CLINICAL THERAPEUTICs®/VoL. 2 6 , NO.

12, 2 0 0 4

Metabolic Risk During Antipsychotic Treatment

John W. Newcomer, MD
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri

ABSTRACT

Background: Compared with the general population, individuals with schizophrenia demonstrate an
increased prevalence of obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). Increased
adiposity is associated with decreases in insulin sensitivity, leading to an increased risk of hyperglycemia and
hyperlipidemia. Antipsychotic medications can increase adiposity, and a range of evidence from case reports,
observational studies, retrospective database analyses, and controlled experimental studies (including random-
ized clinical trials) suggests that treatment with antipsychotic medications may be associated with an increased
risk for insulin resistance, hyperglycemia, dyslipidemia, and T2DM.
Objective: This article reviews current evidence for the hypothesis that treatment with antipsychotic medica-
tions may be associated with increased risks for weight gain, insulin resistance, hyperglycemia, dyslipidemia, and
T2DM, and examines the relationship of adiposity to medical risk.
Methods: Relevant publications were identified through a search of MEDLINE from 1973 to the present using
the primary search parameters "diabetes or hyperglycemia or glucose or insulin or lipids" and "antipsychotic."
Meeting abstracts and earlier nonindexed articles concerning antipsychotic-associated weight gain and metabol-
ic disturbance were also reviewed. Key studies in this emerging literature were summarized, including case
reports, observational studies, retrospective database analyses, and controlled experimental studies.
Results: Individual antipsychotic medications are associated with different degrees of treatment-induced
increases in body weight and adiposity, ranging from modest effects (<2 kg) with amisulpride, ziprasidone, and
aripiprazole to clinically significant increases with olanzapine (4-10 kg). In addition to strong evidence concern-
ing the effect of adiposity on insulin sensitivity in nonpsychiatric populations, increased adiposity in patients
with schizophrenia has been associated with decreases in insulin sensitivity; this and other effects may contribute
to increases in plasma glucose concentrations and lipid levels.
Conclusion: Metabolic changes in psychiatric patients who receive antipsychotic agents can contribute to the
development of the metabolic syndrome and increase the risk for T2DM and CVD. (Clin Ther. 2004;26:
1936-1946) Copyright @ 2004 Excerpta Medica, Inc.
Key words: schizophrenia, adverse effects, type 2 diabetes mellitus (T2DM), dyslipidemia, hyperglycemia.
This publication is based on a presentation at the 6th International Psychiatry Forum, "Mind Matters," held June 19, 2004, in Versailles, France, and spon-
sored by sanofi-aventis.
AcceptedJot publication November 24, 2004.
Express Track online publication December 13, 2004. doi:10.1016/j.clinthera.2004.12.003
Printed in the USA. Reproduction in whole or part is not pennitted. 0149 2918/04/$19.00

]936 Copyright @ 2004 Excerpta Nedica, Inc.


INTRODUCTION
Atypical antipsychotic drugs offer important benefits
for many patients with disorders such as schizophre-
nia, including a reduced risk for the extrapyramidal
side effects associated with conventional antipsy-
chotics. However, certain atypical antipsychotics can
produce substantial weight gain and increased adi-
posity in vulnerable individuals, and these agents
have also been associated with an increased risk for
dyslipidemia and type 2 diabetes mellitus (T2DM).
Patients with mental illness have elevated rates of
mortality and medical comorbidity, including
increased rates of T2DM and cardiovascular disease
(CVD). ~ The data concerning increased risk for
T2DM are particularly strong for depression, and
lifestyle factors (eg, reduced activity, poor nutrition)
may be key.~ Primary and secondary prevention target-
ing risk factors for T2DM and CVD may be particu-
larly important in psychiatric populations.
