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C 2004), pp. 193–208 Cognitive Therapy and Research, Vol. 28, No. 2, April 2004 (°

Benzodiazepine Use Associated With Decreased Memory for Psychoeducation Material in Cognitive Behavioral Therapy for Panic Disorder Henny A. Westra,1,6 Sherry H. Stewart,2 Michael Teehan,1,3 Karen Johl,3 David J. A. Dozois,4 and Todd Hill5

In laboratory studies with nonanxious participants, benzodiazepines (BZ) reliably induce anterograde amnesia. It remains unclear whether memory impairments exist for information presented in therapy among anxiety patients who are concomitantly taking BZs. This naturalistic study compared 16 panic disorder patients who were daily BZ users with 16 age- and education-matched, nonmedicated panic disorder patients. An incidental memory task assessed memory for psychoeducation material on the origins and management of somatic anxiety symptoms presented during group cognitive behavioral therapy (CBT). BZ users showed significantly poorer memory performance than controls although there were no group differences in anxiety symptoms, rates of psychiatric comorbidity, or sedation. Among BZ users, a higher number of minutes away from post peak drug-blood concentration when encoding began, was also associated with better incidental memory performance. Although causation cannot be inferred from this naturalistic study, the memory impairments observed among BZ users may contribute to the poorer efficacy of CBT previously documented in panic disorder patients receiving adjunctive BZs. KEY WORDS: benzodiazepines; memory; cognitive behavioral therapy; psychoeducation.

A large body of research reveals that benzodiazepines (BZs) exert significant impairments on human memory abilities (for reviews see Buffett-Jerrott & Stewart, 2002; Curran, 1986, 1991). Specifically, BZs have been found to induce “anterograde amnesia.” Material that is presented after drug administration is later remembered 1 Anxiety

and Affective Disorders Service, London Health Sciences Centre, London, Ontario.

2 Departments of Psychology, Psychiatry, and Community Health and Epidemiology, Dalhousie University,

Halifax, Nova Scotia. Elizabeth II Health Sciences Centre, Halifax, Nova Scotia. of Psychology and Psychiatry, University of Western Ontario, London, Ontario. 5 Halifax County East Mental Health Services, Dartmouth, Nova Scotia. 6 Correspondence should be directed to Henny Westra, W818 Anxiety and Affective Disorders Service, London Health Sciences Centre, 375 South Street, London, Ontario N6A 4G5, Canada; e-mail: henny. [email protected]. 3 Queen

4 Departments

193 C 2004 Plenum Publishing Corporation 0147-5916/04/0400-0193/0 °


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Westra, Stewart, Teehan, Johl, Dozois, and Hill

less well by those administered BZs, compared to those administered placebo. Controlled, experimental studies have documented BZ-induced impairments both in explicit memory (i.e., conscious, effortful recall) and possibly also implicit memory (i.e., memory without conscious awareness; Bishop, Curran, & Lader, 1996; BuffettJerrott, Stewart, Bird, & Teehan, 1998; Sellal et al., 1992). These memory effects have been obtained with multiple types of BZs. Degree of memory impairment appears to vary by type of BZ (e.g., Curran & Gorenstein, 1993), dose (e.g., Weingartner, Hommer, Lister, Thompson, & Wolkowitz, 1992), and the time at which memory encoding occurs following BZ administration (e.g., Buffett-Jerrott, Stewart, & Teehan, 1998; Stewart, Rioux, Connolly, Dunphy, & Teehan, 1996; Vidailhet et al., 1994). In general, higher potency BZs and higher BZ doses exert greater memory impairments and these impairments are maximal when encoding occurs at peak blood concentrations of drug (Curran, 1991; Legrand et al., 1995). Moreover, in contrast to other cognitive effects of BZs such as attentional impairments and sedation, these memory effects do not appear to be subject to tolerance with repeated BZ administration (Curran, 1991, 1992; Ghoneim, Mewaldt, Berie, & Hinrichs, 1983). Research suggests that BZ-induced amnesia is either due to difficulties in encoding (see review by Buffett-Jerrott & Stewart, 2002) or to disruptions in the consolidation of information into long-term memory (see review by Curran, 1986). Researchers have documented that BZs impair episodic memory (i.e., memory for a sequence of occurrences; Hommer, 1991), or personally experienced events (Curran, 1991). Recall of news items or short stories is impaired in nonclinically anxious participants receiving BZs, relative to those who are administered placebo (Bishop et al., 1996; Curran, Schiwy, & Lader, 1987; Gorissen, Curran, & Eling, 1998). Although demonstrating that episodic memory is impaired with BZ administration, one criticism of the tasks used in most prior experimental studies (e.g., memory for word lists) is that they may not reflect everyday memory demands. As such, individuals may be less motivated to learn or recall stimuli utilized in experimental paradigms as compared to information directly relevant to important personal tasks or aspirations (Curran, 1986). In response to this concern, BuffettJerrott, Stewart, and Teehan (1998) developed a “movie-memory” paradigm, where memory for details of portions of a movie just viewed was tested in participants who had ingested either a BZ or a placebo. In this paradigm, where participants were arguably more motivated to engage in the task relative to stimuli used in many other experimental paradigms (e.g., memory for word lists), Buffett-Jerrott, Stewart, and Teehan (1998) found evidence of BZ-induced memory impairments. As such, existing data support the potential generalizability of BZ-associated memory impairments to contexts which more closely mimic real-world memory requirements. BZ-associated memory impairments may detract from an individual’s ability to maximally benefit from psychotherapy for anxiety management. For example, cognitive behavioral therapy (CBT), is the most well-supported treatment for the management of panic disorder (Chambless et al., 1996) and relies heavily on encoding and consolidation of new information (Barlow, 2002). Intuitively, memory impairments should serve as a negative prognostic factor in a treatment heavily reliant on new


