Attention-deficit/hyperactivity disorder (ADHD) may be the most common chronic, undiagnosed psychiatric disorder in adults. ADHD is characterized by restlessness, overactivity, disorganization, impulsivity, and inattention; and as further characterized in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). For most cases, an adult ADHD diagnosis is preceded by symptoms in childhood, which is a time when the disorder is rarely inquired about and usually overlooked.

ADHD has been recognized in children for several decades, and the importance of detection and treatment is well established. Whereas it was initially believed that children outgrew the disease, researchers now know that approximately two thirds of children affected with ADHD symptoms carry the condition into adolescence and then into adulthood. Consequently, >4% of adults in the United States have ADHD. Nevertheless, the disorder is unrecognized and untreated in the vast majority of these people.

Schizophrenia affects ~1% of the population and is associated with enormous personal suffering, family distress and burden, and tremendous healthcare and societal costs. Although considerable progress has been made in treating this illness enormous challenges remain.

Early detection and treatment are at present a distant goal. There is undue delay between the onset of full-blown psychosis and appropriate diagnosis and treatment. Continuity of care is often spoken about rather than truly implemented. Adverse effects remain a critical challenge, and comorbid medical conditions as well as suicide result in a markedly diminished life expectancy. Substance abuse affects a substantial proportion of patients, creating an impediment to optimum outcome. Nonadherence remains a very common, but inadequately appreciated obstacle to adequate and sustained treatment response and contributes enormously to a high rate of preventable relapse and rehospitalization.

The focus of this CNS Spectrums supplement is to address many of these topics in a clinically relevant manner by reviewing the latest research findings in pharmacologic and behavioral treatments, with an emphasis on evaluating appropriate treatment for each patient while considering the host of issues that should inform our clinical decision-making. Historically, a major focus of treatment has been positive symptom control. Though this is clearly important, negative symptoms, cognitive dysfunction, depression, demoralization, and comorbid substance abuse are also critical targets in enhancing functional outcome. Concepts such as remission and recovery are useful metrics to help establish targets and goals for treatment planning and for creating a framework for assessing outcome.

Depression is one of the world's great public health problems. As there are no perfect or uniformly effective treatments for depression, it is not surprising that treatment-resistant depression (TRD) is likewise an important public health problem. Although the potential benefits of antidepressants are now well documented, no widely used antidepressant can be expected to be effective in more than half the patients who begin to take it. Even under optimal circumstances (ie, a patient who is fully adherent to 12 weeks of treatment), there is only a 60% to 70% chance that the first choice of medication will be effective. The need for effective alternate strategies for TRD, as well as the need for innovations in service delivery systems to ensure those strategies are implemented in a timely manner, are foremost to fully realizing the potential benefits of antidepressant therapies.

Over the years, hierarchies of treatment strategies for TRD have been based on the widespread use of particular treatments, their ease of use, and their safety or complexity. One of the strategies consistently used since its introduction 20 years ago has been augmentation of the ineffective antidepressant by a second medication. The second agent may or may not have antidepressant effects of its own, but when used in combination with a primary antidepressant the agent reliably increases a patient's likelihood of response and symptom remission.

Involuntary emotional expression disorder (IEED), a distressing and potentially debilitating condition characterized by uncontrollable episodes of laughing and/or crying, causes extensive social and occupational dysfunction amongst patients. However, despite affecting more than one million people worldwide, IEED is often overlooked or misdiagnosed, and current treatments are compromised by uncertain efficacy. In this supplement we review the epidemiology and pathophysiology of IEED, and discuss new pharmacologic interventions which may afford opportunities for symptom control amongst IEED sufferers.

Although the uncontrollable episodes of emotion which characterize IEED were first described more than a century ago, a bewildering profusion of terminology has since confused and hampered the efforts of physicians to recognize and treat this condition. In the first article, John E. Duda, MD, examines the history of IEED in the medical literature, and evaluates the prevalence of the condition amongst patients in whom emotional or affective motor control has become dysregulated, either as a result of brain damage from neurological disease or as a result of brain injury.

Excessive daytime sleepiness (EDS) is a prevalent topic in clinical care. Tiredness, fatigue, lack of energy, and sleepiness are complaints commonly encountered by psychiatrists and other physicians. Many surveys and epidemiological studies indicate that pathological daytime sleepiness, which is sleepiness that interferes with an individual's function most of the time, occurs in 7% to 13% of the population. Studies of patients within primary care practices suggest that this population suffers an even greater prevalence of sleepiness than the general public. Estimates of 20% to 25% or higher have been suggested by studies of large samples of primary care patient populations. Causal or contributing factors leading to a patient's experience of EDS range from the process of simply chronically allowing too little time for sleep on an ongoing basis, to idiopathic but profound central nervous system (CNS)-mediated debilitating hypersomnolence. Common among the causes of EDS are insufficient sleep, circadian rhythm disorders such as delayed sleep-phase syndrome, sleep disorders such as obstructive sleep apnea (OSA), CNS-related disorders such as post-infectious syndromes or CNS injury or lesions, and drugs—prescribed or otherwise.

