East Asian Arch Psychiatry 2013;23:21-8 Review Article

Metabolic Complications of Schizophrenia

and Antipsychotic Medications — An Updated
Review
精神分裂症和抗精神病藥引發的代謝併發症：更新回顧
J Yogaratnam, N Biswas, R Vadivel, R Jacob

Abstract
Metabolic syndrome is a cluster of risk factors comprising obesity, dyslipidaemias, glucose intolerance,
insulin resistance (or hyperinsulinaemia), and hypertension, and is highly predictive of type 2 diabetes
mellitus and cardiovascular disease. The life expectancy of people with schizophrenia is reduced by 20%,
with 60% of the excess mortality due to physical illness. Schizophrenia itself may be a risk factor for
metabolic syndrome and there is also increasing concern that antipsychotic drugs, particularly second-
generation antipsychotics, have metabolic consequences that contribute to the risk. Various diagnostic
guidelines, updated facts with regard to epidemiology, pathophysiology, risk factors, and complications
of metabolic syndrome are discussed in this review. Moreover, the impact of various antipsychotics
on metabolic syndrome and their possible mechanisms are comprehensively reviewed. The authors
emphasise that, while many adults with schizophrenia receive little or no medical care, such care is
important given the risk of metabolic abnormalities associated not only with antipsychotic medications,
but also with schizophrenia in general.

Key words: Antipsychotic agents; Metabolic syndrome X; Metabolism; Schizophrenia

摘要

代謝綜合症是肥胖、血脂異常、葡萄糖耐受不良、胰島素抗性（或稱高胰島素血症）和高血壓
等的風險因素群，並且能高度預測二型糖尿病和心血管疾病。精神分裂症患者的壽命一般縮短
20%，而因身體疾病導致的額外死亡率也達到60%。精神分裂症本身也許是代謝綜合症的風險
因素，而抗精神病藥，尤其是第二代抗精神病藥對代謝功能的影響也漸受關注。本文回顧並討
論代謝綜合症各種診斷指南以及有關其流行病學、病理生理學以及風險因素和併發症的最新資
訊。本文也回顧各種抗精神病藥對代謝綜合症的影響和其可能機制。代謝異常的風險不僅與抗
精神病藥，且與精神分裂症相關。因此，在現行對成人精神分裂症患者相關護理不足甚至缺乏
的情況下，作者強調它的重要性。

關鍵詞：抗精神病藥、代謝綜合症、代謝、精神分裂症

Dr Jegan Yogaratnam, MBBS, MD, Institute of Mental Health / Woodbridge
Hospital, Singapore.
Dr Neetesh Biswas, MBBS, Institute of Mental Health / Woodbridge Hospital,
Singapore.
Dr Ramyadarshni Vadivel, MBBS, Institute of Mental Health / Woodbridge
Hospital, Singapore.
Dr Rajesh Jacob, MBBS, MD, Institute of Mental Health / Woodbridge Hospital,
Singapore.
Address for correspondence: Dr Jegan Yogaratnam, Woodbridge Hospital /
Institute of Mental Health, 10 Buangkok View, Singapore 539747.
Tel: (65) 6389 2000; Fax: (65) 6385 5900; email: jegany@gmail.com
Submitted: 25 June 2012; Accepted: 10 September 2012
Introduction
Metabolic syndrome is a cluster of risk factors comprising
obesity (central and abdominal), dyslipidaemias, glucose
intolerance, insulin resistance (or hyperinsulinaemia), and
hypertension, and is highly predictive of type 2 diabetes
mellitus and cardiovascular disease.1 The mean age of
death is 61 years for patients with schizophrenia, which
is considerably younger than 76 years for the general
population.2 Life expectancy in people with schizophrenia
is reduced by 20%,3 with 60% of the excess mortality due
to physical illness.4
Schizophrenia itself may be a risk factor for metabolic
syndrome in addition to many other factors in patients
with schizophrenia, and there is also increasing concern
that antipsychotic drugs, particularly second-generation
antipsychotics (SGAs), have metabolic consequences that
contribute to the risk.5 The precise relationship between
antipsychotic drugs and metabolic syndrome remains
uncertain, but it is clear that people with schizophrenia

