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Abnormalities in Glucose Regulation During Antipsychotic Treatment of Schizophrenia
John W. Newcomer, MD;
Dan W. Haupt, MD;
Robert Fucetola, PhD;
Angela K. Melson, MA;
Julie A. Schweiger;
Benjamin P. Cooper, BA;
Gregg Selke, BA
Arch Gen Psychiatry. 2002;59:337-345.
ABSTRACT
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Background Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia
than in the general population. Glucoregulatory abnormalities have also been
associated with the use of antipsychotic medications themselves. While antipsychotics
may increase adiposity, which can decrease insulin sensitivity, disease- and
medication-related differences in glucose regulation might also occur independent
of differences in adiposity.
Methods Modified oral glucose tolerance tests were performed in schizophrenic
patients (n = 48) receiving clozapine, olanzapine, risperidone, or typical
antipsychotics, and untreated healthy control subjects (n = 31), excluding
subjects with diabetes and matching groups for adiposity and age. Plasma was
sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load.
Results Significant time x treatment group interactions were detected
for plasma glucose (F12,222 = 4.89, P<.001)
and insulin (F12,171 = 2.10, P = .02)
levels, with significant effects of treatment group on plasma glucose level
at all time points. Olanzapine-treated patients had significant (1.0-1.5 SDs)
glucose elevations at all time points, in comparison with patients receiving
typical antipsychotics as well as untreated healthy control subjects. Clozapine-treated
patients had significant (1.0-1.5 SDs) glucose elevations at fasting and 75
minutes after load, again in comparison with patients receiving typical antipsychotics
and untreated control subjects. Risperidone-treated patients had elevations
in fasting and postload glucose levels, but only in comparison with untreated
healthy control subjects. No differences in mean plasma glucose level were
detected when comparing risperidone-treated vs typical antipsychotic–treated
patients and when comparing typical antipsychotic–treated patients vs
untreated control subjects.
Conclusion Antipsychotic treatment of nondiabetic patients with schizophrenia can
be associated with adverse effects on glucose regulation, which can vary in
severity independent of adiposity and potentially increase long-term cardiovascular
risk.
INTRODUCTION
ABNORMALITIES in peripheral glucose regulation1-8
and type 2 diabetes mellitus9-12
can occur more commonly in schizophrenia, and possibly in the family members
of patients,13 compared with healthy individuals.9, 11-12 Diabetes mellitus
is characterized by hyperglycemia caused by abnormalities in insulin secretion,
insulin action, or both. Abnormalities in glucose regulation were first reported
in schizophrenia before the introduction of antipsychotic medications.1-2 Phenothiazine treatment was subsequently
observed to contribute to glucoregulatory abnormalities,14-18
including reports of aggravation of existing diabetes19
and new-onset type 2 diabetes.20-22
This association is not consistently found for all older antipsychotics,23 with few reports implicating higher-potency agents
like haloperidol.
Recent reports suggest that newer antipsychotic medications may also
contribute to clinically significant hyperglycemia. Hyperglycemia, exacerbation
of existing diabetes, new-onset type 2 diabetes, and diabetic ketoacidosis
have all been associated with newer antipsychotic medications, with multiple
reports for clozapine24-43
and olanzapine,34, 44-48
and more limited reports of significant hyperglycemia for quetiapine49-51 and risperidone.52-54 Diabetic ketoacidosis,
a serious acute complication, is characterized by hyperglycemia, ketosis,
and acidosis, with mortality rates ranging from 2% to 20% or higher, depending
on factors such as age, social circumstances, and comorbid conditions, especially
psychiatric comorbidity.55-56
Multiple cases of diabetic ketoacidosis have been reported during treatment
with clozapine25-26,28, 31-33,39, 43
and olanzapine,46-47,57-58
including a fatality attributed to diabetic ketoacidosis during olanzapine
use.59 There is a single case report of diabetic
ketoacidosis during quetiapine therapy.50 Also,
a single case report describes diabetic ketoacidosis during risperidone treatment.53-54 It is not clear whether the limited
number of reports for risperidone, despite extensive use, reflects less frequent
or smaller glucoregulatory effects similar to haloperidol, or a reporting
bias. Other currently published reports concerning risperidone describe uncomplicated
use in patients with preexisting diabetes.34, 60-61
Increased abdominal adiposity can decrease skeletal muscle insulin sensitivity
and contribute to hyperglycemia.62-63
Antipsychotic treatments produce weight gain of varying magnitude,64-66 with larger effects
for agents like clozapine66-69
and olanzapine.69-71
Therefore, reported changes in glucose regulation during antipsychotic treatment
have been assumed to be entirely secondary to increased adiposity. However,
clinical reports suggest that changes in glucose regulation can also be observed
without differences in weight,24, 27, 34, 36, 47, 58
suggesting the potential for additional adverse effects that may not require
drug-induced increases in adiposity.
Studies from this laboratory concerning glucose and insulin effects
on cognitive function7-8,72
provided glucoregulatory data concerning different antipsychotics. The goal
of this study was to use modified oral glucose tolerance tests (OGTTs) to
compare glucose regulation among patients with schizophrenia receiving newer
and typical antipsychotics, and in untreated healthy control subjects. Individuals
with diagnosed or probable diabetes mellitus were excluded to evaluate treatment-related
disturbances in glucose regulation in patients without abnormalities at a
severity level associated with diabetes. The study aimed to test the hypothesis
that differences in glucose regulation could occur without differences in
adiposity.
SUBJECTS AND METHODS
SUBJECTS
Forty-eight patients with schizophrenia and 31 healthy adult control
subjects participated after giving written informed consent. Subjects included
individuals who had participated in modified OGTTs conducted over several
years, studying the cognitive effects of glucose and insulin.7-8
Studies were approved by the institutional review boards for Washington University
School of Medicine, St Louis, Mo, and the Department of Mental Health, Jefferson
City, Mo. Patients with schizophrenia were recruited through outpatient clinics,
as well as a single inpatient unit, associated with Washington University
School of Medicine. Patients recruited as outpatients were studied while taking
stable doses of clinically assigned antipsychotics, with treatment duration
greater than 3 months (14 subjects,  1 year; 12 subjects, 6 months
to <1 year; and 14 subjects, 3 to <6 months). Of 8 subjects recruited
as inpatients, treatment duration ranged between 3 and 6 weeks (5 subjects,
>30 days; 1 subject, 27 days; 1 subject, 20 days; and 1 subject, 19 days),
with most of these subjects previously untreated or medication noncompliant.
Healthy control subjects were recruited through advertising. Subjects were
divided into 5 groups composed of patients receiving primary treatment with
typical antipsychotics, clozapine, olanzapine, or risperidone, as well as
untreated healthy control subjects. Groups were matched for body mass index
(BMI; calculated as weight in kilograms divided by the square of height in
meters), an indicator of adiposity that is strongly predictive of changes
in glucose regulation,73 and age, another predictor
of glucoregulatory status,74 and balanced for
ethnicity. No previously recruited study subjects were excluded; rather, the
final phases of recruitment were completed by entering consecutively referred
subjects taking relevant medications who had appropriate BMIs and age for
maintaining comparable treatment groups. This process specifically involved
not studying several olanzapine-treated subjects with higher BMI, as their
inclusion would have made that group's mean BMI too high. Based on the well-described
association between BMI and insulin resistance, the inclusion of these subjects
would further increase group mean skeletal muscle insulin resistance, potentially
increasing plasma glucose to higher levels than would be observed in a BMI-matched
sample.
