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The Effects of Clozapine on Alcohol and Drug Use Disorders Among Patients With Schizophrenia by Robert E. Drake, Haiyi Xie, Qregory J. McHugo, and Alan I. Qreen with a variety of serious adverse consequences such as relapse (Linszen et al. 1994), hospitalization (Swofford et al. 1996), violence (Cuffel et al. 1994), decreased functioning (Chouljian et al. 1995), homelessness (Drake et al. 1989), and human immunodeficiency virus (HTV) infection (Coumos et al. 1991). Recent research suggests that comprehensive dual-disorder treatment programs are effective in reducing substance abuse over several months or years (Drake et al. 1998b), but there is no clear evidence that typical antipsychotic medications, per se, decrease substance abuse. Several investigators have in fact argued that antipsychotic drugs may actually precipitate or worsen the abuse of alcohol and other drugs (Siris 1990; Voruganti et al. 1997), and one study showed that patients starting a traditional antipsychotic drug increased nicotine use (McEvoy et al. 1995a). Contrary to concerns that typical antipsychotic medications may worsen substance abuse, several recent case reports have suggested that clozapine may have the effect of decreasing the use of nicotine, alcohol, or other drugs of abuse among patients with schizophrenia. Marcus and Snyder (1995) found that 11 of 13 patients who had histories of nicotine dependence (eight also abused other drugs) reduced their usage of all drugs or attained abstinence while taking clozapine. McEvoy et al. (1995ft) reported that 8 of 12 patients treated with clozapine in a State hospital reduced their intake of cigarettes during breaks in a smoking area, George et al. (1995) also found an overall decrease in smoking, especially among the heaviest smokers, among 18 patients with chronic schizophrenia on clozapine. Albanese et al. (1994) reported that two State hospital patients stopped using alcohol while on clozapine, although one of the patients remained in the hospital and thus had limited access to alcohol. Yovell and Opler (1994) observed that clozapine eliminated craving for cocaine in a patient with schizophrenia. Buckley et al. (1994) reported that 29 patients with schizophrenia with a Abstract Several case studies indicate that clozapine use is associated with reductions in the use of nicotine, alcohol, or illicit drugs. Although not designed to assess clozapine, this study explored a posteriori the effects of clozapine on alcohol and drug use disorders among schizophrenia patients. Among 151 patients with schizophrenia or schizoaffective disorder and co-occurring substance use disorder who were studied in a dual-disorder treatment program, 36 received clozapine during the study for standard clinical indications. All participants were assessed prospectively at baseline and every 6 months over 3 years for psychiatric symptoms and substance use. Alcohol-abusing patients taking clozapine experienced significant reductions in severity of alcohol abuse and days of alcohol use while on clozapine. For example, they averaged 54.1 drinking days during 6-month intervals while off clozapine and 12.5 drinking days while on clozapine. They also improved more than patients who did not receive clozapine. At the end of the study, 79.0 percent of the patients on clozapine were in remission from alcohol use disorder for 6 months or longer, while only 33.7 percent of those not taking clozapine were remitted. Findings related to other drugs in relation to clozapine were also positive but less clear because of the small number of patients with drug use disorders. This study was limited by the naturalistic design and the lack of prospective, standardized measures of clozapine use. The use of clozapine by patients with co-occurring substance disorders deserves further study in randomized clinical trials. Keywords: Schizophrenia, substance abuse, substance use disorder, clozapine. Schizophrenia Bulletin, 26(2):441-449, 2000. Comorbid substance use disorder is common in patients with schizophrenia (Regier et al. 1990) and is associated Sendreprintrequeststo Dr. R. Drake, Psychiatric Research Or., 2 Whipple Race, Lebanon, NH 03766; email: RobatE.Drake@Daitinouthxdu. 441 Schizophrenia Bulletin, Vol. 26, No. 2, 2000 R.E. Drake et al. history of comorbid substance use disorder (only seven had a current disorder) improved on clozapine as much as those without substance abuse comorbidity. On the basis of the low rate of substance abuse observed during clozapine therapy and a small number of retrospective interviews, they speculated that clozapine may have reduced cravings. Finally, in a recent, retrospective survey, Zimmet et al. (2000) reported that among 36 patients with schizophrenia or schizoaffective disorder and current comorbid substance use disorder, over 80 percent decreased their use of substances while taking clozapine. While suggestive, these case studies are limited by small numbers; the lack of controls; the