© 2013 Hong Kong College of Psychiatrists 21

J Yogaratnam, N Biswas, R Vadivel, et al
treated with antipsychotic medications develop individual
features of metabolic syndrome, and the syndrome itself,
at a higher rate than the general population. Antipsychotic
polypharmacy, which is a common practice in many
psychiatric settings, as compared with monotherapy,
may be independently associated with increased risk of
pre-metabolic syndrome and higher rates of metabolic
syndrome and lipid markers of insulin resistance, even
after adjusting for patients’ lifestyle characteristics.6,7 A
recent study concluded that switching to monotherapy was
appropriate and reasonable as long as patients could return
to polypharmacy when necessary, and switching from a
higher- to a lower-risk agent or from polypharmacy to
monotherapy may facilitate metabolic improvement.8
Many reviews have concluded that there is a need for
active routine physical health screening of all individuals
receiving treatment with antipsychotic drugs,9 which is in
keeping with the recommendations of the National Institute
for Health and Clinical Excellence treatment guidelines
for schizophrenia. While many adults with schizophrenia
receive little or no medical care, such care is important,
given the risk of metabolic abnormalities associated not only
with antipsychotic medications, but also with schizophrenia
in general.10
Diagnostic Guidelines for Metabolic Syndrome
Guidelines for diagnosis of metabolic syndrome are listed
in Table 1.1,11-15 The most commonly used definitions
for metabolic syndrome are in keeping with the Adult
Treatment Panel III (ATP III) of the National Cholesterol
Education Program (NCEP) definition and the adapted
ATP III recommendation proposed by the American Heart
Association which follows the International Diabetes
Federation (IDF) guideline of lowering the threshold for
impaired fasting glucose to 5.56 mmol/L (100 mg/dL).11
An important difference between the NCEP / ATP III and
the IDF definitions is that of the values for central obesity,
which are defined as > 102 cm for men and > 88 cm for
women in the NCEP / ATP III definition, the IDF values are
comparatively lower at 94 cm and 80 cm, respectively, with
a lower value of 80 cm for South-Asian men.16
Epidemiology of Metabolic Syndrome
Metabolic syndrome is a burgeoning global problem,
with approximately 25% of adult Europeans and Latin
Table 1. Diagnostic guidelines for metabolic syndrome.
• American Heart Association / National Heart, Lung, and Blood Institute (2004)1
• International Diabetes Federation (2005)11
• World Health Organization (1998)12
• European Group for the Study of Insulin Resistance (1999)13
• American Diabetes Association (2003)14
• National Cholesterol Education Program Adult Treatment Panel III (2001)15
22
Americans, 22% of US adults, and 32% of Mexican
Americans17 estimated to have the condition. Additionally,
metabolic syndrome is considered an emerging epidemic in
developing East-Asian countries, including China, Japan,
and Korea, where the prevalence ranged from 8 to 13% in
men and 2 to 18% in women depending on the population
and definitions used.18 Even in many other countries
worldwide, metabolic syndrome has been recognised as a
highly prevalent health problem19 demanding attention and
intervention. The exact prevalence of metabolic syndrome
in patients with schizophrenia is unknown. Using baseline
data from the Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) schizophrenia trial, the prevalence
of metabolic syndrome was 40.9% and 42.7% according
to the NCEP and the American Heart Association /
National Heart, Lung, and Blood Institute–derived criteria,
respectively.20
Pathophysiology of Metabolic Syndrome
Metabolic syndrome is thought to be caused by adipose
tissue dysfunction and insulin resistance. Dysfunctional
adipose tissue results in the release of proinflammatory
cytokines such as tumour necrosis factor, adiponectin, leptin,
resistin, and plasminogen activator inhibitor, which play an
important role in the pathogenesis of obesity-related insulin
resistance, the primary mediator of metabolic syndrome.21
Risk Factors for Metabolic Syndrome in
Patients with Schizophrenia
People with schizophrenia on average have a sedentary
lifestyle involving lack of regular physical activity, poor food
intake, substance abuse, and high rates of smoking,22 which
increase their risk for development of metabolic syndrome
in addition to the risk from antipsychotic medications.
These lifestyle factors are partly influenced by aspects of
the illness such as negative symptoms and vulnerability to
stress. Moreover, earlier studies have shown an increased
risk for people with schizophrenia to develop metabolic
abnormalities in the absence of antipsychotic medication,
and there are indications of an increased risk for diabetes in
first-degree relatives of patients with schizophrenia.23
Other possibilities to explain these associations
in schizophrenia include stress and abnormalities of the
hypothalamic-pituitary-adrenal axis.24 A study showed that
people with schizoaffective disorder are more vulnerable
East Asian Arch Psychiatry 2013, Vol 23, No.1
 Metabolic Complications of Schizophrenia and Antipsychotics

