Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities.

OBJECTIVE: To review published and nonpublished literature describing changes in weight, glucose homeostasis, and lipid milieu with antipsychotics. METHODS: A Medline search was completed using the words weight gain, diabetes mellitus, cholesterol, triglycerides, risperidone, clozapine, olanzapine, quetiapine, ziprasidone, predictors, prolactin, obesity, and conventional antipsychotics. Publications, including original articles, review articles, letters to the editor, abstracts or posters presented at professional meetings in the last 4 years, and references from published articles, were collected. Manufacturers, including Eli Lilly Canada Inc, JanssenOrtho Inc, Pfizer Canada Inc, AstraZeneca Inc, and Novartis Pharmaceuticals, were contacted to retrieve additional medical information. RESULTS: The topic of antipsychotic-induced weight gain is understudied, and there are relatively few well-controlled studies. Weight gain as a side effect has been described with both conventional and atypical antipsychotics. Moreover, some atypical antipsychotics are associated with de novo diabetes mellitus and increased serum triglyceride levels. Predictors of weight gain may be age, baseline body mass index, appetite stimulation, previous antipsychotic exposure, and antipsychotic treatment duration. CONCLUSION: Significant weight gain is reported with the existing atypical antipsychotics. The weight gain described is highly distressing to patients, may reduce treatment adherence, and may increase the relative risk for diabetes mellitus and hypertriglyceridemia. Physicians employing these agents should routinely monitor weight, fasting blood glucose, and lipid profiles.     

Prolactin-related and metabolic adverse effects of atypical antipsychotic agents

While there are many effective antipsychotics available to clinicians for treating schizophrenia or bipolar mania, the onset of antipsychotic-associated prolactin-related and metabolic adverse effects can diminish the effectiveness of treatment. Increased levels of prolactin (hyperprolactinemia) associated with some antipsychotics raises the risk of sexual side effects. The increased appetite and/or sedation (reduced activity levels) induced by other antipsychotics can lead to weight gain, dyslipidemia, and high blood pressure and, if unchecked, ultimately to cardiovascular disease, diabetes, and metabolic syndrome. Clinicians should take steps to help their patients avoid unnecessary risks associated with antipsychotic use. These steps include monitoring risk factors for developing these illnesses by taking careful patient histories and baseline measurements of patients' weight and blood chemistry. Patients should be made aware of potential metabolic and prolactin-related side effects, and periodic checks should also be made to watch for changes in weight, body mass index, waist size, blood pressure, fasting glucose, or lipid levels that could be harmful and may increase risk for cardiovascular disease.     

Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin

BACKGROUND: Many adverse effects of atypical antipsychotic treatment are associated with antagonism of monoamine receptors; however, data indicate that important metabolic effects, such as hypertriglyceridemia and impairment in glucose/insulin homeostasis, may not be related to these mechanisms, leading investigators to explore alternative hypotheses. Promising candidates include a possible impact of antipsychotics on peptide hormonal regulators of metabolic control such as leptin, ghrelin, and adiponectin. The purpose of this review is to summarize recent data on changes in these hormones during atypical antipsychotic treatment. METHODS: A Medline search was performed for papers published from January 1999 to January 2007 using key words antipsychotic, atypical antipsychotic, and individual atypical antipsychotic drug names cross-referenced with leptin, ghrelin, and adiponectin. RESULTS: The bulk of the published work focused on changes in body weight and serum leptin, with far less data on ghrelin, and adiponectin, and nonweight metabolic changes. Leptin changes were directly related to a medication's weight gain liability, with no added antipsychotic effects on leptin signaling. Conflicting results emerged for the other markers, but all three long-term studies on ghrelin showed increased levels in patients on atypical antipsychotics with weight gain liabilities. CONCLUSIONS: Leptin increases during antipsychotic treatment are a result of weight gain rather than a direct impact of atypical antipsychotics on leptin physiology. Preliminary long-term data show increased ghrelin levels, but this finding must be replicated. The association with antipsychotic effects on glucose and lipid metabolism and these hormones remains virtually unstudied. Future research should indicate whether ghrelin and other peptide hormones may be useful predictors of weight gain or metabolic changes in patients on antipsychotics.     

Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents

When taking antipsychotic medications, children and adolescents seem to have a higher risk than adults for experiencing adverse events such as extrapyramidal symptoms, prolactin elevation, sedation, weight gain, and metabolic effects. Side effects may be predicted by the pharmacologic binding profiles of antipsychotics to certain neuroreceptors. Data from 7 recently completed randomized placebo-controlled trials in adolescent schizophrenia and pediatric bipolar disorder that included a total of 1480 patients extend prior results and provide numbers-needed-to-harm as a clinically useful measure of risk. Results from these pediatric studies indicate that adverse effect profiles differ among commonly used antipsychotics. However, more detailed data are needed, as information is lacking regarding carryover or withdrawal effects from prior medications and regarding the masking of effects by adjunctive treatments used to treat agitation, insomnia, or extrapyramidal symptoms and akathisia in these studies. Moreover, randomized head-to-head trials and large-scale studies that investigate predictors of adverse effects as well as the safety and efficacy of interventions aimed at preventing and reversing negative effects of antipsychotics with relevant impact on psychological, psychiatric, and physical functioning are lacking. When choosing an antipsychotic treatment, patients and their families should be included in a careful risk-benefit assessment. Consideration of adverse effects, as well as dietary and lifestyle counseling, should be part of any antipsychotic treatment initiation and continuation. Routine, proactive monitoring of side effects is essential to optimize patient outcomes. In all treatment decisions, the benefits of improving often severe and debilitating manic, psychotic, and aggressive symptomatology must be balanced against the varying risks of adverse effects associated with specific antipsychotic agents in child and adolescent patients.     

Long-term adverse effects of novel antipsychotics

The introduction of novel antipsychotics for the treatment of patients with serious psychiatric illness has alleviated the burden of managing some of the side effects of conventional agents. However, the novel agents may also cause adverse events. The long-term adverse events of concern include weight gain, diabetes, tardive dyskinesia (TD), and those associated with hyperprolactinemia. Recent studies with the novel agents have prompted clinicians to revisit antipsychotic-induced weight gain. Clinically significant weight gain puts patients at risk for coronary heart disease, hypertension, type II diabetes, dyslipidemia, and some types of cancer. More recently, case reports of glucose abnormalities and diabetes have emerged, indicating that some novel antipsychotics may be associated with altered glucose metabolism or insulin sensitivity. The novel antipsychotics may also have a lower propensity for causing TD than the conventional antipsychotics. Side effects associated with hyperprolactinemia include galactorrhea, gynecomastia, and menstrual and sexual dysfunction. All of these adverse events can cause patients to become non-compliant and may thus predispose them to relapse. In this review, the authors summarize the literature on the long-term side effects of the novel antipsychotics and examine the severity of the problem, with recommendations for management. When selecting treatments, clinicians should consider the side-effect profiles of the various antipsychotic agents.     

Metabolic risks and effects of atypical antipsychotic treatment

Weight gain and the associated increased risk of diabetes and cardiovascular disease may be problems for individuals who receive long-term treatment with atypical antipsychotics. Atypical antipsychotics differ in their propensity to cause obesity and other metabolic disturbances. If a patient gains substantial weight while taking atypical antipsychotics, the physician should consider switching him or her to a drug with a lower risk of weight gain. The physician should also address patient lifestyle issues such as a poor diet and lack of exercise.     

