This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions.

Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

In many ways, multiple sclerosis (MS) is among the most frustrating and vicious of human diseases. Although we can readily see the demyelinating effect of MS lesions on postmortem examination, the diagnosis during life is fraught with difficulty. Advances in cerebrospinal fluid analysis and neuroimaging techniques have contributed to a recent revision of diagnostic criteria for MS, yet the majority of patients still wait for years until a definitive diagnosis is reached. They then face a disease that is both highly unpredictable and, in most cases, severely debilitating.

The unpredictable nature of MS is particularly distressing and many patients exist in a persistent state of fear and anxiety about their next MS exacerbation. Despite improved treatments, MS leaves some of the most severely affected patients wheelchair-bound by their early twenties. The more fortunate ones learn to deal with sporadic functional impairments for the rest of their lives. The unpredictable nature of MS leaves its victims always wondering about the next phase of their illness. For some, a more negative but definitive prognosis would be easier to accept than one for which the outcome is so unclear.

To make matters worse, the cause of MS remains an elusive one. Research points to an infectious and/or autoimmune etiology. The disorder is more common among those living in northern hemispheres, afflicts women more often than men, and has a partial genetic basis as evidenced by a greater concordance rate for monozygotic than dizygotic twins that nevertheless, falls far short of what would be expected of an autosomal, Mendelian disease. Drugs that modulate the immune system, from steroids to interferons, are somewhat helpful. Yet despite this, the long-term prognosis for MS has not changed much in recent decades and no therapy exists that addresses the root pathophysiology of the disease—demyelination.

The role of race and ethnicity in psychiatric diagnosis and treatment has received increased attention over the last 2 decades. In addition, recent studies conducted to determine the effects of psychotropic drugs among various racial and ethnic groups highlight the importance of considering race and ethnicity during psychopharmacologic interventions.

Information regarding differences in drug metabolism, effectiveness, and incidence of adverse effects provides opportunities for psychiatrists to adjust pharmacologic treatment to achieve optimal treatment outcomes while minimizing intolerable side effects. These differences have been explained by inconsistencies in access, stigma, fear of medicines, differing spiritual and cultural beliefs about mental illness, and general mistrust of the healthcare system by many racial and ethnic groups.

The articles in this supplement offer a significant contribution to the scientific foundation needed to minimize the patient and clinician factors contributing to the current disparities in mental health care. Recent data, such as those presented in this supplement, describe the role of ethnicity in the pharmacologic treatment of psychiatric disorders and offer hope for improved quality of care for ethnically diverse patient populations. The authors discuss differences in drug metabolism, the impact of these differences on development of various metabolic disorders, and how these differences may be useful in managing intolerable side effects and improving patient compliance and treatment outcome. The information included in these articles should assure that clinical decision making and prescribing practices include sensitivity to safety, tolerability, and dosing for an increasingly ethnically diverse population.

Faye is a 44-year-old woman who presented complaining of tension. She felt tense in her muscles, her whole body felt “on edge,” and she was unable to relax or to fall asleep easily. The tension was not only physical but also mental, she experienced anxiety on and off throughout the day, had multiple worries, and often felt irritable. Ever since she could remember, she had been somewhat highly strung, but in her thirties she took a more stressful job, and there were often times when the physical symptoms became more intense and even interfered with her work function. During these periods of increased anxiety, she resorted to using benzodiazepine tablets prescribed by her primary care physician for poor sleep.

Panic disorder (PD) is typically a distressing, chronic, and recurrent mental disorder associated with a high rate of comorbidity with other mood, anxiety, and substance abuse disorders, increased risk of medical morbidity and mortality, and marked impairment of functioning and reduced quality of life. Most patients with PD first seek treatment in emergency room or general practice settings. In the overwhelming majority of cases, PD patients present with primarily somatic symptoms, many of which are common to medical illnesses. It is, therefore, not surprising that PD is often misdiagnosed and that patients with this disorder often spend years seeking treatment and undergoing costly and unnecessary tests and medical consultations before receiving a correct diagnosis. Better diagnosis and treatment of PD to achieve remission and prevent relapse has the potential to reduce the burden of this illness to the individual and society.

Atypical antipsychotics—clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole—differ from conventional antipsychotics primarily by virtue of their actions at multiple central receptor sites. Each agent has its own unique receptor profile. The discovery of dopaminergic receptor-blocking capabilities of conventionblockingal antipsychotic drugs led to the dopamine hypothesis of schizophrenia. More recently, the role of serotonergic and other receptors in the pathophysiology and symptomology of schizophrenia and schizoaffective disorder has been identified, and the receptor actions of atypical antipsychotics have been linked to both antipsychotic efficacy and the propensity for extrapyramidal symptoms and other adverse effects. Receptor occupancy is directly related to antipsychotic dose, and the nature of the relationship between clinical utility and receptor occupancy is beginning to emerge. As our understanding of this relationship becomes more clear, the mechanism underlying clinical distinctions between agents will be understood.

Objectives: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20,40, and 60 mg.

Methods: Study A, an open-label single-period study, and Study B, a randomized, open-label, three threeway crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20,40, and 60 mg separated by 7-14-day washout periods.

Findings: Plasma dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of D-amphetamine to L-amphetamine was observed for AUC0-∞ and Cmax. Tmax was 4.2 and 4.3 hours for D-amphetamine to Lamphetamine, respectively. In Study B, for D- and Lamphetamine, statistically significant differences were observed for AUC0-t, AVC0-∞, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5–5.3 hours) with all given MAS XR doses.

Conclusion: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of D-amphetamine to L-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

Evidence exists for both cholinergic and glutamatergic involvement in the etiology of Alzheimer's disease. Acetylcholine (ACh), a neurotransmitter essential for processing memory and learning, is decreased in both concentration and function in patients with Alzheimer's disease. This deficit and other presynaptic cholinergic deficits, including loss of cholinergic neurons and decreased acetylcholinesterase activity, underscore the cholinergic hypothesis of Alzheimer's disease. The glutamatergic hypothesis links cognitive decline in patients with Alzheimer's to neuronal damage resulting from overactivation of N-methyl-D-aspartate (NMDA) receptors by glutamate. The sustained low-level activation of NMDA receptors, which are pivotal in learning and memory, may result from deficiencies in glutamate reuptake by astroglial cells in the synaptic cleft. This article reviews the roles of ACh and glutamate in Alzheimer's disease, with particular attention given to the overlap between cholinergic and glutamatergic pathways. In addition, the potential synergy between cholinesterase inhibitors and the NMDA receptor antagonist memantine in correcting neurologic abnormalities associated with Alzheimer's disease is addressed.

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.