Clinical Management of Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) continues to be an unpredictable and rare, but potentially fatal complication of antipsychotic medications. Presumptively linked to dopamine blockade, it nonetheless occurs in patients receiving newer atypical antipsychotics. The features of NMS, its pathophysiology, differential diagnosis, clinical course, risk factors, and morbidity and motality are reviewed. Nonpharmacologic management centers on aggressive supportive care including vigilant nursing, physical therapy, cooling, rehydration, anticoagulation. Pharmacologic interventions include immediate discontinuation of antipsychotics, judicious use of anticholinergics, and adjunctive benzodiazepines. The utility of specific agents in actively treating NMS is reviewed. Bromocriptine and other dopaminergic drugs and dantrolene sodium have alternatively been considered without merit or efficacious. Guidelines for using these agents are presented. Electroconvulsive therapy, also somewhat controversial, is identified as a second line of treatment. Finally, management of the post-NMS patient is also reviewed.     

The effects of antipsychotic therapy on serum lipids: a comprehensive review

OBJECTIVES: The purpose of this paper is to review the literature since 1970 documenting the effects of antipsychotic agents on serum lipids, including a discussion of possible mechanisms for the observed phenomena, the clinical significance and recommendations for monitoring hyperlipidemia during antipsychotic therapy. RESULTS: High-potency conventional antipsychotics (e.g., haloperidol) and the atypical antipsychotics, ziprasidone, risperidone and aripiprazole, appear to be associated with lower risk of hyperlipidemia. Low-potency conventional antipsychotics (e.g., chlorpormazine, thioridazine) and the atypical antipsychotics, quetiapine, olanzapine and clozapine, are associated with higher risk of hyperlipidemia. Possible hypotheses for lipid dysregulation include weight gain, dietary changes and the development of glucose intolerance. CONCLUSIONS: Given the multiple cardiovascular risk factors seen in patients with schizophrenia, great care must be exercised in the choice of antipsychotic therapy to minimize the medical burden of additional risk imposed by hyperlipidemia. It is recommended that a lipid panel be obtained at baseline in all patients with schizophrenia, annually thereafter for patients on agents associated with lower risk of hyperlipidemia and quarterly in patients on agents associated with higher risk for hyperlipidemia. All patients with persistent dyslipidemia should be referred for lipid-lowering therapy or switched to a less lipid-offending antipsychotic agent.     

Weight gain and increase of body mass index among children and adolescents treated with antipsychotics: a critical review

We performed an updated review of the available literature on weight gain and increase of body mass index (BMI) among children and adolescents treated with antipsychotic medications. A PubMed search was conducted specifying the following MeSH terms: (antipsychotic agents) hedged with (weight gain) or (body mass index). We selected 127 reports, including 71 intervention trials, 42 observational studies and 14 literature reviews. Second-generation antipsychotics (SGAs), in comparison with first-generation antipsychotics, are associated with a greater risk for antipsychotic-induced weight gain although this oversimplification should be clarified by distinguishing across different antipsychotic drugs. Among SGAs, olanzapine appears to cause the most significant weight gain, while ziprasidone seems to cause the least. Antipsychotic-induced BMI increase appears to remain regardless of the specific psychotropic co-treatment. Children and adolescents seem to be at a greater risk than adults for antipsychotic-induced weight gain; and the younger the child, the higher the risk. Genetic or environmental factors related to antipsychotic-induced weight gain among children and adolescents are mostly unknown, although certain genetic factors related to serotonin receptors or hormones such as leptin, adiponectin or melanocortin may be involved. Strategies to reduce this antipsychotic side effect include switching to another antipsychotic drug, lowering the dosage or initiating treatment with metformin or topiramate, as well as non-pharmacological interventions. Future research should avoid some methodological limitations such as not accounting for age- and sex-adjusted BMI (zBMI), small sample size, short period of treatment, great heterogeneity of diagnoses and confounding by indication.     

