Evidence-Based Reviews

UPDATE ON ATYPICALS: Practical tips to manage common side effects

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Using these agents to their greatest advantage requires careful clinical monitoring to prevent their potential disadvantages.



Atypical antipsychotics are powerful medications for acute and chronic psychotic disorders, with a similarly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must balance the benefits against the risks.

We often see patients with weight gain, diabetes, dyslipidemia, cardiac toxicity, hyperprolactinemia, and sexual dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips for using clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and preliminary impressions about the newly approved agent, aripiprazole.

Weight gain

Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most older antipsychotics.1 Overweight and obesity are associated with increased risks of hypertension, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and some forms of cancer. Moreover, obesity’s socially stigmatizing effect can discourage patients with schizophrenia—particularly adolescents—from taking their medication.

Table 1


Metabolic changesWeight gainIncreased prolactinQT intervalEPSSedationOrthostasis

Comparative effects. Olanzapine and clozapine are associated with greater weight gain (Table 1)1-3 than risperidone and ziprasidone.4 Data regarding quetiapine are inconsistent—some studies show weight gain similar to that caused by olanzapine, and others find much less.5 Weight gain associated with quetiapine, ziprasidone, and risperidone tends to plateau within the first few months, whereas patients taking olanzapine and clozapine may continue to gain weight for 9 months or more.6

Adolescents and young adults may be particularly susceptible to antipsychotic-induced weight gain.7 No studies have directly compared weight gain in adults versus adolescents, but adolescents are exceedingly susceptible to the atypicals’ metabolic dysregulation. For example:

  • A higher prevalence of extreme weight gain (>7% of baseline body mass) with olanzapine and risperidone has been reported in adolescent inpatients than among adults.7
  • Extreme weight gain was seen in 78% of a group of risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8

These findings suggest that risperidone’s apparent metabolic advantage in adults disappears in children and adolescents. Risperidone’s effect on prolactin may account for a higher risk of weight gain in younger patients. These populations have exquisite end-organ sensitivity to changes in prolactin levels and may be more susceptible to the weight gain—and perhaps diabetes—believed related to hyperprolactinemia.9

Mechanisms. The mechanism(s) of weight gain may be related to the receptor systems upon which the atypicals act. These agents block noradrenergic, dopamine, serotonin, and histamine receptors, all of which are thought to affect metabolism or appetite control. Stimulation of alpha and D2 receptors by sympathomimetic amines causes weight loss, as does stimulation of certain 5HT receptors by weight-loss drugs such as fenfluramine.10 With respect to appetite, it has been suggested that peripheral antagonism of H1 receptors interferes with normal satiety signals.11 This may explain why affinity to histamine H1 receptors is among the best of correlates with potential for weight gain.12

Increases in serum levels of leptin—a peptide hormone produced in direct proportion to adiposity and thought to be anorexigenic, possibly through effects on satiety13 —parallel weight gain during treatment with atypicals. However, there is no indication that leptin imbalance causes weight gain; it may instead be the result. Altered sensitivity to leptin may be a contributing factor, perhaps at the hypothalamus.14


The risk of type 2 diabetes increases with weight gain,15 so it is no surprise that diabetes is more prevalent among patients taking atypicals. In a study of 38,000 schizophrenic patients, those taking atypicals were 9% more likely to have diabetes than those receiving typical antipsychotics,16 and all atypicals were associated with a significant increase in diabetes risk in patients younger than 40. The pervasiveness of diabetes17 and reports of new-onset diabetes in non-overweight patients18 suggest that—in addition to their effect on weight—atypicals may alter insulin and glucose metabolism.19

Atypical antipsychotics probably increase diabetes risk in a number of ways:

  • An increase in adipose tissue can lead to insulin resistance, glucose intolerance, and ultimately diabetes.20
  • Serotonin receptor antagonism may lead to hyperglycemia by decreasing pancreatic beta cell response to signals that advance insulin production.21
  • Atypicals may contribute to hyperglycemia by impeding cellular uptake of glucose.22
  • The increase in free fatty acids associated with atypicals can alter glucose metabolism. This may explain why clozapine and olanzapine—the atypicals with the greatest potential for severe hyperlipidemia—have the strongest association with new-onset diabetes.


Case reports and controlled studies have linked atypical antipsychotics with hyperlipidemia. Whether the hyperlipidemia is a consequence of weight gain or some other metabolic disturbance is unknown. Even without conclusive data, however, the link is of concern because elevated triglyceride levels represent an independent risk factor for heart disease.23


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