All subjects underwent a medical screening and diagnostic evaluation,
including the Diagnostic Interview for Genetic Studies75
and a review of available medical records, with a final research diagnosis
made by a research psychiatrist or psychologist using DSM-III-R76 algorithms. Subjects were excluded
for (1) Axis I disorders except schizophrenia, and substance abuse and/or
dependence occurring less than 6 months before study entry; (2) medical conditions
that could confound glucoregulatory assessments, including history of diabetes
mellitus, recognized cardiovascular and respiratory conditions with hemodynamic
compromise or hypoxia, malignancy, epilepsy, endocrine disease (excluding
corrected thyroid abnormalities), current fever, dehydration, nausea, body
weight less than 80% of ideal, pregnancy or high-dose estrogen therapy, narcotic,
corticosteroid or spironolactone therapy, sedative hypnotic withdrawal, or
any changes in medications within 10 days of study. All subjects had baseline
fasting and post–glucose load glucose determinations, and 18 schizophrenic
subjects had hemoglobin A1c measurements. To exclude subjects with
probable diabetes mellitus, subjects were excluded for fasting plasma glucose
levels of 126 mg/dL (7 mmol/L) or more,77 or
for postglucose (eg, 2 values 200 mg/dL [11.1 mmol/L]) and hemoglobin
A1c (eg, >6.1%) values strongly suggestive of diabetes mellitus.78-79 All patients were additionally characterized
by means of the Brief Psychiatric Rating Scale80
(BPRS; 18 items, 1-7 scale).
Baseline clinical data as well as mean doses of the primary antipsychotic
treatments for each patient group are listed in Table 1. Seventeen of the 48 patients were receiving typical antipsychotic
therapy. Of these 17 subjects, 11 were receiving oral agents only (haloperidol
decanoate, 5; trifluoperazine hydrochloride, 3; and thiothixene hydrochloride,
fluphenazine hydrochloride, and perphenazine, 1 each), 2 were receiving oral
agents in combination with depot preparations (haloperidol decanoate, 200
mg/4 wk, plus haloperidol in 1 patient and fluphenazine decanoate, 12.5 mg/2
wk, plus fluphenazine in 1 patient), and 4 subjects were receiving haloperidol
decanoate as their only antipsychotic treatment (mean ± SD, 91.67 ±
14.43 mg/4 wk). Mean antipsychotic dose for typical oral agents (n = 13;
haloperidol equivalents) is listed in Table
1. Eleven of the 17 subjects taking typical agents were receiving
anticholinergics (benztropine mesylate [mean daily dose, 2.21 ± 1.35
mg] in 7 and trihexyphenidyl hydrochloride [mean daily dose, 4.30 ±
3.38 mg] in 4), 3 of 17 were receiving antidepressants (sertraline hydrochloride,
150 mg/d; sertraline, 50 mg/d, plus buspirone hydrochloride, 10 mg/d; and
amitriptyline hydrochloride, 10 mg/d, in 1 each), 2 were receiving benzodiazepines
(temazepam, 30 mg/d, and lorazepam, 1.5 mg/d, in 1 each), and 1 patient was
receiving carbamazepine (400 mg/d).
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Table 1. Descriptive Statistics for Treated Patients With Schizophrenia
and Untreated Healthy Control Subjects Receiving Modified Oral Glucose Tolerance
Tests*
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Ten of 48 patients were receiving risperidone (Table 1). Of those 10, 2 were receiving anticholinergics (benztropine
mesylate, 2 mg/d, and diphenhydramine, 50 mg/d, in 1 each), and 4 were receiving
antidepressants (buspirone hydrochloride, 40 mg/d, plus sertraline, 30 mg/d;
clomipramine hydrochloride, 75 mg/d; fluoxetine, 20 mg/d; and bupropion, 300
mg/d, in 1 each). In addition, 1 subject was receiving adjunctive haloperidol
decanoate (100 mg/4 wk).
Twelve of the 48 patients were receiving olanzapine (Table 1). Of these, 2 were being treated with benztropine mesylate
(mean daily dose, 1.25 ± 1.06 mg), 2 were receiving antidepressants,
(citalopram, 20 mg/d, and bupropion, 250 mg/d, in 1 each), 1 was receiving
clonazepam (3 mg/d), and 4 were receiving other psychotropic agents (valproic
acid [mean daily dose, 833.33 ± 381.88 mg] in 3 and lithium carbonate,
600 mg/d, in 1). In addition, 2 subjects were receiving adjunctive haloperidol
(decanoate, 75 mg/4 wk, and hydrochloride, 10 mg/d, in 1 each).
Nine of the 48 patients were receiving clozapine (Table 1). Within the clozapine group, 2 patients were receiving
benztropine mesylate (mean [SD] daily dose, 5.00 ± 1.41 mg), and 2
were receiving antidepressants (sertraline, 50 mg/d, and paroxetine, 10 mg/d,
in 1 each).
PROCEDURE
Study protocols were approved and conducted through the General Clinical
Research Center at Washington University School of Medicine. A modified OGTT
was used. Standard clinical OGTTs do not require a fasting baseline and only
measure plasma glucose level at 120 minutes after load. For this study, subjects
had fasting (baseline) and multiple postload (15, 45, and 75 minutes) plasma
samples for glucose, insulin, C-peptide, glucagon, and cortisol, originally
intended to characterize glucose regulation during administration of a cognitive
battery of similar length.8 Although the standard
120-minute duration used for diagnostic testing may offer additional sensitivity
to separate diabetic and nondiabetic subjects, this study excluded diabetic
subjects. After at least a 9-hour overnight fast, subjects came to the laboratory
between approximately 8 and 9 AM and had an intravenous catheter placed in
the nondominant upper extremity for blood sampling. After baseline sampling,
subjects consumed a 453.5-g (16-oz) orange-flavored beverage containing 50
g of anhydrous dextrose powder. Sixty-four milligrams of sodium saccharin
was added to the dextrose beverage to make taste comparable with that of a
placebo (saccharin) control used for the cognitive studies.7-8
Plasma glucose level was acutely monitored during the OGTT with a blood glucose
meter (SureStep; LifeScan, Milpitas, Calif) or a glucose analyzer (Beckman
Instruments, Fullerton, Calif). Assays were performed through the laboratory
of the General Clinical Research Center. Plasma glucose concentrations were
measured by the glucose oxidase method81-82
(Beckman Instruments). Plasma insulin and C-peptide,83
glucagon,84 and cortisol85
concentrations were measured by radioimmunoassay.
DATA ANALYSIS
Data for plasma glucose level, BMI, and age within each treatment group
approximated normal distributions, without evidence of significant heteroscedasticity
for plasma glucose (Table 2).
Analysis of variance (ANOVA) was used to test the primary study hypothesis
that different antipsychotic treatments would be associated with alterations
in plasma glucose level independent of differences in adiposity. For the main
models, mixed-design ANOVAs were constructed with 1 within-subjects repeated
measure (time), 1 between-subject factor (treatment group), and either plasma
glucose or insulin values as dependent variables. Significant time x
treatment condition interactions were further analyzed with factorial ANOVA
to test the effect of treatment group at each time point, with Bonferroni-Dunn
post hoc tests used to compare individual treatment conditions. The overall
significance level was set at P = .05. In the Bonferroni-Dunn
post hoc tests, this corresponds to the assignment of statistical significance
for P values less than .005.