lack of standardized, multimodal measures of substance abuse; and in most cases, the lack of independent assessment The purpose of the current report is to examine temporal changes in substance use in relation to clozapine use among a large study group of patients with schizophrenia or schizoaffective disorder and co-occurring substance use disorder who were assessed prospectively by independent researchers using standardized, multimodal measures of substance abuse. Patients taking clozapine were compared with themselves as controls (i.e., on clozapine vs. off clozapine) as well as with patients who were not receiving clozapine (i.e., clozapine vs. no clozapine). Methods Participants. A total of 223 patients with schizophrenia, schizoaffective disorder, or bipolar disorder were recruited from seven community mental health centers in New Hampshire to participate in a study of case management interventions for dual disorders, and 203 (91%) completed 3 years in the study between 1989 and 1995 (Drake et al. 1998a). Of the 203 patients, 151 were diagnosed with DSM—III-R schizophrenia or schizoaffective disorder, and thus were eligible for treatment with clozapine, which became widely available in New Hampshire during the course of the study. The majority of the 151 patients were young (average age 32.3 ± 7.1 years), male (775%), never married (68.9%), non-Hispanic white (96.7%), and high school graduates (62.7%). Over two-thirds (70.2%) were diagnosed with schizophrenia and the others with schizoaffective disorder (29.8%). The most frequent substances of current use disorder (denned as DSM-III-R abuse or dependence within the past 6 months) were alcohol (69.5%), cannabis (31.8%), and cocaine (11.3%). Among the 105 patients with current alcohol use disorder, 41.0 percent also had current other drug use disorders (30.5% cannabis use disorder, 143% polydrug use disorder, and 9.5% cocaine use disorder). Among the 65 patients with current drug use disorder, the most commonly abused drugs were cannabis (73.8%) and cocaine (26.1%); two-thirds (66.2%) of those with drug use disorder also had current alcohol use disorder. Treatments. All participants in the study received treatments in dual-disorder programs in the seven participating mental health centers. The interventions included medication management, case management, and rehabilitation services for severe mental illness, and substance abuse counseling in individual and group sessions, as well as linkage with substance abuse self-help groups in the community, for substance use disorder (Drake et al. 19906). For the main experimental study, one-half of the participants were randomly assigned to receive these dual-disorder services through assertive community treatment, and the other half through standard case management. The major difference between these service models was greater integration of outpatient services through assertive community treatment because of smaller case load sizes (Teague et al. 1995). Despite differences in the level of integration, patients in the two case management conditions received similar amounts of overall outpatient services (Clark et al. 1998) and attained similar rates of remission of substance use disorder (Drake et al. 1998a). Staff psychiatrists within the participating community mental health centers and in local hospitals made all decisions regarding medications on clinical grounds. As clozapine became available in New Hampshire and was funded by Medicaid, patients were evaluated clinically for eligibility by their treating psychiatrists. Decisions regarding clozapine use were made according to the standard criteria of nonresponsiveness to or inability to tolerate typical antipsychotic medications. Substance abuse was considered neither a specific indication nor a contraindication for clozapine at the time, and substance-abusing patients were therefore eligible for clozapine. Ten of the 32 patients who started clozapine during the study did so during brief hospitalizations and thus were stabilized before initiating clozapine. Patients on clozapine received standard blood tests for agranulocytosis, but were not tested for clozapine blood levels. Decisions regarding dose and continuation of clozapine were made by individual psychiatrists in community mental health centers based on clinical response. Patients' psychosocial treatments did not change while they were taking clozapine. Measures. Prior to admission to the study, research psychiatrists established co-occurring diagnoses of severe mental illness and current substance use disorder using the Structured Clinical Interview for DSM-III-R (SCTD; Spitzer et al. 1988). The time interval for defining substance use disorder as current was 6 months. Assessments of substance use at baseline and followup included (1) research interviews using the 6-month 442 Effects of Clozapine on Alcohol and Drug Use Disorders Schizophrenia Bulletin, Vol. 26, No. 2,2000 Tune-Line Follow-Back (TLFB; Sobell et al. 1980) and the alcohol and drug use