Bipolar depression certainly poses the greatest challenge to clinicians treating bipolar patients. Having a widespread disability associated with it, bipolar depression is often chronic, is less responsive to medication treatment, and has a particularly high rate of suicide. There are currently no drugs approved by the Food and Drug Administration for the treatment of bipolar depression, although full trials have been conducted with lithium, the antipsychotic olan-zapine, and the antiepileptic (AED) lamotrigine. Data for the other AEDs are quite limited and not controlled. The American Psychiatric Association guidelines recommends maximizing the dose in patients who are already on a mood stabilizer and initiating lithium or lamotrigine in patients who are not on a mood stabilizer.

Zornberg and Pope reviewed nine studies comparing lithium to placebo in bipolar depression. Among the 145 patients in these studies, there was detectable response in 79% and an unequivocal response in 36%. Although the studies varied in their methodological design and rigor, they argue quite strongly that lithium is an effective anti-depressant. In addition, six of the seven pre1990 studies evaluating lithium for bipolar depression indicated that the drug had significant antidepressant effects.

The most recent study of lithium for bipolar depression randomly assigned 117 outpatients with acute bipolar depression to treatment with either placebo, Imipramine, or paroxetine. At the 10-week study endpoint, lithium monotherapy was as effective as the addition of an antidepressant, suggesting lithium's antidepressant properties.

What are the symptoms of panic disorder and how is the disorder most effectively treated? One of the most commonly encountered anxiety disorders in the primary care setting, panic disorder is a chronic and debilitating illness. The core symptoms are recurrent panic attacks coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Patients with panic disorder have medically unexplained symptoms that lead to overutilization of healthcare services. Panic disorder is often comorbid with agoraphobia and major depression, and patients may be at increased risk of cardiovascular disease and, possibly, suicide. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors have emerged as the most favorable treatment, as they have a beneficial side-effect profile, are relatively safe (even if taken in overdose), and do not produce physical dependency. High-potency benzodiazepines, reversible monoamine oxidase inhibitors, and tricyclic antidepressants, have also shown antipardc efficacy. In addition, cognitive-behavioral therapy has demonstrated efficacy in the acute and long-term treatment of panic disorder. A n integrated treatment approach that combines pharmacotherapy with cognitive-behavioral therapy may provide the best treatment. Long-term efficacy and ease of use are important considerations in treatment selection, as maintenance treatment is recommended for at least 12–24 months, and in some cases, indefinitely.

Studies have shown that there is some efficacy for a number of agents, most notably lithium, in treating bipolar depression. However, the studies also highlight the unfortunate reality that many patients fail to respond adequately to first-line therapies and that there is a need to identify additional options for patients and clinicians. The atypical antipsychotics clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole, have been the focus of increased interest in the treatment of bipolar depression.

The use of antipsychotics in the treatment of depressive episodes is not a particularly novel idea. In 1982, Robertson and Trimble reviewed 34 studies examining the use of typical antipsychotics to augment an antidepressant and noticed modest but generally consistent benefits. More widespread use of these agents in the management of depression has been limited, however, because of concerns about the long-term risk of tardive dyskinesia and the induction of extrapyramidal symptoms that often mimic depressive symptoms.

Clozapine, the first of the atypicals, was applied initially in the treatment of schizophrenia and schizoaffective disorder, where antidepressant effects were noted during open treatment. Subsequent case series described some benefit in dysphoric manias in bipolar disorder as well.

Much of the inditect evidence for antidepressant effects of the atypicals came from studies in major depressive disorder (MDD). For example, a series of eight patients with MDD who failed treatment with a selective serotonin reuptake inhibitor (SSRI) achieved marked and rapid response when risperidone was added to the SSRI. All patients remitted within 1 week; Hamilton Rating Scale for Depression score in these patients declined from a mean of 20.5 to a mean of 2.4 (Slide 11). A subsequent series of 30 patients yielded similar results.

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.

