Current p SYCHIATRY UPDATE ON ATYPICALS Practical tips to manage common side effects Using these agents to their greatest advantage requires careful clinical monitoring to prevent their potential disadvantages. typical antipsychotics are powerful medications for Donna A. Wirshing, MD A acute and chronic psychotic disorders, with a simi- Associate professor in residence larly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must bal- Itai Danovitch, BA ance the benefits against the risks. Medical student We often see patients with weight gain, diabetes, dys- Stephen M. Erhart, MD lipidemia, cardiac toxicity, hyperprolactinemia, and sexual Lecturer dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips Joseph M. Pierre, MD for using clozapine, olanzapine, quetiapine, risperidone, Assistant clinical professor and ziprasidone, and preliminary impressions about the William C. Wirshing, MD newly approved agent, aripiprazole. Professor of clinical psychiatry Department of psychiatry and biobehavioral sciences Weight gain The David Geffen School of Medicine at UCLA Clinical trials have shown convincingly that atypical Department of psychiatry antipsychotics pose a greater risk of weight gain and central VA Greater Los Angeles Healthcare System adiposity than do most older antipsychotics.1 Overweight VOL. 2, NO. 3 / MARCH 2003 49 Atypical antipsychotics Table 1 POTENTIAL FOR ADVERSE EFFECTS WITH ATYPICAL ANTIPSYCHOTICS Metabolic Weight Increased QT changes gain prolactin interval EPS Sedation Orthostasis Risperidone + + +++ + ++ + ++ Ziprasidone ++ – +++++ Clozapine +++ +++ – ++ +/- +++ +++ Olanzapine +++ +++ – + + ++ + Quetiapine ++ ++ – ++ + ++ ++ Aripiprazole ++ – + ++/-+/- and obesity are associated with increased risks of hyperten- for a higher risk of weight gain in younger patients. These sion, type 2 diabetes, coronary heart disease, stroke, gall- populations have exquisite end-organ sensitivity to changes bladder disease, osteoarthritis, and some forms of cancer. in prolactin levels and may be more susceptible to the weight Moreover, obesity’s socially stigmatizing effect can discour- gain—and perhaps diabetes—believed related to hyperpro- age patients with schizophrenia—particularly adolescents— lactinemia.9 from taking their medication. Mechanisms. The mechanism(s) of weight gain may be Comparative effects. Olanzapine and clozapine are associ- related to the receptor systems upon which the atypicals act. ated with greater weight gain (Table 1)1-3 than risperidone These agents block noradrenergic, dopamine, serotonin, and and ziprasidone.4 Data regarding quetiapine are inconsis- histamine receptors, all of which are thought to affect metab- tent—some studies show weight gain similar to that caused olism or appetite control. Stimulation of alpha and D2 by olanzapine, and others find much less.5 Weight gain asso- receptors by sympathomimetic amines causes weight loss, as ciated with quetiapine, ziprasidone, and risperidone tends to does stimulation of certain 5HT receptors by weight-loss plateau within the first few months, whereas patients taking drugs such as fenfluramine.10 With respect to appetite, it has olanzapine and clozapine may continue to gain weight for 9 been suggested that peripheral antagonism of H1 receptors months or more.6 interferes with normal satiety signals.11 This may explain Adolescents and young adults may be particularly sus- why affinity to histamine H1 receptors is among the best of ceptible to antipsychotic-induced weight gain.7 No studies correlates with potential for weight gain.12 have directly compared weight gain in adults versus adoles- Increases in serum levels of leptin—a peptide hormone cents, but adolescents are exceedingly susceptible to the produced in direct proportion to adiposity and thought to be atypicals’ metabolic dysregulation. For example: anorexigenic, possibly through effects on satiety13—parallel • A higher prevalence of extreme weight gain (>7% of base- weight gain during treatment with atypicals. However, there line body mass) with olanzapine and risperidone has been is no indication that leptin imbalance causes weight gain; it reported in adolescent inpatients than among adults.7 may instead be the result. Altered sensitivity to leptin may be • Extreme weight gain was seen in 78% of a group of a contributing factor, perhaps at the hypothalamus.14 risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8 Diabetes These findings suggest that risperidone’s apparent The risk of type 2 diabetes increases with weight gain,15 so it metabolic advantage in adults disappears in children and is no surprise that diabetes is more prevalent among patients adolescents. Risperidone’s effect on prolactin