Patients with psychiatric disorders have an increased rate of cardiovascular morbidity and mortality compared with the general population. Metabolic issues such as weight gain, dyslipidemia, diabetes mellitus, diabetic ketoacidosis, and pancreatitis have been reported with the use of antipsychotic agents. Although atypical antipsychotics have not been linked directly to the development of metabolic syndrome, these medications have been shown to increase risk factors that can lead to metabolic and endocrine disturbances. Therefore, clinicians should provide ongoing monitoring for patients who are being treated for psychiatric disorders with these agents. According to the 2004 Consensus Report on Antipsychotics, screening measures should include baseline and follow-up monitoring of personal/family histories, weight (body mass index), waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile.

According to the National Comorbidity Study Replication, >25% of people in the United States have some type of mental illness. The prevalence of serious mental illness has been estimated at 6.2%. Patients with severe and persistent mental illness have significantly reduced life expectancy relative to the general population. On average, pooled populations of public sector inpatients and outpatients die 25–30 years earlier than unaffected individuals in the general population, according to recent data from multiple states in the US. Schizophrenia and bipolar disorder together account for ∼23,000 deaths and >20 million life-years of disability worldwide each year. The most common cause of mortality in these individuals is cardiovascular disease (CVD), not, as might be assumed, suicide (Figure 1). Heart disease and stroke are the most common causes of death in patients with serious mental illness, accounting for ∼40% of deaths, underlying the dramatically decreased life expectancy in these patients.

Cardiovascular disease (CVD) remains the number one cause of death in the United States and most developed countries and is expected to remain so for much of this century. Rates of obesity have increased 2–4-fold over the last 2 decades in the US and this condition is linked with early development of hypertension, hyperlipidemia, diabetes, and atherosclerosis. The prevalence of diabetes is also increasing, and the rise of diabetes in young people 18–29 years of age was 40% in the period between 1990 and 2001. The World Heart Federation (WHF) has estimated that CVD will become the number one cause of death in the world by 2020, surpassing infectious disease in developing countries. Metabolic disorders are on the rise in general. However, as highlighted in the discussions presented in this supplement, patients with serious mental illness appear to represent a special population who are particularly vulnerable, with rates that surpass the general population.

Patients with psychiatric disorders have an increased rate of cardiovascular morbidity and mortality compared with the general population. Metabolic issues such as weight gain, dyslipidemia, diabetes mellitus, diabetic ketoacidosis, and pancreatitis have been reported with the use of antipsychotic agents. Although atypical antipsychotics have not been linked directly to the development of metabolic syndrome, these medications have been shown to increase risk factors that can lead to metabolic and endocrine disturbances. Therefore, clinicians should provide ongoing monitoring for patients who are being treated for psychiatric disorders with these agents. According to the 2004 Consensus Report on Antipsychotics, screening measures should include baseline and follow-up monitoring of personal/family histories, weight (body mass index), waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile.

Patients with schizophrenia have a 20% shorter lifespan than people without the disorder. An increased risk of cardiovascular morbidity and mortality is also associated with schizophrenia. Atypical antipsychotics may contribute to the prevalence of cardiovascular disease by causing weight gain and increased adiposity, risk of insulin resistance, hyperglycemia, diabetes, and hyperlipidemia. Atypical antipsychotics that produce the greatest degree of weight gain also appear to impose the greatest risk of diabetes and hyperlipidemia. Recent evidence suggests that atypical antipsychotics may even affect glucose and lipid metabolism independent of weight gain. Among the currently marketed antipsychotics, clozapine and olanzapine appear to produce the greatest degree of weight gain. Moderate increases in weight are also observed with quetiapine and risperidone. Only ziprasidone and aripiprazole appear to be weight neutral. Atypical antipsychotics that produce the greatest degree of weight gain also appear to carry the greatest risk of diabetes and hyperlipidemia. Because of the potential for atypical antipsychotics to cause weight gain and adversely affect glucose and lipid metabolism, clinical monitoring of these parameters is critical. Dietary modification and exercise may be critical to addressing antipsychotic-induced weight gain and its consequences. In patients with persistent weight gain, evaluation of the risks and benefits of ongoing medications and consideration of switching to an antipsychotic with lower weight-gain liability may improve health outcomes.