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Table 2. Additional Plasma Measurements During Modified Oral Glucose
Tolerance Tests in Treated Patients With Schizophrenia and Healthy Control
Subjects*
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To ensure group comparability, ANOVA was used to test for an effect
of treatment group on either BMI or age. In addition to effects of BMI73 and age,74 variables
such as race and sex may also be associated with differences in glucose regulation.73 As an additional precaution against confounders to
the interpretation of the results, each of these variables was individually
added as either a covariate term (analysis of covariance) or factor to the
main model for glucose. The relationship of symptom severity (BPRS total)
to glucose and insulin levels was explored by means of Spearman rank-order
correlations. Data were analyzed with Statview/SuperANOVA software (SAS Institute
Inc, Cary, NC).
Insulin resistance (IR) and decreased insulin secretion due to decreased
beta-cell function can be involved in type 2 diabetes mellitus.86
Homeostasis model assessment (HOMA) has been used by Haffner et al87 and others88 to assess
IR and beta-cell function on the basis of the known relationship between fasting
glucose and insulin concentrations. The HOMA measures of IR have been well
validated for characterizing diabetes and impaired glucose tolerance in population-based
studies.87 Differences in HOMA IR were tested
across specific treatment groups, indicated by significant group comparisons
for plasma glucose level in the main analysis, calculating HOMA IR by means
of a previously described formula: HOMA IR = [fasting insulin (µU/mL)
x fasting glucose (mmol/L)]/22.5.
RESULTS
GROUP-RELATED DIFFERENCES IN FASTING AND POSTLOAD PLASMA GLUCOSE LEVEL
Significant differences in plasma glucose levels across treatment groups
were observed at all time points, beginning at the fasting baseline measurement
(Figure 1 and Table 2). In the primary ANOVA model, a significant time x
treatment group interaction was detected for plasma glucose level (F12,222 = 4.89, P<.001), with significant
main effects of time (F3,222 = 166.52, P<.001)
and treatment group (F4,74 = 12.94, P<.001).
In separate ANOVAs for each time point, the effect of treatment group on plasma
glucose concentration was significant at 0 minutes (fasting; F4,74
= 11.20, P<.001), 15 minutes (F4,74
= 6.79, P<.001), 45 minutes (F4,74
= 9.66, P<.001), and 75 minutes after glucose
load (F4,74 = 10.34, P<.001). Bonferroni-Dunn
post hoc comparisons indicate that olanzapine-treated patients had significant
(approximately 1.0-1.5 SDs) elevations in fasting and postload plasma glucose
level at all measured time points, in comparison with untreated healthy control
subjects and patients receiving typical antipsychotic treatment (Figure 1 and Table 2; P<.005 for both comparisons
at all time points). Clozapine-treated patients had significant (approximately
1.0-1.5 SDs) elevations in fasting and 75-minute postload plasma glucose levels,
again in comparison with both untreated healthy controls and patients taking
typical antipsychotics (Figure 1; P<.005 for both comparisons at both time points). Mean
plasma glucose level for clozapine-treated subjects was still rising at the
final measurement time point. Risperidone-treated subjects had significant
(approximately 1.0-1.5 SDs) elevations in fasting as well as 45- and 75-minute
postload plasma glucose level, but only in comparison with untreated healthy
control subjects (Figure 1; P<.005 at each time point). When risperidone-treated
patients were compared with those receiving typical antipsychotic medications,
no significant difference in plasma glucose levels were detected at any time
point. No significant differences in plasma glucose levels were detected at
any time when patients receiving typical antipsychotics and untreated healthy
controls were compared.
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Figure 1. Plasma glucose values at fasting
and postglucose time points during a modified oral glucose tolerance test
in patients with schizophrenia (n = 48) treated with either typical antipsychotic
medication (n = 17), clozapine (n = 9), olanzapine (n = 12), or risperidone
(n = 10), and untreated healthy control subjects (n = 31). Significant time
x treatment group interactions for glucose were accompanied by effects
of treatment group at various time points (asterisk indicates P<.05) (see "Group-Related Differences in Fasting and Postload Plasma
Glucose Level" subsection of "Results" section). Individual treatment group
comparisons using Bonferroni-Dunn post hoc tests are discussed in the text.
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EVALUATING ADDITIONAL CLINICAL AND TREATMENT EFFECTS ON PLASMA GLUCOSE
LEVEL
Increases in BMI and age, the latter related to increased adiposity,
are associated with hyperglycemia, and both variables were well matched across
treatment groups (Table 1); no
significant effect of treatment group was detected for BMI (F4,74
= 1.64, P = .18) or age (F4,74 = 0.67, P = .62). As an additional precaution, however, BMI was
separately added as a covariate term in a reanalysis of the main model for
plasma glucose. This addition did not alter the level of significance of the
time x treatment group interaction (F12,207 = 1.93, P = .03), or the main effect of time (F3,207
= 4.11, P = .007), while reducing the main effect
of treatment group (F4,69 = 1.88, P =
.12). No 2-way interaction between group and BMI (F4,69 = 1.33, P = .27) and no 3-way interaction between time, treatment
group, and BMI (F12,207 = 1.51, P = .12)
was detected. We also explored interactions with ethnicity and sex, which
might complicate the interpretation of results. The separate addition of ethnicity
or sex to the main ANOVA model for plasma glucose did not alter the significance
level of the time x treatment group interaction (F12,204
= 3.71, P<.001, and F12,210 = 3.76, P<.001, respectively), or the main effects of time (F3,204 = 117.51, P<.001, and F3,210 = 43.67, P<.001, respectively) or treatment
group (F4,68 = 10.40, P<.001, and F4,70 = 6.09, P<.001, respectively). No 2-way
interactions between treatment group and either ethnicity or sex (F4,68 = 1.53, P = .20, and F3,70 = 0.40, P = .76, respectively) and no 3-way interactions between
time, treatment group, and either race or sex (F12,204 = 1.27, P = .24, and F9,210 = 0.64, P = .76, respectively) were detected.
Additional reanalyses concerning plasma glucose level were performed
to address a variety of possible confounders to the interpretation of the
results of the main ANOVA model. Restricting the typical control group to
treatment with haloperidol (n = 10), previously associated with minimal changes
in glucose control, and excluding subjects (n = 3) treated with atypical antipsychotics
plus typical decanoate preparations, could provide a typical control group
with the smallest risk of glucoregulatory effects and avoid modulating any
effects associated with atypical agents. The significant time x treatment
group interaction for plasma glucose level was not altered in this reanalysis
by restricting the typical antipsychotic treatment group to haloperidol (F12,192 = 4.90, P<.001), with persistent
main effects of time (F3,192 = 135.59, P<.001)
and treatment condition (F4,64 = 11.99, P<.001).
Significant main effects of treatment condition were still observed at 0 minutes
(F4,64 = 10.62, P<.001), 15 minutes
(F4,64 = 5.73, P<.001), 45 minutes
(F4,64 = 9.70, P<.001), and 75 minutes
(F4,64 = 9.78, P<.001) after load,
with no changes in significant Bonferroni-Dunn comparisons except the detection
of a single additional significant comparison between risperidone and haloperidol
treatment at 45 minutes only. Excluding subjects receiving concomitant treatment
with antidepressants and/or mood stabilizers (n = 15) could reduce concerns
that drug-drug interactions contributed to effects observed in the main analysis.
