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Contents lists available at ScienceDirect

Primary Care Diabetes

journal homepage: http://www.elsevier.com/locate/pcd

Review

Clinical monitoring and management of the metabolic

syndrome in patients receiving atypical antipsychotic
medications
Mehrul Hasnain a, , W. Victor R. Vieweg b,c,e,f , Sonja K. Fredrickson c,f ,
Mary Beatty-Brooks d , Antony Fernandez b,e , Anand K. Pandurangi e
a

Department of Psychiatry, Western Regional Integrated Health Authority, Sir Thomas Roddick Hospital,
Stephenville, Newfoundland, Canada
b Psychiatry Services, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United States
c Medical Services, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United States
d Medical Media, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United States
e Department of Psychiatry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, United States
f Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, United States

a r t i c l e

i n f o

a b s t r a c t

Article history:

Individuals with major mental illness are a high-risk group for cardio-metabolic derange-

Received 26 June 2008

ments due to genetic predisposition, developmental and environmental stressors, and

Received in revised form

lifestyle. This risk is compounded when they receive antipsychotic medications. Guidelines

23 October 2008

for screening, monitoring, and managing these patients for metabolic problems have been in

Accepted 24 October 2008

place for several years. Despite this, recent reports document that this population continues
to receive poor care in this regard. In this article, we review the metabolic prole of atypical
antipsychotic medications and offer guidelines to reduce the metabolic complications of

Keywords:
Antipsychotic drugs

these agents.
2008 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Overweight
Obesity
Diabetes mellitus
Dyslipidemia
Metabolic syndrome
Primary care

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Metabolic syndrome and cardio-metabolic risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author at: Sir Thomas Roddick Hospital, 142 Minnesota Drive, Stephenville, Newfoundland A2N 2V6, Canada.
Tel.: +1 709 643 1973; fax: +1 709 643 7911.
E-mail address: mehrul hasnain@yahoo.com (M. Hasnain).
1751-9918/$ see front matter 2008 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.pcd.2008.10.005

Please cite this article in press as: M. Hasnain, et al., Clinical monitoring and management of the metabolic syndrome in patients receiving
atypical antipsychotic medications, Prim. Care Diab. (2008), doi:10.1016/j.pcd.2008.10.005

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3.

4.
5.

6.
7.

1.

Atypical antipsychotic medications and metabolic disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1. Weight gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Dyslipidemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Insulin and glucose metabolism abnormalities and diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. Metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Atypical antipsychotics and the metabolic syndrome: pathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Assessing, monitoring, and managing patients receiving atypical antipsychotic medications . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Baseline assessment and follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Liaison between the primary care physician and the psychiatrist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Selection of atypical antipsychotic medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Patient education and interventions for modiable risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacological interventions for antipsychotic-induced metabolic derangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction

The prevalence of the metabolic syndrome and individual

cardiovascular risk factors including obesity, dyslipidemia,
diabetes mellitus, cigarette smoking, and hypercortisolemia
are greater in individuals with major mental illness compared
with the general population [16]. While unhealthy lifestyle
[1,7,8] and apparent genetic predisposition [911] contribute
to this, there is growing evidence that treatment with antipsychotic medications may be a factor in the increased prevalence
of the cardio-metabolic problems among patients with major
mental illness [1215].
Guidelines to screen and monitor patients receiving atypical antipsychotic drugs have emerged over the last few years
[16,17]. Despite these guidelines, screening for, monitoring of,
and managing metabolic disturbances among patients with
major mental illness remains poor [1821], underscoring the
need to further improve awareness among clinicians on this
important subject. In this article, we review the metabolic
side effects of atypical antipsychotic medications, discuss
the mechanisms that may underlie the medication-associated
metabolic effects, and recommend monitoring and management strategies.

2.
Metabolic syndrome and
cardio-metabolic risk factors
Metabolic syndrome refers to a group of metabolic disturbances that interact synergistically to increase the risk of
atherosclerotic cardiovascular disease. The syndrome also
predisposes to diabetes mellitus, onset of which increases
cardiovascular risk even further, such that diabetes is
considered a cardiovascular risk equivalent [22,23]. Core
features of metabolic syndrome are overweight including
increased abdominal (visceral) fat, atherogenic dyslipidemia,
insulin resistance, and hypertension. Pro-thrombotic and proinammatory states are found in this setting. Organizations
vary in their denition of the metabolic syndrome (Table 1).
Questions remain as to whether the metabolic syndrome
can predict cardiovascular disease and diabetes mellitus more
accurately than its components [24,25]. For purposes of this

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review, we will embrace the clinical utility of this syndrome.

