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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.
Table 2 Monitoring protocol for patients during treatment with psychotropic drugs
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
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
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.
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
Table 3 Controlled trials of behavioural interventions in the management of antipsychotic-induced weight gain
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
Table 4 Comparison of different pharmacological interventions in the treatment of antipsychotic-induced weight gain
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).
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
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%)
• 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
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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