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

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1 Psychiatr Clin N Am 26 (2003) Understanding the new and evolving profile of adverse drug effects in schizophrenia Donna A. Wirshing, MD*,a,b, Joseph M. Pierre, MD a,b, Stephen M. Erhart, MD a,b, Jennifer A. Boyd, PharmD a,b a Department of Psychiatry, Schizophrenia Treatment Unit, Veterans Administration West Los Angeles Healthcare Center, Wilshire Boulevard, Building 210, Room15, Los Angeles, CA b Department of Psychiatry and Biobehavioral Sciences, University of Los Angeles, Los Angeles, CA The novel antipsychotic medications, or second-generation antipsychotic medications clozapine, olanzapine, quetiapine, risperidone, and ziprasidone have been gaining wide usage throughout the United States since the late 1980s. These medications generally are perceived as effective antipsychotic agents with more favorable extrapyramidal side-effect profiles compared with conventional antipsychotic medications. Despite their efficacy and the lack of extrapyramidal side effects, these medications have their own unique side-effect profiles. The most important side effects that are emerging as the tardive dyskinesia equivalent of the conventional antipsychotic medications are weight gain and metabolic disturbances. Cardiovascular effects and hyperprolactinemia are troublesome issues for some of the members of this class of agents. Weight gain and sexual dysfunction can lead to nonadherence to treatment and ultimately contribute to psychotic relapse. Cardiovascular and metabolic disturbances can lead to long-term health consequences, such as diabetes and coronary artery disease. This article reviews the current state of knowledge about these side effects, monitoring recommendations, and treatment of these medication liabilities. * Corresponding author. address: ames@ucla.edu (D.A. Wirshing) X/03/$ - see front matter, Published by Elsevier Science (USA). All rights reserved. PII: S X ( 0 2 )

2 166 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) 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 ( 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 haloperidol ( kg) [1]. Allison and colleagues [2] comprehensive meta-analysis of 81 clinical trials with data on antipsychotic-induced weight gain echoed this work. These investigators found that the novel antipsychotics clozapine and olanzapine showed weight gain at 10 weeks of therapy (clozapine, 4.45 kg; olanzapine, 4.15 kg), which exceeded that seen with thioridazine (3.19 kg), a conventional agent known for its weight gain liability; lesser gains were seen with risperidone (2.1 kg) and ziprasidone (0.04 kg). Tenweek data were not available to analyze the effect of quetiapine on shortterm weight changes. Long-term data for clozapine-treated and olanzapine-treated patients document weight gain in excess of that seen with risperidone and ziprasidone. Conflicting data exists about long-term weight gain with quetiapine. Average increases reported during the first year are 5.3 to 6.3 kg for clozapine and 6.8 to 11.8 kg for olanzapine, with substantial subgroups gaining more than 20% of their initial body weight [3 5]. Package insert information on olanzapine revealed that more than 50% of patients treated in long-term studies gained greater than 7% of their initial body weight. Although risperidone and quetiapine have more weight gain than that associated with high potency conventional agents, their reported mean weight gains of 2 to 2.3 kg and 2.77 to 5.6 kg over 12 months compare favorably with clozapine, olanzapine, and low-potency typical antipsychotics [6,7]. Long-term data from Canada showed weight gain related to quetiapine therapy of 7.6 kg, much closer to that seen with olanzapine and clozapine [8,9]. Retrospective data published by Reinstein and colleagues [10] found that quetiapine, when added to patients clozapine regimen after clozapine dose reduction, resulted in weight loss. It is difficult to know, however, if coadministration of quetiapine or the dosage reduction of clozapine was responsible for the weight loss observed. Ziprasidone was released in the United States in 2001, and longterm studies are few, but show a mean weight gain of 0.23 kg at 6 months, with 14% of subjects gaining greater than or equal to 7% of their baseline weight at approximately one year [11]. Another reflection of the relative propensity for weight gain of atypical antipsychotic medications is reflected in the manufacturer s package inserts, which must include Food and Drug Administration (FDA) mandated data on the percentage of patients who gained greater than or equal to 7% of their initial body weight during short-term premarketing clinical trials. The reported percentages are as

