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

Particularly, second-generation antipsychotics (SGAs)


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

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

ª 2007 The Authors


Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
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 Different antipsychotic drugs were tested on their
insulin response correlated with the weight gain but effect on pancreatic beta-cells in an in vitro study to
no significant change in insulin secretion or insulin investigate a possible influence on the insulin secre-
sensitivity was detected (34). Recent publications tion. Basal insulin secretion was stimulated by cloza-
describe an increase of haemoglobin A1C (HbA1C) pine, whereas no significant increase could be found
during treatment with olanzapine. Possible mecha- for olanzapine (42,43).
nisms include weight gain, changes of insulin secre- The development of insulin resistance could
tion, development of peripheral insulin resistance explain the various disturbances of the glucose
and changes of cellular glucose uptake (35,36). homeostasis and could be caused by alterations of
Several authors suggest that the onset of diabetes insulin sensitivity in peripheral and/or hepatic tissues
during antipsychotic therapy is secondary to drug- mediated through humoral and/or cellular signalling
induced weight gain (26), possibly both induced by pathways. Several insulin resistance inducing factors
histamine antagonism (37,38). However, the rapid have been identified in the past. FFAs derived from
onset of diabetes, the disappearance of hyperglycae- adipocytes are consistently elevated in insulin-resist-
mia after discontinuation of the drug and recurrence ant subjects (Figure 2). FFAs inhibit glucose uptake,
after reintroduction support the development of glycogen synthesis and glucose oxidation and
diabetes in patients on SGAs being a drug-related increase hepatic glucose output as well as very low-
effect, especially with regard to olanzapine and cloza- density lipoprotein (VLDL) triglyceride production
pine. This was confirmed in a study comparing (44). The molecular mechanisms of action of adipo-
clozapine and amisulpride in respect to their impact nectin, leptin and resistin, which have a potential
on glucose metabolism, where some patients showed insulin resistance enhancing or also protective effect,
signs of insulin resistance even without experiencing are not yet clear.
weight gain (39). A direct mechanism seems to be
more likely also when considering that not all medi- Disturbances of lipid metabolism
cations causing substantial weight gain induce DM Dyslipidaemia is characterised by increased FFAs, ele-
(40). Results from in vitro experiments on L6-skeletal vated triglycerides, low high-density lipoprotein
muscle cells showed that olanzapine impairs the (HDL) cholesterol, increased small, dense low-density
phosphatidylinositol-3-kinase (PI3K) dependent lipoprotein (LDL) cholesterol and increased apolipo-
insulin signalling pathway and significantly reduces protein B (45).
glycogen synthesis, whereas amisulpride, which is The high prevalence of hyperlipidaemia in the gen-
not associated with diabetes, had none of these eral population and the heterogeneity in the defini-
effects (41). 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.

ª 2007 The Authors


Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
1360 Metabolic side effects of antipsychotic medication

