doi: 10.1111/j.1742-1241.2007.01416.

REVIEW ARTICLE
Metabolic side effects of antipsychotic medication
A. Tschoner,1 J. Engl,1 M. Laimer,1 S. Kaser,1 M. Rettenbacher,2 W. W. Fleischhacker,2
J. R. Patsch,1 C. F. Ebenbichler1

1
Clinical Division of General
Internal Medicine, Department
of Internal Medicine, Medical
University Innsbruck,
Anichstrasse, Innsbruck, Austria
2
Clinical Division of Biological
Psychiatry, Department of
Psychiatry, Medical University
Innsbruck, Anichstrasse,
Innsbruck, Austria
Correspondence to:
C. F. Ebenbichler, MD,
Clinical Division of General
Internal Medicine,
Clinical Department of Internal
Medicine,
Medical University Innsbruck,
Anichstrasse 35, 6020
Innsbruck, Austria
Tel.: + 43 512 504 28537
Fax: + 43 512 504 28539
Email: christoph.ebenbichler@
i-med.ac.at
SUMMARY
The use of second-generation antipsychotics (SGAs) is associated with metabolic
side effects including weight gain, diabetes mellitus and an atherogenic lipid profile.
These adverse effects are not only the risk factors for cardiovascular disease, insulin
resistance and diabetes mellitus leading to increased morbidity and mortality but
may also impair the patient’s adherence to treatment. SGAs in particular are associ-
ated with significant weight gain with clozapine and olanzapine carrying the highest
risk, whereas newer agents, such as risperidone and aripiprazole, are considered to
be less prone to cause weight gain. Consequently, a consensus development confer-
ence convened issuing recommendations on patient monitoring when treated with
SGAs. The metabolic effects of antipsychotic drugs should be of concern when plan-
ning a patient’s treatment strategy. Baseline screening and regular follow-up monit-
oring whose intervals should depend on the individual predisposition are advised.
Possible therapeutical strategies for the management of drug-induced obesity
include therapeutic approaches, such as life style change and pharmaceutical inter-
vention. Drugs with a weight reducing effect become more important because of
the lack of compliance with behavioural intervention. Topiramate, histamine-
antagonists, dopaminergic- and serotoninergic agents have shown positive results in
the management of psychotropic medication induced weight gain. However, further
trials are required to support a specific therapeutical approach as well as studies to
investigate the underlying mechanisms for future drug development.
Review Criteria
Information was gathered by searching MEDLINE
using the terms antipsychotics in combination with
weight gain, diabetes, metabolism and weight loss.
Additional references were obtained from
bibliographies of articles retrieved through MEDLINE
search. Reviews and original articles were
considered for inclusion in the manuscript.
Message for the Clinic
Weight gain is a common side effect of
antipsychotic medication and should be taken into
account in every psychiatric patient, particularly in
those who are overweight/obese when treatment is
initiated. Recent clinical trials on drug-induced
weight gain proved the efficacy of both lifestyle
intervention and antiobesity drugs to prevent the
sequelae of weight gain.

Particularly, second-generation antipsychotics (SGAs)

Introduction
Metabolic disturbances, especially weight gain, are
associated with the use of many psychotropic
drugs, including antidepressants, mood stabilisers,
antipsychotic drugs, and may have serious long-
term consequences. Overweight (BMI ¼ 25–29.9 kg/m2)
and obesity (BMI ‡ 30 kg/m2) pose serious health
risks leading to increased morbidity and mortality.
Moreover, weight gain exacerbates these condi-
tions in patients with a pre-existing metabolic
condition. Overweight and obesity are the main
modifiable risk factors for type 2 diabetes mellitus
(T2DM) – 80% of patients are overweight when
they are diagnosed T2DM (1). According to
patients, psychosocial consequences of weight gain,
such as a sense of demoralisation, physical
discomfort and being the target of substantial
social stigma are so intolerable that they may
discontinue the treatment even if it is effective.
This may result in relapse or hospitalisation com-
plicating treatment strategies.
are associated with significant weight gain, insulin
resistance and an atherogenic lipid profile (Table 1).
For this reason a consensus development conference
on atypical antipsychotics issued guidelines recom-
mending baseline screening and follow-up monitoring
of patients when treated with SGAs (Table 2) (2).
The clinical importance of preventing weight gain
is evident considering that the rate of obesity among
people with schizophrenia even before antipsychotic
treatment is two to threefold greater than in the
general population (3). This makes treatment of anti-
psychotic drug-induced metabolic disturbances as
important as the actual treatment of schizophrenia.
Metabolic side effects
Weight gain
The NHIS data in 1989 revealed that 42% of schizo-
phrenic patients have a BMI > 27 compared to
approximately 25% of the general population with a
significantly greater proportion of female patients

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1356 Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
 Metabolic side effects of antipsychotic medication 1357

weight gain also results in noncompliance, reduced

Table 1 Atypical antipsychotics and metabolic side
effects
quality of life and social retreat (9). Significant
weight gain is observed during treatment with cloza-
Atypical Weight Risk for pine and olanzapine, with an increase in body fat
antipsychotic gain diabetes Dyslipidaemia being mainly responsible for olanzapine-induced
weight gain (10–13). The increase in body fat mass
Clozapine +++ + +
was accompanied by significant higher serum levels
Olanzapine +++ + +
of leptin in olanzapine-treated patients (10). In gen-
Risperidone ++ IR IR
Quetiapine ++ IR IR
eral, weight gain is observed during the first
Aripiprazole +/) ) ) 4–12 weeks of treatment with most SGAs. After this
Ziprasidone +/) ) ) initial medication phase weight gain continues at a
Amisulpride ) ) ) lower level or even stabilises. Clozapine and olanza-
pine cause weight gain that continues over a pro-
+, increasing effect; ), no effect; IR, inconclusive results. longed period (14). Results of a metaanalysis showed
Reproduced and modified from ref. no. (2). a mean weight gain of 4.45 kg under treatment with
clozapine, 4.15 kg for olanzapine, 2.10 kg for risperi-
done and 0.04 kg for ziprasidone respectively
being overweight or obese compared with their (Figure 1) (15,16). In another important study, the
counterparts in the general population. A trend body weight of schizophrenic patients was measured
towards greater BMI was also seen among schizo- at first admission to a hospital and 5 years later and
phrenic male patients (4). subsequently, these results were compared to the
Psychiatric disease itself can contribute to BMI-distribution data of the general population. At
increased storage of fat by changes in energy intake the time of the first hospitalisation, the BMI in all
and expenditure, e.g. changes in patterns of food age groups was lower than in the general population
intake and/or lifestyle. Both increased adiposity and but showed a higher weight gain during the follow-
reduced physical activity are strong and independent up. After 5 years the proportion of overweight and
predictors of coronary heart disease, although weight obese patients (BMI > 30) was higher than in the
gain during adulthood is an independent risk factor general population and particularly women being sig-
for premature death regardless of the level of phys- nificantly overweight (17). Similar results were
ical activity (5,6). There is some evidence that sub- obtained in a different study focusing on weight loss
jects with schizophrenia have greater visceral in overweight patients during antipsychotic therapy.
adiposity than healthy individuals (7). Additionally, During an average treatment duration of 7.6 years
psychotropic weight gain is associated with increased patients gained 24.6 kg weight with a mean annual
fat deposition in the visceral adipose tissue (8). weight gain of 5.81 kg. Olanzapine resulted in the
Excess visceral fat leads to dyslipidaemia, hyperten- highest weight gain, followed by risperidone, cloza-
sion, increased risk for T2DM and is, therefore, a pine and ziprasidone (18). Based on the 1948 Fra-
key factor in the development of cardiovascular dis- mingham Heart Study’s public use data set, Fontaine
ease and associated morbidity and mortality, et al. estimated the expected impact of different
although the exact mechanism behind visceral fat degrees of antipsychotic-induced weight gain on
increasing cardiovascular risk and impairing glucose mortality among the US adults. Mortality is directly
metabolism is still unclear. Consequently, excessive related to the magnitude of weight gain. The authors

Table 2 Monitoring protocol for patients during treatment with psychotropic drugs

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

Medical history
Weight/BMI
Waist-circumference
Blood pressure
Fasting glucose
Fasting lipid profile
X X X
X X X X X X X
X X X
X X X X X X X
X X X X X X X
X X X X X

Reproduced and modified from ref. no. (2).

