Clozapine-Induced Prevalence and
Weight Gain: Clinical Relevance
Robert Leadbetter, M.D., Michael Shutty, Ph.D., Diane Pavalonis, R.N., M.S.N., Victor Vieweg, M.D., Patricia Higgins, M.S.W., and Marylou Downs, R.N., Ph.D.
Objective: The aim of this study was to determine the prevalence and clinical relevance of weight gain during clozapine treatment. Previous reports indicated clinically significant weightgain in 13% to 85% ofpatients andan averagegain of9.O to 24.7lb. Method: Twentyone state hospital patients with treatment-resistant schizophrenia or schizoaffective disorder were weighed weekly for 12 weeks before clozapine treatment and during the first 16 weeks oftreatment. Psychiatric symptoms were rated with a modified version ofthe Brief Psychiatric Rating Scale (BPRS). Results: The mean weightgain for the entire group was 13.9 Ib, or 8.9% ofbody weight. During the 16 weeks ofclozapine treatment, 38% ofthe patients experienced marked weight gains and 29% had moderate weight gains. The improvements in BPRS total score and composite negative symptom score were significantly greater for the eight patients with marked weightgains than for the other 13 patients. Conclusions: Clozapine’s propensity to induce weight gain may relate to the drug’s efficacy and/or its unique neuropharmacologic effects. Increased attention to this phenomenon is important because ofthe morbidity associated with obesity. (Am J Psychiatry 1992; 149:68-72)
M
any patients with schizophrenia suffer from obesity (1-3), which is associated with excessive rates of morbidity and mortality (4). Institutionalization, lack of exercise, poor diet, and misperception of satiety have been linked to the high prevalence of obesity in schizophrenia (2, 3, 5, 6). Studies have shown that weight changes relate to the severity of psychosis (3) and that weight gain is associated with clinical improvement (3, 7-9). Chlorpromazine treatment is frequently associated with weight gain (3, 4, 8-12). Other standard antipsychotic
drugs
associated
phenazine and and thiothixene, contrast,
molindone
with
clopenthixol halopenidol, (10,
weight
gain
include
(4), fluphenazine and thionidazine
17) and
loxapine
(12)
pen-
(12-16), (12). In appear
to
Presented at the 143rd annual meeting of the American Psychiatric Association, New York, May 12-17, 1990. Received Dec. 10, 1990; revision received May 29, 1991; accepted July 24, 1991. From the Clinical Studies Unit, Western State Hospital, Department of Mental Health and Mental Retardation and Substance Abuse Services, Commonwealth of Virginia, and the Department of Behavioral Medicine and Psychiatry, University ofVirginia School ofMedicine, Charlottesville. Address reprint requests to Dr. Leadbetter, Western State Hospital, P.O. Box 2500, Staunton, VA 24401. The authors thank the staff of the Western State Hospital Clinical Studies Unit for help with this study and Drs. Hundley and McKeegan for help in identifying and understanding clozapine-induced weight gain. Copyright © 1992 American Psychiatric Association.
68
cause weight loss. Amdisen (4) found that patients treated with antipsychotic agents reached weights associated with mortality
rates
35%
to 100%
higher
than
normal.
Singh
et al. (7) showed that perphenazine increases appetite and caloric intake and perhaps increases metabolic efficiency and alters the body weight set point. Clozapine is an atypical antipsychotic considered to have superior efficacy for patients with treatment-resistant
psychosis
% prevalence (1 9). However, (20) reported 1
( 1 8). The
drug’s
manufacturer
of weight gain among as early as 1 975 Norris dramatic clozapine-induced
noted
a
13,000 patients and Isnaelstam weight gain
in a group of 1 3 hospitalized adolescents with behaviomal problems or acute schizophrenia. Nine of these patients “experienced an enormous increase in appe-
tite,” and four patients 2 months of treatment. 27)
have
ment
associated
in 13%
weight
gain
to was
gained 22-44 lb during the first Since then, various studies (21weight
85% 9.0
gain
with
of patients,
to 24.7
lb. This
clozapine
and
the
wide
range
treat-
average of ne-
ported weight gains stems in part from methodological differences among studies. For example, whether weight fluctuations were assessed during medication withdrawal is unclear in most reports. Also, other clinical
or
neurobiological
factors
correlating
with
weight
changes were not accounted for in these patients. During the preclinical trials of clozapine, we noted that many patients gained weight early in treatment
Am
J
Psychiatry
149:1,
January
1992
LEADBE1TER,
(28). Because weight gained
of the wide in previous
variance studies
between these findings and we examined the prevalence
in the and the
amounts discrepancy
of
METhOD
Subjects
and
Procedure
We studied
21 patients
The
facility.
