Decades of research have shown that youths with disruptive behavior disorders (DBD) are a heterogeneous population. Over the past 20 years, researchers have distinguished youths with DBD as those displaying high (DBD/HCU) versus low (DBD/LCU) callous-unemotional (CU) traits. These traits include flat affect and reduced empathy and remorse, and are associated with more severe, varied, and persistent patterns of antisocial behavior and aggression. Conduct problems in youths with HCU and LCU are thought to reflect distinct causal vulnerabilities, with antisocial behavior in youths with DBD/HCU reflecting a predominantly genetic etiology, while antisocial behavior in youths with DBD/LCU is associated primarily with environmental influences. Here we selectively review recent functional (fMRI) and structural (sMRI) magnetic resonance imaging research on DBD, focusing particularly on the role of CU traits. First, fMRI studies examining the neural correlates of affective stimuli, emotional face processing, empathy, theory of mind, morality, and decision-making in DBD are discussed. This is followed by a review of the studies investigating brain structure and structural connectivity in DBD. Next, we highlight the need to further investigate females and the role of sex differences in this population. We conclude the review by identifying potential clinical implications of this research.

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.

Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to mode Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

There has been increasing recognition that antipsychotic nonadherence is common across all stages of schizophrenia, starting from the first episode. Moreover, numerous meta-analyses of the existing literature indicate superiority of long-acting injectable (LAI) over oral antipsychotics when one adjusts for the greater illness severity and duration among patients in LAI antipsychotic trials. The increasing availability of LAI antipsychotic options has raised interest in converting patients from oral medication; however, the successful transition from oral to the comparable LAI antipsychotic requires an understanding of the current extent of antipsychotic exposure, the kinetics of the LAI preparation, and the expected plasma levels achieved by the LAI formulation. The purpose of this article is to provide, in a concise format, the essential information for converting patients to the LAI forms of haloperidol, fluphenazine, risperidone, paliperidone, olanzapine, and aripiprazole from the comparable oral medication, and how the use of plasma antipsychotic levels can be invaluable for this process.

The boundaries between obsessive-compulsive disorder (OCD) and other neuropsychiatric disorders remain unresolved and may well differ from one disorder to another. Endophenotypes are heritable, quantitative traits hypothesized to more closely represent genetic risk for complex polygenic mental disorders than overt symptoms and behaviors. They may have a role in identifying how closely these disorders are associated with another and with other mental disorders with which they share major comorbidity. This review maps the nosological relationships of OCD to other neuropsychiatric disorders, using OCD as the prototype disorder and endophenotype markers, such as cognitive, imaging, and molecular data as well as results from demographic, comorbidity, family, and treatment studies. Despite high comorbidity rates, emerging evidence suggests substantial endophenotypic differences between OCD and anxiety disorders, depression, schizophrenia, and addictions, though comparative data is lacking and the picture is far from clear. On the other hand, strong relationships between OCD, Tourette syndrome, body dysmorphic disorder, hypochondriasis, grooming disorders, obsessive-compulsive personality disorder, and pediatric autoimmune neuropsychiatric disorders associated with streptococcus are likely. Studies designed to delineate the cause, consequences, and common factors are a challenging but essential goal for future research in this area.

Posttraumatic stress disorder (PTSD) is a common and disabling condition. In addition to combat-related PTSD, the disorder occurs in civilians exposed to severe traumatic events, with the community prevalence rate for the combined populations reaching as high as 12%. If left untreated, PTSD may continue for years after the stressor event, resulting in severe functional and emotional impairment and a dramatic reduction in quality of life, with negative economic consequences for both the sufferer and society as a whole. Although PTSD is often overlooked, diagnosis is relatively straight-forward once a triggering stressor event and the triad of persistent symptoms—reexperiencing the traumatic event, avoiding stimuli associated with the trauma, and hyperarousal—have been identified. However, comorbid conditions of anxiety and depression frequently hamper accurate diagnosis. Treatment for PTSD includes psychotherapy and pharmacotherapy. The latter includes selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Only SSRls have been proven effective and safe in long-term randomized controlled trials. Current guidelines from the Expert Consensus Panel for PTSD recommend treatment of chronic PTSD for a minimum of 12–24 months.

Parkinson's disease is primarily considered to be a movement disorder and is defined by its motor signs. Yet, the behavioral manifestations of the disease are often more debilitating than its motor complications. This review will focus on the non-motor aspects of Parkinson's disease, including mood, psychosis, cognitive, sleep, fatigue, apathy, delirium, and repetitive disorders, that may occur. The phenomenology, pathology, and treatment of the behavioral symptoms of Parkinson's disease will be discussed.

Since their introduction 50 years ago, antidepressants have been used in a wide variety of settings involving gastrointestinal (GI) disease. In the 1950s, antidepressants were shown to have some efficacy for the treatment of peptic ulcer disease. This is most likely due to their antihistaminic and anticholinergic effects. Since then, more efficacious and more disease-specific treatments have become available. In the last 20 years, antidepressants have been increasingly used for the treatment of functional gastrointestinal disorders such as irritable bowel syndrome, noncardiac chest pain, and other functional GI disorders. This article will review the rationale for the use of antidepressant drugs for the treatment of functional GI disorders. The role of psychiatric comorbidity in functional GI disorders, the impact of antidepressants on GI motility and visceral sensation, and the ability of these agents to produce improvements in the global well-being and overall quality of life will be reviewed. Finally, guidelines for prescribing and barriers to a patient's acceptance of these agents will be discussed.