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1358 Metabolic side effects of antipsychotic medication

5 first SGA, is associated with a 1.4-fold higher preval-

ence than the classical antipsychotics and for olanza-
4
pine the factor is approximately 1.3. The relative risk
of developing T2DM seems to be slightly lower with
3
quetiapine and risperidone, whereas amisulpride,
2 ziprasidone and aripiprazole, the first of the new
generation antipsychotics (NGA), hold no increased
1 risk for diabetes compared to FGAs considering the
current data.
0
Since the introduction of the SGAs several case
Ziprasidone

Aripiprazole

Amisulpride

Haloperidol

Risperidone

Quetiapine

Olanzapine

Clozapine
reports of new-onset diabetes and diabetic ketoazido-
sis have been published and have, therefore, received
increased scientific and clinical attention. In sum-
Figure 1 Mean weight gain during treatment with mary, 27 case reports of new-onset diabetes were
antipsychotic drugs. Reproduced and modified from ref. found for clozapine, 39 for olanzapine, four for ris-
no. (16) peridone and three for quetiapine (26). In most
patients, the hyperglycaemia occurred within 6 weeks
after start of treatment with the antipsychotic drug
assume that by the use of a drug conferring a mean (26), in two patients, one with severe hyperglycaemia
weight gain of 4.0 kg, 24,560 additional deaths would and one with ketoazidosis, within 1 week (27,28).
be predicted over a 10-year period for all adults in Most cases of new-onset disturbances of the glucose
the USA taking antipsychotic medication (19). homeostasis were reversible after discontinuation of
Increased food intake is partly being held respon- the antipsychotic medication. Koller et al. (29) ana-
sible for the weight gain in psychotic patients and is lysed 69 case reports of quetiapine-associated hyper-
possibly a consequence of the antipsychotic drug’s glycaemia and T2DM. In a large retrospective case–
interaction with neuronal dopamine-, serotonin- and control study, patients taking olanzapine had a signi-
histamine-receptors (20). An increase in central sero- ficant higher risk of developing T2DM than patients
tonin transmission leads to reduced food intake in without olanzapine (odds ratio 5.8) or patients trea-
humans as well as in animals (21,22), whereas low ted with FGAs (odds ratio 4.2) (30). In our prospect-
levels of serotonin were reported in the cerebrospinal ive study pancreatic beta-cell function remained
fluid of obese women (23). Antipsychotic agents unaltered during olanzapine therapy, while the
block the 5-HT2 receptor system resulting in a homeostasis model assessment index for insulin
decreased serotoninergic transmission and thereby resistance (HOMA-IR) increased significantly (31).
causing obesity. For this reason the serotoninergic Tumour necrosis factor alpha (TNF-a), free fatty
agent sibutramine is used in the treatment of obesity acids (FFAs), leptin, adiponectin and resistin are
because it reduces food intake by enhancing the phy- considered to be potent factors involved in the devel-
siological response of post-ingestive satiety (24). opment of insulin resistance, but no significant chan-
Research on specific interactions of antipsychotic ges could be shown in the same population during
drugs with appetite regulating hormones, such as the 8-week study period (32). Henderson et al. con-
insulin, leptin and ghrelin, showed inconsistent firmed and extended these results. In this study the
results. glucose metabolism of non-obese patients treated
with clozapine, olanzapine or risperidone was studied
Changes of glucose homeostasis in a cross-sectional design. Significant differences
The prevalence of T2DM and the metabolic syn- among groups were found concerning fasting serum
drome is significantly higher in patients with a chro- insulin concentration, insulin sensitivity index (SI)
nic psychiatric disease, particularly schizophrenia and and HOMA-IR. In the olanzapine- and clozapine-
major mood disorders. A retrospective cohort study group levels of fasting plasma glucose were signifi-
showed that the prevalence of diabetes was over cantly lower and the HOMA-IR significantly higher
20%, with no significant difference between SGAs or than in the risperidone group, both indicating induc-
first-generation antipsychotics (FGAs), in patients tion of insulin resistance (33). Furthermore, the
with schizophrenia and therefore threefold higher effect of olanzapine and risperidone on beta-cell
than in the general population (25). A more detailed function was studied in healthy volunteers: weight
analysis of the data showed that during treatment increased significantly in both groups, while an
with FGAs the risk of diabetes was three times higher increase in the insulin response to hyperglycaemia
compared to the general population. Clozapine, the and a decrease of the SI could be observed after

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Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
 Metabolic side effects of antipsychotic medication 1359

treatment. Taking the BMI changes into account the
insulin response correlated with the weight gain but
no significant change in insulin secretion or insulin
sensitivity was detected (34). Recent publications
describe an increase of haemoglobin A1C (HbA1C)
during treatment with olanzapine. Possible mecha-
nisms include weight gain, changes of insulin secre-
tion, development of peripheral insulin resistance
and changes of cellular glucose uptake (35,36).
Several authors suggest that the onset of diabetes
during antipsychotic therapy is secondary to drug-
induced weight gain (26), possibly both induced by
histamine antagonism (37,38). However, the rapid
onset of diabetes, the disappearance of hyperglycae-
mia after discontinuation of the drug and recurrence
after reintroduction support the development of
diabetes in patients on SGAs being a drug-related
effect, especially with regard to olanzapine and cloza-
pine. This was confirmed in a study comparing
clozapine and amisulpride in respect to their impact
on glucose metabolism, where some patients showed
signs of insulin resistance even without experiencing
weight gain (39). A direct mechanism seems to be
more likely also when considering that not all medi-
cations causing substantial weight gain induce DM
(40). Results from in vitro experiments on L6-skeletal
muscle cells showed that olanzapine impairs the
phosphatidylinositol-3-kinase (PI3K) dependent
insulin signalling pathway and significantly reduces
glycogen synthesis, whereas amisulpride, which is
not associated with diabetes, had none of these
effects (41).
Different antipsychotic drugs were tested on their
effect on pancreatic beta-cells in an in vitro study to
investigate a possible influence on the insulin secre-
tion. Basal insulin secretion was stimulated by cloza-
pine, whereas no significant increase could be found
for olanzapine (42,43).
The development of insulin resistance could
explain the various disturbances of the glucose
homeostasis and could be caused by alterations of
insulin sensitivity in peripheral and/or hepatic tissues
mediated through humoral and/or cellular signalling
pathways. Several insulin resistance inducing factors
have been identified in the past. FFAs derived from
adipocytes are consistently elevated in insulin-resist-
ant subjects (Figure 2). FFAs inhibit glucose uptake,
glycogen synthesis and glucose oxidation and
increase hepatic glucose output as well as very low-
density lipoprotein (VLDL) triglyceride production
(44). The molecular mechanisms of action of adipo-
nectin, leptin and resistin, which have a potential
insulin resistance enhancing or also protective effect,
are not yet clear.
Disturbances of lipid metabolism
Dyslipidaemia is characterised by increased FFAs, ele-
vated triglycerides, low high-density lipoprotein
(HDL) cholesterol, increased small, dense low-density
lipoprotein (LDL) cholesterol and increased apolipo-
protein B (45).
The high prevalence of hyperlipidaemia in the gen-
eral population and the heterogeneity in the defini-
tion of hyperlipidaemia make conclusions about

Figure 2 Pathophysiology of obesity-induced dyslipidaemia. Visceral obesity and a decreased effect of insulin on adipose
tissue resulting in reduced inhibition of HSL lead to an excess release of FFAs. In the liver, FFAs are synthesised to
triglyceride-rich VLDL. CETP mediates the transfer of cholesteryl esters from cholesteryl ester-rich lipoproteins to TG-rich
lipoproteins in exchange for TGs. HDL and LDL particle size is further decreased by HL-mediated loss of TGs. FFA, free
fatty acid; TG, triglyceride; LDL, low-density lipoprotein; HDL, high-density lipoprotein; VLDL, very low-density
lipoprotein; CETP, cholesteryl ester transfer protein; HSL, hormone-sensitive lipase; HL, hepatic lipase. Reproduced and
modified from reference number 113.

