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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 receivingatypical antipsychotic medications, Prim. Care Diab. (2008), doi:10.1016/j.pcd.2008.10.005

ARTICLE IN PRESSPCD-96; No. of Pages11

p r i m a r y c a r e d i a b e t e s x x x ( 2 0 0 8 ) xxxxxx

Contents lists available atScienceDirect

Primary Care Diabetes

j o u r n a l h o m e p a g e : h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / p c d

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-Brooksd

, Antony Fernandezb,e

, Anand K. Pandurangie

a Department of Psychiatry, Western Regional Integrated Health Authority, Sir Thomas Roddick Hospital,

Stephenville, Newfoundland, Canadab Psychiatry Services, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United Statesc Medical Services, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United Statesd Medical Media, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA, United Statese Department of Psychiatry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, United Statesf 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

Article history:

Received 26 June 2008Received in revised form

23 October 2008

Accepted 24 October 2008

Keywords:

Antipsychotic drugs

Overweight

Obesity

Diabetes mellitus

Dyslipidemia

Metabolic syndrome

Primary care

a b s t r a c t

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

ments due to genetic predisposition, developmental and environmental stressors, andlifestyle. This risk is compounded when they receive antipsychotic medications. Guidelines

for screening, monitoring, and managing thesepatients for metabolicproblems have beenin

place for severalyears. Despite this, recentreports document that this population continues

to receive poor care in this regard. In this article, we review the metabolic profile of atypical

antipsychotic medications and offer guidelines to reduce the metabolic complications of

these agents.

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

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2. Metabolic syndrome and cardio-metabolic risk factors .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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 [email protected](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
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2 p r i m a r y c a r e d i a b e t e s x x x ( 2 0 0 8 ) xxxxxx

3. Atypical antipsychotic medications and metabolic disturbances .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 00

3.1. Weight gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.2. Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.3. Insulin and glucose metabolism abnormalities and diabetes mellitus. . .. . .. .. .. . .. .. .. . .. .. . .. .. .. . .. .. . .. .. .. . .. . 00

3.4. Metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Atypical antipsychotics and the metabolic syndrome: pathogenesis.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . 00

5. Assessing, monitoring, and managing patients receiving atypical antipsychotic medications . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5.1. Baseline assessment and follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.2. Liaison between the primary care physician and the psychiatrist. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 00

5.3. Selection of atypical antipsychotic medication.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5.4. Patient education and interventions for modifiable risk factors. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 00

6. Pharmacological interventions for antipsychotic-induced metabolic derangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. 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 antipsy-

chotic medications maybe 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 atypi-

cal 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 mayunderliethe medication-associated

metabolic effects, and recommend monitoring and manage-

ment strategies.

2. Metabolic syndrome andcardio-metabolic risk factors

Metabolic syndrome refers to a group of metabolic distur-bances 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 pro-

inflammatory states are found in this setting. Organizations

vary in their definition 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

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, andBlood Institute and the American Heart Association

[23,26].

Cardiovascular risk factors expand beyond the various def-

initions of the metabolic syndrome. The National Cholesterol

Education Programs Adult Treatment Panel (ATP III) cate-

gorizes 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 majorrisk factors are cigarette-smoking,

hypertension, elevated LDL, low HDL, family history of pre-

mature coronary heart disease, and aging. The emerging

risk factors include elevated triglycerides, small LDL parti-

cles, insulin resistance, glucose intolerance, pro-inflammatorystate, and pro-thrombotic state.

3. Atypical antipsychotic medications andmetabolic 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 avail-

able 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 findings 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 quanti-

fied for short-term use with olanzapine having high risk,
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Pleasecitethisarticlein

pressas:M

Hasnain

etalClinicalmonitoringandmanagementofthemetabolicsyndromeinpatientsreceiving

Table 1 The metabolic syndrome as defined by the World Health Organization [100,101],Adult Treatment Panel III[22,26],Internat

World Health Organization (1998) Adult Treatment Panel III (2001) In

2 or more of the following 3 or more of the following

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

women AND/OR BMI >30 kg/m2Waist circumference 102cm (40 in.) for

men and 88cm (35in.) for women

C

E

h

Microalbuminuria Urinary albumin excretion rate

20g/min OR albumin-to-creatinine

ratio30mg/g

Hypertriglyceridemia Serum triglycerides 1.7mmol/L

(150mg/dL)

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

Low high density l ipoproteins HDL


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

Medication Weight gain Glucose metabolism abnormalities Dyslipidemia Metabolic syndrome

Amisulpride Low Low Low

Aripiprazole Low Low Low Low

Clozapine High High High High

Melperone Olanzapine High High High High

Paliperidone

Risperidone Medium Medium to low Low

Sulpiride

Quetiapine Medium Medium to low High

Sertindole Low

Ziprasidone Low Low Low Low

Zotepine Medium

quetiapine and possibly zotepine having moderate risk, and

risperidone, sertindole, amisulpride, aripiprazole, and ziprasi-

done having mild risk. With long-term use, differencesin weight-gain liability of these agents are not as great

[29].