In this reanalysis, the significant time x treatment group interaction
for plasma glucose was retained (F12,177 = 3.86, P<.001), with persistent main effects of time (F3,177
= 118.07, P<.001) and treatment condition (F4,59 = 8.73, P<.001). Significant main effects
of treatment condition were still observed at 0 minutes (F4,59
= 7.22, P<.001), 15 minutes (F4,59
= 4.19, P = .005), 45 minutes (F4,59 =
6.56, P<.001), and 75 minutes (F4,59
= 7.33, P<.001) after load. Significant Bonferroni-Dunn
comparisons present in the original analysis were retained with the exception
of (1) clozapine vs typical antipsychotics at 0 and 75 minutes (comparison
with healthy controls still significant at both time points), (2) typical
agent vs olanzapine at 45 and 75 minutes (all other comparisons between olanzapine
and typical agents or control subjects still significant), and (3) healthy
control subjects vs risperidone at 0 and 75 minutes.
GROUP-RELATED DIFFERENCES IN FASTING AND POSTLOAD PLASMA INSULIN LEVEL
Modest differences in plasma insulin levels across the treatment groups
were observed (Table 2). In the
main ANOVA model, a significant time x treatment group interaction was
detected for plasma insulin level (F12,171 = 2.10, P = .02), with a significant main effect of time (F3,171
= 50.42, P<.001) and no main effect of treatment
group (F4,57 = 1.40, P = .25). In separate
ANOVAs for each time point, the effect of treatment group on plasma insulin
concentration only approached significance at 75 minutes after glucose load
(F4,58 = 2.39, P = .06) (Figure 1; Bonferroni-Dunn post hoc test, P
= .007; threshold for significance, P<.005). The
effect of treatment group at 75 minutes (F4,52 = 2.95, P = .03), as well as the post hoc comparison of olanzapine-treated
and healthy subjects (Bonferroni-Dunn post hoc test, P<.005),
were significant when subjects receiving typical antipsychotic decanoate preparations
in addition to treatment with olanzapine or risperidone were excluded and
the typical treatment group was restricted to haloperidol.
HOMA IR ANALYSIS
The HOMA IR values were calculated for all subject groups by means of
the formula listed in the "Subjects and Methods" section. Unpaired t tests were performed to explore differences in HOMA IR across specific
treatment groups, targeting group comparisons associated with significant
differences in plasma glucose level in the main analysis. Modest increases
in HOMA IR values were detected for patients treated with olanzapine (t23 = -2.07, P<.05)
and clozapine (t18 = -2.03, P = .06), in comparison with patients taking typical antipsychotics
only (Figure 2). No significant
alterations in HOMA IR were detected for patients treated with risperidone
or typical antipsychotics, as compared with control subjects.
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Figure 2. Homeostatic model assessment (HOMA)
insulin resistance, calculated by means of fasting plasma glucose and insulin
(see "Subjects and Methods" section), in patients with schizophrenia (n =
42) treated with either typical antipsychotic medication (n = 13), clozapine
(n = 7), olanzapine (n = 12), or risperidone (n = 10), and untreated healthy
control subjects (n = 22). Asterisk indicates P=
.06; dagger, P= .05 (see "HOMA IR Analysis" subsection
of "Results" section).
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ADDITIONAL PLASMA VARIABLES AND CLINICAL MEASURES
Spearman correlations indicated no significant association in patients
between BPRS total scores and either fasting (rs = -0.24, corrected for ties, P = .12,
n = 45) or 75-minute postload plasma glucose level (rs = -0.19, corrected for ties, P = .21,
n = 45). Modest correlations were detected between BPRS total scores and fasting
(rs = -0.40, corrected for ties, P = .01, n = 38) and 75-minute postload plasma insulin
level (rs = -0.31, corrected for
ties, P = .06, n = 37). Mean plasma C-peptide, cortisol,
and glucagon values for all treatment groups are provided in Table 2 and may be useful for hypothesis generation. While reduced
sample sizes argue against formal analysis, C-peptide values were numerically
higher in certain treatment groups (eg, olanzapine group values approximately
2 SDs higher than those of typical treatment group, and approximately 3 SDs
higher than those of healthy controls). No treatment-related effects were
apparent for cortisol and glucagon levels.
COMMENT
The results of this study measuring fasting plasma glucose and modified
OGTTs indicate that newer antipsychotic treatments such as clozapine and olanzapine,
in comparison with typical agents, are associated with adverse effects on
plasma glucose regulation, which can vary in severity independent of adiposity
and age. The HOMA calculations suggest that at least some of this effect may
involve group-related differences in insulin resistance. This is consistent
with the observation that patients taking clozapine and olanzapine had mean
plasma insulin values that were still rising at the final sample time point,
in comparison with falling insulin levels in the other treatment groups. These
results extend previous case reports suggesting that clinically significant
hyperglycemia, and diabetic complications, can occur during antipsychotic
treatment with and without changes in weight.24, 27, 36, 47, 58
Although this study used nondiabetic subjects, limiting the magnitude of glucose
excursions, differences in plasma glucose values approximating 1.0 to 1.5
SDs (eg, olanzapine vs typical antipsychotics or control subjects) were still
observed. Differences in fasting, postglucose load, and postprandial glucose
level of this magnitude have been associated with long-term increases in cardiovascular
morbidity and mortality (eg, myocardial infarction), even when plasma glucose
values remain below diabetic and impaired thresholds.89-93
Antipsychotic treatments, particularly clozapine and olanzapine,66-71
can induce clinically significant gains in weight and adiposity,94-95
with insulin resistance and the risk of diabetes mellitus increasing with
abdominal adiposity.96 Differences in plasma
glucose level were observed in this study with subjects matched for adiposity.
In clinical practice, where there is no matching for adiposity and some treatments
produce more weight gain than others, additional adiposity-related differences
in insulin resistance and plasma glucose level may occur.
There were several limitations to this study. The comparison of plasma
glucose levels between antipsychotic-treated subjects and untreated healthy
controls did not disassociate glucoregulatory effects associated with antipsychotic
treatment from any glucoregulatory changes associated with schizophrenia itself.
In contrast, the comparison between groups receiving newer and typical antipsychotic
treatments tested potential differences between the glucoregulatory effects
associated with one antipsychotic treatment vs the other, with both groups
vulnerable to disease effects. Conclusions regarding relative differences
in glucoregulatory effects between specific antipsychotic treatments may be
limited by the sample size in this study, and a type II error cannot be excluded
(eg, additional treatment groups might show differences in larger samples).
However, the large effect sizes observed in this study with this sample size
produced power of 0.99 or greater to detect the effect of treatment group
on plasma glucose level at all time points. Random treatment assignments in
this study would eliminate concerns about nonrandom sampling bias that could,
for example, preferentially assign patients to one group or another on the
basis of glucoregulatory status or risk (eg, preferentially assigning patients
with risk factors like obesity away from treatment with olanzapine). The time
course for developing glucoregulatory changes was not addressed by this study.
