Although risperidone seems to be a safe and effective treatment for the management of psychotic symptoms, its acquisition cost is considerably higher than that ...
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Risperidone: Clinical Outcome Predictors and Cost-Effectiveness in a Naturalistic Setting Patrick R. Finley, Pharm.D., BCPP, 1 Barbara R. Sommer, M.D., 2 Joseph L. Corbitt, M.S., R.Ph.,3 Gregory H. Brunson, Pharm.D., 4 and Bert L. Lum, Pharm.D. 5 Abstract Although risperidone seems to be a safe and effective treatment for the management of psychotic symptoms, its acquisition cost is considerably higher than that of conventional antipsychotics, and its precise role in managing psychiatric illnesses has yet to be defined. The purpose of this investigation was to examine the relationship of patient demographic variables to therapeutic outcomes and to analyze the financial impact of risperidone on the treatment of psychotic symptoms. Subjects included in this 2-year, retrospective cohort, intent-to-treat analysis were all patients initiated on risperidone therapy at an inpatient psychiatric treatment facility. Clinical outcomes were assessed from the absolute change in hospitalized days, total number of psychotropic medications prescribed, and historic Clinical Global Impression severity scores. Logistic regression analysis was conducted to analyze the potential relationship to certain demographic variables to therapeutic response. The cost-benefit analysis compared the direct treatment costs incurred by the institution before and after risperidone initiation. Of the 66 patients originally started on risperidone, 57 completed a therapeutic trial. A clinical response was evident in 54 percent of these patients overall. Logistic regression analysis identified previous treatment intolerance and a negative history of substance abuse as predictive of therapeutic success with risperidone (p:.0006 and p:.01, respectively). Hospitalization rates declined by 43 percent among treatment responders and by 1.3 percent among nonresponders resulting in a net annual savings of $147,962. Psychopharmacology Bulletin 34(1 ):75-81, 1998. Keywords: risperidone, schizophrenia, cost-effectiveness, atypical antipsychotics, outcomes. 1
Department of Clinical Pharmacy, University of California at San Francisco, San Francisco, CA. Geriatric Psychiatry Program, Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, CA. 3 Psychiatry, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA. 4 United Behavioral Health, San Francisco, CA. 5 University of the Pacific, School of Pharmacy, Stockton, CA. 2
Reprint requests: Dr. Patrick R. Finley, 521 Parnassus, Room C-152, University of California, San Francisco, CA 94143-0622.
Risperidone may be efficacious in many patients who had previously failed antipsychotic trials. Patients who had been unable to tolerate traditional antipsychotics and those who lacked a documented history of substance abuse were uniquely responsive to risperidone treatment. The significant decline in hospitalized days that was observed among responsive patients seems to indicate that risperidone may be a cost-effective approach to the management of psychotic symptoms.
Introduction Although the lifetime incidence of schizophrenia is comparatively low (e.g., less than 1% of the general population is afflicted), the combined direct and indirect care costs are estimated to exceed $32.5 billion annually in the United States (Sevy & Davidson 1995). Much of this financial burden may be attributed to the severe limitations of traditional pharmacological agents. Conventional antipsychotic compounds are effective in only 60 to 70 percent of patients diagnosed with schizophrenia (Kane 1987), and adverse effects are extremely common and occasionally prohibitive. Because of these side effects, noncompliance with antipsychotic medications is a frequent occurrence among schizophrenia patients, contributing to high rates of recidivism (Corrigan et al. 1990). Clozapine, the first atypical antipsychotic approved by the Food and Drug Administration, has been heralded as a historic breakthrough in the management of schizophrenia. With a unique mechanism of action, clozapine is virtually free of the adverse neurological sequelae commonly associated with conventional