Patients with Parkinson’s disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent’s pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2–6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

Serious mental illness is associated with a significant reduction in life expectancy of ≤30 years. Among patients with schizophrenia, mortality due to coronary heart disease is ∼50% higher than that of the general population.

Patients with schizophrenia have substantially higher rates of cardiovascular risk factors (smoking, high cholesterol, hypertension, physical inactivity, obesity/overweight, and diabetes) than the general population. Approximately 75% of individuals with schizophrenia smoke compared to ∼25% of the general population. Patients with schizophrenia also have lipid profiles that are significantly worse than those of individuals in the general population.

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.

Optimal treatment for patients with mental health illness depends upon accurate diagnosis, individualized treatment, patient adherence to effective agents, and an intact family support system. Healthcare system (eg, limited access to certain medications), provider (eg, bias and discrimination), and patient factors (eg, biologic and cultural) greatly influence the level of mental health care given, especially to minority populations. Furthermore, limited data in African Americans, Hispanics, and Asians suggest that there are racial, ethnic, and cultural variations in responsiveness to antipsychotic medications, as well as potential differences in the types, rates, and severity of adverse events. Non-Caucasian patients tend to receive older, less-expensive agents, sometimes at higher doses (African Americans, leading to potentially intolerable side effects and early withdrawal of therapy or a less than optimal therapeutic response, respectively. Differences in response may have a biologic, pharmacokinetic, or pharmacodynamic basis and may also be influenced by lifestyle factors (eg, diet, smoking). Variations in dopamine receptor occupancy and cytochrome P450 polymorphism may explain some racial/ethnic differences in antipsychotic effects and adverse-event profiles, suggesting that dosing may need to be individualized based on ethnicity. The newer atypical antipsychotics, while seemingly better tolerated compared with conventional antipsychotics, may not be totally devoid of bothersome side effects (eg, extrapyramidal side effects) in minorities. While further research is needed, recognition of potential interracial/ethnic pharmacogenetic differences may help minimize intolerable side effects and achieve optimal psychosis management.

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.

Atypical antipsychotics have become widely accepted as the first-line standard of care in the treatment of psychotic disorders, such as schizophrenia and bipolar disorder, which occur in ethnically and racially diverse patients. Accumulating data indicate that ethnicity factors may impact the efficacy and safety of atypical antipsychotics. Given the increasingly heterogeneous ethnic and racial composition of the United States, it is important for practicing clinicians to understand how race and ethnicity may influence the pharmacotherapeutic use of atypical antipsychotics.

The three articles in this supplement to CNS Spectrums, address how race and ethnicity may influence the efficacy, safety, tolerability, and dosing of atypical antipsychotics in today’s heterogeneous patient population.

L. DiAnne Bradford, PhD, reviews the most recent advances in ethnopharmacology and how gender, race, and ethnicity can influence, through metabolic biotransformation, the pharmacokinetic and pharmacodynamic properties of atypical antipsychotics. Dr. Bradford will also review how antipsychotic-related adverse events may be associated with the differences in oxidative enzyme activity across ethnic and racial groups and how these factors should be given careful consideration in the management of patients of different ethnic/genetic profiles.

David C. Henderson, MD, examines the emerging data that suggest metabolic differences among various racial and ethnic groups may predispose patients to serious medical complications, such as obesity, dyslipidemia, and diabetes mellitus. Dr. Henderson discusses the impact of these racial/ethnic metabolic differences when clinicians are prescribing atypical antipsychotics and also compares the risks of metabolic issues associated with specific agents within the class of atypical antipsychotics.

The articles in this supplement demonstrate that ethnicity and ethnopharmacology have emerged as important considerations in the treatment of patients with mental illness. Patients from ethnically diverse backgrounds often demonstrate varying levels of response and tolerability to drugs such as atypical antipsychotics. In part, this response may be due to the particular agent itself, yet metabolic differences between populations may also impact these varied effects. Specific isoforms of the cytochrome P450 enzyme system can dictate the rate at which patients metabolize certain medications, thus genotypic variability among these enzymes predicts the phenotypic response or metabolic rate. For example, patients from certain ethnic groups such as Caucasians and Hispanics tend to be extensive metabolizers, while African Americans and Asians tend to be slower metabolizers.

Total dose and resulting plasma drug levels are closely related to adverse effects. Thus, patients exhibiting slow or poor oxidative enzyme activity may face increased drug exposure and potentially higher rates of adverse events. The undesirable antipsychotic-induced side effects include metabolic issues such as weight gain, insulin resistance, and dyslipidemia. Certain ethnic groups are at a higher risk for developing these metabolic problems. Side effects such as extrapyramidal symptoms and tardive dyskinesia, which have traditionally been attributed to conventional antipsychotics, may occur with atypicals although much less frequently. Movement disorders caused by the use of an atypical antipsychotic become particularly apparent when plasma drug levels are high. Patients with a slow metabolism will be exposed to high plasma drug levels, even on standard dosages of an atypical antipsychotic.

