Diabetes mellitus among outpatients receiving clozapine: Prevalence and clinical-demographic correlates

Article (PDF Available)inThe Journal of Clinical Psychiatry 66(7):900-6 · August 2005with111 Reads
DOI: 10.4088/JCP.v66n0713 · Source: PubMed
Abstract
Treatment with antipsychotic drugs has been associated with increased risk for developing diabetes mellitus. Recent consensus statements suggest that clozapine may pose an especially high risk. The purpose of this study is to examine the prevalence and clinical-demographic correlates of diabetes among outpatients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder receiving clozapine. One hundred one outpatients receiving clozapine at the University of Rochester Department of Psychiatry, Rochester, N.Y., were evaluated between September 2002 and September 2003. Demographic data were collected from medical records, and body mass index (BMI) and body fat measurements were conducted. Diagnosis of diabetes was established through review of medical records and fasting blood glucose testing. Associations between clinical and demographic variables and diabetes were examined using t tests, Fisher exact tests, and logistic regression. Mean (SD) age of patients was 40.4 (9.5) years, and 79% were white. Mean (SD) dose and duration of clozapine treatment were 426 (164) mg/day and 5.7 (3.6) years, respectively. Point prevalence of diabetes was 25.7%. Mean (SD) BMI was 32.6 (8.0) kg/m(2), and mean (SD) body fat was 34.0% (11.0%). Logistic regression revealed significant associations between diabetes and nonwhite race/ethnicity and family history of diabetes (p = .02 and .002, respectively). No significant associations were found between diabetes prevalence and BMI or body fat. Patients receiving clozapine are at substantial risk for developing diabetes, although the level of risk relative to other antipsychotic medications has not been fully determined. Clinicians should monitor all severely mentally ill patients receiving antipsychotic drugs for diabetes, with closer monitoring of patients with established demographic risk factors.
Lamberti et al.
900 J Clin Psychiatry 66:7, July 2005
rowing evidence suggests that clozapine treatment
is associated with an increased risk for developing
Diabetes Mellitus Among Outpatients Receiving Clozapine:
Prevalence and Clinical-Demographic Correlates
J. Steven Lamberti, M.D.; G. Oana Costea, M.D.;
David Olson, Ph.D., R.Ph.; John F. Crilly, M.D.; Kumar Maharaj, R.Ph., M.S.B.A.;
Xin Tu, Ph.D.; Adrienne Groman, M.S.; Marci B. Dietz, M.S., R.N., C.S.;
Margaret P. Bushey, M.S., N.P.; Telva Olivares, M.D.; and Karen Wiener, M.D.
Background: Treatment with antipsychotic
drugs has been associated with increased risk
for developing diabetes mellitus. Recent consen-
sus statements suggest that clozapine may pose
an especially high risk. The purpose of this
study is to examine the prevalence and clinical-
demographic correlates of diabetes among outpa-
tients with DSM-IV–diagnosed schizophrenia or
schizoaffective disorder receiving clozapine.
Method: One hundred one outpatients receiv-
ing clozapine at the University of Rochester De-
partment of Psychiatry, Rochester, N.Y., were
evaluated between September 2002 and Septem-
ber 2003. Demographic data were collected from
medical records, and body mass index (BMI) and
body fat measurements were conducted. Diagno-
sis of diabetes was established through review of
medical records and fasting blood glucose testing.
Associations between clinical and demographic
variables and diabetes were examined using
t tests, Fisher exact tests, and logistic regression.
Results: Mean (SD) age of patients was 40.4
(9.5) years, and 79% were white. Mean (SD)
dose and duration of clozapine treatment were
426 (164) mg/day and 5.7 (3.6) years, respec-
tively. Point prevalence of diabetes was 25.7%.
Mean (SD) BMI was 32.6 (8.0) kg/m
2
, and mean
(SD) body fat was 34.0% (11.0%). Logistic re-
gression revealed significant associations be-
tween diabetes and nonwhite race/ethnicity and
family history of diabetes (p = .02 and .002, re-
spectively). No significant associations were
found between diabetes prevalence and BMI or
body fat.
Conclusion: Patients receiving clozapine
are at substantial risk for developing diabetes,
although the level of risk relative to other antipsy-
chotic medications has not been fully determined.
Clinicians should monitor all severely mentally
ill patients receiving antipsychotic drugs for dia-
betes, with closer monitoring of patients with
established demographic risk factors.
(J Clin Psychiatry 2005;66:900–906)
G
diabetes mellitus. Since publication of the first report
of hyperglycemia associated with clozapine in 1994,
1
37 additional cases have been described in case reports
and small case series.
2–28
These reports describe cases
of transient hyperglycemia,
1,8,11,20,21,24
diabetic ketoacido-
sis,
2–4,6,7,10,13–18,23–28
new onset diabetes mellitus,
7,10,12,19,22
and exacerbation of preexisting diabetes.
7,9
In addition to
case reports, recently published clinical studies have ex-
amined the association between clozapine, insulin levels,
glucose abnormalities, and diabetes.
29–49
The prevalence
of diabetes in these studies has ranged from 4% in a Med-
icaid claims study of 531 patients
44
to 36.6% in a 5-year
naturalistic study of 82 patients.
36
Some studies suggest that clozapine is associated with
a greater risk of diabetes than other antipsychotic medica-
tions,
31–37
while other studies do not.
42–48,50
Despite incon-
sistencies in the literature, a consensus is emerging that
clozapine treatment is associated with an especially high
risk of diabetes relative to other medications.