3 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) follows: olanzapine, 29%; quetiapine, 23%; risperidone, 18%; and ziprasidone, 10% [11 14]. The duration of weight increase varies amongst the antipsychotic medications. Some authors suggest weight gain with olanzapine and clozapine plateaus between 39 and 52 weeks, although patients taking clozapine may continue to gain approximately 4 lbs per year through the fourth year [4,5]. For patients taking ziprasidone, risperidone, or quetiapine, the plateau occurs much earlier, usually within the first few months [7,15,16]. In a retrospective study, the authors noted that patients treated with clozapine and olanzapine had weight gain over longer periods of time compared with patients treated with risperidone and haloperidol [1]. The authors observed that patients gained weight over at least 20 weeks during treatment with clozapine and olanzapine compared with approximately 10 weeks during treatment with risperidone. The literature on weight gain with second-generation antipsychotics indicates that certain groups of patients, such as adolescents, may be particularly susceptible to this problem. In a retrospective study, Theisen and colleagues [17] reported that the prevalence of obesity in adolescent patients was 64% on clozapine (n ¼ 69) and 56% on other atypicals (olanzapine, sulpiride, and risperidone; n ¼ 27) compared with 30% for adolescent patients on conventional antipsychotics (n ¼ 20) and 28% for patients on no medications (n ¼ 25). To understand patient characteristics that may be predictors of weight gain on atypical antipsychotics, several retrospective studies attempted to find correlations between clinical response and weight gain. There are several conflicting reports about the relationship between weight gain and clinical improvement on atypical antipsychotic medications [18 20]. Investigators from Eli Lilly retrospectively analyzed their data set and concluded that patients who were thinnest gained the most weight [21]. The same investigators found a correlation between clinical improvement and weight gain. No relationship between olanzapine dose and weight gain has been established. Based on data from AstraZeneca, no relationship between quetiapine dose and weight gain was found [15]. Prospective research to determine which patient population or patient characteristics increase vulnerability to weight gain must be completed to assist clinicians and consumers in decisions about which medication is best for an individual patient. 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

4 168 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) promote weight loss. All antipsychotic medications block dopamine D 2 and noradrenergic a 1 -receptors, the same sites stimulated by amphetamines and sympathomimetic amine drugs used to promote weight loss. Psychotropic drugs influence serotonin (5HT) and histamine H 1 neurotransmission, both of which have been reported to affect food intake and cause fluctuations in weight. In examining the profiles of antipsychotic agents, the authors observed that the receptor affinity characteristic that most closely correlated with weight gain among novel antipsychotic medications was H 1 [1]. Although H 1 blockade also causes sedation, the mechanism by which H 1 receptor antagonism may increase weight is by peripherally interfering with normal satiety signals from the gut, resulting in overeating [22]. Low-potency conventional agents and novel antipsychotics with higher weight gain potential have substantial affinity for this receptor [23]. The greater weight gain seen with some of the novel antipsychotics also may be an effect of 5HT 2C antagonism. Since the advent of clozapine, novel antipsychotics have been designed primarily to be relatively weak D 2 antagonists and potent antagonists at 5HT 2A receptors, yet these agents also have substantial affinity for the closely related 5HT 2C receptor. Compounds that stimulate 5HT transmission reduce food consumption and cause weight loss (eg, m-chlorphenylpiperazine, fenfluramine, sibutramine), whereas drugs that decrease 5HT transmission increase food intake and are associated with weight gain [24,25]. It is unclear which 5HT receptor type is responsible for stimulating food intake and weight gain [26], but data implicate antagonism of 5HT 2C receptors as a possible site where novel antipsychotics might have an impact on weight [27]. Support for this assertion comes from two types of data. First, appetite-suppressing drugs, such as fenfluramine, are thought to act via 5HT 2C agonism [28]. Second, Tecott and colleagues [27] developed a strain of mice in which the gene coding for the 5HT 2C receptor was knocked out. As these mice aged, they became obese and developed type 2 diabetes mellitus. Although most of the novel antipsychotic medications are 5HT 2C antagonists, the propensity for weight gain best correlates not with the rank order of 5HT 2C antagonism, but rather the potency of histamine H 1 antagonism. Another mechanism by which novel antipsychotics may have an impact on weight is via effects on peptide hormones. Leptin is a hormone produced by adipose tissue that is thought to signal the size of the pool of adiposity to the brain and decrease feeding behavior. In humans, circulating leptin correlates closely with body mass index [29]. Mice and humans deficient in leptin are obese, whereas parenteral administration of exogenous leptin reverses the abnormalities in food intake and weight in leptin-deficient individuals [30]. An early article examining clozapine-treated patients found increases in adipose tissue and circulating levels of leptin [31]. A subsequent study found that leptin was increased in patients treated with clozapine and olanzapine but not patients treated with haloperidol. The investigators