What is the best approach for treating patients with social phobia (social anxiety disorder) over the long term? Social phobia is the most common anxiety disorder, with reported prevalence rates of up to 18.7%. Social phobia is characterized by a marked and persistent fear of being observed or evaluated by others in social performance or interaction situations and is associated with physical, cognitive, and behavioral (ie, avoidance) symptoms. The onset of social phobia typically occurs in childhood or adolescence and the clinical course, if left untreated, is usually chronic, unremitting, and associated with significant functional impairment. Social phobia exhibits a high degree of comorbidity with other psychiatric disorders, including mood disorders, anxiety disorders, and substance abuse/dependence. Few people with social phobia seek professional help despite the existence of beneficial treatment approaches. The efficacy, tolerability, and safety of the selective serotonin reuptake inhibitors (SSRIs), evidenced in randomized clinical trials, support these agents as first-line treatment. The benzodiazepine clonazepam and certain monoamine oxidase inhibitors (representing both reversible and nonreversible inhibitors) may also be of benefit. Treatment of social phobia may need to be continued for several months to consolidate response and achieve full remission. The SSRIs have shown benefit in longterm treatment trials, while long-term treatment data from clinical studies of clonazepam are limited but support the drug's efficacy. There is also evidence for the effectiveness of exposure-based strategies of cognitive-behavioral therapy, and controlled studies suggest that the effects of treatment are generally maintained at long-term follow-up. In light of the chronicity and disability associated with social phobia, as well as the high relapse rate after short-term therapy, it is recommended that effective treatment be continued for at least 12 months.

Anxiety and depression are common disorders that frequently co-exist. Both disorders show good response to antidepressants, especially the selective serotonin reuptake inhibitors. Some suggest that these disorders are variants of the same underlying brain pathology. This review examines the similarities and differences between anxiety and depression in terms of the known neurobiological etiologic mechanisms as well as their biological underpinnings and response to treatment. Sufficient and significant differences between these disorders support the view that they are independent entities. Shared abnormalities in the 5HT1A receptor function, for example, may help explain some of the comorbidity.

Introduction: The co-occurrence of obsessive-compulsive disorder (OCD) in patients with schizophrenia and related disorders has been increasingly recognized. However, the rate of psychosis comorbidity in OCD patients has yet to be systematically evaluated.

Methods: The prevalence of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition psychotic disorders was evaluated in 757 subjects consecutively referred to a specialised diagnostic and treatment facility for OCD. Demographic and clinical characteristics were assessed.

Results: Thirteen OCD patients (1.7%) also met the DSM-IV criteria for a psychotic disorder. We found no significant differences in clinical characteristic between OCD patients with and without a psychotic disorder, although patients with OCD and a psychotic disorder more likely used illicit substances and more likely were male.

Conclusion: Relatively few patients referred to a specialized treatment OCD center suffer from a psychotic disorder.

Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. PTSD is disabling and commonly follows a chronic course. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. A twin study of Vietnam veterans has shown significant genetic contribution to PTSD. The fact that PTSD's underlying genotypic vulnerability is only expressed following trauma exposure limits the usefulness of family-based linkage approaches. In contrast to the other major psychiatric disorders, large studies for the search of underlying genes have not been described in PTSD to date. Complementary approaches for locating involved genes include association-based studies employing case-control or parental genotypes for transmission dysequilibrium analysis and quantitative trait loci studies in animal models. Identification of susceptibility genes will increase our understanding of traumatic stress disorders and help to elucidate their molecular basis. The current review provides an up-to-date outline of progress in the field of PTSD.

Introduction: Body dysmorphic disorder (BDD) is an often severe disorder, but few treatment studies have been conducted.

Objective: This pilot study explored the efficacy and safety of the antiepileptic medication levetiracetam for BDD.

Methods: Seventeen subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition BDD participated in a 12-week open-label levetiracetam trial. Subjects were assessed at regular intervals with standard measures.

Results: In intent-to-treat analyses, scores on the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS), the primary outcome measure, decreased from 32.5±4.7 at baseline to 21.5±11.0 at endpoint (P<.001). Approximately 60% (n=9) of subjects were responders (≥30% decrease on the BDD-YBOCS). The mean time to response was 4.6±2.8 (range: 2-10) weeks. Scores also significantly improved on the Brown Assessment of Beliefs Scale, the Hamilton Rating Scale for Depression, the Global Assessment of Functioning Scale, and the Social and Occupational Functioning Assessment Scale. Scores did not significantly improve on the Quality of Life Enjoyment and Satisfaction Questionnaire, the Beck Anxiety Inventory, or the Social Phobia Inventory. The mean endpoint dose of levetiracetam was 2,044.1±1,065.2 (range: 250–3,000) mg/day, and it was relatively well-tolerated.

Conclusion: Randomized, double-blind placebo-controlled studies of levetiracetam for BDD are needed to confirm these preliminary findings.

Learning Objective: Discuss the theory of modulation of receptor activity or the blockade of the reuptake of multiple neurotransmitter systems for the future treatment of MDD.

Major depressive disorder (MDD) is a serious and often crippling psychiatric illness with a high risk of relapse and treatment resistance. In this article, we discuss the role of the serotonergic system in MDD including our current understanding of how various serotonin (5HT) receptors modulate monoamine neurotransmission and behavior. We also discuss how pharmacologic interventions, including novel and existing antidepressants and atypical antipsychotics, may be utilized to adjust serotonergic neurotransmission and provide more effective treatments for patients with MDD.