agents (e.g., extrapyramidal reactions and tardive dyskinesia) and it seems to be particularly efficacious in patients who are intolerant or unresponsive to older compounds. Unfortunately, clozapine has its own unique sideeffect profile, inducing sedation, sialorrhea, weight gain, and, most important, leukopenia. The high cost of this medication and the mandatory weekly blood monitoring further discourage the use of clozapine as a first-line agent for psychotic symptoms. Nevertheless, clozapine has been demonstrated to be a cost-effective remedy for schizophrenia, with significant savings attributed to a dramatic decline in hospitalization rates (Meltzer et al. 1993; Revicki et al. 1990). As the second atypical antipsychotic released in North America, risperidone also possesses a pharmacological profile that is distinct from older agents. Like clozapine, risperidone is unlikely to induce debilitating neurological effects and may be of therapeutic benefit for certain schizophrenia patients. For example, short-term double-blind comparative trials with haloperidol have revealed substantial reductions in the positive and negative symptoms of schizophrenia, and in daily doses of 6 mg or less, risperidone was associated with an incidence of extrapyramidal side effects that was statistically indistinguishable from that for placebo (Borison et al. 1992; Chouinard et
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al. 1993; Marder & Meibach 1994). An additional advantage to risperidone treatment is the absence of hematological toxicity, obviating the need for weekly blood monitoring that currently complicates clozapine therapy. Although risperidone may be an appealing· addition to the antipsychotic roster, its wholesale acquisition costs are substantially higher than those of traditional compounds and have already inflated mental health care budgets. Studies examining the financial impact of risperidone on disease management have been small, brief, and inconclusive, and consequently, the cost-effectiveness of this new agent remains largely unknown (Addington et al. 1993; Albright et al. 1996; Lindstrom et al. 1995). Information regarding a differential response in certain patient populations is also scarce, but could be influential in ensuring the most judicious use of risperidone in clinical practice (Keck et al. 1995). In an effort to determine the financial and clinical impact ofrisperidone on the treatment of psychotic symptoms in a veteran population, we undertook the naturalistic intent-to-treat analysis of cost factors and demographic variables described in this article.
Methods
Subjects included in this retrospective investigation were all adult patients initiated on risperidone therapy at the inpatient psychiatric facility of the Department of Veterans Affairs (VA) Palo Alto Health Care System, Menlo Park Division. As the clinical use of risperidone was subject to explicit prescribing guidelines at this institution, all patients were demonstrated (and verified by the authors: PF and JC) to satisfy one of the following criteria before initiation of therapy: (1) treatment resistance, defined as failure to respond to a dose of at least 500 mg of chlorpromazine equivalents of two different conventional antipsychotics after a minimum of 6 weeks of continuous therapy, or (2) treatment intolerance, defined as the emergence of moderate to severe tardive dyskinesia or extrapyramidal effects unresponsive to dosage reduction of the antipsychotic or the administration of anticholinergic agents. Once approved, patients were tapered off previous antipsychotic agents over a period of 1 to 7 days and initiated on the manufacturer's recommended starting dose for risperidone, depending on their age and liver or kidney function. Patients' doses of risperidone were rapidly titrated in the inpatient setting, with maintenance dose requirements ultimately determined by evidence of a therapeutic response or medication intolerability. On discharge, the patients' progress was followed in VA outpatient mental health facilities by licensed therapists. For patients discharged to facilities outside the VA Palo Alto catchment area, regular contact was initiated with the treating clinician or other.responsible parties, such as relatives, spouses, or case managers.
