Excessive body weight gain (BWG) is a common side effect of some typical and 
atypical antipsychotic drugs (APs). Convergent evidence suggests a hierarchy in 
the magnitude of BWG that may be induced by diverse agents, being very high for 
clozapine and olanzapine; high for quetiapine, zotepin, chlorpromazine, and 
thioridazine; moderate for risperidone and sertindole; and low for ziprazidone, 
amisulpiride, haloperidol, fluphenazine, pimozide, and molindone. BWG may be 
related to increased appetite that is due to drug interaction with the brain 
monoaminergic and cholinergic systems and to the metabolic/endocrine effects of 
hyperprolactinemia. Subjects with schizophrenia and bipolar disorders manifested 
a significantly high prevalence of diabetes, even before the introduction of 
atypical APs. However, clozapine and olanzapine appear to display a high 
propensity to induce glucose dysregulation and dyslipidemia. Sudden BWG, insulin 
resistance, increased appetite, and related endocrine changes also may be 
involved in the development of glucose intolerance and dyslipidemia in 
predisposed individuals. Patients should be informed of these side effects in 
order to prevent excessive BWG, and their blood glucose and lipids should be 
monitored before treatment and then at regular intervals. Nutritional advice 
must be given and regular physical exercise recommended. An appropriate 
selection of APs ought to be based on drug efficacy for specific patients and 
assessment of relevant risk factors such as propensity to gain weight; family or 
personal history of diabetes or hyperlipidemia; and elevated fasting serum 
glucose, lipid, or insulin levels. At present, there is no standardized 
pharmacological treatment for AP-induced BWG. Some studies have assessed the 
effects of agents such as amantadine, orlistat, metformin, nizatidine, and 
topiramate on AP-induced BWG. Further studies will provide tools to identify 
patients at high risk for obesity and metabolic abnormalities during AP 
administration. Excessive body weight gain (BWG), glucose intolerance, and 
dyslipidemia during treatment with antipsychotic drugs (APs) were reported in 
the late 1950s [14,101]. However, after 1990, interest in these problems 
increased noticeably, mainly because of the high propensity of some new atypical 
APs to induce these side effects (Fig.1). The APs are currently used in diverse 
mental disorders. Hence, excessive BWG and metabolic dysfunction are not 
exclusive of subjects with schizophrenia. In the case of bipolar disorders, 
AP-induced BWG may be additive to that induced by mood stabilizers [14,48,101]. 
The clinical features [2,14,24,133,139,140] and mechanisms 
[14,34,68,87,93,101,130] of BWG and metabolic dysfunction have been previously 
reviewed. In this article, we focus on a unified theory to explain these side 
effects, based on the interaction of APs with brain neurotransmitters involved 
in appetite regulation. This review comprises the following sections: 1) the 
clinical features of AP-induced BWG; 2) the effects of APs on carbohydrate and 
lipid metabolism in humans and experimental animals; 3) mechanisms involved in 
BWG, glucose, and lipid dysregulation; 4) strategies for prevention and 
treatment of these side effects; and 5) research perspectives in the field. The 
following sources were consulted: MEDLINE, Cochrane database system, and 
PsychINFO. Numerous articles referred to in leading articles also were 
consulted. The literature on this subject has increased so rapidly that it was 
impossible to include all the data recently published. For the first two 
sections, references that illustrate current controversies in the field were 
selected.