sections from the Addiction Severity Index (ASI; McLellan et al. 1980); (2) urine drug toxicology screens in our laboratory using Enzyme Multiplied Immunoassay Technique (EMIT, from SyvaBehring); and (3) clinician ratings using the Alcohol Use Scale (AUS), the Drug Use Scale (DUS), and the Substance Abuse Treatment Scale (SATS). The TLFB assesses days of alcohol use and drug use over 6 months, and the ASI yields composite scores for alcohol and drug use. The AUS and DUS are 5-point scales based on DSM-III-R criteria for severity of disorder: 1 = abstinence, 2 = use without impairment, 3 = abuse, 4 = dependence, and 5 = severe dependence (Drake et al. 1990a). The SATS is an 8-point scale that indicates progressive movement toward recovery from a substance use disorder (McHugo et al. 1995). Clinician ratings using these three scales are reliable and valid in this population (Drake et al. 1989, 1990a; McHugo et al. 1995; Carey et al. 19%) and in this study (Drake et al. 1998a). Self-report regarding substance use in persons with severe mental illness, especially using the ASL may be suspect for a variety of reasons (Goldfinger et al. 19%; Carey et al. 1997; Wolford et al. 1999), but the TLFB has been shown to be a reliable and valid measure in this population (Carey 1997). For the analyses of alcohol and drug use outcomes in this study, we therefore used both self-report based on the TLFB and multimodal ratings of severity. For multimodal ratings, a team of three independent raters, blind to study conditions, considered all available data on substance use (from the ASI, the TLFB, clinician ratings, and urine drug screens) to establish separate ratings on the AUS, DUS, and SATS scales, following procedures validated previously (Drake et al. 1995). To determine the interrater reliabilities, researchers independently rated a randomly selected subgroup of 65 patients. Intraclass correlation coefficients were high for all three scales: 0.94 on the AUS, 0.94 on the DUS, and 0.93 on the SATS (Drake et al. 1998a). In practice, the urine drug tests, done at 6-month intervals, were rarely positive and added little information. Symptoms were assessed at baseline and at 6-month intervals using the expanded Brief Psychiatric Rating Scale (BPRS; Lukoff et al. 1986). Recent factor analyses of BPRS data from outpatients with schizophrenia have yielded four factors: thought disorder, anergia, affect, and disorganization (Mueser et al. 1997). Thought disorder refers to positive symptoms of psychosis (unusual thought content, grandiosity, suspiciousness, and hallucinations). Anergia includes items considered to reflect negative symptoms (blunted affect, emotional withdrawal, and motor retardation). These recent factors differ somewhat from the traditional BPRS factors identified in inpatient studies but fit our own data better than the earlier factors. 443 Procedures. Patients were referred by clinicians, families, or themselves between 1989 and 1992. They were evaluated for study criteria by reviews of clinical records and research interviews with the SCID. All participants gave written informed consent. They were assessed for substance use and psychiatric symptoms through independent research interviews, clinician ratings, and laboratory tests at baseline and every 6 months for 3 years. Clozapine use was assessed by interviews at 6-month intervals. Patients were coded as taking clozapine during the previous assessment period if during an interview they reported taking the medication. We obtained exact start dates for 27 of the 36 clozapine patients from clinical records and the month clozapine was started for the other 9. For those who started clozapine during the study, the average time on clozapine prior to interview was approximately 100 days. At the time of this retrospective analysis, clozapine doses were in archived records for some patients and not easily retrieved. Group equivalence (patients taking clozapine vs. patients not on clozapine) was assessed at baseline via t tests and chi-square tests. To determine within-group differences on substance use status for patients who spent some time taking clozapine and some time not taking clozapine, paired t tests were used. Longitudinal outcomes were evaluated with chi-square tests and with mixed-effects linear models (Jennrich and Schluchter 1986; McLean et al. 1991) using SAS PROC MIXED. Mixed-effects models represent a collection of modeling techniques that assume that observations within clusters (participants in our case) are correlated. Such serial correlations can be modeled either by imposing an appropriate correlation structure or by incorporating random components into the model (e.g., for the time effect). Other advantages of mixed-effects modeling include the ability to handle missing values and time-varying covariates. For the current analysis, we used an approach to mixedeffects models termed analysis of variance (ANOVA) with unstructured variance/covariance. Clozapine use was treated as a time-varying categorical