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learning. Curran (1991) argued that BZs should impede progress in CBT because this type of therapy involves episodic learning which is impaired by BZs. Similarly, Westra and Stewart (1998) have hypothesized that memory impairments may be one mechanism accounting for the poorer CBT performance observed in those anxiety disorder patients concomitantly utilizing BZs, relative to nonmedicated anxiety disorder patients (Westra, Stewart, & Conrad, 2002) or those administered placebo (Marks et al., 1993). A further problem with the extant literature on BZ-induced memory effects is that the large majority of such studies have been conducted with nonclinical participants who are BZ-na¨ıve, using single doses of BZs (see review by Buffett-Jerrott & Stewart, 2002). These studies do not make clear the extent to which these memory impairments generalize to clinical patients who take BZs more chronically. In a study of individuals who had taken BZs regularly for an average of 10 years, Ghoneim et al. (1983) found that attention and sedation were not affected after an acute dose of BZ, whereas some aspects of memory performance were significantly impaired. In another study of clinical patients, Curran (1992) used a pre–post design and a variety of experimental cognitive tasks with 20 chronic BZ users who presented for BZ discontinuation therapy (cf., Otto, Hong, & Safren, 2002). The purpose of this study was to investigate the cognitive effects of a single, daily dose of BZ. The patients in this study did not show evidence of the sedative effects normally observed in laboratory studies with BZ-na¨ıve volunteers (Curran, 1986, 1991), suggesting the development of tolerance. However, memory effects of a normal daily dose were observed in this study. Thus, the Curran (1992) and Ghoneim et al. (1983) studies suggest that memory effects may be present even among chronic BZ users. In contrast, a study by Gladsjo et al. (2001) failed to demonstrate memory deficits in a sample of chronic BZ users. Moreover, it remains to be determined whether BZassociated memory impairments are actually operative among patients with DSMIV anxiety disorders and for information presented in psychotherapy. Delineating whether BZ-associated memory impairments exist among panic disorder patients presenting for CBT for anxiety management is particularly important given that up to 60% of panic disorder patients presenting for psychotherapy are taking an anxiolytic, most often a BZ (Otto, Pollack, Penava, & Zucker, 1999; Stewart & Westra, 2002). In this naturalistic study, performance on an ecologically valid incidental memory task was assessed in patients with panic disorder who were undergoing CBT. Patients with panic disorder were selected for inclusion in one of two age- and education-matched groups: daily BZ users versus nonmedicated patients. Immediately following videotaped presentation of psychoeducation information (during the second session of an anxiety and panic management group), an incidental memory test was administered assessing recall of the content of the presentation. Given the experimental data supporting memory deficits with BZs, it was hypothesized that the daily BZ users would perform more poorly on the incidental memory task, relative to the nonmedicated controls. It was also hypothesized that these BZ-associated episodic memory impairments would not be secondary to group differences in sedation, diagnostic comorbidity, or panic disorder symptom severity.