In addition, this report did not address the glucoregulatory effects of quetiapine,
and clinical reports suggest that treatment with this agent, like other antipsychotics,
may be associated with adverse glucoregulatory effects.49-51
Subjects taking adjunctive agents, such as valproic acid, lithium, and
antidepressants, which may themselves contribute to changes in weight and
glucose regulation,97-105
were included in the different patient groups, along with subjects taking
decanoate preparations of typical antipsychotics within the olanzapine and
risperidone treatment groups. This approach increases the generalizability
of results but could potentially contribute to increases or decreases in observed
glucoregulatory changes. When patients receiving concomitant mood stabilizers
and/or antidpressants were removed from the main analysis, there was still
a significant time x treatment group interaction, effects of treatment
condition at each time point, and still significant differences between individual
groups. In the case of valproic acid, an adjunctive agent in 3 of the olanzapine-treated
subjects, the package insert warns of hyperglycemia as a possible adverse
effect, but other reports describe hypoglycemia with valproic acid.103-104 This study used a plasma sampling
schedule that ended at 75 minutes after glucose load (along with cognitive
batteries related to original experimental aims) rather than the single conventional
120-minute end point used in World Health Organization and American Diabetes
Association criteria for the diagnosis of diabetes mellitus. In contrast,
research evaluations routinely use fasting as well as various, preferably
frequent, postglucose plasma time points less than 120 minutes, with briefer
times (eg, 60 minutes) remaining clinically predictive and longer periods
potentially allowing better rather than worse separation of diabetic, impaired,
and normoglycemic subjects.106 Future studies
might consider the use of dual-energy x-ray absorptiometry or magnetic resonance
imaging to measure and match for adiposity, rather than BMI. While BMI is
strongly associated with insulin resistance and hyperglycemia,73
abdominal adiposity acting at least in part through the hormone resistin107 plays a critical role in increasing insulin resistance.62-63 Future studies should also consider
standardizing carbohydrate intake before measurements.
Hyperglycemia in type 2 diabetes is related to impaired pancreatic beta-cell
function, which decreases insulin secretion, along with insulin resistance
in skeletal muscle (causing decreased glucose uptake) and liver (causing increased
glucose production). The results of this study suggest hyperglycemia-related
increases in plasma insulin levels, numeric increases in C-peptide levels,
and HOMA IR. Results for the postload insulin values, suggesting treatment-related
hyperinsulinemia and insulin resistance, are consistent with the HOMA calculations
we performed on fasting glucose and insulin values in the same subjects, which
also suggested treatment-related differences in insulin sensitivity. These
results do not exclude defects in beta-cell function. From the standpoint
of hypothesis generation, measures of counterregulatory hormones like glucagon
and cortisol in this study did not suggest a contribution to treatment effects
on plasma glucose or insulin. Serotonin receptor activity has been hypothesized
to be involved in glucose regulation, with both 5-HT1A and 5-HT2 receptors implicated; however, their exact roles appear complex.108-113
Earlier studies have suggested that phenothiazines decrease insulin secretion16 or release catecholamines that inhibit insulin secretion,114 or that chlorpromazine has some other anti-insulin
action.115 The results of the present study
suggest treatment effects on IR, and Dwyer et al116
recently reported effects of antipsychotic medications on glucose transporters.
Hyperglycemia is an underrecognized comorbid complication of schizophrenia.
Diabetes mellitus has well-defined acute (eg, diabetic ketoacidosis) and chronic
complications associated with increased morbidity and mortality. Diabetic
ketoacidosis, more typical of type 1 but increasingly observed in type 2 diabetes,117
has been reported during antipsychotic
treatment,28, 31-33,39, 46-47,50, 57-58
including a fatality.59 Hyperglycemia can cause
or contribute to long-term medical complications including peripheral neuropathy,
retinopathy, and nephropathy, as well as cardiovascular and cerebrovascular
disease.118 Recent reports indicate a progressive
relationship between hyperglycemia and cardiovascular event risk (eg, myocardial
infarction, stroke) beginning with glucose levels well below diabetic thresholds.74, 89, 91, 93, 119-121
Hyperglycemia can interact with treatment-induced increases in adiposity,66, 122 treatment-related triglyceride elevations,40, 123-126
and factors such as smoking,127 sedentary lifestyle,
and reduced access to care, to increase the risk of adverse cardiovascular
outcomes in patients with schizophrenia. The results of this study provide
additional motivation to clinically monitor plasma glucose, on the basis of
the risk that changes in glucose control could occur without easily observed
increases in weight or adiposity.
AUTHOR INFORMATION
Submitted for publication September 7, 2000; final revision received
August 3, 2001; accepted August 13, 2001.
This study was supported by grants MH01510, MH53363, and MH63985 from
the National Institutes of Health, Bethesda, Md (Dr Newcomer); the National
Alliance for Research on Schizophrenia and Depression, Great Neck, NY (Drs
Newcomer and Fucetola); grants P30 DK56341 (Washington University Clinical
Nutrition Research Unit Center) and P60 DK20579 (Washington University Diabetes
Research Training Center) from the National Institutes of Health; and grant
5MO1 RR00036 (General Clinical Research Center) from the Public Health Service,
Bethesda.
We thank Brenda Rosen for expert secretarial assistance.
Corresponding author and reprints: John W. Newcomer, MD, Department
of Psychiatry, Washington University School of Medicine, 660 S Euclid, St
Louis, MO 63110-1093 (e-mail: newcomerj{at}psychiatry.wustl.edu).
From the Departments of Psychiatry (Drs Newcomer and Haupt, Mss Melson
and Schweiger, and Messrs Cooper and Selke) and Neurology (Dr Fucetola), Washington
University School of Medicine, St Louis, Mo.
REFERENCES
| |
1. Meduna LJ, Gerty FJ, Urse VG. Biochemical disturbances in mental disorders. Arch Neurol Psychiatry. 1942;47:38-52.
FREE FULL TEXT
2. Braceland FJ, Meduna LJ, Vaichulis JA. Delayed action of insulin in schizophrenia. Am J Psychiatry. 1945;102:108-110.
FREE FULL TEXT
3. Henneman DH, Altschule MD, Goncz RM. Carbohydrate metabolism in brain disease. Arch Intern Med. 1954;94:402-416.
FREE FULL TEXT
4. Martin FI, Alford FP. Insulin sensitivity in schizophrenia [letter]. BMJ. 1970;2:50.
5. Brambilla F, Guastalla A, Guerrini A, Riggi F, Rovere C, Zanoboni A, Zanoboni-Muciaccia W. Glucose-insulin metabolism in chronic schizophrenia. Dis Nerv Syst. 1976;37:98-103.
ISI
| PUBMED
6. Yaryura-Tobias JA, Chang A, Neziroglu F. A study of relationships of serum glucose, insulin, free fatty acids,
and free and total tryptophan to mental illness. Biol Psychiatry. 1978;13:243-254.
ISI
| PUBMED
7. Newcomer JW, Craft S, Fucetola R, Moldin SO, Selke G, Paras L, Miller R. Glucose-induced increase in memory performance in patients with schizophrenia. Schizophr Bull. 1999;25:321-335.
8. Fucetola R, Newcomer JW, Craft S, Melson AK. Age- and dose-dependent glucose-induced increases in memory and attention
in schizophrenia. Psychiatry Res. 1999;88:1-13.
FULL TEXT
|
ISI
| PUBMED
9. Marinow A. Diabetes in chronic schizophrenia. Dis Nerv Syst. 1971;32:777-778.
ISI
| PUBMED
10. Waitzkin L. A survey for unknown diabetics in a mental hospital, I: men under age
fifty. Diabetes. 1966;15:97-104.
ISI
| PUBMED
11. Waitzkin L. A survey for unknown diabetics in a mental hospital, II: men from age
fifty. Diabetes. 1966;15:164-172.
ISI
| PUBMED
12. Mukherjee S, Decina P, Bocola V, Saraceni F, Scapicchio PL. Diabetes mellitus in schizophrenic patients. Compr Psychiatry. 1996;37:68-73.
FULL TEXT
|
ISI
| PUBMED
13. Mukherjee S, Schnur DB, Reddy R. Family history of type 2 diabetes in schizophrenic patients [letter]. Lancet. 1989;1:495.