changes of lipid metabolism of psychiatric patients


Therapeutic interventions
during therapy with psychotropic drugs difficult.
Additionally to weight gain and diabetes, some Overweight
SGAs cause hypertriglyceridaemia, which is an inde- Treating or preventing drug-induced weight gain
pendent risk factor of coronary arteriosclerosis (46). should be a major concern in the treatment of schi-
Increased adiposity can result in excess FFA release zophrenic patients as weight gain does not only pose
from hypertrophic adipocytes leading to higher FFA a serious health risk but also adversely affects com-
concentrations. These can induce muscle and hepatic pliance with antipsychotic medication. A linear
insulin resistance, endothelial- and pancreatic-cell association between the patients BMI and the likeli-
dysfunction and increased VLDL triglyceride produc- hood of noncompliance was shown by Weiden et al.
tion (Figure 2). A recent prospective study compar- (51), with obese patients being about 2.5 times more
ing the effects of the SGAs clozapine, olanzapine, likely to stop their medication than those who are
risperidone and the FGA sulpiride on glucose and not obese. It is, therefore, important to choose an
lipid metabolism in first-episode schizophrenia at appropriate strategy for weight management based
baseline and 8 weeks after inclusion showed that on the prescribed antipsychotic drug, individual risk
besides higher C-peptide, fasting insulin and insulin factors, concomitant diseases and the patient’s moti-
resistance index (IRI), cholesterol and triglyceride vation for losing weight. Even modest weight loss
levels were significantly increased in the clozapine can reduce health risks in obese patients with med-
and olanzapine groups (47). Because of these results ical benefits beginning to accrue with weight losses
the authors recommend that baseline and 6-month as little as 5–10% of the initial weight (52,53).
monitoring of fasting blood glucose, fasting choles-
terol and triglyceride levels should be obtained in Non-pharmacological treatment
routine clinical practice with all antipsychotics to Switching antipsychotic medication:
monitor the risk for development of hyperglycaemia Although there are only few studies investigating the
and hypercholesterolaemia. effect of medication dosage on weight gain it appears
In a comparative study, treatment with various that varying dosage within therapeutic range has no
antipsychotics resulted in significantly elevated trigly- significant impact on antipsychotic-induced weight
ceride levels in 56% of clozapine, 39% of olanzapine gain (54). This and the fact that newer SGAs like ari-
and 21% of risperidone-treated patients compared to piprazole or ziprasidone bear a lesser risk for weight
none of haloperidol and 8% of fluphenazine-treated gain than older drugs, such as clozapine or olanza-
patients (48). The same study showed a reduction of pine, make switching to an antipsychotic regimen
HDL cholesterol during treatment with clozapine with a better metabolic profile a sensible therapeutic
and olanzapine, whereas total cholesterol levels were approach to manage excessive weight gain (2).
significantly lower in risperidone- and fluphenazine- One study reported a 32% reduction in the preva-
treated patients. Koro et al. observed a threefold lence of the metabolic syndrome in overweight or
higher risk of hyperlipidaemia for FGAs when com- obese patients (mean BMI 35.1 ± 7.3 kg/m2) when
pared with a control population without antipsychot- they were switched from olanzapine to risperidone.
ic exposure. SGA treatment associated odds varied: Additionally body weight, BMI, waist circumference
olanzapine use was associated with a nearly fivefold and blood pressure were significantly reduced after
higher increase in the risk of developing hyperlipid- 20 weeks (55). In a different trial patients were
aemia, whereas risperidone showed no significant dif- switched from olanzapine, risperidone or conven-
ference (49). A more recent study described a tional antipsychotic to ziprasidone and results
negative effect of olanzapine administration on total showed the greatest metabolic benefit being depend-
cholesterol and triglycerides, whereas favourable ent on the previous medication. Patients initially
metabolic effects were observed in ziprasidone-trea- treated with olanzapine experienced greater weight
ted patients with regard to total cholesterol, LDL and loss ()1.76 kg) compared to those switched from ris-
HDL (35). These results were confirmed in another peridone ()0.86 kg), whereas significant reductions
study with 1493 patients (36). An increase of serum of non-fasting total cholesterol and triglycerides were
lipid levels was already seen after 4 weeks of seen in both groups. The switch from conventional
treatment with olanzapine or clozapine and was antipsychotics to ziprasidone had no significant effect
significantly correlated with increasing BMI. As ami- on either weight or the lipid profile (56).
sulpride and ziprasidone had no significant effect on The main problem with switching agents is the
serum lipid levels, the authors suggest these drugs as potential for worsening or re-emerging psychotic
a favourable alternative treatment for already over- symptoms along with side effects as nausea, vomit-
weight patients (50). ing, insomnia, agitation and anxiety (57,58). To

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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 1361