Clinical Outcome Analysis
We collected data for the outcome analysis from a combination of institutional compute1ized resources, inpatient and outpatient treatment records, and telephone contact with mental health providers. As this was a retrospective analysis, we were unable to implement any routine clinical outcome instruments (e.g., Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale) into the study protocol. The patients were considered, therefore, to be therapeutic responders a priori if they continued to receive risperidone for the entire 12-month period (after the 2-week dose-stabilization phase). The population of patients who did not fit the criteria for therapeutic response were individuals who were (1) unresponsive to treatment (as documented by the prescribing physician after a minimum of 2 weeks of continuous treatment), (2) intolerant of medication, or (3) noncompliant with psychiatric treatment or otherwise lost to followup. We used several measures to assess the effect of medication and also to validate our operational definition of therapeutic response. These measures included the number of hospitalized days in the 12 months before and after risperidone initiation, change in the number of psychotropic medications concurrently prescribed, and change in historic Clinical Global Impressions (CGI; National Institute of Mental Health 1985). Hospitalized days were calculated by dete1mining the number of days hospitalized in an acute care psychiatric facility for the 12 months immediately preceding risperidone therapy and for the 12 months after the 2-week dose-stabilization phase. Historic CGI scores were determined from documented evidence of patient progress in the medical record just before active treatment and at the time of dose stabilization or discharge. Similarly, the number of psychotropic medications was compiled from the patient's medication regimen before starting risperidone and at the time of discharge. Psychotropic medications included all antipsychotic medications, antidepressants, mood stabilizers, anxiolytics, and agents used for the management of antipsychotic side effects. The specific demographic variables included age, primary psychiatric diagnosis (DSM-W criteria, Axis I; American Psychiatric Association 1994), pretreatment history, history of substance abuse, and indication for risperidone therapy (i.e., treatment-intolerant vs. treatment-resistant). Pretreatment history was evaluated by a review of the number of days hospitalized during the 12 months prior to risperidone and by the number of previous documented antipsychotic medication hials before active treatment. A total of 66 subjects met prescribing guideline criteria and were sta1ied on risperidone therapy; 57 were included in the entire analysis. All subjects were male, and the average age at the time of initiation was 45.8 years (range, 28-70). Chronic schizophrenia (paranoid, disorganized, and undifferentiated)
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was the most common Axis I diagnosis (31), followed by schizoaffective disorder (18), bipolar affective disorder (5), and depression with psychotic features (3). Economic Outcome Analysis Measurement of direct care costs included estimates of inpatient expenditures and wholesale acquisition costs of the medication. · Total inpatient expenditures were estimated from the product of hospitalization rates and financial data obtained from the administrative offices of the department of psychiatty at this medical center and pertained to inpatient psychiatric services rendered during the previous fiscal year (1994-1995). The average wholesale costs of risperidone also reflect the acquisition costs incurred at this medical center and may be lower than those encountered in the private sector. Statistical Analysis Data were tested for normality using the Wilk-Shapiro statistic. The Wilcoxon signed rank test was used to test the potential differences between paired data (i.e., before and after risperidone treatment for such variables as the number of days hospitalized, the number of psychotropic medications prescribed, and CGI severity scores). Unpaired data within groups (such as between responders and nonresponders) were tested for significant differences using the Mann-Whitney rank sum test. Nominal data (such as the proportion having a specified outcome between groups) were tested for significance with the Yate's corrected chi-square analysis of the Fisher exact test for small samples. The identification of variables significantly influencing the dependent variable, or probability of response (such as age, diagnosis, and pretreatment functioning), was assessed by univariate fogistic regression analysis. The a priori level of significance was set at p=.05.
Of the 50 evaluable subjects, 27 continued to receive risperidone for the entire 12-month post-treatment period and were therefore considered to be therapeutic responders. The average daily dose for these patients was 6.0 mg (SD = 1.2) at the end of the study period. For the 23 subjects who did not exhibit a therapeutic response, mean duration of medication treatment was 37 .2 days, and the mean maximum daily dose achieved was 6.2 mg (SD = 1.9). Clinical Outcome Analysis Hospitalization rates for therapeutic responders declined by 42.6 percent on average (43.9 days before risperidone and 25.2 days after risperidone), whereas those of nonresponders declined by 1.3 percent (59.1 days before, 58.3 days after; se~ Table 1). When analyzed by the Mann-Whitney U test, the difference between these two groups did not achieve statistical significance (p=.096). A reduction in CGI scores was observed for responders and nonresponders, though the difference was greatest among responsive patients (Mann-Whitney U test; p=.001). A decline in the number of concurrent psychotropic medications was also apparent in both patient groups (p=.984). We also analyzed the potential association of certain demographic variables to positive treatment outcome (i.e., continued therapy for 12 months) (Table 2). From a chi-square analysis, the two variables that appeared to be of greatest prognostic value were (1) treatment intolerance to previous antipsychotics (p=.006; chi-square= 11.7; df=l) and (2) a negative history of substance abuse (p=.0097; chi-square = 6.7; df=l). Among patients with a history of treatment intolerance as an indication for risperidone, 89 percent exhibited a therapeutic response to the atypical antipsychotic. By comparison, only 34 percent of patients with an indication of treatment TABLE 1. Chi-Square Analysis of Clinical Outcomes for Patients Receiving a Therapeutic Trial of Risperidone (n=50).