A key risk factor for CVD is excess adiposity, which
can be indirectly estimated using the weight and
height function of body mass index (BMI). In adults,
increases in BMI beyond a threshold of 25 kg/m2 are
associated with increasing risk of medical illness and
mortality.2,s Importantly, not all body fat is associated
with the same degree of risk. Increases in abdomi-
nal adiposity, particularly visceral abdominal fat, are
strongly associated with decreases in insulin sensitiv-
ity.~ Decreased insulin sensitivity, sometimes referred
to as insulin resistance, is associated with physiolog-
ic changes that include impaired glucose control, an
atherogenic dyslipidemia that involves increases in
plasma triglycerides and more-oxidized low-density
lipoprotein (LDL) particles, increased blood pressure,
increased risk of blood clotting, and increases in
markers of inflammation, all associated with an
increased risk for CVD. s Based on National Cho-
lesterol Education Program Adult Treatment Panel
(ATP) guidelines, 6 a patient with any 3 of the follow-
ing is considered to have metabolic syndrome (an
important risk factor for T2DM r and CVDS): obesity
(defined as waist circumference >102 cm for men,
88 cm for women), low levels of high-density lipo-
protein cholesterol (<40 mg/dL for men, 50 mg/dL
for women), high triglyceride levels (>150 mg/dL),
elevated blood pressure (>130 mm Hg systolic or
>85 mm Hg diastolic), or increased fasting blood glu-
cose levels (>110 mg/dL).
J.W. Newcomer
The long-term risks of hyperglycemia include
microvascular disease (retinopathy, nephropathy,
and neuropathies) and macrovascular disease, the
latter encompassing atherosclerosis-related CVD
(ie, coronary heart disease, cerebrovascular disease,
and peripheral vascular disease). In addition,
T2DM is associated with a risk of short-term com-
plications, including diabetic ketoacidosis (DKA)
and nonketotic hyperosmolar states, which, al-
though relatively uncommon, can be severe, s,9-1s
The mortality risk of DKA is -2% in optimal clini-
cal settings and rises as high as 20% in elderly
patients, with mortality risk generally increasing
with age, intercurrent illness, and delay in the initi-
ation of insulin therapy, l<~s
The American Diabetes Association (ADA) consen-
sus statement, ~6 cosponsored by the American
Psychiatric Association, the American Association of
Clinical Endocrinologists, and the North American
Association for the Study of Obesity, noted that cloza-
pine and olanzapine treatment are associated with the
greatest potential weight gain and with consistent evi-
dence for an increased risk of T2DM and dyslipi-
demia. The report emphasized that physicians should
consider multiple factors, including the presence of
medical and psychiatric conditions, when evaluating
the risks and benefits of prescribing specific antipsy-
chotic agents, and that the potential benefits of drugs
with metabolic liabilities may under certain cir-
cumstances outweigh the potential risks (eg, use of
clozapine therapy in patients with treatment-resistant
schizophrenia).
This article reviews current evidence for the
hypothesis that treatment with antipsychotic medica-
tions may be associated with increased risks for
weight gain, insulin resistance, hyperglycemia, dys-
lipidemia, and T2DM, and examines the relationship
of adiposity to medical risk. Relevant publications
were identified through a search of MEDLINE from
1975 to the present using the primary search param-
eters "diabetes or hyperglycemia or glucose or insulin
or lipids" and "antipsychotic." Meeting abstracts and
earlier nonindexed articles concerning antipsychotic-
associated weight gain and metabolic disturbance
were also reviewed. Key studies in this emerging lit-
erature were summarized, including case reports,
observational studies, retrospective database analy-
ses, and controlled experimental studies.
1937
CLINICAL THERAPEUTICS®
OBESITY, DIABETES, AND ANTIPSYCHOTICS
Certain antipsychotic medications can cause clinical-
ly significant weight gain, which is a growing concern
given the known health consequences of obesity.
Obesity and weight gain are major risk factors for
insulin resistance and T2DM, ~r leading to concerns
about the weight gain induced by some psychotropic
treatment regimens, particularly certain antipsychot-
ic medications.
The hypothesis that weight gain is a risk factor
only in the general population and is not related to
the risk of T2DM during antipsychotic treatment ~s
would seem to depend on the existence of u n k n o w n
protective factors that block the adverse effects of
adiposity that have been well established in a variety
of species and human populations. Given the evi-
dence for a higher rather than lower prevalence of
diabetes in psychiatric populations in almost all data
sets examined to date, >-2s it seems unlikely that
such protective factors are operating in individuals
with psychiatric illness. Therefore, it would seem
prudent to assume that antipsychotic-induced
weight gain, like any other increase in total fat mass,
may be associated with a variety of adverse physio-
logic effects.
A review of absolute weight gain in various placebo-
controlled trials and head-to-head comparisons
5-
4-
O
o0
._c
2-
t~
_c
(o
0.80
Ig
l 1
Ziprasidone Amisulpride
Figure. Mean changes in body weight associated with different atypical antipsychotic medications. Adapted from Allison et al 3°
and Leucht et al. 31
1938
found that the relative incidence and magnitude of
weight gain was not equal among antipsychotic medi-
cations. 29 Short-term treatment with various agents
has been reported to produce increases in body
weight ranging from <1 kg to >4 kg (Figure)) °,31
Studies of the long-term effects on body weight of
antipsychotic drugs are more relevant to clinical prac-
tice, in which long-term treatment is the routine.