Insomnia is a disorder characterized by chronic sleep disturbance associated with daytime disability or distress, such as memory impairment and fatigue, that occurs despite adequate opportunity for sleep. Insomnia may present as difficulty falling/staying asleep or as sleep that is nonrestorative. Studies show a strong correlation between insomnia and impaired quality of life. Pain conditions and depression are commonly associated with insomnia, either as secondary or comorbid conditions. In addition, a greater incidence of anxiety, alcohol and drug dependence, and cardiovascular disease is found in people with insomnia. Data indicate insomnia results from over-engaged arousal systems. Insomnia patients experience increased metabolic rate, body temperature, and heart rate, and elevated levels of norepinephrine and catecholamines. Pharmacologic options for the treatment of insomnia include benzodiazepine hypnotics, a selective melatonin receptor agonist, and sedating antidepressants. However, insomnia may be best treated with cognitive-behavioral therapy and instruction in good sleep hygiene, either alone or in concert with pharmacologic agents. Studies on the effects of insomnia treatment use variable methodologies or do not publish negative results, and there are currently no studies of treatment focusing on morbidity. Further research is necessary to better understand the effects of insomnia therapies on medical and psychiatric disorders.

In this Clinical Information Supplement, Thomas Roth, PhD, describes the nature of insomnia and its pathophysiology. Next, Andrew D. Krystal, MD, MS, reviews morbidities associated with insomnia. Finally, Joseph A. Lieberman III, MD, MPH, provides an overview of therapeutics utilized in patients with insomnia, including behavioral therapies and pharmacologic options.

Major depressive disorder (MDD) is widespread, costly, and frequently chronic. Internationally, the burden of depression is large and growing. By the year 2020, this disorder is projected to be the world's second leading cause of disease burden. The costs associated with depression are enormous; people with depression tend to have approximately double the health care costs of unaffected individuals. There are few other major disorders that have a negative health impact of the same magnitude.

Early onset of depressive symptoms, along with underdiagnosis and undertreatment, contribute to the burden of MDD, which is also characterized by chronicity, frequent relapses, and recurrences. Risk factors for depressive recurrence include the presence of residual symptoms, >3 prior depressive episodes, chronic depression lasting more than 2 years, a family history of mood disorders, other comorbidities (eg, terminal illness, diabetes), and late onset (>60 years of age). Patients who have any of these factors should be candidates for maintenance treatment.

Naturalistic studies have demonstrated that most patients with MDD without sustained treatment will eventually experience a relapse or recurrence. Furthermore, depressive episodes tend to become more autonomous over time, with decreased linkage to stressful life events, more severe, and potentially more refractory with each new relapse or recurrence. Researchers and clinicians have observed that rather than only treat or manage relapses or recurrences of MDD, the best strategy may be prevention of depressive episodes. As a result, current strategies seek to treat patients to remission, which translates to a lower overall risk of developing relapses or recurrences compared with those patients who continue to demonstrate residual symptoms. Thus, a consistent body of evidence now supports continuous pharmacotherapy for the prevention of depressive relapse and recurrence.

Pharmacoepidemiology, the study of the effects of drugs in large numbers of people, is a relatively new discipline that applies the methods of epidemiology to clinical pharmacology. Premarketing clinical trials remain the only way to scientifically determine whether a drug is causally effective, yet these trials do not provide information that allows for estimates about rare, late, or off-label toxicities associated with the drug in question. Increasing concern about common and debilitating adverse effects of medications has highlighted the need for enhanced postmarketing surveillance to follow up on clinical trials. There is a further concern regarding the broader issue of the risk-benefit ratio of certain medications. Computerized databases are a good source of information on which to lay the foundations of postmarketing research. A system of cross-linked computerized medical records may better enable researchers and physicians to realistically monitor postmarketing safety and incorporate monitoring benefits. The same research could also elucidate the net public health effect of regulatory decisions. The Veterans Affairs database in the United States and PHARMO in the Netherlands may represent good models on which to base future postmarketing surveillance studies.