variable, and time was treated as a classification variable. Results can be interpreted like traditional repeated-measures ANOVA. Results Clozapine Use. Of the 151 eligible patients, 36 received clozapine during at least part of the 3-year study. Most of the 36 patients began using clozapine during the middle of the study and remained on the medication when the study ended. However, four patients were already taking clozapine when they entered the study, and four patients, including one of those taking the medication at baseline, discon- Schizophrenia Bulletin, Vol. 26, No. 2, 2000 R.E. Drake et al. tinued clozapine because of side effects before the last followup interview. Of the four who discontinued clozapine, three were on the medication for less than 1 month. To examine baseline differences, we compared the 29 patients who began clozapine after entering the study and continued on the medication to the end of the study with the 118 patients who had either no exposure to clozapine (n = 115) or only brief exposure (n - 3). The two groups did not differ in age, marital status, education, or primary diagnosis (schizophrenia vs. schizoaffective disorder), but women were slightly more likely to receive clozapine than men (32.4% vs. 15.9%; x 2 = 4.45, df=l,p = 0.035). The two groups did not differ at baseline on any of our five substance abuse variables (alcohol severity, drug severity, days of alcohol use, days of drug use, and stage of substance abuse treatment). For current symptoms, the two groups did not differ on BPRS total score or on BPRS affect or disorganization factors, but the clozapine group had more severe symptoms on the thought disorder factor (3.46 ± 1.82 vs. 2.59 ± 1.41; t = 3.46, df= 137, p = 0.007) and a trend toward more symptoms on the anergia factor (2.40 ± 1.37 vs. 1.92 ± 0.93; t = 1.79, df= 34.7, p = 0.08). average scores while not taking clozapine, using paired t tests. These analyses excluded patients who were taking clozapine throughout their 3 years in the study because they had no off-clozapine scores. Table 1 shows that patients significantly improved while taking clozapine in terms of stage of substance abuse treatment, severity of alcohol abuse, severity of drug abuse, and days of alcohol use, but not days of drug use. To examine the timing of decreases in relation to starting clozapine, we examined days of alcohol use during each 6-month interval. As shown in figure 1, the reduction in days of alcohol use is apparent during the first interval on clozapine. Since ten patients started clozapine in the hospital, some of the initial reduction in days of use may be attributed to restricted access to alcohol. None of these patients remained in the hospital for more than a few weeks, however, and the reductions clearly continued after discharge. The relationship between greater length of time on clozapine and likelihood of remission of substance use disorder at 3-year followup approached significance for alcohol (r = 0.43, n-l9,p = 0.07) but not for other drugs (r = 0.16, n = 11, ns). Within-Group Analysis. To conduct a within-group analysis of patients who took clozapine, we compared their average scores while taking clozapine with their Between-Group Analysis. Since most of the patients in the within-group analysis began taking clozapine during the middle of the study and remained on clozapine at the Table 1. Within-group comparison of patients' substance abuse while taking and while not taking clozapine Variable n1 Off clozapine2 On clozapine3 t P Stage of substance abuse treatment4 34 4.0411.25 5.3511.41 5.14 0.0001 Severity of alcohol abuse5 22 3.09 1 0.78 2.03 1 0.65 4.92 0.0001 Days of alcohol use 6 22 54.1 149.3 12.5114.4 4.52 0.0002 7 13 2.91 1 0.73 2.3311.01 2.09 0.058 Days of drug use 8 13 30.9127.1 32.7161.2 0.12 0.90 Thought disorder9 33 3.0611.42 2.88 11.47 1.09 0.28 Anergia9 34 1.9710.88 1.8610.95 0.83 0.41 Severity of drug use 1 n varies according to the number of patients with substance use disorder, the number with alcohol use disorder, the number with drug use disorder, and missing data. 2 Average score during periods not taking clozapine. 3 Average score during periods taking clozapine. 4 Based on 7-point Substance Abuse Treatment Scale; higher scores Indicate greater progress in treatment. 5 Based on 5-point Alcohol Use Scale; higher scores indicate greater severity. 6 Based on 6-month Timeline Follow-Back. 7 Based on 5-point Drug Use Scale; higher scores indicate greater severity. 8 Based on 6-month Timeline Follow-Back. Scores on this measure were extremely skewed because of outliers. The log-transformed data show a more accurate, but still nonsignificant, decrease in days of drug use: 2.42 ± 1.19 vs. 1.59 ± 1.93, f - 0 . 8 3 , df~ 12, p = 0.16. 9 Based on Brief Psychiatric Rating Scale subscales. 