6.2b Final dose (mg/d), mean ± SD 162.5 ± 90.8 *Abbreviations: BDI = Beck Depression Inventory, HAM-D = Hamilton Rating Scale for Depression. a t = 8.18, df = 16, p < .001 compared with baseline. b t = 7.59, df = 16, p < .001 compared with baseline.


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RESULTS

Table 1: Patient Characteristics*


Venlafaxine in Dysthymic Disorder

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tion in dosing as noted above. Patients in the low-dose responding group for the most part showed considerable improvement for both the HAM-D-17 and the BDI by the second week of treatment. Ratings for the BDI paralleled changes for the HAM-D-17, and significant (p < .05) improvement over baseline ratings was noted by the end of the first treatment week and at each subsequent treatment interval. Side effects were noted by 13 of the 14 completing patients. For the most part, side effects in these patients were mild and consisted of nausea (10 patients), insomnia (4 patients), headaches (5 patients), sedation (5 patients), dry mouth (4 patients), decrease in appetite (4 patients), constipation (3 patients), sexual dysfunction (3 patients), and light-headedness (3 patients). At the end of the study, medication was tapered over a 1-week period and patients were followed up. No patient had significant discontinuation side effects.

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DISCUSSION


large placebo-controlled multicenter trial of sertraline in dysthymic patients who had no history of major depressive episodes. They found sertraline to be superior to placebo in efficacy and to imipramine in tolerability. Treatment studies of dysthymic patients, with the exception of the study by Thase et al.,15 involve relatively small sample sizes. Our sample has somewhat different demographic characteristics compared with other treatment samples. Most were men, most were currently married, and most had primary dysthymia that was uncomplicated by comorbid psychiatric conditions. However, the severity of depression ratings is similar to that in other samples. These factors may influence the generalizability of our findings. In summary, dysthymic disorder is a form of chronic depression. Treatment outcome studies have shown that psychotherapy and pharmacotherapy are effective in alleviating the symptoms of this disorder. Our study supports the treatment of dysthymic patients with venlafaxine. Pharmacotherapy studies increasingly support the use of newer medications, which have equal efficacy but greater tolerability than tricyclic antidepressants, in the treatment of patients with dysthymic disorder.

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REFERENCES

1. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients: results from the Medical Outcomes Study. JAMA 1989;262:914–919 2. Friedman RA. Social impairment in dysthymia. Psychiatric Annals 1993;23:632–637 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition. Washington, DC: American Psychiatric Association; 1980 4. Dunner DL. Efficacy of selective serotonin re-uptake inhibitors in the treatment of dysthymia. In: Feighner JP, Boyer WF, eds. Selective Serotonin Re-Uptake Inhibitors: Advances in Basic Research and Clinical Practice. 2nd ed. New York, NY: John Wiley & Sons; 1996:223–232 5. Elkin I, Shea TM, Watkins JT, et al. The National Institute of Mental Health Treatment of Depression Collaborative Research Program: general effectiveness of treatments. Arch Gen Psychiatry 1989;46:971–982 6. Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47–53 7. Khan A, Fabre LF, Rudolph R. Venlafaxine in depressed outpatients. Psychopharmacol Bull 1991;27:141–144 8. Schweiger E, Weise C, Clary C, et al. Placebo-controlled trial of venlafaxine for the treatment of major depression. J Clin Psychopharmacol 1991;11:233–236 9. Montgomery SA, chairperson. Venlafaxine: a new dimension in antidepressant pharmacotherapy [ACADEMIC HIGHLIGHTS]. J Clin Psychiatry 1993;54:119–126 10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994 11. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62 12. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–571 13. Fawcett J, Epstein P, Fiester SJ, et al. Clinical management-impairment imipramine/placebo administration manual: NIMH Treatment of Depression Collaborative Research Program. Psychopharmacol Bull 1978;

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Drug names: fluoxetine (Prozac), imipramine (Tofranil and others), sertraline (Zoloft), venlafaxine (Effexor).

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In this study, there appeared to be two groups of responders. One group responded quickly to low-dose venlafaxine, and another group required higher doses but ultimately responded, although only half of the latter group recovered. Venlafaxine was well tolerated. Only 2 of the patients discontinued because of side effects, and none of the patients developed increased blood pressure. It should be pointed out that recovery criteria for dysthymic disorder have not been established but that the recovery criteria proposed by Frank et al.14 for major depressive disorder and for dysthymic disorder by Thase et al.15 may provide useful guidelines for improvement of depressive mood disorders. However, dysthymic disorder is a condition characterized by fluctuations and inconsistent symptoms when assessed on a weekly basis, and placebo-controlled trials are clearly necessary to establish efficacy. Although this was not a placebo-controlled study, our results suggest that a significant proportion of dysthymic patients may respond promptly to treatment with low doses of venlafaxine. Another subgroup may require longer treatment at higher doses to achieve response. Perhaps one benefit of the present study is to define a dosing methodology that might be appropriate for a placebocontrolled double-blind study of venlafaxine to more clearly demonstrate its efficacy in dysthymic disorder. In other studies of patients with dysthymic disorder treated at our site, we have noted improvement with fluoxetine and with cognitive therapy.16 Other investigators have shown that SSRIs are quite effective in the treatment of dysthymic disorder. Hellerstein et al.17 reported a significantly greater response rate in dysthymic patients treated with fluoxetine compared with placebo. Openlabel studies of fluoxetine have also shown positive results.18–21 Thase et al.15 recently reported the results of a

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23:309–324 14. Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale of consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991;48: 851–855 15. Thase ME, Fava M, Halbreich U, et al. A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry 1996;53:777–784 16. Dunner DL, Schmaling KB, Hendrickson HE, et al. Cognitive therapy versus fluoxetine in the treatment of dysthymic disorder. Depression 1996;4: 34–41 17. Hellerstein DJ, Yanowitch P, Rosenthal J, et al. A randomized double-blind study of fluoxetine versus placebo in the treatment of dysthymia. Am J Psychiatry 1993;150:1169–1175

18. Rosenthal J, Hemlock C, Hellerstein DJ, et al. A preliminary study of serotonergic antidepressants in treatment of dysthymia. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:933–941 19. Ravindran AV, Bialik RJ, Lapierre YD. Therapeutic efficacy of specific serotonin reuptake inhibitors (SSRIs) in dysthymia. Can J Psychiatry 1994; 39:21–26 20. Ravindran AV, Bialik RJ, Lapierre YD. Primary early onset dysthymia, biochemical correlates of the therapeutic response to fluoxetine, I: platelet monoamine oxidase and the dexamethasone suppression test. J Affect Disord 1994;31:111–117 21. Nobler MS, Devanand DP, Singer TM, et al. Fluoxetine treatment for elderly patients with dysthymic disorders: a pilot study. In: New Research Program and Abstracts of the 1994 Annual Meeting of the American Psychiatric Association; May 23, 1994; Philadelphia, Pa. Abstract NR142:91

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Bupropion SR and Sertraline in Depressed Outpatients

Double-Blind Comparison of Bupropion Sustained Release and Sertraline in Depressed Outpatients

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Richard J. Kavoussi, M.D., R. Taylor Segraves, M.D., Arlene R. Hughes, Ph.D., John A. Ascher, M.D., and J. Andrew Johnston, Pharm.D.

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Background: A sustained-release formulation of bupropion (bupropion SR), developed with an improved pharmacokinetic profile to permit less frequent dosing than the immediate-release form, has not been evaluated in active comparator trials. This randomized, double-blind, parallel-group trial was conducted to compare the efficacy and safety of bupropion SR and sertraline. Method: Outpatients with moderate to severe major depressive disorder (DSM-IV) received bupropion SR (100–300 mg/day) or sertraline (50–200 mg/day) for 16 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), the Clinical Global Impressions scale for Severity of Illness (CGI-S), and for Improvement (CGI-I) were completed, and adverse events were assessed in the clinic periodically throughout treatment. Patients’ orgasm function was also assessed. Results: Mean HAM-D, HAM-A, CGI-I, and CGI-S scores improved over the course of treatment in both the bupropion SR group and the sertraline group; no between-group differences were observed on any of the scales. Orgasm dysfunction was significantly (p < .001) more common in sertraline-treated patients compared with bupropion SR–treated patients. The adverse events of nausea, diarrhea, somnolence, and sweating were also experienced more frequently (p < .05) in sertraline-treated patients. No differences were noted between the two treatments for vital signs and weight. Conclusion: This double-blind comparison of bupropion SR and sertraline demonstrates that bupropion and sertraline are similarly effective for the treatment of depression. Both compounds were relatively well tolerated, and orgasm dysfunction, nausea, diarrhea, somnolence, and sweating were reported more frequently in sertraline-treated patients. (J Clin Psychiatry 1997;58:532–537)

Received May 7, 1997; accepted Oct. 10, 1997. From Allegheny University of the Health Sciences, Philadelphia, Pa. (Dr. Kavoussi), Case Western Reserve University and MetroHealth Medical Center, Cleveland, Ohio (Dr. Segraves), and International CNS Clinical Research, Glaxo Wellcome Inc., Research Triangle Park, N.C. (Drs. Hughes, Ascher, and Johnston). Supported by a grant from Glaxo Wellcome Inc., Research Triangle Park, N.C. Reprint requests to: Richard J. Kavoussi, M.D., Allegheny University of the Health Sciences, Department of Psychiatry, 3200 Henry Avenue, Philadelphia, PA 19129.

dvances in neuroscience research have yielded new treatment options for depression, including the serotonin selective reuptake inhibitors (SSRIs), the mixed serotonin-norepinephrine reuptake inhibitors, and the atypical antidepressants.1,2 These classes of antidepressants generally cannot be distinguished from one another or from the older tricyclic antidepressants or monoamine oxidase inhibitors on the basis of efficacy, but, consistent with their distinct mechanisms of action, their side effect profiles differ.1–3 Side effects of the older antidepressants are often attributed to their anticholinergic, antihistaminergic, and α-adrenergic blocking activity.1–4 Although side effect profiles of the new-generation antidepressants are improved relative to older agents’ profiles,1,2 many of the new-generation antidepressants are associated with side effects predominantly related to serotonergic activity.5,6 The antidepressant bupropion hydrochloride, chemically unrelated to other antidepressant medications, is thought to act by enhancing noradrenergic (as reflected by reductions in norepinephrine turnover and in firing rates of locus ceruleus neurons) and/or dopaminergic (via dopamine reuptake blockade) function.7 Bupropion does not affect serotonergic function and has no known affinity for postsynaptic receptors.7,8 Bupropion has consistently been demonstrated to be relatively free of sexual, cardiovascular, and sedative side effects.9–13 In double-blind studies of depression, bupropion was more effective than placebo14,15 and as effective as other antidepressants, including amitriptyline,12,13 doxepin,10 trazodone,11 and fluoxetine.9

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A sustained-release formulation of bupropion (bupropion SR) was developed that has an improved pharmacokinetic profile compared with the immediate-release formulation (bupropion IR). The altered distribution half-life of bupropion SR permits less frequent dosing, and the reduced peak concentrations may result in improved safety. This double-blind trial compares the efficacy and safety of bupropion SR and the SSRI sertraline. METHOD

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Patients Men and women at least 18 years of age who were diagnosed with major depressive disorder (DSM-IV) and currently experiencing a major depressive episode with duration ≥ 4 weeks but ≤ 24 months were eligible for the study if they provided written, informed consent. Patients were required to be in a stable relationship with normal sexual functioning. Excluded were pregnant or lactating women, patients with a history or current diagnosis of bulimia and/or anorexia nervosa, patients with a known predisposition to seizures, and patients who were actively suicidal. Patients could not have been previously treated with either bupropion or sertraline and could not have received any psychoactive drug within 1 week of study drug treatment (2 weeks for monoamine oxidase inhibitors or protriptyline, and 4 weeks for fluoxetine). Patients were stratified by gender at randomization to ensure equivalence between treatment groups in their proportion of men and women.

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Clinic visits were conducted on the first days of the screening and treatment phases and at the end of treatment Weeks 1, 2, 3, 4, 6, 8, 12, and 16. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D),16,17 the Hamilton Rating Scale for Anxiety (HAM-A),18 and the Clinical Global Impressions scale for Severity of Illness (CGI-S),19 were completed at each visit. The Clinical Global Impressions scale for Improvement (CGI-I)19 was completed at each visit beginning with the end of treatment Week 1 visit (i.e., not at the screen visit). Adverse events (defined as any untoward medical occurrence, potentially drug-related or not) were also assessed at each clinic visit. Reports of adverse events were elicited by the investigators by asking patients, “Have you had any difficulties or has anything unusual occurred since I last saw you?” In addition, patients’ orgasm functioning was assessed in investigatorconducted structured interviews/questionnaires modified from those employed in the Kinsey Institute Interviewer Ratings of Sexual Function.20,21

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Study Design and Procedures This randomized, double-blind, parallel-group, multicenter study was conducted to compare the efficacy and safety of bupropion SR (100–300 mg/day) administered twice daily and sertraline (50–200 mg/day) administered once daily in the outpatient treatment of moderate to severe depression. The study comprised a 1-week screening phase, which served as a washout period for other psychotropic medications, and a 16-week treatment phase, during which patients received bupropion SR or sertraline using a double-dummy technique. No other psychoactive drugs, with the exception of chloral hydrate for nighttime sedation (Days 1–14), were permitted during the treatment phase. Patients receiving bupropion SR initiated dosing on treatment Day 1 at 100 mg/day for 3 days. If clinically appropriate, the dose could be increased on treatment Day 4 to 200 mg/day and again on treatment Day 7 to 300 mg/day. Patients receiving sertraline initiated dosing on treatment Day 1 at 50 mg/day for 7 days. If clinically appropriate, the dose could be increased on treatment Day 8 to 100 mg/day and again on treatment Days 15 and 22 to 150 mg/day and 200 mg/day, respectively. Compliance with the prescribed dosing regimen was determined by returned tablet counts.

Data Analysis Mean daily dose and medication compliance. All patients who received at least one dose of study medication and completed at least one postbaseline efficacy assessment were included in the daily dose and compliance analyses. Mean daily dose was calculated for each patient over the duration of treatment. Medication compliance during the 112-day treatment phase (expressed as a percentage) was calculated by dividing total dose taken across patients by total dose prescribed across patients. Efficacy scales. All patients who received at least one dose of study medication and completed at least one postrandomization efficacy assessment were included in the efficacy analyses, which were conducted on both observed and last-observation-carried-forward (LOCF) scores. In the LOCF method, the last known observation was carried forward to subsequent weeks that had missing observations. Differences between the bupropion SR group and the sertraline group at each treatment week were tested using analysis of variance (ANOVA) for the HAM-D and HAM-A scores and using the Cochran-Mantel-Haenszel test for the CGI-S and CGI-I scores. Adverse events. The frequency of patients’ reporting a treatment-emergent adverse event (one emerging or worsening after the beginning of study medication treatment) with an incidence of at least 5% in either group was compared between groups using Fisher’s exact test. Sexual function. Because sexual function was assessed in investigator-conducted structured interviews, it was not analyzed as an adverse event. The percentage of patients experiencing orgasm delay or failure was compared between groups at each treatment week using the Cochran-Mantel-Haenszel test. J Clin Psychiatry 58:12, December 1997

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Characteristic Number of patients Mean age, y (range) Gender, N (%) Female 59 (48) Male 63 (52) Ethnic origin, N (%) White 113 (93) Black 7 (6) Other 2 (2) Prior antidepressant use for current episode, N (%) 27 (22) Duration of present episode, N (%) 4 w–2 mo 11 (9) 3–6 mo 26 (21) 7–12 mo 44 (36) 13–24 mo 41 (34) Reason for premature discontinuation, N (%) Adverse experience 4 (3) Condition deteriorated 0 (0) Inadequate response 8 (7) Lost to follow-up 7 (6) Consent withdrawn 12 (10) Protocol violation 3 (2) Other 1 (1) Total discontinued 35 (29) Mean dose over treatment phase, mg/d 238 Compliance, mean % of prescribed dose 98

Sertraline 126 40 (18–74) 60 (48) 66 (52) 119 (94) 4 (3) 3 (2)

Figure 1. Mean 21-Item Hamilton Rating Scale for Depression Scores (LOCF) in Depressed Outpatients Receiving Bupropion SR or Sertraline for 16 Weeks 30

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Efficacy Results Observed and LOCF data were similar for both the bupropion SR and the sertraline groups for all four efficacy scales. LOCF data are reported. HAM-D scores. Mean baseline HAM-D scores were similar between the bupropion SR group and the sertraline group (Figure 1). Both groups demonstrated a greater than 50% improvement in HAM-D scores by Day 42. This degree of improvement was maintained through the remainder of the 16-week treatment phase. There were no statistically significant differences between the bupropion SR group and the sertraline group at any treatment week. CGI-S scores. Mean baseline CGI-S score was 4.4 in both the bupropion SR group and the sertraline group (Figure 2). CGI-S scores improved steadily throughout the treatment phase. There were no statistically significant differences between the bupropion SR group and the sertraline group at any treatment week. CGI-I scores. Mean baseline CGI-I scores were similar between the bupropion SR group and the sertraline group (Figure 3). CGI-I scores steadily improved throughout the treatment phase. There were no statistically significant differences between the bupropion SR group and the sertraline group at any treatment week.

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Patient Demography and Compliance Forty-eight percent of patients in each treatment group were women (Table 1). Patients’ mean ages in the bupropion SR and sertraline groups were 39 (range, 19–76) and 40 (range, 18–74) years, respectively. Less than one quarter of the population had received antidepressant treatment for their current episode of depression. In the bupropion SR and sertraline groups, the mean daily doses were 238 and 114 mg/day, respectively, and the mean compliance rates (total dose taken/total dose prescribed) were 98% and 99%, respectively.

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Sample Composition Two hundred forty-eight patients (122 bupropion SR and 126 sertraline) were randomly assigned to treatment. All 248 patients were included in the safety analyses; the 241 patients (119 bupropion SR and 122 sertraline) who received at least one dose of study medication and completed at least one postrandomization efficacy assessment were included in the efficacy, orgasm function, and compliance analyses. Approximately two thirds of the patients in each group (87 of 122 in the bupropion SR group and 83 of 126 in the sertraline group) completed the study. Reasons for patient discontinuation are listed in Table 1.

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Figure 2. Mean Clinical Global Impressions for Severity of Illness Scores (LOCF) in Depressed Outpatients Receiving Bupropion SR or Sertraline for 16 Weeks

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17 (13) 2 (2) 6 (5) 1 (1) 14 (11) 3 (2) 0 (0) 43 (34) 114 99

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Bupropion SR 122 39 (19–76)

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Table 1. Patient Demographics and Dosing



Figure 3. Mean Clinical Global Impressions for Improvement Scores (LOCF) in Depressed Outpatients Receiving Bupropion SR or Sertraline for 16 Weeks

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Figure 4. Mean Hamilton Rating Scale for Anxiety Scores (LOCF) in Depressed Outpatients Receiving Bupropion SR or Sertraline for 16 Weeks

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Bupropion SR Sertraline (N = 122) (N = 126) Event N % N % Headache 42 34 40 32 12 10 38 30 Nauseaa Insomnia 22 18 24 19 Dry mouth 19 16 19 15 Infection 22 18 12 10 Diarrheaa 4 3 28 22 Flu syndrome 15 12 7 6 Anxiety 9 7 12 10 Dyspepsia 10 8 9 7 Somnolencea 3 2 16 13 Asthenia 6 5 11 9 Nervousness 5 4 11 9 Dizziness 10 8 6 5 Rhinitis 10 8 6 5 Sweatinga 2 2 12 10 Tremor 3 2 7 6 *Adverse events occurring in > 5% of patients in either group are reported. a p < .05 sertraline vs bupropion SR.

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Table 2. Number and Percentage of Patients Experiencing an Adverse Event During the Treatment Phase*

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Table 3. Number of Patients Prematurely Discontinued From the Study Due to Sexual Dysfunction and Other Adverse Events

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the study due to sexual dysfunction or other adverse effects (p = .004; Table 3). Sexual dysfunction, nausea/ vomiting, and nervousness accounted for the majority of withdrawals in the sertraline group. Baseline orgasm function scores were not significantly different between groups. Orgasm function was impaired in more sertraline-treated patients than in bupropion SR– treated patients throughout the 16-week treatment phase. Beginning on treatment Day 7, a significantly (p < .001) greater proportion of sertraline-treated patients compared with bupropion SR–treated patients experienced orgasm delay and/or failure (Figure 5). Also, gender-specific analyses demonstrated that between-group differences in rates of patients who experienced orgasm dysfunction at any time during the study were observed for both men (10% for bupropion SR, 61% for sertraline; p < .001) and

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Adverse Events and Other Safety Data Adverse events that emerged during the treatment phase and were experienced by > 5% of patients in either the bupropion SR or the sertraline group are listed in Table 2. The most common adverse event was headache, experienced by 34% of bupropion SR–treated patients and 32% of sertraline-treated patients. Significantly more patients in the sertraline group (p < .05) experienced the gastrointestinal adverse events of nausea (30% of sertraline patients; 10% of bupropion SR patients) and diarrhea (22% of sertraline patients; 3% of bupropion SR patients). Similarly, significantly more patients in the sertraline group (p < .05) had somnolence (13% of sertraline patients; 2% of bupropion SR patients) and sweating (10% of sertraline patients; 2% of bupropion SR patients). Seventeen patients in the sertraline group and 4 patients in the bupropion SR group were discontinued from

Sertraline (N = 126) 4 4 2 1 1 1 1 1 1 1 0 0 0 0

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HAM-A scores. Mean baseline HAM-A scores were similar between the bupropion SR group and the sertraline group (Figure 4). By Day 56, both groups demonstrated a 50% improvement, which was maintained through the remainder of the treatment phase. There were no statistically significant differences between the bupropion SR group and the sertraline group at any treatment week.

Bupropion SR (N = 122) 0 0 0 0 0 0 0 0 0 0 1 1 1 1

Event Sexual dysfunction Nausea/vomiting Nervousness Headache Generalized anxiety Activation Loose bowels Rash Insomnia Poor concentration Flu syndrome Nose bleed Fatigue Hostility

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Figure 5. Percentage of Patients Experiencing Orgasm Failure and/or Delay During Treatment With Bupropion SR or Sertraline for 16 Weeks 50

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The results of this study demonstrate that bupropion SR and sertraline are similarly efficacious in the treatment of depression. Comparable improvements were observed with the HAM-D, the CGI-S, the CGI-I, and the HAM-A. There were no statistically significant differences between bupropion SR and sertraline in scores for any of these four scales at any assessment point. The similar improvement in HAM-D and HAM-A scores over time for both bupropion SR and sertraline is noteworthy. These results demonstrate that as depression improves, anxiety improves equally for both bupropion SR and sertraline. This finding confirms the results of an earlier study in which corresponding improvements in depression and the symptoms of anxiety associated with depression were observed in patients treated with bupropion and fluoxetine.9 Results from that study and the one presented here indicate that bupropion is beneficial not only for symptoms of depression but also for relief of the symptoms of anxiety associated with depression. The magnitude of improvement in efficacy scale scores in this study is similar to that observed in controlled clinical trials in which bupropion or sertraline had been demonstrated to be statistically and clinically superior to placebo.14,15,22,23 This across-study consistency in response rates lends support to the contention that the improvements observed in our study are attributable to study drug medication. However, the absence of a placebo group in our study precludes an estimate of the degree to

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women (7% for bupropion SR, 41% for sertraline; p < .001). Abnormalities in systolic blood pressure, diastolic blood pressure, or pulse were infrequent and occurred with similar frequency in the bupropion SR and sertraline groups. After 16 weeks, patients in both treatment groups experienced a small and similar mean decrease in body weight (sertraline = –0.7 lb; bupropion SR = –1.2 lb).

which clinical improvements are attributable to study drug treatment. In addition to complementing the results of placebocontrolled studies, this study extends the data describing comparative effectiveness of antidepressants by demonstrating that bupropion SR and sertraline are similarly efficacious. Both bupropion and sertraline have been shown previously to be at least as effective as amitriptyline in the treatment of depression.12,13,22,23 Bupropion has also been shown to be as effective as fluoxetine,9 trazodone,11 and doxepin.10 Although bupropion SR and sertraline were similarly effective in alleviating depression in this study, their side effect profiles differed. More withdrawals due to adverse events, most commonly sexual dysfunction and nausea/ vomiting, were observed in patients receiving sertraline compared with bupropion SR. Of the treatment-emergent adverse events reported by > 5% of patients in either treatment group, headache, insomnia, and dry mouth occurred with approximately equal frequency in bupropion SR– and sertraline-treated patients; however, sertraline was significantly more likely than bupropion SR to be associated with gastrointestinal adverse events such as nausea and diarrhea. In addition, a significantly greater proportion of sertraline-treated patients compared with bupropion-treated patients reported somnolence and sweating. These data corroborate results of previous studies.9,11,23 Bupropion SR and sertraline also differed in their effects on orgasm function. Sertraline was consistently associated with impairment in orgasm function compared with bupropion SR. Onset of impairment occurred as early as treatment Day 7 at daily doses as low as 50 mg and persisted for the duration of the treatment phase. The data from this double-blind study suggest that the incidence of sexual dysfunction with sertraline (41%–61% for orgasm delay and/or failure) may be higher than the 15.5% incidence rate for sexual dysfunction quoted in package labeling.24 Because incidence rates quoted in package labeling and cited in most studies rely on spontaneous reports of sexual dysfunction, they may underestimate actual incidence rates; whereas the current study employed explicit questioning about sexual function. In contrast to previous reports,23,25 the data from the current study also suggest that sexual function impairments observed with sertraline are not transient but last throughout a 16-week course of treatment. Sertraline is not unique among SSRIs in its side effect profile or its association with the development of sexual dysfunction. While the relative incidence of side effects for both treatment groups was lower in a previous study comparing bupropion SR with fluoxetine,9 an SSRI different from that used in the current study, the difference is most likely related to methodological differences (e.g., study duration) rather than to differences in SSRI side efJ Clin Psychiatry 58:12, December 1997


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fect profiles. The few studies that have directly compared SSRIs have found no statistical differences in efficacy or side effects and similar rates of withdrawal due to adverse events.26 Meta-analytic reviews have also failed to demonstrate any significant differences in adverse events between SSRIs.27 Sexual dysfunction, in particular, has been reported as an important side effect for other SSRIs, including fluoxetine,28,29 paroxetine,30 and fluvoxamine,31 presumably reflecting the serotonergic activity of that class of drugs.6 The current study had the advantage over other studies of obtaining sexual dysfunction information through explicit questioning, leading to more realistic and complete data than in previous reports.9,32 There are also several limitations of the current study design. First, patients with chronic (> 24 months’ duration) depression were excluded. Also, the equivalent gender distribution created by stratification and the entry criterion of normal sexual functioning at baseline, both required for the purposes of obtaining definitive data on the effects of these antidepressants on sexual function in both sexes, influenced the population of depressed patients studied and may influence the comparison of these results with those of other studies. Lastly, a placebo arm was not included. The results of this double-blind trial comparing bupropion SR and sertraline with respect to efficacy, safety, and effects on orgasm function demonstrate that bupropion is as effective as sertraline. Both medications were well tolerated, although their side effect profiles differed. Sertraline was much more likely than bupropion SR to be associated with gastrointestinal adverse events. A higher percentage of sertraline-treated patients compared with bupropion-treated patients experienced impaired orgasm function. Therefore, bupropion SR may be an antidepressant of choice if avoidance of sexual dysfunction is of importance to the patient.