Pooling multiple doses assessed in the clinical trials
programs, aripiprazole32-36 and ziprasidone3°,3r-39 have
been associated with a mean weight gain of -1 kg
over 1 year; amisulpride (not approved for use in
the United States) with a gain o f - 1 . 5 kg over 1
year31; quetiapine ~°#1 and risperidone ~2#3 with a
gain of 2 to 3 kg over 1 year; and olanzapine with a
gain of >6 kg over 1 year. **-.6 A mean weight gain of
>10 kg was observed in patients who received olan-
zapine at doses between 12.5 and 17.5 mg, the high-
est doses tested in large-scale pivotal trials. ** The
results of prospective randomized comparisons of
individual agents have been consistent with the re-
suits for individual agents from the pivotal trials. For
example, after 6 months of treatment with amisul-
pride (n = 189) and olanzapine (n = 188), the latter
was associated with a significantly greater mean
increase in body weight (3.9 kg vs 1.6 kg, respective-
ly; P < 0.01). *r
4.45
4.15
2.92
2.10
T T
Risperidone Sertindole Olanzapine Clozapine
I 0-Week Weight Gain

I N S U L I N RESISTANCE, DIABETES, A N D
ANTIPSYCHOTIC TREATHENT
A range of evidence suggests that treatment with cer-
tain antipsychotic medications is associated with an
increased risk for insulin resistance, hyperglycemia,
dyslipidemia, and T2DM compared with no treat-
ment or treatment with alternative antipsychotics. 1
Interpretation of the literature has been complicated
by reports that patients with major mental disorders
such as schizophrenia have an increased prevalence
of abnormalities in glucose regulation (eg, insulin
resistance) before the initiation of antipsychotic the>
apy. .8 Early studies did not control for age, body
weight, adiposity, ethnicity, or diet, 2<~9 and most
experts hypothesized that differences in key factors
such as diet and activity level between patients and
control subjects contributed to at least some of the
observed abnormalities.
A recent cross-sectional study in 26 hospitalized
first-episode antipsychotic-naive patients with schizo-
phrenia found that 15% of these patients had
impaired fasting glucose. 28 The patients with schizo-
phrenia had significantly higher values compared
with control subjects matched for lifestyle and
anthropometric measures for the following parame-
ters: mean fasting plasma glucose (95.8 vs 88.2
mg/dL, respectively; P < 0.03, Student 2-tailed t test),
insulin (9.8 vs 7.7 pU/mL; P < 0.05), and cortisol lev-
els (499.4 vs 303.2 nmol/L; P < 0.01). The elevated
plasma cortisol levels observed in this sample proba-
bly contributed to some of the increase in insulin
resistance and plasma glucose concentrations.
However, hypercortisolemia is not typically observed
in antipsychotic-treated patients with schizophrenia, 5°
so this study may have overestimated the degree of
insulin resistance and hyperglycemia that can be
expected to persist past the acute psychotic episode
and/or agitated condition that led to hospitalization.
In any case, this study complements earlier reports
supporting the view that patients with schizo-
phrenia and perhaps those with other major mental
disorders may have an increased risk for insulin
resistance and T2DM independent of their exposure
to antipsychotic medications. 2<~9
LEVELS OF EVIDENCE
Evidence spanning case reports and prospective
observational studies (typically useful for hypothesis
J.W. Newcomer
generation), retrospective database analyses (often
useful for hypothesis testing, although methodologic
concerns can limit interpretability, as discussed later),
and controlled experimental studies, including ran-
domized clinical trials (generally recognized as
hypothesis testing), have identified an association
between certain antipsychotic medications and
adverse metabolic events, including hyperglycemia,
dyslipidemia, insulin resistance, exacerbation of
existing type 1 diabetes mellitus or T2DM, new-onset
T2DM, and DKA. 1 Adverse effects on glucose and
lipid metabolism (eg, T2DM, dyslipidemia) have
more frequently and consistently been associated
with clozapine and olanzapine treatment than with
quetiapine or risperidone treatment. 16 Reports detail-
ing limited short- and long-term weight gain with
ziprasidone, amisulpride, and aripiprazole are consis-
tent with little or no evidence of adverse effects on
metabolic outcomes. 1,1<~9,51
Although the relative risk for T2DM during anti-
psychotic treatment appears to match the rank order
of weight-gain potential for the different agents,
weight gain may not explain all the observed meta-
bolic adverse effects. Newcomer et al 5° examined the
effects of conventional and atypical antipsychotics on
glucose regulation in chronically treated nondiabetic
patients with schizophrenia compared with untreated
healthy control subjects. All patient and control
groups were carefully matched for adiposity and age.