444 Effects of Clozapine on Alcohol and Drug Use Disorders Schizophrenia Bulletin, Vol. 26, No. 2, 2000 Figure 1. Mean number of days of alcohol consumption during consecutive 6-month periods before and after starting clozapine 60 20 i |n=12l • |n=13| 1 • JbJLJL t-3 t-2 jfl°14| |n-17l to t-1 |n'10| t+1 t+2 t+3 Assessmant Point 1 1 All patients had alcohol use disorder at study entry, t refers to the 6-month period in which each person started on clozapine. t-1 refers to the 6-month period prior to to, and t=1 refers to the 6-month period after to. 3-year followup, their improvement could be related to maturation or substance abuse counseling. To examine this possibility, we compared all patients taking clozapine with those not on clozapine during each interval, using mixed-effects analyses with clozapine status as a timevarying independent variable. We included as a covariate baseline the patient's SATS score, which was the only significant covariate among our baseline variables. Clozapine use produced a significant main effect on all five outcomes: improved stage of substance abuse treatment (F = 8.89, df = 1,147, p = 0.003), decreased severity of alcohol abuse (F = 8.68, df = 1,104, p 0.004), decreased days of alcohol use (F = 14.42, df = 1,104, p = 0.0002), decreased severity of drug abuse (F = 16.83, df= 1,64, p - 0.0001), and decreased days of drug use (F = 14.35, df=\,(A,p = 0.0003). Time effects were also significant for each variable. T tests for group differences at each assessment point were generally significant whenever there were sufficient numbers of patients on clozapine. The specific pattern of mean differences for days of alcohol use is depicted in figure 2, which indicates again a stable reduction related to clozapine. Figure 2 also reveals little improvement for patients who did not take clozapine. Neither main effects for case management group assignment nor interactions between group assignment and clozapine use were significant 445 Another measure of the effectiveness of clozapine is the proportion of patients with active disorder at baseline who attain remission (AUS or DUS score < 3) after starting clozapine. Among the 105 patients with alcohol use disorder, 79.0 percent of the 19 patients taking clozapine at the end of the study were in remission, compared with only 33.7 percent of the 86 patients not on clozapine (x2 = 13.07, df = l,p = 0.001). Remission of alcohol use disorder was related neither to the alcohol abuse versus dependence distinction nor to the presence of comorbid drug use disorder. Among the 65 patients with drug use disorder, 63.6 percent of the 11 patients taking clozapine attained remission of the drug use disorder, whereas only 29.6 percent of the 54 patients not taking clozapine were in remission at the end of the study (x 2 = 4.62, df = \,p = 0.032). Relationships Between Changes in Alcohol Use and Symptoms. Because the relationship between clozapine use and reductions in alcohol use could be related to the well-documented effects of clozapine on positive or negative psychotic symptoms, we examined the covariation of overall changes in BPRS thought disorder and BPRS anergia factor scores with reductions in alcohol use. Patients who began clozapine during the study experienced nonsignificant reductions in symptoms of thought Schizophrenia Bulletin, Vol. 26, No. 2, 2000 R.E. Drake et al. Figure 2. Mean number of days of alcohol consumption in the past 6 months for clozaplne users and nonusers1 90 n = 105 80 a r - | n =>88 I a £ 50 O 40 o o < 30 1 n »103 •L. n = 97 1• ' n = 9 6 "•" A Jt 1I 11 n =93 1 n = 86 | • • clozaplne • no ctoz j\ = 17J n = 1 10 1 baseline 6 mo. 12 mo. 18 mo. 24 mo. 30 mo. 36 mo. The study group includes patients with schizophrenia/schizoaffective disorder and alcohol use disorder at baseline (n = 105). Group sizes at each assessment point are indicated above each bar. in a dual-disorder treatment program cannot be determined from our data. However, Zimmet et al. (2000) have reported similar rates of improvement of substance use disorder in relation to clozapine use in a different treatment setting that did not emphasize dual-disorder treatment Moreover, our data reveal little reduction of alcohol use among the nonclozapine patients, suggesting that clozapine may have been more effective than the psychosocial interventions. The findings reported here were not based on a randomized clinical trial design. Although causal inferences should be cautious, our data offer much stronger evidence than previous case reports and a single retrospective survey for the effects of clozapine on psychoactive substance use because of the large study group, the use of a comparison group that received similar psychosocial interventions, and the prospective, independent, multimodal assessments of substance use. Nevertheless, changes in substance abuse could have been related to readiness for change when starting clozapine or some other underlying factor. We are currently beginning studies employing a prospective design with random assignment to clozapine treatment to confirm the findings reported here. If clozapine is truly more effective than typical neuroleptics in reducing substance use disorder in patients with