Alzheimer's disease is the most common form of dementing illness, affecting nearly 4.5 million Americans according to current estimates. The disease exhibits a strong association with old age, and is not commonly observed in individuals <65 years of age. Among individuals >65 years of age, the prevalence of Alzheimer's disease is ∼10%, and nearly half of all persons >85 years of age are affected by this condition. Given the apparent link between Alzheimer's risk and increasing age, as well as expected changes in the demographic structure of the United States population, it has been projected that the number of Americans with Alzheimer's disease will reach unprecedented levels in the coming years. In fact, it has been predicted that, barring the development of novel preventive therapies, the number of US residents with Alzheimer's will increase to 11–16 million by the year 2050.

The expected rise in the number of Alzheimer's disease cases represents a daunting challenge, due to the far-reaching negative impact of the disease. Alzheimer's disease is a condition that not only has profound effects on the affected patient but also takes a dramatic toll on the patient's primary caregiver, who is in many cases the spouse or an adult child of the patient. Patients with Alzheimer's experience cognitive and functional declines, often in association with behavioral disturbances, while caregivers frequently suffer reductions in quality of life attributable to the immense emotional, physical, and financial burdens associated with the task of providing care.

Social anxiety disorder (SAD) is a common, chronic psychiatric disorder characterized by a persistent fear of social or performance situations in which embarrassment can occur. This disorder typically appears during the mid-adolescent years and is unremitting throughout life if not properly treated. SAD presents as two subtypes: the more common and debilitating generalized form, and the nongeneralized form, which consists predominantly of performance anxiety. The majority of patients with SAD have comorbid mental disorders, including mood, anxiety, and substance abuse. No single development theory has been proposed to account for the origins of SAD, although current understanding of the etiology of SAD posits an interaction between psychological and biological factors. Risk factors include environmental and parenting influences and dysfunctional cognitive and conditioning events in early childhood. The neurobiology of SAD appears to involve neurochemical dysfunction, as evidenced by studies of neuroreceptor imaging, neuroendocrine function, and profiles of response to specific medications. Clinical trials have demonstrated that benzodiazepines and antidepressants are effective in the treatment of SAD. The selective serotonin reuptake inhibitors are emerging as the first-line treatment for SAD, based on their proven safety, tolerability, and efficacy. Goals for ongoing future research include development of approaches to achieve remission, to convert nonresponders and partial responders to full responders, and to prevent relapse and maintain long-term efficacy.

This monograph explores the epidemiology, clinical presentation, and differential diagnosis of SAD, with a focus on neural circuitry of social relationships and neurochemical dysfunction. The prevalence, rates of recognition and treatment, patterns of comorbidity, quality-of-life issues, and natural history of SAD are discussed as well as pharmacologic and psychosocial treatment strategies for SAD.

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.

Acute agitation is a common psychiatric emergency often treated with intramuscular (IM) medication when rapid control is necessary or the patient refuses to take an oral agent. Conventional IM antipsychotics are associated with side effects, particularly movement disorders, that may alarm patients and render them unreceptive to taking these medications again. Ziprasidone (Geodon®) is the first second-generation, or atypical, antipsychotic to become available in an IM formulation. Ziprasidone IM was approved by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia. In October 2004, a roundtable panel of physicians with extensive experience in the management of acutely agitated patients met to review the first 2 years of experience with this agent. This monograph, a product of that meeting, discusses clinical experience to date with ziprasidone IM and offers recommendations on its use in various settings.