avoid adverse reactions, pre-existing conditions and sessions provided by a dietitian. The amount of
concomitant medication should be taken into patients gaining clinically significant weight (‡ 7% of
account when switching to a different agent. There is their baseline weight) after commencement of ola-
no consensus on the best way to switch from one nzapine could be reduced from 68% to 13%. The
antipsychotic drug to another. Some studies have intervention group continued to gain significantly
shown that abrupt discontinuation of the prior anti- less weight during the 3-month follow-up (62). Sig-
psychotic drug may be tolerated by some patients nificant weight loss was experienced by both the
while gradual reduction in dose with immediate ini- intervention and the treatment-as-usual group in a
tiation of the new drug may be required by others. randomised, controlled, multicenter study. The fact
The most successful switching strategy may be the that the patients had been switched to risperidone
gradual discontinuation of the current antipsychotic before the intervention was initiated may have con-
drug and immediate initiation of the new treatment tributed to this finding. However, more participants
(57,58). However, all three strategies have shown to in the behavioural treatment group lost more than
be well tolerated and induce modest weight loss 5% of their initial body weight (63). Patients treated
()1.3 to )1.7 kg) in patients switching to aripipraz- with olanzapine undergoing a 12-week weight man-
ole with no evidence of a deterioration in schizo- agement programme focusing on diet and exercise
phrenia symptoms (59). exhibited significant reductions in weight ()3.94 kg
Behavioural intervention: vs. )1.48 kg) and BMI compared with patients
The NHLBI/NIH clinical guidelines recommend receiving usual outpatient treatment (64). In a rand-
weight reduction therapy for individuals with a BMI omised trial, the effectiveness of cognitive/beha-
‡ 25 kg/m2 consisting of three main components. vioural interventions modified after the Diabetes
These include a calorie-restricted diet with a calorie Prevention Project (DPP) was examined over
deficit of 500–1000 kcal/day less than the patient’s 16 weeks. The group receiving the intervention lost
baseline and an increase in physical activity com- an average of 2.9 kg (range )0.5 to )10 kg) of their
bined with behavioural strategies to reinforce these body weight (mean BMI at baseline 33 kg/m2) in
lifestyle changes. comparison to an average loss of 0.6 kg in the group
Such measures were shown to be effective in a with treatment as usual (65). Results from a long-
group of patients receiving an SGA for at least term prospective trial suggest that patients with
3 months in which the BMI became > 26 kg/m2 or severe mental illness and antipsychotic-associated
weight gain of at least 2.3 kg was experienced. After weight gain benefit from an intensive weight control
12 weeks participants receiving the intervention had programme. Patients enrolled in the 12-month pro-
a mean weight loss of 2.7 kg and a mean BMI reduc- gramme lost significant amounts of weight and signi-
tion of 0.98 kg/m2 in comparison to a matched con- ficantly reduced their BMI. Improvements in blood
trol group not taking part in the weight management pressure and HbA1C were also reported (66). O’Keefe
programme, where patients gained a mean 2.9 kg et al. (67) reviewed charts of patients who gained at
resulting in a mean BMI increase of 1.2 kg/m2 (60) least 9 kg after initiation of an antipsychotic agent
(Table 3). A different study examined the impact of and found that approximately one quarter of the
an intensive programme of diet, exercise and coun- patients experiencing weight gain may eventually
selling in antipsychotic-treated patients with a weight be able to reverse the process, particularly when
gain of more than 4.5 kg and an increase in BMI of behavioural interventions, e.g. dietitian counselling,
more than 5% since the start of antipsychotic treat- self-directed diet, are used. Some evidence suggests
ment. During 24 weeks the mean weight loss was that use of multiple weight loss interventions is more
6.0 kg and BMI was reduced by 5.7%. A subgroup of effective.
the study population participated in an additional Early intervention should be promoted shortly
24 weeks, less-intensive extension phase and regained after initiation of antipsychotic therapy as it helps
minimal weight (0.43 kg). However, the mean BMI attenuating drug-induced weight gain in drug-naive
was still 36.2 kg/m2 (18). In contrast, weight control patients receiving antipsychotic medication (68).
was achieved in patients with a mean BMI of 26 by Despite the fact that mentally ill patients often lack
weekly educational interventions for 4 months. This compliance and motivation for treatment, patients
beneficial effect could be maintained for 2 months seem to gain more interest in their diet and the
after the completion of the intervention (61). Similar behavioural treatment when in a controlled setting
results are reported in a randomised controlled trial leading to more concerted efforts to change their eat-
where the control group gained significantly more ing and exercise behaviour patterns (60). Weight
weight (mean + 9 kg) than the intervention group control interventions may potentially be most effect-
(mean + 2 kg) receiving six one-on-one educational ive by emphasising dietary education and calorie

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Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
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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Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
Metabolic side effects of antipsychotic medication 1363

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

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

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Metabolic side effects of antipsychotic medication 1365