to metabolic syndrome than people with schizophrenia for
unexplained reasons.25
Complications of the Metabolic Syndrome
The complications of metabolic syndrome are broad. Table
226-30 shows that metabolic syndrome is a multisystem
disorder involving the cardiovascular, hepatobiliary, and
central nervous / psychological systems.
Antipsychotics and Metabolic Syndrome
dyslipidaemia and hypertension in the absence of type 2
diabetes mellitus) may be mechanistically linked to lower
academic and professional potential in adolescents, as lower
cognitive performance and reduction in brain structural
integrity among adolescents with metabolic syndrome has
been documented in studies.32
While there appears to be a dose-dependent
relationship between the dose of clozapine or olanzapine
and metabolic complications, aripiprazole, quetiapine,
and ziprasidone do not show a causal relationship, and
risperidone has mixed results.33

Notwithstanding the therapeutic effectiveness of Antipsychotics and Weight Gain

antipsychotic drugs in many illnesses such as schizophrenia,
increased attention has turned to the possible deleterious
side-effects of these agents. Metabolic derangements
associated with antipsychotic agents have been the focus
of considerable interest and debate for many years. While
metabolic syndrome affects all ages of patients who take
antipsychotic medications, children and adolescents
receiving atypical antipsychotic medications are particularly
vulnerable to these effects.31 Notably, obesity-associated
metabolic disease short of type 2 diabetes mellitus (i.e.
Interestingly, an independent association between
schizophrenia and physical illnesses that have a metabolic
signature, including obesity, has been proposed, with
several studies reporting significantly higher (p < 0.001)
prevalences of overweight (body mass index [BMI]
≥ 25 kg/m2) and obesity (BMI > 30 kg/m2) in patients with
psychotic disorders than in the general population.34 Drug-
naïve schizophrenia patients have also been found to have
more than 3 times as much intra-abdominal fat (which

Table 2. Complications of metabolic syndrome.26-30

System Complication
Cardiovascular Coronary heart disease, atrial fibrillation,26 heart failure, aortic stenosis
Hepatobiliary Non-alcoholic fatty liver disease27
Central nervous system / psychological Ischaemic stroke, accelerated cognitive ageing, anger, depression, hostility28
Cancer Breast, colon, gall bladder, kidney, prostate gland, hepatocellular
carcinoma,29 and intrahepatic cholangiocarcinoma
Other Obstructive sleep apnoea, association with psoriasis30

Table 3. Relationship between second-generation antipsychotic medications and metabolic abnormalities.38

Drug Weight gain Risk for type 2 diabetes mellitus Worsening lipid profile
Clozapine +++ +++ +++
Olanzapine +++ +++ +++
Risperidone ++ ++ / + +
Quetiapine ++ ++ ++ / +
Aripiprazole* +/– +/– +
Ziprasidone* +/– + +
Amisulpride* +/– – –
Paliperidone* + + +
Asenapine* ++ / + + D
Iloperidone* ++ / + + D
Bifeprunox* +/– +/– D
Abbreviations: + = increased effect; – = no effect; D = discrepant results.
*
Newer drugs with limited long-term data.