5 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) speculated that the normal hormonal feedback mechanism was impaired in patients taking those novel antipsychotic medications. Patients continue to overeat despite high circulating leptin levels [29]. An 8-week study found significant increases in body weight, serum leptin levels, and percentage of body fat in patients treated with olanzapine but not in the drug-free comparison group [32]. 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 factors for diabetes, as did seven of the nine previously reported in the literature. Four of the six patients and four of the prior cases in which such data were reported experienced substantial weight gain after starting their second-generation antipsychotic medication. Since this publication in 1998, there have been 17 additional case reports of olanzapine-associated diabetes [34]. In all of these cases, the patients were obese, and most had gained weight on olanzapine. All but two of these cases occurred in white individuals, and only three of the patients were female. Henderson and colleagues [4] published a 5-year naturalistic study that showed 36.6% of patients started on clozapine in their clinic were diagnosed with diabetes. The FDA published a report summarizing their Medwatch program, a program in which physicians voluntarily reported 384 cases of diabetes associated with clozapine [35]. Of cases, 242 were new-onset cases; 54 were diabetic exacerbations; and 80 were cases of diabetic ketoacidosis, a potentially life-threatening condition. The average age of the patients in the report was years, and the male-tofemale ratio was 2:1. Diabetes usually occurred within 6 months of starting clozapine. Quetiapine also has been associated with diabetes and ketoacidosis [36,37]. At the time of this writing, there have been three reports of possible risperidone-associated diabetes [34,38]. Larger scale retrospective studies are being done to examine the prevalence of diabetes among patients taking atypical antipsychotics. The authors reviewed the charts of 590 patients taking antipsychotics and found that there were statistically significant shifts in blood glucose among the clozapine-treated and olanzapine-treated patients but not among the risperidone-treated and quetiapine-treated patients [39]. Sernyak and colleagues [40] published a study examining the records of more than 30,000 patients in a Veterans Administration database and found that the prevalence of the diagnosis of diabetes was higher among patients treated with atypical antipsychotics compared with patients treated with conventional agents.

6 170 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) Clozapine, olanzapine, and quetiapine were associated with much higher rates of diabetes than conventional agents for all age ranges, whereas risperidone was not. 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 increased insulin resistance. A randomized trial comparing ziprasidone with olanzapine showed an increase in insulin and measures of insulin resistance among olanzapine-treated patients that was not observed in the ziprasidone-treated group [42]. A similar study still under way is designed to look at insulin production and measures of insulin resistance in patients transitioned from olanzapine to risperidone. Preliminary data suggest that insulin levels decline with this transition [43]. The function of 5HT in glucose regulation is extremely complex, and the literature on this phenomenon is often contradictory [44 46]. It generally is believed that agonism of 5HT 1A receptors lowers blood glucose levels, whereas antagonism leads to a decrease in insulin and to hyperglycemia [44, 45]. In a predisposed subject, this effect might be sufficient to cause diabetes. Several demographic trends were noted among the authors cases of diabetes associated with novel antipsychotics. First, most of the published case reports involve men [33]. The significance of this is unclear but may reflect some hormonal interaction with glucose metabolism [47] or, more likely, selection bias, in which fewer women are placed on novel drugs. Second, 5 of the authors 6 case reports and 11 of the 14 published cases in which the ethnicity of the patient was disclosed involved African Americans [33]. As noted by Popli and coworkers [48], there is a higher prevalence of non insulin-dependent diabetes in African Americans compared with whites in the United States, and this is likely due to nutritional factors and impaired access to health care. In contrast, the preponderance of olanzapine-associated diabetes cases were also white. More prospective work is needed to determine which factors, if any, most likely are related to the risk of developing diabetes in patients treated with second-generation antipsychotics. Another possible cause of diabetes is that medications that increase free fatty acids can alter glucose metabolism [49]. Patients taking clozapine and olanzapine are not only more likely to develop elevations in triglycerides compared with patients on other agents, but also these agents have been associated with more reports of diabetes compared with the other atypicals [39].

7 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) 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 case reports revolving around risperidone and quetiapine suggests that changes in triglycerides occur less frequently with these agents. The mechanism behind elevations in triglycerides is largely unknown. It seems reasonable that these elevations may occur in relation to weight gain. Ghaeli and Dufresne [50] performed a retrospective review of patients taking clozapine versus patients taking typical antipsychotics. This review included 24 men and 15 women taking clozapine and 13 men and 15 women taking typical antipsychotics (primarily high-potency agents). All patients had been taking these agents for at least 1 year. Patient age, gender, concomitant medications, and dose of the antipsychotics were covaried for in the analysis. Patients taking clozapine showed significantly higher triglyceride levels than patients taking typical agents (mean triglyceride level, mg/dl in the clozapine group versus mg/dl in the typical agent group; P < 0.001). A retrospective review by Gaulin and coworkers [51] (117 patients taking clozapine compared with 45 patients taking haloperidol) showed significant increases in triglyceride levels for men and women taking clozapine (a mean increase from mg/dl to mg/dl for the men [P < 0.01] and a mean increase from mg/dl to mg/dl for the women [P < 0.05]). No correlation was found between antipsychotic dose and changes in triglyceride levels. The authors could not determine if the changes in triglycerides were due in part to changes in weight because body weights were not consistently available owing to the retrospective nature of the study. Spivak and colleagues [52] reported on a retrospective study of 70 patients being treated with clozapine for 6 months. They reported a significant increase in triglyceride levels from 69.6 mg/dl before the initiation of clozapine to 77.3 mg/dl 6 months after initiation (P < 0.05). This finding not only suggests clozapine can increase triglyceride levels, but also that it can do so over a relatively short period. Another prospective review of eight clozapine-treated patients showed an 11% increase in triglycerides (P < 0.05) after 12 weeks of therapy with an average dose of 352 mg/d of clozapine and no significant changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol [53]. Sheitman and associates [54] reported a case series of nine patients (seven men and two women) who had been receiving olanzapine (mean dose, 19 mg/d) for an average of 16 months. They reported an increase in triglycerides