51,52
Yet clo-
zapine remains a valuable treatment for schizophrenia be-
cause of its superior effectiveness.
52
Research is therefore
needed to identify risk factors for diabetes among patients
requiring clozapine therapy.
The relationship between established risk factors
for diabetes mellitus and the likelihood of developing
clozapine-associated diabetes is unclear. Increasing age is
a known risk factor for diabetes in general,
53
and some
Received Sept. 10, 2004; accepted Jan. 1, 2005. From the Department
of Psychiatry, University of Rochester Medical Center, Rochester, N.Y.
This work was supported by a grant from the Committee to Aid
Research to End Schizophrenia, Pittsford, N.Y.
Presented at the 156th annual meeting of the American Psychiatric
Association, San Francisco, Calif., May 17–22, 2003.
Dr. Lamberti has been a consultant for and has served on the
speakers or advisory boards of Eli Lilly, Janssen, Pfizer, AstraZeneca,
and Novartis; and has received grant/research support from Eli Lilly,
Janssen, and Bristol-Myers Squibb. Dr. Weiner has served on the
speakers or advisory boards of AstraZeneca and Eli Lilly. No other
author reported any disclosures.
Corresponding author and reprints: J. Steven Lamberti, M.D.,
Department of Psychiatry, University of Rochester Medical Center,
300 Crittenden Blvd., Rochester, NY 14642
(e-mail: steve_lamberti@urmc.rochester.edu).
Diabetes Mellitus in Outpatients Receiving Clozapine
J Clin Psychiatry 66:7, July 2005 901
studies have reported a higher prevalence of glucose ab-
normalities among older clozapine-treated patients.
34–36
However, in a U.S. Food and Drug Administration (FDA)
database study,
37
Koller et al. found the highest frequency
of clozapine-associated diabetes among 31 to 50 year
olds. This finding contrasted with the general population,
where the frequency of diabetes peaks in the 65- to
74-year-old cohort.
37
Lund et al.
44
found an increased risk
of diabetes with clozapine only among patients aged 20 to
34 years, while Buse et al.
46
failed to find a significant
hazard ratio of diabetes for age with clozapine. Likewise,
Sernyak et al.
33
found clozapine to be associated with an
increased prevalence of diabetes in patients younger than
50 years, while no significant increase was found in pa-
tients older than 60.
The prevalence of diabetes is approximately 2-fold
greater in African Americans, Hispanic Americans, and
Native Americans compared with non-Hispanic whites,
53
but few studies have examined the role of race/ethnicity
in clozapine-associated diabetes. Of FDA database cases
in which racial information was provided, 58% of patients
with clozapine-associated diabetes were of African
descent.
37
Also, African Americans and African Caribbe-
ans are overrepresented in case reports of clozapine-
associated glucose abnormalities, totaling nearly half of
all reported cases.
1,2,4,7,10,13,14,17,21,24,26
Family history is another well-established risk factor
for diabetes mellitus within the general population.
53
Of
23 case reports that contained information about family
history, 6 patients had a positive family history of diabe-
tes.
2–4,7,10,16
Also, 4 of 13 diabetic clozapine-treated pa-
tients in a study by Hägg et al.
32
had positive family histo-
ries. However, Henderson et al.
36
reported a positive
family history of diabetes in only 2 of 82 clozapine-
treated patients, of which 30 developed diabetes. Results
regarding gender as a risk factor for clozapine-associated
diabetes have also been mixed. While 32 of 38 published
case reports have involved male patients, increased preva-
lence of clozapine-associated diabetes among women has
been reported by both Koller et al.
37
and Hägg et al.
32
Obesity is a strong predictor of diabetes in the general
population.
53
However, few published studies have exam-
ined the relationship between clozapine-associated obe-
sity and diabetes to date. In Henderson and colleagues’
5-year study
36
of 82 outpatients receiving clozapine,
weight and body mass index (BMI) were not associated
with the development of diabetes. Also, Lindenmayer and
colleagues’ 14-week study
49
that included 27 clozapine-
treated patients found no treatment interaction for the re-
lationship between glucose change and weight gain at
endpoint.
Our current understanding of clozapine-associated dia-
betes is limited by available data that primarily consist of
case reports and small clinical studies. This article pre-
sents a study of a sizeable group of persons with schizo-
phrenia or schizoaffective disorder receiving clozapine
within an outpatient treatment setting. The goal of the
study is to examine the relationship between the presence
of diabetes mellitus and established clinical-demographic
risk factors within this cohort.
METHOD
Subjects
This study was conducted at Strong Ties Community
Support Program, an outpatient clinic of the University
of Rochester Medical Center Department of Psychiatry,
Rochester, N.Y., specializing in care of severely mentally
ill adults. In addition to outpatient psychiatric treatment
and case management services, Strong Ties offers phar-
macy and primary medical care services to all enrolled
patients. The study was approved by the University of
Rochester Medical Center Research Subjects Review
Board.
Patients receiving clozapine were identified through
review of the Strong Ties pharmacy database and were
contacted and given a complete description of the study.
Written informed consent was subsequently obtained
from 101 patients who participated in the study between
September 2002 and September 2003. Patients receiving
clozapine less than 3 months or with a documented his-
tory of diabetes prior to age 18 were excluded from study
participation.