East Asian Arch Psychiatry 2013, Vol 23, No.1 23

J Yogaratnam, N Biswas, R Vadivel, et al

is correlated with insulin resistance) as age- and BMI-
matched control participants,35 supporting the independent
association between psychosis and weight gain. Additionally,
weight gain typically occurs within the first 4 to 12 weeks
of treatment and may not reach a plateau.36
While the prevalence of obesity in the medicated
schizophrenic population is currently estimated to range from
40 to 60% versus 30% of the general adult population, the
differences between typical and atypical agents with regard
to the risk for weight gain and disorders of carbohydrate and
lipid metabolism remain unclear, although weight gain and
carbohydrate and lipid metabolism disorders may be more
common in patients taking atypical agents.9 Several studies
have supported the claim that treatment with atypical
antipsychotics was associated with more weight gain than
treatment with typical antipsychotics.37,38
Of the typical antipsychotics, lower potency agents
(chlorpromazine and thioridazine) induce greater weight gain
than higher potency drugs (fluphenazine and haloperidol).
Typical antipsychotic-associated weight gain appears to
be comparable for oral and depot formulations of the same
drug.39 Of those atypical antipsychotics (SGAs), clozapine
and olanzapine appear to have the greatest propensity
to induce weight gain, quetiapine and risperidone have
intermediate risk, followed by aripiprazole, ziprasidone, and
amisulpride which carry the least risk (Table 338). Weight
gain associated with risperidone and quetiapine does appear
to correlate with dose, and newer antipsychotics such as
bifeprunox, asenapine, iloperidone, and paliperidone are
known to cause low weight gain.40
The mechanism of antipsychotic-induced weight gain
is undetermined, but several neurotransmitter systems have
been implicated (Table 441,42). Olanzapine, which has the
highest affinity for histaminic receptors, is associated with
high rates of weight gain, while ziprasidone and aripiprazole,
with lower affinities for histamine receptors, are associated
with lower rates of weight gain. A genetic predisposition
for aberrant folate metabolism and hyperhomocysteinaemia
and genetic markers, such as 5-hydroxytryptamine (5-HT)
2C receptor and brain-derived neurotrophic factor, and
blockade of the serotonin receptor 5-HT2C have also been
linked to risk for weight gain.43
Antipsychotics and Diabetes Mellitus
Additional studies have found the prevalence of both
diabetes and obesity to be 2 to 4 times higher in people
with schizophrenia than in the general population, with
overall prevalence estimates for diabetes among patients
with schizophrenia ranging from 16 to 25%.44 Poor
outcomes for diabetes in patients with schizophrenia are
due to the reasons that their high rates of smoking (up to
75%) worsens the prognosis of diabetes and increases non-
adherence to treatment for diabetes, which is estimated to
be about 50%.45 Most cases of new-onset type 2 diabetes
caused by antipsychotic medications occur within the first
6 months of treatment and are often, although not always,
associated with significant weight gain or obesity. A family
history of diabetes is also associated with an increased risk
in this population.46
A large population-based case-control study found
the risk of diabetes associated with antipsychotic agents
to be quite variable.46 Olanzapine and risperidone had 4.2
and 1.6 times the risk associated with conventional agents,
and 5.8 and 2.2 times the risk associated with no treatment,
respectively. Several large retrospective population studies
have found that olanzapine and clozapine are associated
with a significantly higher rate of diabetes than the other
agents, with a particular risk for younger patients.47
Quetiapine appears to be more likely than conventional
drugs to be associated with diabetes, but may ameliorate
clozapine-related diabetes when given in conjunction with

Table 4. Mechanisms of metabolic complications of antipsychotic medications.41,42

Metabolic complication
Weight gain
Diabetes mellitus / hyperlipidaemia
Abbreviation: 5-HT = 5-hydroxytryptamine.
Possible mechanism
• Histamine receptor blockade
• Blockade of the serotonin receptor 5-HT2C
• Aberrant folate metabolism and hyperhomocysteinaemia
• Genetic markers, such as 5-HT2C receptors
• Brain-derived neurotrophic factor levels
• Weight gain
• Disruption of hypothalamic regulation of glucose serum levels
• Potent anticholinergic activity
• Hyperprolactinaemia
• Others:
o 5-HT2A / 5-HT2C antagonism
o Weight gain
o Leptin resistance