For a detailed discussion of the metabolic syndrome and its
components, please see the reports by the National Heart,
Lung, and Blood Institute and the American Heart Association
[23,26].
Cardiovascular risk factors expand beyond the various definitions of the metabolic syndrome. The National Cholesterol
Education Programs Adult Treatment Panel (ATP III) categorizes cardiovascular risk factors into underlying, major,
and emerging risk factors [23]. The underlying risk factors
are obesity (especially abdominal), physical inactivity, and
atherogenic diet. The major risk factors are cigarette-smoking,
hypertension, elevated LDL, low HDL, family history of premature coronary heart disease, and aging. The emerging
risk factors include elevated triglycerides, small LDL particles, insulin resistance, glucose intolerance, pro-inammatory
state, and pro-thrombotic state.

3.
Atypical antipsychotic medications and
metabolic disturbances
Atypical antipsychotics currently available in the United
States (in order of market approval) are: clozapine (1990),
risperidone (1994), olanzapine (1996), quetiapine (1997),
ziprasidone (2000), aripiprazole (2001), and paliperidone [the
main active metabolite of risperidone] (2006). All these agents
are available in Europe as well. Atypical antipsychotics available in Europe but not in the United States are amisulpride,
melperone, sertindole, sulpiride, and zotepine. The relative
potential for these agents to cause metabolic disturbances is
reviewed below and is summarized in Table 2. Information
available for melperone, sertindole, sulpiride, and zotepine is
very limited. Preliminary ndings suggest that paliperidone
has low metabolic liability [27].

3.1.

Weight gain

The risk and magnitude of short-term and long-term weight

gain are highest for clozapine and lowest for ziprasidone
[12,28,29]. For other antipsychotics the risk can be quantied for short-term use with olanzapine having high risk,

Please cite this article in press as: M. Hasnain, et al., Clinical monitoring and management of the metabolic syndrome in patients receiving
atypical antipsychotic medications, Prim. Care Diab. (2008), doi:10.1016/j.pcd.2008.10.005

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Abdominal girth

World Health Organization (1998)

Adult Treatment Panel III (2001)

2 or more of the following

3 or more of the following

Waist-to-hip ratio >0.9 in men, >0.85 in

women AND/OR BMI >30 kg/m2

Waist circumference 102 cm (40 in.) for

men and 88 cm (35 in.) for women

International Diabetes Federation (2005)

Must have central obesity
Central obesity (waist circumference
94 cm for European men and 80 cm for
European women; other ethnic groups
have specic values)

Plus any 2 of the following 4 factors

Hypertriglyceridemia
Low high density lipoproteins
Hypertension

Urinary albumin excretion rate

20 g/min OR albumin-to-creatinine
ratio 30mg/g
Serum triglycerides 1.7 mmol/L
(150 mg/dL)
HDL <0.9 mmol/L (35 mg/dL) in men and
<1.0 mmol/L (39 mg/dL) in women
Blood pressure 140/90 mmHg

Triglycerides 1.7 mmol/L (150 mg/dL)a

Triglycerides 1.7 mmol/L (150 mg/dL)a

HDL <1.03 mmol/L (40 mg/dL) in men and

<1.3 mmol/L (50 mg/dL) in womena
Blood pressure 130/85 mmHga

Low HDL <1.03 mmol/L (40 mg/dL) in men

and <1.29 mmol/L (50 mg/dL) in womena
Blood pressure 130/85 mmHga

Fasting plasma glucose 6.1 mmol/L

(110 mg/dL)a , b

Fasting plasma glucose 5.6 mmol/L

(100 mg/dL) OR previously diagnosed
type 2 diabetes

Plus any 1 of the following

Diabetes mellitus or pre-diabetes

a
b

Type 2 diabetes mellitus: Fasting plasma

glucose 7 mmol/L (126 mg/dL) OR 2-h
post-glucose load 11.1 mmol/L
(200 mg/dL)
Impaired glucose tolerance: Fasting
plasma glucose <7 mmol/L (126 mg/dL)
AND 2-h post-glucose load 7.8 mmol/L
(140 mg/dL) and <11.1 mmol/L (200 mg/dL)
Impaired fasting glucose: Fasting plasma
glucose 6.1 mmol/L (110 mg/dL) and
<7 mmol/L (126 mg/dL) AND 2-h
post-glucose load <7.8 mmol/L
(140 mg/dL)
Insulin resistance: Glucose uptake below
lowest quartile for background
population under investigation under
hyperinsulinemic, euglycemic conditions

Or on specic treatment for these conditions.