In this expert roundtable supplement, Brian L. Strom, MD, provides an overview of the appropriate use of large computer databases in pharmacoepidemiology studies. Philip Wang, MD, DrPH, discusses the advantages of pharmacoepidemiologic studies over clinical trials in correctly detecting drug safety issues. Francesca Cunningham, PharmD, reviews a large computer database that is currently in use within the VA healthcare system, and Ron M.C. Herings, PharmD, PhD, discusses the development of the PHARMO system in the Netherlands.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent chronic condition that affects people of all ages, including young children, school-aged children, adolescents, and adults. Symptoms can be noted as early as preschool age, tend to progress into functional impairment and behavioral problems in later childhood, and typically persist into adulthood. Contrary to previous belief, the disorder does not resolve with puberty for the majority of children; rather, the symptoms are manifested differently throughout the lifecycle. Presentation in adults is heavily biased toward inattentive symptoms, which are less likely to draw notice than hyperactive or impulsive symptoms and may contribute to the underrecognition of ADHD in this patient population. Diagnosis is particularly difficult due in large part to the pronounced comorbidity of psychiatric disorders in this patient population. Identification may be even more difficult in adults than children as the diagnostic criteria are not as clear, adults have difficulty remembering symptoms prior to 7 years of age, and there is a high prevalence of comorbid psychiatric disorders in adults. Early identification and treatment of symptoms of ADHD in preschool-age children is essential to effective long-term management of the disorder. Both medication and behavioral treatments appear to alleviate the symptoms of ADHD, and evidence suggests that discontinuation of treatment leads to the reemergence of the condition. Efforts are currently continuing toward understanding the genetic underpinnings of ADHD.

This expert review supplement will address the prevalence, comorbidity, treatment issues, and special considerations surrounding ADHD management throughout each stage of the lifecycle beginning with ADHD in preschool-aged children, continuing with school-aged children and adolescents, and ending with adulthood.

Attention-deficit/hyperactivity disorder (ADHD) is an impairing but usually treatable condition. Popular culture propagates the myth that ADHD recedes with age; this is not the case. Although it is common, <20% of adults with ADHD are diagnosed or treated. Adults with ADHD show significant comorbidities with depressive disorders, anxiety disorders, substance use, oppositional defiant disorder, personality disorders, sleep problems, and learning disabilities. However, symptoms that result from ADHD, such as mood symptoms or lability, are often mistaken for comorbid disorders. Comorbidity with ADHD impacts treatment compliance, treatment response, and patient insight. Insufficient data on the interaction between ADHD and comorbidities impedes proper diagnosis and treatment. Better clinical tools for assessing these conditions are needed. Food and Drug Administration-approved pharmacologic treatments for adult ADHD include stimulants, dexmethylphenidate, and the nonstimulant atomoxetine. Effect sizes of approved medicines at approved doses are half those seen in children. Adults may also need longer duration of medication effects than children. Short-acting stimulants are likely to result in poorer adherence and have a higher risk for diversion or abuse. Risk of abuse is a major concern; stimulant treatments are controlled substances, and children with ADHD show increased risk of substance abuse. Psychosocial interventions may be beneficial in treating both ADHD and comorbidities.

In this expert roundtable supplement, Margaret Weiss, MD, PhD, presents a comprehensive overview of complications surrounding differential diagnosis in adults with ADHD. Next, Mark A. Stein, PhD, reviews evaluation, comorbidity, and development of a treatment plan in this population. Finally, Jeffrey H. Newcorn, MD, provides a discussion on the pharmacologic options available for adults with ADHD, considering dosages specific to adults and common comorbidities.

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

Bipolar disorder is a prevalent psychiatric disorder with a high rate of misdiagnosis and evidence of degenerative progression. Research indicates that the interval between bipolar episodes decreases steadily until the patient settles into a relatively frequent course of mania and depression. Various imaging techniques have been used in the understanding of the brain pathology underlying bipolar disorder through identification of patterns consistent with disruption of the normal brain activity in bipolar patients. These techniques have demonstrated evidence of abnormalities in the structure and function of the prefrontal cortex. In addition, the cerebellar vermis, which serves as an error-detection function to modulate the iterative network, appears to shrink with recurrent episodes. Functional imaging demonstrates that the anterior limbic network is overactivated and overresponsive in patients with bipolar disorder. In many patients, those deficits are often compensated for by activation of other brain areas. Ultimately, when the compensation fails, expression of bipolar symptoms arise. Using magnetic resonance spectroscopy, simple models can be constructed based on the hypothesis that mitochondrial function may be impaired in bipolar disorder. There is also increasing evidence that psychotropic medications can affect specific brain regions that are thought to be involved in the pathogenesis of psychiatric disorders. Glutamate levels appear to be elevated in untreated patients with bipolar disorder, which may cause glutamatergic neurotoxicity and negative therapeutic implications. Further advances in brain imaging may contribute to the improvement of available therapies and the understanding which treatments will be most suitable for specific patients.