Intervention in the progression of schizophrenia is an effort not just to deter psychosis but also to protect the brain from physiologic deterioration. Neurodegeneration is believed to result from neurochemical dysregulation during the onset of schizophrenia. Deterioration accrued over recurring psychotic episodes causes cumulative loss of cell processes, loss of gray matter volume, and apoptosis. Neurodegeneration ultimately results in persistent symptomology and functional impairment. Functional decline occurs early in the course of schizophrenia, and the symptoms that emerge during the prodromal stage may derail the normal adolescent neurodevelopment. Both first-episode psychosis and the prodrome may be opportunities to forestall neurodegeneration. Unfortunately, people with schizophrenia often experience a long duration of untreated psychosis. Treatment of first-episode psychosis with antipsychotic agents shows robust response. However, early-stage patients have very high rates of medication noncompliance. Treatment in the prodrome may offer the best chance to delay the onset of illness, mitigate its severity after onset, or even prevent onset of symptoms entirely. Nonpharmacologic treatments during the prodrome, such as education, treatment for substance use, and cognitive-behavioral therapy, are low-risk interventions that are potentially beneficial. Pharmacologic interventions during the prodrome are also effective in delaying onset of illness, but carry the risk of adversely affecting patients who are false positives for prodromal schizophrenia.

In this Expert Roundtable Supplement, Jeffrey A. Lieberman, MD, provides an overview of the neurobiological basis of neurodegeneration and the concept of neuroprotection. Next, Peter F. Buckley, MD, reviews the importance of first-episode psychosis, including duration of untreated illness and medication adherence. Finally, Diana O. Perkins, MD, MPH, reviews treatment strategies for prodromal schizophrenia.

Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia.

In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.

Acute agitation is a nonspecific term applied to an array of syndromes and behaviors. It is frequently defined as an increase in psychomotor activity, aggression, disinhibition/impulsivity, and irritable or labile mood. Etiologies of acute agitation include medical disorders, delirium, substance intoxication or withdrawal, psychiatric disorders, and medication side effects. Treatment of acute agitation requires both environmental and pharmacologic intervention. Patients should be calmed with sedating agents early in the course of treatment, allowing for diagnostic tests to take place. Failure to correctly diagnose causes of agitation may lead to delayed treatment for serious conditions, and can even exacerbate agitation.The most common cause of agitation in patients with schizophrenia is psychotic relapse due to medication nonadherence. Pharmacologic treatment options for these patients include lorazepam and antipsychotic agents. Lorazepam causes nonspecific sedation and treats some substance withdrawal, but has little effect on psychosis. First-generation antipsychotics treat psychosis and, at high enough doses, cause sedation, but may induce extrapyramidal side effects (EPS). Some second-generation antipsychoticshave been approved for the treatment of agitation in schizophrenia. These agents treat psychosis with a favorable EPS profile, but are comparatively expensive and cause risks such as hypotension. However, avoiding EPS may reduce patients' resistance to antipsychotic treatment.

In this expert roundtable supplement, Joseph Battaglia, MD, provides an overview of the definition of acute agitation. Next, Delbert, G. Robinson, MD, outlines evaluation methods for actue agitation. Finally, Leslie Citrome, MD, MPH, reviews interventions for acute and ongoing management of agitation.

The general goals for recovery of patients with schizophrenia are relatively simple: to improve patients' functioning, enable them to return to work or school, and allow them resume normal lives. However, there are differences between inpatient and outpatient treatment as it relates to some of these goals. For example, a hospitalized patient who has just suffered an acute episode may not be able to realistically meet the abovementioned goals. In such cases, clinicians must try to meet more feasible goals: moving patients from an acute episode to remission, reducing symptoms, improving function, and achieving stability outside of the hospital (Slide 1). This road to recovery involves two phases of treatment, inpatient and outpatient, which differ in their pursuit of patient stability. This discussion will touch on some of the differences between inpatient and outpatient treatment as it relates to acute goals and successful long-term treatment.

In awareness of recent developments and upcoming future changes in the conceptualization of obsessive-compulsive disorders (OCDs), a group of 14 experts with specific experience in this area decided that a consensus statement on the present and future of OCD is timely. The group, with their long-term interest and productivity in the area of OCD, met with the specific aim of providing a global perspective. Ten countries from four continents were represented in this 2-day consensus meeting.