24 East Asian Arch Psychiatry 2013, Vol 23, No.1


clozapine.48 Data for aripiprazole and ziprasidone suggested
that neither drug alters glucose homeostasis. Aripiprazole
may even reverse diabetes caused by other drugs, although
ketoacidosis has been reported with aripiprazole.49
Among the traditional neuroleptics, chlorpromazine and
thioridazine50 are the agents most closely associated with
diabetes mellitus, although the associations are weaker
than those with olanzapine or clozapine. The prevalence
of impaired glucose tolerance seems to be higher with
aliphatic phenothiazines than with fluphenazine or
haloperidol, although haloperidol has been reported to
increase insulin resistance and to be associated with higher
fasting glucose levels in obese women compared with
control participants.51
Interestingly, some studies have suggested that first-
generation antipsychotics are no different from SGAs in
their propensity to cause diabetes, whereas others have
suggested a modest, but statistically significant excess
incidence of diabetes with SGAs.52
A number of mechanisms for antipsychotic
medication–induced diabetes mellitus have been
suggested, although none has been proven with certainty
(Table 441,42). While drug-induced weight gain has been
highly associated with diabetes, diabetes has occurred in
the absence of weight gain, and hypothalamic dopamine
antagonism by antipsychotic medications or disruption
of hypothalamic regulation of glucose serum levels have
been suggested, along with potent anticholinergic-induced
inhibition of insulin secretion.53 Other mechanisms
suggested include increased insulin resistance in peripheral
tissues caused by hyperprolactinaemia, 5-HT2A / 5-HT2C
antagonism, increased lipids, weight gain, and leptin
resistance.54
Antipsychotics and Hyperlipidaemia
Phenothiazines are known to be associated with increased
levels of triglycerides and low-density lipoprotein
cholesterol and a decreased level of high-density
lipoprotein cholesterol.55 Higher cholesterol levels have
been reported with chlorpromazine-treated patients than
those receiving haloperidol.56 The CATIE study showed
that of the atypical antipsychotic agents, olanzapine and
quetiapine are associated with increases in total cholesterol
levels and triglyceride levels.56 Notably, risperidone and
ziprasidone are associated with decreases in cholesterol and
triglyceride levels, and patients treated with clozapine have
triglyceride levels that are almost double those treated with
typical antipsychotic agents.57 Aripiprazole and ziprasidone
have minimal adverse effects on blood lipids and may
even reverse dyslipidaemias associated with previous
antipsychotic use.58
Although the exact mechanism of causation of
hyperlipidaemia is unknown, one or more of the mechanisms
described above as causes for antipsychotic medication–
induced diabetes mellitus (Table 338) may be involved in the
pathogenesis.
East Asian Arch Psychiatry 2013, Vol 23, No.1
Metabolic Complications of Schizophrenia and Antipsychotics
Typical versus Atypical Antipsychotic
Medications in Metabolic Syndrome
Although most of the emphasis on metabolic syndrome
is aimed at SGAs, several studies have failed to detect
differences in the prevalences of metabolic syndrome
between patients taking SGAs and those taking conventional
antipsychotic agents.59 It may be possible that the effects
of conventional antipsychotic agents on metabolic
symptoms have been underestimated. Support for this
possibility comes from a study that compared olanzapine
and haloperidol in patients with first-episode psychosis — a
group of patients who were comparatively free of previous
treatment and symptom chronicity.60 After 2 years, patients
taking olanzapine had gained a mean of 33.9 lb (15.4
kg), and those taking haloperidol had gained 16.5 lb (7.5
kg) —a considerable weight gain indicating that typical
antipsychotic agents are associated with weight gain and
related metabolic abnormalities. A recent systematic review
compared the metabolic effects among the different SGAs
and showed that clozapine and olanzapine had the highest
incidences.61
Management Strategies for Metabolic
Syndrome
The following strategies have been suggested for directly
caused adverse effects of antipsychotic agents on glucose–
insulin homeostasis and lipid metabolism:
1. Patients with previously diagnosed diabetes mellitus
and / or hyperlipidaemia should be given conventional
antipsychotic agents or atypical agents such as
aripiprazole, which have no or few effects on glucose-
insulin homeostasis and lipid metabolism.62
2. For patients who develop hyperinsulinaemia and /