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1. Preskorn SH. Antidepressant drug selection: criteria and options. J Clin Psychiatry 1994;55(9, suppl A):6–22 2. Nemeroff CB. Evolutionary trends in the pharmacotherapeutic management of depression. J Clin Psychiatry 1994;55(12, suppl):3–15 3. Preskorn SH, Burke M. Somatic therapy for major depressive disorder: selection of an antidepressant. J Clin Psychiatry 1992;53(9, suppl):5–18 4. Salzman C. Monoamine oxidase inhibitors and atypical antidepressants. Clin Geriatr Med 1992;8:335–348 5. Segraves RT. Overview of sexual dysfunction complicating the treatment of depression. J Clin Psychiatry Monograph 1992;10(2):4–10 6. Goodwin GM. How do antidepressants affect serotonin receptors? the role of serotonin receptors in the therapeutic and side effect profile of the


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SSRIs. J Clin Psychiatry 1996;57(suppl 4):9–13 7. Ascher JA, Cole JO, Colin J-N, et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 1995;56:395–401 8. Ferris RM, Cooper BR. Mechanism of antidepressant activity of bupropion. J Clin Psychiatry Monograph 1993;11(1):2–14 9. Feighner JP, Gardner EA, Johnston JA, et al. Double-blind comparison of bupropion and fluoxetine in depressed outpatients. J Clin Psychiatry 1991; 52:329–335 10. Feighner J, Hendrickson G, Miller L, et al. Double-blind comparison of doxepin versus bupropion in outpatients with a major depressive disorder. J Clin Psychopharmacol 1986;6:27–32 11. Weisler RH, Johnston JA, Lineberry CG, et al. Comparison of bupropion and trazodone for the treatment of major depression. J Clin Psychopharmacol 1994;14:170–179 12. Mendels J, Amin MM, Chouinard G, et al. A comparative study of bupropion and amitriptyline in depressed outpatients. J Clin Psychiatry 1983; 44(5, sec 2):118–120 13. Chouinard G. Bupropion and amitriptyline in the treatment of depressed patients. J Clin Psychiatry 1983;44(5, sec 2):121–129 14. Fabre LF, Brodie KH, Garver D, et al. A multicenter evaluation of bupropion versus placebo in hospitalized depressed patients. J Clin Psychiatry 1983;44(5, sec 2):88–94 15. Lineberry CG, Johnston JA, Raymond RN, et al. A fixed-dose (300 mg) efficacy study of bupropion and placebo in depressed outpatients. J Clin Psychiatry 1990;51:194–199 16. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62 17. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychology 1967;6:278–296 18. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50–55 19. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Dept Health, Education, and Welfare publication (ADM) 76-338. Rockville, Md: National Institute of Mental Health; 1976:218–222 20. Cawood EHH, Bancroft J. Steroid hormones, the menopause, sexuality and well-being of women. Psychol Med 1996;26:925–936 21. Graham CA, Ramos R, Bancroft J, et al. The effects of steroidal contraceptives on the well-being and sexuality of women: a double-blind, placebocontrolled, two-centre study of combined and progestogen-only methods. Contraception 1995;52:363–369 22. Shelton RC. The role of sertraline in the management of depression. Clin Ther 1994;16:768–782 23. Reimherr FW, Chouinard G, Cohn CK, et al. Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. J Clin Psychiatry 1990;51(12, suppl B):18–27 24. Zoloft (sertraline). Physicians’ Desk Reference. Montvale, NJ: Medical Economics; 1996:2217–2220 25. Murdoch D, McTavish D. Sertraline: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder. Drugs 1992;44:604–624 26. Bennie EH, Mullin JM, Martindale JJ. A double-blind multicenter trial comparing sertraline and fluoxetine in outpatients with major depression. J Clin Psychiatry 1995;56:229–237 27. Preskorn SH. Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 1995;56(suppl 6):12–21 28. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry 1992;53:119–122 29. Balon R, Yeragani VK, Pohl R, et al. Sexual dysfunction during antidepressant treatment. J Clin Psychiatry 1993;54:209–212 30. Singh AN, Scurlock H, Catalan J. Paroxetine-induced erectile dysfunction successfully treated with yohimbine in patients suffering from HIV infection. Journal of Serotonin Research 1995;4:283–285 31. Dorevitch A, Davis H. Fluvoxamine-associated sexual dysfunction. Ann Pharmacother 1994;28:872–874 32. Thase ME, Fava M, Halbreich U, et al. A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry 1996;53:777–784

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Risperidone in Schizophrenia

The Effects of Risperidone on the Five Dimensions of Schizophrenia Derived by Factor Analysis: Combined Results of the North American Trials

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Stephen R. Marder, M.D., John M. Davis, M.D., and Guy Chouinard, M.D., F.R.C.P.(C.)

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wo pivotal controlled trials of risperidone have been conducted in North America, the Canadian study of Chouinard et al.1 and the United States study of Marder and Meibach.2 In this report, we present the results of an analysis of the combined data from the two trials to determine whether risperidone differs qualitatively from the conventional neuroleptic haloperidol. Unlike haloperidol, risperidone blocks both serotonin 5-HT2A and dopamine D2 receptors, and the question is whether the additional pharmacologic property (5-HT2A antagonism) could produce a qualitatively different set of antipsychotic actions from the conventional agents and enhance the overall antipsychotic effects of risperidone. The development of risperidone has its roots in the 1950s when Woolley and Shaw3 noted that lysergic acid diethylamide, which “calls forth in man mental distur-

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Background: In two double-blind trials conducted in North America, 513 patients with chronic schizophrenia received risperidone, haloperidol, or placebo. In the present study, combined data from the two trials were analyzed. Method: Patients were randomly assigned to receive placebo, fixed doses of risperidone (2, 6, 10, and 16 mg/day), or 20 mg/day of haloperidol for 8 weeks. Factor analysis of scores on the Positive and Negative Syndrome Scale (PANSS) produced five dimensions (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression), similar to the five dimensions of previous factor-analytic studies of PANSS data. Results: Mean changes (symptom reductions) in PANSS factor scores from baseline to treatment Weeks 6 and 8 were significantly greater in patients receiving 6–16 mg/day of risperidone than in patients receiving placebo or haloperidol. The advantages of risperidone were greatest for negative symptoms, uncontrolled hostility/excitement, and anxiety/depression. Even at the lowest dose, 2 mg/day, risperidone was significantly (p ≤ .05) superior to haloperidol in reducing negative symptoms. The differences in outcomes between risperidone and haloperidol on PANSS scores were not related to extrapyramidal symptoms. Conclusion: Risperidone produced significantly (p ≤ .05) greater improvements than haloperidol on all five dimensions. The large between-group differences on negative symptoms, hostility/excitement, and anxiety/depression suggest that risperidone and other serotonin/dopamine antagonists have qualitatively different effects from those of conventional antipsychotic agents. (J Clin Psychiatry 1997;58:538–546)

Received April 8, 1997; accepted Aug. 26, 1997. From West Los Angeles Veterans Affairs Medical Center, Los Angeles, Calif. (Dr. Marder), The Psychiatric Institute, University of Illinois at Chicago (Dr. Davis), and Hôpital Louis-H. Lafontaine, Montréal, Québec, Canada (Dr. Chouinard). Supported by the Janssen Research Foundation, Titusville, N.J., which also supplied the medication and placebo. The data analysis was performed independently by Dr. Davis without support from the Janssen Research Foundation. The principal investigators in the North American trials were the following: Joyce Small, M.D., Indianapolis, Ind.; Richard Borison, M.D., Ph.D., Augusta, Ga.; John H. Krystal, M.D., West Haven, Conn.; Alan I. Green, M.D., Boston, Mass.; Jan Volavka, M.D., Orangeburg, N.Y.; Daniel Luchins, M.D., Chicago, Ill.; Robert Baker, M.D., and Nina Schooler, Ph.D., Pittsburgh, Pa.; Fred W. Reimherr, M.D., Salt Lake City, Utah; Rajiv Tandon, M.D., Ann Arbor, Mich.; Larry Ereshefsky, Pharm.D., and Janet True, M.D., San Antonio, Tex.; Jean-Pierre Lindenmayer, M.D., Bronx, N.Y.; James Garbutt, M.D., Raleigh, N.C.; Theodore Van Putten, M.D. (deceased), Los Angeles, Calif.; Jose M. Cañive, M.D., and Vicente Tuason, M.D., Albuquerque, N.M.; Joseph McEvoy, M.D., Butner, N.C.; B. D. Marshall, M.D., Camarillo, Calif.; John Carman, M.D., Atlanta, Ga.; John Herrera, Ph.D., and Michael Davidson, M.D., Elmhurst, N.Y.; John Rotrosen, M.D., New York, N.Y.; George M. Simpson, M.D., Philadelphia, Pa. Guy Chouinard, M.D., F.R.C.P.(C.), Montreal, Québec; Barry Jones, M.D., F.R.C.P.(C.), Ottawa, Ontario; Gary Remington, M.D., Ph.D., F.R.C.P.(C.), Toronto, Ontario; David Bloom, M.D., F.R.C.P.(C.), and N. P. Vasavan Nair, M.D., F.R.C.P., Verdun, Québec; Donald Addington, M.B.B.S., F.R.C.P.(C.), Calgary, Alberta; G. William MacEwan, M.D., F.R.C.P.(C.), Port Coquitlam, B.C.; Raymond J. Ancill, M.D., F.R.C.P.(C.), Vancouver, B.C. Reprint requests to: Stephen R. Marder, M.D., Psychiatry Service 116A, West Los Angeles VA Medical Center, Brentwood Division, 11301 Wilshire Boulevard, Los Angeles, CA 90037.

538 539

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bances resembling those of schizophrenia,” acted as an antimetabolite of serotonin on smooth muscles, and thus proposed that serotonin was involved in the pathogenesis of schizophrenia. It was not until the late 1970s, however, that compounds with serotonin antagonist properties were developed.4 In 1985, setoperone, a neuroleptic with potent 5-HT2 antagonism but weak dopamine antagonism, was administered to patients with schizophrenia and found to ameliorate negative symptoms without causing extrapyramidal symptoms, and to have little effect on positive symptoms.5 It was then shown that ritanserin, a pure 5-HT2 antagonist, when combined with the dopamine antagonist haloperidol, improved negative symptoms in schizophrenic patients and reduced extrapyramidal symptoms.6,7 At about the same time, Kane and coworkers8 showed that clozapine, which also blocks 5-HT2 receptors, was significantly and clinically more effective than a conventional neuroleptic in the treatment of chronic schizophrenia. In addition to risperidone and clozapine, a number of new 5-HT2\D2 antagonists are now approved for use (olanzapine and quetiapine) or are under investigation (sertindole and ziprasidone, for example) so that it is appropriate to investigate how each member of this new class of drugs differs clinically from conventional neuroleptics. Kapur and Remington9 have recently reviewed the neural basis and clinical relevance of the serotonin-dopamine interaction. The primary measure of treatment efficacy in the North American risperidone trial was the Positive and Negative Syndrome Scale (PANSS).10 This is based on Crow’s seminal paper11 of 1980 in which he proposed that there were two predominant clusters of symptoms in schizophrenia, positive symptoms and negative symptoms. A number of authors have assessed Crow’s hypothesized two-factor classification of schizophrenic symptoms (positive and negative), and all have concluded that the model is inadequate to explain the variance in these studies using several rating scales,12–17 including the PANSS.18–25 These studies include the factor analysis by Lindenmayer et al.24 of the baseline PANSS scores of the patients in the present study. The factor-analytic studies of the PANSS produce five factors or dimensions of schizophrenia; thus, we investigated the differences between risperidone and haloperidol in the North American trials according to these five dimensions.

a statistical analysis using the database from the North American trials. This analysis was carried out independently and without funding from the study’s sponsor, the Janssen Research Foundation.

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Study Design The two parallel, randomized, double-blind, placebocontrolled multicenter trials were conducted at 20 centers in the United States and 6 centers in Canada. A total of 523 hospital patients (436 men and 87 women) with diagnoses of chronic schizophrenia participated. Ten subjects dropped out of the study at baseline and 1 had some missing data, so that the sample used in the present study was 512 or 513 subjects. The small number of women is due to the inclusion of a number of U.S. Department of Veterans Affairs medical centers (with mostly men) and, according to initially restrictive Food and Drug Administration guidelines at the beginning of the study, to the exclusion of women of childbearing potential. Approval was obtained from the institutional review board at each site and renewed annually, and each patient (and/or his or her legal representative when required) gave written, informed consent to participate in the trial.

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Detailed descriptions of the study design, patient selection criteria, and efficacy and safety measures are included in the two reports of the North American trials1,2 and will only be briefly described here. The two trials had identical protocols but separate investigator meetings, training sessions for raters, and monitoring, and were published separately. For this report, Dr. Davis performed

Procedure Patients were required to discontinue all psychotropic and antiparkinsonian medication and to enter a 7-day, single-blind, placebo washout period (28 days for patients receiving depot neuroleptics). Patients were permitted to proceed to the double-blind phase of the trial after 3 days of placebo washout if significant psychopathology emerged. The study protocols precluded the use of any psychotropic medication other than the study drugs, although chloral hydrate or a benzodiazepine and antiparkinsonian medication (biperiden or procyclidine) could be administered if required. Patients were randomly assigned to one of six fixeddose, parallel-treatment groups for 8 weeks: 2, 6, 10, or 16 mg/day of risperidone, 20 mg/day of haloperidol, or placebo. In the present investigation, we chose as the primary analysis the most conservative one, that is, responses to doses of 6 to 16 mg/day of risperidone, assuming a conventional dose-response curve where 6 to 16 mg/day of risperidone would be on the flat maximal-response part of

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METHOD

Selection Criteria Men and women inpatients aged 18 to 65 years with primary diagnoses of chronic schizophrenia (DSM-III-R26) and a PANSS total score between 60 and 120 were eligible for inclusion. Patients with clinically significant abnormal laboratory or electrocardiograph findings, histories of mental disorders other than chronic schizophrenia, epilepsy, alcoholism or drug abuse (within 6 months prior to selection), or clinically significant organic or neurologic disease were excluded.



Table 1. Adjusted Mean Changes in Total PANSS and PANSS Factor Scores From Baseline to Weeks 6 and 8 in Patients Receiving Placebo (Plac), Risperidone, or Haloperidol (Hal), Effect Size Units, and Results of Analyses of Covariancea Adjusted Mean Changes in Scores Risperidone Placebo 6–16 6 2 –3.8 –14.1 –18.6 –5.3 0.2 –2.6 –3.4 –2.1 0.9 –4.4 –5.7 –1.8

Risperidone 6–16 mg/d Effect Effect Size Size vs Plac t vs Hal t 0.29 6.64‡ 0.15 3.29† 0.15 3.44‡ 0.14 3.10† 0.26 5.96‡ 0.10 2.31*

Risperidone 2 mg/d Risperidone 6 mg/d Haloperidol vs Placebo Effect Effect Effect Effect Effect Size Size Size Size b vs Plac t vs Hal t Size t F vs Plac t vs Hal tb 0.12 2.79† 0.00 0.06 0.12 2.72† 16.20‡ 0.53 6.98‡ 0.31 4.05‡ 0.10 2.32* 0.11 2.04* 0.01 0.28 5.92‡ 0.27 3.46‡ 0.26 3.34† 0.11 2.50* –0.03 –0.50 0.13 2.98† 12.67‡ 0.48 6.23‡ 0.22 2.85†

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PANSS Hal Total PANSS –5.1 1: Negative –0.1 2: Positive –2.3 3: Disorganized thought 0.1 –3.5 –4.6 –0.6 –0.2 0.26 5.99‡ 0.09 1.99* 0.08 1.76 –0.08 –1.53 0.14 3.38‡ 13.91‡ 0.43 5.60‡ 0.24 3.15† 4: Uncontrolled hostility/ excitement 0.2 –1.6 –2.5 0.3 –0.1 0.30 6.76‡ 0.12 2.76† 0.12 2.61† –0.04 –0.65 0.14 3.25† 16.66‡ 0.47 6.21‡ 0.29 3.77‡ 5: Anxiety/ depression –0.1 –1.8 –2.5 –0.3 –0.6 0.18 4.11‡ 0.13 2.98† 0.10 2.26* 0.07 1.33 0.04 0.92 6.98‡ 0.36 4.71‡ 0.30 3.95‡ *p ≤ .05. †p < .01. ‡p < .001. a Effect size = changes from baseline with risperidone minus the changes with haloperidol or placebo, divided by the pooled standard deviations. b We do not present an F value as well as a t value for the two drug comparisons because F is equal to t2.

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statistical method was analysis of covariance (ANCOVA) with four levels of the drug factor (placebo, haloperidol, and risperidone at 2 mg and 6–16 mg) and baseline as the covariant. Tables 1 and 2 show effect size units and results of ANCOVAs, which are presented as t values of simple contrasts. Results of the ANCOVAs of 6 mg/day of risperidone versus placebo and 6 mg/day of risperidone versus haloperidol are also presented in Table 1. Kraemer29 has noted that the power of statistical analysis can be increased without increasing the sample size by increasing the reliability of important ratings. Since improvement (reductions in PANSS scores) had started to level off at Weeks 6 or 8, we averaged the scores at Weeks 6 and 8 for certain endpoint analyses. This was done in order to have the most reliable measure, particularly in determining whether moderator variables such as extrapyramidal symptoms or background or clinical values might affect the results. If these variables were dichotomous, they were treated as a second factor, and if continuous, as a second covariant. We performed a principal components analysis to extract the five factors, using equimax rotation on PANSS scores at selection and baseline (before and after the washout period); at Weeks 1, 2, 4, 6, and 8; and at Weeks 6 and 8 (average). We used the most common solution weighted by sample size to define which items entered each factor; each item was equally weighted in defining the factor scores. The equimax rotation was used to be consistent with most of the previous factor-analytic studies of the PANSS. We also performed varimax rotation, and the results were virtually identical with those from equimax rotation (data not shown).

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Statistical Analyses A last-observation-carried-forward (LOCF) method was used in the analysis of the data, which included all randomized patients who had at least one observation during the double-blind phase of the trial. This analysis, which carried forward the last recorded observation for each patient who prematurely withdrew from the trial, was considered the primary efficacy analysis because it provides a more accurate and conservative assessment of efficacy than an observed-case analysis, which is based solely on patients who completed the trial. Our principal

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Assessments Clinical interviews and PANSS assessments were conducted by a psychiatrist on each of seven visits: at selection, at baseline (after the placebo washout period), and at Weeks 1, 2, 4, 6, and 8. Investigators were trained in the use of the PANSS with the aid of videotapes of patient interviews; to participate in the trial, a minimum of 80% of their ratings of individual items were required to fall within ± 1 point of the consensus rating. Severity of extrapyramidal symptoms was evaluated by means of the Extrapyramidal Symptom Rating Scale27 (ESRS) at each visit. The same procedures as for the PANSS were used in training investigators in the use of the ESRS. To investigate the association between the occurrence of extrapyramidal symptoms and changes in PANSS factor scores, scores on two of the ESRS clusters (parkinsonism total, which is the sum of all parkinsonism items, and Clinical Global Impression-Severity of Parkinsonism scale27 [CGI-Parkinsonism]) were analyzed. Results of an analysis of the total ESRS data in the combined North American trials are being published elsewhere.28

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19

the curve. As secondary analyses, we examined the optimal dose in the North American trials, 6 mg/day, and the lowest dose, 2 mg/day.

RESULTS Most of the patients were white (71%) men (83%) with a mean ± SD age of 37 ± 10.3 years (range, 18 to 67) and a DSM-III-R diagnosis of paranoid (56%) or undifferenti540 541

Marder et al.

Table 2. Improvements in Individual PANSS Items With Risperidone Compared With Haloperidol (Effect Size Units) and Results of Analysis of Covariance

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Effect Size Unit –0.60 –0.53 –0.52 –0.44 –0.44 –0.46 –0.41 –0.32 –0.36 –0.59 –0.44 –0.42 –0.47 –0.34 –0.31 –0.32 –0.39 –0.29 –0.32 –0.34 –0.24 –0.36 –0.46 –0.22 –0.14 –0.22 –0.22 –0.09 –0.10 –0.26

t 4.0‡ 3.5‡ 3.5‡ 3.3† 3.1† 3.0† 3.0† 2.7† 2.7† 2.6† 2.6* 2.4* 2.1* 2.0* 1.8 1.8 1.8 1.5 1.5 1.5 1.5 1.2 1.2 1.2 1.0 1.0 0.9 0.7 0.5 –0.1

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Item Passive social withdrawal Active social avoidance Hostility Depression Emotional withdrawal Disturbance of volition Poor impulse control Uncooperativeness Blunted affect Suspiciousness Anxiety Tension Delusions Lack of spontaneity Somatic concern Difficulty in abstract thinking Unusual thought content Lack of judgment and insight Poor attention Excitement Mannerisms and posturing Preoccupation Hallucinatory behavior Grandiosity Motor retardation Poor rapport Stereotyped thinking Disorientation Guilt Conceptual disorganization *p < .05. †p < 0.01. ‡p < .001.

Changes in PANSS Factor Scores Figure 1 shows the mean changes in factor scores from baseline to Weeks 6 and 8 in patients receiving placebo, risperidone, or haloperidol. Risperidone improved symptoms on each of the factors, and the changes with risperidone at 6–16 mg/day were significantly greater than with placebo or haloperidol on each factor (Table 1). Factor 1. Patients receiving 2 mg/day or 6–16 mg/day of risperidone showed a substantial reduction in negative symptoms, whereas an increase in symptoms was seen with haloperidol. This potent effect of risperidone on negative symptoms is also seen in the analysis of individual PANSS items (Table 2): risperidone had a significantly larger effect than haloperidol on five of the seven items included in the factor (passive social withdrawal, active social avoidance, emotional withdrawal, blunted affect, and lack of spontaneity). Factor 2. A robust beneficial effect of haloperidol was seen on positive symptoms, but at Week 8, risperidone at 6–16 mg/day produced almost twice the reduction in symptoms as haloperidol. Factor 3. Risperidone at 6–16 mg/day was significantly superior to haloperidol in ameliorating symptoms of disorganized thought. Both drugs, however, produced a substantial improvement, suggesting that thought disorder is affected by a property common to both drugs. Factor 4. Uncontrolled hostility/excitement was substantially benefited by risperidone at 6–16 mg/day. Little

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ated (32%) chronic schizophrenia.1,2 The mean age at onset of psychotic symptoms was 21.5 ± 5.8 years and age at the time of first psychiatric hospitalization 23.1 ± 6.5 years. The mean number of previous hospitalizations was 8.1 ± 7.2 and duration of the current hospitalization 48.0 ± 145.9 weeks. Almost half (46.2%) of the patients had a family history of mental illness. The patients’ mean total PANSS scores at baseline ranged from 89.2 to 94.9 in the six treatment groups. There were no statistically significant differences between treatment groups with respect to sex, race, age, weight, height, type of schizophrenia, age at onset of psychotic symptoms, age at time of first psychiatric hospitalization, number of previous hospitalizations, or severity of illness (CGI-Parkinsonism, PANSS, and PANSS factor scores at baseline). The 8-week treatment period was completed by 49.8% of the patients, including 31% of the patients in the placebo group, 41% of the haloperidol group, and 41%, 60%, 55%, and 61% of the patients receiving 2, 6, 10, and 16 mg/day of risperidone, respectively. Of the patients who withdrew from the study because of an insufficient response, most were receiving placebo (N = 51), 20 mg/day of haloperidol (N = 36), or 2 mg/day of risperidone (N = 41). Only 12 patients from the risperidone 6-mg group withdrew because of insufficient response. 542 541

Five Factors of Schizophrenia Five factors were identified and labeled: (1) negative symptoms, (2) positive symptoms, (3) disorganized thought, (4) uncontrolled hostility/excitement, and (5) anxiety/depression. The items included in each factor are listed in Table 3. The negative symptoms factor is similar to the PANSS negative symptom cluster proposed a priori by Kay et al.,10 except that the item “difficulty in abstract thinking” is now found in Factor 3 (disorganized thought), and “stereotyped thinking” is now found in Factor 2 (positive symptoms). The positive factor is also somewhat similar to the positive symptom cluster of Kay et al., except that three of the seven symptoms are in different factors: “conceptual disorganization” has been moved to Factor 3 and the items “excitement” and “hostility” to Factor 4 (uncontrolled hostility/excitement). Items in Kay and colleagues’ original general psychopathology cluster are now found in Factors 3, 4, and 5. The proposed five-factor structure was unchanged in patients receiving placebo (as expected) and was essentially the same during treatment with risperidone and haloperidol (Table 3). At almost all time points and for the Week 6 and 8 average, each item had its highest loading on the same factor as at baseline; exceptions are noted in the Table 3 footnote (the data are not shown for each time point in Table 3 but can be obtained from the authors).



Table 3. PANSS Items Included in Each Factor at Treatment Weeks 6 and 8 (the Factor on Which Each Item Had Its Highest Loading) Factor Loadings Risperidone Haloperidol

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78 69 73 76 78 61 45a 14

83 69 61 55 50 34c 84 55 14

80 45 72 60 62 55 79 41e 15

60 66 64 64 41 43f 51 12

54 73 67 65 52 30g 72 12

65 82 77 80 13

72 79 80 84 15

83 66 68 67 10 65

70 68 55 77 10 67

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Effects of Patient Characteristics on Treatment Response To determine whether patient responses to treatment were affected by demographic or clinical differences, we performed two-way ANCOVAs on the following variables: sex of patient, age, race (white, black, other), schizophrenia diagnosis (paranoid, disorganized, or undifferentiated), high and low dichotomized baseline scores on each of the five factors and each of the 30 PANSS items, global severity (CGI-Parkinsonism scores) at baseline, number of hospitalizations per years at risk (years since first psychiatric symptoms), and early (< 21 years) versus late (≥ 21 years) onset of psychotic symptoms. None of these variables were significantly associated with differences in patient responses to risperidone, haloperidol, or placebo, with one exception: a higher score on the PANSS item “conceptual disorganization” was almost significantly associated with greater improvement with risperidone (p = .07). This is probably a chance association. In their analysis of the data from the U.S. trial, Marder and Meibach2 reported that, whereas 6 mg/day of risperidone was significantly superior to placebo (total PANSS scores) for all patients, regardless of duration of hospitalization, haloperidol was significantly superior to placebo only for patients hospitalized for less than a month. We examined whether patients with current hospitalization ≤ 1 week had a more favorable outcome on total PANSS and Factors 1 through 5 than patients hospitalized ≥ 2

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change was seen with 2 mg/day of risperidone or haloperidol, and deterioration is evident in the placebo group. Risperidone was significantly superior to haloperidol on three of the four individual items included in this factor (hostility, poor impulse control, and uncooperativeness) (Table 2). Factor 5. Symptoms of anxiety and depression were slightly reduced with placebo and haloperidol; in contrast, risperidone at both 2 mg/day and 6–16 mg/day produced considerable improvement. Significantly greater improvement with 6–16 mg/day of risperidone than haloperidol was seen on three of the four individual items inJ Clin Psychiatry 58:12, December 1997

PANSS Total Scores A rapid improvement in symptoms (PANSS total scores) is seen over the first 2 weeks in patients receiving 6–16 mg/day of risperidone, and this effect is maintained during the course of the trial (Figure 2). At Weeks 1 and 2 and thereafter, the reduction in total PANSS scores was significantly greater with 6–16 mg/day of risperidone than haloperidol (at Week 1, t = 2.4, p = .02; at Week 2 and later, t > 3, p < .001). The placebo patients deteriorated from Weeks 1 to 6 and then showed little change from Weeks 6 to 8. The responses to haloperidol and 2 mg/day of risperidone were similar. At Weeks 6 and 8, the reduction in total PANSS scores was twice as great with 6–16 mg/day of risperidone as with haloperidol (risperidone, –14.1; haloperidol, –5.1; t = 3.3, p < .001) (Table 1). Mean changes from placebo scores are shown in Figure 3.


19

74 81 64 82 80 71 71 16

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Factor and Items Placebo 1: Negative symptoms Blunted affect 60 Emotional withdrawal 82 Poor rapport 76 Passive social withdrawal 78 Lack of spontaneity 73 Motor retardation 59 Active social avoidance 57 % of variance 14 2: Positive symptoms Delusions 83 Hallucinatory behavior 52 Grandiosity 31b Suspiciousness 64 Stereotyped thinking 65 Somatic concern 47 Unusual thought content 83 Lack of judgment and insight 25d % of variance 13 3: Disorganized thought Conceptual disorganization 69 Difficulty in abstract thinking 69 Mannerisms and posturing 75 Poor attention 72 Disturbance of volition 69 Preoccupation 54 Disorientation 70 % of variance 15 4: Uncontrolled hostility/excitement Excitement 68 Hostility 88 Uncooperativeness 88 Poor impulse control 89 % of variance 14 5: Anxiety/depression Anxiety 71 Guilt 60 Tension 62 Depression 71 % of variance 8 Total % of variance 64 a Also loaded on Factor 4 (46). b Also loaded on Factor 4 (43). c Also loaded on Factor 5 (40). d Also loaded on Factor 4 (36). e Also loaded on Factor 4 (46). f Also loaded on Factor 2 (52). g Also loaded on Factor 2 (55).

cluded in this factor (depression, anxiety, and tension) (Table 2). Risperidone at 2 and 6 mg/day. Risperidone at 2 mg/day was significantly superior to placebo on Factors 1, 2, 4, and 5 and significantly superior to haloperidol against negative symptoms (Factor 1) (Table 1). A curvilinear response to risperidone doses is apparent in Table 1—6 mg/day is superior to both lower and higher doses.

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Figure 1. Mean Changes in PANSS Factor Scores From Baseline to Week 8 (LOCF Analysis) Factor 1: Negative Symptoms

Factor 2: Positive Symptoms

0.10

0.20

0.05

0.10

0.00

0.00

Change Score

Change Score

–0.05 –0.10 –0.15 –0.20 –0.25

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–0.30

–0.10 –0.20 –0.30 –0.40

–0.35

1

2

0.20 0.10

6

8

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8

6

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0.60 0.50 0.40 0.30

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–0.10

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Factor 4: Uncontrolled Hostility/Excitement

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0.00 Change Score

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Factor 3: Disorganized Thought

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Change Score

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–0.40

0.10 0.00

–0.10 –0.20

–0.40

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–0.50

–0.40

–0.60

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2

4 Week

Factor 5: Anxiety/Depression 0.00 –0.05

8

2

4 Week

Placebo (N=86)

–0.15 –0.20

Haloperidol 20 mg/d (N=85)

–0.25 –0.30

Risperidone 2 mg/d (N=87)

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–0.40

Risperidone 6–16 mg/d (N=255)

–0.45 –0.50 2

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6

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weeks and found no effect of hospital duration on the relatively better outcome in patients receiving 6–16 mg/day of risperidone than the other treatments. In each of the comparisons of changes in total PANSS scores and Factors 1 through 5, outcome was slightly better in newly admitted patients than in patients hospitalized ≥ 2 weeks in each treatment group, but none of the interactions of treatment group and length of hospitalization were statistically significant; that is, the relative effect of the various drug groups was not affected by hospital duration.