Using a modified oral glucose tolerance test, these
investigators found that patients receiving olanzapine
(n = 12) and clozapine (n = 9) had significantly high-
er fasting and postload plasma glucose values com-
pared with patients receiving conventional antipsy-
chotics (n = 17) and untreated healthy control
subjects (n = 31) (all comparisons, P < 0.001). The
group that received risperidone did not differ from
the group that received conventional antipsychotics,
but it had higher postload glucose levels compared
with controls (P < 0.01). Patients who received olan-
zapine and clozapine had higher calculated insulin
resistance compared with those who received con-
ventional agents (P < 0.05 and P < 0.08, respective-
ly), whereas those who received risperidone or typi-
cal antipsychotics did not differ from controls.
Retrospective analyses of cases of new-onset T2DM
associated with clozapine, 1~ olanzapine, 52 and risperi-
done 53 in the US Food and Drug Administration
1939
CLINICALTHERAPEUTICS®
(FDA) MedWatch database have suggested that
whereas the majority of new-onset T2DM cases were
associated with substantial weight gain or obesity,
-25% were not. These analyses also have suggested
that most new-onset cases of T2DM occurred within
the first 6 months after initiation of treatment. These
cases were typically associated with substantial weight
gain or obesity (ie, -75% of the time), and as many as
half of them involved individuals with no family histo-
ry of diabetes. Some of the cases exhibited a close tem-
poral relationship between initiation/discontinuation
of treatment and development/resolution of the
hyperglycemia-associated adverse event.
There have been at least 17 reported retrospec-
tive analyses that used large administrative or health
plan databases to test the strength of the association
between treatment with specific antipsychotic medi-
cations and the presence of T2DM. 5*-r° Their com-
mon approach was to measure the association within
a database between the use of specific antipsychotic
medications and the presence of >1 surrogate indica-
tor of T2DM (eg, prescription of a hypoglycemic
agent, relevant International Classification of Diseases,
Ninth Revision [ICD-9] codes). Approximately two
thirds of these studies had findings suggesting that
drugs associated with greater weight gain (eg, olanza-
pine) were also associated with an increased risk for
T2DM compared with either no treatment, conven-
tional treatment, or a drug producing less weight gain
(eg, risperidone). Although explicit tests of the rela-
tionship between diabetes risk and weight gain were
not possible in these studies, none of them indicated
that any drug with high weight-gain potential was
associated with a lower risk for T2DM compared with
an alternative treatment. Approximately one third of
the studies detected no difference between groups or
a nonspecific increase in the association for all treat-
ed groups compared with untreated controls.
The most important problem with retrospective
database analyses involves the use of insensitive and
unreliable surrogate diagnostic indicators for T2DM
(eg, prescription of a hypoglycemic drug, ICD-9
codes). Based on ADA estimates that -33% of individ-
uals with T2DM in the general population are undiag-
nosed, rl many individuals with psychiatric disorders
will have no associated hypoglycemic prescription or
diabetes-related ICD-9 code to be detected in this type
of analysis. Given that antipsychotic-related differ-
1940
ences in the prevalence of T2DM are probably <33%,
measurement error may complicate the detection of
potentially relevant target signals. The considerable
problem of signal-to-noise ratio in studies of this type
suggests that variable results can be expected, includ-
ing potential failure to detect the target signal.
The final level of evidence for an association
between antipsychotics and metabolic outcomes is
derived from controlled experimental studies and ran-
domized clinical trials. There is a growing body of evi-
dence supporting the key observation that treatments
producing the greatest increases in body weight and
adiposity are also associated with the most consistent
pattern of clinically significant adverse effects on
insulin sensitivity and blood glucose and lipid levels.
