Attention-deficit/hyperactivity disorder is a prevalent and disabling disorder that is characterized by inattention and/or hyperactivity-impulsivity, impairment in executive functions, structural and functional abnormalities in frontal-striatal circuitry, associations with particular catecholamine gene variants, and responsiveness to dopaminergic and noradrenergic agents. There is a growing integration of findings from basic and clinical studies, of data from different methods (eg, genetics and imaging), and of empirical data with hypotheses drawn from evolutionary thinking. Here we briefly summarize work on the cognitive-affective neuroscience of attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a lifelong condition that begins in childhood and continues with adult manifestations related to the core symptoms. Approximately 50% to 75% of children with ADHD continue to meet criteria for the disorder as adolescents and adults. Adults with the disorder increasingly present to primary care physicians, psychiatrists, and other practitioners for diagnosis and treatment. Understanding the diagnosis of ADHD in adults requires knowledge of age-dependent decline of symptoms over time. Retrospective recall of symptoms and impairment are valid methods of diagnosing the disorder. ADHD is also a brain disorder with a strong neurobiologic basis, complex etiology, and genetic component. Genetic and environmental vulnerabilities give rise to abnormalities in the brain and subsequent behavioral and cognitive deficits, which may produce the symptoms associated with ADHD. Magnetic resonance imaging studies of ADHD have provided evidence that abnormalities in the brain are caused by the disorder itself rather than treatment of the disorder. Psychiatric comorbidity is common among patients with ADHD and tends to complicate treatment. Acute and long-term use of long-acting stimulant formulations (methylphenidate and amphetamine compounds) have shown robust efficacy and tolerability consistent with the treatment response established in children with ADHD. Non-stimulant medications have demonstrated efficacy as well, and may be preferred in patients with tic and substance use disorders.

In this expert roundtable supplement, Timothy E. Wilens, MD, reviews the epidemiology and clinical presentation of adult ADHD. Next, Joseph Biederman, MD, provides an overview of recent advances in the neurobiology of ADHD. Thomas J. Spencer, MD, reviews stimulant treatment of adult ADHD, and Lenard A. Adler concludes with a discussion of non-stimulant trials in adult ADHD.

Introduction: While both blunted and enhanced cortisol suppression following a dexamethasone suppression test (DST) are described in eating disorders, some evidence suggests that enhanced cortisol suppression might be associated with the presence of trauma history. The objective of this study is to investigate hypothalamic-pituitary-adrenal axis response to a modified DST in eating disorders and its relationship with childhood trauma.

Methods: Fifty-two patients with eating disorders were studied with a 0.25 mg DST and with measures of childhood trauma.

Conclusion: Patients with bulimia symptoms had significantly greater cortisol suppression than controls and restrictive anorexia patients (F=8.2, P<.05). Cortisol suppression was significantly correlated with intensity of childhood traumatic events (F=0.32, P<.05). Hypersensitive hypothalamic-pituitary-adrenal axis response to DST in eating disorders may be related with a history of childhood trauma and suggests some biological similarities with posttraumatic syndromes that should be further explored.

Obsessive-compulsive disorder (OCD) is a formidable public health problem, rated by the World Health Organization as one of the top 20 most disabling diseases.The shame and secrecy associated with OCD, as well as the lack of recognition of its characteristic symptoms, particularly by primary care physicians, hinders appropriate diagnosis and treatment. Most adults with OCD report a late adolescent or early adulthood onset, yet OCD can occur throughout the life span. Pre-school children have been known to develop the disorder, as have elderly persons. OCD can cause considerable distress and disability; for example, children may fall behind in their education, and adults can become housebound. Comorbid psychiatric disorders have become an area of intense interest. Comorbid depression for example, is frequently the symptom that leads the individual to seek treatment. Patients with schizophrenia frequently develop obsessions and compulsions, and these symptoms are associated with a poorer outcome. The role of second-generation antipsychotics merits further study in the treatment of this subset of patients. An important step toward delineating specific subgroups within the OCD-schizophrenia axis may be the use of endophenotypic markers. Unfortunately, many patients with OCD will have a less than optimal treatment response. Poor treatment response is associated with serious social disability, but there are few clues to guide clinicians in predicting treatment response in patients with OCD, in terms of specific demographic variables, clinical symptoms, or the presence of comorbid psychiatric disorders.