Data Collection
Medical records were reviewed, and the following data
were obtained for all subjects: age, race/ethnicity, gender,
presence or absence of diabetes diagnosis, clozapine dose
and start date, date of first antipsychotic drug use, and
number and type of concomitant medications. Family his-
tory of diabetes was determined by review of medical
records and by subject interview in the absence of docu-
mentation. All patients had received a DSM-IV clinical
diagnosis of either schizophrenia (N = 62) or schizoaffec-
tive disorder (N = 39) from their treating psychiatrists.
For subjects with documented diabetes, date of diabe-
tes diagnosis, presence of diabetes treatment, and the date
of the last normal fasting blood glucose prior to diabetes
diagnosis were recorded. Whenever pertinent dates in the
medical record were unclear, either the last day of the
month or the last month of the year was used. When dates
of psychiatric hospitalizations were available without in-
formation about drug therapy at the time, the date of dis-
charge from the second hospitalization was used as the
date of first antipsychotic use. The first documentation in
the chart of diabetes was used as the date of diagnosis
whenever the actual date of diagnosis was unclear.
Subjects received BMI and percentage body fat mea-
surements using a Tanita Body Composition Analyzer
model TBF-300 (Tanita Corp. of America, Inc., Arlington
Lamberti et al.
902 J Clin Psychiatry 66:7, July 2005
Heights, Ill.). This device is accurate within ± 5% of dual
energy X-ray absorptiometry (DEXA),
54
the institutional
standard of body composition analysis. Subjects without
a documented history of diabetes mellitus underwent fast-
ing blood glucose testing using standard procedures. Di-
agnosis of diabetes was made for subjects having a fasting
blood glucose level equal to or greater than 126 mg/dL on
2 occasions, consistent with American Diabetes Associa-
tion diagnostic criteria.
55
All data were transcribed into
data collection forms and entered into a secure Microsoft
Access (Microsoft Corp., Redmond, Wash.) database.
Data Analysis
Data analysis was conducted using SAS version 8.2
(SAS Institute, Inc., Cary, N.C.). The following continu-
ous variables were examined on study subjects: age, per-
centage body fat, BMI, total years of antipsychotic drug
treatment, years of clozapine treatment, clozapine dose,
and age when clozapine was first prescribed. To deter-
mine if the means of the continuous variables varied be-
tween diabetics and nondiabetics, t tests were performed
on each variable. Categorical variables collected on each
of the patients included gender, race/ethnicity, family
history, use of a selective serotonin reuptake inhibitor
(SSRI), use of divalproex sodium, and use of a second
antipsychotic drug. Fisher exact tests were used to test for
associations between the categorical variables and diabe-
tes status.
All tests performed were 2-sided, with significance
level α = .05, unless noted otherwise. A stepwise selection
logistic regression model with the response variable dia-
betes (yes/no) was used to determine all significant pre-
dictors of the presence of diabetes.
RESULTS
Mean (SD) age of subjects was 40.4 (9.5) years, and
66.3% were male. Eighty subjects (79.2%) were white,
and the remaining 21 (21.8%) were African American
(16 subjects), Hispanic (2 subjects), Native American (2
subjects), and other race/ethnicity (1 subject). Twenty-six
subjects (25.7%) had a positive family history of diabetes.
Mean (SD) age upon initiation of clozapine treatment was
34.6 (8.9) years, and mean (SD) age at time of diabetes
diagnosis was 38.9 (8.04) years. Mean (SD) dose of cloza-
pine at the time of study enrollment was 426 (164)
mg/day. Mean (SD) duration of clozapine treatment was
5.7 (3.6) years, and mean (SD) total duration of anti-
psychotic drug treatment was 15.4 (7.9) years. The most
commonly prescribed concomitant medications were ben-
zodiazepines (31.7%, 32 subjects), divalproex sodium
(26.7%, 27 subjects), and SSRIs (21.8%, 22 subjects). In
addition, 25.7% (26 subjects) were receiving a second
antipsychotic medication in addition to clozapine at the
time of enrollment. Of the 26 subjects receiving a second
antipsychotic medication, 12 received quetiapine, 7 re-
ceived risperidone, 3 received haloperidol, 2 received
ziprasidone, 1 received thiothixene, and 1 received olan-
zapine. No subjects were receiving corticosteroids or
protease inhibitors, both medications known to cause
diabetes.
Point prevalence of diabetes mellitus in the study group
was 25.7% (26 subjects). Twenty-one of the 26 subjects
had a documented diagnosis of diabetes in their medical
records at the time of study enrollment, with 5 subjects
being newly diagnosed by fasting blood glucose testing
under the study protocol. Among patients diagnosed with
diabetes after clozapine initiation, mean (SD) time to di-
abetes diagnosis following initiation was 3.7 (3.1) years
(range, 0.04–9.7 years). Prevalence rates of diabetes by
age, gender, race/ethnicity, family history of diabetes,
body mass index, and percentage body fat appear in Table
1. Mean (SD) BMI for the group was 32.6 (8.0) kg/m
2
.
Mean (SD) percentage body fat was 34.0% (11.0%), with
percentages for men and women of 29.2% (9.1%) and
43.7% (7.2%), respectively. Analyses of the continuous
variables and diabetes status resulted in only 1 significant
association. Mean (SD) age at clozapine initiation was
significantly older for patients with diabetes (37.6 years
[7.9]) than for those without (33.6 years [9.1]) (t test,
p=.05), although mean ages of the groups did not differ
significantly.
