Therapeutic Controversies

Relationship of Atypical Antipsychotics with Development of

Diabetes Mellitus

Leslie L Citrome and Ari B Jaffe

OBJECTIVE: To review the pharmacoepidemiologic evidence for the link between exposure to atypical antipsychotics and the
development of diabetes mellitus.
DATA SOURCES: A MEDLINE search (1990–March 2003) was conducted.

STUDY SELECTION AND DATA EXTRACTION: The search was limited to articles that described findings from analyses of large
databases and used the words diabetes or hyperglycemia, and antipsychotic or clozapine or olanzapine or risperidone or quetiapine
or ziprasidone or aripiprazole in the title or abstract. The odds ratio or relative risk, together with their corresponding confidence
interval, was extracted.
DATA SYNTHESIS: Results are conflicting, and this variability may be due to the different populations studied, different study designs,
and the possibility of publication bias related to funding by the pharmaceutical industry. Nevertheless, an increased risk for diabetes
mellitus appears to be present for patients receiving atypical antipsychotics. However, differential risk among the atypical antipsychotics
is difficult to ascertain.
CONCLUSIONS: Clinicians are urged to manage risk by regularly monitoring all patients receiving atypical antipsychotics for the
emergence of diabetes mellitus. Future studies should carefully control for confounding variables such as age, diagnosis, change in
weight, activity level, family history, and ethnicity.
KEY WORDS: clozapine, diabetes mellitus, olanzapine, quetiapine, risperidone, ziprasidone.

Ann Pharmacother 2003;37:1849-57.

Published Online, 5 Nov 2003, www.theannals.com, DOI 10.1345/aph.1D142

everal reports have raised the concern that atypical an-
S tipsychotic medications may cause or exacerbate prob-
lems with glucose regulation. This has been a major thera-
peutic controversy and was featured recently in the Wall
Street Journal.1
Although adverse effects of conventional (typical) an-
tipsychotics (e.g., chlorpromazine) on glucose homeostasis
were known before the introduction of atypical antipsy-
chotics,2 much attention is being placed on this problem
with the new generation of antipsychotics. Data from the
Author information provided at the end of the text.
In the past 5 years, Dr Citrome has received honoraria for lectures
or advisory board participation or research support from Abbott
Laboratories, AstraZeneca, BMS, Eli Lilly, Janssen, Novartis, and
Pfizer. Dr Jaffe has received research support from Eli Lilly.
Food and Drug Administration (FDA) MedWatch surveil-
lance program implicate clozapine, olanzapine, risperi-
done, and quetiapine in new-onset diabetes, including dia-
betic ketoacidosis. Reports have pooled FDA data with
published cases.3-6 Clozapine had 384 reported cases of di-
abetes,3 olanzapine 237,4 risperidone 131,5 and quetiapine
46.6 These cases included instances of diabetic ketoacido-
sis (80 for clozapine, 80 for olanzapine, 26 for risperidone,
21 for quetiapine), as well as death (25 for clozapine, 15
for olanzapine, 4 for risperidone, 11 for quetiapine).
The incidence and prevalence of diabetes among pa-
tients exposed to atypical antipsychotics cannot be calcu-
lated using the number of case reports alone, but the small
number of cases does provide a signal that merits further
attention. Temporal association was observed for some
cases, with 46 patients on clozapine, 60 on olanzapine, and