8 172 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) from a mean of 170 mg/dl to a mean of 240 mg/dl. In addition, five of the nine patients showed an increase in triglycerides by 50% or more. Osser and colleagues [55] performed a prospective review of 25 patients (21 men and 4 women) who were being started on olanzapine. They measured lipid levels and weights before antipsychotic initiation and 12 weeks thereafter. Overall the patients showed a significant increase in body weight by a mean of 12 lb (P < 0.05) and a significant increase in serum triglycerides from a mean of 162 mg/dl to 222 mg/dl (P < 0.05). In addition, 8 of the 25 patients required pharmacotherapy to lower lipids (gemfibrozil, pravastain, simvastatin) or dietary intervention. They found the change in triglycerides to be highly correlated with the change in weight (P < 0.02). Meyer [56] reported significant hyperlipidemia among patients treated with quetiapine and olanzapine. He also retrospectively compared olanzapine with risperidone and observed greater increases in lipids among the olanzapine-treated patients compared with the risperidone group. Overall, there is little published information regarding elevated triglycerides among patients taking risperidone, quetiapine, or ziprasidone. Most of the available information stems from premarketing clinical drug trials or package insert information. Janssen (Janssen Pharmaceutica, Titusville NJ) reported hypertriglyceridemia as a rare side effect in the package insert for risperidone, stating an incidence of fewer than 1/1000 patients. AstraZeneca reported a 17% increase in triglycerides in patients being treated with quetiapine (from a pool of 3- to 6-week placebo-controlled trials) and an 11% increase in total cholesterol. They suggested that these changes in lipid parameters are weakly related to increases in weight, which seems reasonable given that quetiapine generally is not associated with much change in weight [7]. Pfizer (Pfizer Pharmaceutica, New York NY) reported hyperlipidemia as a rare side effect for ziprasidone, occurring in fewer than 1/1000 patients in premarketing trials. Because this agent is the newest of the atypicals, there is not yet enough postmarketing data available to assess its effects on triglycerides with certainty. The authors group published the first study to compare several secondgeneration antipsychotics (clozapine, risperidone, olanzapine, and quetiapine) with each other and with the typical agents (fluphenazine and haloperidol) in regards to their propensity to affect lipid parameters [39]. This study was a retrospective review of the charts of 590 patients on antipsychotics (clozapine, olanzapine, risperidone, quetiapine, haloperidol, or fluphenazine). Of the patients reviewed, only 215 had adequate laboratory data for inclusion in the study. Lipid data from 2.5 years before and after initiation of the target antipsychotic were included. Covariates, including patient age, the duration of time on an antipsychotic, other medications that could affect lipids, and the initial laboratory values, were controlled for in the analyses. Patients receiving clozapine and olanzapine showed statistically significant increases in triglyceride levels compared with the other groups (triglyceride levels increased >30% for clozapine and olanzapine compared with only

9 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) % for risperidone; patients on haloperidol and fluphenazine developed decreases in triglyceride levels). Patients taking olanzapine, risperidone, and quetiapine also showed statistically significant decreases in LDL values. Although these changes could be presumed beneficial, patients taking clozapine and olanzapine also experienced decreases in HDL, which may offset these positive effects and increase a patient s risk for coronary artery disease [39]. One of the most intriguing findings in the aforementioned study is that all of the novel antipsychotic medications caused clinically significant elevations in triglycerides compared with the conventional agents. The clinical implications of this observation are thought provoking for example, could triglyceride elevation account for the beneficial psychiatric effect of these medications through stabilization of neuronal membranes? Some authors suggested that changes in triglycerides may have an impact on serotonin activity. Diebold and colleagues [57] postulated that elevated triglyceride levels result in increases in brain cell membrane fluidity, which in turn leads to increased presynaptic reuptake of serotonin and decreased postsynaptic serotonin functioning; this may enhance the ability of atypical antipsychotics to inhibit serotoninergic activity and contribute to their mechanism of action [58]. Studies also found correlations between elevations in triglyceride levels and changes in mood. Increases in triglyceride levels were shown to be associated with decreases in hostility [57]. Spivak and coworkers [59] showed that patients taking clozapine who developed increases in triglycerides also showed decreases in aggression and suicidal behavior compared with patients on typical antipsychotics, although the difference was not significant (P ¼ 0.07). Muldoon and associates [60] reviewed numerous randomized clinical trials that focused on reducing lipid levels for primary prevention of coronary artery disease. They concluded that the risk of death from accidents, suicide, or violence was significantly higher in patients who had reduced lipid levels (P ¼ 0.004). Little is known in regards to the mechanism in which antipsychotics cause dyslipidemia. Sheitman and colleagues [54] noted that in their case series of nine patients taking olanzapine, patients experienced an average weight gain of 22 lb. Other studies implied, however, that changes in triglycerides are not completely dependent on changes in body mass index [58]. 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