In clinical trials, patients treated with ziprasidone IM demonstrated significant and rapid (within 15-30 minutes) reduction in agitation and improvement in psychotic symptoms, agitation, and hostility to an extent greater than or equal to that attained with haloperidol IM. Tolerability of ziprasidone IM was superior to that of haloperidol IM, with a lower burden of movement disorders. Clinical trials have also shown that ziprasidone IM can be administered with benzodiazepines without adverse consequences. Transition from IM to oral ziprasidone has been well tolerated, with maintenance of symptom control. The most common adverse events associated with ziprasidone IM were insomnia, headache, and dizziness in fixed-dose trials and insomnia and hypertension in flexible-dose trials. No consistent pattern of escalating incidence of adverse events with escalating ziprasidone doses has been observed. Changes in QTc interval associated with ziprasidone at peak serum concentrations are modest and comparable to those seen with haloperidol IM. Results of randomized clinical trials of ziprasidone IM have been corroborated in studies in real-world treatment settings involving patients with extreme agitation or a recent history of alcohol or substance abuse. In these circumstances, clinically significant improvement was seen within 30 minutes of ziprasidone IM administration, without regard to the suspected underlying etiology of agitation. Agents with a good safety/tolerability profile, such as ziprasidone IM, may be more cost effective long term than older agents, due to reduced incidence of acute adverse effects (eg, acute dystonia) that often require extended periods of observation. Additional trials of ziprasidone IM in agitated patients in a variety of clinical settings are warranted to generate comparative risk/benefit data with conventional agents and other second-generation antipsychotics.

Depression is a common, recurring illness that continues to be underdiagnosed and undertreated in both psychiatric and primary care settings. It is increasingly being recognized that painful physical symptoms, which commonly exist comorbid with depressive disorders, play a role in complicating diagnosis of depression. Patients tend to discuss physical pain with primary care physicians and emotional pain with psychiatrists, often oblivious to the fact that both may be aspects of one disorder. Those who present with somatic complaints are three times less likely to be accurately diagnosed than patients with psychosocial complaints. However, thorough evaluation of mood and anxiety disorders in primary care is sparse due to the limited time primary care physicians can spend with each patient. Better recognition and treatment of both physical and emotional symptoms associated with mood disorders may increase a patient's chance of achieving remission, which is the optimum therapeutic goal.

Abnormalities of serotonin and noradrenaline are strongly associated with depression and are thought to play a role in pain perception. Brain-derived neurotrophic factor, which is increased with antidepressant treatment, appears to influence regulation of mood and perception of pain. Clinical evidence indicates that dual-acting agents may have an advantage in modulating pain over those agents that increase either serotonin or noradrenaline alone. The novel dual-acting agents, such as venlafaxine and duloxetine, are better tolerated than tricyclic antidepressants and monoamine oxidase inhibitors. These agents have demonstrated efficacy in depression and in diabetic neuropathic pain independently. Therefore, unless otherwise stated, all inferences to studies of pain in this monograph refer to neuropathic pain in nondepressed patients.

Depression affects 6.5 million of the 35 million Americans ≥65 years of age. While depression usually begins earlier in life and recurs periodically, it can present for the first time in people 80–90 years of age as well. Depression throughout the lifespan has a genetic/biological component but is also very much affected by social environmental factors. As people age, demographic factors, social support, and negative life events remain important to overall mental health, while physical illness and disability begin to take on a much more prominent role. Depression in the elderly is associated with impairment, dependency, disability, and significant distress for the individual and their family. This population is likely to present with concomitant cognitive dysfunction and medical illness, which can complicate the identification and treatment of psychiatric conditions. Bereavement is almost universal in late life and is sometimes a deterrent to appropriate diagnosis and treatment of depression. Physical frailty and diminishing social resources further complicate the treatment of depression in the elderly. Elderly individuals respond well to standard pharmacotherapy and psychotherapy treatments for depression. However, due to the high rate of relapse of depression in this population, continuous treatment is often warranted. This monograph will review depression in the elderly in the context of social disruptions, such as bereavement, caregiver strain, interpersonal conflict, role transitions, and social isolation; late-onset vascular depression and cognitive impairment; and physical illness including disability.

Attention-deficit/hyperactivity disorder (ADHD) is widely recognized as one of the most common psychiatric disorders initially diagnosed and treated in childhood; however, it is less widely recognized as a disorder that often persists into adolescence and adulthood. In recent years, there has been increased awareness that adult ADHD is marked by significant impulsivity and impairments of attention and executive function, symptoms that can be linked to, personal, social, and professional dysfunction. Clinicians are increasingly recognizing adult ADHD as a disorder linked to considerable dysfunction and distress, warranting appropriate pharmacologic treatment.