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1360 Metabolic side effects of antipsychotic medication
changes of lipid metabolism of psychiatric patients
during therapy with psychotropic drugs difficult.
Additionally to weight gain and diabetes, some
SGAs cause hypertriglyceridaemia, which is an inde-
pendent risk factor of coronary arteriosclerosis (46).
Increased adiposity can result in excess FFA release
from hypertrophic adipocytes leading to higher FFA
concentrations. These can induce muscle and hepatic
insulin resistance, endothelial- and pancreatic-cell
dysfunction and increased VLDL triglyceride produc-
tion (Figure 2). A recent prospective study compar-
ing the effects of the SGAs clozapine, olanzapine,
risperidone and the FGA sulpiride on glucose and
lipid metabolism in first-episode schizophrenia at
baseline and 8 weeks after inclusion showed that
besides higher C-peptide, fasting insulin and insulin
resistance index (IRI), cholesterol and triglyceride
levels were significantly increased in the clozapine
and olanzapine groups (47). Because of these results
the authors recommend that baseline and 6-month
monitoring of fasting blood glucose, fasting choles-
terol and triglyceride levels should be obtained in
routine clinical practice with all antipsychotics to
monitor the risk for development of hyperglycaemia
and hypercholesterolaemia.
In a comparative study, treatment with various
antipsychotics resulted in significantly elevated trigly-
ceride levels in 56% of clozapine, 39% of olanzapine
and 21% of risperidone-treated patients compared to
none of haloperidol and 8% of fluphenazine-treated
patients (48). The same study showed a reduction of
HDL cholesterol during treatment with clozapine
and olanzapine, whereas total cholesterol levels were
significantly lower in risperidone- and fluphenazine-
treated patients. Koro et al. observed a threefold
higher risk of hyperlipidaemia for FGAs when com-
pared with a control population without antipsychot-
ic exposure. SGA treatment associated odds varied:
olanzapine use was associated with a nearly fivefold
higher increase in the risk of developing hyperlipid-
aemia, whereas risperidone showed no significant dif-
ference (49). A more recent study described a
negative effect of olanzapine administration on total
cholesterol and triglycerides, whereas favourable
metabolic effects were observed in ziprasidone-trea-
ted patients with regard to total cholesterol, LDL and
HDL (35). These results were confirmed in another
study with 1493 patients (36). An increase of serum
lipid levels was already seen after 4 weeks of
treatment with olanzapine or clozapine and was
significantly correlated with increasing BMI. As ami-
sulpride and ziprasidone had no significant effect on
serum lipid levels, the authors suggest these drugs as
a favourable alternative treatment for already over-
weight patients (50).
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
Therapeutic interventions
Overweight
Treating or preventing drug-induced weight gain
should be a major concern in the treatment of schi-
zophrenic patients as weight gain does not only pose
a serious health risk but also adversely affects com-
pliance with antipsychotic medication. A linear
association between the patients BMI and the likeli-
hood of noncompliance was shown by Weiden et al.
(51), with obese patients being about 2.5 times more
likely to stop their medication than those who are
not obese. It is, therefore, important to choose an
appropriate strategy for weight management based
on the prescribed antipsychotic drug, individual risk
factors, concomitant diseases and the patient’s moti-
vation for losing weight. Even modest weight loss
can reduce health risks in obese patients with med-
ical benefits beginning to accrue with weight losses
as little as 5–10% of the initial weight (52,53).
Non-pharmacological treatment
Switching antipsychotic medication:
Although there are only few studies investigating the
effect of medication dosage on weight gain it appears
that varying dosage within therapeutic range has no
significant impact on antipsychotic-induced weight
gain (54). This and the fact that newer SGAs like ari-
piprazole or ziprasidone bear a lesser risk for weight
gain than older drugs, such as clozapine or olanza-
pine, make switching to an antipsychotic regimen
with a better metabolic profile a sensible therapeutic
approach to manage excessive weight gain (2).
One study reported a 32% reduction in the preva-
lence of the metabolic syndrome in overweight or
obese patients (mean BMI 35.1 ± 7.3 kg/m2) when
they were switched from olanzapine to risperidone.
Additionally body weight, BMI, waist circumference
and blood pressure were significantly reduced after
20 weeks (55). In a different trial patients were
switched from olanzapine, risperidone or conven-
tional antipsychotic to ziprasidone and results
showed the greatest metabolic benefit being depend-
ent on the previous medication. Patients initially
treated with olanzapine experienced greater weight
loss ()1.76 kg) compared to those switched from ris-
peridone ()0.86 kg), whereas significant reductions
of non-fasting total cholesterol and triglycerides were
seen in both groups. The switch from conventional
antipsychotics to ziprasidone had no significant effect
on either weight or the lipid profile (56).
The main problem with switching agents is the
potential for worsening or re-emerging psychotic
symptoms along with side effects as nausea, vomit-
ing, insomnia, agitation and anxiety (57,58). To
ª 2007 The Authors

avoid adverse reactions, pre-existing conditions and
concomitant medication should be taken into
account when switching to a different agent. There is
no consensus on the best way to switch from one
antipsychotic drug to another. Some studies have
shown that abrupt discontinuation of the prior anti-
psychotic drug may be tolerated by some patients
while gradual reduction in dose with immediate ini-
tiation of the new drug may be required by others.
The most successful switching strategy may be the
gradual discontinuation of the current antipsychotic
drug and immediate initiation of the new treatment
(57,58). However, all three strategies have shown to
be well tolerated and induce modest weight loss
()1.3 to )1.7 kg) in patients switching to aripipraz-
ole with no evidence of a deterioration in schizo-
phrenia symptoms (59).
Behavioural intervention:
The NHLBI/NIH clinical guidelines recommend
weight reduction therapy for individuals with a BMI
‡ 25 kg/m2 consisting of three main components.
These include a calorie-restricted diet with a calorie
deficit of 500–1000 kcal/day less than the patient’s
baseline and an increase in physical activity com-
bined with behavioural strategies to reinforce these
lifestyle changes.
Such measures were shown to be effective in a
group of patients receiving an SGA for at least
3 months in which the BMI became > 26 kg/m2 or
weight gain of at least 2.3 kg was experienced. After
12 weeks participants receiving the intervention had
a mean weight loss of 2.7 kg and a mean BMI reduc-
tion of 0.98 kg/m2 in comparison to a matched con-
trol group not taking part in the weight management
programme, where patients gained a mean 2.9 kg
resulting in a mean BMI increase of 1.2 kg/m2 (60)
(Table 3). A different study examined the impact of
an intensive programme of diet, exercise and coun-
selling in antipsychotic-treated patients with a weight
gain of more than 4.5 kg and an increase in BMI of
more than 5% since the start of antipsychotic treat-
ment. During 24 weeks the mean weight loss was
6.0 kg and BMI was reduced by 5.7%. A subgroup of
the study population participated in an additional
24 weeks, less-intensive extension phase and regained
minimal weight (0.43 kg). However, the mean BMI
was still 36.2 kg/m2 (18). In contrast, weight control
was achieved in patients with a mean BMI of 26 by
weekly educational interventions for 4 months. This
beneficial effect could be maintained for 2 months
after the completion of the intervention (61). Similar
results are reported in a randomised controlled trial
where the control group gained significantly more
weight (mean + 9 kg) than the intervention group
(mean + 2 kg) receiving six one-on-one educational
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Metabolic side effects of antipsychotic medication 1361
sessions provided by a dietitian. The amount of
patients gaining clinically significant weight (‡ 7% of
their baseline weight) after commencement of ola-
nzapine could be reduced from 68% to 13%. The
intervention group continued to gain significantly
less weight during the 3-month follow-up (62). Sig-
nificant weight loss was experienced by both the
intervention and the treatment-as-usual group in a
randomised, controlled, multicenter study. The fact
that the patients had been switched to risperidone
before the intervention was initiated may have con-
tributed to this finding. However, more participants
in the behavioural treatment group lost more than
5% of their initial body weight (63). Patients treated
with olanzapine undergoing a 12-week weight man-
agement programme focusing on diet and exercise
exhibited significant reductions in weight ()3.94 kg
vs. )1.48 kg) and BMI compared with patients
receiving usual outpatient treatment (64). In a rand-
omised trial, the effectiveness of cognitive/beha-
vioural interventions modified after the Diabetes
Prevention Project (DPP) was examined over
16 weeks. The group receiving the intervention lost
an average of 2.9 kg (range )0.5 to )10 kg) of their
body weight (mean BMI at baseline 33 kg/m2) in
comparison to an average loss of 0.6 kg in the group
with treatment as usual (65). Results from a long-
term prospective trial suggest that patients with
severe mental illness and antipsychotic-associated
weight gain benefit from an intensive weight control
programme. Patients enrolled in the 12-month pro-
gramme lost significant amounts of weight and signi-
ficantly reduced their BMI. Improvements in blood
pressure and HbA1C were also reported (66). O’Keefe
et al. (67) reviewed charts of patients who gained at
least 9 kg after initiation of an antipsychotic agent
and found that approximately one quarter of the
patients experiencing weight gain may eventually
be able to reverse the process, particularly when
behavioural interventions, e.g. dietitian counselling,
self-directed diet, are used. Some evidence suggests
that use of multiple weight loss interventions is more
effective.
Early intervention should be promoted shortly
after initiation of antipsychotic therapy as it helps
attenuating drug-induced weight gain in drug-naive
patients receiving antipsychotic medication (68).
Despite the fact that mentally ill patients often lack
compliance and motivation for treatment, patients
seem to gain more interest in their diet and the
behavioural treatment when in a controlled setting
leading to more concerted efforts to change their eat-
ing and exercise behaviour patterns (60). Weight
control interventions may potentially be most effect-
ive by emphasising dietary education and calorie
1362 Metabolic side effects of antipsychotic medication

Table 3 Controlled trials of behavioural interventions in the management of antipsychotic-induced weight gain

Number of Body weight Compliance;

Type (reference) Intervention Duration patients (n) change ± SD drop outs

RCT (61) Standard care 6 months n ¼ 35 +4.34 kg ± 5.89 92%;

Weekly 1 h sessions about 4 months n ¼ 35 )0.27 kg ± 4.28 no drop outs
nutrition, exercise and lifestyle intervention,
change 2 months
follow-up
Open label Usual clinical care 14 weeks n ¼ 37 )1.1 kg ± 3.1 15/28 attended all sessions;
RCT (63) 6 weeks two weekly sessions, n ¼ 34 )2.3 kg ± 4.0 21% drop out
8 weeks one weekly session of diet
and exercise education
RCT (62) Usual care 6 months n ¼ 22 +9.9 kg ± 7.4 11*, 3 
Six 1 h one-on-one sessions over 3 months n ¼ 29 +2.0 kg ± 5.0 6*, 12 ; compliance not reported;
3 months on diet, exercise and intervention, 21% drop out
change of eating behaviour 3 months
follow-up
RCT (65) Treatment as usual 16 weeks n¼7 )0.61 kg ± 3.33 Compliance not reported;
Weekly 1 h group sessions for 16 n¼8 )2.45 kg ± 2.97 no drop outs
weeks of diet and exercise
education based on DPP strategies
Open label (60) Standard care 12 weeks n ¼ 15 +2.9 kg 77% attendance for group sessions,
Two group sessions and one 15-min n ¼ 31 )2.7 kg 82% attendance for individual sessions;
individual session each week no drop outs
(25 visits total) including nutrition
counselling, exercise and
behavioural interventions
RCT (68) Standard physical care 3 months n ¼ 33 +6.98 kg ± 4.50 Compliance not reported;
10–14 individual sessions including n ¼ 28 +4.10 kg ± 3.99 no drop outs
psychoeducation, dietary counselling,
exercise programme and behaviour
therapy
Open label (66) Usual care 12 months n ¼ 20 +3.18 kg Mean attendance 69% (range 9–96%);
Multimodal weight control programme n ¼ 31 )2.99 kg 11 drop outs
with biweekly group sessions and
one 15-min individual session for
12 weeks followed by weekly group
sessions and monthly individual
sessions for 12 weeks; 6 months
weight-maintenance programme
with weekly group sessions and
monthly individual sessions
RCT (64) Routine care 12 weeks n ¼ 15 (1)à )1.48 kg ± 1.88 22/22 patients > 80% compliant with diet,
Four weekly visits followed by n ¼ 33 (4)à )3.94 kg ± 3.63 12/22 patients > 80% compliant with exercise;
visits every other week on diet seven drop outs
and exercise management based on
cognitive and behavioural therapy

Based on ref. no. (110).