and their
subjects
mean
inclusionary
at a 600-bed
were
age was 32.6
criteria
were
state
1 3 men
years
and
psychiatric
eight
women,
(range=19-47).
a diagnosis
The
of schizophrenia
or schizoaffective disorder (DSM-III-R) and one of the following: 1 ) lack of response to adequate trials of 5evenal standard antipsychotic drugs, 2) intolerable side effects of those drugs, on 3) tandive dyskinesia. The exclusionany criteria were 1) a history of drug-induced agranulocytosis,
primary
2) bone
seizure
Treatment
marrow
abnormalities,
or 3)
a
disorder. with
and
carbamazepine
depot
neuroleptic
agents was stopped 2 weeks before the beginning of dozapine treatment. Standard antipsychotic and anticholinergic drugs were tapered over 1-4 weeks; the drug-free period was 24 to 48 hours. We increased the clozapine
dose the
from dose
weighed weight)
25 to 125 mg/week until
the
a therapeutic
patients
as tolerated response
weekly
and
was
with
We
(counter-
hospital scales during the 12 weeks before and after the beginning of clozapine treatment, and weight was based on established formulae (29).
1 6 weeks
ideal
Marked weight gain 1 2 3 4 S 6 7 8 Moderate weight gain 9 10 11 12 13 14 Mild/minimal weight gain
is 16 17 18 Weight 19 20 21
We chose a modified version of the Brief Psychiatric Rating Scale (BPRS) to rate symptoms (30). A trained
(1 8). Where
RESULTS
correlation coefficient interviews was 0.77 staff members.
Analyses
analyses
in three
phases.
First, we compared the patients’ weekly weights during the 12-week baseline period to the weights in the first 12
weeks
of clozapine
treatment,
both
as a group
and
individually, to assess whether a net weight gain was evident after conversion from standard neuroleptics to clozapine. We evaluated pre-post changes in weight gain using two-tailed, pained t tests. All remaining analyses focused on the weight changes from the start
of clozapine treatment to the 16th week of treatment. We divided the patients into two groups on the basis of amount of weight gained and determined group differences
Am
in age,
J
Psychiatry
gender,
149:1,
pretreatment
January
deviation
1992
Clozapine
16
M M F M M F M F
158.0 194.0 148.0 152.0 161.0 120.0 147.0 155.0
197.0 239.0 178.5 179.0 188.0 140.0 170.0 174.0
+39.0 +45.0 +30.5 +27.0 +27.0 +20.0 +23.0 +19.0
24.7 23.2 20.6 17.0 16.8 16.7 15.6 12.3
M M M F F M
119.0 183.3 153.5 135.0 170.0 155.0
130.0 196.5 164.0 144.0 180.0 163.5
+11.0 +13.2 +10.5 +9.0 +10.0 +8.5
9.2 7.2 6.8 6.7 5.8 5.5
M M F M
116.0 203.5 178.5 172.8
121.0 210.5 182.0 173.0
+5.0 +7.0 +3.5 +0.2
4.3 3.4 1.9 0.1
F F M
131.0 111.5 201.3
128.0 107.5 191.0
-3.0 -4.0 -10.3
2.3 3.6 5.1
Pounds
%
from
ideal
amount of weight change during taantipsychotics. Third, we explored
the clinical aspects of weight gain by comparing differences in concurrent treatment with lithium psychiatric symptom ratings, using BPRS total and composite positive and negative symptom
ing the prior week. The intraclass for BPRS ratings of 13 videotaped for eight trained multidisciplinary
our statistical
Sex
body weight, and pening of standard
the three statistical
We conducted
Change
Week
loss
rater used a semistructured interview format to interview the patient and then consulted with other staff members and reviewed the patient’s record before deriving a BPRS scone. All ratings related to the patient’s functioning dur-
Statistical
Clozapine
titrated
achieved.
standard
Patient
ET AL.
(lb)
Berore
clinical correlates of this factors that might ex-
PAVALONIS,
in Patients R eceiving
1. Individ ual Weigh t Changes
Weight
the drug company’s data, and magnitude of cloza-
pine-induced weight gain, the problem, and the neurobiological plain this phenomenon.
TABLE
SHUTIY,
t tests
roni
and
appropriate, chi-squane
corrections
we used analyses
to adjust
sets of analyses significance.
two-tailed,
and our
the preceding
df=20,
12 weeks
13 (62%) (Bonfernoni
experienced correction,
tients lost weight chotics, but the
was significantly
(t=2.86,
examined
during absolute
individually,
p
Weight Gain: Clinical Relevance
Robert Leadbetter, M.D., Michael Shutty, Ph.D., Diane Pavalonis, R.N., M.S.N., Victor Vieweg, M.D., Patricia Higgins, M.S.W., and Marylou Downs, R.N., Ph.D.