Five studies have reported statistically significant
increases in plasma insulin levels during olanzapine
treatment compared with various control conditions,
such as placebo or another antipsychotic (all, P <
0.05), 5°,r2-r5 suggesting decreased insulin sensitivity
(ie, insulin resistance), and 2 of these studies reported a
significant increase in insulin resistance from baseline
during olanzapine therapy (both studies, P < 0.05).r3,r*
With the exception of clozapineJ <5° other agents have
not been reported to have this effect. Two studies
reported elevated insulin levels in 31% to 71% of
patients receiving olanzapine treatment (P < o.o5), r<rr
The findings of these studies are consistent with the
evidence from general-population samples suggesting
that conditions that increase adiposity tend to be asso-
ciated with increases in insulin resistance, potentially
leading to compensatory insulin secretion in persons
with pancreatic beta-cell reserve and to hyperglycemia
in individuals with relative beta-cell failure, r<r9
A randomized, double-blind trial in 157 patients
with schizophrenia consisted of an 8-week fixed-dose
period and a 6-week variable-dose period of treatment
with clozapine, olanzapine, risperidone, or haloperi-
dol. 8° There were significant increases from baseline in
mean glucose levels at the end of the 6-week variable-
dose period in the 22 patients who received olanza-
pine (P < 0.02), and at the end of the 8-week fixed-
dose period in the 27 patients who received clozapine
(P < 0.01) and the 25 who received haloperidol (P <
0.03). The authors indicated that a trend-level differ-
ence was seen between treatments at the end of the
fixed-dose period (P = 0.06) but not at the end of the
variable-dose period. Mean cholesterol levels were

increased at the end of the variable-dose period in
patients who received olanzapine (P < 0.01), and at
the end of the fixed-dose period in patients who
received clozapine (P < 0.02) or olanzapine (P < 0.04).
This study was complicated by baseline and end-point
body weights in some groups not typically seen in
clinical practice or in other trials, underscoring the
need to control for previous treatments and baseline
status in future trials. A pooled analysis of safety data
from short-term (4-6 wk) controlled trials of aripipra-
zole in patients with schizophrenia found that
changes in fasting serum glucose concentrations were
similar between patients who received aripiprazole
(n = 860) and those who received placebo (n = 392).32
A 26-week controlled study of aripiprazole for relapse
prevention in 310 patients with schizophrenia found
no clinically or statistically significant change from
baseline in fasting glucose concentrations (change
from baseline, 0.13 mg/dL). 33
Limited findings to date suggest that quetiapine
therapy is not associated with a consistent increase in
the risk for T2DM or dyslipidemia. However, a possi-
ble increase in metabolic risk would be predicted in
association with any treatment that produces increas-
es in body weight and adiposity, and quetiapine typi-
cally produces modest weight gain (-2-3 kg over the
long term). A 6-week randomized study of atypical
antipsychotics in 56 patients with schizophrenia (14
patients each received clozapine, olanzapine, quetia-
pine, and risperidone) found significant changes from
baseline in triglyceride levels with quetiapine thera-
py.81 In quetiapine recipients, the mean increase in
triglyceride levels from baseline was significant at
week 6 (11.64 mg/dL; P < 0.05), although this mean
increase was -3 times less than that observed in
clozapine recipients (36.28 mg/dL) or olanzapine
recipients (31.23 mg/dL) (both, P < 0.01). No signif-
icant increase from baseline in triglyceride levels was
observed in risperidone recipients.
Fasting glucose, insulin, and lipid parameters were
assessed in a 6-week, randomized, double-blind com-
parison of olanzapine and ziprasidone therapy in 269
inpatients with an acute exacerbation of schizophrenia
or schizoaffective disorder, r* Statistically significant
increases from baseline in median fasting plasma
insulin levels and insulin resistance calculated using
the homeostasis model assessment were observed
during olanzapine treatment but not ziprasidone
J.W. Newcomer
treatment (both parameters, P < 0.001). Median body
weight increased from baseline by 7.2 lb (3.3 kg)
with olanzapine, compared with 1.2 lb (0.5 kg) with
ziprasidone, and median body weight was significant-
ly higher in the olanzapine group than in the ziprasi-
done group at end point (P < 0.001). In this nonelder-
ly sample (mean [SD] age, 37.7 [9.71] years) with a
significant compensatory hyperinsulinemic response,
fasting plasma glucose levels did not change signifi-
cantly in either the olanzapine or ziprasidone group.
Statistically significant increases from baseline in
median levels of fasting total cholesterol (20 mg/dL;
P < 0.001), LDL cholesterol (13 mg/dL; P < 0.001),
and triglycerides (26 mg/dL; P < 0.001) were observed
with olanzapine therapy. In contrast, minimal changes
in these measures were observed with ziprasidone
therapy (-1,-1, and -2 mg/dL, respectively).
