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

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DOI: 10.4088/JCP.v66n0713 · Source: PubMed
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
, 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)
diabetes mellitus. Since publication of the first report
of hyperglycemia associated with clozapine in 1994,
37 additional cases have been described in case reports
and small case series.
These reports describe cases
of transient hyperglycemia,
diabetic ketoacido-
new onset diabetes mellitus,
and exacerbation of preexisting diabetes.
In addition to
case reports, recently published clinical studies have ex-
amined the association between clozapine, insulin levels,
glucose abnormalities, and diabetes.
The prevalence
of diabetes in these studies has ranged from 4% in a Med-
icaid claims study of 531 patients
to 36.6% in a 5-year
naturalistic study of 82 patients.
Some studies suggest that clozapine is associated with
a greater risk of diabetes than other antipsychotic medica-
while other studies do not.
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.
Yet clo-
zapine remains a valuable treatment for schizophrenia be-
cause of its superior effectiveness.
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,
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.
However, in a U.S. Food and Drug Administration (FDA)
database study,
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.
Lund et al.
found an increased risk
of diabetes with clozapine only among patients aged 20 to
34 years, while Buse et al.
failed to find a significant
hazard ratio of diabetes for age with clozapine. Likewise,
Sernyak et al.
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,
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
Also, African Americans and African Caribbe-
ans are overrepresented in case reports of clozapine-
associated glucose abnormalities, totaling nearly half of
all reported cases.
Family history is another well-established risk factor
for diabetes mellitus within the general population.
23 case reports that contained information about family
history, 6 patients had a positive family history of diabe-
Also, 4 of 13 diabetic clozapine-treated pa-
tients in a study by Hägg et al.
had positive family histo-
ries. However, Henderson et al.
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.
and Hägg et al.
Obesity is a strong predictor of diabetes in the general
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
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
that included 27 clozapine-
treated patients found no treatment interaction for the re-
lationship between glucose change and weight gain at
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.
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
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
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),
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.
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.
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
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
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
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
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
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
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).
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
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.
While previous studies examining clozapine-associated
weight gain and diabetes
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
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,
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.
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.
These rates are substantially higher than the 1.2% to 6.3%
rates among the general population
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.
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.
This finding was
recently replicated by Ryan and colleagues,
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.
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
or in
comparison to patients receiving other drugs.
pine causes the most weight gain of any antipsychotic
and obesity is a well-established risk factor for
diabetes in the general population.
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.
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.
viewing available data, the American Psychiatric Associa-
tion Practice Guideline for the Treatment of Patients with
and the national Consensus Development
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
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,
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-
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-
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).
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    • "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
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