Clozapine administration may lead to weight gain of

412kg in 1385% of patients[30]. In a recent review, New-

comer 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 ziprasi-

done, about 1.5kg with amisulpride, 23kg with quetiapine

and risperidone, and over 6kg with olanzapine (>10kg in

patients who received a daily dose between 12.5 mg and

17.5mg). The authors of this review noted that their find-

ings paralleled the results of recent prospective randomized

comparisons of individual agents. In another recent reviewof 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

antipsychoticdrug-induced weight tends to stabilizein several

months to a year[32].

3.2. Dyslipidemia

Dyslipidemia associated with atypical antipsychotic drug

administration was comprehensively reviewed by Meyer andKoro[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 aripipra-

zoleare least likely (or unlikely) to cause dyslipidemiaand may

improve the lipid profile of patients switched from another

antipsychotic drug to one of these agents [38,42]. Weight

gain associated with atypical antipsychotic drug administra-

tion may explain dyslipidemia, but this lipid disturbance may

occur independent of weight gain[41,43].

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].Specif-

ically, the risk of insulin resistance and hyperglycemia is high

with clozapine and olanzapine, moderate to low with quetiap-

ine and risperidone, and low with aripiprazole, amisulpride,

and ziprasidone.

Treatment with antipsychotic medications may be asso-

ciated 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, therankingof 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 antipsy-

chotic medications and new onset diabetes mellitus or

worsening of existing diabetes mellitus [12,15,4952] is dif-

ficult to interpret and evidence for a causative association

between use of antipsychotic medications and diabetes melli-

tus is inconclusive[53].We have drawn a few generalizations

fromthe 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, olan-

zapine, risperidone, and quetiapine[54],especially in young

adults [55]. (2) Age appears to be a factor contributing to

antipsychotic-induced diabetes mellitus, with younger adultsbeing 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],

implyingthat adiposityalone doesnot explain the association.

(4) In somecases, medication-induced diabetesmellitusmight

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 syn-

drome among patients taking atypical antipsychotic drugs.

Again, this risk is high with clozapine and olanzapine and


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p r i m a r y c a r e d i a b e t e s x x x ( 2 0 0 8 ) xxxxxx 5

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 relation-

ship between quetiapine and risperidone and the metabolic

syndrome[13,59].

4. Atypical antipsychotics and themetabolic syndrome: pathogenesis

Metabolic risk factors associated with major mental illness

among patients taking atypical antipsychotic medications

appear inFig. 1.Certain antipsychotic medications increase

appetite and this leads to adiposity. Affinity of the antipsy-

chotic drugs for histamine-1 (H1) receptors closely correlates

with their weight-gainingpotential [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 sup-

pression[65,67].Adiposity alone does not explain the diabetogenic poten-

tial of atypical antipsychotic medications [12]. Animal and

human studies describe the acute adverse effect of clozap-

ine and olanzapine on insulin and glucose metabolism[68].

Significant insulin resistance has also been documented in

non-obese individuals receiving clozapine or olanzapine ver-

sus those receiving risperidone[45].Diminished or inefficient

insulin release from pancreatic beta cells as well as periph-

eral insulin resistance may underlie the diabetogenic effect of

certain antipsychoticmedications. Blocking muscarinic type 3

(M3) and5-HT1A receptors may be a factor to diminished pan-

creatic 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 progres-

sive lipid accumulation [69]. The impaired effect of insulin

on adipocytes may partly explain weight-gain independent

dyslipidemia [41,43]. Increased food intake and periph-

eral insulin resistance perpetuate adiposity and release of

several adipocytokinessome of which contribute to cardio-

metabolic risk[70].

5. Assessing, monitoring, and managingpatients receiving atypical antipsychoticmedications

We will use consensus guidelines (Table 3)developed jointly

by the American Diabetes Association, American Psychiatric

Association, American Association of Clinical Endocrinolo-

gists,and North American Association forthe Studyof 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 mindthat psychotropicmedications

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 inTable 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 forbaseline assessment and monitoring of patients receiving atypical antipsychotic medications[71]a.

Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years

Personal/family historyb X X

Weight (body mass index) X X X X X

Waist circumference X X

Blood pressure X X XFasting plasma glucose X X X

Fasting lipid profile X X X

a More frequent assessments may be warranted based on clinical status.b Personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.