2001 denition identied fasting plasma glucose of 110 mg/dL as elevated. This was modied in 2004 to be 100 mg/dL (5.6 mmol/L) [26].

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Table 1 The metabolic syndrome as dened by the World Health Organization [100,101], Adult Treatment Panel III [22,26], International Diabetes Federation [102].

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Table 2 Approximate relative likelihood of metabolic disturbances with atypical antipsychotic medications (see text for
discussion).
Medication

Weight gain

Amisulpride
Aripiprazole
Clozapine
Melperone
Olanzapine
Paliperidone
Risperidone
Sulpiride
Quetiapine
Sertindole
Ziprasidone
Zotepine

Low
Low
High

High

Medium

Medium
Low
Low
Medium

Glucose metabolism abnormalities

Low
Low
High

High

Medium to low

Medium to low

Low

quetiapine and possibly zotepine having moderate risk, and

risperidone, sertindole, amisulpride, aripiprazole, and ziprasidone having mild risk. With long-term use, differences
in weight-gain liability of these agents are not as great
[29].
Clozapine administration may lead to weight gain of
412 kg in 1385% of patients [30]. In a recent review, Newcomer and Haupt [12] based on pooled multiple doses data
from the clinical trial programs reported that mean weight
gain over one year is about 1 kg with aripiprazole and ziprasidone, about 1.5 kg with amisulpride, 23 kg with quetiapine
and risperidone, and over 6 kg with olanzapine (>10 kg in
patients who received a daily dose between 12.5 mg and
17.5 mg). The authors of this review noted that their ndings paralleled the results of recent prospective randomized
comparisons of individual agents. In another recent review
of pivotal trials, Conley and Kelly [31] reported that 29% of
patients receiving olanzapine, 25% taking quetiapine, 18%
receiving risperidone, 10% taking ziprasidone, and 7% of
patients taking aripiprazole can expect greater than 7%
increase in their baseline body weight in the short-term.
Some assert that with the exception of clozapine, atypical
antipsychotic drug-induced weight tends to stabilize in several
months to a year [32].

3.2.

Dyslipidemia

Dyslipidemia associated with atypical antipsychotic drug

administration was comprehensively reviewed by Meyer and
Koro [33] a few years ago and several studies on this subject
have appeared since then [3441]. This literature suggests that
administration of atypical antipsychotic drugs may result in
dyslipidemia including reduced HDL and elevated cholesterol,
triglycerides, and LDL. The risk of dyslipidemia appears to
be high with clozapine, olanzapine, and quetiapine and mild
with risperidone and amisulpride. Ziprasidone and aripiprazole are least likely (or unlikely) to cause dyslipidemia and may
improve the lipid prole of patients switched from another
antipsychotic drug to one of these agents [38,42]. Weight
gain associated with atypical antipsychotic drug administration may explain dyslipidemia, but this lipid disturbance may
occur independent of weight gain [41,43].

Dyslipidemia

Metabolic syndrome

Low
Low
High

High

Low

High

Low

Low
High

High

Low

3.3.
Insulin and glucose metabolism abnormalities
and diabetes mellitus
Atypical antipsychotic medications may have unfavorable
effects on insulin and glucose regulation [12,40,4447]. Specifically, the risk of insulin resistance and hyperglycemia is high
with clozapine and olanzapine, moderate to low with quetiapine and risperidone, and low with aripiprazole, amisulpride,
and ziprasidone.
Treatment with antipsychotic medications may be associated with sudden onset of hyperglycemia with or without
complications [12]. Bayesian data-mining analysis of the FDA
adverse event reporting system (19682004) [48] showed that
on average, the ranking of association strength in this regard is
strong for clozapine and olanzapine, medium for quetiapine,
and low for ziprasidone, aripiprazole and risperidone.
Literature describing the association between antipsychotic medications and new onset diabetes mellitus or
worsening of existing diabetes mellitus [12,15,4952] is difcult to interpret and evidence for a causative association
between use of antipsychotic medications and diabetes mellitus is inconclusive [53]. We have drawn a few generalizations
from the literature. (1) Atypical antipsychotics associated with
greater weight gain are generally associated with a higher
risk for type 2 diabetes mellitus. Some studies, however,
report a comparable diabetogenic effect for clozapine, olanzapine, risperidone, and quetiapine [54], especially in young
adults [55]. (2) Age appears to be a factor contributing to
antipsychotic-induced diabetes mellitus, with younger adults
being at greater risk than older adults [49,5658]. (3) Although
most new-onset type 2 diabetes mellitus cases are associated
with substantial weight gain or obesity, about 25% are not [12],
implying that adiposity alone does not explain the association.
(4) In some cases, medication-induced diabetes mellitus might
remit after switching from a high potential medication to
one with a low potential.