*Participants withdrawn from the study before the 3-month follow-up.
 Participants withdrawn from the study before the 6-month follow-up.
àNumber in brackets are patients with incomplete data with regards to weight and were excluded from statistical analysis.

restriction in patients requiring antipsychotic treat- Pharmacological intervention

ment, but may be an unrealistic option for most Although weight gain is a common adverse effect of
mentally ill individuals because of the relatively high SGAs experience regarding a specific therapeutic
costs (18). approach to the management of drug-induced weight

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gain with adjunctive pharmacological treatment has
been mainly limited to small, observational studies
and case reports. The results of pharmacological
studies on the treatment of drug-induced weight gain
are summarised in Table 4.
The goal of pharmacotherapy is to lose 5–10% of
the initial body weight over 3–6 months. If no
weight loss can be achieved during that time, treat-
ment should be stopped. After this period weight can
plateau, but this is no indication for discontinuation
of the drug. Drug treatment of obesity should be
considered as long-term therapy as most patients
regain weight upon stopping medication (69).
Of the discussed drugs only orlistat and sibutramine
are FDA-approved antiobesity medications, whereas
topiramate, metformin, nizatidine and amantadine
are medications used off-label for weight loss as
case reports and clinical trials have uncovered anti-
obesity properties during treatment for other health
conditions (70).
Sibutramine
Sibutramine was originally developed as an antide-
pressant blocking presynaptic nerve terminal reup-
take of noradrenaline, serotonin and dopamine.
Although yielding no clinically significant antidepres-
sant effect, sibutramine has been shown to be an
effective and well-tolerated weight loss agent (71). A
double-blind placebo-controlled study examined the
effect of sibutramine combined with group and indi-
vidual behavioural nutrition counselling in olanza-
pine-treated obese patients with schizophrenia in a
12 weeks trial. The additional administration of
sibutramine resulted in a mean weight loss of 6.85 kg
compared with 3.86 kg weight gain in the control
group. There was also a relative decrease in HbA1C
and a mean increase in systolic blood pressure while
adverse events were limited to slight anticholinergic
events (blurred vision, constipation, excessive thirst)
and sleep disturbances. However, 3 months after the
end of the trial weight change from baseline of the
sibutramine group was not statistically different from
that of the placebo group (72). The combined use of
clozapine and sibutramine bears the risk of increased
clozapine plasma levels because of their common
metabolic degradation through the cytochrome-P450
isoenzyme CYP-3A4 (73).
Orlistat
Orlistat, an enteric inhibitor of pancreatic lipase, redu-
ces fat absorption in the intestinal tract by about 30%.
Orlistat should be taken in combination with a mildly
hypocaloric, low fat diet as high fat alimentation
together with orlistat can lead to unpleasant side-
effects, such as flatulence and steatorrhea. Because of
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Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
Metabolic side effects of antipsychotic medication 1363
its local mechanism of action in the intestine and,
therefore, lesser risk for interaction, orlistat is consid-
ered a beneficial alternative for patients already taking
other systemically acting drugs, as one study could
show that there were no clinically relevant changes in
plasma levels of the tested antipsychotic substances
after administration of orlistat. In the same study, all
eight patients lost weight over the 8-week study period
with a mean decrease of 6.1% in body weight and a
mean decrease in BMI of 2.1 kg/m2 (74). Results of a
case series investigating the use of orlistat in 13
patients with a mean weight gain of 16.4 kg secondary
to psychotropic drug use showed that orlistat, admin-
istered in three daily doses with meals, was safe, well-
tolerated and effective, resulting in an average weight
loss of 35% during an acute treatment period of
3 months (75). There are several reports of orlistat
administration stopping or reducing neuroleptic
drug-induced weight gain. Two patients who had
experienced weight gain while on olanzapine were
concomitantly administered orlistat. One patient lost
9 pounds over the first 4 weeks and continued to lose
weight at approximately 1 pound per week for the
next 2 months, while the second patient lost
29 pounds over 14 weeks (76). Another case report
describes orlistat-induced weight loss of 3 kg within
3 months during amisulpride treatment (77).
Topiramate
Topiramate is an anticonvulsant agent with mood-
stabilising properties exerting its effect primarily by
antagonising glutamate receptors. A recent publica-
tion describes a weight gain limiting effect of topira-
mate in patients receiving olanzapine. Weight at
baseline was the same in both groups. After 12 weeks
the mean weight gain of the group with both drugs
was 2.66 kg, whereas the group solely treated with
olanzapine gained 4.02 kg (78). Vieta et al. (79)
investigated the long-term effect of olanzapine–topir-
amate cotherapy in 13 patients with bipolar disorder
over 12 months. Despite an early weight gain during
the first month, there was a slight weight loss of
0.5 kg (±1.1 kg) at the 12-month end-point. Consid-
ering BMI only obese patients lost weight. A rand-
omised placebo-controlled clinical trial was
conducted to assess the efficacy of topiramate at
doses of 100 and 200 mg in overweight schizophre-
nic patients (BMI ‡ 25). A significantly greater
weight loss occurred in the 200-mg/day topiramate
group compared with the placebo group and the
100-mg/day topiramate group after 12 weeks. Mean
changes were 0.3 kg (placebo), 1.68 kg (topiramate
100 mg) and 5.35 kg (topiramate 200 mg) respect-
ively. Particularly in the 200 mg topiramate group,
patients were more likely to withdraw from the study
1364 Metabolic side effects of antipsychotic medication

Table 4 Comparison of different pharmacological interventions in the treatment of antipsychotic-induced weight gain

Drug Number of Dose

(reference) Type Antipsychotic patients (n) Duration (mg/day) Body weight change

Amantadine (88) Open label reversal APs n ¼ 10 3 weeks 200–300 )3.7 kg ()1.4 to )5.9)
Amantadine (85) Open label Olanzapine n ¼ 6 3–6 months 1 · 100 )4.1 kg (±2.7)
n ¼ 6 2/3 · 100 )2.9 kg (±1.1)
Amantadine (86) RCT Olanzapine n ¼ 60 (+AMT) 16 weeks 100–300 )0.19 kg (±4.58)
n ¼ 65 (+PLC) +1.28 kg (±4.26)
Amantadine (87) Observational case series Olanzapine n ¼ 38 12 weeks 100–300 )2.2 kg
Amantadine (89) RCT Olanzapine n ¼ 12 (+AMT) 12 weeks )300 )0.36 kg (±3.54)
n ¼ 9 (+PLC) +3.95 kg (±5.31)
Topiramate (79) Open label Olanzapine n ¼ 13 12 months 271.1 ± 117.6 )0.5 kg (±1.1)
Topiramate (78) Randomised open label Olanzapine n ¼ 25 (+TOP) 12 weeks 50 +2.66 kg (±1.79)
n ¼ 23 ()TOP) +4.02 kg (±2.52)
Topiramate (82) Open label case report Olanzapine n ¼ 1 3 months 200 )11.3 kg
Topiramate (81) Open label case report Clozapine n ¼ 1 5 months 125 )21 kg
Topiramate (83) Open label Quetiapine n ¼ 2 20 months 600 )20.9 kg
Clozapine 19 months 1200 )13 kg
Topiramate (80) RCT APs n ¼ 20 (PLC) 12 weeks 100 )0.3 kg
n ¼ 16 (+TOP) 200 )1.68 kg
n ¼ 17 (+TOP) )5.35 kg
Orlistat (77) Open label case report Amisulpride n ¼ 1 3 months 3 · 120 )3 kg
Orlistat (74) Open label APs n ¼ 8 8 weeks 3 · 120 )6.1% ± 2.2%
(range 0.5–13 kg)
Orlistat (76) Open label case reports Olanzapine n¼2 13 weeks 3 · 120 )8.16 kg
14 weeks )13.15 kg
Nizatidine (94) RCT Quetiapine n ¼ 12 (+PLC) 8 weeks 2 · 150 +1.2 kg (±1.2)
n ¼ 13 (+NZT) )1.0 kg (±0.6)
Nizatidine (91) Open label case report Olanzapine n ¼ 1 8 weeks 2 · 150 )4 kg
Nizatidine (92) RCT Olanzapine n ¼ 56 (+PLC) 16 weeks 2 · 150 +4.18 kg (±4.33)
n ¼ 56 (+NZT) 2 · 300 +3.56 kg (±4.95)
n ¼ 57 (+NZT) +3.29 kg (±5.33)
Nizatidine (93) RCT Olanzapine n ¼ 17 (+PLC) 8 weeks 2 · 150 +2.3 kg (±0.9)
n ¼ 17 (+NZT) )4.5 kg (±2.2)
Metformin (97) Double blind placebo APs n ¼ 5 4 weeks 500–2550 )3.3 kg (±1.7)
controlled (AP + PLC) )1.3 kg (±1.1)
8 weeks
(AP + MET)
Metformin (96) RCT Olanzapine n ¼ 18 (+PLC) 14 weeks 850–1700 +6.3 kg (±2.3)
n ¼ 19 (+MET) +5.5 kg (±3.3)
Sibutramine (72) RCT Olanzapine n ¼ 18 (+PLC) 12 weeks 2–3 · 5 +3.86 kg
n ¼ 19 (+SIB) )6.85 kg