Schizophrenia, diabetes mellitus and antipsychotics

During the last years, a contribution of antipsychotic drugs in the increase of diabetes prevalence in schizophrenic population has been repetitively suggested. The debate focused mainly on the second-generation antipsychotics. The analysis of the scientific literature indicates however that this discussion is not recent and an increase of diabetes prevalence in schizophrenic populations was already described before the introduction of neuroleptics. Then, after the introduction of the first neuroleptics in the 1950s, an increase of diabetes prevalence was reported among treated patients and the same alarms occurred in the 1990s after the introduction of second-generation antipsychotics. These treatments were related to an increase of glucose tolerance impairment, type II diabetes and diabetic acidoketosis. Recent epidemiological studies have confirmed the increase prevalence of diabetes in schizophrenic patients, particularly in schizophrenic patients before any antipsychotic treatment. Among the suggested mechanisms, there are sedentary life (due to hospitalisation and sedative effects of neuroleptics), food imbalance, shared genetic factors for diabetes and schizophrenia. Moreover, the frequency of the metabolic syndrome is increased in schizophrenic populations. This syndrome associates blood glucose increase, lipid metabolism disorders and android obesity. This could explain--via an increase of the cortisol production--the increase of mortality due to cardiovascular diseases observed in schizoprhenic patients. Thus, it seems well established that schizophrenia is associated with an increased risk for diabetes. It is however more difficult to evaluate the role of antipsychotic treatment as a causative factor of diabetes. Indeed, there are many published case reports or diabetes or diabetic acidoketosis after an antipsychotic treatment, but the level of evidence in controlled trials is low. Many studies were performed on large databases, but were retrospective and subjected to many flaws: concomitant diseases not taken into account, diabetes status evaluated by drug consumption, unknown diabetes status before antipsychotic treatment, etc. In the few prospective studies performed, no significant differences between the atypical versus typical antipsychotics were evidenced for new cases of diabetes. Moreover, in general population, the glucose tolerance impairment is underdiagnosed and it is estimated that people with a glucose tolerance impairment have a 5-10% annual risk of type II diabetes. Thus, this concern has to be replaced among the world epidemic increase of diabetes and in a population of patients whose the disease itself and life style are risk factors for diabetes. Some studies have explored the pathophysiological mechanisms that could support a diabetogenic effect of antipsychotics. Although it does not seem to be a direct effect of antipsychotics on insulin secretion by pancreatic cells, body weight increase has been evidence for both typical and atypical antipsychotics. However, it remains unclear whether this weight increase is responsible for a visceral adiposity, which is a risk factor better fitted to the cardiovascular mortality tha the body weight itself. Other hypotheses involving an effect on the leptin, which regulates the appetite, have been proposed. In waiting of new prospective controlled studies, and without denying the impact of antipsychotics on the glucose and lipid metabolisms (on the weight increase, for example), it should be recognized that the benefit/risk ratio remains largely in favour of the treatment, particularly for the atypical antipsychotics, more effective and better tolerated at the neurological level than the conventional antipsychotics. One of the benefits of the mainly articles in professional media about this concern is to draw attention on the metabolism disorders in schizophrenic patients, which are important risk factor of their frequent cardiovascular surmortality whatever the causes. Consequently, it is advised to monitor glucose and lipid metabolisms of schizophrenic patients before and during their treatment (body weight, fast blood glucose, blood cholesterol and triglycerides). In conclusion, schizophrenic patients are a population with an increased metabolic risk, which is a cause of their increased mortality. Although these data are known since a long time ago, this population does not benefit from the same metabolic follow-up than the non-schizophrenic population. The debate on the possible relationship between diabetes and antipsychotics should be also taken as a helpful recall of the necessity to follow simple rules of prevention and monitoring in this at-risk population. This should make it possible to preserve the benefit of the antipsychotics, the contribution of which in the treatment of schizophrenia is not any more to demonstrate.     

Use of antipsychotics in the treatment of depressive disorders

Summary： There is a long history of using antipsychotic medications in the treatment of depressive disorders. Atypical antipsychotics, which have fewer side effects than traditional antipsychotics, have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical ant-ipsychotics involves regulation of monoamine, glutamate, gamma-aminobutyric acid （GABA）, cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration （USFDA） has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatment- resistant depression. When using atypical ant-ipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects including extrapyramidal symptoms （EPS）, weight gain, and hyperglycemia.     

Bipolar disorder maintenance treatment: monitoring effectiveness and safety

Bipolar disorder is a chronic illness that requires long-term treatment, the goal of which is to shorten or prevent mood episodes without increasing cycle frequency, thereby increasing the length of well periods. Treatment guidelines recommend mood stabilizers as first-line medications, and several atypical antipsychotics are also approved as monotherapy or as adjuncts to mood stabilizers for maintenance treatment. Combination therapy with 2 mood stabilizers or with a mood stabilizer and an antipsychotic may be necessary to achieve or maintain remission of the patient's symptoms. When treating patients with mood stabilizers and atypical antipsychotics during the maintenance phase, physicians should systematically monitor for adverse effects, particularly weight gain, and tolerability issues, and address those issues in a timely manner in order to enhance treatment adherence and improve patient outcomes.     

Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia

Psychosis occurs commonly in patients with mood disorders and has traditionally been treated with typical antipsychotics. Exposure to typical antipsychotics poses a risk for the emergence of tardive dyskinesia. Atypical antipsychotics may have advantages over typical agents in the treatment of patients with mood disorders complicated by psychotic features. The studies of typical and atypical antipsychotics in the treatment of mood disorders were reviewed. Similarly, studies regarding the risk of tardive dyskinesia from typical and atypical agents in patients with mood disorders were surveyed. Typical and atypical antipsychotics appear to be comparably effective in the treatment of acute mania. Limited data regarding these medications in psychotic depression are available. Advantages of atypical antipsychotics include, for most agents, minimal extrapyramidal and prolactin effects, inherent thymoleptic activity, and lower rates of tardive dyskinesia. Atypical antipsychotics appear to have a number of advantages over typical agents in the treatment of patients with psychotic mood disorders.