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6

Extrapyramidal Symptoms and PANSS Factors To determine whether there was an association between extrapyramidal symptoms and symptoms of schizophrenia, we performed a Pearson product-moment correlation analysis of scores on the two measures of parkinsonism (ESRS clusters) with the five PANSS factors. Mean parkinsonism total and CGI-Parkinsonism scores at selection and baseline (before and after the washout period) for all patients and at 1, 2, 4, 6, and 8 weeks for the placebo group were significantly correlated with Factors J Clin Psychiatry 58:12, December 1997


Figure 2. Mean Changes in PANSS Total Scores From Baseline to Week 8 (LOCF Analysis) 6

Table 4. Correlations of Two ESRS Clusters With PANSS Factor 1 (Negative Symptoms) and Factor 3 (Disorganized Thought) at Baseline (All Patients, N = 514) and at Treatment Weeks 1–8 (Placebo Patients Only, N = 86)

Placebo (N=86) Haloperidol 20 mg/d (N=85) Risperidone 2 mg/d (N=87) Risperidone 6–16 mg/d (N=255)

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Variable Baseline Parkinsonism total Factor 1 0.22‡ Factor 3 0.19‡ Parkinsonism severity Factor 1 0.17‡ Factor 3 0.16‡ *p < .05. †p < .01. ‡p < .001.

Change Score

0 –2 –4 –6

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–10

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–12 –14 –16

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6

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–2 †

–6 Change Score

0.22* 0.12 0.19 0.24* 0.34† 0.28† 0.28† 0.29†

0.21 0.28†

0.17 0.17

0.16 0.24*

0.11 0.19 0.18 0.23* 0.28* 0.27*

Change Score

4

5

0.0

–0.5

†

–4

–1.0

*

*

–8

–1.5

1

–10 –12

Risperidone 6–16 mg/d (N=255) Haloperidol 20 mg/d (N=85)

–14 –16 –18

8

0.5


Factor 3

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1.0

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1

Week 4

Figure 4. Mean Changes in Parkinsonism Total Scores From Baseline to Week 8 (LOCF Analysis)

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Figure 3. Mean Changes From Placebo Scores at Weeks 6 and 8 (LOCF Analysis) 0

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†

–20

*p ≤ .05. †p < .01.

8

Risperidone 6 mg/d (N = 85) Risperidone 10 mg/d (N = 85) Risperidone 16 mg/d (N = 87)

change scores with covariant adjustment for baseline; that is, using ANCOVA, we examined whether the occurrence of extrapyramidal symptoms (maximum scores on both parkinsonism total and severity of parkinsonism at any time point) altered the change scores of the five factors at Weeks 6 and 8 in patients receiving 6–16 mg/day of risperidone in comparison with the haloperidol group. Among the 10 comparisons, none were statistically significant (Table 5), indicating that treatment-related changes in factor scores were not influenced by these extrapyramidal symptoms. We repeated the ANCOVA in patients stratified by whether they did or did not receive antiparkinsonian medications and found no effects on treatment outcome (changes in PANSS factors or total PANSS scores), nor did addition of this factor alter the failure of extrapyramidal symptoms to influence improvement (data not shown). If extrapyramidal symptoms produce or aggravate negative symptoms, as has been proposed, patients treated with 10 or 16 mg/day, which produced more extrapyramidal symptoms than 6 mg/day, could be expected to have a lower improvement rate on negative symptoms than patients receiving 6 mg/day of risperidone. This was not the

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Placebo (N = 87) Haloperidol (N = 83) Risperidone 2 mg/d (N = 87)

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Effects of Extrapyramidal Symptoms on Improvement Figure 4 shows the effects of placebo, four doses of risperidone, and haloperidol (20 mg/day) on mean parkinsonism total scores during the 8 weeks of treatment. Haloperidol was associated with substantially more severe parkinsonism symptoms than placebo or risperidone. Severity of these symptoms tended to be higher at higher doses of risperidone, but at endpoint (Week 8) was similar in patients receiving placebo and 2–10 mg/day of risperidone. Because baseline parkinsonism scores were significantly correlated with Factors 1 and 3 at baseline (Table 4), we held the effect of baseline constant by using the PANSS factor change scores and the maximum ESRS

4 Week

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1 (negative symptoms) and 3 (disorganized thought) (Table 4). These correlations are statistically significant, but the magnitude is small (a correlation of .15 would account for about 2% of the variance). The other three factors were clearly unrelated to extrapyramidal symptoms.

2

544 545

Marder et al.

Table 5. The Effects of Maximum ESRS Scores (Parkinsonism Total and Severity of Parkinsonism) on PANSS Factor Change Scores at Weeks 6 and 8 (N = 514)

©

Factor 1: Negative symptoms Parkinsonism total Severity of parkinsonism 2: Positive symptoms Parkinsonism total Severity of parkinsonism 3: Disorganized thought Parkinsonism total Severity of parkinsonism 4: Uncontrolled hostility/excitement Parkinsonism total Severity of parkinsonism 5: Anxiety/depression Parkinsonism total Severity of parkinsonism

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p Value

0.52 –0.00

.63 .99

–1.08 0.02

.28 .99

–1.85 0.41

.07 .68

–0.75 –0.22

.46 .83

0.72 0.81

.43 .42

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DISCUSSION

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Dimensions of Psychopathology in Schizophrenia Our findings agree with previous reports18–25 indicating that psychopathology as measured by the PANSS can be described according to five dimensions (factors). Results of the factor analysis from our sample indicate that these factors represent negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. Factor-analytic studies14,30,31 of the Scales for the Assessment of Negative and Positive Symptoms (SANS and SAPS) clearly identified Factors 1, 2, and 3 of the present study but only included items relevant to these three factors (positive symptoms, negative symptoms, and disorganization). An important feature of the three-factor model is that it includes only symptoms that appear as part of the schizophrenic syndrome. However, hostility/excitement and anxiety/depression are common affective symptoms in schizophrenia, and since patients and their caregivers expect treatment plans to attend to these symptoms, we used the five-factor model to evaluate the effectiveness of risperidone and haloperidol. In the present study, the factor structure was unchanged during 8 weeks of treatment with risperidone and haloperidol. In addition, the structure was stable over time in the placebo group, and, as Lindenmayer et al.24 also noted, was essentially the same before the washout period, when most patients were receiving conventional neuroleptics, and just after washout. It appears that treatment with a conventional agent such as haloperidol or with a newer 546 545

Differential Responsiveness to Risperidone and Haloperidol We found that improvement in all five dimensions with risperidone was not only consistent but substantially greater than in patients receiving haloperidol. The differential advantages of risperidone relative to haloperidol were greatest for negative symptoms, uncontrolled hostility/excitement, and anxiety/depression (Figure 1). The notion that the most important contrast between the two agents is in their effects on negative symptoms, hostility/excitement, and anxiety/depression is reinforced by the findings that risperidone at 2 mg/day was significantly more effective than haloperidol in reducing negative symptoms and that haloperidol was not significantly more effective than placebo for negative symptoms and anxiety/depression. The different effects of risperidone and haloperidol are also seen in the comparison of the individual PANSS items (Table 2). In this analysis, the five items with the highest t values (in descending order) were passive social withdrawal, active social avoidance, hostility, depression, and emotional withdrawal. Again, these symptoms are not usually associated with the psychotic component of schizophrenia, suggesting that risperidone differs from haloperidol in its qualitative effects. These data also suggest that the newer antipsychotic is effective not only for socially withdrawn patients but also for those having difficulty with hostility and impulse control (Factor 4). Significantly greater improvement with risperidone than haloperidol was seen at Week 1, and indeed by Week 1, patients treated with risperidone showed greater improvement than haloperidol patients at Week 4; the cost implications of this more rapid response with risperidone are apparent. The greater improvement in patients receiving risperidone as opposed to receiving haloperidol was not influenced by severity or chronicity of illness and was evident in all clinical subtypes as defined by high or low PANSS factor or item scores. Mattes33 has recently suggested that the greater efficacy shown by risperidone than by haloperidol is seen only in the more chronic, treatmentresistant patients or in patients with severe negative symptoms or depression. However, we could find no evidence that any subtype of patient was more responsive to risperidone than any other. According to the total PANSS data reported in Figure 3, the superiority of risperidone (6–16 mg/day) over placebo (change score, –17.9) was almost nine points greater


19

case. There were significantly greater improvements with 6 mg/day than 10 or 16 mg/day on Factor 4 (t = 2.3, p = .02), Factor 5 (t = 2.5, p = .01), and total PANSS (t = 2.15, p < .05), but not on the other factors, although the differences were in the same direction (Factor 1, t = 1.2, p = .22; Factor 2, t = 1.8, p = .07; and Factor 3, t = 1.8, p = .07).

agent such as risperidone decreases the intensity of each factor without changing the factor structure or the pattern of correlations between items. A similar five factors were found in schizophrenic patients in Sweden by Lindström and von Knorring19 and in Japan by Kawasaki et al.,32 evidence of the cross-cultural stability of the factor structure.



than that of haloperidol over placebo (–9.1). A nine-point difference is substantial enough to be considered of clinical significance.

©

Effects of Extrapyramidal Symptoms on Drug-Induced Improvement We also investigated whether the differences in effects between the two drugs could be related to extrapyramidal symptoms. Four doses of risperidone were compared with a single daily 20-mg dose of haloperidol, a dose likely to result in substantial extrapyramidal symptoms, particularly akathisia and akinesia. The results of our analysis, however, suggest that the differences in outcome between the two agents cannot be explained by extrapyramidal symptoms: changes in PANSS factor scores at Weeks 6 and 8 were not influenced by the effects of treatment on extrapyramidal symptoms. We performed many other statistical analyses in our attempts to discover effects of extrapyramidal symptoms on changes in PANSS scores, but could find no appreciable and consistent evidence of this.

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Our findings suggest that risperidone has important advantages compared with haloperidol. When administered in an effective dose range, risperidone produced greater improvements on all five dimensions of schizophrenia. This difference was most apparent on three dimensions (negative symptoms, uncontrolled hostility/excitement, and anxiety/depression), which suggests that risperidone—and perhaps other serotonin/dopamine antagonists—has qualitatively different effects from those of conventional neuroleptics. Drug names: biperiden (Akineton), chloral hydrate (Noctec), clozapine (Clozaril), haloperidol (Haldol and others), olanzapine (Zyprexa), procyclidine (Kemadrin), quetiapine (Seroquel), risperidone (Risperdal).

REFERENCES

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1. Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993;13:25–40 2. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825–835 3. Woolley DW, Shaw E. A biochemical and pharmacological suggestion about certain mental disorders. Proc Natl Acad Sci U S A 1954;244: 228–231 4. Leysen JE, Niemegeers CJE, Tollenaere JP, et al. Serotonergic component of neuroleptic receptors. Nature 1978;272:168–171 5. Ceulemans D, Gelders Y, Hoppenbrouwers ML, et al. Effect of serotonin antagonism in schizophrenia: a pilot study with setoperone. Psychopharmacology (Berl) 1985;85:329–332 6. Reyntjens A, Gelders YG, Hoppenbrouwers ML, et al. Thymosthenic effects of ritanserin (R 55667), a centrally acting serotonin-S2 receptor blocker. Drug Development and Research 1986;8:205–211

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CONCLUSIONS

7. Gelders YG. Thymosthenic agents, a novel approach in the treatment of schizophrenia. Br J Psychiatry 1989;155:33–36 8. Kane J, Honigfeld G, Singer J, et al, and the Clozaril Collaborative Study Group. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789–796 9. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996;153:466–476 10. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–276 11. Crow T. Molecular pathology of schizophrenia: more than one dimension of pathology? BMJ 1980;280:66–68 12. Van der Does AJ, Dingemans PM, Linszen DH, et al. Dimensions and subtypes of recent-onset schizophrenia: a longitudinal analysis. J Nerv Ment Dis 1995;183:681–687 13. Liddle PF. The symptoms of chronic schizophrenia: a re-examination of the positive-negative dichotomy. Br J Psychiatry 1987;151:145–151 14. Andreasen NC, Arndt S, Alliger R, et al. Symptoms of schizophrenia: methods, meanings, and mechanisms. Arch Gen Psychiatry 1995;52: 341–351 15. Schroder J, Buchsbaum MS, Siegel BV, et al. Structural and functional correlates of subsyndromes in chronic schizophrenia. Psychopathology 1995;28:38–45 16. Overall JE, Hollister LE, Pichot P. Major psychiatric disorders: a fourdimensional model. Arch Gen Psychiatry 1967;16:146–151 17. Lépine JP, Piron JJ, Chapatot E. Factor analysis of the PANSS in schizophrenia. In: Stefanis CN, Soldatos CR, Rabavilas AD, eds. Psychiatry Today: Accomplishments and Promises. Amsterdam, The Netherlands: Excerpta Medica; 1989 18. Kay SR, Sevy S. Pyramidical model of schizophrenia. Schizophr Bull 1990;16:537–545 19. Lindström E, von Knorring L. Principal component analysis of the Swedish version of the Positive and Negative Syndrome Scale for schizophrenia. Nordic Journal of Psychiatry 1993;47:257–263 20. Von Knorring L, Lindström E. Principal components and further possibilities with the PANSS. Acta Psychiatr Scand 1995;91(suppl 388):5–10 21. Bell MD, Lysaker PH, Beam-Goulet JL, et al. Five-component model of schizophrenia: assessing the factorial invariance of the Positive and Negative Syndrome Scale. Psychiatry Res 1994;52:295–303 22. Lindenmayer JP, Bernstein-Hyman R, Grochowski S, et al. Psychopathology of schizophrenia: initial validation of a five-factor model. Psychopathology 1995;28:22–31 23. Lindenmayer JP, Grochowski S, Hyman RB. Five factor model of schizophrenia: replication across samples. Schizophr Res 1995;14:229–234 24. Lindenmayer JP, Bernstein-Hyman R, Grochowski S. A new five factor model of schizophrenia. Psychiatr Q 1994;65:299–322 25. White L, Opler L, Lindenmayer JP, et al. Empirical evaluation of alternative models of schizophrenic symptoms. In: New Research Program and Abstracts of the 149th Annual Meeting of the American Psychiatric Association; May 8, 1996; New York, NY: Abstract NR555:221 26. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Washington, DC: American Psychiatric Association; 1987 27. Chouinard G, Ross-Chouinard A, Annable L, et al. Extrapyramidal Symptom Rating Scale [abstract]. Can J Neurol Sci 1980;7:233 28. Simpson GM, Lindenmayer JP. Extrapyramidal symptoms in patients treated with risperidone. J Clin Psychopharmacol 1997;17:194–201 29. Kraemer HC. To increase power in randomized clinical trials without increasing sample size. Psychopharmacol Bull 1991;27:217–224 30. Andreasen NC, Arndt S, Miller D, et al. Correlational studies of the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms: an overview and update. Psychopathology 1995;28:7–17 31. Arndt S, Andreasen NC, Flaum M, et al. A longitudinal study of symptom dimensions in schizophrenia. Arch Gen Psychiatry 1995;52:352–360 32. Kawasaki Y, Maeda Y, Sakai N, et al. Evaluation and interpretation of symptom structures in patients with schizophrenia. Acta Psychiatr Scand 1994;89:399–404 33. Mattes JA. Risperidone: how good is the evidence for efficacy? Schizophr Bull 1997;23:155–161

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Letters to the Editor


Clozapine-Benzodiazepine Interactions

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Sir: Clozapine is an atypical antipsychotic often used in the treatment of refractory schizophrenic patients. The manufacturer recommends caution when combining clozapine therapy with other CNS-active drugs, particularly benzodiazepines. Sassim and Grohmann1 first reported two cases of severe collapse with this combination. The first patient was a 51-year-old man on diazepam 20 mg/day. He was placed on clozapine 25 mg because of nonresponse to other neuroleptics. On the first day of treatment with clozapine 25 mg, a severe collapse took place. The second patient was a 36-year-old man who was on diazepam 5 mg/day for 2 weeks and had received 30 mg of flurazepam the day before clozapine treatment was initiated. On the second day of treatment with clozapine 12.5 mg/day, the patient became delirious and collapsed, similar to the first patient. The authors then reviewed the charts of 39 patients at the psychiatric university hospital at Munich who had been exposed to this combination. They found that 3 patients (7.7%) had collapsed while undergoing treatment with clozapine plus benzodiazepine, versus only 1 patient (2.6%) treated with clozapine alone. Other side effects reported to be significantly increased with this combination were dizziness, sedation, and elevations of SGPT and GGT. Grohmann et al.2 reviewed data on 959 patients taking clozapine. Four cases of severe cardiovascular and respiratory dysregulation were observed with clozapine-benzodiazepine combinations. All cases occurred at the beginning of clozapine initiation; the common findings were unconsciousness, delirium, severe hypotension, and respiratory arrest; nevertheless, all patients recovered under intensive medical management. The investigators concluded that among the 189 patients exposed to the clozapine-benzodiazepine combination, there was a risk of 2.1% for these severe drug interactions. Klimke and Klieser3 described the case of a 43-year-old refractory schizophrenic who was started on clozapine therapy and the dosage increased to 400 mg over 2 weeks. After 17 days of clozapine treatment, the patient refused clozapine, became agitated, and was given three doses of lorazepam 2 mg i.v. over 9 hours. The patient died in sleep that night, most probably due to respiratory arrest. Recently, Jackson et al.4 reported three cases of delirium on clozapine-benzodiazepine combinations. Interestingly, two of these patients were rechallenged with lorazepam and became delirious again; the third patient was not rechallenged. Bredbacka et al.5 described a case of severe orthostatic hypotension on treatment with clozapine-benzodiazepine combination and on clozapine alone. According to unpublished data (data on file, Novartis Pharmaceuticals Corp.), 15,311 patients were treated with clozapine during the first 18 months of its reintroduction in the United States. About 11% of these patients received concomitant benzodiazepine therapy. Six cases of respiratory depression/ arrest were reported, representing 0.31% of the clozapinebenzodiazepine group. Only two of these cases occurred in the context of beginning of treatment, while two cases involved deliberate overdose (one case of clozapine and one case of benzodiazepine overdose). In addition, two patients had prior history of myocardial infarction or “multiple cardiovascular risk fac-

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tors.” The Novartis data are somewhat different from those reported in the European literature insofar as most cases of severe adverse interactions did not occur at the start of treatment with clozapine; also, the incidence of respiratory arrest or cardiovascular collapse was much lower. Finally, all of these patients recovered with proper medical management. Of the more than 63,000 patients exposed to clozapine by September 1993, there were 10 reported instances of cardiorespiratory arrest within the first 3 days of clozapine therapy; “some” of the patients were taking concomitant benzodiazepines. Nonetheless, all of these patients also recovered. The pathophysiology of life-threatening clozapine-benzodiazepine interactions is not well understood. However, it seems to be relatively specific for this combination. Benzodiazepines have been used as adjuncts in the treatment of schizophrenia. The literature on benzodiazepines in schizophrenia is somewhat divided, but tends toward negative or null effects except when anxiety symptoms predominate.6 The combined use of a benzodiazepine and a typical antipsychotic can cause sedation, behavioral disinhibition, exacerbation of psychosis, increase in anxiety and depression, and, at high doses, cognitive impairment.7 Thus, it seems that the respiratory depression and cardiovascular complications, though uncommon, are specific for clozapine-benzodiazepine combinations. It is possible that the benzodiazepines act by increasing the blood clozapine level, as clozapine itself can cause collapse due to severe hypotension in rare cases.2,5 Therefore, we recommend close monitoring of clozapine levels if this combination is used. Blood benzodiazepine levels are not very useful principally because of a lack of data regarding concentration response relationships for benzodiazepines.8 Another relevant issue is the role of individual risk factors as it seems that patients with preexisting cardiovascular, liver, or organic brain disease may be more vulnerable to this adverse interaction (reference 3 and data on file, Novartis Pharmaceuticals Corp.). Also, individuals with obesity or heart failure are at an increased risk of adverse reactions with clozapine.9 Thus, in patients with these risk factors, appropriate investigations, e.g., ECG, liver function tests, and cardiology consultation, may be needed before starting treatment. During treatment, frequent—at least once weekly—monitoring of clozapine levels is in order. Most authorities would discourage the combined use of clozapine and benzodiazepines especially—but not exclusively—with their concurrent initiation.7,10,11 Similarly, in view of the above case reports, it may be dangerous to start clozapine therapy in the context of established benzodiazepine treatment. This recommendation is based on the observation that most serious adverse interactions reported in the literature occurred at the start of this combination or when clozapine was added to an established benzodiazepine regimen. However, if a therapeutic dose (> 300 mg, as per manufacturer) of clozapine has been achieved with an acceptable plasma level, benzodiazepines can be cautiously added since this scenario has not been associated with respiratory depression or cardiovascular complications. Another approach can be to slowly taper the previous antipsychotic at the start of clozapine treatment or to combine clozapine with a small dose of a conventional neuroleptic at the initiation of treatment. The rationale here is that as clozapine is slowly in-

547


creased to a therapeutic level, this strategy may prevent the emergence of severe anxiety or agitation that may necessitate the addition of benzodiazepines. Obviously, future research will help to clarify these issues. REFERENCES

©

1. Sassim N, Grohmann R. Adverse drug reactions with clozapine and simultaneous application of benzodiazepines. Pharmacopsychiatry 1988;21(6):306–307 2. Grohmann R, Ruther E, Sassim N, et al. Adverse effects of clozapine. Psychopharmacology 1989;99(suppl):S101–S104 3. Klimke A, Klieser E. Sudden death after intravenous application of lorazepam in a patient treated with clozapine [letter]. Am J Psychiatry 1994;151:780 4. Jackson CW, Markowitz JS, Brewerton TD. Delirium associated with clozapine and benzodiazepine combinations. Ann Clin Psychiatry 1995;7(3):139–141 5. Bredbacka P-E, Paukkula E, Kinnunen E, et al. Can severe cardiorespiratory dysregulation induced by clozapine monotherapy be predicted? Int Clin Psychopharmacol 1993;8(3):205–206 6. Wirshing WC, Marder SR, Van Putten T, et al. Acute treatment of schizophrenia. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:1263 7. Treatment with antipsychotics. In: Janicak PG, Davis JM, Preskorn SH, et al, eds. Principles and Practice of Psychopharmacotherapy. Baltimore, Md: Williams & Wilkins; 1993:114,153 8. Bailey L, Ward M, Musa MN. Clinical pharmacokinetics of benzodiazepines. J Clin Pharmacol 1994;34(8):804–811 9. Clardy J, Gale RH. Mortality risk and clozapine [letter]. Am J Psychiatry 1995;152:651 10. Buckley PF, Meltzer HY. Treatment of schizophrenia. In: Schatzberg AF, Nemeroff CB, eds. The American Psychiatric Press Textbook of Psychopharmacology. Washington, DC: American Psychiatric Press; 1995:632 11. Owens MJ, Risch SC. Atypical antipsychotics. In: Schatzberg AF, Nemeroff CB, eds. The American Psychiatric Press Textbook of Psychopharmacology. Washington, DC: American Psychiatric Press; 1995:273

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Imran Faisal, M.D. J. P. Lindenmayer, M.D. Zebulon Taintor, M.D. Robert Cancro, M.D. New York, New York

Mania From Dexfenfluramine

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Case report. Ms. A, a 56-year-old white woman, had had bipolar II disorder since age 18. She had been married and di-

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Sir: A wide range of medications has been reported to induce manic episodes. These include stimulant drugs, such as dextroamphetamine. A drug recently approved for treatment of obesity, dexfenfluramine, is not reported to have adverse effects of mania, hypomania, psychosis, or other similar behavioral effects. A review of published literature yielded only one relevant clinical article that reported a study in which fenfluramine was used to augment the effects of desipramine in refractory patients. One patient with unipolar psychotic melancholia exhibited a clear worsening of her dysphoria, suicidal ruminations, hallucinations, and oppositional behavior, coupled with a refusal to eat or take fluids.1 We report the case of a woman with bipolar disorder who developed mixed mania shortly after prescription of dexfenfluramine and the cessation of the mixed mania after discontinuation of dexfenfluramine.

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vorced twice, the last time more than 20 years ago. She had worked as a librarian in the past but had been unable to for the last 10 years secondary to her illness. She had been living with her mother for many years. During the course of her illness, depressive episodes predominated, with over 10 severe major depressive episodes and nine suicide attempts, most by overdose. Depressive symptoms had included depressed mood, pessimism, guilt, waking during the night, and social withdrawal, with most episodes lasting less than a month, but several requiring hospitalization. Hypomanic episodes had been characterized by elated mood, speeded thoughts, impaired judgment, promiscuous sexuality, and reduced need for sleep. During a 6year period of treatment with one of us (C.L.B.), after the retirement of her previous psychiatrist, her regimen was gradually evolved to a stable dosage of divalproex 1000 mg/day, carbamazepine 600 mg/day, molindone 50 mg/day, zolpidem 20 mg h.s., and occasional alprazolam 0.5 mg for anxiety. On this regimen, she had functioned well for 4 years, with only occasional increased sleep difficulty and increased symptomatology following efforts to reduce molindone (impaired judgment, tearfulness, fearfulness, and disturbed insight) or divalproex (mild rapid-cycling mood episodes, partial panic attacks, and migraine type headaches). Ms. A was mildly overweight and had been unsuccessful at reducing her weight by diet and exercise. With the introduction of dexfenfluramine, she asked that she be prescribed the drug. The psychiatrist explained the general experience of anorectic agents as historically associated with precipitation of mania and mood destabilization, but that no evidence of such disturbances with dexfenfluramine had been published. Despite his general discouragement of the trial and explanation of possible risks, Ms. A wished to try dexfenfluramine. She commenced treatment with 15 mg daily, which was increased after about 10 days to 15 mg b.i.d. Within 2 weeks of commencing treatment, she began to have distinct mood cycles, usually of less than a day’s duration, often somewhat provoked by perceived criticism from her mother. Her symptoms included rapid onset and escalation of anger, rageful and even homicidal thoughts toward her mother, verbally but not physically expressed anger, racing thoughts, severely impaired concentration, and labile mood with easy shifts into tearfulness. She was unable to restrain her escalated, out-of-control mood and affect, which heretofore she had done readily. Her sleep changed minimally with continued use of zolpidem. She became more anxious and mildly agitated. She recognized the inappropriateness of her rapid mood shifts and hostility, and felt increasingly guilty about these. On several occasions, she reverted to a long quiescent pattern of alcohol abuse, once drinking over 500 mL of spirits in an effort to quiet her out-of-control temper. The patient, who was usually fully adherent and cooperative with the overall treatment plan, uncharacteristically did not inform the psychiatrist of the disturbance for 6 weeks, at least in part because she anticipated that the dexfenfluramine would be discontinued, which she felt was contributing to a 7-lb (3-kg) weight loss during the period. On examination, her speech was rapid, her motor behavior agitated, and her mood distraught with frequent tearfulness, and she was feeling quite guilty. Cognition was not impaired. The dexfenfluramine was discontinued, after discussion regarding its likely role in her symptomatology. Alprazolam dosage was increased to 2 mg b.i.d., but other medications were unchanged. Within 3 days, her mixed manic, rapid-cycling state had improved, and within 2 weeks, she was fully back to her baseline status. Following the episode, her recollection of the period was faulty. She was unable to recognize the severity of her impairment during the time.



In conclusion, psychiatrists and other physicians treating patients with dexfenfluramine should be aware of the possible, albeit not conclusively established, risk of worsening the course of bipolar disorder with this drug. REFERENCE 1. Price L, Charney D, Delgado P, et al. Fenfluramine augmentation in tricyclic-refractory depression. J Clin Psychopharmacol 1990;10: 312–317

©

Charles L. Bowden, M.D. James Dickson, Jr., M.D. San Antonio, Texas

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Effects of Olanzapine on Polydipsia and Intermittent Hyponatremia

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In this case, unlike conventional medications, olanzapine appears to have substantially reduced psychotic symptoms and prevented the recurrence of polydipsia and intermittent hyponatremia. Further studies of the use of olanzapine for polydipsia and hyponatremia will be important in determining the relative efficacy and safety in the treatment of this syndrome.

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Sir: The syndrome of polydipsia and intermittent hyponatremia is a well-documented problem affecting psychotic patients. Recent studies, however, indicate the treatment with atypical antipsychotic agents is associated with decreased water consumption and normalization of serum sodium levels.1–4 Olanzapine recently became available in the United States and is characterized as a selective monoaminergic antagonist with high affinity binding to serotonin, dopamine, muscarinic, histamine, and adrenergic receptors (package insert, 1996). Presented is a single case, included in a 12-month open-label study, demonstrating improvement in polydipsia and serum sodium levels with olanzapine at therapeutic dosage levels.

chotic symptoms. On Visit 4, the family reported that Ms. A had again begun to drink water and iced tea excessively. They reported increased fluid intake (> 5 liters per day), irritability at home, and nocturnal enuresis. Ms. A admitted to increased fluids and feelings of nausea, stating that she felt “sick to her stomach” and that the increased fluids “helped to settle her stomach.” Laboratory findings revealed a sodium level of 131 mEq/L (normal, 135–147) with a urine specific gravity of 1.002. Olanzapine was increased to 20 mg at bedtime. Within 5 days, the family reported a decrease in water intake, improvement in mood, and cessation of enuresis. Laboratory findings from Visits 5, 6, and 7 were within normal limits, with sodium levels of 138, 139, and 135 mEq/L, respectively. Results of 6month follow-up laboratory work, including Visits 8 through 13, confirmed stabilization of serum sodium between 135 and 139 mEq/L and urine specific gravity between 1.010 and 1.020. The PANSS also showed a marked reduction from 125 to 44 over the 6-month period. AIMS scores decreased from 21 to 5 during the same period. Subsequently, the patient and her family have reported a continuing reduction of fluids and elimination of enuresis and nausea. According to the family, 6 months is the longest time that Ms. A has gone without water loading.

