Conference report: Belgian consensus on metabolic problems associated with atypical antipsychotics

BACKGROUND: The current literature supports that schizophrenia (and bipolar disorders) appear to be associated with a higher prevalence of type 2 diabetes. Because of the silent nature of diabetes mellitus, and the fact that schizophrenic patients are not screened comprehensively for the disease, the true prevalence of hyperglycemia and diabetes may be substantially underestimated. Notably, it has been suggested that schizophrenia as such carries an increased risk, as certain characteristics of schizophrenic patients such as unhealthy life style promote the diabetes risk. LITERATURE FINDINGS: This risk may be increased by antipsychotic drug treatment, as was already suggested for first-generation antipsychotics (FGA). The amount of literature on the association of SGA and metabolic disorders is much larger however, although well-controlled prospective data are sparse. Reports comprise abnormal glucose regulation, exacerbation of existing type 1 and 2 diabetes, new-onset pseudo-type 1 or type 2 diabetes, diabetic ketoacidosis, coma and death. In large-scale studies (mostly retrospective), reviews and meta-analyses, the association was not found for all drugs. NEW DATA: According to recent reviews, the risk of developing diabetes was highest for clozapine and olanzapine, followed by quetiapine and risperidone. The hierarchy of liability of weight gain, or differential effects on insulin resistance was also in the described order. Apart from disturbances in glucose metabolism, further frequent metabolic abnormalities in schizophrenic patients on SGA include features of the metabolic syndrome. Antipsychotics such as clozapine and olanzapine have also been associated with hypertriglyceridemia, while agents such as haloperidol, risperidone and ziprasidone were associated with reductions in plasma triglycerides. Amisulpride, aripiprazole and ziprasidone seem to carry the lowest risk for weight gain, diabetes and effects on insulin resistance. CONCLUSION: As a consequence, there is a shift in attention toward physical health monitoring in patients with mental health disorders. The APA and ADA as well a British working group have recently published the findings on SGA and metabolic abnormalities in a joint statement (table I).     

Metabolic side effects of antipsychotics: focus on hyperglycemia and diabetes

Approximately 16 million people in the United States have diabetes, and the World Health Organization has estimated that the worldwide prevalence of diabetes will more than double from 1995 to 2025. Type 2 diabetes, the most common form of diabetes, may be 2 to 4 times more prevalent in patients with severe mental disorders. Within the psychiatric community, there is a great deal of concern about diabetes as a potential side effect of antipsychotic agents. An important population to remember in the context of treatment-emergent hyperglycemia is the 20 million people with impaired glucose tolerance (IGT) (fasting plasma glucose > 110 mg/dL and < 126 mg/dL or 2-hour postload glucose > 140 mg/dL and < 200 mg/dL according to the American Diabetes Association). This prediabetic condition has a 5% to 10% annual risk of converting to diabetes. One hypothesis for antipsychotic treatment-emergent diabetes during double-blind, randomized, controlled trials is that people who develop diabetes soon after the initiation of drug therapy for schizophrenia may have had undiagnosed IGT or diabetes before they started treatment. The emergence of diabetes in clinical practice may be due to an observation effect, but because the incidence of diabetes is greater in people with severe mental illnesses, it is crucial for psychiatrists to be aware of national guidelines for the diagnosis and treatment of type 2 diabetes.     

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.     

Unmet treatment needs in schizophrenia patients: is asenapine a potential therapeutic option?

Adverse metabolic events, such as increased adiposity, hyperglycemia, diabetes mellitus and dyslipidemia, have been associated with treatment using atypical antipsychotic medications. However, the complexity of some of the reports on this problem and marketing efforts in this area may make it difficult for psychiatrists to remain fully and accurately informed about the metabolic complications of atypical antipsychotic therapy. Little is currently known about how psychiatrists view what they have read or heard, how they perceive the available information and how this affects their management of patients with schizophrenia. A number of studies have demonstrated that nonadherence to the medication regimen in schizophrenia is associated with poor symptomatic outcome, increased risk of relapse, more frequent use of compulsory treatment and increased risk of suicide and severe self-harm. Suicide is a major cause of death among schizophrenic patients, and their attitude toward medication can make the difference between a proper therapeutic regimen that protects patients from suicide risk versus discontinuation of treatments that are associated with disabling symptoms, some of which are risk factors for suicide. We review the characteristics of a new drug, asenapine, that may improve adherence in patients as a result of a distinctive receptor profile that may be associated with fewer side effects than other second-generation antipsychotic drugs.     

Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms,management and research perspectives

Excessive body weight gain (BWG) is a common side effect of some typical and atypical antipsychotic drugs (APs). Convergent evidence suggests a hierarchy in the magnitude of BWG that may be induced by diverse agents, being very high for clozapine and olanzapine; high for quetiapine, zotepin, chlorpromazine, and thioridazine; moderate for risperidone and sertindole; and low for ziprazidone, amisulpiride, haloperidol, fluphenazine, pimozide, and molindone. BWG may be related to increased appetite that is due to drug interaction with the brain monoaminergic and cholinergic systems and to the metabolic/endocrine effects of hyperprolactinemia. Subjects with schizophrenia and bipolar disorders manifested a significantly high prevalence of diabetes, even before the introduction of atypical APs. However, clozapine and olanzapine appear to display a high propensity to induce glucose dysregulation and dyslipidemia. Sudden BWG, insulin resistance, increased appetite, and related endocrine changes also may be involved in the development of glucose intolerance and dyslipidemia in predisposed individuals. Patients should be informed of these side effects in order to prevent excessive BWG, and their blood glucose and lipids should be monitored before treatment and then at regular intervals. Nutritional advice must be given and regular physical exercise recommended. An appropriate selection of APs ought to be based on drug efficacy for specific patients and assessment of relevant risk factors such as propensity to gain weight; family or personal history of diabetes or hyperlipidemia; and elevated fasting serum glucose, lipid, or insulin levels. At present, there is no standardized pharmacological treatment for AP-induced BWG. Some studies have assessed the effects of agents such as amantadine, orlistat, metformin, nizatidine, and topiramate on AP-induced BWG. Further studies will provide tools to identify patients at high risk for obesity and metabolic abnormalities during AP administration. Excessive body weight gain (BWG), glucose intolerance, and dyslipidemia during treatment with antipsychotic drugs (APs) were reported in the late 1950s [14,101]. However, after 1990, interest in these problems increased noticeably, mainly because of the high propensity of some new atypical APs to induce these side effects (Fig.1). The APs are currently used in diverse mental disorders. Hence, excessive BWG and metabolic dysfunction are not exclusive of subjects with schizophrenia. In the case of bipolar disorders, AP-induced BWG may be additive to that induced by mood stabilizers [14,48,101]. The clinical features [2,14,24,133,139,140] and mechanisms [14,34,68,87,93,101,130] of BWG and metabolic dysfunction have been previously reviewed. In this article, we focus on a unified theory to explain these side effects, based on the interaction of APs with brain neurotransmitters involved in appetite regulation. This review comprises the following sections: 1) the clinical features of AP-induced BWG; 2) the effects of APs on carbohydrate and lipid metabolism in humans and experimental animals; 3) mechanisms involved in BWG, glucose, and lipid dysregulation; 4) strategies for prevention and treatment of these side effects; and 5) research perspectives in the field. The following sources were consulted: MEDLINE, Cochrane database system, and PsychINFO. Numerous articles referred to in leading articles also were consulted. The literature on this subject has increased so rapidly that it was impossible to include all the data recently published. For the first two sections, references that illustrate current controversies in the field were selected.     

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.     

Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine

Treatment of schizophrenics with some antipsychotic drugs has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. Some of these drugs also inhibit glucose transport in rat pheochromocytoma (PC12) cells. The current study was designed to examine the effects of the atypical antipsychotic drugs--risperidone, clozapine and analogs of clozapine on glucose uptake in PC12 cells. Glucose transport was measured in cells incubated with vehicle or drug over a range of concentrations (0.2-100 microM). Uptake of 3H-2-deoxyglucose was measured over 5 min and the data were normalized on the basis of total cell protein. Risperidone and clozapine inhibited glucose transport in a dose-dependent fashion with IC(50)'s estimated to be 35 and 20 microM, respectively. The clozapine metabolite, desmethylclozapine, was considerably more potent than the parent drug, whereas clozapine N-oxide was essentially inactive. The structural analogs of clozapine, loxapine and amoxapine, both inhibited glucose transport with amoxapine being the least potent. The ability of the drugs to inhibit glucose transport was significantly decreased by including 2-deoxyglucose (5 mM) in the uptake medium. Schild analysis of the glucose sensitivity of clozapine, loxapine and risperidone indicated that 2-deoxyglucose non-competitively antagonized the inhibitory effects of these drugs. Moreover, clozapine and fluphenazine inhibited glucose transport in the rat muscle cell line, L6. These studies suggest that the drugs may block glucose accumulation directly at the level of the glucose transporter (GLUT) protein in cells derived from both peripheral and brain tissue. Furthermore, this work may provide clues about how the antipsychotic drugs produce hyperglycemia in vivo.     

Diabetes mellitus type II--induced by "atypical" neuroleptics?

After the introduction of the so-called "atypical antipsychotics" in the clinical practice hyperglycemia as well as increased triglyceride and cholesterol serum levels were reported in patients treated with some of these agents. The studies and case reports available up to now were reviewed. Some epidemiologic studies show that diabetes mellitus occurs more often in patients treated with atypical antipsychotics if compared to conventional antipsychotics. The available data show that hyperglycemia and diabetes mellitus type II were particularly observed in patients receiving clozapine and olanzapine. Also diabetic ketoacidosis was most frequently reported in patients treated with these drugs. The underlying pathomechanism still remains widely unclear. There is some evidence for an important role of insulin and also leptin. Their secretion seems to be influenced by some atypical antipsychotics. Since overweight is a known risk-factor for diabetes mellitus type II, the weight inducing effect of atypical antipsychotics may also play an important role. Since diabetes mellitus type II often lead to severe diseases, the serum glucose levels should be paid more attention in the treatment with atypical neuroleptics.     

抗精神病药物对首发精神分裂症患者糖脂代谢和体重的影响

目的比较抗精神病药物对首发精神分裂症患者血糖、血脂及体重的影响,评价不同药物的安全性。方法对门诊／住院首发精神分裂症患者作为期一年药物治疗的随访观察,比较单一使用非典型抗精神病药（维思通、喹硫平、阿立哌唑）和典型抗精神病药（氯丙嗪）患者的空腹血糖、体重指数（BMI）、血脂的变化。结果完成一年随访患者179例,其中出现空腹血糖超标22例（12．3％）,确诊糖尿病1例;新增高甘油三脂48例（26．8％）、高胆固醇31例（17．3％）;单因素相关分析显示,血糖超标与体重指数、年龄、病程及高甘油三脂呈显著性相关,而与用药选择无显著性相关;各组药物对糖脂代谢均有影响,阿立哌唑对精神分裂症患者的体重、血糖、血脂影响最小;Logistic回归分析结果显示体重指数增加、病程长是血糖超标的危险因素。结论抗精神病药物对精神分裂症患者糖脂代谢、体重增加等方面均有不同程度的影响,应预测性评估、定期监测和提早干预。     

Current status of the Matson Evaluation of Drug Side Effects (MEDS)

The Matson Evaluation of Drug Side Effects (MEDS) is currently the best established and most researched measure of drug side effects in the intellectual disability (ID) literature. Initial research was conducted on its psychometric properties such as reliability and validity. More recent research studies have used the measure to determine the interactive effects of severity of drug side effects on adaptive and social behaviors as well as symptoms of commonly medicated psychiatric conditions among persons with ID. Most recently the MEDS has been used to study potential risk factors of psychotropic drugs. The present study was written to review the current status of MEDS research in the broader context of psychotropic drug side effect research in general.