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METHOD Participants Thirty-two participants (24 women and 8 men; mean age = 39.2 years) were selected from among successive referrals to anxiety disorder treatment programs at the London Health Sciences Centre (London, Ontario, Canada; n = 10) and the Queen Elizabeth II Health Sciences Centre (Halifax, Nova Scotia, Canada; n = 22).7 Both sites are public hospitals seeing predominantly Caucasian patients of low to middleclass socioeconomic status. To be included in the study, patients were required to meet DSM-IV (American Psychiatric Association [APA], 1994) diagnostic criteria for panic disorder with or without agoraphobia based on the Structured Clinical Interview for diagnosis (SCID-IV; Spitzer, Williams, & Gibbon, 1994). Patients were selected from one of two medication groups (daily BZ users vs. nonmedicated controls; n = 16 per group) that were matched as closely as possible on age and years of education. The two oldest BZ users were deleted from this group to equate the groups on age. Next, the two most highly educated individuals in the unmedicated group were excluded to equate the groups on education. Exclusion criteria included numerous psychiatric and medical conditions which could potentially affect performance on the memory task (cf., Curran, 1992). Patients were excluded if they reported during an initial intake interview that they had received electroconvulsive therapy in the past (n = 0 excluded on this basis) or that they had a history of any medical condition associated with memory impairment, including head injury, neurological disorder, or learning disability (n = 1 excluded on this basis). Patients were excluded if they had a lifetime history of substance abuse (as assessed by the SCID-IV; n = 2 excluded on this basis) or if they self-reported any consumption of alcohol on the day of memory testing (n = 0 excluded on this basis). An additional four patients were excluded due to nondaily use of BZs and 10 were excluded because they were on antidepressant medication alone. Patients on antidepressants alone were excluded from the study because the focus of the study was on BZ-associated impairments and because there have been recent reports of SSRIs exerting cognitive side effects (e.g., Schmitt, Kruizinga, & Riedel, 2001). Sixtythree percent of the sample also met criteria for another anxiety disorder (13 social phobia, 6 generalized anxiety disorder and 1 posttraumatic stress disorder) and 44% also met criteria for a mood disorder (9 major depressive episode, 5 dysthymia). Materials Self-Report Questionnaires All participants completed a variety of self-report instruments assessing a constellation of panic disorder symptoms and associated features including somatic 7 The

number of BZ medicated and unmedicated patients recruited from each site were identical. No differences between the two sites were found on demographic variables, BZ use parameters, symptom scores, sedation measures or memory test performance. At the LHSC site, patients were significantly more likely to carry a comorbid anxiety disorder diagnosis, χ 2 (1) = 4.69, p < .05, and no differences were found in rates of comorbidity of mood disorder diagnoses between the two sites.


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arousal (Beck Anxiety Inventory [BAI]; Beck, 1990), panic frequency in the past week (Panic Attack Questionnaire, Revised [PAQ-R]; Cox, Norton, & Swinson, 1992), fear of arousal-related sensations (Anxiety Sensitivity Index [ASI]; Peterson & Reiss, 1992), agoraphobic avoidance (Fear Questionnaire, Agoraphobia subscale [FQ-A]; Marks & Mathews, 1979), and depression (Beck Depression Inventory [BDI]; Beck, Ward, Mendelson, Mock, & Erbaugh, 1961). Each of these measures has been recommended for inclusion in a standardized assessment package for research on panic disorder (Shear & Maser, 1994). Participants also completed a questionnaire regarding their medication use history (cf., Stewart, Westra, Thompson, & Conrad, 2000; Westra et al., 2002).

Incidental Memory Task Psychoeducation information related to the origins of panic attacks and strategies for managing physical anxiety symptoms was presented in a didactic fashion during a group meeting. The content of this presentation was based on the psychoeducation material provided to panic disorder patients in established CBT treatments for panic disorder (e.g., Barlow & Craske, 1989). Standardization of the presentation was ensured by showing a videotaped version of this material to the group with the first author as the presenter. Duration of the videotape was approximately 45 min. Moreover, to attempt to mitigate the effects of waning attention while passively watching a videotape, a very brief stretching break was integrated half-way through the video presentation. Immediately following the presentation of this information, participants completed an incidental memory task assessing recall of the major points of the presentation (e.g., “What two situations trigger the Emergency or “fight or flight” response?”; “The people most likely to faint during panic attacks are . . .”; “It is best to breathe from which part of your body?”). In scoring, each item received 1–3 points credit, depending on the number of answers required, for a total possible score of 25 points.