Therefore, given a genetic predisposition and the potential for metabolic side effects with atypical antipsychotics, a careful risk/benefit assessment is crucial for the successful management of patients with mental illness.

Other patient factors as well as clinician factors can influence the response and tolerability of treatment. Provider biases can affect access to certain medications, while misconceptions about how to treat certain ethnic groups can affect the initial choice of medication and dosage. Ultimately, sensitivity and an awareness of pharmacologic issues as they relate to an expanding and ethnically diverse population must become a high priority for clinicians treating patients with atypical antipsychotics. Side effects of these medications can be minimized with vigilance and a thorough understanding of the risks and benefits.

Continued research is necessary to further understand the field of ethnopharmacology and to lead psychiatry into the future of individualized, metabolically directed therapies.

The overall effectiveness of antipsychotics for the management of schizophrenia is restricted by their side-effect profiles, particularly over an extended treatment period. Intolerable side effects can reduce patient adherence to medication and often lead to treatment discontinuation. Some side effects that result from antipsychotic use are precursors to the metabolic syndrome, which is prevalent among individuals with schizophrenia and represents a significant source of cardiovascular risk. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study assessed the efficacy of the atypical antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone relative to the conventional drug perphenazine. Additional assessments included the metabolic effects of these agents in patients with schizophrenia and the incidence of negative side effects. No significant differences were found between treatment groups for time to discontinuation due to intolerability, but the rates of side effects significantly differed (P=.04). For metabolic parameters, olanzapine was associated with greater and significant adverse effects on weight, lipids, and glucose metabolism versus the other antipsychotics tested. The CATIE results show that important distinctions exist among currently available atypical antipsychotics. Physicians should be aware of the propensity of these drugs to increase the risks of cardiovascular disease and diabetes in treated patients and tailor individual treatment decisions accordingly. This article highlights the metabolic findings from the CATIE schizophrenia study, and explores the differences shown by atypical antipsychotics, with regard to metabolic side effects that increase cardiovascular risk.

Many structural brain abnormalities have been described in schizophrenia, consistent with a neurodevelopmental model for this disease. We report here a study of the cavum septum pellucidum (CSP) in schizophrenia compared to control groups, as well as the clinical correlates of this congenital anomaly in schizophrenia. We conducted a magnetic resonance imaging (MRI) study to compare rates of CSP in schizophrenia (N = 67) v. psychiatric controls (bipolar and schizoaffective, N = 60) and healthy controls (N = 37). Of the controls 18·9 %, and of all psychotic subjects 18·1 % had a CSP of any size and there was no difference in the frequency of large CSP among the groups. Males had higher rates of CSP than females (25% v. 9·7%, P = 0·01) in all groups. Schizophrenics had higher CSP rates than affective patients (25%, v. 10%, P = 0·02). No clinical difference was found between schizophrenics with or without CSP.

Tardive dyskinesia is widely believed to be a state of relative hyperdopaminergic and hypocholinergic imbalance in the striatum of patients chronically treated with neuroleptics. However, not all patients with tardive dyskinesia respond to cholinergic drugs, which theoretically should restore the balance and improve the symptoms. We report a controlled, double-blind, crossover study of choline chloride in 11 patients with persistent tardive dyskinesia. Seven patients showed partial or minimal improvement, while two did not change and two deteriorated. The results are discussed in the light of other similar findings in the literature, and the implications for pharmacological subtypes of tardive dyskinesia using cholinergic probes are explored.

A retrospective case-control study was performed using the records of 59 catatonies, 59 non-catatonic schizophrenies, 59 manies, 59 depressives and 59 surgical Controls. The findings suggest that prior brain injury and physical illness at onset of psychosis are much more common in subjects with catatonia. While these findings do not account for all cases of catatonia, they may indicate an aetiology for some phenotypic cases of catatonia.

In an effort at replication of the original report (Rosenthal and Bigelow, 1972) of increased callosal thickness in schizophrenic brains, the corpus callosum was measured in a blind study of 64 brains autopsied between the years 1972 and 1976. Diagnosis was established by independent chart review. The mean corpus callosum mid sections of 21 early onset chronic schizophrenic brains were found to have a significantly greater thickness when compared with 8 subjects with late onset schizophrenia, 13 patients with neurological diagnoses, or 14 patients with other psychiatric diagnoses. These studies, if independently confirmed, should provide an impetus for testing the hypothesis that some chronic schizophrenic patients have an illness associated with a pathological process in the corpus callosum.