Metabolic risk during antipsychotic treatment in patients with schizophrenia

Compared with the general population, persons with schizophrenia are characterized with an increased prevalence of obesity, type 2 diabetes mellitus, and cardiovascular disease. Weight gain and increased adiposity is associated with decreases in insulin sensitivity, leading to an increased risk of hyperglycaemia and hyperlipidemia. Antipsychotic drugs can increase adiposity and the range of trials suggests that treatment with antipsychotic medications may be associated with an increased risk of acute (ketoacidosis), subacute (weight gain, glucose intolerance, insulin resistance, dyslipidemia), and chronic (diabetes, hypertension, coronary heart disease) metabolic complications. Conclusions regarding the relative effects of various antipsychotic agents on different components of the metabolic syndrome were reviewed, as well as recommendations for monitoring these effects were noted. Selection and management of the antipsychotic agent reflects a balance between optimizing therapeutic effectiveness, modifying diet and exercise, and avoiding excessive weight gain, dyslipidemia, and insulin resistance.     

Cardiovascular effects of antipsychotics

There is great concern over cardiovascular disease in the schizophrenic population owing to the high incidence of cardiovascular mortality. Increased cardiovascular mortality is related to lifestyle choices (e.g., smoking and sedentary lifestyle) and a high prevalence of comorbid medical conditions, including dyslipidemia, the metabolic syndrome and Type 2 diabetes. One factor that increases cardiovascular risk is the medications used to treat the core features of schizophrenia. Adverse cardiovascular effects of antipsychotic treatment have been recognized for many decades, especially tachycardia, orthostatic hypotension and rare instances of sudden death; but, since 2000, there has been a significant shift in the focus of risk perception. The older antipsychotic literature is replete with papers primarily concerned with the physiological consequences of muscarinic cholinergic antagonism, alpha(1)-adrenergic antagonism or receptors associated with cardiac conduction, but the current literature recognizes that, for most antipsychotic-exposed patients, the more significant cardiovascular burden of treatment is mediated by metabolic adverse effects such as weight gain, dyslipidemia and diabetes mellitus. The purpose of this review is to examine the cardiovascular risks of treatment with antipsychotic medications, elucidating relevant mechanisms and differences between various agents, especially for metabolic adverse effects seen with atypical antipsychotics.     

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.     

The metabolic effects of antipsychotic medications.

OBJECTIVES: To review current evidence for the hypothesis that treatment with antipsychotic medications may be associated with increased risks for weight gain, insulin resistance, hyperglycemia, dyslipidemia, and type 2 diabetes mellitus (T2DM) and to examine the relation of adiposity to medical risk. METHODS: We identified relevant publications through a search of MEDLINE from the years 1975 to 2006, using the following primary search parameters: "diabetes or hyperglycemia or glucose or insulin or lipids" and "antipsychotic." Meeting abstracts and earlier nonindexed articles were also reviewed. We summarized key studies in this emerging literature, including case reports, observational studies, retrospective database analyses, and controlled experimental studies. RESULTS: Treatment with different antipsychotic medications is associated with variable effects on body weight, ranging from modest increases (for example, less than 2 kg) experienced with amisulpride, ziprasidone, and aripiprazole to larger increases during treatment with agents such as olanzapine and clozapine (for example, 4 to 10 kg). Substantial evidence indicates that increases in adiposity are associated with decreases in insulin sensitivity in individuals both with and without psychiatric disease. The effects of increasing adiposity, as well as other effects, may contribute to increases in plasma glucose and lipids observed during treatment with certain antipsychotics. CONCLUSION: Treatment with certain antipsychotic medications is associated with metabolic adverse events that can increase the risk for metabolic syndrome and related conditions such as prediabetes, T2DM, and cardiovascular disease.     

Atypical antipsychotic therapy and hyperlipidemia: a review

Ziprasidone (Geodon), risperidone (Risperdal), and aripiprazole (Abilify) appear to be associated with a relatively low risk for hyperlipidemia, whereas quetiapine (Seroquel), olanzapine (Zyprexa), and clozapine (Clozaril) are associated with a relatively high risk for hyperlipidemia. Possible underlying causes of lipid dysregulation include weight gain, dietary changes, and glucose intolerance. Given the multiple cardiovascular risk factors reported for patients with schizophrenia, great care must be exercised to minimize the additional risk for hyperlipidemia when choosing antipsychotic therapy. It is recommended that a lipid panel be obtained at baseline for all patients with schizophrenia and annually thereafter for patients taking relatively low-risk agents or quarterly thereafter for patients taking relatively high-risk agents. Patients with persistent dyslipidemia should be referred for lipid-lowering therapy or switched to a less lipid-enhancing antipsychotic agent.     