Subjective Sedation Participants also completed a series of Visual Analogue Scales assessing degree of sedation. Such scales are often used to assess subjective mood and sedation (e.g., Schotte, Cools, & McNally, 1990) and their validity is well established (Bond & Lader, 1974). Individuals were instructed to place a mark to indicate how they felt in the moment, on five 100-mm lines with anchors describing opposite poles of various subjective states (i.e., alert–drowsy, excited–calm, clearheaded– fuzzy, energetic–lethargic, quick–slow; Buffett-Jerrott, Stewart, & Teehan, 1998; Danion, Zimmerman, Willard-Schroeder, Grange, & Singer, 1989). Each scale was scored as the number of mm from the left anchor where the participant placed his/her mark. The average across the five bipolar dimensions was calculated to arrive at an average sedation score for each subject (cf., Buffett-Jerrott, Stewart, & Teehan, 1998).


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Procedure All participants were enrolled in a CBT group for treatment of panic disorder. Prior to beginning the group, patients completed the various self-report anxiety and mood symptom measures, and also reported on their BZ use (chronicity, dose, type, frequency). The videotaped presentation of psychoeducation material was presented during the second group CBT meeting. Following presentation of the videotape, participants completed the incidental memory task and then subjective sedation VAS’s. Participants also provided information on the exact time that they had taken their last dose of BZ medication prior to the group meeting and were also asked to indicate whether they had consumed any alcohol on the day of testing.

RESULTS Table I presents means and standard deviations for demographic, sedation and anxiety, and mood measures for BZ medicated and unmedicated groups. As illustrated in this table, there were no significant group differences in either age or years of education, indicating success of the matching procedure in equating groups on these two potentially confounding variables. There were also no significant differences between groups on pretreatment anxiety or mood symptom measures, rates of comorbidity with other anxiety and mood disorders, or self-reported sedation levels at the time of the psychoeducation session. Because almost half the sample had comorbid diagnoses of social phobia, which is often associated with anxiety in a group setting and test anxiety, we also tested for group differences in rates of comorbid social phobia to ensure that greater rates of social phobia in the BZ users group did not contribute to worse memory test performance. The two groups did not differ in rates of comorbid social phobia (see Table I). Of the 16 BZ users, 12 (75%) were using clonazepam, three were using alprazolam, and one was using temazepam.8 Of these, five (31%) individuals were on a BZ alone and 11 were also concurrently using antidepressant medication.9 Of those concurrently on an antidepressant, all but one (tricyclic antidepressant) was on a selective serotonin reuptake inhibitor (SSRI). Because BZ users differed in terms of the specific BZ that was currently being used, all dose measures were converted to diazepam equivalents (cf., Curran, 1992; Stewart et al., 2000) to provide dosage comparability across BZ users: 5 mg diazepam was equated with 0.25 mg clonazepam, 0.5 mg alprazolam, and 15 mg temazepam (Maxmen & Ward, 1995). The average daily dose in diazepam equivalents was 23.13 mg (SD = 16.24) with the average frequency of BZ use being 2.19 (SD = 1.33) dosing occasions per day. Dose and frequency of use are consistent with a previous naturalistic study involving BZ users 8 The

sample consisted of a high proportion of clonazepam users as this study is part of a larger study in which existing BZ users were switched to clonazepam 5 weeks prior to beginning the CBT group. In this sample, 6 BZ users were switched to clonazepam from their original BZ, and they were switched to the equivalent dose and frequency of use as their original BZ. 9 Patients who were concurrent users of both BZs and antidepressants were not excluded from the BZ user group because of the practical difficulty in recruiting sufficient numbers of panic disorder patients who were only taking a BZ.


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Table I. Means and Standard Deviations for BZ Medicated and Unmedicated Patients on Demographic, Sedation, and Anxiety Symptom Measures

Age Gender Education (in years) Comorbid anxiety disorder Comorbid social phobia Comorbid mood disorder VAS subjective sedation BAI BDI # panic attacks in past week (PAQ-R) ASI FQ-A

BZ medicated (n = 16)

Nonmedicated (n = 16)

40.88 (7.99) N = 12 females N = 4 males 13.38 (1.71) N=8 N=7 N=8 44.7 (22.6) 26.93 (11.22) 26.15 (10.30) 10.23 (14.60)

