With the introduction of conventional antipsychotics in the 1950s, clinicians began to expect effective treatment of positive symptoms of schizophrenia. However, these drugs do not resolve negative and cognitive symptoms of schizophrenia and are also associated with serious side effects, including extrapyramidal side effects (EPS) and tardive dyskinesia. In 1989, clozapine was introduced and labeled the first new antipsychotic owing to its improved efficacy and side-effect profile. Clozapine proved effective in alleviating many of the positive, negative, and cognitive symptoms of schizophrenia, without causing inevitable EPS or tardive dyskinesia. Over the past decade, a number of different new antipsychotics have been developed. These drugs have an affinity for multiple dopamine-receptor subtypes as well as serotonin, norepinephrine, and glutamate receptors, allowing for better treatment outcomes. The antagonism of the 5-HT2A receptor may be responsible for improvement in negative symptoms and decrease in EPS. In addition to providing enhanced efficacy, the affinity of the new drugs for multiple receptors introduces new side effects not seen with the conventional agents, including weight gain. Each new antipsychotic has a unique receptor-binding profile that corresponds to its pharmacologic and side-effect profile. Understanding the differences in mechanisms of action of new antipsychotics will allow physicians to better choose treatment that meets the needs of each individual patient.

In treating and managing acute psychosis in patients with schizophrenia, early intervention may be valuable. The need to quickly control severe symptoms, however, must be balanced with a treatment algorithm that is both safe and effective. The present management of acute psychotic agitation varies among clinicians. Key treatment goals have been to calm the agitated, assaultive, violent, or disruptive patient, minimize the danger to self and others, and achieve a smooth transition from intramuscular to oral maintenance. For many years, intramuscular treatment with benzodiazepines and/or conventional antipsychotics, such as haloperidol, has been the mainstay of treatment for acute psychosis. Unfortunately, the poor tolerability of conventional antipsychotics compromises their usefulness for both short- and long-term treatment. Although new antipsychotics have a more favorable side-effect profile, the transition from an intramuscular formulation has been problematic. Fortunately, the development of intramuscular formulations of olanzapine and ziprasidone offer new treatment options for patients experiencing acute psychotic episodes. This article will review the use of intramuscular agents, standard antipsychotics, and new antipsychotics in the emergency room setting. The strengths and limitations of each will be discussed.

From the perspective of efficacy, the main advantages of the group of new antipsychotic drugs, including ziprasidone, clozapine, quetiapine, olanzapine, and risperidone, are their ability to improve cognitive function. Other advantages are more selective, eg, clozapine in treatment-resistant schizophrenia, while the advantages for positive and negative symptoms in neuroleptic responsive patients are modest and sometimes difficult to demonstrate. The advantage for cognitive function is important because of abundant evidence that cognitive function is a key predictor of work and social function acquisition. The drug-induced cognitive improvement can synergize with typical rehabilitation programs and more experimental cognitive retraining programs to optimize these areas of improvement. Improved cognition also has implications for better compliance and decreased caretaker burden. It is also important to consider the efficacy of antipsychotics to improve mood and negative symptoms and to provide a biological framework for their ability to achieve these advantages over typical neuroleptic drugs. This article will provide new data on efficacy of this class of drugs relative to each other and to typical neuroleptics. Current theories linking efficacy in cognition to unique effects on cortical dopaminergic and cholinergic function and improved patterns of connectivity in the brain during cognitive task performance will be discussed. Finally, pharmacologic strategies to augment affect and cognitive improvements due to the new antipsychotic drug therapies will be discussed.

Obesity and diabetes continue to be national health epidemics. Greater than 50% of adults in the United States are overweight, and >17 million people have diabetes—one third of whom are not diagnosed. Diabetes ranks number 1 in direct health care costs of any disease category. Patients who suffer from schizophrenia may be at twice the risk of developing diabetes compared with the general population. Some new antipsychotic agents are among several types of medications that may potentially impair glucose metabolism. For example, studies have shown that people treated with clozapine and olanzapine have developed elevated fasting serum insulin levels, suggestive of insulin resistance. Insulin resistance may be a result of irregularities in the insulin action sequence and it may occur long before overt diabetes. The further study of the effects of medications on glucose metabolism and their mechanisms, therefore, is essential to developing better treatment regimens that minimize insulin resistance and avoid associated health risks such as obesity and diabetes.

With the widespread use of atypical antipsychotics over the past several years, adverse metabolic effects have emerged as the most serious medical consequences of pharmacotherapy with some of these agents. Initially, weight gain and obesity were observed (especially with clozapine and olanzapine), but subsequently, type 2 diabetes and dyslipidemia became apparent as well. Further, many reports suggest that sudden and severe (occasionally fatal) diabetes ketoacidosis (DKA) can emerge during treatment with some atypical antipsychotics, even in the absence of adiposity. A marked increase of serum lipids (especially triglycerides) has also been reported, to varying degrees, with different atypicals. This article reviews the data regarding metabolic dysfunction in patients with psychosis (schizophrenia and bipolar disorder). Populations with psychosis have a 2–3-fold higher prevalence of diabetes even before treatment with any antipsychotics, suggesting a possible genetic linkage or comorbidity; this was confirmed with glucose regulation studies in schizophrenia and mania. The induction of type 2 diabetes with atypicals has further increased the prevalence of noninsulin-dependent diabetes from about 6%–8% to 11%–15% according to recent studies, and even higher rates of subclinical hyperglycemia. Serious weight gain (eg, 26–29 lbs after 1 year of clozapine or olanzapine treatment) is an important risk factor, but sudden DKA has now been reported in patients with minimal weight gain, suggesting alternative mechanisms, such as insulin resistance, as a direct effect of some atypicals. Psychiatrists can reduce the risk of metabolic disorders in schizophrenia and bipolar disorder by avoiding the use of certain atypicals as first-line treatment in patients with a personal or family history of diabetes, obesity, and hyperlipidemias. Regulatory agencies in some countries have already taken action in this regard.

The long-term management of schizophrenia with a goal of functional rehabilitation remains an enormous challenge to clinicians despite improvements in drug therapy, psychosocial treatments, and family and community interventions. The goals of long-term therapy are to preserve the gains made during acute treatment, prevent symptom exacerbation, enhance psychosocial functioning, and improve quality of life. Schizophrenia is an illness that disrupts broad areas of mental function, including thought, cognition, affect, and motor performance. The new antipsychotics should aid physicians in meeting higher treatment goals for persons with schizophrenia. These agents combine high efficacy with improved tolerability, mainly through a low liability for extrapyramidal symptoms and probably improve cognitive affect. Recent studies have demonstrated efficacy of these new antipsychotics in improving psychopathology and symptoms and in preventing relapse during long-term use. These drugs are likely to provide physicians with an increasingly viable option in the long-term treatment and rehabilitation of patients with schizophrenia.