10 174 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) every 3 months thereafter is prudent during the course of therapy with novel antipsychotics. The development of weight gain, diabetes, and dyslipidemias is consistent with the development of the metabolic syndrome. The metabolic syndrome is defined as abdominal circumference greater than 102 cm in men or greater 88 cm in women, triglycerides greater than or equal to 150 mg/dl, HDL cholesterol less than 40 mg/dl in men or less than 50 mg/dl in women, blood pressure greater than or equal to 130/85 mm Hg, and fasting glucose greater than or equal to 100 mg/dl. The associated risk of coronary artery disease is increased regardless of LDL cholesterol level. When three or more of the components that make up the metabolic syndrome are present, intervention is indicated. First-line therapy includes weight reduction and increased physical activity. Treatment should be directed at reducing blood pressure, lowering triglycerides, and raising HDL cholesterol. The National Cholesterol Education Program recommends weight reduction and increased physical activity for patients with borderline high triglycerides (ie, 150 to 199 mg/dl) and drug therapy for patients with high triglyceride levels (ie, 200 to 499 mg/dl) [61]. The available literature suggests that some novel antipsychotics cause less weight gain than others; it may be possible to switch patients from agents associated with the most weight gain to agents with lower weight gain liability [1,2]. Before switching, however, it is important to remember that the most difficult symptoms to control are those of psychosis. A switch of antipsychotic medication makes sense particularly if the patient is nonresponsive to the antipsychotic effects and having side effects, such as weight gain. As discussed, weight gain can be a significant cause of nonadherence with medication; in cases in which a patient refuses to take medication because of weight gain concerns, a switch is advisable [62 64]. A switch study sponsored by Pfizer showed that subjects switched from olanzapine to ziprasidone lost a statistically significant 2.2 kg on average over 6 weeks [58]. Ghaeli and Dufresne [50,65] reported a case series of four clozapinetreated patients whose triglyceride levels decreased on changing from clozapine to risperidone (over a period of 12 days to 4 months). In addition, on restarting clozapine in two of the patients, triglyceride levels increased to their previous levels within 4 months of rechallenge. Preliminary data from a Janssen-sponsored study suggest improvements in weight and markers of glucose tolerance in patients switched from olanzapine to risperidone [43]. There is no current evidence that medications other than clozapine are extremely effective in treatment-refractory patients; a switch from clozapine could result in an exacerbation or relapse of psychosis. There have been few studies of administering weight loss agents to psychotic patients. The National Institutes of Health guidelines permit the use of weight loss agents for patients with a body mass index greater than or equal to 27 kg/m 2 and obesity-related complications. Weight loss agents also can be administered to patients with body mass index greater than or equal

11 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) to 30 kg/m 2 who do not have obesity-related complications [66]. Amantadine, fenfluramine, and chlorphentermine have been used with moderate success [67,68], although there have been concerns that these drugs could worsen psychotic symptoms, and fenfluramine is no longer available on the market because of complications of cardiac valve dysfunction and pulmonary hypertension. The efficacy of medications that have been approved more recently for weight loss, such as sibutramine and orlistat [69], have not yet been tested in this patient population. Sibutramine is a serotonin and norepinephrine reuptake inhibitor that originally was developed as an antidepressant but instead was approved by the FDA as a treatment for obesity [70 72]. Orlistat is an inhibitor of gastric and pancreatic lipases that decreases dietary fat absorption, resulting in lowering of plasma cholesterol and body weight [69]. Orlistat requires three-times-daily dosing and vitamin supplementation and can be difficult to use from an adherence standpoint. Because it does not have central nervous system effects, however, it may be a safe alternative for psychiatric patients [73]. The new anticonvulsant topiramate has not yet been studied systematically as primarily a weight loss agent, but it has been associated with decreases in appetite and weight loss in patients with epilepsy and bipolar disorders [74 76]. It also is being tested in binge-eating disorder [77]. The use of histamine H 2 antagonists for weight loss has been suggested in the literature, although these agents are not approved for this indication. It has been speculated that H 2 antagonism may affect weight by decreasing appetite via increases in cholecystokinin, a hormone that may signal satiety to the brain, or by suppression of gastric acid secretion, resulting in decreased appetite [78]. Nizatidine was compared with placebo as an adjunct to olanzapine treatment. Modest reductions in weight gain were seen in patients receiving 300 mg of nizatidine compared with placebo; however, weight gain still occurred in these olanzapine-treated patients [79]. Metformin, an oral hypoglycemic agent used for treatment of type 2 diabetes that increases insulin sensitivity in insulin-resistant patients, also may be useful as a weight loss agent [80,81]. Cottingham [82] used metformin (500 mg three times per day) in seven adolescent patients who experienced weight gain on olanzapine or valproate for greater than 3 months and had a weight increase of 10% compared with baseline. The addition of metformin for 4 to 12 weeks with no changes made to food intake or physical activity resulted in statistically significant reductions in weight (P < 0.05) and body mass index (P < 0.02). Although these preliminary results are encouraging, data from prospective, controlled, and adequately powered studies are needed to guide evidence-based clinical practice. 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