A centenary is often an excuse for reminding people of la fin des siècles, and there seems to be recurrent revivals of interest in the psychological, the mysterious, and their related medical syndromes. Only history will tell if the same occurred at the turn of the millennium, but to date there does not appear to be a flood of novels equivalent to, for example, Dr. Jekyll and Mr. Hyde, in which the two opposing poles of the human psyche are laid out with dramatic effect. At that time there was much interest in hypnosis, automatisms, sonambulism, and their relationship to human happenstance. However, there have been recent novels about Tourette syndrome, such as Johnathan Letham's Motherless Brooklyn. There may also be a revival of interest about epilepsy, and two recently published novels are of particular neuropsychiatric relevance. The first is Lauren Slater's Spasm, and the second Mark Salzman's Lying Awake.

The subtitle of Spasm hints at what is to come. It is a “Memoir With Lies.” Chapter 1 begins with the words “I exaggerate.” The tale is an autobiographical account of the growing up of a young girl with seizures, diagnosed as epilepsy, and who is put through all the traumas associated with the disorder. With auras of strange smells and seizure descriptions that would be called partial and secondarily generalized seizures, she gets examined by her pediatrician, given phenobarbital (600 mg!), has psychotherapy, and goes to a special school run by nuns. However, her seizures are relentless, she sees a neurologist who stimulates her cortex and recommends that she has a corpus callosotomy, which she then undergoes.

Almost 100 years ago, Alois Alzheimer described the case of Auguste D., a woman who developed delusions and memory impairment at 56 years of age. Alzheimer went on to detail the symptoms and neuropathology of the disease that came to carry his name. For most of the subsequent century, however, little more was learned: Alzheimer's disease remained an entity with a well-described syndromal presentation, clinical course, and a distinct neuropathology but little else appreciated. Only in the past 20 years have findings regarding the pathogenesis of AD and potential treatments emerged. The emergence of standardized criteria for both the clinical diagnosis of AD and its pathological definition; the mainstreaming of a pathogenetic theory; the development of animal models; the identification of specific gene risk factors; and the first round of approved treatments have recently come to light.

This wealth of discovery has been fueled by the development of new techniques and technologies. Equally important has been the shift in attitude regarding cognition in the elderly. The notion of “senility” has been largely supplanted by a growing appreciation that cognitive decline is not the rule and is indicative of a distinct disease process. This realization spurs the research to determine who declines, who does not, and the risks factors for decline. This paradigm shift has allowed a renewed focus on disease processes related to memory decline in aging, and particularly AD. This issue of CNS Spectrums focuses on the shift in thinking about AD. We are on the cusp of a dramatic change in our understanding of the risks for AD, the mechanisms for its genesis, and how it might be prevented and treated.

Hillel Grossman, MD, expands the paradigm shift by focusing on diabetes mellitus and its relationship to AD. Early epidemiologic studies saw a seeming protective effect from AD among patients with diabetes mellitus. More recent prospective studies note that diabetes mellitus and insulin resistance seem to heighten the risk for AD. This finding has moved to the laboratory, where observations related to insulin-degrading enzyme and its role in amyloid metabolism suggest a potential mechanism for this heightened risk.

Repetitive transcranial magnetic stimulation (rTMS), defined as the administration of a series of magnetic stimuli to the brain for the purpose of altering brain function, is an experimental medical intervention. rTMS currently is used to probe various aspects of brain function in the context of research studies approved by local ethics committees. rTMS also is under investigation as a potential treatment for various neurologic and psychiatric disorders. In light of the growing interest in using rTMS in a variety of experimental and therapeutic settings, the International Society for Transcranial Stimulation has recognized the need to formulate a consensus statement to assist the field in developing guidelines for its safe application. Whether the intended use is experimental or therapeutic, certain principles regarding the safety of rTMS apply. This statement is not aimed at guiding the therapeutic use of rTMS in any given condition or its application in any research paradigm, but rather is meant to apply broadly wherever rTMS is used.

rTMS has significant risks, most importantly that of producing epileptic seizures. The degree of risk varies with the dosing parameters and individual subject factors. Therefore, rTMS should be administered only under a licensed physician's orders (ie, by prescription or through some other mechanism that makes a physician directly responsible for its administration to the individual patient or research subject). Because rTMS has potential behavior-changing effects, undesirable side effects, and therapeutic impact, careful assessment of the risk and appropriateness of rTMS in each clinical or scientific context is critical and can only be made by, or in consultation with, a physician knowledgeable and experienced in the use of rTMS and fully trained in neurology, psychiatry, or another appropriate specialty.