37.50 (11.07) N = 12 females N = 4 males 13.81 (1.51) N = 12 N=8 N=6 43.7 (17.7) 27.14 (13.72) 25.79 (13.75) 7.14 (10.21)

t(30) = 0.99 χ 2 (1) = 0.00

37.77 (12.92) 17.54 (9.46)

37.29 (13.53) 14.36 (10.31)

t(30) = 0.10 t(30) = 0.83

Significance test

t(30) = 0.77 χ 2 (1) = 2.13 χ 2 (1) = 0.13 χ 2 (1) = 0.51 t(30) = 0.13 t(30) = 0.05 t(30) = 0.08 t(30) = 0.64

Notes. BAI = Beck Anxiety Inventory; BDI = Beck Depression Inventory; ASI = Anxiety Sensitivity Index; FQ-A = Fear Questionnaire—Agoraphobia subscale; PAQ-R = Panic Attack Questionnaire— revised; VAS subjective sedation is the average of the five 100 mm visual analogue scales measuring sedation; all tests nonsignificant at α = .05.

(Westra et al., 2002). Average BZ use chronicity was over 4 years (range = 2 months– 13 years). Although not specifically instructed to do so, all BZ medicated participants indicated that they had taken their BZ medication prior to the commencement of the group session where the memory testing took place (M number of minutes BZ taken before the session = 132; range = 15–330 min). Given that the time to theoretical peak for each of the BZs used by patients in this study is about 90 min. (Cooper, 1982), this means that the average BZ using patient was about 42 min. postpeak blood concentration of drug at the start of the encoding phase (range = 75 min. prepeak to 240 min. postpeak). Interrater Agreement on Memory Test Scoring Two experimenters (one a registered clinical psychologist and the other a research assistant), blind to participants’ medication group status, independently scored each of the 32 incidental memory test forms. The correlation between ratings was .92, p < .05, which indicates excellent interrater reliability. Given the high rate of agreement, the first experimenter’s (i.e., clinical psychologist’s) ratings were used in all subsequent analyses. BZ Use and Scores on the Incidental Memory Test Scores on the incidental memory test were found to be normally distributed. A independent-groups t-test using scores on the incidental, session-specific memory test as the dependent variable revealed a significant between-groups difference, t(30) = 4.83, p < .05. BZ medicated patients obtained significantly lower scores on the memory test compared to nonmedicated patients. Whereas nonmedicated


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patients on average recalled 78% of the material on the incidental memory test, BZ medicated patients recalled only 58% (see Fig. 1). On average, BZ medicated patients recalled about 20% less of the psychoeducational material than unmedicated participants (see Fig. 1). In a cursory examination of the effects of concurrent antidepressant use on memory performance, a between-groups t-test of BZ only users (n = 5) and BZ/ antidepressant users (n = 11) revealed no significant difference in memory test scores, t(14) = 0.06, ns. These results suggest no significant contribution of concurrent antidepressant medication usage to incidental memory test scores, although power to detect such a difference in this analysis is admittedly low. Predicting Memory Test Performance Despite matching BZ medicated and unmedicated groups on education and age, not surprisingly, significant correlations ( p < .025) were evident between both education and age with incidental memory performance, r ’s = .44 and −.44, respectively. Higher levels of education and younger age were associated with better memory performance. In fact, of all the non-medication-related measures employed in the study (i.e., demographic variables, anxiety and mood measures, and VAS subjective sedation), only age and education were significantly correlated with memory performance. As a result, the relative contributions of age and education level compared with medication status (BZ medicated or nonmedicated) were examined in a stepwise regression. Incidental memory test score served as the criterion variable and age, education, and medication status were predictor variables that were allowed to enter in a forward stepwise fashion.

Fig. 1. Mean scores on incidental memory test for BZ users and unmedicated patients.


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Table II. Results of Stepwise Regression Predicting Incidental Memory Test Performance

STEP 1: Medication status STEP 2: Education (in years) STEP 3: Age

F-change

Cumulative r 2

β for final model

F(1, 30) = 18.34, p < .05 F(1, 29) = 7.26, p < .05 F(1, 28) = 4.44, p < .05

.38 .47 .53

−.56 .30 −.27

Note. Medication status was coded as 0 = unmedicated, 1 = BZ medicated.