Objective: The aim of this study was to determine the prevalence and clinical relevance of weight gain during clozapine treatment. Previous reports indicated clinically significant weightgain in 13% to 85% ofpatients andan averagegain of9.O to 24.7lb. Method: Twentyone state hospital patients with treatment-resistant schizophrenia or schizoaffective disorder were weighed weekly for 12 weeks before clozapine treatment and during the first 16 weeks oftreatment. Psychiatric symptoms were rated with a modified version ofthe Brief Psychiatric Rating Scale (BPRS). Results: The mean weightgain for the entire group was 13.9 Ib, or 8.9% ofbody weight. During the 16 weeks ofclozapine treatment, 38% ofthe patients experienced marked weight gains and 29% had moderate weight gains. The improvements in BPRS total score and composite negative symptom score were significantly greater for the eight patients with marked weightgains than for the other 13 patients. Conclusions: Clozapine’s propensity to induce weight gain may relate to the drug’s efficacy and/or its unique neuropharmacologic effects. Increased attention to this phenomenon is important because ofthe morbidity associated with obesity. (Am J Psychiatry 1992; 149:68-72)
M
any patients with schizophrenia suffer from obesity (1-3), which is associated with excessive rates of morbidity and mortality (4). Institutionalization, lack of exercise, poor diet, and misperception of satiety have been linked to the high prevalence of obesity in schizophrenia (2, 3, 5, 6). Studies have shown that weight changes relate to the severity of psychosis (3) and that weight gain is associated with clinical improvement (3, 7-9). Chlorpromazine treatment is frequently associated with weight gain (3, 4, 8-12). Other standard antipsychotic
drugs
associated
phenazine and and thiothixene, contrast,
molindone
with
clopenthixol halopenidol, (10,
weight
gain
include
(4), fluphenazine and thionidazine
17) and
loxapine
(12)
pen-
(12-16), (12). In appear
to
Presented at the 143rd annual meeting of the American Psychiatric Association, New York, May 12-17, 1990. Received Dec. 10, 1990; revision received May 29, 1991; accepted July 24, 1991. From the Clinical Studies Unit, Western State Hospital, Department of Mental Health and Mental Retardation and Substance Abuse Services, Commonwealth of Virginia, and the Department of Behavioral Medicine and Psychiatry, University ofVirginia School ofMedicine, Charlottesville. Address reprint requests to Dr. Leadbetter, Western State Hospital, P.O. Box 2500, Staunton, VA 24401. The authors thank the staff of the Western State Hospital Clinical Studies Unit for help with this study and Drs. Hundley and McKeegan for help in identifying and understanding clozapine-induced weight gain. Copyright © 1992 American Psychiatric Association.
68
cause weight loss. Amdisen (4) found that patients treated with antipsychotic agents reached weights associated with mortality
rates
35%
to 100%
higher
than
normal.
Singh
et al. (7) showed that perphenazine increases appetite and caloric intake and perhaps increases metabolic efficiency and alters the body weight set point. Clozapine is an atypical antipsychotic considered to have superior efficacy for patients with treatment-resistant
psychosis
% prevalence (1 9). However, (20) reported 1
( 1 8). The
drug’s
manufacturer
of weight gain among as early as 1 975 Norris dramatic clozapine-induced
noted
a
13,000 patients and Isnaelstam weight gain
in a group of 1 3 hospitalized adolescents with behaviomal problems or acute schizophrenia. Nine of these patients “experienced an enormous increase in appe-
tite,” and four patients 2 months of treatment. 27)
have
ment
associated
in 13%
weight
gain
to was
gained 22-44 lb during the first Since then, various studies (21weight
85% 9.0
gain
with
of patients,
to 24.7
lb. This
clozapine
and
the
wide
range
treat-
average of ne-
ported weight gains stems in part from methodological differences among studies. For example, whether weight fluctuations were assessed during medication withdrawal is unclear in most reports. Also, other clinical
or
neurobiological
factors
correlating
with
weight
changes were not accounted for in these patients. During the preclinical trials of clozapine, we noted that many patients gained weight early in treatment
Am
J
Psychiatry
149:1,
January
1992
LEADBE1TER,
(28). Because weight gained
of the wide in previous
variance studies
between these findings and we examined the prevalence
in the and the
amounts discrepancy
of
METhOD
Subjects
and
Procedure
We studied
21 patients
The
facility.