Results Of the 66 patients initiated on risperidone, 50 received a minimum trial of 14 days of continuous tt·eatment and had complete medical record data permitting study inclusion. Seven patients did not receive a minimum trial because of the emergence of intolerable adverse effects but were included in the statistical analysis when applicable. The side effects necessitating discontinuation of risperidone included sedation (2), syncope, dizziness, increased depression, nightmares, and emesis. Of the remaining 9 patients excluded from analysis, 3 received an inadequate trial (i.e., left the facility against medical advice) and 6 were lost to followup.
Score Outcome Measure
Before
After
pValue
Days hospitalized (12-month period) Responders Nonresponders
43.9 59.1
25.2 58.3
.030* .447
CGI severity scores Responders Nonresponders
5.04 4.91
3.96 4.39
.0001 * .015*
Concurrent psychotropic medications Responders Nonresponders
3.3 3.3
2.6 2.7
.017* .029*
CGI ~ Clinical Global Impressions Rating Scale. • Statistically significant difference (p 3 trials) 43.7% (7/16)
.488
* Statistically significant difference (ps.05).
resistance continued to receive risperidone for a full 12 months of therapy. Patients without a history of substance abuse had an 82 percent response rate, in comparison with a response rate of 39 percent for those who had such a history. Univariate logistic regression analysis confirmed these results. For treatment-intolerant patients, the odds ofresponding were 9.7 times higher than for those who had been treatment resistant (p=.002), and the odds of responding for patients without a history of substance abuse were 7.2-fold higher than those with a positive history (p=.006). Analysis of patients with a primary psychiatric diagnosis of chronic schizophrenia revealed that 59.3 percent responded to risperidone. This success rate was only slightly higher than that observed in patients with a history of affective disorders (47.8%), and this difference did not achieve statistical significance (chi-square analysis,p=.793). Older subjects (at least 50 years of age) exhibited a mild trend toward better outcome than younger subjects (66.7% response rate vs. 58.3%), as did subjects who had received fewer than three previous medication trials. Neither of these two factors, or any other demographic variables, demonstrated a prognostic value of statistical significance.
Economic Outcome Analysis We assessed the potential cost efficacy of risperidone by comparing the savings associated with reduced hospitalization
rates with the acquisition costs of the medication (Table 3). The total cost of medication was calculated from data pertaining to all evaluable patients (n=57). As the average dose of medication was approximately 3 mg twice daily in therapeutic responders, we multiplied the wholesale cost of a 3-mg tablet ($2.51) by the number of responsive patients (27) and the number of doses annually administered to each patient (2 tablets per day X 365 days= 730 tablets) to arrive at an annual cost of $49,472. For the other subjects (nonresponders and dropouts due to side effects), the cost of a tablet ($2.51) was multiplied by the number of patients (30), the number of daily doses (2), and the average length of a medication trial (37.2 days), resulting in an acquisition cost of $5,602. Therefore, the total annual acquisition cost of risperidone in this intent-totreat analysis was $55,074. The potential changes in hospitalization rates were calculated for the evaluable subjects who completed a medication trial (patients withdrawing because of side effects were not included in this portion of this analysis since it was determined that the natural course of the illness would not be affected by brief medication intervention). The total number of inpatient days decreased from 2,547 before risperidone to 2,021 days after, a decline of 526 inpatient days overall. At the time of this inves.tigation, the direct cost of inpatient psychiatric hospitalization was estimated to be $386 daily per patient. Therefore the total decline in direct hospitalization costs yielded a savings of $203,036. A net savings of $147,962 was calculated for the institution.