12 176 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) 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 syncope and ventricular arrhythmias, including torsades de pointes. To date, there have been no published reports of treatment-emergent arrhythmias in patients receiving novel antipsychotics currently available in the United States with the exception of a case report of ventricular tachycardia in a patient with baseline myocardial ischemia undergoing clozapine titration [83]. Another medication, sertindole, was associated with deaths from cardiac arrhythmias possibly linked with prolongation of the Q-T interval, and was never approved for release in the United States. The awareness of the effect of novel antipsychotics on cardiac conduction was established in a series of preclinical studies of these agents involving animals, although the emergence of ECG changes and cardiac arrhythmias in patients treated by first-generation antipsychotics was already well described. Early experiments measuring the effect risperidone, olanzapine, ziprasidone (and its metabolite, ziprasidone sulfoxide) on mouse atrial tumor cells indicated that all the novel antipsychotics reduced ion flux through delayed rectifier potassium currents, which seem to behave similarly in humans [84]. Membrane channels among Purkinje fibers also have been implicated in animal research involving guinea pigs [85], although this has not been replicated in subsequent animal research [86]. In humans, there is a small and conflicting literature on managing the risk associated with Q-T prolongation. Concern about cardiac liabilities of novel antipsychotics emerged in early case reports of Q-T segment prolongation, followed by several retrospective case series, which coincided with the disapproval of sertindole by the FDA in 1999 and with a request for additional research into ziprasidone in The first large prospective study of ECG changes in 183 patients treated with novel antipsychotics (Study 054) was completed in 2000 by Pfizer, in consultation with the FDA [86]. Although this study may be expected to generate guidelines concerning risk stratification in the future, the clinical significance of Q-T prolongation remains a subject of debate among clinicians and cardiologists [87]. There is no universally acknowledged threshold Q-T segment at which risk of arrhythmias becomes clinically significant. Because most reported cases of torsades de pointes have emerged in individuals with Q-T intervals greater than 500 ms, most but not all studies have adopted the emergence of Q-T intervals greater than 500 ms as a measure of overall risk from medication. Measurement of the Q-T segment is subject to many methodologic considerations. Because Q-T segment duration varies with heart rate, by convention most research employs a corrected Q-T segment (Q-Tc), a mathematical calculation of the Q-T segment that accounts for heart rate. At least 17 methods for applying this correction exist, however, and theoretically may result in

13 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) some research variability, especially because one formula frequently employed (the Bazett correction) may overcorrect for pulse in patients with tachycardia. Additional potential sources of variability among Q-Tc measurements include obesity [88], feeding state, and time of day at measurement [89] and are not typically controlled for in case reports. At the time of this publication, prospective, dedicated studies of the novel antipsychotics on Q-Tc remain limited. One early prospective study of Q-Tc abnormalities [90] included 35 patients treated with risperidone. Although abnormal prolongation of the Q-T segment (defined in this study as segments >456 ms) was observed in four of these patients, the observation was not statistically significant. In 2000, Pfizer in consultation with the FDA sponsored Study 054, an open-label, parallel-group study to assess the effect of oral doses of ziprasidone, olanzapine, risperidone, quetiapine, thioridazine, and haloperidol on the Q-T interval in 183 patients with schizophrenia [86]. In this study, ECGs were performed on patients after a medication washout and repeated after treatment with the agents studied, during dose escalation and at steady state. An additional ECG was obtained after the addition of metabolic inhibitors of each of the medications. Dose ranges corresponded with typical ranges commonly found in outpatient practices. ECGs were timed to coincide with the calculated maximal concentration for each medication. The Q-Tc data are presented using a variety of different correction formulas. In group data, increases in Q-Tc segment duration were observed after the initiation of all the medications sampled, although there were no instances in which Q-Tc was greater than 500 ms. Regardless of the correction formula used, thioridazine was associated with the greatest mean increase in Q-Tc duration. At steady state, increases in Q-Tc ranged from 30 to 40 ms. By contrast, the mean steadystate Q-Tc increase among patients treated with ziprasidone at doses of 160 mg was between 15 and 20 ms, depending on the correction formula, although increases of greater than 75 ms were observed in one patient. The magnitude of Q-Tc increases was not increased by concomitant use of a metabolic inhibitor of ziprasidone metabolism. The Q-Tc prolongation among patients treated with ziprasidone was found to be about 10 ms greater than those of the four other antipsychotics measured (haloperidol, risperidone, quetiapine, and olanzapine). Clinically significant increases of greater than 60 ms were observed in several patients receiving quetiapine and among individual patients receiving risperidone, olanzapine, and haloperidol. The findings that emerged from Study 054 are consistent with other published reports on the effect of novel antipsychotics on ECG, which show no emergence of Q-Tc segments greater than 500 ms and no arrhythmias. A review of pretreatment and posttreatment ECGs from 2700 patients who received olanzapine in preclinical research revealed no increase in the percentage of patients with Q-Tc segments greater than 450 ms between baseline and study conclusion [91]. Several published (and unpublished) case reports also have shown no emergence of arrhythmias in patients who