Analyses of the categorical variables and diabetes sta-
tus resulted in significant associations with race/ethnicity
and with family history. Race/ethnicity was first catego-
rized into 5 groups: white, African American, Hispanic,
Table 1. Diabetes Prevalence by Demographic and Clinical
Categories Among Patients With Schizophrenia and
Schizoaffective Disorder Taking Clozapine (N = 101)
Category N/N Prevalence, % p Value
a
Age group, y .23
18–30 2/16 12.5
31–40 9/35 25.7
41–50 8/34 23.5
Over 50 7/16 43.8
Gender .34
Male 15/67 22.4
Female 11/34 32.4
Race/ethnicity .02
White 16/80 20.0
Nonwhite 10/21 47.6
Family history .002
Positive 13/26 50.0
Negative/unknown 13/75 17.3
Body mass index, kg/m
2
.77
30 17/59 28.4
<25 4/17 23.5
Body fat, men .75
30% 10/37 27.0
< 25% 4/20 20.0
Body fat, women .33
25% 10/32 31.3
< 20% 1/1 100.0
a
p Values are based on Fisher exact test.
Diabetes Mellitus in Outpatients Receiving Clozapine
J Clin Psychiatry 66:7, July 2005 903
Native American, and other. The prevalence of diabetes
for each group was 20.0% (16 of 80 subjects), 43.8% (7 of
16), 50.0% (1 of 2), 100.0% (2 of 2), and 0%, respectively.
A significant difference between groups was found using
Fisher exact test (p = .029). As shown in Table 1, signifi-
cant differences in diabetes prevalence were also noted
comparing the categories white and nonwhite, and family
history positive and negative. Presence of a second anti-
psychotic drug was associated with a trend toward a higher
prevalence of diabetes compared with the absence of a
second antipsychotic drug (38.5% vs. 21.3%, respectively;
p=.118). No association was noted between prevalence of
diabetes and use of divalproex sodium, benzodiazepines,
or SSRIs.
Logistic regression was used to examine variables that
were associated with diagnosis of diabetes. By initially in-
cluding the variables years of antipsychotic drug treat-
ment, years of clozapine treatment, BMI, percentage body
fat, age at the time of clozapine initiation, divalproex, race/
ethnicity (white vs. nonwhite), gender, family history, cur-
rent age, SSRIs, second antipsychotic drug, and benzo-
diazepines, the stepwise model selection procedure was
used to trim the variables in the initial model. The final
reduced model included only race/ethnicity (p = .02) and
family history (p = .002). The odds of a nonwhite patient
having diabetes were 3.6 times the odds of a white patient
when all other variables were held constant (95% CI = 1.2
to 11.1 times). The odds of a patient with a family history
of diabetes having diabetes were 5.5 times the odds of
a patient with a negative or unknown family history when
all other variables were held constant (95% CI = 2.0 to
14.9 times).
DISCUSSION
Our results appear to confirm previous reports of an
increased risk for developing diabetes mellitus among pa-
tients receiving clozapine. The 25.7% diabetes prevalence
is considerably higher than the 7.9% general adult popula-
tion rate, a difference that extends across comparable age
categories.
56
This prevalence rate also exceeds the 14.9%
rate found among adults in the general population with
BMIs between 30 and 39.9, considering the 32.6 BMI of
the study cohort.
56
While previous studies examining clozapine-associated
weight gain and diabetes
36,49
as well as the present study
have found no relationship, these negative results are
likely due to methodologic limitations of each study. Stud-
ies to date have failed to account for the significant delay
between weight gain and the onset of diabetes that typi-
cally occurs in genetically vulnerable patients. It is well
established that increases in adiposity are associated with
decreased insulin sensitivity that leads to compensatory
hyperinsulinemia.
53,57
This process allows plasma glucose
to remain well controlled over many years before the
emergence of diabetes in susceptible individuals. The
present study is also limited by other methodological
weaknesses. Specifically, analysis was performed by us-
ing a cutoff of 126 mg/dL for the diagnosis of diabetes
rather than considering fasting glucose as a continuous
variable that changes over time. In addition, the study’s
substantially obese patient sample provided little oppor-
tunity to compare obese with nonobese patients. Also, the
study examined associations between previous diagnoses
of diabetes and current BMIs. Given the strong associa-
tion between increased adiposity and decreased insulin
sensitivity and diabetes within the general population,
53,57
it seems unlikely that this relationship would not exist in
severely mentally ill patients with clozapine-associated
obesity. Optimal evaluation of associations between dia-
betes and body weight requires a prospective randomized
study in which relationships between diabetes incidence
rates and changes in weight and adiposity are examined
over an extended period of time.
Race/ethnicity and family history of diabetes are well
established risk factors within the general population.
53
Study findings of increased diabetes prevalence rates
among nonwhite patients and those with positive family
histories are consistent with previous reports suggesting
that these variables are important risk factors among
clozapine-treated patients. In addition, the 25.7% rate of
family history of diabetes in this study is consistent with
previous reports of positive family history rates ranging
from 18% to 30% among patients with schizophrenia.
58
These rates are substantially higher than the 1.2% to 6.3%
rates among the general population
59
and may be indic-
ative of vulnerability to diabetes among patients with
schizophrenia. The lack of association between age and
diabetes prevalence is somewhat surprising given the es-
tablished role of age as a general population risk factor.
Considering that numeric differences were found between
age categories, it is possible that significant differences
may have emerged with a larger sample size.
Many additional factors are likely to have contributed
to the high prevalence rate of diabetes found in this study.
Although not assessed in this study, poor diet, lack of ex-
ercise, and substance abuse may have contributed to the
high prevalence of diabetes found in the study group.
