For the first time in 20 years, the American Psychiatric Association (APA) updated the psychiatric diagnostic system for mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Perhaps one of the most notable changes in the DSM-5 was the recognition of the possibility of mixed symptoms in major depression and related disorders (MDD). While MDD and bipolar and related disorders are now represented by 2 distinct chapters, the addition of a mixed features specifier to MDD represents a structural bridge between bipolar and major depression disorders, and formally recognizes the possibility of a mix of hypomania and depressive symptoms in someone who has never experienced discrete episodes of hypomania or mania. This article reviews historical perspectives on “mixed states” and the recent literature, which proposes a range of approaches to understanding “mixity.” We discuss which symptoms were considered for inclusion in the mixed features specifier and which symptoms were excluded. The assumption that mixed symptoms in MDD necessarily predict a future bipolar course in patients with MDD is reviewed. Treatment for patients in a MDD episode with mixed features is critically considered, as are suggestions for future study. Finally, the premise that mood disorders are necessarily a spectrum or a gradient of severity progressing in a linear manner is argued.

The purpose of this article is to review aspects of the neuropsychology of temporal lobe epilepsy. Evidence will be presented to demonstrate that the cognitive consequences of this focal seizure disorder can be more generalized in nature than expected. Consistent with the extratemporal neurocognitive findings, careful quantitative magnetic resonance imaging volumetrics have shown that structural brain changes may be detected outside the temporal lobes. Many factors can potentially affect cognition and brain structure. We focus on the potential neurodevelopmental impact of early-onset temporal lobe epilepsy on brain structure and cognition positing that this disorder can have both immediate and lifespan implications for cognition and psychosocial status.

The predominantly inattentive (IN) subtype of attention-deficit/hyperactivity disorder (ADHD) is a recently defined condition that is often overlooked by professionals and is still not completely understood. Characterized by symptoms of inattentiveness, such as distractibility, failure to complete work, forgetfulness, and disorganization, the IN subtype differs from the more commonly recognized combined (CB) subtype of ADHD in that symptoms of hyper activity and impulsivity are absent or minimal. Large-scale epidemiologic studies suggest that the IN subtype is at least as prevalent as the CB subtype, and is at least as likely to be associated with academic and/or social impairment. Diagnosis of the IN subtype, however, may be more challenging because in addition to inattentiveness, other symptoms, including learning problems, depression, and anxiety, may also present without externalizing behaviors. Several studies have shown that compared with the CB subtype, the IN subtype has a later age of onset and referral, a relatively larger proportion of affected females, and is much less likely to be associated with symptoms of oppositional defiant disorder or conduct disorder. Research is currently under way to examine the cognitive characteristics of the IN subtype and its genetic and neurobiologic underpinnings, as well as to evaluate the effectiveness of pharmacotherapy and other treatments.

The amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

There are specific challenges to studying the design of pharmacologic trials in child/adolescent and adult autism, such as subject stratification and parallel versus crossover designs. This article describes how optimal study design is influenced by subject selection and outcome measures chosen. Lessons learned in study design from the Research Units on Pediatric Psychopharmacology Autism Network trial with risperidone, Seaver Center trials with fluoxetine and valproate, Dartmouth trials with amantadine, and National Institutes of Health secretin trials are highlighted. The Internet System for Assessing Autistic Children system for managing multicenter clinical trials in autism and statistical issues in autism research are also described.

Forensic psychiatric settings contain a high prevalence of treatment-resistant violent schizophrenia patients. Clozapine therapy has the most robust data for the management of violence in patients with schizophrenia, but for those who cannot tolerate or refuse clozapine, high-dose antipsychotic treatment to high achieve high plasma levels remains a viable option despite limited evidence for efficacy in controlled trials. This article enumerates rational guidelines for employing high plasma level strategies, emphasizing the appropriate interpretation of, and reaction to high plasma antipsychotic levels in these treatment resistant patients, and the need to push treatment to the limits of tolerability or clinical response.

In the last decade, increasing literature focused on camouflaging as a strategy adopted to cope with social environment by patients with autism spectrum disorder (ASD). A better understanding of this phenomenon may shed more light on cognitive mechanisms and coping strategies of patients in the autism continuum, eventually leading to reconsider some previous “dogmas” in this field, such as the gender discrepancy in ASD diagnosis. Moreover, shared features can be observed in the camouflaging strategies adopted among the general population, among patients of the autism spectrum, and among patients with different kinds of psychiatric disorders, further challenging our perspectives. Camouflaging behaviors might be considered as a transdiagnostic element, closely associated with the continuous distribution of the autism spectrum among the general and the clinical population.