As shown in Table II, BZ medication status was the best predictor of memory test performance, accounting for 38% of the variance in memory test performance. BZ users performed more poorly than the nonmedicated patients. Education was also a significant incremental predictor of memory test scores, entering the regression equation in the second step and accounting for a significant additional 12% of the variance. Higher education scores were associated with higher memory test scores. Finally, age was also a significant incremental predictor of memory performance, entering the regression equation last and accounting for a significant additional 7% of the variance. Older age was related to poorer memory performance. Together, these three variables accounted for a substantive 57% of the variance in sessionspecific memory test scores in the final regression equation. Relationship of BZ Use Parameters to Memory Performance Simple correlations using BZ medicated participants were computed to examine the relationship between various BZ use parameters (chronicity, frequency of use, dose per medication taking occasion, total daily dose, and timing of BZ taking relative to encoding) and incidental memory test performance. Given the effects of age and education on memory test performance, partial-correlations were calculated between each BZ use parameter and memory test score, controlling for both age and education. These analyses revealed that chronicity of BZ use and frequency of BZ use were not significantly related to memory performance, r ’s (14) = −.10 and −.11, respectively (both ns). Moreover, total daily BZ dose and BZ dose per medication taking occasion (both in diazepam equivalents) were also not significantly related to incidental memory test scores among BZ users, r ’s(14) = −.20 and −.24, (both ns). Timing of BZ taking has been found to be related to the amnestic effects of BZs (Stewart et al., 1996). In this study, increased time from peak blood-drug concentration (either before or after peak and calculated using the theoretical peaks for each type of BZ) to encoding were significantly positively correlated (r = .55, p < .05) with memory test score, after partialling out the effects of both age and education. In other words, being further away from peak blood-drug concentration when encoding began was associated with significantly better memory test performance. DISCUSSION The results of this naturalistic study consistently supported the hypothesis that BZ-medicated patients exhibited poorer recall of psychoeducational material


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relevant to their treatment for panic disorder, compared to their unmedicated counterparts. This between-group difference was not only statistically significant, but also clinically significant in that while nonmedicated patients, on average, recalled about three-quarters of the previously presented information, the BZ users recalled only about half of this information. Moreover, BZ medication status (use or no use) was the strongest predictor of incidental memory performance in the stepwise regression, accounting for more unique variance than education level and age. Finally, time from peak blood-drug concentration when encoding began, relative to other BZ parameters such as chronicity and frequency of use, was significantly related to memory test performance, with better recall being associated with being further away from BZ peak during encoding. This finding is consistent with previous studies showing a time-dependent relationship between BZ peak and memory performance (Stewart et al., 1996; Buffett-Jerrott & Stewart, 2002). The present findings are consistent with the direction of that relationship in previous research. The present study is the first investigation to suggest that the BZ memory impairments observed under controlled laboratory conditions (e.g. Curran, 1991; McGaugh, 1992; Weingartner, Sirocco, curran, & Wolkowitz, 1995) generalize to psychoeducational material presented in the clinical setting in the treatment of panic disorder. As such, even when participants are presumably highly motivated to recall personally relevant information, such as material related to their management of a clinically significant personal problem, BZ memory impairments appear to remain operative. These findings may have important implications for those panic disorder patients undergoing nonpharmacologic therapy for anxiety management who are also concomitantly taking BZs. The addition of BZs to psychotherapies (e.g., CBT) for panic disorder and agoraphobia is associated with less effective long-term anxiety management and results in poorly consolidated treatment gains and increased anxiety relapse potential (Clum, Clum, & Surls, 1993; Echeburua, DeCorral, Bajos, & Borda, 1993; Marks et al., 1993). The findings of the present study suggest that one possible cognitive mechanism to explain the interference of BZs with CBT outcome. In CBT for panic disorder/agoraphobia, much emphasis is placed on the necessity of learning from exposure to fear-provoking stimuli (Barlow, 2002; Foa & Kozak, 1986; Rachman & Wilson, 1980; Williams & Falbo, 1996), which requires memory for those experiences. Consistent with hypotheses proposed by Westra and Stewart (1998), memory impairments for information presented in CBT for panic disorder might result in poorer encoding or consolidation of new, belief-challenging information essential for modification of preexisting catastrophic beliefs. Consequently, this effect of BZs on memory would be expected to detract from the efficacy of a treatment, such as CBT, which places much emphasis on learning and subsequent integration of new material. Moreover, the consistently demonstrated interference of BZs with effortful recall (i.e., explicit memory; Curran, 1986, 1991) suggests that BZ medicated patients might have difficulty remembering belief-challenging information taught in therapy that is essential to successful anxiety management in CBT (e.g., remembering that the worst outcome of the fight or flight response is fainting, not death or insanity). Future research should investigate whether these memory impairments extend to memory for exposure exercises. It would also be of interest to investigate the impact of these