RCT, randomised controlled trial; APs, different antipsychotic drugs; AMT, amantadine; PLC, placebo; TOP, topiramate; NZT, nizatidine; MET, metformin; SIB, sibutr-
amine.
Based on ref. nos (110,111).

because of adverse events with paresthesia being the
most common (80). These results suggest topiramate
at 200 mg/day to be effective in the short-term treat-
ment of excess weight while further studies are needed
to evaluate the effect of lower doses for long-term
weight management. Most findings about topira-
mate-induced weight loss in psychiatric patients are
limited to case reports. In one schizophrenic cloza-
pine-treated patient topiramate led to a weight loss
of 21 kg at 5 months (81). In two other cases
patients lost substantial weight (13 and 20.9 kg)
when topiramate was given for 20 months, although
doses of up to 1200 mg/day were used, while a
weight loss of 11.3 kg was reported when given at
200 mg/day for 3 months (82,83). There are several
open label trials suggesting that topiramate may lead
to substantial weight loss in patients with bipolar
affective disorder (84).

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Amantadine
With its dopamine receptor antagonistic effect,
amantadine is used in the treatment of extrapyrami-
dal symptoms, idiopathic Parkinsonism and influ-
enza. An anorectic effect could be shown in
olanzapine-treated patients receiving 100–300 mg
amantadine for 3–6 months. After a mean initial
weight gain of 7.3 kg during olanzapine treatment
the patients’ weight stabilised and, subsequently,
these patients lost an average of 3.5 kg (85). In a
randomised controlled trial, Deberdt et al. observed
a mean weight loss of 0.19 kg (±4.58) after 16 weeks
in psychiatric patients receiving amantadine in addi-
tion to their olanzapine-regimen. However this was
not significant compared to a mean weight gain of
1.28 kg (±4.26) in the group receiving olanzapine
and placebo. Amantadine induced some weight loss
in obese patients (BMI ‡ 30) while it limited weight
gain in overweight patients (BMI 25–30) suggesting
that amantadine might be effective in attenuating or
preventing weight gain earlier in the course of ola-
nzapine treatment (86). Patients with schizophrenia
taking olanzapine started to lose weight almost
immediately after initiation of amantadine co-treat-
ment. After 12 weeks the greatest weight loss was
experienced by those patients with a BMI > 27 and
those treated with olanzapine ‡ 1 year ()2.6 and
)2.5 kg) (87). In an open-label reversal drug study
the impact of amantadine on neuroendocrine side
effects was assessed in 10 neuroleptic-treated schizo-
phrenic inpatients with a significant reduction in
body weight during the 3-week antipsychotic-amant-
adine co-medication (88). In a small randomised,
placebo-controlled trial amantadine displayed a
weight stabilising effect, but no changes in fasting
glucose, insulin, leptin, prolactin and lipid levels
were seen (89). The simultaneous treatment of affect-
ive and physical disorder may be complicated by
drug interaction. Amantadine may directly reverse
D2 blockade and exacerbate psychosis, although this
remains subject to debate (90).
Nizatidine
It is not yet understood how H2-receptor-anatgonists
may induce weight loss, but it may involve appetite
regulation and suppression of gastric acid secretion.
One case report describes lesser weight gain and con-
sequently a weight reduction of 5% in a patient trea-
ted with olanzapine in combination with nizatidine
(91). To evaluate the efficacy of two fixed nizatidine
doses in the prevention of olanzapine-associated
weight gain three groups (n ¼ 169) received either
placebo, nizatidine 150 mg b.i.d. or nizatidine
300 mg b.i.d. in a 16-week double blind clinical trial.
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Metabolic side effects of antipsychotic medication 1365
There were no significant differences between groups
when comparing weight gain from baseline to end-
point, despite a numerically lesser weight gain in the
nizatidine 300 mg group (3.29 kg vs. 4.18 kg in the
placebo group). Analyses showed a noticeable differ-
ence between the nizatidine 300 mg and placebo
group at weeks 3 and 4, but also without statistical
significance (92). In a 8-week placebo-controlled
trial, patients significantly lost weight ()4.5 kg) when
nizatidine was added to the olanzapine regimen,
whereas the placebo group receiving olanzapine alone
significantly gained weight (+2.3 kg) (93). However,
in a different 8-week double-blind, placebo con-
trolled trial by the same research group results failed
to demonstrate a significant weight loss for nizatidine
in quetiapine-treated patients despite the similar
molecular structure with olanzapine. The authors
found that nizatidine treatment stopped the weight
gain rather than reducing quetiapine-induced weight
gain (94). Given the above findings and the relatively
mild side effects it may be safe to consider nizatidine
for the management of antipsychotic drug-induced
weight gain when other measures fail (92,93).
Glucose homeostasis
Metformin
The antidiabetic biguanide metformin is a therapeu-
tic option for improvement of glucose homeostasis
and also reduction of psychotropic medication-
induced weight gain, although there has been only
limited evidence of metformin being an effective
agent in the treatment of weight gain when given in
combination with antipsychotic drugs. One open-
label study reported metformin to reverse weight
gain of paediatric patients receiving olanzapine, ris-
peridone and quetiapine. Results showed a statisti-
cally significant decrease in BMI (2.22 kg/m2) and
weight (2.93 kg) after 12 weeks (95). However
co-administration of metformin could not prevent
weight gain in adult patients with schizophrenia trea-
ted with olanzapine but displayed a positive meta-
bolic effect with the exception of triglyceride levels
(96). A pilot study with obese psychiatric patients
showed that weight loss was higher during placebo
than during metformin administration (97). In a
large trial conducted by the DPP Research Group
with non-diabetic patients with elevated fasting and
postload plasma glucose the effect of metformin was
compared to the effect of a behavioural intervention
programme, consisting of diet and exercise, on the
development of diabetes. While the mean weight loss
in the metformin group was 2.1 kg, those taking part
in the lifestyle intervention lost an average 5.6 kg
1366 Metabolic side effects of antipsychotic medication
and the incidence of diabetes was 39% lower in the
lifestyle-intervention group than in the metformin
group (98). As a consequence the use of metformin
should be carefully considered as the benefit may be
relatively small in relation to risks of adverse events
and potential drug interactions (Table 5).
Insulin-sensitiser
Pioglitazone exerts its effect through activation of per-
oxisome-proliferator activated receptor c (PPARc)
leading to the reduction of insulin resistance and pro-
motion of peripheral glucose uptake. Our preliminary
data proved an antihyperglycaemic effect of pioglita-
zone in a group of patients treated with SGAs (99).
Lipid profile
Data about therapy of psychotropic drug-induced
dyslipidaemia are scarce and literature on concomit-
ant lipid lowering medication is limited to case
reports. In 2002, one case report described severe
cerivastatin-induced rhabdomyolysis in a patient
receiving both risperidone and cerivastatin, which
may be attributable to metabolism of both drugs by
CYP 3A4 (100). Another case report indicates a poss-
ible drug interaction during simultaneous treatment
with simvastatin and risperidone. The patient suf-
fered from rhabdomyolysis and acute compartment
syndrome of the lower extremity, when simvastatin
was added to the antipsychotic therapy (101).
Pravastatin and fluvastatin, which are not predomin-
antly metabolised by CYP 3A4, may be safer in the
Table 5 Adverse drug reactions of weight reducing drugs
Drug Central nervous system ADRs
Sibutramine Insomnia (10%), dry mouth (17%), headache (30%).
Caution in patients with seizures and narrow angle
glaucoma
Orlistat
Topiramate Sedation, confusion and cognitive impairment in > 5%.
Psychosis in 3%, depression possible.
Associated with tinnitus
Amantadine Depression, agitation, delirium psychosis and visual
hallucinations
Nizatidine
Metformin
Pioglitazone Headache (9.1%)
Modified from ref. no. (84).
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
treatment of hyperlipidaemia in schizophrenic
patients receiving risperidone or other SGAs being
metabolised by CYP 3A4, namely clozapine, que-
tiapine and ziprasidone (102). One case of prolonged
QTc interval was described in a patient with schizo-
phrenia while taking quetiapine and lovastatin for
the treatment of his dyslipidaemia. After reducing
the lovastatin dose QTc returned to baseline (103).
In regards to potential adverse reactions with the
novel antipsychotics and concomitant medication,
Spina et al. emphasise that they may be prevented
and minimised by careful dosage adjustments based
on close evaluation of clinical response and, possibly,
plasma antipsychotic concentration monitoring
although in general the currently available newer
antipsychotics do not affect the activity of major
drug-metabolising enzymes and consequently have
minimal effects on the elimination of concomitantly
given medications (104).
Conclusion
Drug-induced weight gain is a serious side effect of
many commonly used psychotropic drugs leading to
noncompliance with therapy and to exacerbation of
comorbid conditions related to obesity. It is a prob-
lematic side effect of therapy because of the known
effect of weight gain on glucose control, blood pres-
sure and lipid levels. Therefore, metabolic distur-
bances induced by psychotropic drugs should be
taken into account when planning the therapeutic
Other ADRs
Tachycardia and hypertension
Flatulence, liquid stools, faecal urgency and
incontinence when not combined with
low-fat diet
Nephrolithiasis (1.5%)
Rash in up to 30%. Associated with livedo
reticularis
One case report of subfulminant hepatic
failure
Risk of lactic acidosis. Consider contraindications
in renal or hepatic impairment
Upper respiratory tract infection (13.2%), tooth
disorders (5.3%), myalgia (5.4%), peripheral
oedema (4.8%)
ª 2007 The Authors
 Metabolic side effects of antipsychotic medication 1367