14 178 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) overdosed with olanzapine at doses of 800 mg [92]. Of patients on quetiapine and ketoconazole in Study 054, 15% experienced a Q-Tc prolongation from baseline greater than 60 ms, which is regarded as a potential threshold for ventricular arrhythmias [47]. Quetiapine was the only novel antipsychotic studied that was associated with an increase in Q-Tc interval after the addition of its metabolic inhibitor compared with Q-Tc at quetiapine steady state (although this was not statistically significant). There have been two published reports of Q-Tc interval prolongation in the setting of quetiapine overdose. The first involved a man who overdosed on 10,000 mg of quetiapine along with an unspecified routine daily dose of fluvoxamine (an inhibitor of CYP 3A4) [66], whereas the second involved a woman who ingested 2000 mg of quetiapine and routine daily doses of other psychotropic medications, including risperidone [93]. The authors group published a case of possible interaction between quetiapine and lovastatin (a medication metabolized by the same pathway), which resulted in an increase in Q-Tc to 569 ms [94]. 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 with other medications that may prolong Q-T interval independently, hypokalemia and hypomagnesemia are risk factors for the development of arrhythmias in patients with prolonged Q-T segments [96]. Fayek and colleagues [95] also recommended discontinuation of the agent if the Q-Tc lengthens by 25% or more after treatment, although this is not a position that has been advanced by other authors. Fayek s recommendation that the choice of antipsychotic be made in consideration of the presence of underlying cardiac disease probably will prove more controversial. In a pro/con discussion of ziprasidone, Keever and Wesley [87] disagreed on the significance of underlying heart disease for the choice of antipsychotic agents. 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

15 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) 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 haloperidol in stimulating prolactin secretion [98]. The propensity of risperidone to induce hyperprolactinemia also was shown in clinical trials. Kleinberg and associates [99] retrospectively reviewed data from the pivotal randomized double-blind comparison studies of risperidone in schizophrenia and found that treatment with risperidone was associated with equivalent or greater levels of hyperprolactinemia compared with treatment with haloperidol in men and women. In these trials, subjects were treated with fixed doses of risperidone ranging from 1 to 16 mg/d, whereas haloperidol was studied at fixed doses of 10 or 20 mg/d. Looking at mean end point prolactin levels for women, moderate hyperprolactinemia was the rule rather than the exception for all of the studied fixed doses of risperidone (serum prolactin, 24 to 60 ng/ml) and haloperidol (serum prolactin, 26 to 44 ng/ml). The rates of hyperprolactinemiaassociated amenorrhea and galactorrhea for women taking risperidone were 8% and 2.4%. For men, risperidone at doses greater or equal to 4 mg/d was associated with mild hyperprolactinemia at study end point (16 to 24 ng/ml), whereas end point prolactin levels were not elevated with haloperidol treatment. Gynecomastia associated with risperidone occurred at a rate of only 0.4% and was no more frequent than with placebo treatment. Other studies found risperidone-associated prolactin elevations two to four fold greater than those associated with neuroleptic treatment. Caracci [100] examined 20 women randomly assigned to treatment with risperidone and found a mean prolactin level of 102 lg/l. This was more than twice the mean prolactin level of subjects treated with conventional antipsychotics (48 lg/l). David and associates [101] reviewed prolactin levels measured during two long-term comparison trials involving risperidone. The mean prolactin level with risperidone treatment increased by 45.4 ng/ml to an end point level of 71.5 ng/ml in the 28-week study, whereas in the 54-week study, mean prolactin increased by 79.8 ng/ml to an end point level of 107 ng/ ml. By comparison, mean prolactin levels during 54 weeks of haloperidol treatment increased by 17.2 ng/ml to an end point level of 42.2 ng/ml. Although hyperprolactinemia with risperidone seems to be dose dependent, it can occur at routine daily doses and in the absence of extrapyramidal symptoms. Kim and associates [102] reported five cases of women with schizophrenia who developed hyperprolactinemia and amenorrhea on risperidone; only one patient was taking more than 4 mg/d. In all five cases, prolactin levels normalized, and menses resumed after discontinuation of risperidone. The other available novel antipsychotic medications do not seem to cause significant prolactin elevation. David and associates [101] examined data

