CLINICAL HANDBOOK OF SCHIZOPHRENIA

17. Side Effects of Antipsychotics 173and 8%, respectively, of patients enrolled in clinical trials. In contrast, some studies havereported that up to 40% of patients prescribed olanzapine will experience significantweight gain. The actual magnitude of antipsychotic-associated weight gain may be minimizedby weight gain results reported from clinical trials that are usually of short duration.Long-term studies of antipsychotic use have reported that weight gain tends to continuebeyond the common 8- to 12-week duration of clinical trials.A variety of hypotheses exist regarding how antipsychotics produce weight gain.One of the most common relates to the fact that many antipsychotics bind to histaminereceptors. The affinity for histamine receptor subtypes has been reported to correlatewith weight gain. For example, olanzapine has the highest affinity of all the atypicalantipsychotics for the histamine type 1 receptor. Conversely, aripiprazole and ziprasidoneexhibit some of the lowest affinities for similar histamine receptor subtypes. Many atypicalantipsychotics exhibit activity at several serotonin receptor subtypes, including the 5-HT 2C subtype. Weight gain associated with antipsychotics may also be a consequence ofsuch serotonergic activity.There is currently no accurate method to predict which patients will experience substantialantipsychotic-induced weight gain. Thus, patients must be informed of the risk,and behavioral interventions such as diet and exercise counseling should be offered. Inpatients who are already overweight, or who have a predisposition to become overweight,selecting an antipsychotic with a reduced potential to cause weight gain is warranted.Behavioral and lifestyle modifications that include both reduced-calorie diets andincreased physical activity have been reported to help prevent and treat antipsychoticinducedweight gain. In patients who become overweight as a result of an antipsychoticdespite nonpharmacological treatment, switching to an antipsychotic that is weight neutralis also warranted. The use of medications with weight-lowering potential (e.g.,sympathomimetic agents, orlistat, metformin, topiramate, and amantadine) have beenexamined in a limited amount of trials and have been shown generally to have limited efficacyon their own.DyslipidemiaA variety of studies (retrospective database analyses, controlled trials, observational investigations)have reported that individual atypical antipsychotics have differing effectson dyslipidemia. In general, clozapine and olanzapine are the largest potential offendersin terms of worsening a patient’s lipid profile, although increases in weight associatedwith these medications likely play an important role. Results of clinical trials, chart reviews,and health care database analyses suggest that clozapine and olanzapine therapyare associated with increases in triglyceride levels. In a Medi-Cal database that includedover 4,000 cases of schizophrenia and 8,000 matched controls, the risk of hyperlipidemiawas increased with the use of both clozapine and olanzapine, but not risperidone orquetiapine. Additionally, a U.K. database study that included over 18,000 patients withschizophrenia and 7,000 case controls compared rates of hyperlipidemia among antipsychotics.No significant increase in the risk of hyperlipidemia was noted with risperidoneor conventional antipsychotics, but patients treated with olanzapine therapy had a significantlyhigher risk of developing hyperlipidemia compared to controls (odds ratio = 4.65,95% confidence interval = 2.44–8.85). In a retrospective chart review that examined cholesterollevels following initiation of antipsychotics, patients in the olanzapine groupexperienced significant increases from baseline in fasting triglycerides (88.2 mg/dl) andfasting total cholesterol (23.6 mg/dl). These changes were significantly greater than thosefound with risperidone-treated patients.