Review article

Understanding the new and evolving profile of adverse drug effects in schizophrenia

Weight gain

In the 1990s, variable weight gain liabilities were observed among the novel antipsychotic agents. The authors published a retrospective study of 122 clinical records of 92 outpatients involved in long-term clinical trials that found clozapine therapy was associated with the most weight gain (6.9±0.8 kg) among the novel antipsychotic medications examined (controlling for patient age and treatment duration), followed by olanzapine (6.8±1 kg), risperidone (5±0.6 kg) and the conventional agent

Psychopharmacology of weight gain

Novel antipsychotic medications and conventional antipsychotic medications affect many central neurotransmitter systems that may have an impact on satiety and feeding behavior. Many of the receptor systems blocked by antipsychotic medications are those that are stimulated by medications that promote weight loss. All antipsychotic medications block dopamine D₂ and noradrenergic α₁-receptors, the same sites stimulated by amphetamines and sympathomimetic amine drugs used to promote weight loss.

Abnormalities of glucose metabolism

Weight gain leads to an increased risk for diabetes. In 1998, the authors reported on a possible association between new-onset diabetes and the use of novel antipsychotics [33]. At the time of this report, there were nine published cases of clozapine-associated diabetes. The authors presented six additional new-onset cases. Two of the cases presented were the first published cases of olanzapine-associated diabetes, and the other four were clozapine associated. Five of the six patients had risk

Possible causes of novel antipsychotic–associated diabetes

Weight gain is often, although not always, seen in patients treated with novel antipsyhotics who develop new-onset diabetes [33]. One potential mechanism of diabetes induction is an increase in adiposity, which leads to insulin insensitivity, glucose intolerance, and, if sufficiently severe, diabetes. This notion is supported by a small study by Yazici and associates [41] that found clozapine increased blood glucose, insulin, and C-peptide, suggesting that glucose intolerance was due to

Dyslipidemias

In addition to glucose abnormalities, there have been reports of elevated triglyceride levels among patients treated with novel antipsychotics, particularly clozapine and olanzapine. Many of these reports are retrospective reviews, and confounding factors, such as weight gain, could not be controlled for in the analysis. Nevertheless, results from numerous studies suggest that triglyceride levels do increase significantly in patients being treated with either clozapine or olanzapine. A lack of

Management of weight gain, diabetes, and dyslipidemias

The first step in managing the triad of weight gain, diabetes, and dyslipidemias is to educate patients and families about the potential risks of these medications to cause weight gain and related difficulties. Patients should be asked routinely if they notice weight gain or change in pant size or belt size or if they experience increased urinary frequency or excessive thirst. Obtaining blood chemistries, fasting glucose levels, and lipid panels at baseline and every 3 months thereafter is

Impact of novel antipsychotic medications on Q-T interval

In addition to the potential cardiovascular risks that may result from the novel antipsychotic medications affecting weight, glucose, and lipids, these medications also have effects on cardiac conduction that are of growing importance. All of the novel antipsychotics can cause prolongation of the Q-T segment (reflecting the duration of cardiac repolarization) of the electrocardiogram (ECG). Q-T segment prolongation is of potential clinical concern because it is associated with the potential for

Management of Q-T prolongation risk

Many recommendations for managing the risks of Q-T segment prolongation have been offered in several articles. Fayek and colleagues [95] recommended pretreatment evaluation of all patients by laboratory tests, ECGs and weight, with yearly follow-up of all measures. Laboratory measures (electrolytes including magnesium, measures of kidney and hepatic function, and a lipid panel) are prudent because with underlying cardiac abnormalities (bradycardia and congenital long Q-T syndrome) and treatment

Hyperprolactinemia

Novel antipsychotic medications have varying effects on prolactin. Hyperprolactinemia is a well-known liability of conventional neuroleptics. The pathophysiology involves the removal of tonic dopaminergic inhibition of prolactin secretion via hypothalamic dopamine receptor blockade in the tuberoinfundibular tract [97].

Among the novel antipsychotics, risperidone carries the greatest risk of hyperprolactinemia. In animal experiments, risperidone was shown to be five times more potent than

Management of novel antipsychotic–associated hyperprolactinemia

From a treatment standpoint, the available data do not support routine screening of prolactin for patients taking novel antipsychotic medications. Asymptomatic hyperprolactinemia warrants further monitoring of prolactin levels and for the development of adverse effects but not a change in pharmacotherapy. Patients often do not spontaneously report symptoms such as gynecomastia or menstrual irregularities, however, and clinicians must remember to ask about these potential side effects. Prolactin

Sexual side effects

Sexual side effects (diminished libido, impaired arousal, erectile and orgasmic dysfunction) can arise from treatment with conventional and novel antipsychotics [117], [118], [119]. Hyperprolactinemia arising from dopamine blockade can produce sexual side effects, and the anticholinergic activity and α₁ inhibition of antipsychotics can impair sexual function [120], [121].

Large-scale clinical trials of atypical antipsychotics do not typically query about sexual side effects and may be too brief

Summary

This article has reviewed the emerging side-effect profiles of second-generation antipsychotic medications. Although these medications have favorable extrapyramidal side-effect profiles, clinicians must be aware of their propensity to cause weight gain, glucose and lipid abnormalities, and cardiac and sexual side effects. If clinicians are proactive about warning patients about these side effects and appropriately monitoring them, further morbidity and mortality may be prevented in this patient

Acknowledgements

The author gratefully acknowledges editorial assistance with this manuscript from Dr. Jonathan M. Meyer and manuscript preparation by Shirley J. Mena.