Kimberly H. Littrell, M.S., A.R.N.P. Craig G. Johnson, M.D. Steven H. Littrell, M.A., L.P.C. Carol D. Peabody, C.M.A. Tucker, Georgia

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1. Leadbetter RA, Shutty MS Jr. Differential effects of neuroleptics and clozapine on polydipsia and intermittent hyponatremia. J Clin Psychiatry 1994;55(9, suppl B):110–113 2. Henderson D, Goff D. Clozapine for polydipsia and hyponatremia in chronic schizophrenics. Biol Psychiatry 1994;36:768–770 3. Khreis IY, Slaughter JR. Risperidone for primary psychogenic polydipsia [poster]. Presented at the 1995 annual meeting of the American Psychiatric Association; May 20–25, 1995; Miami, Fla 4. Byerly MJ, DeVane CL. Pharmacokinetics of clozapine and risperidone: a review of recent literature. J Clin Psychopharmacol 1996;16:177–187

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Case report. Ms. A is a 44-year-old woman with a 25-year history of schizophrenia, paranoid type and 32 hospitalizations. Ms. A’s past medical records documented a positive history for polydipsia with intermittent hyponatremia during treatment with conventional antipsychotic agents. Abnormalities in serum sodium levels (ranging from 129 to 133 mEq/L) were documented, beginning approximately 5 years after her first acute episode. Her polydipsia had been controlled during inpatient stays with behavioral measures and restriction of fluid intake. Despite encouragement, she had not maintained normal sodium levels for more than 4 months continuously. Records showed numerous trials of conventional antipsychotics, including chlorpromazine, thioridazine, thiothixene, perphenazine, haloperidol, and trifluoperazine, as well as a confirmed history of medication noncompliance. Previous pharmacotherapy displayed limited effect on positive and negative symptoms. The patient never received a trial of clozapine despite her refractory psychosis and positive history for polydipsia. Ms. A was receiving haloperidol decanoate 50 mg i.m. q 1 week at the time of our initial contact. After one dosing cycle of haloperidol decanoate (1 week) was withheld, Ms. A was seen for her first study visit. Results of a physical examination and ECG were normal, and all laboratory findings were within normal limits, including serum sodium level of 136 mEq/L and urine specific gravity of 1.010. The baseline Positive and Negative Syndrome Scale (PANSS) score was 125, and the baseline Abnormal Involuntary Movement Scale (AIMS) score was 21. On Visit 2, Ms. A was started on olanzapine 10 mg at bedtime (48 hours later). She was scheduled for subsequent visits every 7 days for the next 6 weeks, as indicated by the study design. On Visit 3, olanzapine was increased by 5 mg/day (15 mg q.h.s.) due to persistent psy-

REFERENCES

A Possible Pharmacokinetic Interaction Between Fluoxetine and Acetylsalicylic Acid Sir: In rare instances, fluoxetine has been shown to cause skin rashes.1 During fluoxetine treatment, our patient experienced hives that resolved after antidepressant discontinuation, only to recur when the patient took acetylsalicylic acid (ASA, aspirin) for pain relief. Case report. A 44-year-old healthy, physically active, white man developed major depressive disorder after a period of extreme stress. He was started on an oral dose of 20 mg of fluoxetine per day. Early during the treatment, the patient complained of transient diarrhea and headache. On the 23rd day of treat-

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ment, the patient developed hives believed to be due to fluoxetine, which was discontinued. The patient was given an oral dose of 25 mg of diphenhydramine as needed. The hives persisted for 11 days after the discontinuation of fluoxetine. The treatment plan was to wait for at least 48 hours after the disappearance of all hives and then to start a structurally dissimilar serotonin selective reuptake inhibitor (SSRI) such as sertraline. However, 36 hours into the hive-free period, the patient took an oral dose of two tablets (650 mg) of acetylsalicylic acid for an unrelated painful joint condition, and the hives reappeared. Despite the recurrence of hives, he continued to take two tablets of ASA every 6 hours. The hives eventually resolved. At that point, sertraline was started after a 48-hour hivefree period without subsequent problems.

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According to the Physicians’ Desk Reference (PDR),1 skin rash was reported by 2.7% of the patients using fluoxetine and 1.8% of the patients taking placebo in clinical trials. The appearance of hives in our patient on the 23rd day of treatment and persistence of hives for 11 days after the discontinuation of fluoxetine are consistent with a causal role for fluoxetine and/or its metabolite norfluoxetine because of their long half-lives (3–5 and 7–15 days, respectively). Further, ASA and its metabolite salicylic acid may have altered the protein binding of fluoxetine and/or norfluoxetine, resulting in higher free plasma levels of fluoxetine and/or norfluoxetine sufficient to trigger a recurrence of the hives. ASA may alter protein binding by two mechanisms. First, ASA itself acetylates serum albumin, which alters binding of other drugs to the protein.2 Second, the deacetylated ASA, i.e., salicylic acid, is bound strongly to serum albumin3 and can displace other drugs from their protein binding sites. Chronic salicylate use has been shown to significantly reduce the plasma protein binding of acetazolamide in four volunteers via competitive inhibition of protein binding by salicylates.2 ASA also increased the plasma levels of unbound valproic acid.3 Fluoxetine is strongly bound to plasma proteins,4 including albumin and α1-acid glycoprotein, and the extent of protein binding appears to be independent of plasma concentrations of fluoxetine.5 A careful literature search produced no reports in which one drug worsened an allergic response to another drug. However, a case report documents a severe allergic reaction and shock resulting from coadministration of ASA and sunflower seeds in a patient who had no allergic reaction with ASA and developed only oral paresthesia with sunflower seeds when the two agents were administered separately.6 Based on this case report, there is a possibility that a pharmacodynamic interaction occurred between ASA and fluoxetine, in which ASA may have sensitized the patient to develop hives during the falling plasma levels of fluoxetine after it was discontinued. However, the similarities in appearance and distribution of the hives with fluoxetine and then with ASA suggest a pharmacokinetic interaction as explained above. The rarity of this phenomenon in clinical practice may be due to the fact that the incidence of skin rash among patients taking fluoxetine is 2.7%, which is only 0.9% greater than the incidence with placebo according to the PDR. Levels of acute phase proteins (e.g., α1-acid glycoproteins and serum albumin) change in stressful situations,5,7 which may result in an increased protein binding and decreased free fraction of protein bound drugs like fluoxetine. Similarly, a decrease in the level of stress may decrease the protein binding and increase the free fraction of fluoxetine. However, the patient continued to suffer from considerable stress during fluoxetine treatment and after it was discontinued. Thus, it is unlikely

that the hives developed secondary to changes in the plasma protein levels due to altered stress. If another highly protein bound drug had been given instead of ASA, as was the plan, the hives might have recurred for the same reason (e.g., displacement of fluoxetine and/or norfluoxetine). However, the conclusion might have been that the patient was allergic to the new SSRI as well as fluoxetine, resulting in an unnecessary switch to another class of antidepressants. This case report suggests that caution is needed whenever highly protein bound drugs are used together. It may be better to wait longer than the usual 48 hours after the resolution of an allergic reaction before switching to another drug, especially if it is highly protein bound and has a long plasma half-life. REFERENCES

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1. Prozac (fluoxetine). Physicians’ Desk Reference. Montvale, NJ: Medical Economics; 1997:935–940 2. Sweeney KR, Chapron DJ, Brandt JL, et al. Toxic interaction between acetazolamide and salicylates: case reports and a pharmacokinetic explanation. Clin Pharmacol Ther 1986;40(5):518–524 3. Miners JO. Drug interactions involving aspirin and salicylic acid. Clin Pharmacokinet 1989;17(5):327–344 4. Aronoff GR, Bergstrom RF, Pottratz ST, et al. Fluoxetine kinetics and protein binding in normal and impaired renal function. Clin Pharmacol Ther 1984;36(1):138–144 5. Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982;389:39–48 6. Moller R, Paul E. Acetylsalicylic acid as an augmentation factor in food allergy. Hautarzt 1996;47(4):281–283 7. Alper CA. Plasma protein measurements as a diagnostic aid. N Engl J Med 1974;291:287–290

Asystole in ECT

Sir: In an excellent discussion of asystole in electroconvulsive therapy,1 Dr. McCall makes a number of useful suggestions to minimize the likelihood that asystole will occur. I would like to amplify his treatment recommendation of intravenous atropine injection. Without cardiac function during asystole, atropine administered through a peripheral vein will not reach the heart unless “pushed” by a 20- to 30-mL fluid bolus followed by elevation of the arm. However, there is no certainty that the atropine will reach the heart even with this maneuver in the absence of circulation. External cardiac massage should also be initiated to assist the atropine in reaching its intended site of action. If intravenous access is compromised, endotracheal administration of atropine can be used. Transcutaneous cardiac pacing should be performed immediately if atropine does not overcome the asystole.

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Mujeeb U. Shad, M.D. Anne T. Harvey, Ph.D. Wichita, Kansas James B. Lucot, Ph.D. Dayton, Ohio

REFERENCE 1. McCall WV. Asystole in electroconvulsive therapy: report of four cases. J Clin Psychiatry 1996;57:199–203

Raymond A. Faber, M.D. San Antonio, Texas


Book Reviews

Book Reviews

A New Chapter

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fter 12 years of tireless efforts, Hagop S. Akiskal, M.D., is relinquishing his editorship of the Journal’s book review section. Thanks to his dedication, Dr. Akiskal, along with his reviewers, has guided our readers in building personal libraries of lasting value. Throughout his tenure, Dr. Akiskal sought out young and upcoming clinicians to write the reviews that appeared in the pages of the Journal. His choices were designed to provide an opportunity to worthy young reviewers to reach a worldwide audience. Our readers have greatly benefited during Dr. Akiskal’s stewardship. We are all in his debt and hope to take advantage of his keen insights and advice as he becomes a member of our Editorial Board. It is also our pleasure to announce that Michael H. Ebert, M.D., has been appointed as a second Deputy Editor of The Journal of Clinical Psychiatry and, in this capacity, will oversee the book review section. Dr. Ebert is Chairman of the Department of Psychiatry at Vanderbilt University and is a world-renowned researcher and educator. Under Dr. Ebert’s watchful eye, the Journal will continue its long-standing tradition of offering our readers concise and practical reviews of some of the most interesting and worthwhile books available today.

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Alan J. Gelenberg, M.D. Editor in Chief

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Irving Shelton Publisher


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Book Reviews

A Renaissance of Clinical Psychiatry Through Books Published During the Past Decade Hagop S. Akiskal, M.D. Department of Psychiatry, University of California at San Diego

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Through a group review of representative books published during the last decade, the author hails a renaissance in clinical psychiatry. This is characterized by renewed interest in psychopathology, focus on discrete mental disorders, sophisticated methodology, greater appreciation of the biological underpinnings of mental phenomena, and integration of traditional psychological approaches within a general medical framework. Although an evolutionary perspective is not yet a dominant theme of the new psychiatry, it is predicted that it will play an increasingly important role in helping the integration of physiology, psychoanalysis, and contemporary psychopathology.

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am formally signing off as Book Review Editor after 12 years. Major changes have occurred in psychiatry during this period. These changes have brought psychiatry closer to medicine. This was reflected in a group review that I published in 1987, entitled “The New Biopsychiatry” (JCP 48:382–384). Since then, the trend has continued toward greater refinement in biological methodology and sophisticated clinical approaches that integrate biomedicine with the more classical concerns of psychiatry. The result has been a true Renaissance in psychopathology. The 25 books that constitute this review illustrate this transformation of psychiatry into a clinical science. The brief descriptions which I give of each book will explain my specific choices in each instance. This farewell review is largely confined to the books that are sent to us for review; nonetheless, I actively sought certain books from publishers that I felt to be relevant to my theme. The list of books is, therefore, representative and not exhaustive. I have chosen them because they exemplify new developments in specific areas of clinical psychiatry. Also, I had to limit myself to first editions and excluded edited books and textbooks. They are listed in alphabetical order by author and no price is quoted: these are priceless books that reflect some of the very best of the new psychiatry.

Berrios, German E. The History of Mental Symptoms: Descriptive Psychopathology Since the Nineteenth Century. Great Britain: Cambridge University Press, 1996, 565 pages. An elegant book, it relates modern psychopathology to its historical roots.

New York: WW Norton & Co., 1996, 215 pages. Documents the pioneering contributions of the authors in establishing childhood depression as a clinical entity.

Gilbert, Paul. Human Nature and Suffering. New York: Lawrence Erlbaum Associates, 1989, 407 pages. Fascinating analysis of the evolutionary underpinnings of negative affective arousal.

Goodwin, Donald W. Alcoholism: The Facts. Oxford: Oxford University Press, 1994, 177 pages. A concise summary of the fundamental facts of this disease with the author’s customary wit, incisive analysis, scholarship, and literary flair.

Goodwin, Frederick K., and Kay Redfield Jamison. Manic-Depressive Illness. New York: Oxford University Press, 1990, 938 pages. 552

Kaplan, Helen Singer. The Sexual Desire Disorders: Dysfunctional Regulation of Sexual Motivation.

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Cytryn, Leon, and Donald McKnew. Growing Up Sad: Childhood Depression and Its Treatment.

Washington D.C.: American Psychiatric Press, 1993, 239 pages. I chose this book because of its provocative title and content, which provide a futuristic vision for our field.

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Compassionate and in-depth coverage of the topic unavailable elsewhere under one cover.

Hyman, Steven E., and Eric J. Nestler. The Molecular Foundations of Psychiatry.

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Brockington, Ian F. Motherhood and Mental Health. Oxford: Oxford University Press, 1996, 612 pages.

I can’t say it better than what I said in a review published in the American Journal of Psychiatry when the book first came out: “The best since Kraepelin.”

New York: Brunner/Mazel Publishers, 1995, 332 pages. Dr. Kaplan has been one of my heroes since her first book on The New Sex Therapy (1974). As before, she provides a clinically sensitive synthesis of the best knowledge in physiology, psychodynamic understanding, and behavioral techniques.

Katon, Wayne J. Panic Disorder in the Medical Setting. Washington D.C.: NIH Publishers, 1993, 135 pages. A clinically cogent summary of the impact of panic disorder in the general medical setting.

Kellner, Robert. Somatization and Hypochondriasis. New York: Praeger, 1986, 401 pages. A scholarly, clinically insightful, and practical treatise on the subject.

Lipowski, Zbigniew J. Delirium: Acute Confusional States. New York: Oxford University Press, 1990, 490 pages. J Clin Psychiatry 58:12, December 1997

Book Reviews

A compendium of the author’s contributions, which have helped in redefining the entire field of consultation-liaison psychiatry.

Lowman, Rodney L. Counseling and Psychotherapy of Work Dysfunctions. Washington D.C.: American Psychological Association, 1993, 328 pages. This book by psychologist Rodney Lowman will provide psychiatrists extensive and well-researched information on how to help their patients find the best jobs commensurate with their abilities, temperament, and level of psychopathology.

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Marks, Isaac M. Fears, Phobias, and Rituals: Panic, Anxiety, and Their Disorders.

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New York: Oxford University Press, 1987, 682 pages. All that you need to know about the subject from a master on anxiety and related disorders.

MacLean, Paul D. The Triune Brain in Evolution: Role in Paleocerebral Functions.

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New York: Plenum Press, 1990, 672 pages. A masterpiece that every psychiatrist should attempt to read, to understand how mental functions and behavior have evolved as part of the triune brain.

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A highly enjoyable book on SAD, written by the clinical scientist who has probably done the greatest amount of work on it.

Sandler, Joseph, Christopher Dare, and Alex Holder. The Patient and the Analyst: The Basis of the Psychoanalytic Process, 2nd ed. Madison: International Universities Press, 1992, 238 pages. This is an exception to my rule of excluding second editions and edited books. I could not resist the temptation to acquaint the reader with pithy descriptions of psychoanalytic concepts that are clinically useful in daily practice. (I must confess, I have not come across any new book that meets these qualifications.)

Shuchter, Stephen R., Nancy Downs, and Sidney Zisook. Biologically Informed Psychotherapy for Depression. New York: Guilford Press, 1996, 224 pages. The original focus of this book is to help practitioners to utilize psychological principles in the treatment of depression in light of a biological understanding of the disease.

Stahl, Stephen M. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. New York: Cambridge University Press, 1996, 379 pages. Finally, an elegant and beautiful psychopharmacology text written by a basic scientist who is also a clinician.

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Moore, David P., and James W. Jefferson. Handbook of Medical Psychiatry. St. Louis: Mosby, 1996, 545 pages.

Rosenthal, Norman E. Winter Blues: Seasonal Affective Disorder. New York: Guilford Press, 1993, 325 pages.

A user-friendly reference that covers nearly everything the clinician needs to know about the relationship of physical disease and psychopathology.

Nesse, Randolph M., and George C. Williams. Why We Get Sick: The New Science of Darwinian Medicine. New York: Time Books, 1994, 290 pages. A thought-provocative and delightful book on the evolutionary explanations of physical and mental dysfunction.

Neziroglu, Fugen, and Jose A. Yaryura-Tobias. Over and Over Again: Understanding Obsessive-Compulsive Disorder. San Francisco: Jossey-Bass Publishers, 1997, 228 pages. The authors tell the reader everything that their clinical experience has taught them about the private daily hell that this disease represents for its sufferers.

Stone, Michael H. The Fate of Borderline Patients: Successful Outcome and Psychiatric Practice. New York: Guilford Press, 1990, 240 pages. Every book that Michael Stone has written is a masterpiece. In this 20-year personal follow-up of more than 200 patients conducted without the benefit of any research dollars, he utilizes the Kraepelinian approach to a psychostructurally defined construct, to prognosticate the outcome of a baffling disorder that over time largely ceases to be itself. As Mike once told me, the “borderline” construct will eventually self-destruct (personal communication, December 1980).

Yamashita, Itaru. Taijin-Kyofu or Delusional Social Phobia. Sapporo: Hokkaido University Press, 1993, 147 pages. In this penetrating evaluation of the psychopathology of social phobia, the author documents, one clinical case after another, how this disorder often acquires delusional proportions (and I don’t think this is peculiar to Japan).

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New York: Oxford University Press, 1996, 357 pages. Dr. Phillips illustrates how astute clinical observation and systematic follow-up can shed light on the suffering of this particular brand of private hell, leading to new treatments.

In this highly original book, the authors tell us how an evolutionary understanding of human behavior can enrich our approach to psychiatric disorders.

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Phillips, Katharine A. The Broken Mirror: Understanding and Treating Body Dysmorphic Disorder.

Stevens, Anthony, and John Price. Evolutionary Psychiatry: A New Beginning. London: Routledge, 1996, 267 pages.

The reader will note perhaps that some major clinical areas are not represented in the foregoing review: schizophrenia, substance abuse, eating disorders, and sleep disorders. Their omission is due to my judgment that no definitive books written by one or two authors have appeared on these topics during the past decade. I hope this will provoke the talent in our field to undertake the ambitious task! Finally, I trust that Jeffrey Cummings will write the definitive book on dementia and neuropsychiatry; meanwhile, the interested reader should read his superb summaries dispersed in the literature. If I have succeeded in surprising some readers for having chosen four titles devoted to evolutionary aspects of psychopathology, this was intended. Psychiatry can no longer neglect an evolutionary framework. Such a framework promises to provide clinically meaningful links between our biological nature and adaptation to geologic, social, and cultural change. This framework also provides the opportunity of a rapprochement between biological psychiatry and psychoanalysis. Finally, evolutionary considerations can cross-fertilize the field of psychotherapy, which has been in search of a scientific perspective since Freud. A beginning towards this end has been made by Kalman Glantz and John Pearce (Exiles From Eden, New York: WW Norton, 1989). ■ J Clin Psychiatry 58:12, December 1997

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CATEGORY 1

CME

CME Activity

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Sponsored by Physicians Postgraduate Press, Inc.

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CME Objectives After completing this CME activity, the reader will be able to: • Identify currently available effective treatments for panic disorder • Appreciate the importance of choosing effective medication and use an appropriate dose and duration of treatment • Recognize that true treatment resistance is uncommon and that treatment failure is most often due to medication intolerance or inadequate medication trials.

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Medical Education Essentials, Standards, and Guidelines, all faculty for this CME activity were asked to complete a full disclosure statement. The information received is as follows: Dr. Cowley has received research grants from Pfizer Inc. and is a member of the Advisory Board for Eli Lilly and Company. Ms. Ha has no significant relationships with any providers of support that may have influenced her presentation in any way. Dr. Roy-Byrne has received grants from BristolMyers Squibb, Pfizer Inc., Abbott Laboratories, Eli Lilly and Company, and Zeneca Pharmaceuticals; has received honoraria from Pfizer Inc., SmithKline Beecham, and Wyeth-Ayerst Laboratories; and is a member of the Advisory Board for SmithKline Beecham and Pfizer Inc.

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Faculty Disclosure In the spirit of full disclosure and in compliance with all Accreditation Council for Continuing

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Credit Designation Physicians Postgraduate Press designates this educational activity for 1 hour of Category 1 credit toward the American Medical Association Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. To obtain credit, please read the following article and complete the quiz as instructed on page 562.

Discussion of Investigational Information During the course of their talks and discussions in this Journal, faculty may be presenting investigational information about pharmaceutical agents that is outside Food and Drug Administration–approved labeling. This information is intended solely as continuing medical education and is not intended to promote offlabel use of any of these medications. Please refer to page 561 for a list of indications of offlabel usage describing any medication discussed in this enduring material that, in the authors’ clinical estimation, is outside the manufacturer’s current recommendations for standard prescribing practices.

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Accreditation Statement Physicians Postgraduate Press is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education.


ARTICLE

CME

Determinants of Pharmacologic Treatment Failure in Panic Disorder

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Deborah S. Cowley, M.D., Eileen H. Ha, and Peter P. Roy-Byrne, M.D.

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everal effective treatments for panic disorder are now available. These include tricyclic antidepressants,1 monoamine oxidase inhibitors (MAOIs),2 benzodiazepines,1,3 serotonin selective reuptake inhibitors (SSRIs),4 and cognitive-behavioral therapy.5 However, although these modalities yield response rates of 50%– 90% in placebo-controlled clinical trials, a significant number of patients fail initial treatment and thus fall into a category anecdotally referred to as “treatment-resistant panic disorder.”6–9 Patients treated in naturalistic settings fare worse, with “zero panic attack” rates of 30%–80% reported in studies following up patients after 1–8 years.10 The majority of patients continue to suffer from chronic or recurring anxiety, panic, phobic avoidance, and functional impairment. The higher rates of “treatment resistance” or incomplete recovery in naturalistically treated samples are doubtless due to the highly selected nature of clinical trial participants, who are younger, healthier, more willing to withstand the rigors of a medication study, and less likely to have comorbid psychiatric disorders. Furthermore, cognitive-behavioral therapy remains unavailable to many patients with panic disorder. Thus, poor response to initial pharmacologic treatment of panic disorder is a significant problem in naturalistic treatment settings. In spite of this, there are scant data available to shed light on the reasons for treatment failure or optimal therapeutic approaches to these patients. Several authors of review articles have used clinical experience to outline factors that may contribute to treatment failure.6–9 These have included medical and psychiatric comorbidity; discontinuation of medication due to adverse side effects; and inadequate dose, duration, or frequency of administration of medication. Indeed, a number of reports suggest that only a minority of

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Background: We systematically assessed reasons for failure of pharmacologic treatment for panic disorder in patients referred to a specialty anxiety and mood disorders clinic and examined possible determinants of treatment-resistant panic disorder. Method: Interview data were obtained from 106 patients with DSM-III-R panic disorder seen in consultation. Data for each of 252 past medication trials included dose, duration of treatment, side effects, outcome, and reason for discontinuation. T tests and chi-square analyses were used to compare demographic and clinical characteristics of patients failing versus responding to adequate trials and those with and without intolerable medication side effects. Results: Of 252 medication trials, 190 used effective antipanic medications, and only 59 (23%) were adequate in dose and duration. The most common reason for treatment failure was intolerable side effects, occurring in 51 (27%) of 190 trials using effective antipanic medications. Patients discontinuing treatment due to adverse effects had higher Hamilton Rating Scale for Anxiety scores and were less likely to have a history of substance abuse. Discontinuation due to side effects was significantly more common with tricyclic antidepressants than with benzodiazepines. True treatment resistance was reported in 14 (24%) of 59 adequate medication trials. Treatment-resistant patients were younger and had a higher lifetime rate of major depression. Conclusion: Although use of ineffective medications or inadequate trials were important factors, the most common reason for treatment failure was side effects, especially with tricyclic antidepressants. True treatment resistance was less common, since few medication trials were adequate in dose and duration, and may be associated with comorbidity. (J Clin Psychiatry 1997;58:555–561)

Received May 14, 1997; accepted Aug. 8, 1997. From the Department of Psychiatry and Behavioral Sciences, University of Washington and Harborview Medical Center, Seattle. Reprint requests to: Deborah S. Cowley, M.D., Department of Psychiatry and Behavioral Sciences, Box 356560, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195.

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ARTICLE

CME

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patients with panic disorder receive optimal pharmacologic treatment.11–14 The aim of the present study was to identify more systematically the reasons for failure of prior naturalistic pharmacologic treatment in 106 consecutive patients with panic disorder referred to a specialty anxiety and mood disorders clinic. Specifically, we sought to determine the relative importance of clinician-related factors, such as choice of a medication ineffective for panic disorder and use of inadequate doses or duration of treatment, versus patient- or illness-related factors, such as intolerance of medication side effects and comorbid conditions. In those tolerating adequate medication trials, we aimed to determine the rate of true “treatment resistance,” or failure to respond to an effective medication given at a therapeutic dose for an appropriate length of time. Finally, we wished to examine whether any demographic or clinical characteristics are associated with the patient-related phenomenon of medication intolerance or the illness-related phenomenon of true “treatment resistance.” On the basis of prior long-term naturalistic outcome studies,10 we hypothesized that failure to respond to adequate medication trials would be associated with patient characteristics of phobic avoidance and Axis I and II comorbidity.

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subjective, retrospective assessment of whether the medication had been of benefit (complete or partial response) or not (minimal or no response). Reasons for discontinuation were classified as lack or loss of therapeutic benefit, dose-limiting side effects, concerns about dependency, pregnancy, or “other” (e.g., had recovered, did not want to take medication anymore). Other variables to be assessed were derived from an existing database collected during past studies using this patient population.15–18 This database included Axis I and II diagnoses derived from administration of the Structured Clinical Interview for DSM-III-R, and scores on the Hamilton Rating Scale for Depression (HAM-D),19 Hamilton Rating Scale for Anxiety (HAM-A),20 Beck Depression Inventory (BDI),21 and Revised Ways of Coping Checklist.22

METHOD

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Procedure Data were generated as part of a standard initial assessment and subsequent follow-up study15 and were based on a systematic patient interview that included information regarding age at onset of panic disorder, duration of illness, and total number of medications tried in the past. For each medication trial, the dose, frequency of administration, duration of treatment, side effects, compliance, response, and reason for discontinuation were recorded. Response was defined as the patient’s

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Subjects Subjects were 106 consecutive patients with DSMIII-R panic disorder with or without agoraphobia who were evaluated between October 1986 and August 1990 by two psychiatrists (D.S.C., P.R.B.) at the Center for Anxiety and Depression at the University of Washington, Seattle. This fee-for-service clinic serves as a secondary referral source for expert evaluation and treatment services. Most patients are seen for consultation and then referred back to community practitioners with recommendations for future management.