or hyperlipidaemia during treatment with clozapine,
olanzapine, or structurally related agents, a change to
an antipsychotic drug with no or minimal capability
to induce such adverse metabolic effects should be
considered, or maintenance therapy with the lowest
effective dose possible, together with regular follow-
up of metabolic parameters and appropriate treatment
whenever necessary, is advised.62
3. For patients who develop diabetes mellitus during
therapy with antipsychotic agents, a change to an
antipsychotic agent with no or little propensity to
cause the condition is the first recommendation. For
patients taking clozapine, the lowest effective dose
possible should be given, with clinical evaluation and
determination of serum antipsychotic concentration,
along with concomitant therapy for hyperlipidaemia /
hyperglycaemia.62
General Advice for Prevention of the
Development of Metabolic Syndrome
1. All patients who are going to start treatment with, or
25
J Yogaratnam, N Biswas, R Vadivel, et al
are already using an antipsychotic drug with high or
intermediate propensity to induce weight gain should
undergo regular monitoring of weight and lifestyle
modifications / therapy such as dietary adjustments,
weight reduction, and physical training, if necessary.
2. If such a patient gains a considerable amount of weight
or has become overweight or obese already, a change
of the antipsychotic agent to a less weight-inducing
drug should be considered. Another possibility to
decrease antipsychotic-induced weight gain may be
dose reduction. In the general population, controlled
clinical trials have established modest efficacy
for obesity drugs in combination with lifestyle
therapy.63 Orlistat (a lipase inhibitor) and sibutramine
(a serotonin-dopamine-norepinephrine reuptake
inhibitor) are the only drugs currently approved for
long-term weight loss.
3. Interventions to stop cigarette smoking and to reduce
physical inactivity are also of great importance in
decreasing the risk of insulin resistance and type 2
diabetes mellitus in patients treated with antipsychotic
agents.63
4. In order to further decrease the risk for development
of insulin resistance and type 2 diabetes mellitus in
antipsychotic medication–treated patients, daytime
sedation caused by these drugs, leading to physical
inactivity, has to be recognised and handled properly.63
5. Psychiatrists also have to be aware of those
antipsychotic medication–treated patients who
are older, have a family history of type 2 diabetes
mellitus, and / or are of an ethnic group with high
genetic susceptibility to type 2 diabetes mellitus
(e.g. American Indians, Mexican Americans, and
Hispanics) and, therefore, have an increased risk of
developing insulin resistance and type 2 diabetes
mellitus.63
Screening and Monitoring during the Use of
Antipsychotic Medications
In view of the evidence for an increased prevalence of
metabolic syndrome in schizophrenia, individuals presenting
with a first episode of psychosis should be screened using the
appropriate diagnostic criteria.15 According to the Maudsley
guidelines,40 metabolic parameters should be measured with
the frequency as described below:
1. Plasma glucose (fasting blood sample, if possible)
should be done at baseline, at 4 to 6 months, and then
yearly. Ideally, all patients should have oral glucose
tolerance tests performed as this is the most sensitive
method of detection of diabetes mellitus. Fasting
plasma glucose tests are less sensitive but are still
recommended.
2. Blood pressure should be measured at the baseline
and frequently during dose titration.
3. Fasting blood lipids (cholesterol and triglycerides)
should be measured at baseline, at 3 months, and then
26
yearly. Patients prescribed clozapine, olanzapine,
quetiapine, or phenothiazines should ideally have
their serum lipids measured every 3 months for the
first year of treatment.
4. Weight (including waist circumference and BMI, if
possible) should be measured at baseline, frequently
for 3 months, and then yearly.
Conclusion
In summary, while many adults with schizophrenia
receive little or no medical care, such care is important
given the risk of metabolic abnormalities and metabolic
syndrome associated with schizophrenia and with the
antipsychotic medications used to treat the condition. There
is a need for active routine physical health screening of all
individuals receiving treatment with antipsychotic drugs.
The implementation of such guidelines can substantially
improve the health of patients with schizophrenia.
However, adopting the guidelines in clinical practice can
be challenging.
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