Amantadine There were no significant differences between groups


With its dopamine receptor antagonistic effect, when comparing weight gain from baseline to end-
amantadine is used in the treatment of extrapyrami- point, despite a numerically lesser weight gain in the
dal symptoms, idiopathic Parkinsonism and influ- nizatidine 300 mg group (3.29 kg vs. 4.18 kg in the
enza. An anorectic effect could be shown in placebo group). Analyses showed a noticeable differ-
olanzapine-treated patients receiving 100–300 mg ence between the nizatidine 300 mg and placebo
amantadine for 3–6 months. After a mean initial group at weeks 3 and 4, but also without statistical
weight gain of 7.3 kg during olanzapine treatment significance (92). In a 8-week placebo-controlled
the patients’ weight stabilised and, subsequently, trial, patients significantly lost weight ()4.5 kg) when
these patients lost an average of 3.5 kg (85). In a nizatidine was added to the olanzapine regimen,
randomised controlled trial, Deberdt et al. observed whereas the placebo group receiving olanzapine alone
a mean weight loss of 0.19 kg (±4.58) after 16 weeks significantly gained weight (+2.3 kg) (93). However,
in psychiatric patients receiving amantadine in addi- in a different 8-week double-blind, placebo con-
tion to their olanzapine-regimen. However this was trolled trial by the same research group results failed
not significant compared to a mean weight gain of to demonstrate a significant weight loss for nizatidine
1.28 kg (±4.26) in the group receiving olanzapine in quetiapine-treated patients despite the similar
and placebo. Amantadine induced some weight loss molecular structure with olanzapine. The authors
in obese patients (BMI ‡ 30) while it limited weight found that nizatidine treatment stopped the weight
gain in overweight patients (BMI 25–30) suggesting gain rather than reducing quetiapine-induced weight
that amantadine might be effective in attenuating or gain (94). Given the above findings and the relatively
preventing weight gain earlier in the course of ola- mild side effects it may be safe to consider nizatidine
nzapine treatment (86). Patients with schizophrenia for the management of antipsychotic drug-induced
taking olanzapine started to lose weight almost weight gain when other measures fail (92,93).
immediately after initiation of amantadine co-treat-
ment. After 12 weeks the greatest weight loss was Glucose homeostasis
experienced by those patients with a BMI > 27 and
those treated with olanzapine ‡ 1 year ()2.6 and Metformin
)2.5 kg) (87). In an open-label reversal drug study The antidiabetic biguanide metformin is a therapeu-
the impact of amantadine on neuroendocrine side tic option for improvement of glucose homeostasis
effects was assessed in 10 neuroleptic-treated schizo- and also reduction of psychotropic medication-
phrenic inpatients with a significant reduction in induced weight gain, although there has been only
body weight during the 3-week antipsychotic-amant- limited evidence of metformin being an effective
adine co-medication (88). In a small randomised, agent in the treatment of weight gain when given in
placebo-controlled trial amantadine displayed a combination with antipsychotic drugs. One open-
weight stabilising effect, but no changes in fasting label study reported metformin to reverse weight
glucose, insulin, leptin, prolactin and lipid levels gain of paediatric patients receiving olanzapine, ris-
were seen (89). The simultaneous treatment of affect- peridone and quetiapine. Results showed a statisti-
ive and physical disorder may be complicated by cally significant decrease in BMI (2.22 kg/m2) and
drug interaction. Amantadine may directly reverse weight (2.93 kg) after 12 weeks (95). However
D2 blockade and exacerbate psychosis, although this co-administration of metformin could not prevent
remains subject to debate (90). weight gain in adult patients with schizophrenia trea-
ted with olanzapine but displayed a positive meta-
Nizatidine bolic effect with the exception of triglyceride levels
It is not yet understood how H2-receptor-anatgonists (96). A pilot study with obese psychiatric patients
may induce weight loss, but it may involve appetite showed that weight loss was higher during placebo
regulation and suppression of gastric acid secretion. than during metformin administration (97). In a
One case report describes lesser weight gain and con- large trial conducted by the DPP Research Group
sequently a weight reduction of 5% in a patient trea- with non-diabetic patients with elevated fasting and
ted with olanzapine in combination with nizatidine postload plasma glucose the effect of metformin was
(91). To evaluate the efficacy of two fixed nizatidine compared to the effect of a behavioural intervention
doses in the prevention of olanzapine-associated programme, consisting of diet and exercise, on the
weight gain three groups (n ¼ 169) received either development of diabetes. While the mean weight loss
placebo, nizatidine 150 mg b.i.d. or nizatidine in the metformin group was 2.1 kg, those taking part
300 mg b.i.d. in a 16-week double blind clinical trial. in the lifestyle intervention lost an average 5.6 kg

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Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370
1366 Metabolic side effects of antipsychotic medication