Data Analysis The adequacy of medication trials (effective medication, sufficient dose and duration) was assessed using criteria proposed by Yonkers et al.14 In that report, a review of published literature was used to categorize medications as being effective or not and, for each effective medication, to specify low, standard, and high dosage ranges. For example, alprazolam is listed as an effective medication for which < 2.0 mg/day is a low dose, 2.0– 8.0 mg daily is a standard dose, and > 8.0 mg daily is a high dose. Dose ranges for imipramine are < 150 mg (low), 150–300 mg (standard), and > 300 mg (high), while those for phenelzine are < 45 mg (low), 45–90 mg (standard), and > 90 mg (high). Data on established efficacy for SSRIs were added to the Yonkers criteria. For example, paroxetine was considered to have a standard dose of 20–60 mg daily. Medications prescribed at low doses or for inadequate durations according to Yonkers and colleagues’ guidelines were considered inadequate medication trials. Ineffective medications included bupropion, buspirone, β-blockers, and antihistamines. To examine possible determinants of medication intolerance and true treatment resistance, we compared demographic and clinical characteristics in those who discontinued one or more effective antipanic medications due to side effects (N = 38) versus those who did not (N = 53), and in those who failed an adequate medication trial (N = 13) versus those who responded (N = 30). Comparisons were performed using t tests for continuous and chi-square or Fisher’s exact test for categorical variables. Stepwise logistic regression was then performed to determine the relative contributions of those variables that differed significantly between groups. J Clin Psychiatry 58:12, December 1997

ARTICLE

CME

Table 1. Outcome of 190 Trials of Effective Antipanic Medication in 91 Patients

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Reason for Benzodiazepine Discontinuation Trials (N = 105) Still taking medication 54 (51%) Intolerable side effects 7 (7%) Lack/loss of benefit 26 (25%) Other (improved, did not want to take medication) 9 (9%) Concerns about dependency 8 (8%) Pregnancy 1 (1%)

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Antidepressant Trials (N = 85)

Total (N = 190)

18 (21%)

72 (38%)

44 (52%)

51 (27%)

20 (24%)

46 (24%)

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(4%) (0%) (0%)

12

(6%)

8 (4%) 1 (0.5%)

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Sample Characteristics Of 106 cases, 30 were men and 76 were women. Mean ± SD age at intake was 37.4 ± 12.0 years (range, 18–72). The mean age at onset of panic disorder was 29.0 ± 10.6 years (range, 8–62), while the mean duration of illness was 8.4 ± 9.6 years (range, 0.2–52). Forty (38%) had panic disorder alone and 66 (62%) had panic disorder with agoraphobia. Seventy percent had at least two Axis I diagnoses. The overall mean number of Axis I diagnoses was 2.4 ± 1.2 (range, 1–6). Of note, 54 (51%) reported current and 61 (58%) reported lifetime major depression. Forty percent of the sample had at least one comorbid Axis II diagnosis, with the overall mean number of Axis II diagnoses being 0.97 ± 1.5 (range, 0–6).

DSE N = 38 N % 31 82 14 37 29 76 26 68

29 33 19

22 24 6

55 62 36

χ2 3.29 10.10 2.81 0.06

Analysis df 1 7 5 1

p .07 NS NS NS

0.09 0.01 4.47

1 1 1

NS NS .03

58 63 16

Mean SD Mean SD t df p 36.2 9.3 42.5 13.3 1.78 32 .08 Age (y) Age (y) 36.8 10.1 39.6 13.9 1.12 89 NS Age at onset of panic disorder (y) 29.1 10.2 30.6 11.4 0.66 89 NS Duration of panic disorder (y) 7.5 6.9 9.0 11.3 0.77 89 NS # Axis I diagnoses 2.5 1.4 2.3 1.1 0.99 89 NS # Axis II diagnoses 1.0 1.4 1.1 1.6 0.23 76 NS Coping Avoidance 0.18 0.04 0.18 0.06 0.08 88 NS Self-blame 0.20 0.07 0.18 0.09 0.87 88 NS Problem-focused coping 0.19 0.05 0.19 0.07 0.20 88 NS Seeks social support 0.22 0.07 0.23 0.08 0.57 88 NS Wishful thinking 0.22 0.06 0.22 0.06 0.19 88 NS HAM-A 21.9 7.9 27.1 11.3 2.38 74 .02 HAM-D 15.3 6.7 18.0 8.2 1.60 74 .11 BDI 15.8 9.0 18.9 11.8 1.37 85 NS *Abbreviations: DSE = discontinued at least one medication due to side effects, nonDSE = no history of discontinuing medication due to side effects; BDI = Beck Depression Inventory; HAM-A = Hamilton Rating Scale for Anxiety; HAM-D = Hamilton Rating Scale for Depression.

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Of all 252 medication trials in the whole patient group, only 190 (75%) used medications likely to be effective for panic disorder and prescribed regularly rather than only as needed. Of these 190 trials with effective medications, 105 used benzodiazepines, 66 were of tricyclic antidepressants, 12 used MAOIs, and 7 used SSRIs. Fifty-nine trials (23% of all medication trials) were adequate in dose and duration. Of the remaining 131 trials of effective antipanic medication, only 28 were rated by the patient as having been of no or minimal therapeutic benefit.

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Use of Effective Medications and Adequate Medication Trials Of the 106 patients, 8 had never taken antipanic medication, 5 had been prescribed p.r.n. benzodiazepines only, 17 had tried one medication, 20 had tried two, 12 had tried three, 13 had tried four, and 31 had tried five or more antipanic medications. Detailed information was available for a total of 252 medication trials. Only 91 (86%) of 106 patients had been treated with at least one effective antipanic medication prescribed regularly, rather than on an as-needed basis. Forty-three of these 91 also received an adequate medication trial, while 48 did not. However, only 11 of the 48 reported obtaining no benefit from treatment. Thus, overall, 15 patients did not undergo any trial of regularly prescribed, effective antipanic medication, and 11 patients received inadequate medication trials, despite tolerating the medication and obtaining no therapeutic benefit from the dose prescribed. J Clin Psychiatry 58:12, December 1997

Variable Female College degree Married Agoraphobia Depression Current Lifetime Substance abuse

nonDSE N = 53 N % 34 64 19 37 42 79 35 66


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RESULTS

Table 2. Demographic and Clinical Variables in Patients With and Without a History of Discontinuing a Medication Due to Side Effects (DSE)*

Reasons for Medication Discontinuation Reasons given by patients for discontinuation of trials using effective medications are shown in Table 1. Of note, the most common reason for discontinuation was doselimiting side effects in 51 trials (27% of all trials of effective medication and 43% of those trials of effective medication in which medication was then discontinued). 557

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Table 3. Demographic and Clinical Variables in Patients Who Failed Versus Responded to an Adequate Medication Trial

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Responded N = 30 N % 21 70 9 31 23 77 19 63

77 92 31

53 60 27

Mean SD Mean SD 36.2 9.3 42.5 13.3

0.18 0.04 0.18 0.12

2.11 4.49 0.08

1 1 1

NS .03 NS

t 1.78

df 32

p .08

41

NS

35

10.1 11.6 2.3 1.1 1.1 1.6

0.47 1.22 0.98 0.23

41 41 37

NS NS NS

0.17 0.04 0.82 0.18 0.09 0.08

40 40

NS NS

40 40 40 34 34 40

NS NS NS NS NS NS

0.20 0.06 0.18 0.06 0.22 0.08 0.24 0.08 0.22 0.06 0.23 0.06 25.2 7.6 24.1 11.3 18.7 8.6 16.9 6.6 15.8 12.0 18.3 9.7

0.93 0.67 0.67 0.32 0.71 1.71

Patients Trials

25 20 15 5 0

Ineffective Inadequate Medication Trial of Effective Medication

Intolerant

Treatment Resistant

*Percentage of patients shown is percentage of those tried on medication (N = 98) who failed treatment due to use of ineffective medications only, due to inadequate trials of effective medication (dose not limited by side effects), due to intolerable side effects, and due to failure to respond to an adequate medication trial (treatment resistant). Percentage of medication trials is percentage of all 252 medication trials in 98 patients that failed due to use of ineffective medications, inadequate trials of effective antipanic medications, medication intolerance (side effects), and despite an adequate medication trial.

the numbers of trials using SSRIs and MAOIs were small (7 and 12, respectively), rates of discontinuation due to side effects were lower with these medications than with tricyclic antidepressants. Specifically, medication was discontinued due to side effects in 2 (29%) of 7 SSRI trials, 4 (33%) of 12 MAOI trials, and 38 (58%) of 66 tricyclic antidepressant trials. True Treatment Resistance Forty-three patients received a total of 59 adequate medication trials. As might be expected, adequate trials were more likely to result in therapeutic benefit, which was reported in 45 (76%) of 59 adequate trials as opposed to 61 (47%) of 131 other trials of effective antipanic medications. Of the 43 patients receiving adequate medication trials, 30 (70%) responded to all adequate medication trials, while 13 (30%) failed one or more adequate trials. Demographic and clinical characteristics of these treatmentresponsive versus treatment-resistant patients are shown in Table 3. The treatment-resistant group showed a significantly higher rate of lifetime major depression and a trend toward younger age. Based on stepwise logistic regression, both lifetime major depression (p = .03) and younger age (p = .05) remained significantly associated with treatment resistance (model χ2 = 10.1, df = 2, p = .006).

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Clinical and demographic characteristics of those patients discontinuing at least one medication trial as a result of side effects (DSE group) and those who did not stop medication due to side effects (nonDSE group) are shown in Table 2. The DSE group had significantly higher HAM-A scores and was significantly less likely to have a history of substance abuse or dependence. There was a trend for the DSE group to contain a higher percentage of women. Based on stepwise logistic regression, the factors most significantly associated with medication intolerance were higher HAM-A scores (p = .03) and absence of substance abuse/dependence history (p = .04; model χ2 = 10.3, df = 2, p = .006). To examine to what extent benzodiazepines were better tolerated than antidepressants, we also compared reasons for discontinuation in trials using these two classes of medication (see Table 1). Trials using benzodiazepines were significantly less likely to be discontinued due to side effects (χ2 = 48.7, df = 1, p < .001), were more likely to result in concerns about dependency (χ2 = 6.84, df = 1, p < .01), and were more likely to result in treatment continuation (χ2 = 18.2, df = 1, p < .001). Of note, although 558

30


4.6 0.9 1.2

32.3 12.7

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6.0 2.6 1.0

p NS NS NS NS

19

30.4 11.5

χ2 0.30 4.04 4.30 0.01

10

16 18 8

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Age (y) Age at onset of panic disorder (y) Duration of panic disorder (y) # Axis I diagnoses # Axis II diagnoses Coping Avoidance Self-blame Problem-focused coping Seeks social support Wishful thinking HAM-A HAM-D BDI

10 12 4

40

Analysis df 1 7 4 1

Percentage

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Variable Female College degree Married Agoraphobia Depression Current Lifetime Substance abuse

Failed N = 13 N % 8 62 3 23 10 77 8 62

Figure 1. Overall Summary of Reasons for Treatment Failure*


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Summary of Reasons for Treatment Failure An overall summary of reasons for pharmacologic treatment failure in this patient group and in all 252 medication trials is displayed in Figure 1. Of note, the most common reason for treatment failure, for both individual patients and specific medication trials, was intolerable side effects. Although 13% of patients failed at least one adequate medication trial, only 5% of all medication trials failed due to true treatment resistance.

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DISCUSSION

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To our knowledge, this is the first systematic, databased study of reasons for failure of naturalistic pharmacologic treatment for panic disorder. The results confirm prior clinical impressions6–9 that the major reasons for treatment failure are inadequate dose and duration of treatment, as well as medication intolerance. In fact, the most common reason for discontinuation of treatment in this study was medication side effects. There are several obvious limitations of this study. First, this was a retrospective study relying on selfreported treatment histories of patients, rather than a prospective, controlled trial. However, this method provides a more inclusive and representative sample of patients seen in psychiatric practice. Secondly, the most commonly prescribed agents were benzodiazepines, followed by tricyclic antidepressants. These prescribing practices reflect the lack of knowledge about the antipanic efficacy of SSRIs until quite recently. SSRIs are now generally considered the first-line treatment for panic disorder23,24 and typically result in fewer adverse effects than do tricyclics. Finally, the adequacy of medication trials remains difficult to determine, since dose requirements vary widely among individual patients. Use of standardized dosage ranges may have led to an underestimate of the number of “adequate” trials. The strengths of the current study include the use of structured interviews and standardized rating scales and the inclusion of a wide variety of patients treated naturalistically in the community. Only a minority of patients in this study reported having been treated with an adequate trial of antipanic medication. This is consistent with prior reports demonstrating underutilization of effective treatments in panic disorder.11–14 For example, Taylor et al.,11 in a 1989 report, found that fewer than 15% of volunteers for a panic disorder study had received imipramine. Of 100 patients with panic disorder seen at a university anxiety disorders clinic, only 15% had been treated with imipramine, 13% with alprazolam, and 11% with cognitive-behavioral

therapy.12 Even among patients treated by psychiatrists in academic medical centers, only 54% of the most symptomatic patients had received optimal pharmacologic management.14 The use of ineffective or p.r.n. only medication in our own or other studies may have been a result of a lack of physician knowledge or of patient preference to avoid regularly prescribed medication. In our own patient group, a major reason for not achieving adequate doses or duration of treatment was discontinuation due to intolerable side effects. However, it is also noteworthy that almost 50% of inadequate trials resulted in therapeutic benefit. It is possible that the treating physician felt it unnecessary to increase the dose if the patient was reporting improvement. Without more detailed information regarding the extent of therapeutic benefit obtained, it is difficult to assess whether these patients were responding optimally at lower than the standard doses outlined by Yonkers et al.,14 or whether, as may be more likely, patients were maintained at a dose producing some but not optimal improvement. Intolerable side effects played a major role in treatment failure in the patients in our study. As expected, dose-limiting side effects were significantly more likely to lead to discontinuation of antidepressants than of benzodiazepines. Although this is consistent with results of clinical trials,1,3 the magnitude of the difference is greater than would have been predicted. For example, in the Cross-National Collaborative Panic Study,1 dropouts due to side effects were listed as being 3.4% for the alprazolam group and 5.9% for the imipramine group. Even if all 14.1% of imipramine-treated patients who “refused treatment” did so due to adverse effects, the total dropouts due to side effects from that study (20%) would still be far less than the dropout rate in our patient group. Overall tolerability of tricyclic antidepressants in clinical trials (total number of patients entered minus those dropping out for any reason) has ranged from 50%–80% with acute treatment1,2,25–27 and 45%–58% after 1 year,25,26 while tolerability of benzodiazepines has ranged from 75%–89% with acute treatment1,26,27 and 70% after 1 year.26 Once more, our results are consistent with this pattern, since in 51% of benzodiazepine but only 21% of antidepressant trials were patients still taking the medication. The higher side effect rates and lower tolerability of medications in our group may reflect slower dosage increases and more frequent monitoring in clinical trials or duration of treatment longer than 1 year in our group. However, it is more likely that unselected patients treated in the community include those more vulnerable to or less willing to endure unpleas559

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ant side effects than those patients participating in clinical treatment studies. It would be hoped that dropouts due to side effects will be lower and tolerability higher in community treatment settings with widespread use of SSRIs. Although only 7 of the 252 medication trials that we examined used SSRIs, the rate of discontinuation due to side effects was lower than that seen with tricyclic antidepressants. In a controlled trial of paroxetine,4 the reported dropout rate due to side effects was 6%, and overall tolerability of SSRIs has ranged from 72%–85% acutely4,28–31 and 70%– 76% after 1 year.30,31 These figures are similar to those obtained with benzodiazepines and superior to results with tricyclic antidepressants and provide reason for optimism, although it remains to be seen whether or not increased use of SSRIs to treat panic disorder in unselected community populations will markedly reduce the significance of medication intolerance as a determinant of treatment failure. Treatment failure due to side effects was associated with patient characteristics of higher HAM-A scores and an absence of lifetime substance abuse/dependence. Higher levels of anxiety, reflected by higher HAM-A scores, may contribute to increased sensitivity to somatic symptoms, including adverse medication effects. Those patients with a history of substance abuse or dependence may be less sensitive to bodily changes, either as a preexisting characteristic allowing them to tolerate adverse effects of drugs and alcohol, or due to desensitization resulting from repeated episodes of intoxication and withdrawal.32 Of note, alcoholics with panic attacks have less intense feelings of panic and fear associated with sodium lactate infusion than do non–substance abusing patients with panic disorder, despite reporting similar increases in physical symptoms of anxiety and panic.32,33 In the current study, treatment-resistant patients were more likely to report a lifetime history of major depression. This is consistent with some prior reports that patients with both panic disorder and major depression may have a worse prognosis than those with either disorder alone.34 Our findings reinforce the importance of recognition and aggressive treatment of major depression in patients with panic disorder. Other comorbid conditions, including agoraphobia, Axis I and II disorders, and substance abuse, did not differ between treatment-resistant and treatment-responsive patients. However, the current sample of treatment-resistant patients was quite small, reducing our power to detect group differences. In addition, we were unable to assess a number of factors potentially associated with poor treatment response,35,36 such as use

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Drug names: alprazolam (Xanax), bupropion (Wellbutrin), buspirone (BuSpar), imipramine (Tofranil and others), paroxetine (Paxil), phenelzine (Nardil).

REFERENCES

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of caffeine, alcohol, and over-the-counter medications; sleep deprivation; life events; or medical illness. In summary, our results provide data supporting the clinical impression that patients with panic disorder often receive inadequate medication trials and discontinue medication due to intolerable side effects. A smaller proportion of patients seem to have true treatment resistance or failure to respond to adequate medication trials that are tolerated to completion. These findings are consistent with prior suggestions that only a small proportion of treatment-refractory depressed patients have true treatment resistance37 and was true even in our group of patients referred to a specialty anxiety and mood disorders clinic. Since most patients with panic disorder are treated initially in primary care settings, it is particularly important for psychiatrists to educate their primary care colleagues regarding which medications are effective for panic and the importance of adequate doses and duration of treatment. The importance of dose-limiting side effects may decrease with increased use of SSRIs. However, it is likely that we will need to develop more antipanic medications with less adverse side effects. Cognitive-behavioral therapy has been proved effective as a first-line treatment for panic disorder and to facilitate taper of benzodiazepines.5,38 Increased availability of cognitive-behavioral therapy or development of cognitive-behavioral strategies specifically designed to increase tolerance of medication side effects would be valuable for medication-intolerant patients. Finally, prospective studies using adequate medication trials are necessary to further define the characteristics of patients likely to fail standard treatment for panic disorder.

1. Cross-National Collaborative Panic Study, Second Phase Investigators. Drug treatment of panic disorder: comparative efficacy of alprazolam, imipramine, and placebo. Br J Psychiatry 1992;160:191–202 2. Sheehan D, Ballenger J, Jacobsen G. Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Arch Gen Psychiatry 1980;37:51–59 3. Ballenger J, Burrows G, DuPont R, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. Arch Gen Psychiatry 1988; 45:413–422 4. Oehrberg S, Christiansen P, Behnke K, et al. Paroxetine in the treatment of panic disorder: a randomised, double-blind, placebo-controlled study. Br J Psychiatry 1995;167:374–379 5. Barlow DH. Cognitive-behavioral therapy for panic disorder: current status. J Clin Psychiatry 1997;58(suppl 2):32–36 6. Coplan JD, Tiffon L, Gorman JM. Therapeutic strategies for the patient with treatment-resistant anxiety. J Clin Psychiatry 1993;54(5,


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suppl):69–74 7. Rosenbaum J. Evaluation and management of the treatment-resistant anxiety disorder patient. Bull Menninger Clin 1992;52(2, suppl A):A50–A60 8. Hollander E, Cohen LJ. The assessment and treatment of refractory anxiety. J Clin Psychiatry 1994;55(2, suppl):27–31 9. Rosenbaum JF. Treatment-resistant panic disorder. J Clin Psychiatry 1997; 58(suppl 2):61–64 10. Roy-Byrne P, Cowley D. Course and outcome in panic disorder: a review of recent follow-up studies. Anxiety 1995;1:151–160 11. Taylor C, King R, Margraf J, et al. Use of medication and in vivo exposure in volunteers for panic disorder research. Am J Psychiatry 1989;146: 1423–1426 12. Swinson R, Cox B, Woszczyna C. Use of medical services and treatment for panic disorder with agoraphobia and for social phobia. Can Med Assoc J 1992;147:878–883 13. Bandelow B, Sievert K, Rothmeyer M, et al. What treatments do patients with panic disorder and agoraphobia get? Eur Arch Psychiatry Clin Neurosci 1995;245:165–171 14. Yonkers K, Ellison J, Shera D, et al. Description of antipanic therapy in a prospective longitudinal study. J Clin Psychopharmacol 1996;16:223–232 15. Cowley D, Flick S, Roy-Byrne P. Long-term course and outcome in panic disorder: a naturalistic follow-up study. Anxiety 1996;2:13–21 16. Carlin A, Roy-Byrne P, Cowley D, et al. MMPI differences among patients with depression, panic, and mixed panic and depression: a cluster analytic approach. J Anxiety Disord 1990;4:117–123 17. Flick S, Roy-Byrne P, Cowley D, et al. DSM-III-R personality disorders in a mood and anxiety disorders clinic: prevalence, comorbidity, and clinical correlates. J Affect Disord 1993;27:71–79 18. Roy-Byrne P, Vitaliano P, Cowley D, et al. Coping in panic and major depressive disorder: relative effects of symptom severity and diagnostic comorbidity. J Nerv Ment Dis 1992;180:179–183 19. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62 20. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50–55 21. Beck A, Ward C, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–571 22. Vitaliano P, Russo J, Carr J, et al. The Ways of Coping checklist: revision and psychometric properties. Multivariate Behavioral Research 1985;20: 3–26 23. Jobson K, Davidson J, Lydiard RB, et al. Algorithm for the treatment of panic disorder with agoraphobia. Psychopharmacol Bull 1995;31: 483–485

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24. Roy-Byrne P, Cowley D. Assessment and treatment of panic disorder. In: Dunner D, ed. Current Psychiatric Therapy, II. Philadelphia, Pa: Saunders; 1997:309–316 25. Noyes R Jr, Garvey MJ, Cook BL, et al. Problems with tricyclic antidepressant use in patients with panic disorder or agoraphobia: results of a naturalistic follow-up study. J Clin Psychiatry 1989;50:163–169 26. Schweizer E, Rickels K, Weiss S, et al. Maintenance drug treatment of panic disorder, I: results of a prospective, placebo-controlled comparison of alprazolam and imipramine. Arch Gen Psychiatry 1993;50:51–60 27. Uhlenhuth EH, Matuzas W, Glass RM, et al. Response of panic disorder to fixed doses of alprazolam or imipramine. J Affect Disord 1989;17: 261–270 28. Schneier F, Liebowitz M, Davies S, et al. Fluoxetine in panic disorder. J Clin Psychopharmacol 1990;10:119–121 29. Black D, Wesner R, Bowers W, et al. A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder. Arch Gen Psychiatry 1993;52:44–50 30. Steiner M, Oakes R, Gergel IP, et al. A fixed dose study of paroxetine and placebo in the treatment of panic disorder. In: New Research Program and Abstracts of the 148th Annual Meeting of the American Psychiatric Association; May 24, 1995; Miami, Fla. Abstract NR355:150 31. Dunbar GC. A double-blind placebo controlled study of paroxetine and clomipramine in the treatment of panic disorder. In: New Research Program and Abstracts of the 148th Annual Meeting of the American Psychiatric Association; May 24, 1995; Miami, Fla. Abstract NR376:157 32. George D, Nutt D, Waxman R, et al. Panic response to lactate administration in alcoholic and nonalcoholic patients with panic disorder. Am J Psychiatry 1989;146:1161–1165 33. Cowley D, Jensen C, Johanessen D, et al. Response to sodium lactate in alcoholics with panic attacks. Am J Psychiatry 1989;146:1479–1483 34. Gorman JM, Coplan JD. Comorbidity of depression and panic disorder. J Clin Psychiatry 1996;57(suppl 10):34–41 35. Roy-Byrne PP, Uhde TW. Exogenous factors in panic disorder: clinical and research implications. J Clin Psychiatry 1988;49:56–61 36. Wade S, Monroe S, Michelson L. Chronic life stress and treatment outcome in agoraphobia with panic attacks. Am J Psychiatry 1993;150: 1491–1495 37. Burrows G, Norman T, Judd F. Definition and differential diagnosis of treatment-resistant depression. Int Clin Psychopharmacol 1994;9 (suppl 2):5–10 38. Otto M, Pollack M, Sachs G, et al. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavior therapy for patients with panic disorder. Am J Psychiatry 1993;150:1485–1490

The following agents mentioned in this article are not indicated for treatment of panic disorder: imipramine, MAO inhibitors, e.g., phenelzine.

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DISCLOSURE OF OFF-LABEL USAGE


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QUIZ

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Instructions

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Psychiatrists may receive 1 hour of Category 1 credit toward the American Medical Association Physician’s Recognition Award by reading the article starting on page 555 and correctly answering at least 70% of the questions in the quiz that follows. 1. Read each question carefully and circle the correct corresponding answer on the Registration form. 2. Type or print your full name, address, phone number, and fax number in the spaces provided. 3. Mail the Registration form along with a check, money order, or credit card payment in the amount of $20 to: Physicians Postgraduate Press, Office of CME, P.O. Box 752870, Memphis, TN 38175-2870.

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4. For credit to be received, answers must be postmarked by the deadline shown on the CME Registration form. After that date, correct answers to the quiz will be printed in the next issue of the Journal. All replies and results are confidential. Answer sheets, once graded, will not be returned. Unanswered questions will be considered incorrect and so scored. Your exact score can be ascertained by comparing your answers with the correct answers to the quiz, which will be printed in the Journal issue after the submission deadline. The Physicians Postgraduate Press Office of Continuing Medical Education will keep only a record of participation, which indicates the completion of the activity and the designated number of Category 1 credit hours that have been awarded.

1. Effective medication treatments for panic disorder include all of the following except: a. Imipramine b. Bupropion c. Paroxetine d. Alprazolam e. Phenelzine

7. Compared with medication trials using tricyclic antidepressants, those using benzodiazepines were: a. Less likely to be discontinued due to side effects b. Less likely to be discontinued due to fears of dependency c. Less likely to have been continued d. All of the above e. None of the above

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4. Currently, what class of medications is considered the firstline pharmacologic treatment for panic disorder? a. Tricyclic antidepressants b. Benzodiazepines c. Antihistamines d. Serotonin reuptake inhibitors e. MAO inhibitors

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3. The major reason for medication treatment failure in the patients reported in this article was: a. Side effects b. Use of ineffective medications c. Inadequate medication doses d. Inadequate duration of medication trials e. True treatment resistance

6. Naturalistically treated patients with panic disorder differ from patients treated in clinical trials in that they are: a. Younger b. Healthier c. More likely to have comorbid psychiatric disorders d. Carefully selected for treatment e. More likely to respond to cognitive-behavioral therapy

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2. Based on the findings in this study, which would be the most important improvement in pharmacologic management of treatment-refractory panic disorder? a. Development of medications with greater efficacy b. Development of cheaper medications c. Development of medications with less risk of dependency d. Referral of all patients with panic disorder to psychiatrists e. Development of medications with less adverse side effects

5. Prior studies have shown that: a. Effective antipanic treatments are widely used in the majority of patients with panic disorder b. More patients are treated with cognitive-behavioral therapy than with medication c. Overall tolerability of paroxetine is superior to that of tricyclic antidepressants d. Overall tolerability of tricyclic antidepressants is superior to that of benzodiazepines e. Patients with a history of substance abuse have better outcomes with medication

Answers to the June 1997 CME quiz 1. 2. 3.

d e e


REGISTRATION/EVALUATION

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Circle the one correct answer for each question. a

b

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a

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1. Overall quality of this CME activity ____

3.

a

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3. Format ____

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4. Faculty ____

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Please evaluate the effectiveness of this CME activity on a scale of 1 to 5 (1 being poor, 5 being excellent).

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5. Achievement of educational objectives:

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2. Content ____

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Affiliation _____________________________________

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City, State, Zip _________________________________

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Fax ( ) _____________________________________ E-mail ________________________________________ Hospital: ❏

Private Practice: ❏

Resident: ❏

Deadline for mailing

Intern: ❏

For credit to be received, the envelope must be postmarked no later than June 1998 (outside the continental United States, August 1998).

Keeping a copy for your files

C. Enabled the reader to recognize that true treatment resistance is uncommon and that treatment failure is most often due to medication intolerance or inadequate medication trials. ____

6. This CME activity provided a balanced, scientifically rigorous presentation of therapeutic options related to the topic, without commercial bias. ____ 7. Please comment on the impact that this CME activity might have on your management of patients. ________________________________________________ ________________________________________________

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Retain a copy of your answers and compare them with the correct answers, which will be published after the submission deadline.

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___________________________________________

Payment

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❏ MasterCard

8. Please offer additional comments and/or suggested topics for future CME activities.

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A $20 payment must accompany this form. You may pay by check, money order, or credit card (Visa or MasterCard). Make check or money order payable to Physicians Postgraduate Press. If paying by credit card, please provide the information below.