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LL Citrome and AB Jaffe
13 on risperidone having improved glycemic control after
discontinuation or dose reduction of the drug (these data
were not available in the poster abstract for quetiapine).
Although this finding suggests that antipsychotic use may
unmask or precipitate diabetes in psychotic patients, causali-
ty needs to be ascertained by appropriately designed clini-
cal studies.
Information from double-blind clinical trials regarding
the association of exposure to atypical antipsychotics and
diabetes is limited, but consistent with the case reports
seen in the literature. In 1 double-blind, randomized, con-
trolled clinical trial comparing clozapine, risperidone,
olanzapine, and haloperidol, 14% of 101 subjects devel-
oped hyperglycemia (defined as a fasting plasma glucose
level >125 mg/dL) within 14 weeks.7 Of these patients, 6
had been randomized to receive clozapine, 4 to olanzapine,
3 to risperidone, and 1 to haloperidol.
Determining causality from studies is a difficult chal-
lenge, as diabetes has a number of known risk factors such
as advancing age, weight gain, lack of physical activity,
family history, and ethnicity.8-10 The propensity for atypical
antipsychotics to cause weight gain is well known, with
clozapine having the highest risk of weight gain, followed
by olanzapine and quetiapine11; however, not all case re-
ports of type II diabetes associated with atypical antipsy-
chotics were associated with weight gain.3-5 Not all persons
who have weight gain develop type II diabetes. In addi-
tion, diabetes may also have a long latent period before it
is clinically manifested. It is unknown how long exposure
to a risk factor is necessary before it has an adverse impact.
This too may vary from patient to patient. Moreover, pa-
tients with schizophrenia may be more likely to develop
diabetes mellitus than the general population, and this was
observed before the general availability of atypical an-
tipsychotic medication.12 The Patient Outcomes Research
Team Study reported that the percent prevalence of dia-
betes mellitus from 1991 through 1996 among patients
with schizophrenia ranged from 11.1% to 14.9% compared
with general population prevalence rates of 1.2% (aged
18– 44 y) to 6.3% (aged 45– 64 y). A recent study docu-
mented impaired fasting glucose tolerance in first-episode,
drug-naïve patients with schizophrenia.13
Reviews have discussed possible underlying mecha-
nisms.14,15 Clozapine, olanzapine, and quetiapine are struc-
turally similar, leading to the idea that they may share sim-
ilar risks. Putative mechanisms include insulin resistance
caused by antipsychotic agents’ effects on glucose transporters
and antagonism of serotonin 5-HT1A receptors decreasing
pancreatic β-cell responsiveness.14 However, regarding the lat-
ter mechanism, no significant change in insulin response or
insulin sensitivity was detected when a hyperglycemic
clamp model was used in healthy volunteers randomly as-
signed to single-blind therapy treatment with olanzapine,
risperidone, or placebo.16
Since 2001, pharmacoepidemiologic studies using pre-
scription databases have been used to document the associ-
ation between exposure to antipsychotics and the develop-
ment of diabetes mellitus. Unlike case reports, they are
1850 ■ The Annals of Pharmacotherapy ■ 2003 December, Volume 37
better able to control for potentially confounding variables,
and, unlike double-blind clinical trials, epidemiologic trials
involve much larger numbers of subjects and are thus more
likely to be able to detect relatively rare events. Prior re-
views have emphasized data from case reports, case series,
chart reviews, or naturalistic observations in relatively
small samples.14,15 The purpose of this review is to describe
the disparate findings that have emerged from the large
database studies published so far and to make research and
clinical recommendations.
Data Sources
A MEDLINE search (1990–March 2003) was conduct-
ed regarding pharmacoepidemiologic studies exploring the
linkage between exposure to atypical antipsychotics and
the development of diabetes mellitus. The search was lim-
ited to articles that described findings from analyses of
large databases and used the words diabetes or hyper-
glycemia, and antipsychotic or clozapine or olanzapine or
risperidone or quetiapine or ziprasidone or aripiprazole in
the title or abstract. Included in this report are all studies
that used large databases to identify cases, the smallest
published study examining 99 cases (from a sample of
3013 pts.)17 and the largest, 7246 cases (from a sample of
38 632 pts.).18
Evidence for Atypical Antipsychotic–Associated
Diabetes
The database-driven pharmacoepidemiologic studies
available thus far provide conflicting evidence for the link-
age between exposure to atypical antipsychotics and the
onset or recurrence of diabetes mellitus.17-24 Methodologic
details of the studies are outlined in Table 1. The studies,
with the exception of one,21 provide information about the
risk observed with clozapine, risperidone, olanzapine, or
quetiapine. A summary of comparative risk of diabetes for
atypical compared with conventional antipsychotics17-20,24
or risperidone22,23 is presented in Table 2.
CLOZAPINE
Among the 5 published studies in which information on
clozapine was reported,17-19,22,24 4 implicated clozapine as a
risk factor for diabetes.17,18,22,24 The relative risk (usually de-
termined using cohort studies) or odds ratios (usually de-
termined using case–control studies) in the reports were as
high as 2.5 (95% CI 1.2 to 5.4) among patients aged 20–34
years compared with exposure to typical antipsychotics17
and 7.44 (95% CI 1.603 to 34.751) at 12 months of treat-
ment compared with no exposure to antipsychotics.22 A
negative report regarding risk with clozapine also exists,
where an almost exclusively older population was exam-
ined (mean age of cases 63.6 y, controls 61.9 y).19 This
negative finding is consistent with another showing that
clozapine was associated with a greater risk of diabetes
among younger (20–34 y), but not older patients,17 as well
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 Atypical Antipsychotics and the Development of Diabetes Mellitus

as a report of a lack of statistical significance in patients 8.0) compared with nonusers of antipsychotics was shown,
≥70 years old.18 In another study, an elevated risk for pa- but there was no difference when compared with patients
tients taking clozapine (7 cases; HR 3.3; 95% CI 1.4 to taking haloperidol.24

Table 1. Methodology of Pharmacoepidemiology Studies of Atypical Antipsychotics and Risk for Diabetes Mellitus
Total Cases Comparison
Reference Design Pts. (n) Definition of Case (n) AAP Group Comments