A similar 8-week, prospective, randomized, double-
blind study compared amisulpride and olanzapine in
85 patients with schizophrenia and depression. 82
Mean body weight increased by 0.5 kg in the amisul-
pride group and by 1.45 kg in the olanzapine group,
a difference that was not statistically significant. As in
the study by Simpson et al, r* fasting glucose levels
showed little change, with a difference from baseline
to end point of-0.53 and 0.13 mmol/L for amisul-
pride and olanzapine, respectively. There was no sig-
nificant difference between groups, although the
mean decrease from baseline to end point was statis-
tically significant in the amisulpride group (P =
0.041, Wilcoxon signed rank test).
Using pooled data from two 26-week, randomized,
double-blind, controlled trials, ss,s* a prospective
study compared the effects of aripiprazole, olanza-
pine, and placebo on the incidence of worsening
metabolic syndrome in 624 subjects. 8s The cumula-
tive incidence of worsening metabolic syndrome var-
ied across treatments, from a mean (SE) incidence of
19.2% (4.0%) with olanzapine to 12.8% (4.5%) with
placebo and 7.6% (2.3%) with aripiprazole. A log-
rank test indicated a significant difference between
the 3 rates (P = 0.003), with a 69% relative risk
reduction for aripiprazole versus olanzapine. 83,8.
HONITORING AND TREATHENT
CONSIDERATIONS
It would be prudent for clinicians to monitor patients
taking atypical antipsychotics for weight increase and
1941
CLINICALTHERAPEUTICS®
related metabolic changes, particularly in the first sev-
eral months of treatment. The American Psychiatric
Association recommends that fasting plasma glucose
and lipid levels and blood pressure be assessed within
3 months after initiation of antipsychotic drug thera-
py.1 Subsequent assessments of plasma glucose levels
should be performed at least annually, and more often
for patients with other risk factors for T2DM. If pa-
tients exhibit clinical signs and symptoms of hyper-
glycemia (eg, polyuria, polydipsia), clinicians should
quickly assess plasma glucose concentrations and
begin the process of correcting any abnormalities.
This assessment should include medical or endocrine
consultation, any necessary acute modification to the
treatment regimen (eg, addition of hypoglycemic
agents), active education of patients and their families
about desirable lifestyle changes, and consideration of
the risks and benefits of switching the antipsychotic
medication, if necessary, to one that carries less rela-
tive risk of precipitating weight gain or T2DM. For
patients who have an increased risk for T2DM before
treatment (eg, overweight, obesity), education should
be initiated immediately, and selection of a regimen
should take the patient~ comorbid condition into
account. With careful monitoring and individualized
treatment, patients can receive the maximum benefit
from atypical antipsychotics.
CONCLUSIONS
Data from various sources on the use of atypical
antipsychotics indicate that some drugs in this class
are associated with a significant risk for weight gain
and disordered glucose and lipid metabolism. How-
ever, it is clear that weight gain is not an absolute pre-
requisite for the development of insulin resistance,
impaired glucose tolerance, dyslipidemia, or T2DM.
Additional research is needed to examine the phar-
macologic factors that contribute to these adverse
effects in vulnerable individuals. The FDA has recent-
ly required that the package inserts for all antipsy-
chotics contain a warning concerning hyperglycemia
and has asked for further information from pharma-
ceutical companies concerning treatment-emergent
dyslipidemia and metabolic syndrome. Future
research in this area will be helpful not only to clini-
cians but also to regulatory agencies as they consider
potential adverse effects associated with the use of
these agents.
1942
ACKNOWLEDGHENTS
This article was supported by a grant from sanofi-
aventis, Paris, France.
In 2004, Dr. Newcomer has served as a consultant
for AstraZeneca Pharmaceuticals LP; Bristol-Myers
Squibb Company; GlaxoSmithKline; Janssen Phar-
maceutica Products, LP; Pfizer Inc.; and Wyeth
Pharmaceuticals. He holds research grants from
Janssen, Pfizer, the National Alliance for Research on
Schizophrenia and Depression, the National Institute
of Mental Health, and the Sidney R. Baer Foundation.
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Address correspondence to: John W. Newcomer, MD, Department of Psychiatry, Washington University School
of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: newcomerj@
psychiatry.wustl.edu

1946