Table 6 Possible strategies for management of antipsychotic drug-induced weight gain

• Routine monitoring of weight, blood glucose and lipid levels of patients, who are predisposed to overweight and obesity when new
therapy is initiated
• Avoiding drugs that commonly cause weight gain ‡ 7% of baseline weight in predisposed patients
• Counselling of patients to reduce energy intake and increase daily exercise
• Using the lowest possible dose of the psychotropic drug; if weight gain occurs: dosage reduction and/or combination with another
agent known to be weight neutral or cause weight loss
• Starting adjunctive therapy with weight loss agent whose choice depends on the psychotropic drug, possible metabolic interactions,
comorbidities and adverse effect profile
• Clarifying that the drug may cause weight gain, as this may adversely affect the patient’s adherence
• Developing a plan with the patient of what to do if weight gain occurs, how much weight gain to expect, when to intervene and
what the intervention will be

Modified from ref. no. (112).

proceeding. This should be of particular interest
when treating patients with schizophrenia because of
the early onset of the disease and the requirement of
long-term antipsychotic treatment. Weight gain may
be prevented by adherence to diet and exercise or
combination therapy with weight loss inducing drugs
(Table 6).
The psychiatrics’ understanding of the side effects
of psychotropic drugs, including their metabolic con-
sequences, is essential to avoid a lack of compliance,
which could eventually lead to discontinuation of the
patient’s medication as well as to avoid acute life
threatening events (diabetic ketoazidosis, long-term
risk complications of diabetes and overweight) (105).
The importance of these metabolic side effects in
daily medical practice is emphasised in a recent con-
sensus development conference. The various antipsy-
chotic substances were divided into groups with
different risks for obesity and diabetes (Table 1),
which serves as a basis for patient monitoring
(Table 2).
As low level diet and exercise programmes seem to
be as beneficial as drug treatment it is suggested that
diet and exercise education continue to be frontline
treatment for psychotropic drug-induced obesity, but
that pharmacological approaches should be consid-
ered if behavioural approaches fail (106). Reduction
of medication dosages, which could be another
approach, is not supported by literature as a positive
correlation of dose and weight gain is only shown
with some antipsychotic drugs. Switching to a differ-
ent medication has proven to be a more successful
strategy and should be considered as early as possible
in the course of treatment as weight gain is invaria-
bly progressive and does not resolve spontaneously
(107). However, some authors suggest that actively
treating the side effects of a drug to which the
patient has shown an otherwise good response may
have significant benefits over switching to an alter-
native treatment with which the patient’s response
and tolerance may be uncertain (108). According to
consensus recommendations, the use of weight redu-
cing drugs should only be attempted in patients with
a BMI above 30 kg/m2 and in patients with a BMI
above 27 kg/m2 and concomitant hypertension, dysli-
pidaemia, CVD, diabetes or sleep apnoea (109). For
those with a BMI between 25 and 30 kg/m2 and no
additional risk factors, prevention of further weight
gain, rather than weight loss should be the main
goal. Favourable drugs are topiramate, H2-antago-
nists, dopaminergic or serotoninergic agents.
Additional prospective clinical trials are required
to support a specific therapeutic approach for man-
aging weight gain. Moreover, psychotropic drug-
mediated alterations of the insulin signalling pathway
focusing on the proximal steps of the pathway
should be investigated to provide a basis for future
therapeutical strategies.
References
1 Haslam DW, James WPT. Obesity. Lancet 2005; 366: 1197–209.
2 American Diabetes Association, American Psychiatric Associ-
ation, American Association of Clinical Endocrinologists et al.
Consensus development conference on antipsychotic drugs and
obesity and diabetes. Diabetes Care 2004; 27: 596–601.
3 Coodin S. Body mass index in persons with schizophrenia. Can J
Psychiatry 2001; 46: 549–55.
4 Allison DB, Fontaine KR, Heo M et al. The distribution of body
mass index among individuals with and without schizophrenia.
J Clin Psychiatry 1999; 60: 215–20.
5 Hu FB, Willett WC, Li T et al. Adiposity as compared with
physical activity in predicting mortality among women. N Engl J
Med 2004; 351: 2694–703.
6 Li TY, Rana JS, Manson JE et al. Obesity as compared with
physical activity in predicting risk of coronary heart disease in
women. Circulation 2006; 113: 499–506.