Dr. Nierenberg is associate director of theDepression Clinical and Research Program atMassachusetts General Hospital and associate professor of psychiatry at Harvard MedicalSchool in Boston. He is also director of the National Institute of Mental Health Bipolar Trials Network, a federally funded infrastructure for the next generation of clinical trials to help patients with bipolar disorder. He was the site principal investigator for the Systematic Treatment Enhancement Program for Bipolar Disorder and was involved in the Sequenced Treatment Alternatives to Relieve Depression study. His research interests focus on bipolar disorder, treatment-resistant depression, and the longitudinal course of affective disorders. Dr. Nierenberg has been listed in The Best Doctors in America for the treatment of mood and anxiety disorders in every edition since 1994.

We report two cases of serotonin syndrome in elderly patients during treatment of psychotic depression with atypical antipsychotics and antidepressants. The first case is a 69-year-old man who was admitted for depression with psychosis and treated with trazodone, risperidone, and sertraline. Subsequently, he developed myoclonus, tremor, cogwheel rigidity, and diaphoresis. The second case is a 72-year-old female initially admitted to a medical inpatient unit for a change in mental status that presented as increased confusion, lethargy, slurred speech, and a fever of 101.5°. She had been on phenelzine and quetiapine. In both cases, all symptoms resolved within 24 hours of the psychotropics being stopped. In both cases, we believe that serotonin syndrome was produced by a combination of an antidepressant and an atypical antipsychotic. There have been several case reports of serotonin syndrome from similar combinations of antidepressant and atypical antipsychotic treatment. Clinicians treating elderly patients with a combination of serotonergic antidepressants and atypical antipsychotics for psychotic depression should be aware of the potential for serotonin syndrome.

Patients with involuntary emotional expression disorder (IEED) have impaired social and occupational functioning and there is currently no Food and Drug Administration-approved treatment. Treatment options include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), dopaminergic agents, and a combination of dextromethorphan and quinidine. Studies of monaminergic agents have typically been small and executed in single-center settings. Assessment measures generally show significant symptomatic improvements, including a reduction in the number of laughing or crying episodes and improvements in patients' clinical condition. The tolerability profiles of these agents are well defined, and include dizziness, tachycardia, and QTc prolongation (TCAs), and sleep and sexual disturbances (SSRIs). The combination of dextromethorphan and quinidine has also been assessed in two large multicenter studies in patients with amyotrophic lateral sclerosis and multiple sclerosis. Compared with placebo and either agent alone, there were significant improvements in symptoms, quality of life, and relationships. The most common side effects were dizziness and nausea, and potential drug interactions with quinidine should also be considered. Choice of treatment should be evidence-based, taking into account both efficacy and tolerability.

Escitalopram is the newest selective serotonin reuptake inhibitor (SSRI) available for use in the United States. It has been approved for the treatment of major depression and generalized anxiety disorder. It is the S-enantiomer of the SSRI citalopram and is highly serotonin specific as it has minimal effect on the reuptake of dopamine or norepinephrine. It is also a well-tolerated medication, with a side-effect profile comparable to the other SSRIs. While a number of side effects have been seen during escitalopram therapy, such as insomnia, nausea, and increased sweating, there are no reported cases of serotonin syndrome associated with escitalopram therapy to date. We present the case of a 24-year-old woman who developed serotonin syndrome after an increase in her escitalopram to 30 mg/day. We will review the diagnostic criteria of serotonin syndrome and the clinical scenarios in which serotonin syndrome can develop. We will also discuss the proposed treatments and role that polypharmacology may play in the development of this clinical entity.

Substance use disorder is the most frequent and clinically significant comorbidity among schizophrenia patients today. All schizophrenia patients should be assessed and monitored carefully regarding their substance use. Those with any regular use of alcohol or other drugs should be considered at risk for multiple adverse effects. As therapies for co-occurring substance use disorders have evolved over the past 20 years, medication management, psychosocial interventions, and rehabilitation models have increasingly emphasized the integration of mental health and substance abuse treatments, attention to group and residential interventions, matching interventions to stage of treatment, comprehensiveness, and long-term perspectives on recovery. Clinicians should understand the implications of each of these principles of care.

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.