FULL TEXT
|
ISI
| PUBMED
14. Arneson GA. Phenothiazine derivatives and glucose metabolism. J Neuropsychiatry. 1964;5:181-185.
15. Proakis AG, Mennear JH, Miya TS, Borowitz JL. Phenothiazine-induced hyperglycemia: relation to CNS and adrenal effects. Proc Soc Exp Biol Med. 1971;137:1385-1388.
FULL TEXT
| PUBMED
16. Erle G, Basso M, Federspil G, Sicolo N, Scandellari C. Effect of chlorpromazine on blood glucose and plasma insulin in man. Eur J Clin Pharmacol. 1977;11:15-18.
FULL TEXT
|
ISI
| PUBMED
17. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories
of glucose intolerance. Diabetes. 1979;28:1039-1057.
ISI
| PUBMED
18. Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993;118:529-539.
FREE FULL TEXT
19. Hiles BW. Hyperglycemia and glycosuria following chlorpromazine therapy [letter]. JAMA. 1956;162:1651.
FREE FULL TEXT
20. Cooperberg AA, Eidlow S. Hemolytic anemia, jaundice and diabetes mellitus following chlorpromazine
therapy. CMAJ. 1956;75:746-750.
21. Korenyi C, Lowenstein B. Chlorpromazine induced diabetes. Dis Nerv Syst. 1968;29:827-828.
ISI
| PUBMED
22. Thonnard-Neumann E. Phenothiazines and diabetes in hospitalized women. Am J Psychiatry. 1968;124:978-982.
FREE FULL TEXT
23. Keskiner A. A long-term follow-up of fluphenazine enanthate treatment. Curr Ther Res Clin Exp. 1973;15:305-313.
ISI
| PUBMED
24. Hagg S, Joelsson L, Mjorndal T, Spigset O, Oja G, Dahlqvist R. Prevalence of diabetes and impaired glucose tolerance in patients treated
with clozapine compared with patients treated with conventional depot neuroleptic
medications. J Clin Psychiatry. 1998;59:294-299.
ISI
| PUBMED
25. Avram AM, Patel V, Taylor HC, Kirwan JP, Kalhan S. Euglycemic clamp study in clozapine-induced diabetic ketoacidosis. Ann Pharmacother. 2001;35:1381-1387.
FREE FULL TEXT
26. Pierides M. Clozapine monotherapy and ketoacidosis. Br J Psychiatry. 1997;171:90-91.
27. Popli AP, Konicki PE, Jurjus GJ, Fuller MA, Jaskiw GE. Clozapine and associated diabetes mellitus. J Clin Psychiatry. 1997;58:108-111.
ISI
| PUBMED
28. Peterson GA, Byrd SL. Diabetic ketoacidosis from clozapine and lithium cotreatment. Am J Psychiatry. 1996;153:737-738.
29. Ai D, Roper TA, Riley JA. Diabetic ketoacidosis and clozapine. Postgrad Med J. 1998;74:493-494.
FREE FULL TEXT
30. Kamran A, Doraiswamy PM, Jane JL, Hammett EB, Dunn L. Severe hyperglycemia associated with high doses of clozapine [letter]. Am J Psychiatry. 1994;151:1395.
31. Kostakoglu AE, Yazici KM, Erbas T, Guvener N. Ketoacidosis as a side-effect of clozapine: a case report. Acta Psychiatr Scand. 1996;93:217-218.
ISI
| PUBMED
32. Koval MS, Rames LJ, Christie S. Diabetic ketoacidosis associated with clozapine treatment. Am J Psychiatry. 1994;151:1520-1521.
33. Smith H, Kenney-Herbert J, Knowles L. Clozapine-induced diabetic ketoacidosis. Aust N Z J Psychiatry. 1999;33:120-121.
ISI
| PUBMED
34. Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry. 1998;44:778-783.
FULL TEXT
|
ISI
| PUBMED
35. McKenna K, Thompson C. Osmoregulation in clinical disorders of thirst appreciation. Clin Endocrinol (Oxf). 1998;49:139-152.
PUBMED
36. Yazici KM, Erbas T, Yazici AH. The effect of clozapine on glucose metabolism. Exp Clin Endocrinol Diabetes. 1998;106:475-477.
ISI
| PUBMED
37. McDonnell ME, Ruderman NB. Cutting the Gordian knot: addition of metformin to insulin therapy
in a patient with uncontrolled diabetes and schizophrenia. Diabetes Care. 1999;22:1912-1913.
FREE FULL TEXT
38. Mohan D, Gordon H, Hindley N, Barker A. Schizophrenia and diabetes mellitus. Br J Psychiatry. 1999;174:180-181.
39. Colli A, Cocciolo M, Francobandiera F, Rogantin F, Cattalini N. Diabetic ketoacidosis associated with clozapine treatment. Diabetes Care. 1999;22:176-177.
40. Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, Goff DC. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities:
a five-year naturalistic study. Am J Psychiatry. 2000;157:975-981.
FREE FULL TEXT
41. Wehring H, Alexander B, Perry PJ. Diabetes mellitus associated with clozapine therapy. Pharmacotherapy. 2000;20:844-847.
FULL TEXT
|
ISI
| PUBMED
42. Melson AK, Selke G, Fucetola R, Schweiger JA, Newcomer JW. Clozapine can change glucose regulation in schizophrenia independent
of body mass index (BMI) [abstract]. Soc Neurosci Abstr. 1999;25:2074.
43. Maule S, Giannella R, Lanzio M, Villari V. Diabetic ketoacidosis with clozapine treatment. Diabetes Nutr Metab. 1999;12:187-188.
ISI
| PUBMED
44. Fertig MK, Brooks VG, Shelton PS, English CW. Hyperglycemia associated with olanzapine. J Clin Psychiatry. 1998;59:687-689.
ISI
| PUBMED
45. Ober SK, Hudak R, Rusterholtz A. Hyperglycemia and olanzapine [letter]. Am J Psychiatry. 1999;156:970.
FREE FULL TEXT
46. Goldstein LE, Sporn J, Brown S, Kim H, Finkelstein J, Gaffey GK, Sachs G, Stern TA. New-onset diabetes mellitus and diabetic ketoacidosis associated with
olanzapine treatment. Psychosomatics. 1999;40:438-443.
FREE FULL TEXT
47. Gatta B, Rigalleau V, Gin H. Diabetic ketoacidosis with olanzapine treatment. Diabetes Care. 1999;22:1002-1003.
ISI
| PUBMED
48. Bettinger TL, Mendelson SC, Dorson PG, Crismon ML. Olanzapine-induced glucose dysregulation. Ann Pharmacother. 2000;34:865-867.
ABSTRACT
49. Sobel M, Jaggers ED, Franz MA. New-onset diabetes mellitus associated with the initiation of quetiapine
treatment. J Clin Psychiatry. 1999;60:556-557.
50. Wilson DR, D'Souza L, Sarkar N. Diabetogenesis and ketoacidosis with atypical antipsychotics. In: Scientific abstracts of the American College of Neuropsychopharmacology
38th Annual Meeting; December 12-16, 1999; Acapulco, Mexico. Page 284, abstract
119.
51. Procyshyn RM, Pande S, Tse G. New-onset diabetes mellitus associated with quetiapine. Can J Psychiatry. 2000;45:668-669.
ISI
| PUBMED
52. Wirshing DA, Erhart SM, Pierre JM, Boyd JA. Nonextrapyramidal side effects of novel antipsychotics. Curr Opin Psychiatry. 2000;13:45-50.