Antipsychotic medications: metabolic and cardiovascular risk

Individuals with serious mental illness experience excess morbidity and mortality, including an increased prevalence of diabetes mellitus and cardiovascular disease. Cardiovascular disease is the leading cause of death in persons with serious mental illness, and the elevated prevalence of obesity in this population is of particular concern. Obesity is an independent cardiometabolic risk factor that impacts morbidity and mortality and contributes to the development of other cardiometabolic risk factors, such as dyslipidemia and hypertension. In addition, obesity is a major risk factor for type 2 diabetes, with the relative risk of diabetes increasing with body mass index. Increased abdominal fat is strongly associated with insulin resistance, which can lead to impaired glucose regulation. Abdominal obesity, hyperglycemia, hypertension, and dyslipidemia are key components of the metabolic syndrome, a constellation of cardiometabolic risk factors linked by their common association with insulin resistance. Evidence from large clinical samples indicates a high prevalence of metabolic syndrome and all of its components in persons with serious mental illness, particularly in patients with schizophrenia. In addition, psychotropic agents, including some antipsychotic medications, are associated with substantial weight gain, as well as with adiposity-dependent and possibly adiposity-independent changes in insulin sensitivity and lipid metabolism, which increase the risk of diabetes and cardiovascular disease. Among the second-generation antipsychotics, clozapine and olanzapine are associated with the highest risk of substantial weight gain, similar to the weight gain potential associated with low-potency first-generation antipsychotics such as thioridazine or chlorpromazine, as well as with an increased risk of diabetes and dyslipidemia. Various strategies for monitoring cardiometabolic risk factors in patients with mental illness are discussed in this review.     

Diabetes mellitus and psychiatric diseases

Metabolic disorders, especially diabetes mellitus, occur more often in patients diagnosed with psychiatric diseases than in the general population. The suggested reasons include common environmental factors, like a lifestyle leading to obesity and insulin resistance, social and economic status. Moreover, these disorders partially share a common genetic background. The influence of antipsychotic therapy itself also plays an important role. An increased risk of metabolic disorders, like glucose dysregulation, dyslipidemia or weight gain, exists during antipsychotic treatment. These drugs influence the hypothalamic regions controlling food intake, impair the insulin release by beta cells or induce insulin resistance. Therefore the choice of antipsychotic drug should be dependent on the actual patient's metabolic status and his comorbidities. Patients treated with antipsychotics should be screened for several metabolic disorders. Periodic checks for abnormalities of body weight, waist circumference, blood glucose or lipid profile are recommended in these patients. Any abnormality noticed during such a check is the indication for antipsychotic treatment modification and adequate metabolic disorder treatment.     

Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia: State-of-the-art and future perspectives

Metabolic disturbances and obesity are major cardiovascular risk factors in patients with schizophrenia, resulting in a higher mortality rate and shorter life expectancy compared with those in the general population. Although schizophrenia and metabolic disturbances may share certain genetic or pathobiological risks, antipsychotics, particularly those of second generation, may further increase the risk of weight gain and metabolic disturbances in patients with schizophrenia. This review included articles on weight gain and metabolic disturbances related to antipsychotics and their mechanisms, monitoring guidelines, and interventions. Nearly all antipsychotics are associated with weight gain, but the degree of the weight gain varies considerably. Although certain neurotransmitter receptor-binding affinities and hormones are correlated with weight gain and specific metabolic abnormalities, the precise mechanisms underlying antipsychotic-induced weight gain and metabolic disturbances remain unclear. Emerging evidence indicates the role of genetic polymorphisms associated with antipsychotic-induced weight gain and antipsychotic-induced metabolic disturbances. Although many guidelines for screening and monitoring antipsychotic-induced metabolic disturbances have been developed, they are not routinely implemented in clinical care. Numerous studies have also investigated strategies for managing antipsychotic-induced metabolic disturbances. Thus, patients and their caregivers must be educated and motivated to pursue a healthier life through smoking cessation and dietary and physical activity programs. If lifestyle intervention fails, switching to another antipsychotic drug with a lower metabolic risk or adding adjunctive medication to mitigate weight gain should be considered. Antipsychotic medications are essential for schizophrenia treatment, hence clinicians should monitor and manage the resulting weight gain and metabolic disturbances.     