Lund et al. retrospective 3013 medical claim for ICD-9 99 CLO TAP users hyperlipidemia and hypertension
(2001)17 cohort; code for diabetes or a were also assessed; small
comparison pharmacy claim for number of cases
of incidence; antidiabetic medication;
IA Medicaid preexisting diabetes excluded
program
Sernyak et al. retrospective 38 632 outpatient encounter or 7246 CLO, TAP users not incident cases
(2002)18 cohort; inpatient stay with either a RIS,
comparison of primary or secondary OLZ,
prevalence; diagnosis of diabetes QUE
VA admini-
strative data-
bases
Wang et al. case–control; 14 007 new prescription for anti- 7227 CLO, AP users mean age of cases and controls
(2002)19 NJ Medicaid, (7227 diabetic medication RIS other than 63.6 and 61.9 y, respectively
Pharmaceutical cases, CLO
Assistance to 6780
the Aged and controls)
Disabled, and
Medicare
programs
Koro et al. case–control; 19 637 diagnosis of or treatment for 451 OLZ, AP nonusers; only 15 cases receiving AAP
(2002)20 UK General (451 diabetes; no prescription of RIS TAP users included in the analysis; CLO
Practice cases, antidiabetic medication within not assessed
Research 2696 3 months of index date
Database controls)
Kornegay et al. case–control; 73 428 new diagnosis of diabetes 424 CLO, AP nonusers same database (but different
(2002)21 UK General (424 without prior evidence of the RIS, years) used as Koro et al.20;
Practice cases, disease or treatment in the OLZ, only 7 pts. received AAP
Research 1522 computer record QUE
Database controls)
Gianfrancesco retrospective 7933 new or resurgent cases of type 101, CLO, AP nonusers; small number of cases; exposure
et al. (2002)22 cohort; 2 diabetes; ICD-CM-9 code 206 RIS, RIS users groups differed in diagnosis;
comparison of for type 2 diabetes or OLZ OR vs. risperidone based on
incidence; prescription for an antidiabetic extrapolated data
database from 2 agent; pts. with type 1
mixed indemni- diabetes (receiving insulin
ty and man- without an accompanying
aged-care type 2 diagnosis) excluded;
health plans pts. with preexisting disease in
past 4–8 mo excluded
Caro et al. retrospective 33 946 ICD-CM-9 code for diabetes 536 RIS, RIS although adjusted for, groups
(2002)23 cohort; or prescription for an anti- OLZ differed significantly in gender,
comparison of diabetic agent; pts. with pre- age, diagnosis, and exposure
incidence; existing disease in past year to haloperidol
database from excluded
the public
health plan in
Quebec
Buse et al. retrospective 58 751a new prescription for anti- 948b CLO, AP nonusers; psychiatric diagnosis not available;
(2003)24 cohort; diabetic medication RIS, TAP users; low doses of AP; risk higher for all
comparison of OLZ, haloperidol AP users compared with non-
incidence; QUE users users, but different pattern seen
AdvancePCS when compared with haloperidol
prescription (Table 2)
claim data

AAP = atypical antipsychotics; AP = antipsychotic; CLO = clozapine; ICD = International Classification of Disease25; OLZ = olanzapine; QUE = que-
tiapine; RIS = risperidone; TAP = typical antipsychotics.
a
5 816 473 in general patient population; 58 751 receiving antipsychotic monotherapy.
b
45 513 in general patient population; 948 receiving antipsychotic monotherapy.

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LL Citrome and AB Jaffe

RISPERIDONE
Among the 6 published studies that reported specifically
on the risks associated with risperidone,18-20,22-24 4 showed
no increased risk.19,20,22,23 One trial did show an elevated
odds ratio for younger patients (<40 y old), but not consis-
tently for older patients (statistical significance achieved
for ages 50 –59 y, but not for 40 – 49, 60 – 69, or ≥70 y of
age).18 This study was methodologically limited by its ret-
rospective cohort design and its use of prevalent, as op-
posed to incident, cases of diabetes mellitus. Another retro-
spective cohort study, using a large prescription database,
found an elevated risk for patients using risperidone com-
pared with nonusers of antipsychotics (HR 3.4; 95% CI
3.1 to 3.8) and haloperidol (HR 1.23; 95% CI 1.01 to
1.50).24
OLANZAPINE
All 5 of the published studies providing specific infor-
mation about olanzapine reported an elevated risk with that
agent.18,20,22-24 Relative risk or odds ratios in those reports
were as high as 4.2 (95% CI 1.5 to 12.2) compared with
exposure to typical antipsychotics,20 and 5.8 (95% CI 2.0
to 16.7) compared with no exposure to antipsychotics.20 In
3 of the studies,20,22,23 olanzapine was associated with a
higher risk of diabetes than was risperidone; however, one
trial reported similar statistically significant magnitudes of
odds ratios for all atypical antipsychotics studied when ex-
amining patients <40 years of age (2.13 for clozapine, 1.82
for quetiapine, 1.64 for olanzapine, 1.51 for risperidone).18
Another study found an elevated risk with olanzapine (HR
3.0; 95% CI 2.6 to 3.5) compared with nonuse of antipsy-
chotics, but no difference when compared with haloperidol.24
In a retrospective cohort study, 319 of 19 153 patients
developed diabetes while taking olanzapine, and 217 of
14 793 developed diabetes while on risperidone.23 There
did not appear to be a difference between olanzapine and
risperidone in terms of risk for diabetes using the crude
hazard ratio. However, when the relative risk was adjusted
for age, gender, and haloperidol use, a higher risk for olan-
zapine was observed that was significant for all patients
and more so for female patients (RR 1.30; 95% CI 1.05 to
1.65). Drug exposure time affected the results, with <3
months being statistically significant (RR 1.90; 95% CI
1.40 to 2.57), but not >3 months.
In a case–control study, 451 cases of diabetes were iden-
tified out of a population of 19 637.20 Although the period
from 1987 to 2000 was covered and 3231 patients received
atypical antipsychotics, only 38 patients who developed di-
abetes were exposed to atypical antipsychotics. Of these
cases, 9 received olanzapine, 23 received risperidone, and
6 received other atypical antipsychotics. Because the prin-
cipal analysis used cases involving mutually exclusive sin-
gle-agent exposure, only 15 cases were used. Among these