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memory impairments on actual treatment outcome in CBT for panic disorder to evaluate whether these impairments mediate poorer treatment outcome. The strengths of this study include the careful measurement and control of numerous variables beyond medication status which could be related to memory performance. We excluded those individuals with relevant medical and substance use histories (including alcohol intake on the test day) that might have contributed to memory impairments. We also measured anxiety and mood symptoms, and comorbid anxiety and mood disorders to ensure that groups did not differ on these variables which could conceivably be related to poorer memory task performance. Finally, we assessed subjective sedation level at the time of the memory encoding phase to ensure that impairments on the memory task were not simply secondary to the BZ users being more sedated at the time of the videotape presentation than the unmedicated controls. Other important controls included the use of standardized presentation of material to-be-remembered (i.e., videotaped psychoeducational material) and a check on interrater reliability in the scoring of the memory test forms. Importantly, BZ medicated and unmedicated groups were matched for age and education level. In addition, BZ medication effects were related to memory test performance more strongly than age or education level. Further supporting a unique effect of BZ use beyond age and education was the finding that being further away from peak blood-drug concentration when encoding began was significantly associated with better memory performance. This strengthens the conclusion that BZ use was related to memory performance in this clinical situation, and is consistent with findings from laboratory-based studies showing a positive relationship between timing of BZ taking and degree of memory impairment (see review by Buffett-Jerrott & Stewart, 2002). The principal weakness of this study pertains to its naturalistic design. Because patients were not randomly assigned to medication groups, it is impossible to attribute causality to BZ administration in relation to the memory findings. Although we did control for a number of potentially confounding factors (age, education, anxiety/mood symptoms, comorbidity, sedation at the time of encoding), which assists in making the case that BZ use caused the memory impairments observed here, it is still possible that other uncontrolled differences between groups (e.g., state anxiety levels at the time of testing, general intelligence, motivation to remember, attention at the time of encoding) could have contributed to the group differences observed on the incidental memory task. Moreover, there may be reason to suspect that other important differences between groups were present such as factors which could lead to the taking/prescription of BZs (e.g., unmedicated participants may be more receptive or motivated to manage symptoms psychologically and therefore paid better attention during the video presentation or groups may have differed in treatment history or symptom chronicity such that chronic BZ using participants presenting for CBT might be considered “treatment refractory,” whereas unmedicated patients may have been more treatment na¨ıve). This study was also not placebo-controlled which leaves open the possibility that effects attributed to the pharmacological properties of BZs could actually be due partially or entirely to expectancy effects. Also, this study cannot determine at what stage of information processing memory impairments are taking place, although previous laboratory research suggests that BZs


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most likely exert their adverse effects at the encoding or consolidation, as opposed to retrieval, stage (see reviews by Buffett-Jerrott & Stewart, 2002, and Curran, 1986). Other potential weaknesses of this study include the lack of control over the type and timing of BZ used or concomitant antidepressant medication use (largely SSRIs). With respect to SSRI’s, there are recent reports that this class of medications may also have cognitive side effects (e.g., Schmitt et al., 2001). Moreover, some antidepressants also have clinically significant pharmacokinetic interactions with certain BZs that could alter the effects of a given BZ dose. However, additional statistical analyses revealed no differences in memory performance between BZ-only users and BZ/antidepressant users (although the cell sizes involved in this comparison were admittedly small). Even though the types of BZs used were varied, the three BZs represented in this study (i.e., clonazepam, alprazolam, and temazepam) have similar times to peak (Maxmen & Ward, 1995; Schwarz, 1979) making them comparable on at least this dimension. Moreover, although we did not exert control over patients’ medication-taking on the day of testing, all participants reported having taken a usual dose of their BZ before coming to the session. Findings from nonclinically anxious participants indicate that that timing of BZ use relative to memory testing and type of BZ exert reliable influences on memory (Buffett-Jerrott & Stewart, 2002). The present study also supported that those closer to theoretical peak concentration of drug at the time of encoding tended to show more memory impairments. Thus, future investigations of this type should systematically control these medication use parameters. Finally, patients’ prior knowledge of the psychoeducation information was not assessed at baseline in this study. Because we were using an incidental memory task, exposure to the questions on the memory form prior to the videotape might have drawn participants’ attention to the most relevant material during encoding or might have cued them that memory for the material would later be tested. Moreover, given that our BZ use sample consisted of relatively “chronic” users (i.e., average duration of BZ use was over 4 years), it would not have been possible to obtain a baseline assessment of knowledge of psychoeducation material which was independent of BZ use. Nonetheless, we recommend that future studies attempt to rule out this potential confound. A clear strength of this study is its external validity. This is the first study to demonstrate that BZ-associated memory impairments are operative in the clinical setting with a typical panic disorder patient population (i.e., high diagnostic comorbidity; already chronically BZ-medicated prior to commencing CBT; many also taking SSRIs). If future investigations more clearly establish the causal nature of BZs effects on memory in a clinical context, such findings have important potential implications for BZ medicated individuals with panic disorder receiving CBT for anxiety management. Clinicians need to be cognizant of the potential interference of BZs, particularly the timing of BZ taking, on retention of important psychoeducational material relevant to effective panic and anxiety management. Clinician awareness of these memory effects is particularly important in view of findings from other studies that BZ users are typically not aware of memory impairments with BZ use (Bacon et al., 1998; Barbee, 1993) and that these effects are not subject to tolerance with repeated BZ administration (see reviews by Buffett-Jerrott & Stewart, 2002; Curran, 1991). Clinician awareness of these memory effects with BZs in the clinical context


