Pimavanserin, a novel agent approved for the treatment of Parkinson’s disease psychosis, has potent actions as an antagonist/inverse agonist at serotonin 5HT2A receptors and less potent antagonist/inverse agonist actions at 5HT2C receptors.

In the absence of definitive etiological markers of vulnerability or a unitary profile of pathophysiology for obsessive-compulsive disorder (OCD), obsessive-compulsive (OC) symptom dimensions seem to offer a fruitful point of orientation.The complex clinical presentation of OCD can be summarized using a few consistent and temporally stable symptom dimensions. These can be understood as a spectrum of potentially overlapping features that are likely to be continuous with “normal” worries and extend beyond the traditional nosological boundaries of OCD. Although the understanding of the dimensional structure of obsessive-compulsive symptoms (OCS) is still imperfect, this quantitative approach to phenotypic traits has the potential to advance our understanding of OCD and may aid in the identification of more robust endophenotypes. Preliminary data suggest that these dimensional phenotypes may be useful in studies of the natural history, genetics, neurobiology, and treatment outcome of OCD. A dimensional approach is not mutually exclusive of other methods to parse the larger spectrum of disorders related to OCD. Thus far, age-of-onset of OCS and the individual's “tic-related” status seem to be particularly useful categorical distinctions. Finally, existing assessment methods are inadequate and new dimensional scales are needed to take full advantage of a dimensional approach in clinical and population-based studies.

This article discusses conceptual issues relevant to the prospective diagnosis of the schizophrenic prodrome. Recent efforts to diagnose these patients with operational criteria based on current symptoms are reviewed. Symptomatic patients so identified appear to be treatment-seeking and to have mild cognitive impairments. In addition to being currently symptomatic, these patients are imminently at risk for progression of illness and development of schizophrenia. Data from three international centers suggest that this risk is approximately 40% over the next year of follow-up if untreated. The implications of the reviewed data for the appropriateness of the term “prodromal” and for treatment/prevention research for these patients are discussed.

Previous reports concerning the cerebrospinal fluid (CSF) of pathologic gamblers have described disturbed norepinephrine and dopamine (but not serotonin) functioning in the central nervous system. We analyzed neurotransmitter metabolites in two consecutive 6-mL samples of CSF obtained from 10 pathologic male gamblers punctured at the L4-5 level following 8 hours of fasting along with strict bed rest. Data were compared with those for healthy male controls. In conformity with findings in healthy male controls, we found gradients in CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), but not 4-hydroxy-3-methoxyphenyl glycol (HMPG). Expressing the CSF concentrations as nmol x L-1 x min-1 of tapping time (an estimate of the mass flow through the needle), the levels of 5-HIAA and HMPG (but not HVA) were found to be significantly lower in gamblers. Levels of 5-HIAA and HVA showed a significant correlation in gamblers but not in healthy controls. Taking tapping time into account, the CSF levels of HMPG and 5-HIAA were significantly lower in gamblers. We concluded that, in light of previous CSF findings of disturbed norepinephrine and dopamine function, altered indolamine function cannot be fully ruled out.

Attention-deficit/hyperactivity disorder (ADHD) and conditions involving excessive eating (eg, obesity, binge/loss of control eating) are increasingly prevalent within pediatric populations, and correlational and some longitudinal studies have suggested inter-relationships between these disorders. In addition, a number of common neural correlates are emerging across conditions, eg, functional abnormalities within circuits subserving reward processing and executive functioning. To explore this potential cross-condition overlap in neurobehavioral underpinnings, we selectively review relevant functional neuroimaging literature, specifically focusing on studies probing (i) reward processing, (ii) response inhibition, and (iii) emotional processing and regulation, and we outline 3 specific shared neurobehavioral circuits. Based on our review, we also identify gaps within the literature that would benefit from further research.