FULL TEXT
|
ISI
53. Haupt DW, Newcomer JW. Risperidone-associated diabetic ketoacidosis. Psychosomatics. 2001;42:279-280.
FREE FULL TEXT
54. Croarkin PE, Jacobs KM, Bain BK. Diabetic ketoacidosis associated with risperidone treatment? Psychosomatics. 2000;41:369-370.
FREE FULL TEXT
55. Tunbridge WM for the Medical Services Study Group and British Diabetic Association. Factors contributing to deaths of diabetics under fifty years of age. Lancet. 1981;2:569-572.
ISI
| PUBMED
56. Malone ML, Gennis V, Goodwin JS. Characteristics of diabetic ketoacidosis in older versus younger adults. J Am Geriatr Soc. 1992;40:1100-1104.
ISI
| PUBMED
57. Lindenmayer JP, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus [letter]. Am J Psychiatry. 1999;156:1471.
FREE FULL TEXT
58. Paizis M, Cavaleri S, Schwarz ME, Levin Z. Acute-onset ketoacidosis during olanzapine treatment in a patient without
pretreatment obesity or treatment-associated weight gain. Primary Psychiatry. 1999;6:37-38.
59. Von Hayek D, Huttl V, Reiss J, Schweiger HD, Fuessl HS. Hyperglycemia and ketoacidosis associated with olanzapine [in German]. Nervenarzt. 1999;70:836-837.
FULL TEXT
|
ISI
| PUBMED
60. Melamed Y, Mazeh D, Elizur A. Risperidone treatment for a patient suffering from schizophrenia and
IDDM [letter]. Can J Psychiatry. 1998;43:956.
61. Madhusoodanan S, Brenner R, Araujo L, Abaza A. Efficacy of risperidone treatment for psychoses associated with schizophrenia,
schizoaffective disorder, bipolar disorder, or senile dementia in 11 geriatric
patients: a case series. J Clin Psychiatry. 1995;56:514-518.
ISI
| PUBMED
62. Banerji MA, Lebowitz J, Chaiken RL, Gordon D, Kral JG, Lebovitz HE. Relationship of visceral adipose tissue and glucose disposal is independent
of sex in black NIDDM subjects. Am J Physiol. 1997;273:E425-E432.
63. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects of weight loss on regional fat distribution and insulin sensitivity
in obesity. Diabetes. 1999;48:839-847.
ABSTRACT
64. Pijl H, Meinders AE. Bodyweight change as an adverse effect of drug treatment: mechanisms
and management. Drug Saf. 1996;14:329-342.
ISI
| PUBMED
65. Casey DE. The relationship of pharmacology to side effects. J Clin Psychiatry. 1997;58(suppl 10):55-62.
66. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686-1696.
FREE FULL TEXT
67. Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M. Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry. 1992;149:68-72.
FREE FULL TEXT
68. Lamberti JS, Bellnier T, Schwarzkopf SB. Weight gain among schizophrenic patients treated with clozapine. Am J Psychiatry. 1992;149:689-690.
FREE FULL TEXT
69. Collaborative Working Group on Clinical Trial Evaluations. Adverse effects of the atypical antipsychotics. J Clin Psychiatry. 1998;59 Suppl 12:17-22.
70. Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, Pollmacher T. Body weight and leptin plasma levels during treatment with antipsychotic
drugs. Am J Psychiatry. 1999;156:312-314.
FREE FULL TEXT
71. Gupta S, Droney T, Al-Samarrai S, Keller P, Frank B. Olanzapine-induced weight gain [letter]. Ann Clin Psychiatry. 1998;10:39.
FULL TEXT
| PUBMED
72. Fucetola R, Newcomer JW, Seidman LJ, Schweiger JA, Cooper BP, Melson AK. Influence of oral glucose administration on working memory in schizophrenia
[abstract]. Soc Neurosci Abstr. 2000;26:2013.
73. Resnick HE, Valsania P, Halter JB, Lin X. Differential effects of BMI on diabetes risk among black and white
Americans. Diabetes Care. 1998;21:1828-1835.
ABSTRACT
74. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer HM, Byrd-Holt DD. Prevalence of diabetes, impaired fasting glucose, and impaired glucose
tolerance in U.S. adults: the Third National Health and Nutrition Examination
Survey, 1988-1994. Diabetes Care. 1998;21:518-524.
ABSTRACT
75. Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T and the collaborators from the NIMH Genetics Initiative. Diagnostic interview for genetic studies: rationale, unique features,
and training. Arch Gen Psychiatry. 1994;51:849-859.
FREE FULL TEXT
76. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Third Edition, Revised. Washington, DC: American Psychiatric Association; 1987.
77. The Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus. Report of the Expert Committee on the Diagnosis and Classification
of Diabetes Mellitus. Diabetes Care. 2000;23(suppl 1):S4-S19.
78. World Health Organization. Diabetes Mellitus: Report of a WHO Study Group. Vol 727. Geneva, Switzerland: World Health Organization; 1985.
79. Davidson MB, Schriger DL, Peters AL, Lorber B. Relationship between fasting plasma glucose and glycosylated hemoglobin:
potential for false-positive diagnoses of type 2 diabetes using new diagnostic
criteria. JAMA. 1999;281:1203-1210 [published correction appears in JAMA. 1999;281:2187].
FREE FULL TEXT
80. Overall JE. A brief psychiatric rating scale in psychopharmacology research. Mod Probl Pharmacopsychiatry. 1974;7:67-78.
81. Giampietro O, Buzzigoli G, Boni C, Navalesi R. Four methods for glucose assay compared for various glucose concentrations
and under different clinical conditions. Clin Chem. 1982;28:2405-2407.
FREE FULL TEXT
82. Koch TR, Nipper HC. Evaluation of automated glucose oxidase methods for serum glucose:
comparison to hexokinase of a colorimetric and an electrometric method. Clin Chim Acta. 1977;78:315-322.
FULL TEXT
|
ISI
| PUBMED
83. Kuzuya H, Blix PM, Horwitz DL, Steiner DF, Rubenstein AH. Determination of free and total insulin and C-peptide in insulin-treated
diabetics. Diabetes. 1977;26:22-29.
ABSTRACT
84. Ensinck J. Immunoassays for glucagon. In: Lefebrve P, ed. Handbook of Experimental Pharmacology. Vol 66. New York, NY: Springer Verlag; 1983:203-221.
85. Farmer RW, Pierce CE. Plasma cortisol determination: radioimmunoassay and competitive protein
binding compared. Clin Chem. 1974;20:411-414.
ABSTRACT
86. DeFronzo RA. The triumvirate: beta-cell, muscle, liver: a collusion responsible
for NIDDM: Lilly lecture 1987. Diabetes. 1988;37:667-687.
ISI
| PUBMED
87. Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study. Diabetes Care. 1997;20:1087-1092.
ABSTRACT
88. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function
from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
FULL TEXT
|
ISI
| PUBMED
89. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events:
a metaregression analysis of published data from 20 studies of 95,783 individuals
followed for 12.4 years. Diabetes Care. 1999;22:233-240.
FREE FULL TEXT
90. Temelkova-Kurktschiev T, Henkel E, Schaper F, Koehler C, Siegert G, Hanefeld M. Prevalence and atherosclerosis risk in different types of non-diabetic
hyperglycemia: is mild hyperglycemia an underestimated evil? Exp Clin Endocrinol Diabetes. 2000;108:93-99.
FULL TEXT
|
ISI
| PUBMED
91. Scheidt-Nave C, Barrett-Connor E, Wingard DL, Cohn BA, Edelstein SL. Sex differences in fasting glycemia as a risk factor for ischemic heart
disease death. Am J Epidemiol. 1991;133:565-576.