In this article, the literature examining the relationship between testosterone and various cognitive domains in elderly men is reviewed. The review focuses on the role of endogenous testosterone levels and the effects of androgen depletion and replacement. The cognitive domains most commonly linked to testosterone include memory and visuospatial function. Indeed, the literature suggests that in certain conditions (ie, hypogonadism, cognitive impairment) testosterone levels may be significantly associated with memory and visuospatial function, but not other cognitive functions. Studies with larger sample sizes and more sensitive cognitive measures are indicated, as questions remain about the potential role of testosterone as a cognitive enhancer.

Objectives: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20,40, and 60 mg.

Methods: Study A, an open-label single-period study, and Study B, a randomized, open-label, three threeway crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20,40, and 60 mg separated by 7-14-day washout periods.

Findings: Plasma dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of D-amphetamine to L-amphetamine was observed for AUC0-∞ and Cmax. Tmax was 4.2 and 4.3 hours for D-amphetamine to Lamphetamine, respectively. In Study B, for D- and Lamphetamine, statistically significant differences were observed for AUC0-t, AVC0-∞, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5–5.3 hours) with all given MAS XR doses.

Conclusion: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of D-amphetamine to L-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

While the etiologies of pervasive developmental disorders (PDDs) appear complicated, multifactorial, and relatively poorly understood research over the last 30 to 40 years has implicated certain neurochemicals in the pathophysiology of these diseases. From these studies, a great deal of evidence has emerged supporting a role for serotonergic dysfunction in individuals with autism and related disorders. Recent clinical trials of drugs influencing serotonergic systems have demonstrated promising effects in children, adolescents, and adults with PDDs.

Attention-deficit/hyperactivity disorder (ADHD) is a highly genetic neuropsychiatric disorder that can cause impairment at school, work, home, and in social relationships. Once considered a childhood disorder, as many as 65% of children with ADHD continue to exhibit symptoms into adulthood. While a mainstay of ADHD patient care, immediate-release stimulant use has been constrained by concerns about safety, tolerability, and issues related to nonmedical use and abuse. These concerns have prompted interest in developing modified versions or new delivery systems for stimulants. Prodrugs have been used in pharmaceutical development to optimize delivery of an active drug or to minimize toxicity. Prodrugs are pharmacologically inactive compounds that require in vivo conversion to release therapeutically active medications. Lisdexamfetamine dimesylate (LDX) is an inactive, water-soluble prodrug in which d-amphetamine is bonded to l-lysine, a naturally occurring amino acid. After oral ingestion, LDX is metabolized into l-lysine and active d-amphetamine. This review of LDX presents the efficacy, safety, and pharmacokinetic profile of this novel stimulant medication, and is intended to help clinicians understand its role in treating children and adults with ADHD.

ISSUE:The low incidence of extrapyramidal side effects associated with the atypical antipsychotic iloperidone may be linked to its unique binding profile of high affinity antagonism of both α1 adrenergic receptors and serotonin 2A receptors.

Extensive clinical experience and research suggest that a cortico-limbic-subcortico-thalamic-ponto-cerebellar network plays a significant role in the expression of human emotions. This network includes specific cerebral, cerebellar, and brainstem areas and their multiple projections/pathways, with activity modulated through serotonergic, dopaminergic, glutamatergic, and possibly sigma receptor neurotransmitter systems. Disruptions of regulatory and inhibitory mechanisms in the structure and function of this network likely constitute a pathophysiological basis for the crying and laughing episodes characteristic of involuntary emotional expression disorder. Pharmacologic interventions targeting the neurochemical modulators of the emotional expression systems may afford opportunities for symptom control among persons affected by this disorder.

The DSM–5 incorporates a broad concept of mixed states and captured ≥3 nonoverlapping symptoms of the opposite polarity using a “with mixed features” specifier to be applied to manic/hypomanic and major depressive episodes. Pharmacotherapy of mixed states is challenging because of the necessity to treat both manic/hypomanic and depressive symptoms concurrently. High-potency antipsychotics used to treat manic symptoms and antidepressants can potentially deteriorate symptoms of the opposite polarity. This review aimed to provide a synthesis of the current evidence for pharmacotherapy of mixed states with an emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized controlled trials (RCTs) that were at least moderately sized, included a placebo arm, and contained information on acute-phase and maintenance treatments of adult patients with mixed episodes or mania/hypomania with significant depressive symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from RCTs for acute manic and mixed episodes of bipolar I disorder; only two prospectively examined efficacy for mixed mania/hypomania specifically. Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the strongest evidence of efficacy in acute-phase treatment. Quetiapine and divalproex/valproate were also efficacious. Combination therapies with these atypical antipsychotics and mood stabilizers can be considered in severe cases. Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed the strongest evidence of efficacy in maintenance treatment. Lithium and lamotrigine may be beneficial given their preventive effects on suicide and depressive relapse. Further prospective studies primarily focusing on mixed states are needed.

Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.

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.