The meeting took place in Cape Town on February 27–28, 2006. The participants were asked to prepare and submit a relevant presentation before the meeting in order to enrich the discussion. Six presentations reviewed the following aspects of OCD: diagnosis, epidemiology, neurobiology, treatment, special populations, and pediatric OCD. A draft consensus was prepared, based on the presentations, recent consensus statements, evidence-based guidelines, and the ensuing discussions.

Akathisia is a neurological side effect of antipsychotic medications, which are used to treat various psychiatric disorders. Akathisia is characterized by physical restlessness and a subjective urge to move. Although side effects such as akathisia, dystonia, and dyskinesia are common with the use of conventional antipsychotics, they occur in reduced frequency with the use of new-generation antipsychotics. Despite a lowered incidence profile, akathisia and similar conditions continue to affect patients. Neuroleptic-induced akathisia can present as fidgety movements while seated, rocking in place while standing, pacing, inability to sit or stand still for an extended period of time, and an overwhelming urge to move. These symptoms can cause severe distress and an increased risk of suicide for affected patients. First-line treatment of akathisia includes benzodiazepines or β-blockers for patients who do not have symptoms of Parkinson's disease and anticholinergic medications for patients with Parkinson's symptoms. Clinicians should ensure that an accurate diagnosis of akathisia is made and that target symptoms are decreasing due to treatment. At the same time, it must be ensured that the treatment used does not negatively affect the mental health of the patient. This expert roundtable supplement will address the diagnosis, pathophysiology, phenomenology, classification, and history of akathisiaas well as discuss screening tools and treatment options for the condition.

Patients experiencing a first psychotic episode or early stages of psychosis present with key diagnostic issues for clinicians. At the time of first-episode psychosis presentation, it is crucial that clinicians select the most effective treatment option as immediate intervention offers the best chance for containing the illness. Functional impairment occurs most rapidly at the early stage of illness, and such impairment can influence the patient's future prognosis, alter the level of necessary treatment, and affect morbidity. Although research has shown a decrease in brain gray matter as well as signs of functional impairment in those who develop psychosis, many of these patients remain untreated for extended periods of time and do not visit a clinician due to fear of stigma, a failure to recognize the problem, or complexities of their care system. Prior studies have shown that untreated psychosis results in worse outcome for patients compared to psychosis that is treated earlier in the course of illness. There is a range of treatment options for psychosis, including use of first-generation or second-generation antipsychotic medication. Clinicians should note that both medication types are associated with certain side effects, such as tardive dyskinesia and weight gain, respectively. For all antipsychotics, doses should be lower for patients with a first psychotic episode than for patients with chronic psychosis. Finally, clinicians must consider that patients may present with various comorbidities, such as substance abuse, that also may affect treatment.

This expert roundtable supplement will address the diagnosis and treatment selection for first-episode psychosis as well as comorbidities related to the condition. The use of first- or second-generation antipsychotics for psychosis treatment, dosing guidelines, and the antipsychotic side-effect profile will also be addressed.

Multiple medication use is a common phenomenon, especially in patients with comorbid conditions and those treated with psychiatric drugs such as antidepressants. Combination treatment may result in potentially harmful drug-drug interactions (DDIs). Results of DDIs range from nuisance side effects to serious adverse consequences. DDIs may also result in improved efficacy. Augmentation strategies, for example, are intentional therapeutic DDIs. Pharmacokinetic DDIs occur when a second drug alters the absorption, distribution, metabolism, or clearance of the first drug. Research has concentrated on the relative effects of antidepressants on cytochrome P450 enzymes and, more recently, on drug transporters as potential mediators of clinically important pharmacokinetic DDIs. The most common, clinically relevant pharmacokinetic DDIs involve alteration in oxidative drug metabolism. Pharmacodynamic DDIs occur when the effects of a second drug quantitatively or qualitatively alters those of the first drug. Pharmacodynamic DDIs are not typically studied in vivo because of the potential for a serious adverse effect. All antidepressants can interactpharmacodynamically with certain other drugs. The risk of harmful DDIs can be reduced by recognizing variables that affect dose-concentration-effect relationships. It is important for physicians to weigh the risks and benefits of potential DDIs against the risks thataccompany timid or ineffective disease treatment.

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.

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 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.

Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia.

In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.