Check one:

B. Enabled the reader to appreciate the importance of choosing effective medication and using an appropriate dose and duration of treatment. ____


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A. Enabled the reader to identify currently available effective treatments for panic disorder. ____

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Your signature _________________________________ TEAR OUT AND MAIL THIS PAGE, ALONG WITH YOUR PAYMENT, TO: PHYSICIANS POSTGRADUATE PRESS • OFFICE OF CONTINUING MEDICAL EDUCATION • P.O. BOX 752870 • MEMPHIS, TN 38175-2870 IF YOU ARE PAYING BY CREDIT CARD, YOU MAY FAX THIS PAGE TO: OFFICE OF CONTINUING MEDICAL EDUCATION AT 901-751-3444 J Clin Psychiatry 58:12, December 1997

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Subject Index: Volume 58

Journal of Clinical Psychiatry Subject Index to Volume 58: January 1997 Through December 1997

Abecarnil Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. Pollack, Suppl 11, 19–23 Double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Lydiard, Suppl 11, 11–18 Double-blind, placebo-controlled trial of two doses of abecarnil for geriatric anxiety. Small, Suppl 11, 24–29 Introduction: a new concept in the treatment of anxiety. Rickels, Suppl 11, 3 ACADEMIC HIGHLIGHTS Panic disorder: a treatment update [ACADEMIC HIGHLIGHTS]. Jan 36–42 Panic disorder: making clinical sense of the latest research [ACADEMIC HIGHLIGHTS]. March 127–134 Pharmacologic rationale for the clinical use of antidepressants [ACADEMIC HIGHLIGHTS]. Nov 501–508 Acetylsalicylic Acid Possible pharmacokinetic interaction between fluoxetine and acetylsalicylic acid [letter]. Shad, Dec 549–550 Acquired Immune Deficiency Syndrome see AIDS ADHD Antidepressants in the treatment of attention-deficit/ hyperactivity disorder. Popper, Suppl 14, 14–29 Adolescents Divalproex treatment of disruptive adolescents: a report of 10 cases. Donovan, Jan 12–15 Affective Disorders see Bipolar Disorder; Depression; Mania; Mood; Seasonal Affective Disorder Age Effect of gender and age at onset of depression on mortality. Philibert, Aug 355–360 AIDS Valproic acid treatment of AIDS-related mania [letter]. RachBeisel, Sept 406–407 Akathisia Akathisia as violence [letter]. Galynker, Jan 31–32 Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. Spivak, July 318–322 Alcohol and Alcoholism Alcohol and substance abuse in panic disorder. Marshall, Suppl 2, 46–50 Alprazolam Double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients

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with generalized anxiety disorder. Lydiard, Suppl 11, 11–18 Alzheimer’s Disease see Dementia Amitriptyline Double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression. Lydiard, Nov 484–491 Amobarbital Safety of amobarbital [letter]. McCall, Apr 175 Anemia Dose-related thrombocytopenia and macrocytic anemia associated with valproate use in bipolar disorder [letter]. Fawcett, Mar 125 Anorexia Nervosa Paroxetine-induced anorexia in a patient with bulimia nervosa [letter]. Sagduyu; Vaz reply, May 220–221 Anorgasmia Sertraline-induced anorgasmia treated with intermittent nefazodone [letter]. Reynolds, Feb 89 Anticonvulsants Antiepileptic drug augmentation for treatmentresistant depression [letter]. Feiner; Ketter reply, Aug 361–363 Novel alternatives and supplements to lithium and anticonvulsants for bipolar affective disorder [CME]. Dubovsky, May 224–242 Antidepressants see also specific drugs Antidepressant and double antidepressant treatment for the affective disorder of epilepsy. Blumer, Jan 3–11 Antidepressant effects of nicotine [letter]. Hawkins; Salín-Pascual reply, July 324–325 Antidepressants. Frazer, Suppl 6, 9–25 Antidepressants in panic disorder. Jefferson, Suppl 2, 20–25 Antidepressants in the treatment of attentiondeficit/hyperactivity disorder. Popper, Suppl 14, 14–29 Antidepressants in the treatment of premenstrual dysphoric disorder. Yonkers, Suppl 14, 4–10 Are two antidepressants better than one? [BRAINSTORMS] Stahl, Aug 339–340 Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. Bodkin, Apr 137–145 Cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care settings. Revicki, Feb 47–58 Development of new antidepressants. Sambunaris, Suppl 6, 40–53

Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy? Buysse, Oct 426–432 Efficacy issues with antidepressants. Fawcett, Suppl 6, 32–39 Enhancing patient outcomes: treatment adherence. Frank, Suppl 1, 11–14 Introduction: new uses for antidepressants. Keller, Suppl 14, 3 New developments in the treatment of obsessivecompulsive disorder. Leonard, Suppl 14, 39–45 New uses for antidepressants: social phobia. Keck, Suppl 14, 32–36 Newer antidepressants and the discontinuation syndrome. Haddad, Suppl 7, 17–22 Pharmacologic rationale for the clinical use of antidepressants [ACADEMIC HIGHLIGHTS]. Nov 501–508 Pharmacotherapy of borderline personality disorder. Hirschfeld, Suppl 14, 48–52 Safety and tolerability of the new antidepressants. Nelson, Suppl 6, 26–31 Selection of an antidepressant: mirtazapine. Preskorn, Suppl 6, 3–8 Switching drug class after initial SSRI failure [letter]. Kelsey, July 326–327 Use of newer antidepressants for panic disorder. Gorman, Suppl 14, 54–58 When at first you don’t succeed: sequential strategies for antidepressant nonresponders. Thase, Suppl 13, 23–29 Antiepileptic Agents see Anticonvulsants Antipsychotics see also specific drugs Atypical antipsychotic sertindole: a case series [CME]. Lee, Sept 410–416 “Awakening” from schizophrenia: intramolecular polypharmacy and the atypical antipsychotics [BRAINSTORMS]. Stahl, Sept 381–382 Chronic neuroleptic exposure in bipolar outpatients. Sernyak, May 193–195; Correction, June 275 Decision analysis approach to neuroleptic dosing: insights from a mathematical model. Mossman, Feb 66–73 Olanzapine and the new generation of antipsychotic agents: patterns of use. Glazer, Suppl 10, 18–21 Pharmacoeconomic evaluation of antipsychotic therapy for schizophrenia. Glazer, Suppl 10, 50–54 Relationship of pharmacology to side effects. Casey, Suppl 10, 55–62 Switching antipsychotic medications. Weiden, Suppl 10, 63–72



Treatment of dementia with behavioral disturbance using divalproex or a combination of divalproex and a neuroleptic. Narayan, Aug 351–354 Anxiety Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. Pollack, Suppl 11, 19–23 Anxiety and the irritable bowel syndrome: psychiatric, medical, or both? Lydiard, Suppl 3, 51–61 Anxiety disorders and the syndrome of chest pain with normal coronary arteries: prevalence and pathophysiology. Carter, Suppl 3, 70–75 Anxiety symptoms and anxiety disorders: how are they related to premenstrual disorders? Yonkers, Suppl 3, 62–69 Application of positron emission tomography to the study of normal and pathologic emotions. Reiman, Suppl 16, 4–12 Biological basis of generalized anxiety disorder. Brawman-Mintzer, Suppl 3, 16–26 Cerebral blood flow during anxiety provocation. Fredrikson, Suppl 16, 16–21 Clinical presentation of generalized anxiety in primary care settings: practical concepts of classification and management. Rickels, Suppl 11, 4–10 Detection and consequences of anxiety in clinical depression. Fawcett, Suppl 8, 35–40 Double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Lydiard, Suppl 11, 11–18 Double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Ravindran, Mar 112–118 Double-blind, placebo-controlled trial of two doses of abecarnil for geriatric anxiety. Small, Suppl 11, 24–29 Generalized anxiety disorder in primary care: the precursor/modifer pathway to increased health care utilization. Roy-Byrne, Suppl 3, 34–40 Importance of establishing the diagnosis of persistent anxiety. Zajecka, Suppl 3, 9–15 Introduction: a new concept in the treatment of anxiety. Rickels, Suppl 11, 3 Introduction: advances in the management of chronic depressive and anxiety disorders. Keller, Suppl 13, 3–4 Introduction. Depression and anxiety: implications for nosology, course, and treatment. Angst, Suppl 8, 3–5 Introduction: functional brain alterations in depression and anxiety. Kalin, Suppl 16, 3 Management of patients with depression associated with anxiety symptoms. Nutt, Suppl 8, 11–16 Mixed anxiety and depression: from theory to practice. Boulenger, Suppl 8, 27–34 Mixed depression and anxiety: serotonin1A receptors as a common pharmacologic link. Stahl, Suppl 8, 20–26 Pharmacologic activation of limbic structures and neuroimaging studies of emotions. ServanSchreiber, Suppl 16, 13–15 Placebo response in generalized anxiety: its effect on the outcome of clinical trials. Schweizer, Suppl 11, 30–38 Psychotherapeutic approaches to the treatment of anxiety and depressive disorders. Michels, Suppl 13, 30–32


Recognizing and treating anxiety in the elderly. Small, Suppl 3, 41–50 Strategies for treatment of generalized anxiety in the primary care setting. Schweizer, Suppl 3, 27–33 Subthreshold syndromes of depression and anxiety in the community. Angst, Suppl 8, 6–10 Treatment algorithm for the management of anxiety in primary care practice. Hales, Suppl 3, 76–80 Apoptosis Apoptosis: neuronal death by design [BRAINSTORMS]. Stahl, May 183–184 Attention-Deficit/Hyperactivity Disorder see ADHD Augmentation see Drug Therapy, Combination BATHE BATHE: an approach to the interview process in the primary care setting. Lieberman, Suppl 3, 3–8 Behavior Behavior therapy and serotonin dysregulation [letter]. Taylor, July 323–324 Behavioral pharmacology of olanzapine: a novel antipsychotic drug. Moore, Suppl 10, 37–44 Cognitive-behavioral management of drug-resistant major depressive disorder [CME]. Fava, June 278–282 Cognitive-behavioral therapy for panic disorder: current status. Barlow, Suppl 2, 32–37 Divalproex treatment of disruptive adolescents: a report of 10 cases. Donovan, Jan 12–15 Interactive computer-administered self-assessment and self-help program for behavior therapy. Baer, Suppl 12, 23–28 Novel placebo lead-in behavior strategy for sertraline dosing in a depressed patient highly sensitive to medication side effects [letter]. Moss, Sept 405–406 Violent behavior during sleep [CME]. Ohayon, Aug 369–376 Benzodiazepines see also specific drugs Clozapine-benzodiazepine interactions [letter]. Faisal, Dec 547–548 Use of benzodiazepines in panic disorder. Davidson, Suppl 2, 26–31 Benztropine Benztropine in the treatment of venlafaxineinduced sweating [letter]. Garber, Apr 176–177 Biochemistry In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug. Bymaster, Suppl 10, 28–36 Biological Therapy Biological therapies for posttraumatic stress disorder: an overview. Davidson, Suppl 9, 29–32 Biology Biological basis of schizophrenia: new directions. Weinberger, Suppl 10, 22–27 Bipolar Disorder see also Depression; Mania; Mood Chronic neuroleptic exposure in bipolar outpatients. Sernyak, May 193–195; Correction, June 275 Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. Denicoff, Nov 470–478 Differential diagnosis of multiple sclerosis and bipolar disorder [letter]. Young, Mar 123 Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder. Feldman-Naim, Feb 79–84 Dose-related thrombocytopenia and macrocytic anemia associated with valproate use in bipolar disorder [letter]. Fawcett, Mar 125

Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. Leibenluft, Sept 383–388 Guideline series commentary [letters]. Hartley; Weiss; Kahn reply, Oct 452–453 Is divalproex a cost-effective alternative in the acute and prophylactic treatment of bipolar I disorder? [letter] Dardennes; Keck reply, Nov 495–496 Issues in the treatment of women with bipolar illness. Leibenluft, Suppl 15, 5–11 Lamotrigine in rapid-cycling bipolar disorder. Fatemi, Dec 522–527 Lamotrigine treatment of refractory bipolar disorder [letter]. Fogelson, June 271–273 Novel alternatives and supplements to lithium and anticonvulsants for bipolar affective disorder [CME]. Dubovsky, May 224–242 Pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar disorder. Solomon, Mar 95–99 Body Dysmorphic Disorder Body dysmorphic disorder by proxy [letter]. Josephson, Feb 86–87 Muscle dysmorphia [letter]. Phillips, Aug 361 Books Reviewed Allcorn S, Baum HS, Diamond MA, Stein HF: The Human Cost of a Management Failure: Organizational Downsizing at General Hospital. Wynn, June 276 American Psychiatric Association: American Psychiatric Association Practice Guidelines. Alarcon, Jan 34–35 American Psychiatric Association: DSM-IV Primary Care Version. Manning, Feb 90 Breier A: The New Pharmacotherapy of Schizophrenia. Brown, May 222 Brunello N, Racagni G, Langer SZ, Mendelwicz J (eds): Critical Issues in the Treatment of Schizophrenia. Brown, Mar 126 Davidson T: Trust the Force: Change Your Life Through Attitudinal Healing. Kirola, Feb 90–91 Frances A, First MB, Pincus HA: DSM-IV Guidebook. Alarcon, Apr 180 Lande RG, Armitage DT (eds): Principles and Practices of Military Forensic Psychiatry. Brown, Nov 500 Matthysse S, Levy DL, Kagan J, Benes FM (eds): Psychopathology: The Evolving Science of Mental Disorder. Gold, Oct 454–455 McGovern G: Terry: My Daughter’s Life and Death Struggle With Alcoholism. Howard, July 328 Renaissance of clinical psychiatry through books published during the past decade. Akiskal, Dec 552–553 Schildkraut JJ, Otero A (eds): Depression and the Spiritual in Modern Art: Homage to Miró. Alarcon, Aug 366–367 Winokur G, Tsuang MT: The Natural History of Mania, Depression, and Schizophrenia. Glover, Sept 408 Borderline Personality Disorder Cessation of self-mutilation in a patient with borderline personality disorder treated with naltrexone [letter]. McGee, Jan 32–33 Pharmacotherapy of borderline personality disorder. Hirschfeld, Suppl 14, 48–52 Brain Application of positron emission tomography to the study of normal and pathologic emotions. Reiman, Suppl 16, 4–12

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Brain structure and function and the outcomes of treatment for depression. Leuchter, Suppl 16, 22–31 Cerebral blood flow during anxiety provocation. Fredrikson, Suppl 16, 16–21 Functional magnetic resonance imaging studies of emotional processing in normal and depressed patients: effects of venlafaxine. Kalin, Suppl 16, 32–39 Introduction: functional brain alterations in depression and anxiety. Kalin, Suppl 16, 3 Mental illness may be damaging to your brain [BRAINSTORMS]. Stahl, July 289–290 Pharmacologic activation of limbic structures and neuroimaging studies of emotions. ServanSchreiber, Suppl 16, 13–15 Toward an integrated neurobiology of panic disorder. Goddard, Suppl 2, 4–12 Brain Imaging Application of neuroimaging techniques to drug development. Tamminga, Suppl 10, 3–6 Application of positron emission tomography to the study of normal and pathologic emotions. Reiman, Suppl 16, 4–12 Functional magnetic resonance imaging studies of emotional processing in normal and depressed patients: effects of venlafaxine. Kalin, Suppl 16, 32–39 Pharmacologic activation of limbic structures and neuroimaging studies of emotions. ServanSchreiber, Suppl 16, 13–15 BRAINSTORMS Apoptosis: neuronal death by design [BRAINSTORMS]. Stahl, May 183–184 Are two antidepressant mechanisms better than one? [BRAINSTORMS] Stahl, Aug 339–340 “Awakening” from schizophrenia: intramolecular polypharmacy and the atypical antipsychotics [BRAINSTORMS]. Stahl, Sept 381–382 Estrogen makes the brain a sex organ [BRAINSTORMS]. Stahl, Oct 421–422 Excitotoxicity and neuroprotection [BRAINSTORMS]. Stahl, June 247–248 Mental illness may be damaging to your brain [BRAINSTORMS]. Stahl, July 289–290 Serotonin: it’s possible to have too much of a good thing [BRAINSTORMS]. Stahl, Dec 520–521 Sex therapy in psychiatric treatment has a new partner: reproductive hormones [BRAINSTORMS]. Stahl, Nov 468–469 Breastfeeding Sertraline and norsertraline in three breastfed infants. Mammen, Mar 100–103 Bulimia Nervosa Paroxetine-induced anorexia in a patient with bulimia nervosa [letter]. Sagduyu; Vaz reply, May 220–221 Bupropion Bupropion for SSRI-induced fatigue [letter]. Green, Apr 174 Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. Bodkin, Apr 137–145 Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients. Kavoussi, Dec 532–537 Reversible dyskinesia during bupropion therapy [letter]. Gardos, May 218 Buspirone Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. Pollack, Suppl 11, 19–23

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Clinical effects of buspirone in social phobia: a double-blind placebo-controlled study. van Vliet, Apr 164–168 Carbamazepine Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. Denicoff, Nov 470–478 Resolution of palinopsia with carbamazepine [letter]. Silva, Jan 30 Cardiac Function Anxiety disorders and the syndrome of chest pain with normal coronary arteries: prevalence and pathophysiology. Carter, Suppl 3, 70–75 Asystole in ECT [letter]. Faber, Dec 550 Refractory depression, cardiovascular risk factors, and leukoariosis [letter]. D’Mello, June 274 Children Erotomanic delusions focused on a child [letter]. Remington, Sept 406 Clomipramine Clomipramine treatment of panic disorder: pros and cons. Papp, Oct 423–425 Double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Ravindran, Mar 112–118 Olfactory reference syndrome responds to clomipramine but not fluoxetine: a case report [letter]. Dominguez, Nov 497–498 Clozapine Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage [letter]. Armstrong, Nov 499 Clozapine and associated diabetes mellitus. Popli, Mar 108–111 Clozapine-benzodiazepine interactions [letter]. Faisal, Dec 547–548 Clozapine-related speech disturbance [letter]. Knoll; Bauer reply, May 219–220 Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. Spivak, July 318–322 Clozapine use in two full-term pregnancies [letter]. Stoner, Aug 364–365 Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. Stanilla, June 252–255 Oxybutynin and intranasal desmopressin for clozapine-induced urinary incontinence [letter]. Lurie; Fuller reply, Sept 404 Cognition Impaired neuropsychological performance in euthymic patients with recurring mood disorders. Tham, Jan 26–29 Cognitive Function Guideline series commentary [letters]. Hartley; Weiss; Kahn reply, Oct 452–453 Cognitive Therapy Cognitive-behavioral management of drugresistant major depressive disorder [CME]. Fava, June 278–282 Cognitive-behavioral therapy for panic disorder: current status. Barlow, Suppl 2, 32–37 Comorbidity Posttraumatic stress disorder and comorbidity: recognizing the many faces of PTSD. Brady, Suppl 9, 12–15 Psychopharmacology of comorbid obsessivecompulsive disorder and depression. den Boer, Suppl 8, 17–19 Compliance Antidepressant noncompliance as a factor in the

discontinuation syndrome. Kaplan, Suppl 7, 31–36 Enhancing patient outcomes: treatment adherence. Frank, Suppl 1, 11–14 Compulsive Buying Fluvoxamine in the treatment of compulsive buying. Black, Apr 159–163 Study of compulsive buying in depressed patients. Lejoyeux, Apr 169–173 Computers Interactive computer-administered self-assessment and self-help program for behavior therapy. Baer, Suppl 12, 23–28 Continuing Medical Education (CME) Atypical antipsychotic sertindole: a case series [CME]. Lee, Sept 410–416 Cognitive-behavioral management of drug-resistant major depressive disorder [CME]. Fava, June 278–282 Determinants of pharmacologic treatment failure in panic disorder [CME]. Cowley, Dec 555–561 Determinants of suicidal ideation: the role of substance use disorders [CME]. Pages, Nov 510–515 Dynamics of sex: gender differences in psychiatric disorders [CME]. Suppl 15, 1–40 Effects of race and information variance on disagreement between psychiatric emergency service and research diagnoses in first-episode psychosis [CME]. Strakowski, Oct 457–463 Functional brain alterations in depression and anxiety [CME]. Suppl 16, 1–41 New uses for antidepressants [CME]. Suppl 14, 1–62 Novel alternatives and supplements to lithium and anticonvulsants for bipolar affective disorder [CME]. Dubovsky, May 224–242 Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum [CME]. Williams, July 330–334 Violent behavior during sleep [CME]. Ohayon, August 369–376 Corrections Chronic neuroleptic exposure in bipolar outpatients. Sernyak, May 193–195; Correction, June 275 Comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a doubleblind, 8-week clinical trial. Gillin, May 185–192; Correction, June 275 Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia. Tran, May 205–211; Correction, June 275 Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. Swartz, May 212–216; Correction, June 275 Costs of Medical Care Caring for depression in primary care: defining and illustrating the policy context. Wells, Suppl 1, 24–27 Cost-effectiveness of divalproex versus lithium [letter]. Baker; Keck reply, Aug 363–364 Cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care settings. Revicki, Feb 47–58 Pharmacoeconomic evaluation of antipsychotic therapy for schizophrenia. Glazer, Suppl 10, 50–54 Trauma: prevalence, impairment, service use, and cost. Solomon, Suppl 9, 5–11 Cytochrome P450 System Risperidone and cytochrome P450 3A [letter]. de Leon, Oct 450



Delirium Nizatidine-induced delirium in a nonagenerian [letter]. Galynker, July 327 Delusions Delusional jealousy in dementia. Tsai, Nov 492–494 Dementia Delusional jealousy in dementia. Tsai, Nov 492–494 Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. Swartz, May 212–216; Correction, June 275 Olanzapine and the new generation of antipsychotic agents: patterns of use. Glazer, Suppl 10, 18–21 Treatment of dementia with behavioral disturbance using divalproex or a combination of divalproex and a neuroleptic. Narayan, Aug 351–354 Depression Affective illness and epilepsy [letter]. Kaplan; Blumer reply, Nov 498–499 Antidepressant and double antidepressant treatment for the affective disorder of epilepsy. Blumer, Jan 3–11 Antiepileptic drug augmentation for treatmentresistant depression [letter]. Feiner; Ketter reply, Aug 361–363 Application of positron emission tomography to the study of normal and pathologic emotions. Reiman, Suppl 16, 4–12 Barriers to the diagnosis of depression in primary care. Docherty, Suppl 1, 5–10 Brain structure and function and the outcomes of treatment for depression. Leuchter, Suppl 16, 22–31 Caring for depression in primary care: defining and illustrating the policy context. Wells, Suppl 1, 24–27 Cognitive-behavioral management of drug-resistant major depressive disorder [CME]. Fava, June 278–282 Collaborative management to achieve depression treatment guidelines. Katon, Suppl 1, 20–23 Comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind, 8-week clinical trial. Gillin, May 185–192; Correction, June 275 Depression after stroke: an investigation through catamnesis. Angeleri, June 261–265 Depression during pregnancy and the puerperium. Llewellyn, Suppl 15, 26–32 Detection and consequences of anxiety in clinical depression. Fawcett, Suppl 8, 35–40 Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients. Kavoussi, Dec 532–537 Double-blind comparison of fluvoxamine and paroxetine in the treatment of depressed outpatients. Kiev, Apr 146–152 Double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Ravindran, Mar 112–118 Double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression. Lydiard, Nov 484–491 Double-blind study of long-term treatment with sertraline or fluvoxamine for prevention of highly recurrent unipolar depression. Franchini, Mar 104–107 Effect of gender and age at onset of depression on mortality. Philibert, Aug 355–360


Effect of sertraline on plasma nortriptyline levels in depressed elderly. Solai, Oct 440–443 Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. Thase, Sept 393–398 Enhancing patient outcomes: treatment adherence. Frank, Suppl 1, 11–14 Exaggerated TSH responses to TRH in depressed patients with “normal” baseline TSH. Kraus, June 266–270 Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. Thase, Jan 16–21 Fluvoxamine: a review of the controlled trials in depression. Ware, Suppl 5, 15–23 Functional magnetic resonance imaging studies of emotional processing in normal and depressed patients: effects of venlafaxine. Kalin, Suppl 16, 32–39 Gender differences in depression: implications for treatment. Kornstein, Suppl 15, 12–18 Introduction: advances in the management of chronic depressive and anxiety disorders. Keller, Suppl 13, 3–4 Introduction. Depression and anxiety: implications for nosology, course, and treatment. Angst, Suppl 8, 3–5 Introduction: functional brain alterations in depression and anxiety. Kalin, Suppl 16, 3 Introduction. Management of depression: a successful continuum of care. Kupfer, Suppl 1, 3–4 Management of patients with depression associated with anxiety symptoms. Nutt, Suppl 8, 11–16 Mixed anxiety and depression: from theory to practice. Boulenger, Suppl 8, 27–34 Mixed depression and anxiety: serotonin1A receptors as a common pharmacologic link. Stahl, Suppl 8, 20–26 Novel placebo lead-in behavior strategy for sertraline dosing in a depressed patient highly sensitive to medication side effects [letter]. Moss, Sept 405–406 Open-label study of SSRI treatment in depressed Hispanic and non-Hispanic women [letter]. Alonso, Jan 31 Overcoming obstacles to effective treatment: use of clinical practice improvement methodology. Horn, Suppl 1, 15–19 Pharmacologic activation of limbic structures and neuroimaging studies of emotions. ServanSchreiber, Suppl 16, 13–15 Pimozide-induced depression in men who stutter. Bloch, Oct 433–436 Pindolol augmentation of treatment-resistant depressed patients. Moreno, Oct 437–439 Predicting the short-term outcome of first episodes and recurrences of clinical depression: a prospective study of life events, difficulties, and social support networks. Brugha, July 298–306 Psychopharmacology of comorbid obsessivecompulsive disorder and depression. den Boer, Suppl 8, 17–19 Psychotherapeutic approaches to the treatment of anxiety and depressive disorders. Michels, Suppl 13, 30–32 Recent advances in depression research: from stress to molecular biology and brain imaging. Risch, Suppl 5, 3–6 Refractory depression, cardiovascular risk factors, and leukoariosis [letter]. D’Mello, June 274 Role of the alliance in the pharmacologic treatment of depression. Weiss, May 196–204

Sleep disturbances and suicidal behavior in patients with major depression. Agargün, June 249–251 Strategies and tactics in the treatment of chronic depression. Rush, Suppl 13, 14–22 Study of compulsive buying in depressed patients. Lejoyeux, Apr 169–173 Subthreshold syndromes of depression and anxiety in the community. Angst, Suppl 8, 6–10 Undertreatment of dysthymia. Shelton, Feb 59–65 When at first you don’t succeed: sequential strategies for antidepressant nonresponders. Thase, Suppl 13, 23–29 Desmopressin Oxybutynin and intranasal desmopressin for clozapine-induced urinary incontinence [letter]. Lurie; Fuller reply, Sept 404 Dexfenfluramine Mania from dexfenfluramine [letter]. Bowden, Dec 548–549 Diabetes Mellitus Clozapine and associated diabetes mellitus. Popli, Mar 108–111 Diagnosis Effects of race and information variance on disagreement between psychiatric emergency service and research diagnoses in first-episode psychosis [CME]. Strakowski, Oct 457–463 Discontinuation Antidepressant discontinuation: a review of the literature. Lejoyeux, Suppl 7, 11–16 Antidepressant noncompliance as a factor in the discontinuation syndrome. Kaplan, Suppl 7, 31–36 Clinical management of antidepressant discontinuation. Rosenbaum, Suppl 7, 37–40 Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. Zajecka, July 291–297 Introduction. Antidepressant discontinuation syndrome: an update on serotonin reuptake inhibitors. Schatzberg, Suppl 7, 3–4 Newer antidepressants and the discontinuation syndrome. Haddad, Suppl 7, 17–22 Physicians’ knowledge of antidepressant withdrawal effects: a survey. Young, Suppl 7, 28–30 Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome. Schatzberg, Suppl 7, 23–27 Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Schatzberg, Suppl 7, 5–10 Switching antipsychotic medications. Weiden, Suppl 10, 63–72 Divalproex Cost-effectiveness of divalproex versus lithium [letter]. Baker; Keck reply, August 363–364 Divalproex treatment of disruptive adolescents: a report of 10 cases. Donovan, Jan 12–15 Is divalproex a cost-effective alternative in the acute and prophylactic treatment of bipolar I disorder? [letter] Dardennes; Keck reply, Nov 495–496 Pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar disorder. Solomon, Mar 95–99 Treatment of dementia with behavioral disturbance using divalproex or a combination of divalproex and a neuroleptic. Narayan, Aug 351–354

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Dosage Clinical pharmacokinetics of fluvoxamine: applications to dosage regimen design. DeVane, Suppl 5, 7–14 Decision analysis approach to neuroleptic dosing: insights from a mathematical model. Mossman, Feb 66–73 Dosing the antipsychotic medication olanzapine. Nemeroff, Suppl 10, 45–49 SSRI optimal dose remains at issue [letter]. Rifkin, Feb 87–88 Drug Administration Schedule Rapid conversion from one monoamine oxidase inhibitor to another. Szuba, July 307–310 Drug Development Application of neuroimaging techniques to drug development. Tamminga, Suppl 10, 3–6 Drug Interaction Clozapine-benzodiazepine interactions [letter]. Faisal, Dec 547–548 Drug Therapy, Combination Antiepileptic drug augmentation for treatmentresistant depression [letter]. Feiner; Ketter reply, Aug 361–363 Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. Denicoff, Nov 470–478 Pindolol augmentation of treatment-resistant depressed patients. Moreno, Oct 437–439 Update on pharmacologic management of OCD: agents and augmentation. McDougle, Suppl 12, 11–17 When at first you don’t succeed: sequential strategies for antidepressant nonresponders. Thase, Suppl 13, 23–29 Dyskinesia Clinical manifestations of dystonia and dyskinesia after SSRI administration [letter]. Lauterbach; Leo reply, Sept 403–404 Dyskinesia with fluoxetine: tardive or late-onset persistent, acute norfluoxetine dyskinesia? [letter] Lauterbach; Sandler reply, Feb 85–86 Reversible dyskinesia during bupropion therapy [letter]. Gardos, May 218 Dysthymia Undertreatment of dysthymia. Shelton, Feb 59–65 Venlafaxine in dysthymic disorder. Dunner, Dec 528–531 Dystonia Clinical manifestations of dystonia and dyskinesia after SSRI administration [letter]. Lauterbach; Leo reply, Sept 403–404 Eating Disorders see Anorexia Nervosa; Bulimia Nervosa Elderly Double-blind, placebo-controlled trial of two doses of abecarnil for geriatric anxiety. Small, Suppl 11, 24–29 Effect of sertraline on plasma nortriptyline levels in depressed elderly. Solai, Oct 440–443 Nizatidine-induced delirium in a nonagenerian [letter]. Galynker, July 327 Recognizing and treating anxiety in the elderly. Small, Suppl 3, 41–50 Reversible parkinsonism in a 90-year-old man taking sertraline [letter]. Schechter, June 275 Risperidone in the elderly: a pharmacoepidemiologic study. Zarate, July 311–317 Electroconvulsive Therapy Asystole in ECT [letter]. Faber, Dec 550 Epidemiology Epidemiology of obsessive-compulsive disorder: a world view. Sasson, Suppl 12, 7–10