Table 2. Statistical Comparisons of Risk of Diabetes Mellitus by Exposure to Atypical Antipsychotics

Compared with a Reference Antipsychotic
Industry
Reference Statistic CLO RIS OLZ QUE AAP Sponsor

Lund et al. (2001)17 RR vs. TAP 2.5 NA NA NA NA none

(1.2 to 5.4)a
Sernyak et al. (2002)18 OR vs. TAP ↑ risk 1.51 ↑ risk ↑ risk ↑ risk none
(95% CI) (1.12 to 2.04)b
1.25 1.11 1.31 1.09 none
(1.07 to 1.46) (1.04 to 1.18) (1.11 to 1.55) (1.03 to 1.15)
Wang et al. (2002)19 OR vs. AP no increasec no increasec NA NA NA none
other than CLO
Koro et al. (2002)20 OR vs. TAP NA no increasec ↑ risk NA NA Bristol-Myers
(95% CI) 4.2 Squibb (ARI)
(1.5 to 12.2)
Kornegay et al. OR NA NA NA NA NA none
(2002)21
Gianfrancesco et al. extrapolated ↑ risk NA ↑ risk NA NA Janssen (RIS)
(2002)22 OR vs. RIS 8.45 3.53
(p < 0.05) (p < 0.05)
Caro et al. (2002)23 RR vs. RIS NA NA ↑ risk NA NA Janssen (RIS)
(95% CI) 1.20
(1.00 to 1.43)
Buse et al. (2003)24 HR vs. no increasec ↑ risk no increase decreased risk no increase Eli Lilly (OLZ)
haloperidol 1.23 0.67
(95% CI) (1.01 to 1.50) (0.46 to 0.97)

AAP = atypical antipsychotics as a class compared with typical antipsychotics; AP = antipsychotic; ARI = aripiprazole; CLO = clozapine; NA = not
assessed or not applicable; OLZ = olanzapine; QUE = quetiapine; RIS = risperidone; TAP = typical antipsychotic.
a
Increase for patients aged 20–34 years.
b
Increase for patients <40 years old.
c
RR or OR omitted.

1852 ■ The Annals of Pharmacotherapy ■ 2003 December, Volume 37 www.theannals.com