Ziprasidone is a second-generation antipsychotic that received Food and Drug Administration approval in February 2001. It has a unique receptor profile that includes high-affinity antagonist activity at dopamine D2 receptors, inverse agonist activity at serotonin (5-HT)2A receptors, agonist activity at 5-HT1A receptors, and a relatively high affinity for the serotonin and norepinephrine transporters. The 5-HT1A affinity, together with the inhibitory effect on monoamine reuptake, may underlie the hypothesized beneficial effects on comorbid affective and cognitive abnormalities in schizophrenia and schizoaffective disorder. The short-term efficacy of ziprasidone for core positive symptoms of schizophrenia appears to be comparable to other conventional and atypical antipsychotics. The short-term efficacy of ziprasidone in acute mania has been established based on two 3-week, double-blind, placebo-controlled trials. Open-label treatment for up to 52 weeks confirms the sustained efficacy and safety of ziprasidone in bipolar disorder. Maintenance studies in schizophrenia and schizoaffective disorder indicate that long-term ziprasidone therapy is effective in preventing relapse, while maintaining cognitive and psychosocial benefits. The safety database suggests that the overall cardiovascular and cerebrovascular risk associated with ziprasidone is lower than with other atypicals, with notably lower risk of drug-related increases in weight, glucose, or lipids. The data also suggest a modestly increased risk of QTc prolongation that is not dose related or linked to torsades de pointes. Switching to ziprasidone from other atypicals appears to improve both clinical symptoms and metabolic parameters, though more studies are needed to fully characterize these benefits. This monograph summarizes the efficacy, tolerability, and safety of oral ziprasidone in the treatment of schizophrenia, schizoaffective disorder, and bipolar mania.

Glucocorticoids (GCs), produced by the stress-responsive hypothalamic–pituitary–adrenal axis, are well recognized for their regulatory role in peripheral metabolism. GCs are also known to regulate various brain functions, with well-described effects on human cognition. Increased GC exposure in humans—including exposure to the endogenous GC, cortisol—at levels associated with stress, decreases memory and learning function. These results extend evidence from in vitro studies of synaptic and cell function and evidence from animals indicating the GCs can regulate substrates of memory function. While considerable evidence details these effects in adult humans and animals, relatively less is know about the effect of GCs on cognitive function in children and older adults. Investigators have suggested that children, particularly preschool-aged children, may be vulnerable to adverse consequences of increased GC secretion resulting from stress and neuropsychiatric diseases such as depression. Adverse GC effects on memory substrates and memory function in the adult have also fostered concern that age-related changes, including changes in GC receptors and changes in circulating cortisol levels, could lead to age-related increases in the adverse effect of GCs on brain function. Investigators have reported an association between age-related increases in cortisol levels and age-related memory decline, but this association may or may not be due to a direct effect of cortisol on memory substrates. A number of possible treatment approaches to prevent or remediate adverse GC-induced effects are under development. In general, the use of safe and effective agents for blocking adverse GC effects on brain functions including memory may offer benefits to individuals suffering acute and chronic stressors and could prevent brain changes relevant to stress, aging, and stress-related neuropsychiatric diseases.

Patients developing neuroleptic-induced akathisia have been reported to show higher levels of psychopathology. We sought to replicate this finding and determine its symptom specificity. We confirmed a significant relationship between ratings of akathisia and total score on the Brief Psychiatric Rating Scale (BPRS) during both acute and maintenance neuroleptic treatment. Using stepwise regression models, BPRS anxious-depressive subscale scores were the strongest predictors of akathisia during both treatment conditions. Paranoid subscale scores predicted akathisia only during maintenance treatment. These results suggest that neuroleptic-induced dysphoria largely explains the relationship between akathisia and residual psychopathology during both acute and maintenance neuroleptic treatment.