The symptoms of functional neurological disorder (FND) are a product of its pathophysiology. The pathophysiology of FND is reflective of dysfunction within and across different brain circuits that, in turn, affects specific constructs. In this perspective article, we briefly review five constructs that are affected in FND: emotion processing (including salience), agency, attention, interoception, and predictive processing/inference. Examples of underlying neural circuits include salience, multimodal integration, and attention networks. The symptoms of each patient can be described as a combination of dysfunction in several of these networks and related processes. While we have gained a considerable understanding of FND, there is more work to be done, including determining how pathophysiological abnormalities arise as a consequence of etiologic biopsychosocial factors. To facilitate advances in this underserved and important area, we propose a pathophysiology-focused research agenda to engage government-sponsored funding agencies and foundations.

The last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the role of the cannabinoid system in modulating the neural circuitry that mediates anxiety and fear responses. This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the acquisition, expression, and extinction of conditioned fear as a model of human anxiety. Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.

Obsessive-compulsive disorder (OCD) and related conditions (trichotillomania, pathological skin-picking, pathological nail-biting) are common and disabling. Current treatment approaches fail to help a significant proportion of patients. Multiple tiers of evidence link these conditions with underlying dysregulation of particular cortico-subcortical circuitry and monoamine systems, which represent targets for treatment. Animal models designed to capture aspects of these conditions are critical for several reasons. First, they help in furthering our understanding of neuroanatomical and neurochemical underpinnings of the obsessive-compulsive (OC) spectrum. Second, they help to account for the brain mechanisms by which existing treatments (pharmacotherapy, psychotherapy, deep brain stimulation) exert their beneficial effects on patients. Third, they inform the search for novel treatments. This article provides a critique of key animal models for selected OC spectrum disorders, beginning with initial work relating to anxiety, but moving on to recent developments in domains of genetic, pharmacological, cognitive, and ethological models. We find that there is a burgeoning literature in these areas with important ramifications, which are considered, along with salient future lines of research.

Assessment and treatment of acute responses to traumatic stress has received much attention since September 11, 2001. This article elucidates principles of early intervention with adults in the immediate (within 48 hours) and early recovery phase (within the first week). The principles have been drawn from research on risk and recover factors, stress and traumatic stress theory, and expert consensus recommendations. The debriefing model is discussed, and principle interventions of psychological first aid, pharmacology, and mass trauma systems are described. This article concludes with brief guidelines for longer-term interventions and recommendations for future research.

Findings from research on psychiatric epidemiology, disaster effects, discrepancies in service use, and cross-cultural psychology are reviewed to generate guidelines for culturally responsive postdisaster interventions. Ethnicity and culture influence mental health care at various points: on need for help; on availability and accessibility of help; on help-seeking comfort (stigma, mistrust), and on the probability that help is provided appropriately. There are aspects of disaster mental health practice that may ameliorate many of barriers that contribute to ethnic disparities in service use. It is proposed that interventions should give greater attention to socially engaged emotions and functioning. To promote disaster recovery, practitioners are advised to: assess community needs early and often; provide easily accessible services; work collaboratively and proactively to reduce stigma and mistrust and engage minorities in care; validate and normalize distress and help-seeking; value interdependence as well as independence as an appropriate developmental goal; promote community action; and advocate for, facilitate, or conduct treatment and evaluation research. Notwithstanding the pain and stress they cause, disasters create opportunities to de-stigmatize mental health needs and build trust between providers and minority communities.

In order to determine the extent to which depression complicates Huntington's disease (HD), we have analyzed the existing literature on depression in HD in order to report the prevalence, clinical manifestations, and treatment of HD depression. By means of MEDLINE literature searches and reviews of HD articles' bibliographies, we identified for our analysis 16 HD depression studies. Our results indicate that the prevalence of depression is 30% for all HD patients. Clinical manifestations of HD depression include a marked increased risk for suicide. The etiology of HD depression is unclear, but may be due to a number of factors, such as dysfunction in the caudate nucleus, dysfunction in the ventral striatum, and various genetic factors that are discussed in this review. Case reports and case series support the efficacy of standard antidepressant interventions in resolving symptoms of depression. Efficacious treatments reported in the literature include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and electro-convulsive therapy. In this study, the successful anecdotal treatment of seven consecutive HD depressed patients with sertraline suggests that sertraline may be a safe and efficacious treatment of HD depression.