3.4.

Metabolic syndrome

Several recent studies looked at the risk of the metabolic syndrome among patients taking atypical antipsychotic drugs.
Again, this risk is high with clozapine and olanzapine and

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Fig. 1 Interplay of cardio-metabolic risks associated with major mental illness and the metabolic effects of atypical
antipsychotic medications.

low with aripiprazole [2,5961]. The risk also appears to be

low with ziprasidone [62]. We know less about the relationship between quetiapine and risperidone and the metabolic
syndrome [13,59].

4.
Atypical antipsychotics and the
metabolic syndrome: pathogenesis
Metabolic risk factors associated with major mental illness
among patients taking atypical antipsychotic medications
appear in Fig. 1. Certain antipsychotic medications increase
appetite and this leads to adiposity. Afnity of the antipsychotic drugs for histamine-1 (H1) receptors closely correlates
with their weight-gaining potential [63] and appears to involve
H1 receptor-linked activation of hypothalamic AMP-kinase
[64]. Also, 5-HT2C receptor antagonism may contribute to
weight gain [65]. The effect atypical antipsychotics have on
hormones involved in appetite regulation is not clear [66].
However, the H1 and 5HT2C blocking effects of antipsychotic
medications may interfere with leptin-mediated appetite suppression [65,67].
Adiposity alone does not explain the diabetogenic potential of atypical antipsychotic medications [12]. Animal and
human studies describe the acute adverse effect of clozapine and olanzapine on insulin and glucose metabolism [68].
Signicant insulin resistance has also been documented in
non-obese individuals receiving clozapine or olanzapine versus those receiving risperidone [45]. Diminished or inefcient
insulin release from pancreatic beta cells as well as peripheral insulin resistance may underlie the diabetogenic effect of
certain antipsychotic medications. Blocking muscarinic type 3
(M3) and 5-HT1A receptors may be a factor to diminished pancreatic beta-cell responsiveness and blocking 5HT2A receptor
may suppress glucose uptake in skeletal muscle [63].

Some antipsychotic medications may impair and/or alter

the action of insulin on adipocytes leading to progressive lipid accumulation [69]. The impaired effect of insulin
on adipocytes may partly explain weight-gain independent
dyslipidemia [41,43]. Increased food intake and peripheral insulin resistance perpetuate adiposity and release of
several adipocytokinessome of which contribute to cardiometabolic risk [70].

5.
Assessing, monitoring, and managing
patients receiving atypical antipsychotic
medications
We will use consensus guidelines (Table 3) developed jointly
by the American Diabetes Association, American Psychiatric
Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity
[71] to monitor patients taking atypical antipsychotic drugs.
We are mindful of other guidelines [16,17].

5.1.

Baseline assessment and follow-up

Besides guidelines provided in Table 3, consider ethnicity,

dietary habits, physical activity, support system, cigarette
smoking, and alcohol and drug abuse. Consider previous
response to and side effects of medications that the patient is
using or has used. Keep in mind that psychotropic medications
other than antipsychotic drugs such as some antidepressants
and mood stabilizers may link to weight gain [7274].
Even for patients free of metabolic disturbances, monitor
potential risk factors as show in Table 3. Weight gain may not
be dose-dependent and individuals with low body mass index
(BMI) at baseline may be particularly vulnerable to weight
gain [31]. Glucose and lipid metabolism abnormalities may

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Table 3 American Diabetes Association (ADA) and American Psychiatric Association (APA) consensus guidelines for
baseline assessment and monitoring of patients receiving atypical antipsychotic medications [71]a .
Baseline
Personal/family historyb
Weight (body mass index)
Waist circumference
Blood pressure
Fasting plasma glucose
Fasting lipid prole
a
b

X
X
X
X
X
X

4 weeks

8 weeks

12 weeks

Quarterly

Annually

Every 5 years

X
X
X

X
X
X
X

More frequent assessments may be warranted based on clinical status.

Personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.

occur without weight gain [12,41,43]. For patients who gain

signicant weight (greater than 7% of baseline body weight)
and were free of metabolic abnormalities at the beginning of
treatment, we recommend checking fasting lipid prole and
fasting glucose after 6 months as well. Patients who have
cardio-metabolic risk factors should have their fasting lipid
prole checked every 2 years instead of every 5 years and most
patients with diabetes mellitus should have their fasting lipid
prole measured at least once a year. Central obesity is a better predictor of metabolic derangements than BMI. Because
antipsychotic-induced weight gain can be signicant early in
treatment, we recommend measuring waist circumference
3 and 6 months after starting treatment and then annually.
Antipsychotic medications may contribute to hypertension by
causing weight gain and/or insulin resistance. Blood pressure
should be monitored yearly or more often if indicated. Look for
symptoms and signs of diabetes mellitus and diabetic ketoacidosis during the rst several months, especially in patients
taking clozapine, olanzapine or quetiapine. Checking glycosylated hemoglobin (HbA1c) levels may identify those patients
who are developing glucose metabolism problems [75]. Check
at risk patients 3 and 6 months after starting treatment. The
frequency of monitoring will be different for those patients
who develop metabolic derangement and will be dictated by
the treatment guidelines for that specic derangement.

5.2.
Liaison between the primary care physician and
the psychiatrist
Current studies indicate that patients with major mental
illness do not receive adequate evaluation and effective
treatment of their cardio-metabolic problems [1821,7679].
Effective communication between the primary care physician
and the psychiatrist is particularly important for the chronic
mentally ill because of their impaired capacity to care for
themselves. Such communication will improve monitoring,
help early detection of metabolic derangements, and limit
duplication of clinical or laboratory workup. Monitoring for
metabolic side effects is primarily the responsibility of the
physician prescribing antipsychotic medication and in most
cases that would be a psychiatrist. If the primary care physician observes that the patient is being prescribed such drugs
without being monitored effectively, he/she should discuss
this with the psychiatrist. The psychiatrist may not have the
expertise to manage any abnormalities that are detected and
in such situations the primary care physician will most likely
take over both monitoring and management. Liaison should

extend to any healthcare professionals involved in the care

of patients with chronic mental illness and cardio-metabolic
problems.

5.3.

Selection of atypical antipsychotic medication

Atypical antipsychotic drugs have comparable efcacy and

largely differ based on their side-effect prole [80,81]. Therefore choosing a drug would be based on risk factors and
metabolic state of the patient, metabolic side-effect prole
of the drug (Table 2), responses and side effects to previous
treatments, and patient preference. Combining medications
associated with weight gain will increase the likelihood of
weight gain [73]. If a patient requires several psychotropic
medications (for example, a mood stabilizer or an antidepressant plus an antipsychotic), try to avoid combining drugs
associated with weight gain.

5.4.
Patient education and interventions for modiable
risk factors
Education of the patient and, when possible, signicant others
and other care-providers (e.g., case manager, respite worker)
optimizes treatment and drug compliance, and reduces unfavorable metabolic side effects. Patient education is an ongoing
process and should be provided in a manner and at a pace
manageable for the patient. It should cover topics including
those related to the patients illness, what to expect from the
medication(s) in terms of response and side effects, symptoms
and signs of diabetes and diabetic ketoacidosis, modiable
cardio-metabolic risk factors, and importance of treatment
compliance.
Modiable cardio-metabolic risk factors such as, overweight/obesity, cigarette smoking, lack of physical activity and
unhealthy diet are common in patients with major mental illness [1,7,8,82,83] and should be addressed even in patients free
of metabolic derangements. If resources allow, educate other
relevant health professionals (dietitian, psychologist, activityrecreational therapist, and addiction counselor, etc.).