and their
subjects
mean
inclusionary
at a 600-bed
were
age was 32.6
criteria
were
state
1 3 men
years
and
psychiatric
eight
women,
(range=19-47).
a diagnosis
The
of schizophrenia
or schizoaffective disorder (DSM-III-R) and one of the following: 1 ) lack of response to adequate trials of 5evenal standard antipsychotic drugs, 2) intolerable side effects of those drugs, on 3) tandive dyskinesia. The exclusionany criteria were 1) a history of drug-induced agranulocytosis,
primary
2) bone
seizure
Treatment
marrow
abnormalities,
or 3)
a
disorder. with
and
carbamazepine
depot
neuroleptic
agents was stopped 2 weeks before the beginning of dozapine treatment. Standard antipsychotic and anticholinergic drugs were tapered over 1-4 weeks; the drug-free period was 24 to 48 hours. We increased the clozapine
dose the
from dose
weighed weight)
25 to 125 mg/week until
the
a therapeutic
patients
as tolerated response
weekly
and
was
with
We
(counter-
hospital scales during the 12 weeks before and after the beginning of clozapine treatment, and weight was based on established formulae (29).
1 6 weeks
ideal
Marked weight gain 1 2 3 4 S 6 7 8 Moderate weight gain 9 10 11 12 13 14 Mild/minimal weight gain
is 16 17 18 Weight 19 20 21
We chose a modified version of the Brief Psychiatric Rating Scale (BPRS) to rate symptoms (30). A trained
(1 8). Where
RESULTS
correlation coefficient interviews was 0.77 staff members.
Analyses
analyses
in three
phases.
First, we compared the patients’ weekly weights during the 12-week baseline period to the weights in the first 12
weeks
of clozapine
treatment,
both
as a group
and
individually, to assess whether a net weight gain was evident after conversion from standard neuroleptics to clozapine. We evaluated pre-post changes in weight gain using two-tailed, pained t tests. All remaining analyses focused on the weight changes from the start
of clozapine treatment to the 16th week of treatment. We divided the patients into two groups on the basis of amount of weight gained and determined group differences
Am
in age,
J
Psychiatry
gender,
149:1,
pretreatment
January
deviation
1992
Clozapine
16
M M F M M F M F
158.0 194.0 148.0 152.0 161.0 120.0 147.0 155.0
197.0 239.0 178.5 179.0 188.0 140.0 170.0 174.0
+39.0 +45.0 +30.5 +27.0 +27.0 +20.0 +23.0 +19.0
24.7 23.2 20.6 17.0 16.8 16.7 15.6 12.3
M M M F F M
119.0 183.3 153.5 135.0 170.0 155.0
130.0 196.5 164.0 144.0 180.0 163.5
+11.0 +13.2 +10.5 +9.0 +10.0 +8.5
9.2 7.2 6.8 6.7 5.8 5.5
M M F M
116.0 203.5 178.5 172.8
121.0 210.5 182.0 173.0
+5.0 +7.0 +3.5 +0.2
4.3 3.4 1.9 0.1
F F M
131.0 111.5 201.3
128.0 107.5 191.0
-3.0 -4.0 -10.3
2.3 3.6 5.1
Pounds
%
from
ideal
amount of weight change during taantipsychotics. Third, we explored
the clinical aspects of weight gain by comparing differences in concurrent treatment with lithium psychiatric symptom ratings, using BPRS total and composite positive and negative symptom
ing the prior week. The intraclass for BPRS ratings of 13 videotaped for eight trained multidisciplinary
our statistical
Sex
body weight, and pening of standard
the three statistical
We conducted
Change
Week
loss
rater used a semistructured interview format to interview the patient and then consulted with other staff members and reviewed the patient’s record before deriving a BPRS scone. All ratings related to the patient’s functioning dur-
Statistical
Clozapine
titrated
achieved.
standard
Patient
ET AL.
(lb)
Berore
clinical correlates of this factors that might ex-
PAVALONIS,
in Patients R eceiving
1. Individ ual Weigh t Changes
Weight
the drug company’s data, and magnitude of cloza-
pine-induced weight gain, the problem, and the neurobiological plain this phenomenon.
TABLE
SHUTIY,
t tests
roni
and
appropriate, chi-squane
corrections
we used analyses
to adjust
sets of analyses significance.
two-tailed,
and our
the preceding
df=20,
12 weeks
13 (62%) (Bonfernoni
experienced correction,
tients lost weight chotics, but the
was significantly
(t=2.86,
examined
during absolute
individually,
p