Psychostimulants, such as amphetamines and methylphenidate, are recommended as first-line pharmacotherapeutic agents for the management of ADHD in children, adolescents, and adults. Because most research on psychostimulant use has involved pediatric ADHD patients, little is known about the safety and efficacy of these agents in adult ADHD.

Recognition and treatment of schizophrenia has largely focused on positive symptoms of the disorder, such as delusions, hallucinations, and disorganization. However, other important symptoms, such as depression, cognition, and social functioning, have not received comparable attention. Fifty percent of schizophrenic patients suffer from comorbid depression, which is a major risk factor for suicide in this population, while 10% to 25% suffer from comorbid obsessive-compulsive disorder. Cognitive deficits commonly observed in patients with schizophrenia include problems with concentration, attention, and memory, as well as problem-solving and verbal skills. These deficits are observed at early stages of the illness and can predict deficits in functional capabilities, such as occupational and social skills, educational attainment, and the ability to live independently. The severity of such impairments affects all patients in this population, including up to 10% of patients working full time and up to one third of those working part time. In light of the debilitating effects of depression, cognitive impairment, and other aspects of affective functioning on the quality of life of patients with schizophrenia, physicians need to partner with their patients to address these concerns and determine an appropriate treatment regimen. This can be done with simple functional-based cognitive questioning, the use of evidence-based psychosocial practices, and psychoeducation on the many pharmacotherapeutic options. It is recommended that depressive or suicidal symptoms of schizophrenia be treated with an antidepressant or mood stabilizer only if the symptoms have not subsided after treatment of the psychosis with an atypical antipsychotic. Additionally, relative to older medications, atypicals have demonstrated benefit in improving some of the cognitive impairments.

Treatment options for epilepsy have increased in the last decade with the introduction of several new antiepileptic drugs (AEDs). As drug selection becomes more challenging, the use of evidence-based guidelines to aid in treatment decisions has become increasingly valued. The American Academy of Neurology's (AAN) guidelines for the use of new AEDs in refractory epilepsy offers many benefits, including expert panel recommendations based on clinically relevant questions with evidence-based responses. However, lack of evidence from randomized-controlled trials, particularly as they relate to monotherapy, limits the recommendations and their use in practice. The studies of new AEDs as monotherapy in treatment-refractory epilepsy are difficult to incorporate into clinical use because they are driven by Food and Drug Administration requirements to show superiority over placebo or pseudoplacebo (ie, low dose of active drug) rather than by clinical questions. However, based on Class I evidence, the AAN guidelines have granted Level A recommendations (established effectiveness) for oxcarbazepine and topiramate monotherapy, and a Level B recommendation (probable effectiveness) for lamotrigine monotherapy in the use of refractory partial epilepsy. There is insufficient evidence to recommend gabapentin, levetiracetam, tiagabine, or zonisamide monotherapy. No monotherapy AED trials have been conducted in refractory generalized epilepsy. Because no differences in efficacy have been reported for AEDs as initial therapy of partial seizures, differences in adverse events, such as weight gain, tremor, and hair loss, are key in drug selection. More comparative studies between the AEDs are necessary for both monotherapy and add-on therapy for treatment-refractory epilepsy.

It seems obvious to most people that the brain and the rest of the body interact. Stress seems to worsen most general medical conditions, mortality is higher among widowers than married men, and almost everyone becomes moody when he or she has a viral infection. However, these are mostly anecdotal observations. The precise ways in which mind and body relate in health and disease is more elusive and, at times, controversial.

Perhaps the hardest evidence we have for a mind-body connection comes from studies showing that depression is an independent—and, surprisingly, quite a robust—risk factor for cardiovascular disease. Following acute coronary syndrome depression significantly worsens outcome, including increasing all-cause mortality rates.