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is underscored by the commonality of BZ use in individuals with panic disorder presenting for psychotherapy (Otto et al., 1999; Wardle, 1990). Discontinuation of BZs prior to CBT may not be a reasonable option given high rates of discontinuation effects with BZs including rebound anxiety in panic disorder patients (Otto et al., 2002; Romach et al., 1991). If future more controlled studies replicate these findings of BZ-associated memory impairments in a clinical, treatment context, additional studies should investigate whether strategies developed in the cognitive rehabilitation literature might be used in therapy to assist BZ users in compensating for BZ-associated memory impairments. Such techniques might involve providing patients with assistance in encoding strategies (Leng & Copello, 1990; Parente’ & Anderson, 1983; Van der Linden, 1989), or minimizing cognitive load (Woods, 1996) by breaking up psychoeducational information into smaller portions for those on BZs. Experienced clinicians may well use such compensatory strategies in response to cues that their patient is not optimally encoding therapy information and as such the memory effects may potentially be less in the more typical, interactive presentation of material in CBT than observed in this study with the use of the relatively passive video. Finally, given findings that memory impairments with BZs are maximal at peak blood concentrations of drug (Buffett-Jerrott, Stewart, Bird et al., 1998; Buffett-Jerrott, Stewart, & Teehan, 1998) and that as needed use of BZs is associated with poorer CBT outcomes relative to regularly scheduled use (Westra et al., 2002; Westra & Stewart, 2002), it might be prudent for the clinician and patient to review information on time to peak for the BZ in question (e.g., Maxmen & Ward, 1995; Schwarz, 1979). This may be useful in timing BZ-taking relative to psychotherapy sessions to minimize the likelihood of BZ-associated memory impairments for important psychoeducational information. ACKNOWLEDGMENTS This study was supported by a Queen Elizabeth II Health Sciences Centre Research Grant and a Grant from the Dalhousie University, Department of Psychiatry Research Fund. The second author is supported through an Investigator Award from the Canadian Institutes of Health Research. The authors thank Pamela Loba, Ellen Rhyno, and Jennifer Theakston for their research assistance. REFERENCES American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. Bacon, E., Danion, J. M., Kauffmann-Muller, F., Schelstraete, M. A., Bruant, A., Sellal, F., et al. (1998). Confidence and feelings of knowing for episodic and semantic memory: An investigation of lorazepam effects on meta-memory. Psychopharmacology, 138, 318–325. Barbee, J. G. (1993). Memory, benzodiazepines, and anxiety: Integration of theoretical and clinical perspectives. Journal of Clinical Psychiatry, 54, 86–97. Barlow, D. H. (2002). Anxiety and its disorders: The nature and treatment of anxiety and panic (2nd ed.). New York: Guilford. Barlow, D. H., & Craske, M. G. (1989). Mastery of your anxiety and panic. New York: Graywind. Beck, A. T. (1990). An inventory for measuring clinical anxiety: Psychometric properties. Journal of Consulting and Clinical Psychology, 56, 893–897.


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