60
Schizophrenia itself may also be a risk factor for diabetes
mellitus. Studies prior to the discovery of chlorpromazine
have documented impaired glucose tolerance among pa-
tients with schizophrenia, although fasting blood glucose
was usually normal in these studies.
61–67
This finding was
recently replicated by Ryan and colleagues,
68
who found
increased fasting blood glucose levels and insulin resis-
tance but no diabetes in their comparison of drug-naive
patients to controls. While Mukherjee et al.
69
reported
higher rates of diabetes among patients without antipsy-
chotic drugs than those receiving them, the medication-
free group contained only 8 patients. Conclusive evidence
Lamberti et al.
904 J Clin Psychiatry 66:7, July 2005
that diabetes is more common in schizophrenia indepen-
dent of medications is lacking, but the literature suggests
that adults with schizophrenia are vulnerable to develop-
ing diabetes.
Although antipsychotic medications have long been
associated with diabetes, certain lines of evidence suggest
that clozapine may pose an especially high level of risk.
Some clinical studies have shown high rates of diabetes
among clozapine-treated patients, either alone
34,36,37
or in
comparison to patients receiving other drugs.
32,33,35
Cloza-
pine causes the most weight gain of any antipsychotic
drug,
70
and obesity is a well-established risk factor for
diabetes in the general population.
53
Clozapine levels
have also been shown to correlate positively with insulin
levels, suggesting a stimulating effect of clozapine on
insulin secretion from pancreatic β cells.
31,71
This corre-
lation was not observed with other antipsychotic drugs
studied. A similar finding was noted in vitro, where cloza-
pine, but not typical drugs, olanzapine, or risperidone,
was associated with increased basal insulin release.
72
Re-
viewing available data, the American Psychiatric Associa-
tion Practice Guideline for the Treatment of Patients with
Schizophrenia
52
and the national Consensus Development
Conference
51
of the American Diabetes Association have
placed clozapine in a higher risk category than all other
antipsychotic drugs except olanzapine. Controlled pro-
spective studies are needed to determine whether this cat-
egorization is accurate. Such studies are necessary to con-
trol for the tendency of clinicians to look for diabetes
preferentially among clozapine-treated patients
73,74
as well
as other potentially confounding variables.
It should be noted that the retrospective design and
lack of a control group in this study prevent determination
of the extent to which clozapine is an independent risk
factor for diabetes. Possible confounding factors include
diet, level of exercise, drug and alcohol abuse, cigarette
smoking, and medication nonadherence. Disease severity
may also have impacted the risk of developing diabetes,
but it was not assessed in this study. In addition, im-
pedance measurement tends to underestimate abdominal
adiposity relative to lower extremity adiposity,
75
which
may result in gender-related measurement errors. Also,
subjects who were the most engaged in treatment were
probably overrepresented among those who provided in-
formed consent for study participation. For these reasons,
study results should be interpreted with caution. Large
controlled prospective studies are needed to establish the
level of risk for diabetes attributable to clozapine treat-
ment and how this risk interacts with established clinical
and demographic factors.
Patients receiving clozapine are at increased risk of
developing diabetes mellitus. Despite this problem, cloza-
pine maintains a special place in the treatment of schizo-
phrenia. Decisions to use clozapine require a careful risk-
benefit assessment, as well as a commitment to long-term
monitoring of patients for development of diabetes. Al-
though definitive studies have yet to be done, the existing
literature suggests that antipsychotic drugs in general are
associated with some degree of increased risk for diabe-
tes.
76
Given that persons with schizophrenia appear vul-
nerable to developing diabetes independent of antipsy-
chotic drugs, all patients receiving antipsychotics should
be monitored regularly for diabetes. Current guidelines
suggest that patients should receive fasting blood glucose
testing at baseline, 3 to 4 months later, and annually there-
after.
51,52
Results of this study suggest that nonwhite pa-
tients and those with positive family histories of diabetes
receiving clozapine should be monitored more closely.
In the absence of evidence-based guidelines, clinicians
should consider monitoring clozapine-treated patients
with multiple established risk factors on a quarterly or
semiannual basis rather than annually.
Drug names: chlorpromazine (Thorazine, Sonazine, and others),
clozapine (Clozaril, FazaClo, and others), divalproex sodium
(Depakote), haloperidol (Haldol and others), olanzapine (Zyprexa),
quetiapine (Seroquel), risperidone (Risperdal), thiothixene (Navane
and others), ziprasidone (Geodon).
REFERENCES
1. Kamran A, Doraiswamy PM, Jane JL, et al. Severe hyperglycemia
associated with high doses of clozapine [letter]. Am J Psychiatry 1994;