When symptoms persist: clozapine augmentation strategies

Recent data and clinical experience confirm that, in spite of superior efficacy for treatment-refractory schizophrenia, a substantial proportion of patients receiving clozapine will continue to experience disabling symptoms. Optimizing clozapine monotherapy is the first step in the management of "clozapine nonresponders." Described here is a synthesis of the available literature on the range and efficacy of clozapine augmentation strategies that may be used when monotherapy fails. Treatment options include adjunctive antipsychotic medications, mood stabilizers, selective serotonin reuptake inhibitors, glycinergic agents, and electroconvulsive therapy. The evidence favoring one augmentation strategy over another is lacking; overall, adjunctive therapy is associated with only modest clinical improvement. Moreover, case series and open-labeled clinical trials dominate the extant literature, and there is a dearth of double-blind trials comparing these augmentation agents. Current systematic efforts to enhance the treatment of these patients with adjunctive therapies are worthy of being studied in carefully conducted clinical trials.     

Weight gain from novel antipsychotic drugs: need for action

Obesity is common in schizophrenia, and people with schizophrenia appear to be at increased risk for certain obesity-related conditions, such as type 2 diabetes and cardiovascular disease. Antipsychotic drugs, used chronically to control symptoms of schizophrenia, are associated with often-substantial weight gain, a side effect that is a special concern with the latest generation of highly effective "novel" agents. That the most effective (e.g., novel) antipsychotic medications lead to substantial weight gain presents the field with a critical public health problem. Although preliminary data have been reported regarding the beneficial use of behavior therapy programs for short-term weight control in patients with schizophrenia, the available data are quite limited, and there are no data regarding the long-term beneficial effects of these programs in this population. The obesity field recently has developed programs emphasizing "lifestyle changes" (e.g., diet, exercise, and problem-solving skills) to successfully manage weight in patients without schizophrenia. Such programs can be adapted for patients with schizophrenia through the use of highly structured and operationalized modules emphasizing medication compliance, social skills development, and participation in outpatient programs. Moreover, these programs can potentially be combined with the use of adjunctive pharmacotherapy to maximize and maintain weight loss. The field must solve the paradox that some of our most effective medications for schizophrenia produce substantial weight gain and its associated troubling health risks.     

Management of Weight Gain Associated with Antipsychotics

The prevalence of overweight and obesity in untreated patients with severe mental illness mimicks the trends seen in the general population. Furthermore, weight gain is likely to occur with the addition of pharmacotherapy with an antipsychotic. The literature does indicate that despite fundamental cognitive and psychosocial deficits seen in patients with severe and persistent mental disorders such as schizophrenia and bipolar disorder, it is possible to effectively manage weight gain in this population. In particular, behavioral interventions have been shown to be effective in the prevention and treatment of weight gain associated with antipsychotic therapy. Some success has also been seen with the use of adjunctive medication such as amantadine, histamine (H₂) antagonists, metformin, topiramate, and orlistat. Additional, prospective, controlled studies of long-term antipsychotic drug associated weight gain and its clinical consequences are needed in order to identify the most effective therapy for the reduction and maintenance of body weight in patients taking antipsychotic therapy.     

Which comes first: atypical antipsychotic treatment or cardiometabolic risk?