schizophrenia and schizoaffective disorder, the finding may have important theoretical and clinical implica- disorder and anergia as a group mean (see table 1). Reductions in the severity of alcohol abuse were not significantly correlated with reductions in symptoms of thought disorder (r = 0.005, n = 29, ns), but decreased alcohol severity was strongly correlated with decreases in symptoms of anergia (r = 0.52, n = 32, p = 0.002). Discussion Among this group of patients with schizophrenia or schizoaffective disorder and co-occurring current substance use disorder, clozapine use was strongly related to progress in substance abuse treatment, decreased severity of alcohol abuse, decreased days of alcohol use, and remission of alcohol use disorders. The findings related to other drugs (primarily cannabis) were similar but less consistent and were based on a small number of patients. All of these patients were participating in dual-disorder treatment programs that combined psychosocial interventions for mental illness and substance abuse, and the overall group improved significantly during the 3 years of the study. In this context of active dual-disorder treatment and high rates of remission, those patients who began taking clozapine clearly made greater progress in substance abuse treatment than other patients. Whether or not these patients would have improved without also participating 446 Schizophrenia Bulletin, Vol. 26, No. 2, 2000 Effects of Clozapine on Alcohol and Drug Use Disorders tients with severe mental illness. Assessment, 9:422-428, 1997. tions. From a theoretical perspective, the beneficial effects of clozapine on alcohol use disorder in conjunction with reductions in anergia symptoms suggest that clozapine might have a different effect on the brain reward system than typical antipsychotic drugs (Green et al. 1999). Clozapine has been demonstrated to improve negative as well as positive symptoms of schizophrenia (Kane et al. 1988), and it has been suggested that patients with schizophrenia may use alcohol and other drugs to ameliorate negative symptoms (Khantzian 1997). Several biochemical mechanisms might be involved in clozapine's effects on the central nervous system (Meltzer 1994). Clozapine acts on dopamine, serotonin, and other neurotransmitter systems in the central nervous system (Richelson 1996), and drugs that affect these systems have sometimes been demonstrated to reduce alcohol intake in animal models and in humans (Litten et al. 1996). If our data are confirmed in clinical trials, further studies will be needed to elucidate the mechanisms by which clozapine affects substance use. Our findings are remarkably consistent with several case reports and with the retrospective survey data from Zimmet et al. (2000). If clozapine is truly more effective than traditional antipsychotic medications in reducing comorbid alcohol and drug use disorders among patients with schizophrenia, co-occurrence might be considered another indication for clozapine use. For many patients with schizophrenia, comorbid substance use disorder markedly worsens the course of their illness and adds the additional problems of disinhibition and social instability. Clozapine may be helpful to these patients, and we are aware that clinicians are already trying clozapine based on this possibility. Prospective clinical trials are needed to confirm this potential indication. Carey, K.B.; Cocco, K.M.; and Simons, J.S. 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Journal of Nervous and Mental Disease, 182:591-592,1994. on Alcohol Abuse and Alcoholism grant AA-08341. The authors gratefully acknowledge the assistance of the following individuals in the execution of this work: Lindy Fox, Joan Packard, Theimann Ackerson, Keith Miles, Barbara Helmstetter, and Rosemarie Wolfe. Thanks also to Kim T. Mueser for comments on an earlier draft. The Authors Robert E. Drake, M.D., Ph.D., is Director of the New Hampshire-Dartmouth Psychiatric Research Center, and Professor of Psychiatry, Dartmouth Medical School, Lebanon, NH; Gregory J. McHugo, Ph.D., is a research psychologist at the New Hampshire-Dartmouth Psychiatric Research Center, and Research Associate Professor, Department of Community and Family Medicine, Dartmouth Medical School; Haiyi Xie, Ph.D., is a statistician at the New Hampshire-Dartmouth Psychiatric Research Center, and Research Assistant Professor, Department of Community and Family Medicine, Dartmouth Medical School; and Alan I. Green, M.D., is Director, Commonwealth Research Center, Massachusetts Mental Health Center, and Associate Professor of Psychiatry, Harvard Medical School, Boston, MA. Zimmet, S.V.; Strous, R.D.; Burgess, E.S.; Kohnstamm, S.; and Green, A.I. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: A retrospective survey. Journal of Clinical Psychopharmacology, 20:94-98, 2000. Acknowledgements This work was supported by National Institute of Mental Health grants MH-46072, MH-47567, MH-00839, MH-49891, and MH-52376, and by National Institutes 449