Alzheimer’s disease (AD) has long been recognized as a heterogeneous illness, with a common clinical presentation of progressive amnesia and less common “atypical” clinical presentations, including syndromes dominated by visual, aphasic, “frontal,” or apraxic symptoms. Our knowledge of atypical clinical phenotypes of AD comes from clinicopathologic studies, but with the growing use of in vivo molecular biomarkers of amyloid and tau pathology, we are beginning to recognize that these syndromes may not be as rare as once thought. When a clinician is evaluating a patient whose clinical phenotype is dominated by progressive aphasia, complex visual impairment, or other neuropsychiatric symptoms with relative sparing of memory, the differential diagnosis may be broader and a confident diagnosis of an atypical form of AD may require the use of molecular biomarkers. Despite the evolving sophistication in our diagnostic tools, and the acknowledgment of atypical AD syndromes in the 2011 revised diagnostic criteria for AD, the assessment of such patients still poses substantial challenges. We use a case-based approach to review the clinical and imaging phenotypes of a series of patients with typical and atypical AD, and discuss our current approach to their evaluation. One day, we hope that regardless of whether a patient exhibits typical or atypical symptoms of AD pathology, we will be able to identify the condition at a prodromal phase and institute a combination of symptomatic and disease-modifying therapies to support cognitive processes, function, and behavior, and slow or halt progression to dementia.

This article provides an overview of the etiology, epidemiology, and first-line treatment options for obsessive-compulsive disorder (OCD). The subject of treatment-resistant and treatment-refractory OCD is the discussed, including a definition of these often-debated terms, and the latest treatment options delineated. This includes a review of the latest research concerning the pharmacological agents that have been studied as monotherapy or augmenting agents for the treatment of OCD, the use of experimental medications and procedures, treatment with reversible, minimally invasive procedure, such as vagal nerve stimulation and transcranial magnetic stimulation, invasive but the potentially reversible deep brain stimulation, and irreversible lesioning with ablative psychosurgery. A discussion of the role of psychotherapy in the treatment of OCD is also included.

The management of patients with compulsive sexual behavior requires an understanding of the profile of the sexually compulsive or addicted patient. This article summarizes patient characteristics and their implications for treatment. Data from a study of the recovery of 957 patients who had problematic, sexually excessive behavior are presented. Spanning 5 years, the study shows six distinct stages patients experienced and the clinical activities that were most useful to them. A trajectory of a typical diagnosis and treatment path is provided, as well as important resources for physicians and patients.

Development of extrapyramidal symptoms (EPS), particularly tardive dyskinesia (TD), has long been a troubling side effect for patients taking antipsychotics. Atypical antipsychotics have been hailed as an improvement over conventional antipsychotics, offering similar efficacy with more favorable EPS profiles. In the recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, which compared the conventional antipsychotic perphenazine with atypical antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone in patients with schizophrenia, no significant differences in time to treatment discontinuation due to intolerability were observed between treatment groups. However, perphenazine was associated with a higher rate of patients experiencing EPS as well as a significantly higher rate of discontinuation due to EPS, despite the fact that patients with TD at baseline were excluded from the perphenazine group. Unfortunately, due to short treatment duration, the CATIE study did not have the assay sensitivity to detect differences in TD risk among any of the drugs. Thus, the atypical antipsychotics remain the first line of treatment for most patients, with specific drug selection based on benefit-risk profiles that best fit the individual patient's needs. Frequent monitoring, while noting a patient's subjective experience, remains the best strategy for choosing therapy to maximize symptom relief and minimize the impact of EPS and other side effects over the long-term. This article explores the reported results of the CATIE trial regarding EPS and emphasizes the differentiation of the atypicals from perphenazine on EPS and how these results should be incorporated into daily practice for the clinician.

It has been proposed that certain Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I disorders share overlapping clinical features, genetic contributions, and treatment response and fall within an “obsessive-compulsive” spectrum. Obsessive-compulsive personality disorder (OCPD) resembles obsessive-compulsive disorder (OCD) and other spectrum disorders in terms of phenomenology, comorbidity, neurocognition, and treatment response.This article critically examines the nosological profile of OCPD with special reference to OCD and related disorders. By viewing OCPD as a candidate member of the obsessive-compulsive spectrum, we gain a fresh approach to understanding its neurobiology, etiology, and potential treatments.