151:1395
2. Koval MS, Ramy LJ, Christie S. Diabetic ketoacidosis associated with
clozapine treatment [letter]. Am J Psychiatry 1994;151:1520–1521
3. Kostakoglu AE, Yazici KM, Erbas T, et al. Ketoacidosis as a side effect
of clozapine: a case report. Acta Psychiatr Scand 1996;93:217–218
4. Peterson GA, Byrd SL. Diabetic ketoacidosis from clozapine and
lithium cotreatment [letter]. Am J Psychiatry 1996;153:737–738
5. Koren W, Kreis Y, Duchowiczny K, et al. Lactic acidosis and fatal myo-
cardial infarction due to clozapine. Ann Pharmacother 1997;31:168–170
6. Pierides M. Clozapine monotherapy and ketoacidosis [letter].
Br J Psychiatry 1997;171:90–91
7. Popli AP, Konicki PE, Jurjus GJ, et al. Clozapine and associated diabetes
mellitus. J Clin Psychiatry 1997;58:108–111
8. Good MI. Lethal interaction of clozapine and buspirone [letter]?
Am J Psychiatry 1997;154:1472–1473
9. Dickson RA, Hogg L. Pregnancy of a patient treated with clozapine.
Psychiatr Serv 1998;49:1081–1083
10. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics
and new onset diabetes. Biol Psychiatry 1998;44:778–783
11. Thompson J, Chengappa KN, Good CB, et al. Hepatitis, hyperglycemia,
pleural effusion, eosinophilia, hematuria and proteinuria occurring early
in clozapine treatment. Int Clin Psychopharmacol 1998;13:95–98
12. Brugman NJ, Cohen D, deVries RH. Diabetes mellitus after treatment
with clozapine [in Dutch]. Ned Tijdschr Geneeskd 2000;144:437–439
13. Ai D, Roper TA, Riley JA. Diabetic ketoacidosis and clozapine.
Postgrad Med J 1998;74:493–494
14. Smith H, Kenney-Herbert J, Knowles L. Clozapine-induced diabetic
ketoacidosis [letter]. Aust N Z J Psychiatry 1999;33:120–121
15. Colli A, Cocciolo M, Francobandiera G, et al. Diabetic ketoacidosis
associated with clozapine treatment [letter]. Diabetes Care 1999;22:
176–177
16. Maule S, Giannella R, Lanzio M, et al. Diabetic ketoacidosis with
clozapine treatment [letter]. Diabetes Nutr Metab 1999;12:187–188
17. Mohan D, Gordon H, Hindley NB, et al. Schizophrenia and diabetes
mellitus [letter]. Br J Psychiatry 1999;174:180–181
18. Rigalleau V, Gatta B, Bonnaud S, et al. Diabetes as a result of atypical
anti-psychotic drugs: a report of three cases. Diabet Med 2000;17:
484–486
19. Wehring BA, Alexander B, Perry PJ. Diabetes mellitus associated with
Diabetes Mellitus in Outpatients Receiving Clozapine
J Clin Psychiatry 66:7, July 2005 905
clozapine therapy. Pharmacotherapy 2000;20:844–847
20. Wu G, Dias P, Wu C, et al. Hyperglycemia, hyperlipemia, and periodic
paralysis: a case report of new side effects of clozapine. Prog
Neuropsychopharmacol Biol Psychiatry 2000;24:1395–1400
21. Isakov I, Klesmer J, Masand PS. Insulin-resistant hyperglycemia
induced by clozapine [letter]. Psychosomatics 2000;41:373–374
22. Littrell KH, Petty RG, Peabody CD, et al. Treatment of preexisting
diabetes with olanzapine [letter]. J Clin Psychiatry 2001;62:733–734
23. Avram AM, Patel V, Taylor HC, et al. Euglycemic clamp study in
clozapine-induced diabetic ketoacidosis. Ann Pharmacother 2001;35:
1381–1387
24. Sauer J, Funnell N, Reveley A. Hyperglycaemia and myoclonus
with clozapine. Psychiatr Bull R Coll Psychiatr 2001;25:360–361
25. Nicolai J, Smith SJ, Keunen RW. Simultaneous side effects of both
clozapine and valproate [letter]. Intensive Care Med 2001;27:943
26. Wilson DR, D’Souza L, Sarkar N, et al. New-onset diabetes and
ketoacidosis with atypical antipsychotics. Schizophr Res 2003;59:1–6
27. Lafayette JM, Pirl WF, Henderson DC. Low-dose clozapine and
diabetic ketoacidosis. Psychosomatics 2003;44:249–252
28. Kristensen SH, Porksen NK. Clozapine and diabetic ketoacidosis
[in Danish]. Ugeskr Laeger 2003;165:475–476
29. Koller E, Malozowski S, Doraiswamy PM. Atypical antipsychotic drugs
and hyperglycemia in adolescents [letter]. JAMA 2001;286:2547–2548
30. Yazici KM, Erbas T, Yazici AH. The effect of clozapine on glucose
metabolism. Exp Clin Endocrinol Diabetes 1998;106:475–477
31. Melkersson KI, Hulting A-L, Brismar KE. Different influences of
classical antipsychotics and clozapine on glucose-insulin homeostasis
in patients with schizophrenia or related psychoses. J Clin Psychiatry
1999;60:783–791
32. Hägg S, Joelsson L, Mjörndal T, et al. Prevalence of diabetes and im-
paired glucose tolerance in patients treated with clozapine compared
with patients treated with conventional depot neuroleptic medications.
J Clin Psychiatry 1998;59:294–299
33. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes
mellitus with use of atypical neuroleptics in the treatment of schizophre-
nia. Am J Psychiatry 2002;159:561–566
34. Sernyak MJ, Gulanski B, Leslie DL, et al. Undiagnosed hyperglycemia
in clozapine-treated patients with schizophrenia. J Clin Psychiatry 2003;
64:605–608
35. Gianfrancesco FD, Grogg AL, Mahmoud RA, et al. Differential effects
of risperidone, olanzapine, clozapine, and conventional antipsychotics on
type 2 diabetes: findings from a large health plan database. J Clin Psychi-
atry 2002;63:920–930
36. Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus,
weight gain, and lipid abnormalities: a five-year naturalistic study. Am J
Psychiatry 2000;157:975–981
37. Koller E, Schneider B, Bennett K, et al. Clozapine-associated diabetes.
Am J Med 2001;111:716–723
38. Leonard P, Halley A, Browne S. Prevalence of obesity, lipid and glucose
abnormalities in outpatients prescribed clozapine. Ir Med J 2002;95:
119–120
39. Kivircik BB, Alptekin K, Caliskan S, et al. Effect of clozapine on serum
leptin, insulin levels, and body weight and composition in patients with
schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:
795–799
40. Melkersson KI, Dahl ML. Relationship between levels of insulin or
triglycerides and serum concentrations of the atypical antipsychotics
clozapine and olanzapine in patients on treatment with therapeutic doses.