Discussion The patient outcome data presented suggest that differential patterns of response may be evident among certain patient populations, and that substantial reduction in hospitalization rates may justify the high acquisition costs associated with risperidone. These results should be interpreted with caution, howevTABLE 3. Economic Outcome Analysis of All ~atients Initiated on Risperidone Therapy (n=57). Annual cost of medication Responders: 27 patients x 365 days x 2 tablets/day x $2.51/tablet Nonresponders: 30 patients x 37.2 days x 2 tablets/day x $2.51/tablet Total Annual Cost of Medication
$49,472 $5,602 $55,074
Annual cost savings with reduced hospitalization Total number of inpatient days (pretreatment) Total number of inpatient days (posttreatment) Net change in number of inpatient days Net change in cost of hospitalization: $386/patienl/day x 526 days
$203,036
Annual savings associated with risperidone trial
$147,962
2,547 2,021 (-) 526
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er, because of the retrospective nature of this study. One cannot be certain, for instance, that the decline in hospitalization rates observed among patients who continued to receive risperidone was due to the therapeutic effects of the medication: The statistical analysis of demographic characteristics in this study served to provide preliminary observations on specific patient populations that were more likely to continue receiving the medication. Previous treatment intolerance of conventional antipsychotics (as an indicator for risperidone treatment) was a strong predictor of positive therapeutic outcome, with an odds ratio of 9.7 determined by logistic regression analysis. A negative history of substance abuse was also a favorable demographic descriptor, with an odds ratio of 7 .2. A neurochemical explanation for the superior response of treatment-intolerant patients is not foithcoming but may have important implications regarding the pathophysiology of schizophrenia. This trend has been documented in several studies featuring clozapine (Claghorn et al. 1987; Lieberman et al. 1994; Owen et al. 1989; Pickar et al. 1994). For example, Lieberman and colleagues (1994) compared the clinical effects of clozapine in 66 patients with a history of treatment resistance with clinical effects of 18 patients who had a history of treatment intolerance. After 52 weeks of therapy, 76 percent of the treatment-intolerant group responded to therapy (as measured by total Brief Psychiatric Rating Scale [Overall & Gorham 1988] and CGI scores), and 50 percent of treatmentresistant patients had a favorable outcome. Keck and colleagues (1995) examined the effects of risperidone in patients diagnosed with schizophrenia, as well as schizoaffective disorder and psychotic mood disorders. They reported no apparent association between previous treatment intolerance and a positive therapeutic response but proposed that the small sample size might have given rise to Type II error. The apparent association between a negative history of substance abuse and superior clinical outcome was also quite strong. Previous studies with conventional neuroleptics in schizophrenia have reported an association between substance abuse and poor treatment outcomes (Haywood et al. 1995; Sokolski et al. 1994; Turner & Tsuang 1990), but other investigations have found no differences (Buckley et al. 1994; Zisook et al. 1992). The potential efficacy of atypical antipsychotics among substance abusers has been analyzed in only one study (Bowers et al. 1990), which reported similar improvements with clozapine treatment among substance abusers and nonabusers alike. As clozapine patients have more frequent contact with mental health providers, it is possible that the incidence of substance abuse may decline under these conditions. Noncompliance among substance abusers may have contributed to poor treatment outcome. Alternatively, chronic substance abuse itself may lead to medication refractoriness. For example, there is evidence that certain illicit substances may have irreversible effects on dopaminergic neurons in psychotic patients (Bowers et al. 1990).
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Another objective of this study was to make a preliminary assessment of the cost effectiveness of risperidone through a partial cost-benefit analysis. For the 57 evaluable patients, a net savings of $147,962 was projected for the institution, representing an annual savings of $2,596 per patient initiated on risperidone regardless of outcome. In subjects exhibiting a therapeutic response, a net annual savings of $5,424 per patient was estimated. Although there are many other direct costs associated with the long-term management of schizophrenia patients (i.e., outpatient treatment costs, housing costs, and laboratory monitoring), a previous cost justification study with clozapine (Meltzer et al. 1993) clearly demonstrated that the impact of antipsychotic medication on hospitalization rates had the strongest economic influence on cost effectiveness. The decline in hospitalization rates among responsive patients was substantial in our study and appeared to be greater than that observed among nonresponders. This apparent difference between the two groups did not achieve statistical significance, however. To date, there have been three published studies analyzing the effect of risperidone on hospitalization rates in schizophrenia patients. Addington and co-workers (1993) conducted a retrospective evaluation of risperidone's effectiveness from c!ata gathered during Phase III trials and reported a decline in the mean number of hospitalized days per patient from 106 to 85 annually. Of the 74 patients originally described in this study, 47 withdrew prematurely, and the statistical outcome focused therefore entirely on the remaining 27 subjects. Lindstrom and colleagues (1995) conducted a 2-year openlabel investigation examining the long-term efficacy and safety of risperidone in a population of chronic schizophrenia patients. From a pool of 88 subjects enrolled in the original 8week comparative trial with haloperidol, 18 were included in the 2-year outpatient study, with the authors reporting a 54 percent decline in hospitalization rates (166 days to 77 days). The impact of risperidone on hospitalization rates in Lindstrom's study was quite similar to our own but their failure to account for the vast majority of subjects who were originally enrolled makes comparisons with our intent-to-treat analysis quite difficult. More recently, the impact of risperidone on resource utilization was studied in a population of 146 patients with chronic sc~zophrenia in the Canadian province of Saskatchewan (Albright et al. 1996). The length of hospital stay declined by 58 percent among these patients during the 10 months after risperidone introduction (compared with the preceding 10 months). Unfortunately, this retrospective investigation did not include any clinical measures of outcome and failed to account for treatment failures. Overall, 54 percent of the subjects included in our analysis exhibited a therapeutic response to risperidone, which is similar to the results of prospective studies currently available in the medical literature. Marder and Meibach (1994) coordinat-
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ed a large multicenter ·study of risperidone in 388 chronic schizoplu·enia patients and reported a 57 percent response rate among subjects assigned to a fixed dose of 6 mg daily. Examining the effects of risperidone in subjects with thought and mood disorders, Keck and colleagues (1995) discovered a 58 percent responserate among all subjects (n=144) and also noted a superior therapeutic outcome among patients diagnosed with bipolar disorder or schizoaffective illness, depressed subtype. Additional limitations inherent in our study design are worthy of mention and may restrict the generalizability of our findings. The patient population, for example, was rather homogeneous, consisting entirely of hospitalized male veterans, and extrapolations of results from this study may not apply to other patient populations. The small sample size may have also limited the significance of our results, and the retrospective nature of data collection may introduce biases that we are unable to identify or adjust for. For instance, one compre, hensive review of cost-effectiveness studies with atypical 1 antipsychotics (Hargreaves & Shumway 1996) noted that retrospective "mirror-image" design studies such as our own often show a favorable impact on patient outcomes because subjects begin receiving the study medication at a time when their symptoms are most severe and resource utilization is highest (i.e., regression-to-the-mean phenomenon). It could also be argued that the robust decline in hospitalization rates that we observed among responsive patients may be due to a growing emphasis in health care on outpatient treatment and reduced lengths of hospital stay. Hospitalization rates among nomesponders remained virtually unchanged in our study, however, reducing the likelihood of these scenarios. In the future, it is hoped that a large long-term randomized controlled comparison may be conducted to further distinguish the benefits of this and other atypical antipsychotic medications.
Conclusions
The results of this naturalistic study indicate that risperidone may be an effective alternative for the management of psychotic symptoms in patients for whom conventional antipsychotics had previously failed. Analysis of multiple demographic variables revealed that subjects with a history of treatment intolerance to traditional agents and those who lacked a documented history of substance abuse were much more likely to respond to risperidone than other patients. The significant decline in hospitalization rates that was observed after initiation of risperidone may justify the substantial acquisition costs of this medication and render it a cost-effective approach to the treatment of individuals suffering from psychotic symptoms.
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Revicki, DA; Luce, BR; Weschler, JM; Brown, RE; and Adler, MA. Cost-effectiveness of clozapine for treatment-resistant schizophrenic patients. Hosp. Community Psychiatly 41:850-854, 1990. Sevy, S, and Davidson, M. The cost of cognitive impairment in schizophrenia. Schizoph1: Res. 17:1-3, 1995. Sokolski, KN; Cummings, JL; Abrams, BI; DeMet, EM; Katz, LS; and Costa, JF. Effects of substance abuse on hallucination rates and treatment responses in chronic psychiatric patients. J, Clin. Psychiat1y 55:380-387, 1994. Turner, WM, and Tsuang, MT. Impact of substance abuse on the course and outcome of schizophrenia. Schizop/11: Bull. 16:87-95, 1990. Zisook, S; Heaton, R; Moranville, J; Kuck, J; Jernigan, T; and Braff, D. Past substance abuse and clinical course of schizophrenia. Am. J. Psychiat1y 149:552-553, 1992.