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Epilepsy Affective illness and epilepsy [letter]. Kaplan; Blumer reply, Nov 498–499 Antidepressant and double antidepressant treatment for the affective disorder of epilepsy. Blumer, Jan 3–11 Erotomania Erotomanic delusions focused on a child [letter]. Remington, Sept 406 Estrogen Estrogen makes the brain a sex organ [BRAINSTORMS]. Stahl, Oct 421–422 Evaluation, Psychiatric Applicability of telemedicine for assessing patients with schizophrenia: acceptance and reliability. Zarate, Jan 22–25 BATHE: an approach to the interview process in the primary care setting. Lieberman, Suppl 3, 3–8 Extrapyramidal Side Effects Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. Spivak, July 318–322 Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia. Tran, May 205–211; Correction, June 275 Reversible parkinsonism in a 90-year-old man taking sertraline [letter]. Schechter, June 275 Severe extrapyramidal reaction due to risperidone in a case of neurofibromatosis [letter]. De León, July 323 Fatigue Bupropion for SSRI-induced fatigue [letter]. Green, Apr 174 Fluoxetine Comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind, 8-week clinical trial. Gillin, May 185–192; Correction, June 275 Double-blind trial of fluoxetine in pathologic skin picking. Simeon, Aug 341–347 Dyskinesia with fluoxetine: tardive or late-onset persistent, acute norfluoxetine dyskinesia? [letter] Lauterbach; Sandler reply, Feb 85–86 Fluoxetine efficacy in social phobia. Taylor, Mar 124–125 Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. Thase, Jan 16–21 Olfactory reference syndrome responds to clomipramine but not fluoxetine: a case report [letter]. Dominguez, Nov 497–498 Possible pharmacokinetic interaction between fluoxetine and acetylsalicylic acid [letter]. Shad, Dec 549–550 Resolution of fluoxetine-induced sexual dysfunction with the 5-HT3 antagonist granisetron [letter]. Nelson, Nov 496–497 Fluvoxamine Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage [letter]. Armstrong, Nov 499 Clinical pharmacokinetics of fluvoxamine: applications to dosage regimen design. DeVane, Suppl 5, 7–14 Double-blind comparison of fluvoxamine and paroxetine in the treatment of depressed outpatients. Kiev, Apr 146–152 Double-blind study of long-term treatment with sertraline or fluvoxamine for prevention of

highly recurrent unipolar depression. Franchini, Mar 104–107 Fluvoxamine: a review of the controlled trials in depression. Ware, Suppl 5, 15–23 Fluvoxamine in the treatment of compulsive buying. Black, Apr 159–163 Fluvoxamine in the treatment of obsessivecompulsive disorder and related conditions. Goodman, Suppl 5, 32–49 Issues in the assessment of treatment response in panic disorder with special reference to fluvoxamine. Ninan, Suppl 5, 24–31 Gender see also Sex Differences Effect of gender and age at onset of depression on mortality. Philibert, Aug 355–360 Geriatric Psychiatry see Elderly Glaucoma Acute angle-closure glaucoma and paroxetine [letter]. Lewis, Mar 123–124 Granisetron Resolution of fluoxetine-induced sexual dysfunction with the 5-HT3 antagonist granisetron [letter]. Nelson, Nov 496–497 Guidelines Treatment of obsessive-compulsive disorder [Expert Consensus Guideline Series]. Suppl 4, 3–72 Hallucinogens Sertraline treatment of hallucinogen persisting perception disorder [letter]. Young, Feb 85 Haloperidol Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia. Tran, May 205–211; Correction, June 275 Health Maintenance Organizations Overcoming obstacles to effective treatment: use of clinical practice improvement methodology. Horn, Suppl 1, 15–19 HIV see AIDS Hormones Sex therapy in psychiatric treatment has a new partner: reproductive hormones [BRAINSTORMS]. Stahl, Nov 468–469 Hyponatremia Effects of olanzapine on polydipsia and intermittent hyponatremia [letter]. Littrell, Dec 549 Hypouricemia in chronic schizophrenic patients with polydipsia and hyponatremia. Hanihara, June 256–260 Hypouricemia Hypouricemia in chronic schizophrenic patients with polydipsia and hyponatremia. Hanihara, June 256–260 Incentive Bias Continuing dialogue on incentive bias [letter]. Jefferson; Nemeroff reply, Publishers reply, Oct 450–452 Infants Sertraline and norsertraline in three breastfed infants. Mammen, Mar 100–103 Iron Iron overload among a psychiatric outpatient population. Feifel, Feb 74–78 Irritable Bowel Syndrome Anxiety and the irritable bowel syndrome: psychiatric, medical, or both? Lydiard, Suppl 3, 51–61 Jealousy Delusional jealousy in dementia. Tsai, Nov 492–494 Journal of Clinical Psychiatry Continuing dialogue on incentive bias [letter]. Jefferson; Nemeroff reply, Publishers reply, Oct 450–452



New chapter. Dec 551 Toward the millennium. Mar 94 Lamotrigine Lamotrigine in rapid-cycling bipolar disorder. Fatemi, Dec 522–527 Lamotrigine treatment of refractory bipolar disorder [letter]. Fogelson, June 271–273 Leukoariosis Refractory depression, cardiovascular risk factors, and leukoariosis [letter]. D’Mello, June 274 Light Therapy see Phototherapy Lithium Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. Denicoff, Nov 470–478 Comparison of valproic acid and lithium in mania [letter]. Townes; Altshuler reply, June 273–274 Cost-effectiveness of divalproex versus lithium [letter] Baker; Keck reply, Aug 363–364 Novel alternatives and supplements to lithium and anticonvulsants for bipolar affective disorder [CME]. Dubovsky, May 224–242 Pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar disorder. Solomon, Mar 95–99 Lorazepam Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy? Buysse, Oct 426–432 Magnetic Resonance Imaging see Brain Imaging Managed Care Cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care settings. Revicki, Feb 47–58 Panic disorder in a managed care environment. Rapaport, Suppl 2, 51–56 Mania Comparison of valproic acid and lithium in mania [letter]. Townes; Altshuler reply, June 273–274 Mania associated with serotonin selective reuptake inhibitors [letter]. Vesely, Feb 88 Mania from dexfenfluramine [letter]. Bowden, Dec 548–549 Valproic acid treatment of AIDS-related mania [letter]. RachBeisel, Sept 406–407 Melatonin Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. Leibenluft, Sept 383–388 Mental Health Services, Delivery and Utilization of Importance of establishing the diagnosis of persistent anxiety. Zajecka, Suppl 3, 9–15 Trauma: prevalence, impairment, service use, and cost. Solomon, Suppl 9, 5–11 Mental Illness Mental illness may be damaging to your brain [BRAINSTORMS]. Stahl, July 289–290 Migraine Paroxetine prevents migraines [letter]. Hays, Jan 30–31 Mirtazapine Safety in overdose of mirtazapine: a case report [letter]. Gerritson, June 271 Selection of an antidepressant: mirtazapine. Preskorn, Suppl 6, 3–8 Models, Theoretical Decision analysis approach to neuroleptic dosing: insights from a mathematical model. Mossman, Feb 66–73 Monoamine Oxidase Inhibitors Rapid conversion from one monoamine oxidase inhibitor to another. Szuba, July 307–310


Mood Association between premenstrual dysphoric disorder and other mood disorders. Yonkers, Suppl 15, 19–25 Comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind, 8-week clinical trial. Gillin, May 185–192; Correction, June 275 Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder. Feldman-Naim, Feb 79–84 Impaired neuropsychological performance in euthymic patients with recurring mood disorders. Tham, Jan 26–29 Multiple Sclerosis Differential diagnosis of multiple sclerosis and bipolar disorder [letter]. Young, Mar 123 Naltrexone Cessation of self-mutilation in a patient with borderline personality disorder treated with naltrexone [letter]. McGee, Jan 32–33 Nefazodone Comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind, 8-week clinical trial. Gillin, May 185–192; Correction, June 275 Nefazodone and neurotoxicity [letter]. Yong; Puzantian reply, Aug 365 Sertraline-induced anorgasmia treated with intermittent nefazodone [letter]. Reynolds, Feb 89 Neurofibromatosis Severe extrapyramidal reaction due to risperidone in a case of neurofibromatosis [letter]. De León, July 323 Neuroimaging see Brain Imaging Neuroleptics see Antipsychotics Neuropsychological Functioning see Cognition Neurotoxicity Nefazodone and neurotoxicity [letter]. Yong; Puzantian reply, Aug 365 Neurotransmitters see also specific neurotransmitters Excitoxicity and neuroprotection [BRAINSTORMS]. Stahl, June 247–248 Nicotine Antidepressant effects of nicotine [letter]. Hawkins; Salín-Pascual reply, July 324–325 Nizatidine Nizatidine-induced delirium in a nonagenerian [letter]. Galynker, July 327 Nortriptyline Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy? Buysse, Oct 426–432 Effect of sertraline on plasma nortriptyline levels in depressed elderly. Solai, Oct 440–443 Obsessive-Compulsive Disorder Epidemiology of obsessive-compulsive disorder: a world view. Sasson, Suppl 12, 7–10 Fluvoxamine in the treatment of obsessivecompulsive disorder and related conditions. Goodman, Suppl 5, 32–49 Interactive computer-administered selfassessment and self-help program for behavior therapy. Baer, Suppl 12, 23–28 Introduction. Obsessive-compulsive disorder: the hidden epidemic. Hollander, Suppl 12, 3–6 New developments in the treatment of obsessivecompulsive disorder. Leonard, Suppl 14, 39–45

Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum [CME]. Williams, July 330–334 Olfactory reference syndrome responds to clomipramine but not fluoxetine: a case report [letter]. Dominguez, Nov 497–498 Pharmacologic treatment of obsessive-compulsive disorder: comparative studies. Flament, Suppl 12, 18–22 Psychopharmacology of comorbid obsessivecompulsive disorder and depression. den Boer, Suppl 8, 17–19 Risperidone augmentation of serotonin reuptake inhibitors in obsessive-compulsive and related disorders. Stein, Mar 119–122 Treatment of obsessive-compulsive disorder [Expert Consensus Guideline Series]. Suppl 4, 3–72 Treatment strategies for chronic and refractory obsessive-compulsive disorder. Rasmussen, Suppl 13, 9–13 Update on pharmacologic management of OCD: agents and augmentation. McDougle, Suppl 12, 11–17 Olanzapine Application of neuroimaging techniques to drug development. Tamminga, Suppl 10, 3–6 Behavioral pharmacology of olanzapine: a novel antipsychotic drug. Moore, Suppl 10, 37–44 Dosing the antipsychotic medication olanzapine. Nemeroff, Suppl 10, 45–49 Effects of olanzapine on polydipsia and intermittent hyponatremia [letter]. Littrell, Dec 549 Efficacy of olanzapine: an overview of pivotal clinical trials. Beasley, Suppl 10, 7–12 Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia. Tran, May 205–211; Correction, June 275 In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug. Bymaster, Suppl 10, 28–36 Olanzapine and the new generation of antipsychotic agents: patterns of use. Glazer, Suppl 10, 18–21 Olanzapine in treatment-refractory schizophrenia: results of an open-label study. Martín, Nov 479–483 Safety of olanzapine. Beasley, Suppl 10, 13–17 Olfactory Reference Syndrome Olfactory reference syndrome responds to clomipramine but not fluoxetine: a case report [letter]. Dominguez, Nov 497–498 Onset of Illness Effect of gender and age at onset of depression on mortality. Philibert, Aug 355–360 Outcome Placebo response in generalized anxiety: its effect on the outcome of clinical trials. Schweizer, Suppl 11, 30–38 Predicting the short-term outcome of first episodes and recurrences of clinical depression: a prospective study of life events, difficulties, and social support networks. Brugha, July 298–306 Outpatients Chronic neuroleptic exposure in bipolar outpatients. Sernyak, May 193–195; Correction, June 275 Double-blind comparison of fluvoxamine and paroxetine in the treatment of depressed outpatients. Kiev, Apr 146–152 Double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Lydiard, Suppl 11, 11–18

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Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. Thase, Sept 393–398 Iron overload among a psychiatric outpatient population. Feifel, Feb 74–78 Oxcarbazepine Oxcarbazepine for panic disorder occurring after two grand mal seizures: a case report [letter]. Windhaber, Sept 404–405 Oxybutynin Oxybutynin and intranasal desmopressin for clozapine-induced urinary incontinence [letter]. Lurie; Fuller reply, Sept 404 Palinopsia Resolution of palinopsia with carbamazepine [letter]. Silva, Jan 30 Panic Alcohol and substance abuse in panic disorder. Marshall, Suppl 2, 46–50 Antidepressants in panic disorder. Jefferson, Suppl 2, 20–25 Clomipramine treatment of panic disorder: pros and cons. Papp, Oct 423–425 Cognitive-behavioral therapy for panic disorder: current status. Barlow, Suppl 2, 32–37 Conclusion. Treatment of panic disorder: the state of the art. Rosenbaum, Suppl 2, 66–67 Determinants of pharmacologic treatment failure in panic disorder [CME]. Cowley, Dec 555–561 Introduction. Treatment of panic disorder: the state of the art. Rosenbaum, Suppl 2, 3 Issues in the assessment of treatment response in panic disorder with special reference to fluvoxamine. Ninan, Suppl 5, 24–31 Long-term course and outcome of panic disorder. Pollack, Suppl 2, 57–60 Oxcarbazepine for panic disorder occurring after two grand mal seizures: a case report [letter]. Windhaber, Sept 404–405 Panic and paranoia [letter]. Bermanzohn; Galynker reply, July 325–326 Panic disorder: a treatment update [ACADEMIC HIGHLIGHTS]. Jan 36–42 Panic disorder as a chronic illness. Liebowitz, Suppl 13, 5–8 Panic disorder in a managed care environment. Rapaport, Suppl 2, 51–56 Panic disorder in the medical setting. Ballenger, Suppl 2, 13–19 Panic disorder: making clinical sense of the latest research [ACADEMIC HIGHLIGHTS]. March 127–134 Psychotherapy for panic disorder. Shear, Suppl 2, 38–45 Quality of life and panic-related work disability in subjects with infrequent panic and panic disorder. Katerndahl, Apr 153–158 Toward an integrated neurobiology of panic disorder. Goddard, Suppl 2, 4–12 Treatment-resistant panic disorder. Rosenbaum, Suppl 2, 61–65 Use of benzodiazepines in panic disorder. Davidson, Suppl 2, 26–31 Use of newer antidepressants for panic disorder. Gorman, Suppl 14, 54–58 Paranoia Panic and paranoia [letter]. Bermanzohn; Galynker reply, July 325–326 Parethesias Transient, paroxysmal, shock-like paresthesias associated with paroxetine initiation [letter]. Berigan, Apr 175–176 Parkinsonian Symptoms see Extrapyramidal Side Effects

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Paroxetine Acute angle-closure glaucoma and paroxetine [letter]. Lewis, Mar 123–124 Double-blind comparison of fluvoxamine and paroxetine in the treatment of depressed outpatients. Kiev, Apr 146–152 Double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Ravindran, Mar 112–118 Paroxetine-induced anorexia in a patient with bulimia nervosa [letter]. Sagduyu; Vaz reply, May 220–221 Paroxetine prevents migraines [letter]. Hays, Jan 30–31 Transient, paroxysmal, shock-like paresthesias associated with paroxetine initiation [letter]. Berigan, Apr 175–176 Patient Care Role of the alliance in the pharmacologic treatment of depression. Weiss, May 196–204 Pharmacodynamics Are two antidepressant mechanisms better than one? [BRAINSTORMS] Stahl, Aug 339–340 Pharmacoepidemiology Risperidone in the elderly: a pharmacoepidemiologic study. Zarate, July 311–317 Pharmacology Relationship of pharmacology to side effects. Casey, Suppl 10, 55–62 Phobias Clinical effects of buspirone in social phobia: a double-blind placebo-controlled study. van Vliet, Apr 164–168 Fluoxetine efficacy in social phobia. Taylor, Mar 124–125 New uses for antidepressants: social phobia. Keck, Suppl 14, 32–36 Role of serotonin drugs in the treatment of social phobia. Tancer, Suppl 5, 50–54 Phototherapy Severe atypical symptoms without depression in SAD: effects of bright light therapy [letter]. Ibatoullina, Nov 495 Suicidal tendencies as a complication of light therapy for seasonal affective disorder: a report of three cases. Praschak-Rieder, Sept 389–392 Physicians Physicians’ knowledge of antidepressant withdrawal effects: a survey. Young, Suppl 7, 28–30 Role of the alliance in the pharmacologic treatment of depression. Weiss, May 196–204 Pimozide Pimozide-induced depression in men who stutter. Bloch, Oct 433–436 Pindolol Pindolol augmentation of treatment-resistant depressed patients. Moreno, Oct 437–439 Polydipsia Effects of olanzapine on polydipsia and intermittent hyponatremia [letter]. Littrell, Dec 549 Hypouricemia in chronic schizophrenic patients with polydipsia and hyponatremia. Hanihara, June 256–260 Posttraumatic Stress Disorder Biological therapies for posttraumatic stress disorder: an overview. Davidson, Suppl 9, 29–32 Introduction. Repairing the shattered self: recovering from trauma. Davidson, Suppl 9, 3–4

Posttraumatic stress disorder. Friedman, Suppl 9, 33–36 Posttraumatic stress disorder and comorbidity: recognizing the many faces of PTSD. Brady, Suppl 9, 12–15 Psychobiology of posttraumatic stress disorder. van der Kolk, Suppl 9, 16–24 Trauma and women: course, predictors, and treatment. Foa, Suppl 9, 25–28 Trauma: prevalence, impairment, service use, and cost. Solomon, Suppl 9, 5–11 Prediction Determinants of pharmacologic treatment failure in panic disorder [CME]. Cowley, Dec 555–561 Determinants of suicidal ideation: the role of substance use disorders [CME]. Pages, Nov 510–515 Predicting the short-term outcome of first episodes and recurrences of clinical depression: a prospective study of life events, difficulties, and social support networks. Brugha, July 298–306 Pregnancy Clozapine use in two full-term pregnancies [letter]. Stoner, Aug 364–365 Depression during pregnancy and the puerperium. Llewellyn, Suppl 15, 26–32 Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum [CME]. Williams, July 330–334 Premenstrual Disorders Antidepressants in the treatment of premenstrual dysphoric disorder. Yonkers, Suppl 14, 4–10 Anxiety symptoms and anxiety disorders: how are they related to premenstrual disorders? Yonkers, Suppl 3, 62–69 Association between premenstrual dysphoric disorder and other mood disorders. Yonkers, Suppl 15, 19–25 Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome. Halbreich, Sept 399–402 Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum [CME]. Williams, July 330–334 Primary Care Anxiety disorders and the syndrome of chest pain with normal coronary arteries: prevalence and pathophysiology. Carter, Suppl 3, 70–75 Barriers to the diagnosis of depression in primary care. Docherty, Suppl 1, 5–10 BATHE: an approach to the interview process in the primary care setting. Lieberman, Suppl 3, 3–8 Caring for depression in primary care: defining and illustrating the policy context. Wells, Suppl 1, 24–27 Clinical presentation of generalized anxiety in primary care settings: practical concepts of classification and management. Rickels, Suppl 11, 4–10 Collaborative management to achieve depression treatment guidelines. Katon, Suppl 1, 20–23 Double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Ravindran, Mar 112–118 Generalized anxiety disorder in primary care: the precursor/modifer pathway to increased health care utilization. Roy-Byrne, Suppl 3, 34–40 Panic disorder in the medical setting. Ballenger, Suppl 2, 13–19 Strategies for treatment of generalized anxiety in the primary care setting. Schweizer, Suppl 3, 27–33



Treatment algorithm for the management of anxiety in primary care practice. Hales, Suppl 3, 76–80 Psychobiology Psychobiology of posttraumatic stress disorder. van der Kolk, Suppl 9, 16–24 Psychosis Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. Stanilla, June 252–255 Effects of race and information variance on disagreement between psychiatric emergency service and research diagnoses in first-episode psychosis [CME]. Strakowski, Oct 457–463 Psychotherapy Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy? Buysse, Oct 426–432 Psychotherapeutic approaches to the treatment of anxiety and depressive disorders. Michels, Suppl 13, 30–32 Psychotherapy for panic disorder. Shear, Suppl 2, 38–45 When at first you don’t succeed: sequential strategies for antidepressant nonresponders. Thase, Suppl 13, 23–29 Quality of Life Quality of life and panic-related work disability in subjects with infrequent panic and panic disorder. Katerndahl, Apr 153–158 Undertreatment of dysthymia. Shelton, Feb 59–65 Race Effects of race and information variance on disagreement between psychiatric emergency service and research diagnoses in first-episode psychosis [CME]. Strakowski, Oct 457–463 Risperidone Effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. Marder, Dec 538–546 Risperidone and cytochrome P450 3A [letter]. de Leon, Oct 450 Risperidone augmentation of serotonin reuptake inhibitors in obsessive-compulsive and related disorders. Stein, Mar 119–122 Risperidone in the elderly: a pharmacoepidemiologic study. Zarate, July 311–317 Severe extrapyramidal reaction due to risperidone in a case of neurofibromatosis [letter]. De León, July 323 Schizophrenia Applicability of telemedicine for assessing patients with schizophrenia: acceptance and reliability. Zarate, Jan 22–25 “Awakening” from schizophrenia: intramolecular polypharmacy and the atypical antipsychotics [BRAINSTORMS]. Stahl, Sept 381–382 Biological basis of schizophrenia: new directions. Weinberger, Suppl 10, 22–27 Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. Spivak, July 318–322 Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. Stanilla, June 252–255 Concluding remarks. Tollefson, Suppl 10, 73 Decision analysis approach to neuroleptic dosing: insights from a mathematical model. Mossman, Feb 66–73 Effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. Marder, Dec 538–546


Efficacy of olanzapine: an overview of pivotal clinical trials. Beasley, Suppl 10, 7–12 Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia. Tran, May 205–211; Correction, June 275 Gender and schizophrenia. Tamminga, Suppl 15, 33–37 Guideline series commentary [letters]. Hartley; Weiss; Kahn reply, Oct 452–453 Hypouricemia in chronic schizophrenic patients with polydipsia and hyponatremia. Hanihara, June 256–260 Olanzapine and the new generation of antipsychotic agents: patterns of use. Glazer, Suppl 10, 18–21 Olanzapine in treatment-refractory schizophrenia: results of an open-label study. Martín, Nov 479–483 Pharmacoeconomic evaluation of antipsychotic therapy for schizophrenia. Glazer, Suppl 10, 50–54 Safety of olanzapine. Beasley, Suppl 10, 13–17 Switching antipsychotic medications. Weiden, Suppl 10, 63–72 Seasonal Affective Disorder Severe atypical symptoms without depression in SAD: effects of bright light therapy [letter]. Ibatoullina, Nov 495 Suicidal tendencies as a complication of light therapy for seasonal affective disorder: a report of three cases. Praschak-Rieder, Sept 389–392 Seizures Oxcarbazepine for panic disorder occurring after two grand mal seizures: a case report [letter]. Windhaber, Sept 404–405 Self-Injurious Behavior Cessation of self-mutilation in a patient with borderline personality disorder treated with naltrexone [letter]. McGee, Jan 32–33 Serotonin Antidepressant discontinuation: a review of the literature. Lejoyeux, Suppl 7, 11–16 Behavior therapy and serotonin dysregulation [letter]. Taylor, July 323–324 Bupropion for SSRI-induced fatigue [letter]. Green, Apr 174 Clinical manifestations of dystonia and dyskinesia after SSRI administration [letter]. Lauterbach; Leo reply, Sept 403–404 Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. Bodkin, Apr 137–145 Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. Zajecka, July 291–297 Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. Swartz, May 212–216; Correction, June 275 Introduction. Antidepressant discontinuation syndrome: an update on serotonin reuptake inhibitors. Schatzberg, Suppl 7, 3–4 Mania associated with serotonin selective reuptake inhibitors [letter]. Vesely, Feb 88 Mixed depression and anxiety: serotonin1A receptors as a common pharmacologic link. Stahl, Suppl 8, 20–26 Newer antidepressants and the discontinuation syndrome. Haddad, Suppl 7, 17–22 Open-label study of SSRI treatment in depressed Hispanic and non-Hispanic women [letter]. Alonso, Jan 31 Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome. Schatzberg, Suppl 7, 23–27

Risperidone augmentation of serotonin reuptake inhibitors in obsessive-compulsive and related disorders. Stein, Mar 119–122 Role of serotonin drugs in the treatment of social phobia. Tancer, Suppl 5, 50–54 Serotonin: it’s possible to have too much of a good thing [BRAINSTORMS]. Stahl, Dec 520–521 Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Schatzberg, Suppl 7, 5–10 SSRI optimal dose remains at issue [letter]. Rifkin, Feb 87–88 Switching drug class after initial SSRI failure [letter]. Kelsey, July 326–327 Sertindole Atypical antipsychotic sertindole: a case series [CME]. Lee, Sept 410–416 Sertraline Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients. Kavoussi, Dec 532–537 Double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression. Lydiard, Nov 484–491 Double-blind study of long-term treatment with sertraline or fluvoxamine for prevention of highly recurrent unipolar depression. Franchini, Mar 104–107 Effect of sertraline on plasma nortriptyline levels in depressed elderly. Solai, Oct 440–443 Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. Thase, Jan 16–21 Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome. Halbreich, Sept 399–402 Novel placebo lead-in behavior strategy for sertraline dosing in a depressed patient highly sensitive to medication side effects [letter]. Moss, Sept 405–406 Reversible parkinsonism in a 90-year-old man taking sertraline [letter]. Schechter, June 275 Sertraline and norsertraline in three breastfed infants. Mammen, Mar 100–103 Sertraline-induced anorgasmia treated with intermittent nefazodone [letter]. Reynolds, Feb 89 Sertraline treatment of hallucinogen persisting perception disorder [letter]. Young, Feb 85 Sex Differences Gender and schizophrenia. Tamminga, Suppl 15, 33–37 Gender differences in depression: implications for treatment. Kornstein, Suppl 15, 12–18 Introduction. The dynamics of sex: gender differences in psychiatric disorders. Schatzberg, Suppl 15, 3–4 Issues in the treatment of women with bipolar illness. Leibenluft, Suppl 15, 5–11 Sexual Function Estrogen makes the brain a sex organ [BRAINSTORMS]. Stahl, Oct 421–422 Resolution of fluoxetine-induced sexual dysfunction with the 5-HT3 antagonist granisetron [letter]. Nelson, Nov 496–497 Sex therapy in psychiatric treatment has a new partner: reproductive hormones [BRAINSTORMS]. Stahl, Nov 468–469 Side Effects Relationship of pharmacology to side effects. Casey, Suppl 10, 55–62 Skin Picking Double-blind trial of fluoxetine in pathologic skin picking. Simeon, Aug 341–347

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Sleep Comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind, 8-week clinical trial. Gillin, May 185–192; Correction, June 275 Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers. Salín-Pascual, Aug 348–350 Sleep disturbances and suicidal behavior in patients with major depression. Agargün, June 249–251 Violent behavior during sleep [CME]. Ohayon, Aug 369–376 Smoking Impact of a smoking ban on a locked psychiatric unit [letter]. Pearlman; Haller reply, Apr 179 Social Phobia see Phobias Speech Clozapine-related speech disturbance [letter]. Knoll; Bauer reply, May 219–220 Stereotypic Movement Disorder Stereotypic movement disorder [letter]. Stein; Castellanos reply, Apr 177–178 Stiff-Man Syndrome Psychiatric consultations in stiff-man syndrome. Tinsley, Oct 444–449 Stroke Depression after stroke: an investigation through catamnesis. Angeleri, June 261–265 Stuttering Pimozide-induced depression in men who stutter. Bloch, Oct 433–436 Substance Abuse Alcohol and substance abuse in panic disorder. Marshall, Suppl 2, 46–50 Substance Use Disorders Determinants of suicidal ideation: the role of substance use disorders [CME]. Pages, Nov 510–515 Suicide Determinants of suicidal ideation: the role of substance use disorders [CME]. Pages, Nov 510–515 Sleep disturbances and suicidal behavior in patients with major depression. Agargün, June 249–251