15 cases, 7 patients received olanzapine, 7 received risperi-
done, and 1 received an unspecified newer agent. Olanza-
pine had a significantly increased risk of producing diabetes
than nonuse of antipsychotics (OR 5.8; 95% CI 2.0 to 16.7)
and conventional antipsychotics. Although the analogous
odds ratios for risperidone were elevated, those results were
not statistically significant. Direct comparisons between
olanzapine and risperidone were not made. Clozapine was
not included in the study design.
Another retrospective cohort study eliminated patients
whose diabetes had been reported in the prior 4 months.22
Eighty-three new cases of diabetes were identified among
patients not receiving antipsychotic treatment (out of 3061
pts.), 25 of 1368 patients receiving risperidone, 32 of 1047
receiving olanzapine, 4 of 64 receiving clozapine, and 62
of 1856 receiving conventional antipsychotics. Estimated
odds ratios that reflect diabetic effects associated with 1
month of treatment (compared with no antipsychotic treat-
ment) found an elevated odds ratio for olanzapine (1.099;
95% CI 1.041 to 1.160) and clozapine (1.182; 95% CI
1.040 to 1.344), but not for risperidone (0.989; 95% CI
0.921 to 1.063). These confidence intervals overlap, mak-
ing direct comparisons difficult. To counter this, the au-
thors extrapolated these figures to 12-month ratios to cal-
culate the odds ratio versus risperidone treatment and
found a statistically significant elevation in risk for olanza-
pine (OR 3.53), clozapine (OR 8.45), and low-potency
conventional antipsychotics (OR 3.93).
QUETIAPINE, ZIPRASIDONE, AND ARIPIPRAZOLE
As of March 2003, only 2 published pharmacoepidemio-
logic studies have specifically reported on the risk associated
with quetiapine,18,24 and none has reported on the relative risk
or odds ratios for exposure to ziprasidone or aripiprazole.
Poster presentations have included quetiapine26-28 or ziprasi-
done28; however, these reports were not peer-reviewed and
may represent only interim analyses. The paucity of peer-re-
viewed published studies regarding these newer agents prob-
ably relates to their more recent commercial availability (que-
tiapine released in 1997, ziprasidone in 2001, aripiprazole in
2002) compared with the other atypical antipsychotics.
One trial reported an odds ratio of 1.31 at all ages (95%
CI 1.11 to 1.55) for quetiapine,18 generating a lively ex-
change of correspondence in a subsequent issue of the
American Journal of Psychiatry.29 Another trial found a
hazard ratio of 1.7 (95% CI 1.2 to 2.4) for quetiapine com-
pared with nonuse of antipsychotics, but 0.67 compared
with haloperidol (95% CI 0.46 to 0.97), signifying de-
creased risk.24
CONVENTIONAL ANTIPSYCHOTICS
Some of the published studies found increased risk asso-
ciated with the older medications, although usually not of
the same magnitude attributable to the atypical agents.21
Elevated risks were shown for chlorpromazine (OR 1.31;
95% CI 1.09 to 1.56) and perphenazine (OR 1.34; 95% CI
www.theannals.com The Annals of Pharmacotherapy
Atypical Antipsychotics and the Development of Diabetes Mellitus
1.11 to 1.62) compared with nonuse of these agents.19 An-
other trial found a significantly elevated odds ratio for pa-
tients receiving typical antipsychotics (1.3; 95% CI 1.1 to
1.6) compared with patients not receiving typical antipsy-
chotics (includes both nonusers of antipsychotics and users
of atypical antipsychotics).20 An elevated odds ratio was
reported in 1 study for both high-potency (1.065; 95% CI
1.008 to 1.126) and low-potency (1.109; 95% CI 1.036 to
1.187) typical antipsychotics compared with nonuse of an-
tipsychotics.22 Haloperidol use was shown to be a signifi-
cant predictor for users developing diabetes, with a relative
risk of 1.24 (95% CI 1.05 to 1.47) adjusting for age and
gender when comparing olanzapine and risperidone.23 The
highest risk figures for typical antipsychotics were a haz-
ard ratio of 3.5 (95% CI 3.1 to 3.9) for conventional an-
tipsychotics as a group, 3.1 (95% CI 2.6 to 3.7) for
haloperidol, and 4.2 (95% CI 3.2 to 5.5) for thioridazine
compared with nonuse of antipsychotics.24 There was no
difference between typical and atypical antipsychotics.
Additional Risk Factors for Antipsychotic-
Related Hyperglycemia
The World Health Organization (WHO) maintains a
large database of adverse drug reactions from the national
centers in 63 countries around the world. Reports were
identified for clozapine, olanzapine, and risperidone in the
WHO database that included the following diagnoses: glu-
cose tolerance abnormal, hyperglycemia, diabetes mellitus,
diabetes mellitus aggravated, ketosis, diabetic coma, and
glycosuria.30 The methodology differs significantly from a
retrospective cohort or case–control study, and is thus not
included in Table 1. The report does outline risk factors as-
sociated with hyperglycemia among the antipsychotics.
There were 868 reports of glucose intolerance with cloza-
pine (n = 480), olanzapine (n = 253), and risperidone (n =
138). For clozapine, olanzapine, and risperidone grouped
together, potential risk factors (measured by OR) identified
were an underlying diabetic condition (10.22; 95% CI 8.20
to 12.73), weight increase (2.36; 95% CI 1.76 to 3.17),
male gender (1.27; 95% CI 1.11 to 1.47), and use of val-
proate (1.97; 95% CI 1.61 to 2.40), serotonin-specific re-
uptake inhibitors (1.63; 95% CI 1.33 to 1.99), or buspirone
(2.24; 95% CI 1.33 to 3.77).
Discussion
STUDY VARIATION AND METHODOLOGIC
CONSIDERATIONS
Direct comparisons of risk between different atypical
antipsychotics have for the most part failed to yield any
statistically significant differences. However, studies have
rarely had the statistical power to perform such direct com-
parisons due the relatively small number of cases of new-
onset diabetes mellitus. For example, in one case–control
study, the analysis was limited by the low number of sub-
jects receiving atypical antipsychotics and developing dia-
■ 2003 December, Volume 37 ■ 1853
LL Citrome and AB Jaffe
betes (n = 8).21 Thus, although the odds ratio was elevated
for patients receiving atypical antipsychotics and develop-
ing diabetes compared with those not receiving antipsy-
chotics (OR 4.7; 95% CI 1.5 to 14.9), a direct comparison