and the incidence of diabetes was 39% lower in the treatment of hyperlipidaemia in schizophrenic
lifestyle-intervention group than in the metformin patients receiving risperidone or other SGAs being
group (98). As a consequence the use of metformin metabolised by CYP 3A4, namely clozapine, que-
should be carefully considered as the benefit may be tiapine and ziprasidone (102). One case of prolonged
relatively small in relation to risks of adverse events QTc interval was described in a patient with schizo-
and potential drug interactions (Table 5). phrenia while taking quetiapine and lovastatin for
the treatment of his dyslipidaemia. After reducing
Insulin-sensitiser the lovastatin dose QTc returned to baseline (103).
Pioglitazone exerts its effect through activation of per- In regards to potential adverse reactions with the
oxisome-proliferator activated receptor c (PPARc) novel antipsychotics and concomitant medication,
leading to the reduction of insulin resistance and pro- Spina et al. emphasise that they may be prevented
motion of peripheral glucose uptake. Our preliminary and minimised by careful dosage adjustments based
data proved an antihyperglycaemic effect of pioglita- on close evaluation of clinical response and, possibly,
zone in a group of patients treated with SGAs (99). plasma antipsychotic concentration monitoring
although in general the currently available newer
Lipid profile antipsychotics do not affect the activity of major
Data about therapy of psychotropic drug-induced drug-metabolising enzymes and consequently have
dyslipidaemia are scarce and literature on concomit- minimal effects on the elimination of concomitantly
ant lipid lowering medication is limited to case given medications (104).
reports. In 2002, one case report described severe
cerivastatin-induced rhabdomyolysis in a patient
Conclusion
receiving both risperidone and cerivastatin, which
may be attributable to metabolism of both drugs by Drug-induced weight gain is a serious side effect of
CYP 3A4 (100). Another case report indicates a poss- many commonly used psychotropic drugs leading to
ible drug interaction during simultaneous treatment noncompliance with therapy and to exacerbation of
with simvastatin and risperidone. The patient suf- comorbid conditions related to obesity. It is a prob-
fered from rhabdomyolysis and acute compartment lematic side effect of therapy because of the known
syndrome of the lower extremity, when simvastatin effect of weight gain on glucose control, blood pres-
was added to the antipsychotic therapy (101). sure and lipid levels. Therefore, metabolic distur-
Pravastatin and fluvastatin, which are not predomin- bances induced by psychotropic drugs should be
antly metabolised by CYP 3A4, may be safer in the taken into account when planning the therapeutic

Table 5 Adverse drug reactions of weight reducing drugs

Drug Central nervous system ADRs Other ADRs

Sibutramine Insomnia (10%), dry mouth (17%), headache (30%). Tachycardia and hypertension
Caution in patients with seizures and narrow angle
glaucoma
Orlistat Flatulence, liquid stools, faecal urgency and
incontinence when not combined with
low-fat diet
Topiramate Sedation, confusion and cognitive impairment in > 5%. Nephrolithiasis (1.5%)
Psychosis in 3%, depression possible.
Associated with tinnitus
Amantadine Depression, agitation, delirium psychosis and visual Rash in up to 30%. Associated with livedo
hallucinations reticularis
Nizatidine One case report of subfulminant hepatic
failure
Metformin Risk of lactic acidosis. Consider contraindications
in renal or hepatic impairment
Pioglitazone Headache (9.1%) Upper respiratory tract infection (13.2%), tooth
disorders (5.3%), myalgia (5.4%), peripheral
oedema (4.8%)

Modified from ref. no. (84).

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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 patient has shown an otherwise good response may
when treating patients with schizophrenia because of have significant benefits over switching to an alter-
the early onset of the disease and the requirement of native treatment with which the patient’s response
long-term antipsychotic treatment. Weight gain may and tolerance may be uncertain (108). According to
be prevented by adherence to diet and exercise or consensus recommendations, the use of weight redu-
combination therapy with weight loss inducing drugs cing drugs should only be attempted in patients with
(Table 6). a BMI above 30 kg/m2 and in patients with a BMI
The psychiatrics’ understanding of the side effects above 27 kg/m2 and concomitant hypertension, dysli-
of psychotropic drugs, including their metabolic con- pidaemia, CVD, diabetes or sleep apnoea (109). For
sequences, is essential to avoid a lack of compliance, those with a BMI between 25 and 30 kg/m2 and no
which could eventually lead to discontinuation of the additional risk factors, prevention of further weight
patient’s medication as well as to avoid acute life gain, rather than weight loss should be the main
threatening events (diabetic ketoazidosis, long-term goal. Favourable drugs are topiramate, H2-antago-
risk complications of diabetes and overweight) (105). nists, dopaminergic or serotoninergic agents.
The importance of these metabolic side effects in Additional prospective clinical trials are required
daily medical practice is emphasised in a recent con- to support a specific therapeutic approach for man-
sensus development conference. The various antipsy- aging weight gain. Moreover, psychotropic drug-
chotic substances were divided into groups with mediated alterations of the insulin signalling pathway
different risks for obesity and diabetes (Table 1), focusing on the proximal steps of the pathway
which serves as a basis for patient monitoring should be investigated to provide a basis for future
(Table 2). therapeutical strategies.
As low level diet and exercise programmes seem to
be as beneficial as drug treatment it is suggested that
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2007; 100: 4–22. Paper received September 2006, accepted April 2007

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Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61, 8, 1356–1370