6.
Pharmacological interventions for
antipsychotic-induced metabolic derangements
The primary care physician is central to managing and monitoring the physical health of patients requiring treatment with
antipsychotic drugs [71,84]. The patient benets when there is

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a collaborative approach between the psychiatrist and physician. Such collaboration may require psychiatrists to improve
their knowledge of physical treatments.
There is a growing body of literature [38,42,8588] documenting the benets of switching from an antipsychotic drug
with high risk of metabolic side effects (including weight gain)
to one with low risk (Table 2). This option has been suggested
by Barnett et al. [17] based on the joint guidelines of the American Diabetes Association, American Psychiatric Association,
American Association of Clinical Endocrinologists, and the
North American Association for the Study of Obesity [71]. We
strongly recommend this course as the initial intervention
when possible in all patients who show worsening metabolic
prole including signicant weight gain. Specic guidelines
for switching antipsychotic medications have been developed
[89].
Various agents including ephedrine, sibutramine, orlistat,
topiramate, nizatidine, cimetidine, naltrexone, amantadine,
reboxetine, uoxetine, and topiramate have been studied
as potential anti-obesity treatments in antipsychotic-treated
patients developing metabolic derangements. Two recent publications [90,91], found insufcient evidence to support the
general use of any of these agents to limit or reverse the
metabolic complications associated with antipsychotic-drug
therapy. However, trial of one or more of these medications may be advisable if more conservative interventions
like switching to a metabolically safer antipsychotic is not
possible and lifestyle interventions have failed [92]. Insulinsensitizing agent, Metformin, has been shown to prevent or
attenuate weight gain and insulin resistance associated with
antipsychotic use in several recent studies of short-term duration (816 weeks) [9397]. Most of these studies used adult
patients receiving olanzapine. However, one study on children and adolescents also had subjects taking quetiapine and
risperidone [95]. Another study included patients receiving
clozapine, risperidone, and sulpiride [96]. Dose range of metformin in these studies was 7502550 mg per day and the drug
was tolerated reasonably well.
The benecial effect of metformin administration on
weight and glucose metabolism may be more pronounced in
patients who undergo lifestyle intervention consisting of psychoeducation, dietary modication based on the American
Heart Association step 2 diet (less than 30% of total energy
fraction from fat), and an individualized exercise program
[96]. In this study of 12-weeks duration metformin use alone
was more effective than lifestyle intervention plus placebo in
increasing insulin sensitivity and reversing weight gain but
metformin along with lifestyle intervention offered the greatest benet. A large multicenter study using individuals from
the general US population showed that either metformin use
or intensive lifestyle intervention may delay or prevent the
onset of diabetes mellitus in patients with impaired glucose
tolerance [98]. In this study, the metformin group lost weight
during the rst year of treatment. However, this loss was not
as pronounced or sustained as that observed for the intensive lifestyle group. Taken together, these ndings suggest the
potential use of metformin in patients with major mental illness receiving antipsychotic medications. However, we need
long-term studies to clearly establish the utility of metformin
plus lifestyle modication. Thiazolidinedions (rosiglitazone

and pioglitazone) may improve cardiovascular risk factors

through multiple mechanisms [99] but so far they have not
been systematically studied for treatment of antipsychoticinduced weight gain and metabolic derangements.
If the metabolic derangement evolves into a disorder, then
treatment guidelines specic to that disorder dictate management. Pharmacological interventions should not exclude
non-pharmacologic strategies.

7.

Conclusions

Despite the availability of well-published clinical guidelines, patients with chronic mental illness receiving atypical
antipsychotic medications remain vulnerable to the cardiometabolic complications of these drugs. In general, patients
taking clozapine and olanzapine are most vulnerable and
those taking aripiprazole and ziprasidone are least vulnerable
to these complications. Preliminary data on paliperidone also
suggests it to have low metabolic risk. Patients taking amisulpride, risperidone, and quetiapine fall in between. We have
emphasized the need for screening, monitoring, and management of these patients. Management includes close liaison
between the primary care provider and the psychiatrist.
We recommend large-scale studies using present guidelines that include the primary care provider and the
psychiatrist working together. New strategies and technologies might emerge from such studies, facilitate cooperation
and enhance patient care.

Conict of interest
Dr Pandurangi is on the speakers bureau of Astra-Zeneca,
Bristol Myers Squibb, Janssen and Pzer Pharmaceuticals.
Other authors do not have any conict of interest to declare.

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Please cite this article in press as: M. Hasnain, et al., Clinical monitoring and management of the metabolic syndrome in patients receiving
atypical antipsychotic medications, Prim. Care Diab. (2008), doi:10.1016/j.pcd.2008.10.005

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Please cite this article in press as: M. Hasnain, et al., Clinical monitoring and management of the metabolic syndrome in patients receiving
atypical antipsychotic medications, Prim. Care Diab. (2008), doi:10.1016/j.pcd.2008.10.005