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Suicidal tendencies as a complication of light therapy for seasonal affective disorder: a report of three cases. Praschak-Rieder, Sept 389–392 Suicide assessment and terminology [letter]. Smith, Oct 450 Sweating Benztropine in the treatment of venlafaxine-induced sweating [letter]. Garber, Apr 176–177 Tardive Dyskinesia Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. Spivak, July 318–322 Telemedicine Applicability of telemedicine for assessing patients with schizophrenia: acceptance and reliability. Zarate, Jan 22–25 Thrombocytopenia Dose-related thrombocytopenia and macrocytic anemia associated with valproate use in bipolar disorder [letter]. Fawcett, Mar 125 Thyroid Function Exaggerated TSH responses to TRH in depressed patients with “normal” baseline TSH. Kraus, June 266–270 Tourette’s Syndrome Novel use of tramadol hydrochloride in the treatment of Tourette’s syndrome [letter]. Shapira, Apr 174–175 Tramadol Novel use of tramadol hydrochloride in the treatment of Tourette’s syndrome [letter]. Shapira, Apr 174–175 Trauma see Posttraumatic Stress Disorder Trichotillomania Case of seasonal trichotillomania [letter]. FeldmanNaim, May 218–219 Urinary Incontinence Oxybutynin and intranasal desmopressin for clozapine-induced urinary incontinence [letter]. Lurie; Fuller reply, Sept 404 Utilization see Mental Health Services, Delivery and Utilization of Valproate see also Divalproex Sodium; Valproic Acid Dose-related thrombocytopenia and macrocytic anemia associated with valproate use in bipolar disorder [letter]. Fawcett, Mar 125

Valproic Acid Comparison of valproic acid and lithium in mania [letter]. Townes; Altshuler reply, June 273–274 Valproic acid treatment of AIDS-related mania [letter]. RachBeisel, Sept 406–407 Venlafaxine Benztropine in the treatment of venlafaxineinduced sweating [letter]. Garber, Apr 176–177 Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. Thase, Sept 393–398 Functional magnetic resonance imaging studies of emotional processing in normal and depressed patients: effects of venlafaxine. Kalin, Suppl 16, 32–39 Pharmacologic properties of venlafaxine [letter]. Smith; Findling reply, Apr 178 Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers. Salín-Pascual, Aug 348–350 Venlafaxine in dysthymic disorder. Dunner, Dec 528–531 Violence Akathisia as violence [letter]. Galynker, Jan 31–32 Violent behavior during sleep [CME]. Ohayon, Aug 369–376 Withdrawal of Drugs see Discontinuation Women Association between premenstrual dysphoric disorder and other mood disorders. Yonkers, Suppl 15, 19–25 Clozapine use in two full-term pregnancies [letter]. Stoner, Aug 364–365 Depression during pregnancy and the puerperium. Llewellyn, Suppl 15, 26–32 Guideline series commentary [letters]. Hartley; Weiss; Kahn reply, Oct 452–453 Issues in the treatment of women with bipolar illness. Leibenluft, Suppl 15, 5–11 Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum [CME]. Williams, July 330–334 Open-label study of SSRI treatment in depressed Hispanic and non-Hispanic women [letter]. Alonso, Jan 31 Trauma and women: course, predictors, and treatment. Foa, Suppl 9, 25–28


Author Index: Volume 58

Journal of Clinical Psychiatry

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Author Index to Volume 58: January 1997 Through December 1997

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Åberg-Wistedt A see Tham A Abesgaus J see Spivak B Abrams M see Leuchter AF Adès J see Lejoyeux M Adlersberg S see Spivak B Agargün MY, Kara H, Solmaz M. Sleep disturbances and suicidal behavior in patients with major depression. June 249–251 Akiskal HS. A renaissance of clinical psychiatry through books published during the past decade. Dec 552–553 Alarcon RD. Review of American Psychiatric Association: American Psychiatric Association Practice Guidelines. Jan 34–35 Alarcon RD. Review of Frances A, First MB, Pincus HA: DSM-IV Guidebook. Apr 180 Alarcon RD. Review of Schildkraut JJ, Otero A (eds): Depression and the Spiritual in Modern Art: Homage to Miró. Aug 366–367 Albala BJ see Gillin JC Ali SO see Denicoff KD Alonso M, Val E, Rapaport MH. An open-label study of SSRI treatment in depressed Hispanic and non-Hispanic women [letter]. Jan 31 Altshuler LL, Frye MA. Reply to Townes P: Comparison of valproic acid and lithium in mania [letter]. June 273–274 Alvarez E see Martín J Amagai I see Hanihara T Amsterdam JD see Szuba MP Anderson-Hanley C see Leuchter AF Angeleri F, Angeleri VA, Foschi N, Giaquinto S, Nolfe G, Saginario A, Signorino M. Depression after stroke: an investigation through catamnesis. June 261–265 Angeleri VA see Angeleri F Angst J. Introduction. Depression and anxiety: implications for nosology, course, and treatment. Suppl 8, 3–5 Angst J, Merikangas KR, Preisig M. Subthreshold syndromes of depression and anxiety in the community. Suppl 8, 6–10 Anya I see Stoner SC Apter JT see Thase ME Aquila R see Weiden PJ Arlow PB see Bermanzohn PC Armstrong SC, Stephans JR. Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage [letter]. Nov 499 Ascher JA see Kavoussi RJ Babaie A see Leuchter AF Bachar K see Moreno FA

Bodkin JA, Lasser RA, Wines JD Jr, Gardner DM, Baldessarini RJ. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. Apr 137–145 Bork J see de Leon J Borovicka MC see Fuller MA Boulenger J-P, Fournier M, Rosales D, Lavallée Y-J. Mixed anxiety and depression: from theory to practice. Suppl 8, 27–34 Bourne ML see Strakowski SM Bouwer C see Stein DJ Bowden CL, Dickson J Jr. Mania from dexfenfluramine [letter]. Dec 548–549 Bowden CL see Silva JA Bowers MB Jr see Young CR Brady KT. Posttraumatic stress disorder and comorbidity: recognizing the many faces of PTSD. Suppl 9, 12–15 Braun A see Bloch M Brawman-Mintzer O, Lydiard RB. Biological basis of generalized anxiety disorder. Suppl 3, 16–26 Bray J see Ravindran AV Brown P. Review of Lande RG, Armitage DT (eds): Principles and Practices of Military Forensic Psychiatry. Nov 500 Brown P, Gold DD Jr. Review of Breier A (ed): The New Pharmacotherapy of Schizophrenia. May 222 Brown P, Gold DD Jr. Review of Brunello N, Racagni G, Langer SZ, Mendlewicz J (eds): Critical Issues in the Treatment of Schizophrenia. Mar 126 Brown RE see Revicki DA Brugha TS, Bebbington PE, Stretch DD, MacCarthy B, Wykes T. Predicting the shortterm outcome of first episodes and recurrences of clinical depression: a prospective study of life events, difficulties, and social support networks. July 298–306 Budech CB see Dunner DL Burns C see Zarate CA Jr Bush T see Katon W Buysse DJ, Reynolds CF III, Houck PR, Perel JM, Frank E, Begley AE, Mazumdar S, Kupfer DJ. Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy? Oct 426–432 Buzan RD see Dubovsky SL Bymaster FP, Rasmussen K, Calligaro DO, Nelson DL, DeLapp NW, Wong DT, Moore NA. In vitro and in vivo biochemistry of

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Baer L, Greist JH. An interactive computeradministered self-assessment and self-help program for behavior therapy. Suppl 12, 23–28 Baer L see Zarate CA Jr Baker CB, Woods SW, Sernyak MJ. Costeffectiveness of divalproex versus lithium [letter with reply]. Aug 363 Baldessarini RJ see Bodkin J; Zarate CA Jr Ballenger JC. Panic disorder in the medical setting. Suppl 2, 13–19 Ballenger JC see Lydiard RB Barkin RL see Fawcett J Barlow DH. Cognitive-behavioral therapy for panic disorder: current status. Suppl 2, 32–37 Barnas C see Praschak-Rieder N Barth EM see Tinsley JA Bauer M, Reischies FM. Reply to Knoll JL IV: Clozapine-related speech disturbance [letter]. May 219–220 Bea C see Dunner DL Beasley CM Jr, Tollefson GD, Tran PV. Efficacy of olanzapine: an overview of pivotal clinical trials. Suppl 10, 7–12 Beasley CM Jr, Tollefson GD, Tran PV. Safety of olanzapine. Suppl 10, 13–17 Beasley CM Jr see Tran PV Bebbington PE see Brugha TS Begley AE see Buysse DJ Bennett JA see Keck PE Jr Benvenga MJ see Moore NA Berigan TR, Cannard AW, Cannard KR. Transient, paroxysmal, shock-like paresthesias associated with paroxetine initiation [letter]. Apr 175–176 Bermanzohn PC, Arlow PB, Pitch RJ, Siris SG. Panic and paranoia [letter with reply]. July 325 Binder RL see Haller E Birkett MA see Thase ME Bisserbe J-C see Flament MF Black DW, Monahan P, Gabel J. Fluvoxamine in the treatment of compulsive buying. Apr 159–163 Black JL see Tinsley JA Bloch M, Stager S, Braun A, Calis KA, Turcasso NM, Grothe DR, Rubinow DR. Pimozideinduced depression in men who stutter. Oct 433–436 Blomgren SL see Thase ME Blumer D. Antidepressant and double antidepressant treatment for the affective disorder of epilepsy. Jan 3–11 Blumer D. Reply to Kaplan M: Affective illness and epilepsy [letter]. Nov 498–499

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olanzapine: a novel, atypical antipsychotic drug. Suppl 10, 28–36 Bystritsky A see Small GW Calabrese JR see Fatemi SH Calis KA see Bloch M Callahan AM see Ketter TA Calligaro DO see Bymaster FP Campeas R see Papp LA Cancro R see Faisal I Cannard AW see Berigan TR Cannard KR see Berigan TR Cantor JJ see Rapaport MH Carpenter D see Kahn DA Carter CS, Servan-Schreiber D, Perlstein WM. Anxiety disorders and the syndrome of chest pain with normal coronary arteries: prevalence and pathophysiology. Suppl 3, 70–75 Casey DE. The relationship of pharmacology to side effects. Suppl 10, 55–62 Castellanos FX, Rapoport JL. Reply to Stein D: Stereotypic movement disorder [letter]. Apr 178 Caulet M see Ohayon MM Chandarana PC see Kraus RP Charney DS see Goddard AW Cherkerzian T see Zarate CA Jr Chopra M see Sasson Y Chouinard G see Marder SR Conley RR see Tamminga CA Cook IA see Leuchter AF Coplan JD see Papp LA Cowley DS, Ha EH, Roy-Byrne PP. Determinants of pharmacologic treatment failure in panic disorder [CME]. Dec 555–561 Cowley DS see Pages KP Cuesta M see Martín J Cukor P see Zarate CA Jr Culpepper L see Revicki DA Currie A see Young AH Dalheim L see Weiden PJ Dantendorfer K see Windhaber J Darby AL see Swartz JR Dardennes RM, Even C. Is divalproex a cost-effective alternative in the acute and prophylactic treatment of bipolar I disorder? [letter with reply] Nov 495–496 Davidson JRT. Biological therapies for posttraumatic stress disorder: an overview. Suppl 9, 29–32 Davidson JRT. Introduction. Repairing the shattered self: recovering from trauma. Suppl 9, 3–4 Davidson JRT. Use of benzodiazepines in panic disorder. Suppl 2, 26–31 Davidson JRT see Shelton RC; Solomon SD Davidson RJ see Kalin NH Davis JM see Marder SR DeLapp NW see Bymaster FP de Leon J, Bork J. Risperidone and cytochrome P450 3A [letter]. Oct 450 de Leon J see Stanilla JK De León OA, Jobe TH, Furmaga KM, Gaviria M. Severe extrapyramidal reaction due to risperidone in a case of neurofibromatosis [letter]. July 323 Delgado PL see Moreno FA Dellva MA see Tran PV den Boer JA. Psychopharmacology of comorbid obsessive-compulsive disorder and depression. Suppl 8, 17–19 den Boer JA see van Vliet IM Denicoff KD, Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM. Comparative prophylactic efficacy of lithium, carbamazepine,

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Flament MF, Bisserbe J-C. Pharmacologic treatment of obsessive-compulsive disorder: comparative studies. Suppl 12, 18–22 Flannery DJ see Findling RL Foa EB. Trauma and women: course, predictors, and treatment. Suppl 9, 25–28 Fogelson DL, Sternbach H. Lamotrigine treatment of refractory bipolar disorder [letter]. June 271–273 Foglia JP see Mammen OK Foschi N see Angeleri F Fournier M see Boulenger J-P Frances A see Kahn DA Franchini L, Gasperini M, Perez J, Smeraldi E, Zanardi R. A double-blind study of long-term treatment with sertraline or fluvoxamine for prevention of highly recurrent unipolar depression. Mar 104–107 Frank E. Enhancing patient outcomes: treatment adherence. Suppl 1, 11–14 Frank E see Buysse DJ Frazer A. Antidepressants. Suppl 6, 9–25 Fredrikson M, Fischer H, Wik G. Cerebral blood flow during anxiety provocation. Suppl 16, 16–21 Friedman MJ. Posttraumatic stress disorder. Suppl 9, 33–36 Frye MA see Altshuler LL Fuller MA, Borovicka MC, Jaskiw GE, Simon MR, Kwon K, Konicki PE. Reply to Lurie SN: Oxybutynin and intranasal desmopressin for clozapine-induced urinary incontinence [letter]. Sept 404 Fuller MA see Popli AP Furmaga KM see De León OA Fyer AJ see Papp LA Gabel J see Black DW Galicia-Polo L see Salín-Pascual RJ Galynker I I, Nazarian D. Akathisia as violence [letter]. Jan 31–32 Galynker I I, Tendler DS. Nizatidine-induced delirium in a nonagenarian [letter]. July 327 Galynker I I, Winston A. Reply to Bermanzohn PC: Panic and paranoia [letter]. July 325–326 Garber A, Gregory RJ. Benztropine in the treatment of venlafaxine-induced sweating [letter]. Apr 176–177 García-Bernardo E see Martín J Gardner DM see Bodkin JA Gardos G. Reversible dyskinesia during bupropion therapy [letter]. May 218 Gasperini M see Franchini L Gaston L see Weiss M Gaviria M see De León OA Gelenberg AJ see Moreno FA Gerritsen AW. Safety in overdose of mirtazapine: a case report [letter]. June 271 Giaquinto S see Angeleri F Gill HS see DeVane CL Gillin JC, Rapaport M, Erman MK, Winokur A, Albala BJ. A comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind, 8-week clinical trial. May 185–192. Correction, June 275 Glazer WM. Olanzapine and the new generation of antipsychotic agents: patterns of use. Suppl 10, 18–21 Glazer WM, Johnstone BM. Pharmacoeconomic evaluation of antipsychotic therapy for schizophrenia. Suppl 10, 50–54 Gleason SD see Moore NA Glover SG. Review of Winokur G, Tsuang MT:

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and the combination in bipolar disorder. Nov 470–478 DeQuardo JR see Lewis CF DeVane CL, Gill HS. Clinical pharmacokinetics of fluvoxamine: applications to dosage regimen design. Suppl 5, 7–14 Dickson J Jr see Bowden CL Disney ER see Denicoff KD D’Mello DA, Rooker GM. Refractory depression, cardiovascular risk factors, and leukoariosis [letter]. June 274 Docherty JP. Barriers to the diagnosis of depression in primary care. Suppl 1, 5–10 Docherty JP see Kahn DA Dominguez RA and Puig A. Olfactory reference syndrome responds to clomipramine but not fluoxetine: a case report [letter]. Nov 497–498 Donovan SJ, Susser ES, Nunes EV, Stewart JW, Quitkin FM, Klein DF. Divalproex treatment of disruptive adolescents: a report of 10 cases. Jan 12–15 Drucker-Colín R see Salín-Pascual RJ DuBose C see Lewis CF Dubovsky SL, Buzan RD. Novel alternatives and supplements to lithium and anticonvulsants for bipolar affective disorder [CME]. May 224–242 Dunkin J see Leuchter AF Dunner DL, Hendrickson HE, Bea C, Budech CB. Venlafaxine in dysthymic disorder. Dec 528–531 Edmonds MW see Kraus RP Eisen JL see Rasmussen SA Emsley RA see Stein DJ Engelbrektson K see Tham A Erman MK see Gillin JC Even C see Dardennes RM Faber RA. Asystole in ECT [letter]. Dec 550 Faisal I, Lindenmayer JP, Taintor Z, Cancro R. Clozapine-benzodiazepine interactions [letter]. Dec 547–548 Fallon BA see Papp LA Fatemi SH, Rapport DJ, Calabrese JR, Thuras P. Lamotrigine in rapid-cycling bipolar disorder. Dec 522–527 Fava GA, Savron G, Grandi S, Rafanelli C. Cognitive-behavioral management of drugresistant major depressive disorder [CME]. June 278–282 Fawcett J. The detection and consequences of anxiety in clinical depression. Suppl 8, 35–40 Fawcett J, Barkin RL. Efficacy issues with antidepressants. Suppl 6, 32–39 Fawcett RG. Dose-related thrombocytopenia and macrocytic anemia associated with valproate use in bipolar disorder [letter]. Mar 125 Feifel D, Young CW. Iron overload among a psychiatric outpatient population. Feb 74–78 Feiger A see Kiev A Feiner NF. Antiepileptic drug augmentation for treatment-resistant depression [letter with reply]. Aug 361–362 Feldman-Naim S, Rosenthal NE. A case of seasonal trichotillomania [letter]. May 218–219 Feldman-Naim S, Turner EH, Leibenluft E. Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder. Feb 79–84 Feldman-Naim S see Leibenluft E Findling RL, Schwartz MA, Flannery DJ, Manos MJ. Reply to Smith MW: Pharmacologic properties of venlafaxine [letter]. Apr 178 Fischer H see Fredrikson M Fischer P see Vesely C



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The Natural History of Mania, Depression and Schizophrenia. Sept 408 Goddard AW, Charney DS. Toward an integrated neurobiology of panic disorder. Suppl 2, 4–12 Godleski LS see Sernyak MJ Goessler R see Vesely C Gold DD Jr. Review of Matthysse S, Levy DL, Kagan J, Benes FM (eds): Psychopathology: The Evolving Science of Mental Disorder. Oct 454–455 Gold DD Jr see Brown P Gómez JC see Martín J Gonen N see Spivak B Gonzales J see Revicki DA Goodman WK, Ward H, Kablinger A, Murphy T. Fluvoxamine in the treatment of obsessivecompulsive disorder and related conditions. Suppl 5, 32–49 Gorman JM. The use of newer antidepressants for panic disorder. Suppl 14, 54–58 Gorman JM see Papp LA Grandi S see Fava GA Green TR. Bupropion for SSRI-induced fatigue [letter]. Apr 174 Gregory RJ see Garber A Greist JH see Baer L Greist JH see Jefferson JW Griffin RA see Sernyak MJ Gross S see Simeon D Grothe DR see Bloch M Gurpegui M see Martín J Ha EH see Cowley DS Haddad P. Newer antidepressants and the discontinuation syndrome. Suppl 7, 17–22 Haddad P see Schatzberg AF Hagimoto H see Hanihara T Halbreich U, Smoller JW. Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome. Sept 399–402 Halbreich U see Shelton RC Hales RE, Hilty DA, Wise MG. A treatment algorithm for the management of anxiety in primary care practice. Suppl 3, 76–80 Hales RE see Revicki DA Haller E, McNiel DE, Binder RL. Reply to Pearlman T: Impact of a smoking ban on a locked psychiatric unit [letter]. Apr 179 Hanihara T, Amagai I, Hagimoto H, Makimoto Y. Hypouricemia in chronic schizophrenic patients with polydipsia and hyponatremia. June 256–260 Harrison WM see Lydiard RB Hartley S. Guideline series commentary [letter with reply]. Oct 453 Harvey AT see Shad MU Hawkins JM see Strakowski SM Hawkins JW. Antidepressant effects of nicotine [letter with reply]. July 324 Hawkridge S see Stein DJ Hays P. Paroxetine prevents migraines [letter]. Jan 30–31 Hendler T see Sasson Y Hendrickson HE see Dunner DL Hertzman M see Lydiard RB Hesselink JK see Sambunaris A Hesselmann B see Praschak-Rieder N Hilty DA see Hales RE Hirschfeld RMA. Pharmacotherapy of borderline personality disorder. Suppl 14, 48–52 Hollander E. Introduction. Obsessive-compulsive disorder: the hidden epidemic. Suppl 12, 3–6 Hollander E see Josephson SC; Simeon D Ho Pian KL see van Vliet IM

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Keck PE Jr, Bennett JA, Stanton SP. Reply to Dardennes RM: Is divalproex a cost-effective alternative in the acute and prophylactic treatment of bipolar I disorder? [letter] Nov 495–496 Keck PE Jr, McElroy SL. New uses for antidepressants: social phobia. Suppl 14, 32–36 Keck PE Jr see Nelson EB; Shapira NA; Strakowski SM Keitner GI see Solomon DA Keller MB. Introduction: advances in the management of chronic depressive and anxiety disorders. Suppl 13, 3–4 Keller MB. Introduction: new uses for antidepressants. Suppl 14, 3 Keller MB see Revicki DA; Solomon DA Kelsey JE. Switching drug class after initial SSRI failure [letter]. July 326–327 Ketter TA, Callahan AM, Post RM. Reply to Feiner NF: Antiepileptic drug augmentation for treatment-resistant depression [letter]. Aug 362–363 Kiesler G see Tran PV Kiev A, Feiger A. A double-blind comparison of fluvoxamine and paroxetine in the treatment of depressed outpatients. Apr 146–152 Kirola DB. Review of Davidson T: Trust the Force: Change Your Life Through Attitudinal Healing. Feb 90–91 Klein DF see Donovan SJ; Papp LA Knoll JL IV. Clozapine-related speech disturbance [letter with reply]. May 219 Knoll JL IV see Lee AM Konicki PE see Fuller MA; Popli AP Koran LM see Shelton RC; Williams KE Korff MV see Katon W Kornstein SG. Gender differences in depression: implications for treatment. Suppl 15, 12–18 Kraus RP, Phoenix E, Edmonds MW, Nicholson IR, Chandarana PC, Tokmakejian S. Exaggerated TSH responses to TRH in depressed patients with “normal” baseline TSH. June 266–270 Kupfer DJ. Introduction. Management of depression: a successful continuum of care. Suppl 1, 3–4 Kupfer DJ see Buysse DJ Kwon K see Fuller MA Lasser RA see Bodkin JA Lauterbach EC, Meyer JM, Simpson GM. Clinical manifestations of dystonia and dyskinesia after SSRI administration [letter with reply]. Sept 403 Lauterbach EC, Shillcutt SD. Dyskinesia with fluoxetine: tardive or late-onset persistent, acute norfluoxetine dyskinesia? [letter with reply] Feb 85–86 Lavallée Y-J see Boulenger J-P Leahy L see Zarate CA Jr Leander JD see Moore NA Lee AM, Knoll JL IV, Suppes T. The atypical antipsychotic sertindole: a case series [CME]. Sept 410–416 Leibenluft E. Issues in the treatment of women with bipolar illness. Suppl 15, 5–11 Leibenluft E, Feldman-Naim S, Turner EH, Wehr TA, Rosenthal NE. Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. Sept 383–388 Leibenluft E see Feldman-Naim S Lejoyeux M, Adès J. Antidepressant discontinuation: a review of the literature. Suppl 7, 11–16

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Horn SD. Overcoming obstacles to effective treatment: use of clinical practice improvement methodology. Suppl 1, 15–19 Hornig-Rohan M see Szuba MP Hosmer C see Lurie SN Houck PR see Buysse DJ Howard MO, Walker RD. Review of McGovern G: Terry: My Daughter’s Life and Death Struggle With Alcoholism. July 328 Hughes AR see Kavoussi RJ Hunter BN see Ravindran AV Hwang J-P see Tsai S-J Iancu I see Sasson Y Ibatoullina E, Praschak-Rieder N, Kasper S. Severe atypical symptoms without depression in SAD: effects of bright light therapy [letter]. Nov 495 Irwin W see Kalin NH Islam N see Simeon D Jaskiw GE see Fuller MA; Popli AP Jefferson JW. Antidepressants in panic disorder. Suppl 2, 20–25 Jefferson JW, Greist JH, Katzelnick DJ. Continuing dialogue on incentive bias [letter with replies]. Oct 450–452 Jobe TH see De León OA Johnson CG see Littrell KH Johnson L see Tham A Johnstone BM see Glazer WM Johnston JA see Kavoussi RJ Josephson SC, Hollander E. Body dysmorphic disorder by proxy [letter]. Feb 86–87 Judge R see Ravindran AV Jurjus GJ see Popli AP Kablinger A see Goodman WK Kahn DA, Docherty JP, Frances A, McEvoy JP, Weiden PJ, Carpenter D. Reply to Weiss KM; Hartley S: Guideline series commentary [letter]. Oct 453 Kalin NH. Introduction: functional brain alterations in depression and anxiety. Suppl 16, 3 Kalin NH, Davidson RJ, Irwin W, Warner G, Orendi JL, Sutton SK, Mock BJ, Sorenson JA, Lowe M, Turski PA. Functional magnetic resonance imaging studies of emotional processing in normal and depressed patients: effects of venlafaxine. Suppl 16, 32–39 Kaplan EM. Antidepressant noncompliance as a factor in the discontinuation syndrome. Suppl 7, 31–36 Kaplan EM see Schatzberg AF Kaplan M, Privitera M. Affective illness and epilepsy [letter with reply]. Nov 498 Kara H see Agargün MY Kasper S see Ibatoullina E; Praschak-Rieder N; Vesely C Katerndahl DA, Realini JP. Quality of life and panic-related work disability in subjects with infrequent panic and panic disorder. Apr 153–158 Katon W, Korff MV, Lin E, Simon G, Walker E, Bush T, Ludman E. Collaborative management to achieve depression treatment guidelines. Suppl 1, 20–23 Katon W see Roy-Byrne PP Katzelnick DJ see Jefferson JW Kavoussi RJ, Segraves RT, Hughes AR, Ascher JA, Johnston JA. Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients. Dec 532–537 Kazim A see Solomon DA Keck PE Jr, Bennett JA, Stanton SP. Reply to Baker CB: Cost-effectiveness of divalproex versus lithium [letter]. Aug 364

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Lejoyeux M, Tassain V, Solomon J, Adès J. Study of compulsive buying in depressed patients. Apr 169–173 Lejoyeux M see Schatzberg AF Leonard HL. New developments in the treatment of obsessive-compulsive disorder. Suppl 14, 39–45 Leo RJ. Reply to Lauterbach EC: Clinical manifestations of dystonia and dyskinesia after SSRI administration [letter]. Sept 403–404 Lesser IM see Swartz JR Leuchter AF, Cook IA, Uijtdehaage SHJ, Dunkin J, Lufkin RB, Anderson-Hanley C, Abrams M, Rosenberg-Thompson S, O’Hara R, Simon SL, Osato S, Babaie A. Brain structure and function and the outcomes of treatment for depression. Suppl 16, 22–31 Leverich GS see Denicoff KD Lewis CF, DeQuardo JR, DuBose C, Tandon R. Acute angle-closure glaucoma and paroxetine [letter]. Mar 123–124 Lieberman JA III. BATHE: an approach to the interview process in the primary care setting. Suppl 3, 3–8 Liebowitz MR. Panic disorder as a chronic illness. Suppl 13, 5–8 Liebowitz MR see Papp LA Lindenmayer JP see Faisal I Lin E see Katon W Littrell KH, Johnson CG, Littrell SH, Peabody CD. Effects of olanzapine on polydipsia and intermittent hyponatremia [letter]. Dec 549 Littrell SH see Littrell KH Liu K-M see Tsai S-J Llewellyn AM, Stowe ZN, Nemeroff CB. Depression during pregnancy and the puerperium. Suppl 15, 26–32 Lowe M see Kalin NH Lucot JB see Shad MU Ludman E see Katon W Lufkin RB see Leuchter AF Lurie SN, Hosmer C. Oxybutynin and intranasal desmopressin for clozapine-induced urinary incontinence [letter with reply]. Sept 404 Lustig M see Sasson Y Lydiard RB. Anxiety and the irritable bowel syndrome: psychiatric, medical, or both? Suppl 3, 51–61 Lydiard RB, Ballenger JC, Rickels K. A doubleblind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Suppl 11, 11–18 Lydiard RB, Stahl SM, Hertzman M, Harrison WM. A double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression. Nov 484–491 Lydiard RB see Brawman-Mintzer O; Rickels K Lynch CF see Philibert RA MacCarthy B see Brugha TS Maierhofer D see Windhaber J Makimoto Y see Hanihara T Mammen OK, Perel JM, Rudolph G, Foglia JP, Wheeler SB. Sertraline and norsertraline levels in three breastfed infants. Mar 100–103 Manfro GG see Pollack MH Manning JS. Review of American Psychiatric Association: DSM-IV Primary Care Version. Feb 90 Manos MJ see Findling RL Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of

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