16 180 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) from three comparison trials of olanzapine and revealed that mean baseline prolactin levels increased by only 0.5 to 3.9 ng/ml to 18.7 to 24.1 ng/ml at study end point. In contrast, risperidone and haloperidol treatment were associated with significant prolactin elevations. In their analysis, prolactin levels were unrelated to olanzapine dose (studied at 5 to 20 mg/d). Crawford and coworkers [103] reviewed prolactin data collected from a large multicenter trial comparing olanzapine with placebo and showed a transient dose-related increase in mean prolactin levels for men treated with olanzapine by week 2. Throughout the study and by week 6 end point, however, these mild prolactin elevations with olanzapine did not exceed the threshold for hyperprolactinemia. Women seemed more susceptible to developing hyperprolactinemia on olanzapine, but the number of women studied was small, and some had hyperprolactinemia at baseline. Esel and colleagues [104] compared 29 men with schizophrenia treated with olanzapine, 10 mg/d, or haloperidol, 10 mg/d, after a 2-week drug washout. They found that the mean prolactin level of olanzapine-treated subjects did not increase from baseline to week 6 end point and was not statistically different from baseline prolactin levels in healthy untreated control subjects. Although limited, the available data on clozapine, quetiapine, and ziprasidone also reflect neutral effects on prolactin comparable to treatment with placebo [93, ]. Why these novel antipsychotic medications do not cause prolactin elevation remains unresolved but could be a result of a relative lack of dopamine antagonism in the tuberoinfundibular tract in addition to suppression of prolactin secretion because of serotonin antagonism [97]. Hyperprolactinemia is of clinical importance because uninhibited prolactin release causes hypogonadism (decreased estrogen and testosterone) and can result in galactorrhea, gynecomastia, amenorrhea, anovulation, impaired spermatogenesis, decreased libido and sexual arousal, impotence, and anorgasmia [108]. The loss of the protective effects of estrogen also can increase the risk of cardiac morbidity and osteoporosis in women [108]. Although less well established, hyperprolactinemia may be associated with an increased risk of breast cancer and with mood symptoms, such as anxiety, hostility, and depression [ ]. Hyperprolactinemia is a laboratory finding and is not always associated with clinical symptoms. Kleinberg and coworkers [96] found that although the mean end point prolactin levels at most doses of risperidone were significantly higher than end point prolactin levels on haloperidol, 10 mg/d, no significant differences were found between the frequency of prolactin-related adverse events in the two medication groups. Mean prolactin levels bore no significant relationship to prolactin-related adverse events (amenorrhea, galactorrhea, erectile dysfunction, ejaculatory dysfunction, gynecomastia). The authors noted that although high hyperprolactinemia (>200 ng/ml) almost invariably is associated with adverse effects, minimal-to-moderate hyperprolactinemia (<100 ng/ml) may or may not be symptomatic.

17 D.A. Wirshing et al / Psychiatr Clin N Am 26 (2003) 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 levels should be checked in symptomatic patients, and if hyperprolactinemia is detected, intervention is required. For patients who are not taking conventional antipsychotics or risperidone, a further workup (eg, screening for hypothyroidism or obtaining neuroimaging to rule out a pituitary adenoma) may detect other causes of hyperprolactinemia [111]. Hyperprolactinemia can be managed with the addition of pro-dopaminergic agents, such as amantadine or bromocriptine, but these agents can be difficult to tolerate because of gastrointestinal side effects and have the potential to precipitate or worsen psychosis [112,113]. Antipsychotic-induced hyperprolactinemia should resolve within a few weeks of antipsychotic discontinuation. For patients requiring maintenance antipsychotic therapy, switching to a novel antipsychotic with neutral effects on prolactin can be diagnostic and therapeutic (although with no guarantee of a continued antipsychotic effect). David and colleagues [101] noted that in subjects whose therapy was switched from haloperidol to olanzapine, mean prolactin levels were reduced significantly, resulting in resolution of hyperprolactinemia. Several published case reports noted the resolution of risperidone-induced hyperprolactinemia and its associated adverse effects (amenorrhea, galactorrhea, gynecomastia, sexual side effects) on switching to olanzapine [109, ]. Breier and associates [107] showed that baseline hyperprolactinemia (mean prolactin level, 53.3 ng/ ml) in 14 men and women previously treated with neuroleptics normalized (to 12.2 ng/ml) over 6 weeks of clozapine treatment. One would expect that reversal of neuroleptic-associated or risperidone-associated hyperprolactinemia would occur on switching to quetiapine or ziprasidone as well. Sexual side effects Sexual side effects (diminished libido, impaired arousal, erectile and orgasmic dysfunction) can arise from treatment with conventional and novel antipsychotics [ ]. Hyperprolactinemia arising from dopamine blockade can produce sexual side effects, and the anticholinergic activity and a 1 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 for such side effects to develop or be reported. Endocrine and sexual side effects are prone to underestimation, particularly in women, who often either are excluded from study or are