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

significant weight (greater than 7% of baseline body weight)

and were free of metabolic abnormalities at the beginning of

treatment, we recommend checking fasting lipid profile and

fasting glucose after 6 months as well. Patients who have

cardio-metabolic risk factors should have their fasting lipid

profile checkedevery 2 years instead of every 5 yearsand most

patients with diabetes mellitus should have their fasting lipid

profile measured at least once a year. Central obesity is a bet-

ter predictor of metabolic derangements than BMI. Because

antipsychotic-induced weight gain can be significant 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 ketoaci-

dosis during the first several months, especially in patients

taking clozapine, olanzapine or quetiapine. Checking glycosy-

lated hemoglobin (HbA1c) levels may identify those patients

who are developing glucose metabolism problems[75].Check

at risk patients 3 and 6 monthsafter 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 specific 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 chronicmentally 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 physi-

cian 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 efficacy and

largely differ based on their side-effect profile[80,81].There-

fore choosing a drug would be based on risk factors and

metabolic state of the patient, metabolic side-effect profile

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 antide-

pressant plus an antipsychotic), try to avoid combining drugs

associated with weight gain.

5.4. Patient education and interventions for modifiable

risk factors

Educationof the patient and, when possible, significant others

and other care-providers (e.g., case manager, respite worker)

optimizes treatment and drug compliance, and reduces unfa-

vorable 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 termsof response and sideeffects, symptoms

and signs of diabetes and diabetic ketoacidosis, modifiable

cardio-metabolic risk factors, and importance of treatment

compliance.

Modifiable cardio-metabolic risk factors such as, over-

weight/obesity, cigarettesmoking,lack of physical activity and

unhealthy diet are common in patients with major mental ill-

ness [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, activity-

recreational therapist, and addiction counselor, etc.).

6. Pharmacological interventions forantipsychotic-induced metabolic derangements

The primary care physician is central to managing and moni-

toring the physical health of patientsrequiring treatment with

antipsychotic drugs [71,84]. The patient benefits when there is


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a collaborative approach between the psychiatrist and physi-

cian. Such collaboration may require psychiatrists to improve

their knowledge of physical treatments.

There is a growing body of literature [38,42,8588] docu-

menting the benefits 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

byBarnett et al. [17] based on the joint guidelines of the Amer-ican 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

profile including significant weight gain. Specific guidelines

for switching antipsychotic medications have been developed

[89].

Various agents including ephedrine, sibutramine, orlistat,

topiramate, nizatidine, cimetidine, naltrexone, amantadine,

reboxetine, fluoxetine, and topiramate have been studied

as potential anti-obesity treatments in antipsychotic-treated

patientsdevelopingmetabolic derangements. Two recent pub-lications[90,91], found insufficient 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 medica-

tions may be advisable if more conservative interventions

like switching to a metabolically safer antipsychotic is not

possible and lifestyle interventions have failed[92].Insulin-

sensitizing agent, Metformin, has been shown to prevent or

attenuate weight gain and insulin resistance associated with

antipsychoticuse in several recent studies of short-term dura-

tion (816 weeks) [9397]. Most of these studies used adult

patients receiving olanzapine. However, one study on chil-

dren and adolescents also had subjects taking quetiapine andrisperidone [95]. Another study included patients receiving

clozapine, risperidone, and sulpiride[96].Dose range of met-

formin in these studies was 7502550mg per day and the drug

was tolerated reasonably well.

The beneficial effect of metformin administration on

weight and glucose metabolism may be more pronounced in

patients who undergo lifestyle intervention consisting of psy-

choeducation, dietary modification 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 butmetformin along with lifestyle intervention offered the great-

est benefit. 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 first year of treatment. However, this loss was not

as pronounced or sustained as that observed for the inten-

sive lifestyle group. Taken together, these findings suggest the

potential use of metformin in patients with major mental ill-

ness receiving antipsychotic medications. However, we need

long-term studies to clearly establish the utility of metformin

plus lifestyle modification. 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 antipsychotic-

induced weight gain and metabolic derangements.

If the metabolic derangement evolves into a disorder, then

treatment guidelines specific to that disorder dictate man-

agement. Pharmacological interventions should not exclude

non-pharmacologic strategies.

7. Conclusions

Despite the availability of well-published clinical guide-

lines, patients with chronic mental illness receiving atypical

antipsychotic medications remain vulnerable to the cardio-

metabolic 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 amisul-

pride, risperidone, and quetiapine fall in between. We haveemphasized the need for screening, monitoring, and manage-

ment of these patients. Management includes close liaison

between the primary care provider and the psychiatrist.

We recommend large-scale studies using present guide-

lines that include the primary care provider and the

psychiatrist working together. New strategies and technolo-

gies might emerge from such studies, facilitate cooperation

and enhance patient care.

Conflict of interest

Dr Pandurangi is on the speakers bureau of Astra-Zeneca,Bristol Myers Squibb, Janssen and Pfizer Pharmaceuticals.

Other authors do not have any conflict of interest to declare.

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