may account taking atypicals. In a study of 38,000 schizophrenic patients, continued on page 53 50 Current VOL. 2, NO. 3 / MARCH 2003 p SYCHIATRY Current p SYCHIATRY continued from page 50 those taking atypicals were 9% more likely to Table 2 have diabetes than those receiving typical RECOMMENDED METABOLIC MONITORING antipsychotics,16 and all atypicals were associ- OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS ated with a significant increase in diabetes risk in patients younger than 40. The pervasive- Every visit Check weight ness of diabetes17 and reports of new-onset dia- Check blood pressure betes in non-overweight patients18 suggest Every 3 months Fasting blood glucose that—in addition to their effect on weight— Fasting triglycerides atypicals may alter insulin and glucose Fasting cholesterol metabolism.19 Atypical antipsychotics probably increase diabetes risk in a number of ways: • An increase in adipose tissue can lead to insulin resis- tress.25 Increased triglycerides have been theorized to tance, glucose intolerance, and ultimately diabetes.20 enhance membrane fluidity, which in turn may augment • Serotonin receptor antagonism may lead to hyper- presynaptic reuptake of serotonin and diminish postsynaptic glycemia by decreasing pancreatic beta cell response to serotonin activity.26 In other words, elevated triglyceride signals that advance insulin production.21 levels could play a role in atypical antipsychotic-mediated • Atypicals may contribute to hyperglycemia by imped- inhibition of serotonin transmission. It is not yet known ing cellular uptake of glucose.22 whether lipid-lowering drugs might alter atypicals’ efficacy. • The increase in free fatty acids associated with atypi- cals can alter glucose metabolism. This may explain Metabolic monitoring why clozapine and olanzapine—the atypicals with the Managing mental illness concurrently with weight gain, dia- greatest potential for betes, and hypertriglyceridemia is a challenge. In our severe hyperlipidemia— clinic, we try to diminish the atypicals’ have the strongest association adverse metabolic effects by monitoring a with new-onset diabetes. Never sacrifice few basic parameters and taking preventive antipsychotic efficacy measures (Table 2). Hyperlipidemia in pursuit of a We routinely screen patients for dia- Case reports and controlled studies have betes symptoms by asking questions about regimen with more linked atypical antipsychotics with hyperlipi- changes in belt size (a sign of weight demia. Whether the hyperlipidemia is a con- benign side effects change), urinary frequency, and thirst sequence of weight gain or some other meta- (Table 3). We also document baseline bolic disturbance is unknown. Even without weight, blood glucose (Table 4), blood conclusive data, however, the link is of con- chemistry, and lipid levels, with routine follow-up cern because elevated triglyceride levels throughout therapy and greatest scrutiny during the first represent an independent risk factor for months of a new treatment. heart disease.23 Patients who cannot control their weight with lifestyle Although all atypicals increase serum triglycerides to modifications (Table 5) may require a lipid-lowering med- some degree, severe hypertriglyceridemia occurs predomi- ication—a “statin” and/or fibrate (such as gemfibrozil)—or, nantly with clozapine and olanzapine.24 Both drugs have if those measures are ineffective, a switch to another antipsy- favorable efficacy profiles, and the mechanism of their chotic. Hyperlipidemia and hyperglycemia may be reduced antipsychotic activity may include altering the various substantially when patients discontinue the aggravating lipid pools. medication.27 For example, studies have found that decreased triglyc- Although discontinuing or switching medications may eride levels correlate with hostility and psychological dis- reduce metabolic side effects, the hazard of psychotic VOL. 2, NO. 3 / MARCH 2003 53 Atypical antipsychotics 28 Table 3 QTc. If QTc is prolonged beyond a certain threshold, 5 SCREENING QUESTIONS TO MONITOR repolarization can occur simultaneously with early FOR METABOLIC AND SEXUAL SIDE EFFECTS depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can 1. Has your weight changed? degenerate into ventricular tachycardia, fibrillation, 2. Has your belt or pants size changed? and even death. All the atypicals are thought to prolong QT inter- 3. Are you constantly thirsty? vals to some degree by reducing the flow of repolariz- 4. Do you urinate frequently? ing K+ currents, ultimately making the myocardium 5. Are you having problems with sexual interest or more excitable.29 Although
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