between atypical and typical antipsychotics could not be
made. That trial21 used the same database (United King-
dom’s General Practice Research Database) as another
study20; however, different calendar years were examined
(1994 –199821 vs. 1987–200020), which may help explain
the differences in the number of cases found and the ability
to contrast the atypical antipsychotics.
Psychiatric diagnosis may impact on diabetes risk and
may be a source of bias. Schizophrenia has been associated
with an increased risk of diabetes, regardless of antipsychot-
ic use.12 As discussed briefly in the introduction, there may
be underlying differences among patients with schizophre-
nia in how they maintain glucose homeostasis. In one study,
>15% of the first-episode, drug-naïve patients with schizo-
phrenia had impaired fasting glucose tolerance compared
with none of the matched healthy comparison subjects.13
Patients with schizophrenia had higher levels of plasma
glucose, insulin, and cortisol than the controls. Dysregula-
tion of the hypothalamic–pituitary–adrenal axis and im-
munologic explanations have been offered.13,31 Thus, dif-
ferential use of antipsychotics based on diagnosis can in-
crease the observed risk for antipsychotics used in the
more vulnerable population.
In one trial, 57% of the clozapine patients, 22% of the
olanzapine patients, and 14% of the risperidone patients
were diagnosed with schizophrenia.22 Another study in-
cluded more olanzapine patients diagnosed with schizophre-
nia (62%) than the risperidone group (39%).23 A case–con-
trol study included the “presence of schizophrenia or other
psychotic disorders” in the multivariate logistic regression
model, but did not separate schizophrenia.19 Diagnosis of
schizophrenia was included in one model: 12% of cases
and 10% of controls were diagnosed with schizophrenia.21
No information about diagnosis was included in 1 report,24
and the average daily doses of the atypical antipsychotics
(clozapine 183.1 mg, risperidone 1.2 mg, olanzapine 5.1
mg, quetiapine 79.9 mg) were substantially less than those
used in seriously and persistently mentally ill patients in
state hospitals in New York (most with either schizophre-
nia or schizoaffective disorder and receiving, on average,
daily doses of clozapine 494.7 mg, risperidone 4.9 mg,
olanzapine 18.9 mg, quetiapine 518.4 mg).32 Three trials
examined only patients with schizophrenia, thus avoiding
this possible confounding variable.17,18,20
The choice of differing comparison groups (e.g., pts. re-
ceiving typical antipsychotics17-20,23,24 vs. those not receiving
antipsychotics20-22,24) may also affect the results of a study.
Persons not receiving antipsychotics can represent a sub-
stantially different mix of diagnoses and illness severity.
Classification of subjects may introduce bias. One study
attempted to directly contrast the risk for olanzapine and
risperidone in a cohort of patients who received at least 1
prescription for either medication.23 Patients receiving both
were assigned to the olanzapine group. The number of pa-
1854 ■ The Annals of Pharmacotherapy ■ 2003 December, Volume 37
tients falling into this group was not reported, but may pro-
duce bias against olanzapine. Mutually exclusive cate-
gories were used in another investigation, but that resulted
in the reduction of risperidone-exposed cases from 23 to 7,
and olanzapine-exposed cases from 9 to 7.20 The unequal
dropping of cases for further analysis makes the results
more difficult to correctly interpret.
Other key differences that may affect outcome include
the definition of diabetes mellitus used (most often the
presence of a prescription for an antidiabetic agent and/or
the presence of a diagnosis of diabetes mellitus), time on
medication, length of observation, and calendar year from
which the data were extracted. Over time, the diagnostic
criteria of diabetes may undergo changes. For example, the
1980–1985 WHO criterion of a fasting blood glucose level
≥140 mg/dL for the diagnosis of diabetes is substantially
different from the current American Diabetes Association
definition of ≥126 mg/dL.33 As clinicians become more
aware of the problem of diabetes, there may be earlier
identification and increased surveillance, and some clini-
cians may opt to avoid certain antipsychotics in high-risk
patients. These factors may artificially decrease the ob-
served risk for the suspected agent and increase the ob-
served risk for the alternative antipsychotic. The database-
driven studies published so far use data obtained several
years ago (from 1990–199417 to 1998–200024).
Important missing information common to most of the
pharmacoepidemiologic studies reported is the lack of data
on the extent of laboratory surveillance for the emergence
of diabetes mellitus,17-24 changes in weight or body mass
index (BMI),17-20,22-24 or ethnicity.17,20-24
An additional source of variation in study results may
be sponsor participation, particularly where the studies are
conducted under the financial aegis of the company and
company employees are named authors.20,22-24 This contro-
versy is not new. Others have noted that industry-sponsored
reports have usually favored the company’s product.34-39 Al-
though differing results can be attributable to legitimate
methodologic differences, studies countering the compa-
ny’s commercial interests would probably not be purpose-
ly published. The actual extent of this possible publication
bias is unknown. Industry sponsorship of articles is indi-
cated in Table 2.
Antipsychotic-Related Diabetes Risk in Clinical
Context
Major unresolved issues relate to the magnitude of the at-
tributable risk of atypical antipsychotics in the genesis of dia-
betes mellitus and the acceptable degree of this additional
risk given the efficacy of the antipsychotic medication in
question. Family history, advancing age, obesity, and lack of
physical activity are strong risk factors for diabetes mellitus.10
The relative risks of diabetes attributable to antipsychotic
medications need to be seen in this context.
Data from an epidemiologic study of military personnel
found that increased BMI was associated with an increased
risk of type 2 diabetes mellitus as measured by an odds ra-
www.theannals.com