Objective: To provide an overview for practicing clinicians on the pharmacological basis of cardiometabolic risk induced by antipsychotic drugs in patients with serious mental illness, to propose hypotheses to explain these risks and to give tips for managing cardiometabolic risk during antipsychotic treatment. Method: A MEDLINE search using terms for atypical antipsychotics (including individual drug names), metabolic, cardiovascular, weight gain and insulin resistance, cross‐referenced with schizophrenia was performed on articles published between 1990 and May 2008. Results: Strong evidence exists for significant cardiometabolic risk differences among several antipsychotic agents. Histamine H1 and serotonin 5HT2C antagonism are associated with risk of weight gain, but receptor targets for dyslipidemia and insulin resistance have not yet been identified. Convincing data indicate that hypertriglyceridemia and insulin resistance may occur in the absence of weight gain with certain antipsychotics. Conclusion: Although lifestyle and genetics may contribute independent risks of cardiometabolic dysfunction in schizophrenia and other serious mental illness, antipsychotic treatment also represents an important contributor to risk of cardiometabolic dysfunction, particularly for certain drugs and for vulnerable patients. Mental health professionals must learn to recognize the clinical signposts indicating antipsychotic‐related cardiometabolic problems to forestall progression to type II diabetes, cardiovascular events and premature death.     

Pharmacologic and nonpharmacologic strategies for weight gain and metabolic disturbance in patients treated with antipsychotic medications.

OBJECTIVES: To provide an overview of pharmacologic and nonpharmacologic strategies for antipsychotic-associated weight gain and metabolic disturbance, to identify important areas for future research, and to make practice recommendations based on current knowledge. METHODS: We undertook a selective review of interventions for weight gain and metabolic disturbance in the general population and in individuals treated with antipsychotic medications, focusing on randomized controlled trials in schizophrenia. RESULTS: Pharmacologic strategies include medication choice, medication dosage and formulation, choice of concomitant psychotropic medications, medication switching, medication addition to effect weight loss or prevent weight gain, and medications to increase insulin sensitivity. Medication choice and medication switching may have the most potent influence on weight and metabolic parameters. Modest short-term weight loss can occur with the addition of selective medications and (or) lifestyle interventions. However, more rigorous and longer-term studies are needed. CONCLUSIONS: Although difficult, the prevention of weight gain and the promotion of weight loss are possible for individuals treated with antipsychotic medications. Further research, including diabetes prevention studies, is required. We suggest a pathway for the management of weight gain and emerging metabolic disturbance.     

Metabolic monitoring for patients treated with antipsychotic medications.

OBJECTIVES: Metabolic side effects of antipsychotic treatment include weight gain, dyslipidemia and increased susceptibility to diabetes. Patients with schizophrenia have increased coronary heart disease mortality and reduced life expectancy. There is an urgent clinical need to monitor antipsychotic-treated patients for metabolic disturbance. Our objectives were to review published international monitoring guidelines, establish goals for metabolic monitoring, and make recommendations for practice. METHOD: We reviewed the major published consensus guidelines for metabolic monitoring of patients treated with antipsychotic medications and selectively reviewed practice guidelines for the management of diabetes, dyslipidemia, and hypertension. RESULTS: Patients with serious mental illness have markedly elevated rates of metabolic disturbance and limited access to general medical care. Monitoring, but not necessarily medical treatment of metabolic disorder, falls within the scope of psychiatric practice and should include screening for metabolic disturbance as well as tracking the effects of antipsychotic treatment. In addition, psychiatrists and psychiatric services should work toward facilitating patients' access to medical care. There is considerable consensus in the published guidelines. Areas of dissent include which patients to monitor, the utility of glucose tolerance testing, and the point at which to consider switching antipsychotics. CONCLUSION: We encourage clinicians to adopt a structured system for conducting and recording metabolic monitoring and to develop collaborations with family physicians, diabetes specialists, dieticians, and recreation therapists to facilitate appropriate medical care for antipsychotic-treated patients.     

Addressing adverse effects of antipsychotic treatment in young patients with schizophrenia

Children and adolescents are at a greater risk than adults for antipsychotic-induced adverse effects such as extrapyramidal symptoms, prolactin elevation, sedation, weight gain, and metabolic effects, which can have long-term health consequences for young patients. Clinicians should complete careful baseline assessments and perform dietary and lifestyle counseling when initiating antipsychotic treatment and then proactively monitor for adverse effects to optimize physical as well as psychiatric outcomes. Strategies to manage adverse effects that occur or worsen during treatment include switching medications, lowering the dosage of medications, and initiating targeted treatments to address clinically relevant changes.     

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.