Psychopharmacology (Berl) 2003;170:157–166
41. Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose
regulation during antipsychotic treatment of schizophrenia. Arch Gen
Psychiatry 2002;59:337–345
42. Wirshing DA, Boyd JA, Meng LR. The effects of novel antipsychotics
on glucose and lipid levels. J Clin Psychiatry 2002;63:856–865
43. Wang PS, Glynn RJ, Ganz DA, et al. Clozapine use and risk of diabetes
mellitus. J Clin Psychopharmacol 2002;22:236–243
44. Lund BC, Perry PJ, Brooks JM, et al. Clozapine use in patients with
schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension:
a claims-based approach. Arch Gen Psychiatry 2001;58:1172–1176
45. Renegold WT, Thapar RK, Marano C, et al. Increased prevalence of type
2 diabetes mellitus among psychiatric inpatients with bipolar I affective
and schizoaffective disorders independent of psychotropic drug use.
J Affect Disord 2001;70:19–26
46. Buse JB, Cavazzoni P, Hornbuckle K, et al. A retrospective cohort study
of diabetes mellitus and antipsychotic treatment in the United States.
J Clin Epidemiol 2003;56:164–170
47. Gupta S, Steinmeyer C, Frank B, et al. Hyperglycemia and hypertri-
glyceridemia in real world patients on antipsychotic therapy. Am J Ther
2003;10:348–355
48. Lamberti JS, Crilly JF, Maharaj K, et al. Prevalence of diabetes mellitus
among outpatients with severe mental disorders receiving atypical anti-
psychotic drugs. J Clin Psychiatry 2004;65:702–706
49. Lindenmayer JP, Czobor P, Volavka J, et al. Changes in glucose and
cholesterol levels in patients with schizophrenia treated with typical
or atypical antipsychotics. Am J Psychiatry 2003;160:290–296
50. Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional
antipsychotic drugs in treatment-naive first-episode schizophrenia:
a 52-week randomized trial of clozapine vs chlorpromazine. Neuro-
psychopharmacology 2003;28:995–1003
51. American Diabetes Association, American Psychiatric Association,
American Association of Clinical Endocrinologists, et al. Consensus
Development Conference on antipsychotic drugs and obesity and diabe-
tes. Diabetes Care 2004;27:596–601
52. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Asso-
ciation; Steering Committee on Practice Guidelines. Practice guideline
for the treatment of patients with schizophrenia, second edition. Am J
Psychiatry 2004;161(suppl 2):1–56
53. Powers AC. Diabetes mellitus. In: Braunwald E, Fauci A, Kasper D,
et al, eds. Harrison’s Principles of Internal Medicine. New York, NY:
McGraw-Hill Publishers; 2001:2109–2137
54. Tanita Corp. of America, Inc. Tanita Body Fat Monitor information
page. Available at: www.tanita.com/QuestionsAboutBFMonitor.shtml#5.
Accessed Sept 1, 2004
55. American Diabetes Association. Screening for type 2 diabetes. Diabetes
Care 2003;26:21–24
56. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabe-
tes, and obesity-related health risk factors, 2001. JAMA 2003;289:76–79
57. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North
Am 2004;88:787–835
58. Mukherjee S, Schnur DB, Reddy R. Family history of type 2 diabetes
in schizophrenic patients [letter]. Lancet 1989;1:495
59. Adams PF, Marano MA. Current Estimates From the National Health
Interview Survey, 1994. National Center for Health Statistics. Vital
Health Stat 10 1995;193:1–520
60. Citrome LL. The increase in risk of diabetes mellitus from exposure
to second-generation antipsychotic agents. Drugs Today (Barc) 2004;
40:445–464
61. Freed H, Fortunato E, Ludlum SD, et al. Changes in the glucose toler-
ance test occurring in schizophrenics during and after insulin shock
therapy for schizophrenia. Am J Med 1938;196:36–44
62. Proctor L, Dewan JG, McNeel BH. Variations in the glucose tolerance
observations in schizophrenics before and after shock treatment. Am J
Psychiatry 1944;100:652–658
63. Braceland JF, Meduna LJ, Vaichulis JA. Delayed action of insulin in
schizophrenia. Am J Psychiatry 1945;102:108–110
64. Freeman H, Zaborenke RN. Relation of changes in carbohydrate me-
tabolism to psychotic states. Arch Neurol Psychiatry 1949;61:569–576
65. Freeman H, Elmadjian F. Carbohydrate and lymphoid studies in schizo-
phrenia. Am J Psychiatry 1950;106:660–667
66. Henneman DH, Altschule MD, Goncz RM. Carbohydrate metabolism
in brain disease, pt 2: glucose metabolism in schizophrenic, manic-
depressive, and involutional psychoses. AMA Arch Intern Med 1954;
94:402–416
67. Freeman H, Rodnick EH, Shakow D, et al. The carbohydrate tolerance
of mentally disturbed soldiers. Psychosom Med 1944;6:311–317
68. Ryan MC, Collins P, Thakore J. Impaired fasting glucose tolerance in
first episode, drug naive patients with schizophrenia. Am J Psychiatry
2003;160:284–289
69. Mukherjee SM, Decina P, Bocola V, et al. Diabetes mellitus in schizo-
phrenic patients. Compr Psychiatry 1996;37:68–73
70. Allison D, Mentore JL, Heo M, et al. Antipsychotic-induced weight
gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:
1686–1696
71. Melkersson KI, Hulting AL. Insulin and leptin levels in patients with
schizophrenia or related psychoses: a comparison between different
antipsychotic agents. Psychopharmacology (Berl) 2001;154:205–212
Lamberti et al.