ª 2007 The Authors

Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
1368 Metabolic side effects of antipsychotic medication
7 Thakore JH, Mann JN, Vlahos I et al. Increased visceral fat dis-
tribution in drug-naive and drug-free patients with schizophre-
nia. Int J Obes Relat Metab Disord 2002; 26: 137–41.
8 Zhang ZJ, Yao ZJ, Liu W et al. Effects of antipsychotics on fat
deposition and changes in leptin and insulin levels. Magnetic res-
onance imaging study of previously untreated people with schi-
zophrenia. Br J Psychiatry 2004; 184: 58–62.
9 Kurzthaler I, Fleischhacker WW. The clinical implications of
weight gain in schizophrenia. J Clin Psychiatry 2001; 62 (Suppl.
7): 32–37.
10 Eder U, Mangweth B, Ebenbichler C et al. Association of olanza-
pine-induced weight gain with an increase in body fat. Am J Psy-
chiatry 2001; 158: 1719–22.
11 Gupta S, Droney T, Al-Samarrai S et al. Olanzapine-induced
weight gain. Ann Clin Psychiatry 1998; 10: 39.
12 Henderson DC, Cagliero E, Gray C et al. Clozapine, diabetes
mellitus, weight gain, and lipid abnormalities: a five-year natur-
alistic study. Am J Psychiatry 2000; 157: 975–81.
13 Hummer M, Kemmler G, Kurz M et al. Weight gain induced by
clozapine. Eur Neuropsychopharmacol 1995; 5: 437–40.
14 Wetterling T. Bodyweight gain with atypical antipsychotics. A
comparative review. Drug Saf 2001; 24: 59–73.
15 Allison DB, Mentore JL, Heo M et al. Antipsychotic-induced
weight gain: a comprehensive research synthesis. Am J Psychiatry
1999; 156: 1686–96.
16 Newcomer JW. Second-generation (atypical) antipsychotics and
metabolic effects: a comprehensive literature review. CNS Drugs
2005; 19 (Suppl. 1): 1–93.
17 Wetterling T, Pest S, Mussigbrodt H et al. [Bodyweight in inpa-
tients with schizophrenia]. Psychiatr Prax 2004; 31: 250–4.
18 Centorrino F, Wurtman JJ, Duca KA et al. Weight loss in over-
weight patients maintained on atypical antipsychotic agents. Int J
Obes (Lond) 2006; 30: 1011–6.
19 Fontaine KR, Heo M, Harrigan EP et al. Estimating the conse-
quences of anti-psychotic induced weight gain on health and
mortality rate. Psychiatry Res 2001; 101: 277–88.
20 Ananth J, Venkatesh R, Burgoyne K et al. Atypical antipsychotic
induced weight gain: pathophysiology and management. Ann
Clin Psychiatry 2004; 16: 75–85.
21 Dourish CT. Multiple serotonin receptors: opportunities for
new treatments for obesity? Obes Res 1995; 3 (Suppl. 4):
449S–62S.
22 Heal DJ, Aspley S, Prow MR et al. Sibutramine: a novel
anti-obesity drug. A review of the pharmacological evidence to
differentiate it from d-amphetamine and d-fenfluramine. Int J
Obes Relat Metab Disord 1998; 22 (Suppl. 1): S18–28; discussion
S29.
23 Strombom U, Krotkiewski M, Blennow K et al. The concentra-
tions of monoamine metabolites and neuropeptides in the cere-
brospinal fluid of obese women with different body fat
distribution. Int J Obes Relat Metab Disord 1996; 20: 361–8.
24 Li Z, Maglione M, Tu W et al. Meta-analysis: pharmacologic
treatment of obesity. Ann Intern Med 2005; 142: 532–46.
25 Buse JB, Cavazzoni P, Hornbuckle K et al. A retrospective cohort
study of diabetes mellitus and antipsychotic treatment in the
United States. J Clin Epidemiol 2003; 56: 164–70.
26 Cohen D. Atypical antipsychotics and new onset diabetes melli-
tus. An overview of the literature. Pharmacopsychiatry 2004; 37:
1–11.
27 Brugman NJ, Cohen D, de Vries RH. [Diabetes mellitus after
treatment with clozapine]. Ned Tijdschr Geneeskd 2000; 144:
437–9.
28 Pierides M. Clozapine monotherapy and ketoacidosis. Br J Psy-
chiatry 1997; 171: 90–91.
29 Koller EA, Weber J, Doraiswamy PM et al. A survey of reports
of quetiapine-associated hyperglycemia and diabetes mellitus.
J Clin Psychiatry 2004; 65: 857–63.
30 Koro CE, Fedder DO, L’Italien GJ et al. Assessment of independ-
ent effect of olanzapine and risperidone on risk of diabetes
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
among patients with schizophrenia: population based nested
case-control study. BMJ 2002; 325: 243.
31 Ebenbichler CF, Laimer M, Eder U et al. Olanzapine induces
insulin resistance: results from a prospective study. J Clin Psychi-
atry 2003; 64: 1436–9.
32 Laimer M, Ebenbichler CF, Kranebitter M et al. Olanzapine-
induced hyperglycemia: role of humoral insulin resistance-indu-
cing factors. J Clin Psychopharmacol 2005; 25: 183–5.
33 Henderson DC, Cagliero E, Copeland PM et al. Glucose metabo-
lism in patients with schizophrenia treated with atypical antipsy-
chotic agents: a frequently sampled intravenous glucose tolerance
test and minimal model analysis. Arch Gen Psychiatry 2005; 62:
19–28.
34 Sowell MO, Mukhopadhyay N, Cavazzoni P et al. Hyperglycemic
clamp assessment of insulin secretory responses in normal sub-
jects treated with olanzapine, risperidone, or placebo. J Clin End-
ocrinol Metab 2002; 87: 2918–23.
35 Brown RR, Estoup MW. Comparison of the metabolic effects
observed in patients treated with ziprasidone versus olanzapine.
Int Clin Psychopharmacol 2005; 20: 105–12.
36 Lieberman JA, Stroup TS, McEvoy JP et al. Effectiveness of anti-
psychotic drugs in patients with chronic schizophrenia. N Engl J
Med 2005; 353: 1209–23.
37 Melkersson KI, Hulting AL, Brismar KE. Elevated levels of insu-
lin, leptin, and blood lipids in olanzapine-treated patients with
schizophrenia or related psychoses. J Clin Psychiatry 2000; 61:
742–9.
38 Wirshing DA, Spellberg BJ, Erhart SM et al. Novel antipsychotics
and new onset diabetes. Biol Psychiatry 1998; 44: 778–83.
39 Rettenbacher MA, Hummer M, Hofer A et al. Alterations of glu-
cose metabolism during treatment with clozapine or amisulpride:
results from a prospective 16-week study. J Psychopharmacol
2006; (Epub ahead of print).
40 McIntyre RS, Mancini DA, Basile VS. Mechanisms of antipsy-
chotic-induced weight gain. J Clin Psychiatry 2001; 62 (Suppl.
23): 23–9.
41 Engl J, Laimer M, Niederwanger A et al. Olanzapine impairs gly-
cogen synthesis and insulin signaling in L6 skeletal muscle cells.
Mol Psychiatry 2005; 10: 1089–96.
42 Melkersson K, Khan A, Hilding A et al. Different effects of anti-
psychotic drugs on insulin release in vitro. Eur Neuropsychophar-
macol 2001; 11: 327–32.
43 Melkersson K. Clozapine and olanzapine, but not conventional
antipsychotics, increase insulin release in vitro. Eur Neuropsycho-
pharmacol 2004; 14: 115–9.
44 Bergman RN, Ader M. Free fatty acids and pathogenesis of type
2 diabetes mellitus. Trends Endocrinol Metab 2000; 11: 351–6.
45 Ginsberg HN, Huang LS. The insulin resistance syndrome:
impact on lipoprotein metabolism and atherothrombosis. J Car-
diovasc Risk 2000; 7: 325–31.
46 Patsch JR, Miesenböck G, Hopferwieser T et al. Relation of tri-
glyceride metabolism and coronary artery disease. Studies in the
postprandial state. Arterioscler Thromb 1992; 12: 1336–45.
47 Wu RR, Zhao JP, Liu ZN et al. Effects of typical and atypical
antipsychotics on glucose-insulin homeostasis and lipid metabo-
lism in first-episode schizophrenia. Psychopharmacology (Berl)
2006; 186: 572–8.
48 Wirshing DA, Boyd JA, Meng LR et al. The effects of novel anti-
psychotics on glucose and lipid levels. J Clin Psychiatry 2002; 63:
856–65.
49 Koro CE, Fedder DO, L’Italien GJ et al. An assessment of the
independent effects of olanzapine and risperidone exposure on
the risk of hyperlipidemia in schizophrenic patients. Arch Gen
Psychiatry 2002; 59: 1021–6.
50 Rettenbacher MA, Ebenbichler C, Hofer A et al. Early changes of
plasma lipids during treatment with atypical antipsychotics. Int
Clin Psychopharmacol 2006; 21: 369–72.
51 Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor
for antipsychotic noncompliance. Schizophr Res 2004; 66: 51–57.
ª 2007 The Authors

