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
Abstract
Several case studies indicate that clozapine use is asso-
ciated with reductions in the use of nicotine, alcohol,
or illicit drugs. Although not designed to assess clozap-
ine, this study explored a posteriori the effects of
clozapine on alcohol and drug use disorders among
schizophrenia patients. Among 151 patients with schiz-
ophrenia or schizoaffective disorder and co-occurring
substance use disorder who were studied in a dual-dis-
order treatment program, 36 received clozapine dur-
ing the study for standard clinical indications. All par-
ticipants 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 random-
ized clinical trials.
Keywords: Schizophrenia, substance abuse, sub-
stance 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
441
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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 func-
tioning (Chouljian et al. 1995), homelessness (Drake et al.
1989), and human immunodeficiency virus (HTV) infec-
tion (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 evi-
dence that typical antipsychotic medications, per se,
decrease substance abuse. Several investigators have in
fact argued that antipsychotic drugs may actually precipi-
tate 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 med-
ications 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 histo-
ries of nicotine dependence (eight also abused other
drugs) reduced their usage of all drugs or attained absti-
nence 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 schizo-
phrenia 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
Sendreprintrequeststo Dr. R. Drake, Psychiatric Research Or., 2 Whipple
Race, Lebanon, NH 03766; email: RobatE.Drake@Daitinouthxdu.
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
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 cloza-
pine therapy and a small number of retrospective inter-
views, 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 standard-
ized, multimodal measures of substance abuse; and in
most cases, the lack of independent assessment The pur-
pose 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 manage-
ment 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 diag-
nosed with DSM—III-R schizophrenia or schizoaffective
disorder, and thus were eligible for treatment with clozap-
ine, 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 disor-
der (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 alco-
hol 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%);
442
R.E. Drake et al.
two-thirds (66.2%) of those with drug use disorder also had
current alcohol use disorder.
Treatments. All participants in the study received treat-
ments in dual-disorder programs in the seven participating
mental health centers. The interventions included medica-
tion management, case management, and rehabilitation
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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 com-
munity, for substance use disorder (Drake et al. 19906).
For the main experimental study, one-half of the partici-
pants were randomly assigned to receive these dual-disor-
der 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 condi-
tions received similar amounts of overall outpatient ser-
vices (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 deci-
sions regarding medications on clinical grounds. As cloza-
pine became available in New Hampshire and was funded
by Medicaid, patients were evaluated clinically for eligi-
bility by their treating psychiatrists. Decisions regarding
clozapine use were made according to the standard crite-
ria of nonresponsiveness to or inability to tolerate typical
antipsychotic medications. Substance abuse was consid-
ered 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 individ-
ual psychiatrists in community mental health centers
based on clinical response. Patients' psychosocial treat-
ments did not change while they were taking clozapine.
Measures. Prior to admission to the study, research psy-
chiatrists 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 sub-
stance use disorder as current was 6 months.
Assessments of substance use at baseline and fol-
lowup included (1) research interviews using the 6-month
Effects of Clozapine on Alcohol and Drug Use Disorders
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 Syva-
Behring); 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 = absti-
nence, 2 = use without impairment, 3 = abuse, 4 = depen-
dence, 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 sus-
pect 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 out-
comes in this study, we therefore used both self-report based
on the TLFB and multimodal ratings of severity. For multi-
modal 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 pre-
viously (Drake et al. 1995). To determine the interrater relia-
bilities, 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 prac-
tice, 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
Schizophrenia Bulletin, Vol. 26, No. 2,2000
Procedures. Patients were referred by clinicians, families,
or themselves between 1989 and 1992. They were evalu-
ated for study criteria by reviews of clinical records and
research interviews with the SCID. All participants gave
written informed consent. They were assessed for sub-
stance use and psychiatric symptoms through independent
research interviews, clinician ratings, and laboratory tests
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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 assess-
ment 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 dif-
ferences on substance use status for patients who spent
some time taking clozapine and some time not taking
clozapine, paired t tests were used. Longitudinal out-
comes 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 cor-
relations can be modeled either by imposing an appropri-
ate correlation structure or by incorporating random com-
ponents 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 mixed-
effects 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 clozap-
ine when they entered the study, and four patients, includ-
ing 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 fol-
lowup 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
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.

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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).
To examine the timing of decreases in relation to
starting clozapine, we examined days of alcohol use dur-
ing 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 cloza-
pine 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 Between-Group Analysis. Since most of the patients in
analysis of patients who took clozapine, we compared the within-group analysis began taking clozapine during
their average scores while taking clozapine with their 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
Severity of drug use 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

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

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•
20 |n=12l
|n=13|
1 •
1
JbJLJLt-3 t-2 t-1
|n-17l

to

Assessmant Point 1
jfl°14|

t+1
|n'10|

t+2 t+3

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 time-
varying independent variable. We included as a covariate
baseline the patient's SATS score, which was the only sig-
nificant 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 differ-
ences 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 assign-
ment and clozapine use were significant
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 start-
ing 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 disor-
der was related neither to the alcohol abuse versus depen-
dence distinction nor to the presence of comorbid drug
use disorder. Among the 65 patients with drug use disor-
der, 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 nega-
tive 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 experi-
enced nonsignificant reductions in symptoms of thought

445
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
- |

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n =>88
1
a
I n »103
n = 97
1• 1 n = 86

•
A
•L. |
£ 50 ' n = 9 6 "•"
n =93

Jt
• clozaplne
O 40 • no ctoz

1I 11
o
o

j\ = 17J
< 30

n = 1
10
baseline 6 mo. 12 mo. 18 mo. 24 mo. 30 mo. 36 mo.
1
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.

disorder and anergia as a group mean (see table 1).
Reductions in the severity of alcohol abuse were not sig-
nificantly 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 sub-
stance 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-disor-
der treatment programs that combined psychosocial inter-
ventions 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 tak-
ing clozapine clearly made greater progress in substance
abuse treatment than other patients. Whether or not these
patients would have improved without also participating
in a dual-disorder treatment program cannot be deter-
mined 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 treat-
ment setting that did not emphasize dual-disorder treat-
ment Moreover, our data reveal little reduction of alcohol
use among the nonclozapine patients, suggesting that
clozapine may have been more effective than the psy-
chosocial interventions.
The findings reported here were not based on a ran-
domized clinical trial design. Although causal inferences
should be cautious, our data offer much stronger evidence
than previous case reports and a single retrospective sur-
vey for the effects of clozapine on psychoactive substance
use because of the large study group, the use of a compar-
ison group that received similar psychosocial interven-
tions, 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 neu-
roleptics in reducing substance use disorder in patients
with schizophrenia and schizoaffective disorder, the find-
ing may have important theoretical and clinical implica-

446
Effects of Clozapine on Alcohol and Drug Use Disorders
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 schizo-
phrenia may use alcohol and other drugs to ameliorate
negative symptoms (Khantzian 1997). Several biochemi-
cal 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 con-
firmed in clinical trials, further studies will be needed to
elucidate the mechanisms by which clozapine affects sub-
stance 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.
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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
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
on Alcohol Abuse and Alcoholism grant AA-08341. The
authors gratefully acknowledge the assistance of the fol-
lowing 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.
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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 statisti-
cian 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.
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