Another well-documented finding, going in the opposite direction, is the high rate of depression experienced by those receiving α-interferon for the treatment of hepatitis C or malignant melanoma. Less secure is whether depression increases risk or worsens prognosis for cancer; why patients with schizophrenia are at greater risk for heart disease and cancer than the general population; if it is true that stress plays a role in exacerbations of multiple sclerosis; and what is the relationship between depression and the risk for Alzheimer's disease. In each there are conflicting epidemiological data and difficulties understanding the neural mechanisms that would broker the relationship between brain and targeted peripheral organ.

Ongoing research on attention-deficit/hyperactivity disorder (ADHD) has yielded important new information that has impacted the clinical recognition and management of this disorder. ADHD has long been considered one of the most common psychiatric disorders initially diagnosed and treated in childhood. Contrary to the once widely held assumption that symptoms spontaneously resolved or abated, clinically significant symptoms for most patients persist into adolescence and adulthood. While hyperactivity appears to decrease with age, impaired attention and impulsivity persist into adolescence and are linked to clinically significant functional impairments in academic, social, and family settings.

Like their younger counterparts, adolescents with ADHD exhibit higher rates of comorbid psychiatric illness and concomitant mental health service use. Among the most common comorbid psychiatric disorders seen in adolescents with ADHD are major depression, anxiety disorders, conduct disorder, and oppositional defiant disorder (ODD). In young adults, a direct correlation has been revealed between ongoing ADHD symptom severity and lower levels of academic achievement, greater risk of illicit drug use, and drug-related crime. These findings highlight the potential importance of adequate ADHD symptom management in adolescence in predicting long-term outcomes; as a result, a lifespan approach toward ADHD is beginning to be adopted by many clinicians, and anti-ADHD medication (including psychostimulants) is being recommended for the management of ADHD in all age groups. However, most clinical research involving psychostimulants has been conducted in school-age children <12 years of age, and knowledge concerning the use of medications in adolescents with ADHD is limited. Questions about dosing, safety, level of efficacy to be expected, and optimal duration of treatment in adolescents with ADHD must be addressed. Clinical choice of therapy is also complicated by the fact that the anti-ADHD armamentarium continues to evolve, and now includes long-acting formulations of methylphenidate, mixed amphetamine salts, and nonstimulants.

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.

Attempts to understand the underlying etiology of panic disorder have, at times, oscillated between reductionistic biologic or psychologic characterizations that have put pharmacotherapists and cognitive-behavioral therapists on opposite sides of a fence with patients caught in the middle. However, research emerging over the last couple of decades is pointing to a more complex interplay between dysregulated neurobiological systems and psychological factors that influence the manifestations of fear and anxiety and permit a more nuanced view of the etiology of panic disorder while pointing to potential rational strategies for treating patients. The articles in this supplement explore a range of explanatory models relevant to the underlying etiology of panic disorder, and then focus on treatment, including pharmacologic agents, and a paradigm in which cognitive-behavioral therapy (CBT) can be efficiently and effectively integrated with pharmacotherapy in an attempt to optimize patient care.

In the first article, David Baldwin, MB, BS, DM, FRCPsych, discusses the burden of panic disorder to patients and society; the difficulties associated with misdiagnosis and inadequate treatment; the challenges imposed by excess healthcare utilization, reduced quality of life, and psychiatric and medical comorbidity; and the implications for therapeutics.

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.

This monograph summarizes the proceedings of a roundtable meeting convened to discuss pseudobulbar affect (PBA). Two didactic lectures were presented, followed by a moderated discussion among 11 participants. Post-meeting manuscript development synthesized didactic- and discussion-based content and incorporated additional material from the neuroscience literature. A conceptual framework with which to distinguish between disorders of mood and affect is presented first, and disorders of affect regulation are then reviewed briefly. A detailed description of the most common of these disorders, PBA, is the focus of the remainder of the monograph. The prevalence, putative neuranatomic and neurochemical bases of PBA are reviewed, and current and emerging methods of evaluation and treatment of persons with PBA are discussed. The material presented in this monograph will help clinicians better recognize, diagnose, and treat PBA, and will form a foundation for understanding and interpreting future studies of this condition.