52 Blackburn G. Effect of degree of weight loss on health benefits.
Obes Res 1995; 3 (Suppl. 2): 211s–6s.
53 Goldstein DJ. Beneficial health effects of modest weight loss. Int
J Obes Relat Metab Disord 1992; 16: 397–415.
54 Perry PJ, Argo TR, Carnahan RM et al. The association of weight
gain and olanzapine plasma concentrations. J Clin Psychophar-
macol 2005; 25: 250–4.
55 Meyer JM, Pandina G, Bossie CA et al. Effects of switching from
olanzapine to risperidone on the prevalence of the metabolic
syndrome in overweight or obese patients with schizophrenia or
schizoaffective disorder: analysis of a multicenter, rater-blinded,
open-label study. Clin Ther 2005; 27: 1930–41.
56 Weiden PJ, Daniel DG, Simpson G et al. Improvement in indices
of health status in outpatients with schizophrenia switched to
ziprasidone. J Clin Psychopharmacol 2003; 23: 595–600.
57 Kinon BJ, Basson BR, Gilmore JA et al. Strategies for switching
from conventional antipsychotic drugs or risperidone to olanza-
pine. J Clin Psychiatry 2000; 61: 833–40.
58 Peuskens J. Switching approach in the management of schizo-
phrenia patients. Int Clin Psychopharmacol 2000; 15 (Suppl. 4):
S15–19.
59 Casey DE, Carson WH, Saha AR et al. Switching patients to ari-
piprazole from other antipsychotic agents: a multicenter rand-
omized study. Psychopharmacology (Berl) 2003; 166: 391–9.
60 Vreeland B, Minsky S, Menza M et al. A program for managing
weight gain associated with atypical antipsychotics. Psychiatr Serv
2003; 54: 1155–7.
61 Littrell KH, Hilligoss NM, Kirshner CD et al. The effects of an
educational intervention on antipsychotic-induced weight gain.
J Nurs Scholarsh 2003; 35: 237–41.
62 Evans S, Newton R, Higgins S. Nutritional intervention to pre-
vent weight gain in patients commenced on olanzapine: a rand-
omized controlled trial. Aust N Z J Psychiatry 2005; 39: 479–86.
63 Brar JS, Ganguli R, Pandina G et al. Effects of behavioral therapy
on weight loss in overweight and obese patients with schizophre-
nia or schizoaffective disorder. J Clin Psychiatry 2005; 66: 205–
12.
64 Kwon JS, Choi JS, Bahk WM et al. Weight management program
for treatment-emergent weight gain in olanzapine-treated
patients with schizophrenia or schizoaffective disorder: a 12-week
randomized controlled clinical trial. J Clin Psychiatry 2006; 67:
547–53.
65 Weber M, Wyne K. A cognitive/behavioral group intervention
for weight loss in patients treated with atypical antipsychotics.
Schizophr Res 2006; 83: 95–101.
66 Menza M, Vreeland B, Minsky S et al. Managing atypical anti-
psychotic-associated weight gain: 12-month data on a multimo-
dal weight control program. J Clin Psychiatry 2004; 65: 471–7.
67 O’Keefe CD, Noordsy DL, Liss TB et al. Reversal of antipsychot-
ic-associated weight gain. J Clin Psychiatry 2003; 64: 907–12.
68 Alvarez-Jimenez M, Gonzalez-Blanch C, Vazquez-Barquero JL
et al. Attenuation of antipsychotic-induced weight gain with
early behavioral intervention in drug-naive first-episode psycho-
sis patients: a randomized controlled trial. J Clin Psychiatry 2006;
67: 1253–60.
69 Gursoy A, Erdogan MF, Cin MO et al. Comparison of orlistat
and sibutramine in an obesity management program: efficacy,
compliance, and weight regain after noncompliance. Eat Weight
Disord 2006; 11: e127–132.
70 Moyers SB. Medications as adjunct therapy for weight loss:
approved and off-label agents in use. J Am Diet Assoc 2005; 105:
948–59.
71 Weintraub M, Rubio A, Golik A et al. Sibutramine in weight
control: a dose-ranging, efficacy study. Clin Pharmacol Ther
1991; 50: 330–7.
72 Henderson DC, Copeland PM, Daley TB et al. A double-blind,
placebo-controlled trial of sibutramine for olanzapine-associated
weight gain. Am J Psychiatry 2005; 162: 954–62.
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
Metabolic side effects of antipsychotic medication 1369
73 Himmerich H, Schuld A, Pollmacher T. [Weight gain during
treatment with antipsychotics: clinical relevance, pathophysiolo-
gy, and therapeutical strategies]. Psychiatr Prax 2004; 31 (Suppl.
2): S233–237.
74 Hilger E, Quiner S, Ginzel I et al. The effect of orlistat on
plasma levels of psychotropic drugs in patients with long-term
psychopharmacotherapy. J Clin Psychopharmacol 2002; 22: 68–
70.
75 Schwartz TL, Beale M. Pharmacokinetics and drug interactions
of the sedative hypnotics. Psychopharmacol Bull 2003; 37: 5–9.
76 Dinan T, Tobin A. Orlistat in the management of antipsychotic-
induced weight gain: two case reports. J Serotonin Res 2001; 7:
14–15.
77 Anghelescu I, Klawe C, Szegedi A. Add-on combination and
maintenance treatment: case series of five obese patients with
different eating behavior. J Clin Psychopharmacol 2002; 22:
521–4.
78 Kim JH, Yim SJ, Nam JH. A 12-week, randomized, open-label,
parallel-group trial of topiramate in limiting weight gain during
olanzapine treatment in patients with schizophrenia. Schizophr
Res 2006; 82: 115–7.
79 Vieta E, Sanchez-Moreno J, Goikolea JM et al. Effects on weight
and outcome of long-term olanzapine-topiramate combination
treatment in bipolar disorder. J Clin Psychopharmacol 2004; 24:
374–8.
80 Ko YH, Joe SH, Jung IK et al. Topiramate as an adjuvant treat-
ment with atypical antipsychotics in schizophrenic patients
experiencing weight gain. Clin Neuropharmacol 2005; 28: 169–75.
81 Dursun SM, Devarajan S. Clozapine weight gain, plus topiramate
weight loss. Can J Psychiatry 2000; 45: 198.
82 Gordon A, Price LH. Mood stabilization and weight loss with to-
piramate. Am J Psychiatry 1999; 156: 968–9.
83 Shapira NA, Goldsmith TD, McElroy SL. Treatment of binge-
eating disorder with topiramate: a clinical case series. J Clin Psy-
chiatry 2000; 61: 368–72.
84 Werneke U, Taylor D, Sanders TA. Options for pharmacological
management of obesity in patients treated with atypical anti-
psychotics. Int Clin Psychopharmacol 2002; 17: 145–60.
85 Floris M, Lejeune J, Deberdt W. Effect of amantadine on weight
gain during olanzapine treatment. Eur Neuropsychopharmacol
2001; 11: 181–2.
86 Deberdt W, Winokur A, Cavazzoni PA et al. Amantadine for
weight gain associated with olanzapine treatment. Eur Neuropsy-
chopharmacol 2005; 15: 13–21.
87 Baruch R, Poulin M, Thakur A et al. Amantadine induces weight
loss in patients treated with olanzapine. Schizophr Res 2002; 53
(3 Suppl. 1): 159.
88 Correa N, Opler LA, Kay SR et al. Amantadine in the treatment
of neuroendocrine side effects of neuroleptics. J Clin Psychophar-
macol 1987; 7: 91–5.
89 Graham KA, Gu H, Lieberman JA et al. Double-blind, placebo-
controlled investigation of amantadine for weight loss in subjects
who gained weight with olanzapine. Am J Psychiatry 2005; 162:
1744–6.
90 Silver H, Geraisy N. Amantadine does not exacerbate positive
symptoms in medicated, chronic schizophrenic patients: evidence
from a double-blind crossover study. J Clin Psychopharmacol
1996; 16: 463–4.
91 Sacchetti E, Guarneri L, Bravi D. H(2) antagonist nizatidine may
control olanzapine-associated weight gain in schizophrenic
patients. Biol Psychiatry 2000; 48: 167–8.
92 Cavazzoni P, Tanaka Y, Roychowdhury SM et al. Nizatidine
for prevention of weight gain with olanzapine: a double-blind
placebo-controlled trial. Eur Neuropsychopharmacol 2003; 13:
81–5.
93 Atmaca M, Kuloglu M, Tezcan E et al. Nizatidine treatment and
its relationship with leptin levels in patients with olanzapine-
induced weight gain. Hum Psychopharmacol 2003; 18: 457–61.
1370 Metabolic side effects of antipsychotic medication
94 Atmaca M, Kuloglu M, Tezcan E et al. Nizatidine for the treat-
ment of patients with quetiapine-induced weight gain. Hum Psy-
chopharmacol 2004; 19: 37–40.
95 Morrison JA, Cottingham EM, Barton BA. Metformin for weight
loss in pediatric patients taking psychotropic drugs. Am J Psychi-
atry 2002; 159: 655–7.
96 Baptista T, Martinez J, Lacruz A et al. Metformin for prevention
of weight gain and insulin resistance with olanzapine: a double-
blind placebo-controlled trial. Can J Psychiatry 2006; 51: 192–6.
97 Baptista T, Hernandez L, Prieto LA et al. Metformin in obesity
associated with antipsychotic drug administration: a pilot study.
J Clin Psychiatry 2001; 62: 653–5.
98 Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in
the incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med 2002; 346: 393–403.
99 Edlinger M, Ebenbichler CF, Rettenbacher M et al. Therapy of
antipsychotic-associated diabetes mellitus with pioglitazone, a
case series. Schizophr Res 2006; 81 (Suppl. 1): 133–4.
100. Giner V, Munoz R, Redon J. Risperidone and severe cerivasta-
tin-induced rhabdomyolysis. J Intern Med 2002; 251: 177–8.
101 Webber MA, Mahmud W, Lightfoot JD et al. Rhabdomyolysis
and compartment syndrome with coadministration of risperi-
done and simvastatin. J Psychopharmacol 2004; 18: 432–4.
102 Prior TI, Baker GB. Interactions between the cytochrome P450
system and the second-generation antipsychotics. J Psychiatry
Neurosci 2003; 28: 99–112.
103 Furst BA, Champion KM, Pierre JM et al. Possible association of
QTc interval prolongation with co-administration of quetiapine
and lovastatin. Biol Psychiatry 2002; 51: 264–5.
104 Spina E, de Leon J. Metabolic drug interactions with newer anti-
psychotics: a comparative review. Basic Clin Pharmacol Toxicol
2007; 100: 4–22.
Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
105 Ruetsch O, Viala A, Bardou H et al. [Psychotropic drugs induced
weight gain: a review of the literature concerning epidemiological
data, mechanisms and management]. Encephale 2005; 31 (4 Pt
1): 507–16.
106 Schwartz TL, Jindal S, Simionescu M et al. Effectiveness of orli-
stat versus diet and exercise for weight gain associated with anti-
depressant use: a pilot study. J Clin Psychopharmacol 2004; 24:
555–6.
107 Zimmermann U, Kraus T, Himmerich H et al. Epidemiology,
implications and mechanisms underlying drug-induced weight
gain in psychiatric patients. J Psychiatr Res 2003; 37: 193–220.
108 Van Ameringen M, Mancini C, Pipe B et al. Topiramate treat-
ment for SSRI-induced weight gain in anxiety disorders. J Clin
Psychiatry 2002; 63: 981–4.
109 Clinical guidelines on the identification, evaluation, and treat-
ment of overweight and obesity in adults: executive summary.
Expert panel on the identification, evaluation, and treatment of
overweight in adults. Am J Clin Nutr 1998; 68: 899–917.
110 Faulkner G, Cohn TA. Pharmacologic and nonpharmacologic
strategies for weight gain and metabolic disturbance in patients
treated with antipsychotic medications. Can J Psychiatry 2006;
51: 502–11.
111 Baptista T, Kin NM, Beaulieu S et al. Obesity and related meta-
bolic abnormalities during antipsychotic drug administration:
mechanisms, management and research perspectives. Pharmaco-
psychiatry 2002; 35: 205–19.
112 Malone M. Medications associated with weight gain. Ann Phar-
macother 2005; 39: 2046–55.
113 Waldhäusl W, Gries FA, Scherbaum W. Diabetes in der Praxis,
3rd edn. New York: Springer-Verlag Berlin Heidelberg, 2004.
Paper received September 2006, accepted April 2007
ª 2007 The Authors