FREE FULL TEXT
92. Andersson DK, Svardsudd K. Long-term glycemic control relates to mortality in type II diabetes. Diabetes Care. 1995;18:1534-1543.
ABSTRACT
93. Gerstein HC. Is glucose a continuous risk factor for cardiovascular mortality? Diabetes Care. 1999;22:659-660.
FREE FULL TEXT
94. Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry. 2001;62(suppl 7):22-31.
95. Fontaine KR, Heo M, Harrigan EP, Shear CL, Lakshminarayanan M, Casey DE, Allison DB. Estimating the consequences of anti-psychotic induced weight gain on
health and mortality rate. Psychiatry Res. 2001;101:277-288.
FULL TEXT
|
ISI
| PUBMED
96. Kissebah AH. Intra-abdominal fat: is it a major factor in developing diabetes and
coronary artery disease? Diabetes Res Clin Pract. 1996;30(suppl):25-30.
97. Ginsberg DL, Sussman N. Effects of mood stabilizers on weight. Primary Psychiatry. 2000;7:49-58.
98. Martinez-Maldonado M, Terrell J. Lithium carbonate-induced nephrogenic diabetes insipidus and glucose
intolerance. Arch Intern Med. 1973;132:881-884.
FREE FULL TEXT
99. Petty KJ. Hyperglycemia associated with paroxetine [letter]. Ann Intern Med. 1996;125:782.
FREE FULL TEXT
100. Johnston BB. Diabetes mellitus in patients on lithium. Lancet. 1977;2:935-936.
101. Waziri R, Nelson J. Lithium in diabetes mellitus: a paradoxical response. J Clin Psychiatry. 1978;39:623-625.
ISI
| PUBMED
102. Lustman PJ, Griffith LS, Clouse RE, Freedland KE, Eisen SA, Rubin EH, Carney RM, McGill JB. Effects of nortriptyline on depression and glycemic control in diabetes:
results of a double-blind, placebo-controlled trial. Psychosom Med. 1997;59:241-250.
FREE FULL TEXT
103. Breum L, Astrup A, Gram L, Andersen T, Stokholm KH, Christensen NJ, Werdelin L, Madsen J. Metabolic changes during treatment with valproate in humans: implication
for untoward weight gain. Metabolism. 1992;41:666-670.
FULL TEXT
|
ISI
| PUBMED
104. Turnbull DM, Dick DJ, Wilson L, Sherratt HS, Alberti KG. Valproate causes metabolic disturbance in normal man. J Neurol Neurosurg Psychiatry. 1986;49:405-410.
FREE FULL TEXT
105. Kutnowski M, Daubresse JC, Friedman H, Kolanowski J, Krzentowski G, Scheen A, Van Gaal L. Fluoxetine therapy in obese diabetic and glucose intolerant patients. Int J Obes Relat Metab Disord. 1992;16(suppl 4):S63-S66.
106. Haffner SM, Rosenthal M, Hazuda HP, Stern MP, Franco LJ. Evaluation of three potential screening tests for diabetes mellitus
in a biethnic population. Diabetes Care. 1984;7:347-353.
ABSTRACT
107. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 2001;409:307-312.
FULL TEXT
| PUBMED
108. Chaouloff F, Laude D, Baudrie V. Effects of the 5-HT1C/5-HT2 receptor agonists
DOI and  -methyl-5-HT on plasma glucose and insulin levels in the rat. Eur J Pharmacol. 1990;187:435-443.
FULL TEXT
|
ISI
| PUBMED
109. Baudrie V, Chaouloff F. Repeated treatment with the 5-HT1A receptor agonist, ipsapirone,
does not affect 8-OH-DPAT– and stress-induced increases in plasma adrenaline
levels in the rat. Eur J Pharmacol. 1991;198:129-135.
FULL TEXT
|
ISI
| PUBMED
110. Yamada J, Sugimoto Y, Yoshikawa T, Kimura I, Horisaka K. The involvement of the peripheral 5-HT2A receptor in peripherally
administered serotonin-induced hyperglycemia in rats. Life Sci. 1995;57:819-825.
FULL TEXT
|
ISI
| PUBMED
111. Wozniak KM, Linnoila M. Hyperglycemic properties of serotonin receptor antagonists. Life Sci. 1991;49:101-109.
FULL TEXT
|
ISI
| PUBMED
112. Sugimoto Y, Yamada J, Kimura I, Horisaka K. The effects of the serotonin 1A receptor agonist buspirone on tolbutamide-induced
hypoglycemia in rats. Biol Pharm Bull. 1995;18:1296-1298.
ISI
| PUBMED
113. Uvnas-Moberg K, Ahlenius S, Alster P, Hillegaart V. Effects of selective serotonin and dopamine agonists on plasma levels
of glucose, insulin and glucagon in the rat. Neuroendocrinology. 1996;63:269-274.
ISI
| PUBMED
114. Sato S, Katayama K, Kakemi M, Koizumi T. A kinetic study of chlorpromazine on the hyperglycemic response in
rats, II: effect of chlorpromazine on plasma glucose. J Pharmacobiodyn. 1988;11:492-503.
PUBMED
115. Gupta SK, Patel MA, Joseph AD. Effects of chlorpromazine and epinephrine on blood-sugar of rabbits. Arch Int Pharmacodyn Ther. 1960;128:82-88.
116. Dwyer DS, Liu Y, Bradley RJ. Dopamine receptor antagonists modulate glucose uptake in rat pheochromocytoma
(PC12) cells. Neurosci Lett. 1999;274:151-154.
FULL TEXT
|
ISI
| PUBMED
117. Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med. 1997;157:669-675.
FREE FULL TEXT
118. Ratner RE. Type 2 diabetes mellitus: the grand overview. Diabet Med. 1998;15(suppl 4):S4-S7.
119. Park S, Barrett-Connor E, Wingard DL, Shan J, Edelstein S. GHb is a better predictor of cardiovascular disease than fasting or
postchallenge plasma glucose in women without diabetes: the Rancho Bernardo
Study. Diabetes Care. 1996;19:450-456.
ABSTRACT
120. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary-heart-disease risk and impaired glucose tolerance: the Whitehall
study. Lancet. 1980;1:1373-1376.
ISI
| PUBMED
121. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Mortality from coronary heart disease and stroke in relation to degree
of glycaemia: the Whitehall study. Br Med J (Clin Res Ed). 1983;287:867-870.
122. Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand. 1999;100:3-16.
ISI
| PUBMED
123. Sheitman BB, Bird PM, Binz W, Akinli L, Sanchez C. Olanzapine-induced elevation of plasma triglyceride levels. Am J Psychiatry. 1999;156:1471-1472.
124. Ghaeli P, Dufresne RL. Elevated serum triglycerides with clozapine resolved with risperidone
in four patients. Pharmacotherapy. 1999;19:1099-1101.
FULL TEXT
|
ISI
| PUBMED
125. Gaulin BD, Markowitz JS, Caley CF, Nesbitt LA, Dufresne RL. Clozapine-associated elevation in serum triglycerides. Am J Psychiatry. 1999;156:1270-1272.
FREE FULL TEXT
126. Ghaeli P, Dufresne RL. Serum triglyceride levels in patients treated with clozapine. Am J Health Syst Pharm. 1996;53:2079-2081.
127. McCreadie RG, Kelly C. Patients with schizophrenia who smoke: private disaster, public resource
[editorial]. Br J Psychiatry. 2000;176:109.
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