tio of 3.0 (95% CI 1.4 to 6.4) for BMI at least 30 kg/m2,
and 2.0 (95% CI 1.4 to 3.0) for 25.0 –29.9 kg/m2, com-
pared with the risk with a BMI <20 kg/m2.8 A BMI of
20.0 –24.9 kg/m2 did not confer a statistically significant
increased risk compared with a BMI <20 kg/m2. Non-
white ethnicity resulted in elevated odds ratios of 2.0 (95%
CI 1.6 to 2.6) for African Americans and 1.6 (95% CI 1.1
to 2.4) for Hispanics and others. The military population is
particularly well suited to the study of risk factors associat-
ed with diabetes because regular physical examination
records for a large cohort of young individuals are avail-
able, and the cases of diabetes are all incident cases (dia-
betes is cause for rejection into military service).
A recent report also quantified the risk of diabetes asso-
ciated with television watching and other sedentary behav-
iors, where each 2-h/d increment in watching television
was associated with a 23% (95% CI 17% to 30%) increase
in obesity and a 14% (95% CI 5% to 23%) increase in the
risk of diabetes among women.9 With these data as a com-
parison, it appears that the increased diabetes risk associat-
ed with use of atypical antipsychotic medications is compa-
rable to many of the established risk factors for this illness.
However, any increased risk associated with the medica-
tions needs to be balanced against the significant morbidity
and mortality associated with untreated schizophrenia.
Schizophrenia has a significantly increased mortality from
natural and unnatural causes, with a meta-analysis demon-
strating a 12-fold increase in suicide mortality, a 3-fold in-
crease in accidental death mortality, and a 2.3-fold increase
in natural death mortality.40
Clinical Recommendations
Given that schizophrenia is a devastating illness, and that
finding efficacious treatments remains a significant chal-
lenge, the issue of an incremental risk for diabetes should
not discourage the clinician from using atypical antipsy-
chotics, provided that the risk is appropriately managed.41
This can be done by regularly monitoring all patients receiv-
ing any antipsychotic with fasting blood glucose determina-
tions (baseline, then quarterly or semiannually), especially in
the presence of additional risk factors such as obesity, ad-
vancing age, hypertension, family history of diabetes, and a
low level of physical activity.15
Summary
Given the pattern of results in the database-driven stud-
ies, exposure to atypical antipsychotics increases the risk
for diabetes mellitus. To date, published cohort and case–
control studies have involved only small numbers of cases
(despite relatively large total samples), making assessment
of quantitative differences in relative risk attributable to the
different atypical antipsychotics difficult to ascertain. Ab-
solute risk attributable to specific antipsychotic exposure is
difficult to measure because of the presence of established
risk factors.
Large-scale, long-term prospective epidemiologic co-
hort studies, as well as randomized clinical trials, will be
www.theannals.com The Annals of Pharmacotherapy
Atypical Antipsychotics and the Development of Diabetes Mellitus
needed to better ascertain the nature of the relationship be-
tween exposure to specific atypical antipsychotic medica-
tion and diabetes mellitus, and to determine what interven-
ing factors play a major role, including genetic predisposi-
tion, psychiatric diagnosis, and severity of illness. In the
meantime, clinicians should allow efficacy considerations
to drive treatment decisions. Patients who will develop
clinical difficulties with glucose regulation are not pre-
dictable on the basis of antipsychotic choice alone.
ADDENDUM: In the interval of time between acceptance of
the accompanying article and its publication, there have
been additional contributions to the pharmacoepidemio-
logic literature that are of interest. Two of these articles are
by the same lead author42,43 and are retrospective cohort
studies that are methodologically similar to a prior report.22
The focus of one article, coauthored by employees of
Janssen, was on the differential effects of antipsychotic
agents on the risk for developing diabetes in patients with
mood disorders (n = 5723).42 The study concluded that, un-
like patients who received risperidone or high-potency
conventional antipsychotics, patients who received olanza-
pine and low-potency conventional antipsychotics had sig-
nificantly higher odds for the development of diabetes
compared with untreated patients. Extrapolated odds ratios
were 4.289 (95% CI 2.102 to 8.827) for olanzapine and
4.972 (95% CI 1.967 to 12.612) for low-potency conven-
tional antipsychotics. The other report, coauthored by an
AstraZeneca employee, compared risperidone, olanzapine,
quetiapine, and conventional antipsychotics across a mix
of diagnoses (n = 16 878).43 Extrapolated odds ratios were
significantly higher for olanzapine (1.426; 95% CI 1.046
to 1.955) compared with no exposure to antipsychotics. An
elevation in risk was not observed for risperidone and que-
tiapine.
In a retrospective cohort study conducted in a Veterans
Affairs Integrated Service Network (n = 5837) and coau-
thored by a Janssen employee, olanzapine was associated
with a significantly higher risk of development of diabetes
compared with risperidone (HR 1.37; 95% CI 1.06 to
1.76).44 A number of covariates were used including eth-
nicity, age, and diagnosis. Others, such as weight and fami-
ly history, were not available, a limitation common to the
pharmacoepidemiologic literature on this topic.