906 J Clin Psychiatry 66:7, July 2005
72. Melkersson KI, Khan A, Hilding A, et al. Different effects of antipsy-
chotic drugs on insulin release in vitro. Eur Neuropsychopharmacol
2001;11:327–332
73. Taylor D, Young C, Esop R, et al. Testing for diabetes in hospitalised
patients prescribed antipsychotic drugs. Br J Psychiatry 2004;185:
152–156
74. Citrome L, Jaffe A, Levine J, et al. Relationship between antipsychotic
medication treatment and new cases of diabetes among psychiatric
inpatients. Psychiatr Serv 2004;55:1006–1013
75. Deurenberg P. Limitations of the bioelectrical impedance method for
the assessment of body fat in severe obesity. Am J Clin Nutr 1996;
64(suppl 3):449–452
76. Citrome L, Jaffe A. Relationship of atypical antipsychotics with develop-
ment of diabetes mellitus. Ann Pharmacother 2003;37:1849–1857
    • "This polymorphism seemingly functions as a risk predictor for clozapine-/olanzpaine-induced weight, because the carriers of the C allele gain more weight compared with the subjects homozygous for the GG allele [112]. Regardless of baseline BMI, ethnicity [77] and initial body fat mass, the advanced age, and female gender are more relevant in the clinical manifestation of SGAs side effects, as the female SGA-treated patients had a higher incidence of diabetes compared with the general population [66]. "
    [Show abstract] [Hide abstract] ABSTRACT: Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased the cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jul 2015
    • "This study also suggested that female gender increased the risk for diabetes, which is consistent with previous reports of increased prevalence of clozapineassociated diabetes among women (Koller et al., 2001). However, at least one study has not found gender as a risk factor for clozapine-associated diabetes (Lamberti et al., 2005). Clozapine might increase the risk for diabetes through several proposed mechanisms including suppression of insulin release, insulin resistance, or impairment of glucose utilization through interaction with specific serotonin receptors (Wirshing et al., 1998; Henderson et al., 2000; Starrenburg and Bogers, 2009), but this study did not examine these specific mechanisms nor several behavioral factors associated with diabetes such as physical inactivity, dietary patterns , and perhaps past unreported substance abuse (Citrome and Jaffe, 2003; Citrome, 2004; Citrome et al., 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Objective To examine the prevalence and correlates of diabetes in a large sample of Chinese patients with schizophrenia on long-term clozapine treatment, because this population previously has received little systematic study.Methods Two hundred and six inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizophrenia criteria were recruited in a cross-sectional naturalistic study, and compared with 615 healthy control subjects matched for age, sex, education, and body mass index (BMI). The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Diagnoses of diabetes were established through review of medical records and fasting blood glucose testing, or an oral glucose tolerance test.ResultsDiabetes mellitus was more common in patients than in the normal controls (22.3% vs 6.2%) (odds ratio = 4.37, confidence interval (CI) 2.76–6.92, p < 0.001). The prevalence of diabetes increased with age across five age-groups as compared with normal controls (X2 = 18.0, df = 4, p = 0.001). The PANSS total score and sub-scores showed no differences between the diabetic and non-diabetic groups. Logistic regression in the patients revealed significant associations between diabetes and a family history of diabetes (p < 0.001), age (p < 0.01), and BMI (p < 0.05).Conclusion Long-term clozapine treatment was associated with an increased and clinically important risk of diabetes mellitus in Chinese chronic schizophrenic patients, which is consistent with previous reports in Western populations. Copyright © 2011 John Wiley & Sons, Ltd.
    Full-text · Article · Aug 2011
    Ruiling ZhangRuiling ZhangWei HaoWei HaoMiao PanMiao Pan+1more author...[...]
    • "Our study suggested that female gender increased the risk for diabetes, which is consistent with previous reports of increased prevalence of antipsychotic-associated diabetes among women treated with first generation typical antipsychotic drugs (Dixon et al., 2000). However, some other studies have not found gender as a risk factor for antipsychotic-associated diabetes (Lamberti et al., 2005). In our current study, the higher rate in women than men suggests female gender as a risk factor for the development of DM. "
    [Show abstract] [Hide abstract] ABSTRACT: Gender-specific relationships between diabetes mellitus (DM) and schizophrenia have previously received little systematic study. The results showed that the overall DM prevalence was 20% with rates of 17% (58/343) in males and 27% (46/172) in females (p<0.01). Furthermore, increased body mass index (BMI), abdominal obesity and antipsychotic types were predictors of diabetes in these chronic schizophrenic patients.
    Full-text · Article · Apr 2011
Show more