In August 2003, at a meeting of the International Soci-
ety for Pharmacoepidemiology and the International Soci-
ety of Pharmacovigilance, data were presented that de-
scribed a retrospective cohort study among patients with
schizophrenia in the Department of Veterans Affairs (n =
12 235).45 Compared with exposure to conventional an-
tipsychotics, hazard ratios were significantly elevated for
olanzapine (1.27; 95% CI 1.04 to 1.56), risperidone (1.49;
95% CI 1.22 to 1.81), and quetiapine (3.34; 95% CI 2.51
to 4.45), but not for clozapine (1.48; 95% CI 0.65 to 3.37).
Data were adjusted for age, gender, ethnicity, and mea-
sures of diabetes screening. Although this was not peer-re-
viewed the way a journal article would be, it received a
substantial amount of press coverage.46
■ 2003 December, Volume 37 ■ 1855
LL Citrome and AB Jaffe
Whether there is any predictive value in prescribing 1
atypical antipsychotic over another with respect to the risk
for diabetes mellitus remains unknown. The FDA recently
notified the manufacturers of the atypical antipsychotics
that product labeling for all drugs in that class will require
a new warning about hyperglycemia and diabetes.47 This
will ultimately benefit all of our patients, as it will lead to
improved surveillance for a disease that affects millions of
US adults.48
Leslie L Citrome MD MPH, Professor of Psychiatry, New York Uni-
versity School of Medicine, New York, NY; Director, Clinical Research
and Evaluation Facility, Nathan S Kline Institute for Psychiatric Re-
search, Orangeburg, NY
Ari B Jaffe MD, Assistant Professor of Psychiatry, New York Uni-
versity
Reprints: Leslie L Citrome MD MPH, Nathan S Kline Institute for
Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY
10962-2210, FAX 845/398-5483, citrome@nki.rfmh.org
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EXTRACTO
OBJETIVO: Repasar la evidencia farmacoepidemiológica para el enlace
entre la exposición a antipsicóticos atípicos y el desarrollo de diabetes
mellitus (DM).
FUENTES DE INFORMACIÓN: Se condujo una búsqueda en MEDLINE
(1990–marzo 2003) con relación a estudios farmacoepidemiológicos
explorando el enlace entre la exposición a los antipsicóticos atípicos y el
desarrollo de DM.
SELECCIÓN DE FUENTES Y MÉTODO DE EXTRACCIÓN DE INFORMACIÓN: La
investigación estuvo limitada a los artículos describiendo los hallazgos
de los análisis de bases de datos extensas y que utilizaron las palabras
diabetes o hiperglicemia, y antipsicótico o clozapina u olanzapina o
risperidona o quetiapina o ziprasidona o aripiprazol en el título o en el
extracto. La proporción de la probabilidad o el riesgo relativo, junto con
sus intérvalos de confidencia correspondientes, fueron extraídos.
SÍNTESIS: Los resultados evaluados son conflictivos, y esta variabilidad
se puede deber a las diferentes poblaciones estudiadas, a los diferentes
diseños de los estudios, y a la posibilidad de parcialidad de publicación
relacionada a la provisión de fondos por la industria farmacéutica. No
obstante, un riesgo incrementado para el desarrollo de DM parece estar
presente en pacientes que están recibiendo antipsicóticos atípicos. Sin
embargo, el riesgo diferencial entre los antipsicóticos atípicos es difícil
de determinar.
www.theannals.com The Annals of Pharmacotherapy
Atypical Antipsychotics and the Development of Diabetes Mellitus
CONCLUSIONES: Se recomienda que los médicos manejen el riesgo
regularmente a través de un seguimiento de cerca de todos los pacientes
recibiendo antipsicóticos atípicos, con el propósito de determinar el
desarrollo de DM. Estudios futuros deben ser controlados
cuidadosamente en áreas que pueden ocasionar confusión tales como la
edad, diagnóstico, cambio en peso, nivel de actividad, historial familiar,
y etnicidad.
Brenda R Morand
RÉSUMÉ
OBJECTIF: Réviser les preuves pharmacoépidémiologiques reliant
l’exposition aux antipsychotiques atypiques au développement du
diabète mellitus.
REVUE DE LITTÉRATURE: Une recherche MEDLINE (1990–mars 2003) a
été effectuée pour retrouver les études pharmacoépidémiologiques
traitant du lien entre l’exposition aux antipsychotiques atypiques et le
développement du diabète mellitus.
SÉLECTION DES ÉTUDES ET SÉLECTION DE L’INFORMATION: La recherche a
été limitée aux papiers qui décrivaient les résultats des analyses de
grandes bases de données et qui utilisaient dans le titre ou le résumé les
mots diabetes ou hyperglycemia ou antipsychotics ou clozapine ou
olanzapine ou risperidone ou quetiapine ou ziprasidone ou aripiprazole.
On a extrait de ces analyses le rapport de cotes ou le risque relatif et leur
intervalle de confiance respectifs.
RÉSUMÉ: Les résultats sont contradictoires, et cette variabilité peut être
due aux différences au niveau des populations étudiées et au niveau des
devis expérimentaux utilisés ainsi qu’à la possibilité de biais de
publication liés au financement par des compagnies pharmaceutiques.
Néanmoins, une augmentation du risque de diabète mellitus semble être
présente chez les patients recevant des antipsychotiques atypiques.
Cependant, le risque différentiel entre les antipsychotiques atypiques est
difficile à établir.
CONCLUSIONS: Il est suggéré aux cliniciens de contrôler le risque en
surveillant de façon régulière l’émergence de diabète mellitus chez tous
les patients recevant des antipsychotiques atypiques. Les études futures
devraient soigneusement contrôler les éléments confondants tels l’âge, le
diagnostic, le changement de poids, le niveau d’activité, les antécédents
familiaux, et l’ethnie.
Marie Larouche
■ 2003 December, Volume 37 ■ 1857