Objective: To assess long-term cardiovascular effects of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) combined subtype.

Methods: 223 otherwise healthy adults (≥18 years of age) with ADHD combined subtype were exposed to ≤24 months of MAS XR (20–60 mg/day). Resting sitting diastolic blood pressure (DBP) and systolic blood pressur (SBP) and pulse were measured at baseline and weekly, then monthly during long-term treatment. Twelve-lead electrocardiograms were obtained at screening/baseline, weekly, then at 3-and 6-month intervals up to 24 months.

Findings: With MAS XR 20–60 mg/day, mean changes in DBP (1.3±9.2 mm Hg; P=.O42), SBP (2.3±12.5 mmHg; P=.OO6), and pulse (2.1±13.4 bpm; P=.019) were small and not clinically significant. A clinically insignificant increase in QTcB (corrected by Bazett's formula) interval (7.2 msec; P<.001) was observed at 24 months. No subject exhibited QTcB interval >480 msec (QTcF [corrected by Fridericia's formula] >454 msec). Seven subjects discontinued due to a car-diovascular adverse event (hypertension, n=5, palpitation/tachycardia, n=2); none of these events was reported as serious. Few subjects with normal baseline vital signs (using approved parameters at the time of study initiation) exhibited clinically significant abnormalities at end point; several subjects with borderline baseline values exhibited shifts to abnormal values during MAS XR therapy.

Conclusion: Cardiovascular effects of long-term MAS XR (≤60 mg/day) were minimal in otherwise healthy adults with ADHD. Nevertheless, vital signs should be monitored prior to and during treatment with any stimulant.

What is the impact of attention-deficit/hyperactivity disorder (ADHD) on the phenotypic expression of pediatric obsessive-compulsive disorder (OCD). We examined phenotypic features, and functional and clinical correlates in youths with OCD, with and without comorbid ADHD, from a large sample of consecutively referred pediatric psychiatry patients. Although comorbid ADHD had no meaningful impact on the phenotypic expression or clinical correlates of OCD, it was associated with higher rates of compromised educational functioning compared with other OCD youths. Our findings suggest that the OCD phenotype runs true and is not impacted by comorbid ADHD in youths diagnosed with both OCD and ADHD. In such affected youths, both disorders contribute to morbid dysfunction and require treatment. More work is needed to determine whether OCD plus ADHD represents a developmentally and etiologically distinct form of the OCD syndrome.

The duration of untreated illness (DUI), defined as the interval between the onset of a psychiatric disorder and the administration of the first pharmacological treatment, has been increasingly investigated in the last decade as a predictor of outcome across different psychiatric conditions including schizophrenia and psychotic disorders (duration of untreated psychosis), and mood and anxiety disorders. Converging evidence indicates that a prolonged DUI may be viewed as a negative prognostic factor in schizophrenia and increasing data point toward a similar conclusion in mood and anxiety disorders. Through a Medline search, the present article highlights the role of the DUI in this group of psychiatric disorders, focusing on social and psychopathological determinants of the DUI, as well as the clinical consequences related to a longer DUI in terms of outcome. Hypotheses on neurobiological mechanisms underpinning outcome differences in relation to a prolonged DUI are provided and methodological limitations related to the assessment of the DUI in published studies and clinical practice discussed. Finally, given that DUI is supposed to be a potentially modifiable prognostic factor, intervention programs aimed to reduce this variable are briefly considered and discussed.

Deep brain stimulation (DBS) is established as a therapy for movement disorders, and it is an investigational treatment in other neurologic conditions. DBS precisely targets neuroanatomical targets deep within the brain that are proposed to be centrally involved in the pathophysiology of some neuropsychiatric illnesses. DBS is nonablative, offering the advantages of reversibility and adjustability. This might permit therapeutic effectiveness to be enhanced or side effects to be minimized. Preclinical and clinical studies have shown effects of DBS locally, at the stimulation target, and at a distance, via actions on fibers of passage or across synapses. Although its mechanisms of action are not fully elucidated, several effects have been proposed to underlie the therapeutic effects of DBS in movement disorders, and potentially in other conditions as well. The mechanisms of action of DBS are the focus of active investigation in a number of clinical and preclinical laboratories. As in severe movement disorders, DBS may offer a degree of hope for patients with intractable neuropsychiatric illness. It is already clear that research intended to realize this potential will require a very considerable commitment of resources, energy, and time across disciplines including psychiatry, neurosurgery, neurology, neuropsychology, bioengineering, and bioethics. These investigations should proceed cautiously.

Antidepressants constitute a central cornerstone in the treatment of depressive syndromes. In bipolar patients, however, there is an ongoing controversy about their usefulness for at least 3 decades. Early reports, mainly concerning tricyclic antidepressants, have repeatedly pointed toward unfavorable side effects on the course of the disorder, namely switching into (hypo)mania, induction of rapid cycling, and increased risk of suicide. Most evidence for both unfavorable and favorable effects has been deducted, thus far, from small studies with methodological flaws. More substantiated evidence only recently became available. From this it appears that, at least, the switch risk, and perhaps also the risk for rapid cycling and new-onset suicidality have been overinterpreted. At the same time, these new data raise doubt about the efficacy of anti-depressants as a primary-treatment choice in bipolar depression.

Repetitive transcranial magnetic stimulation (rTMS), defined as the administration of a series of magnetic stimuli to the brain for the purpose of altering brain function, is an experimental medical intervention. rTMS currently is used to probe various aspects of brain function in the context of research studies approved by local ethics committees. rTMS also is under investigation as a potential treatment for various neurologic and psychiatric disorders. In light of the growing interest in using rTMS in a variety of experimental and therapeutic settings, the International Society for Transcranial Stimulation has recognized the need to formulate a consensus statement to assist the field in developing guidelines for its safe application. Whether the intended use is experimental or therapeutic, certain principles regarding the safety of rTMS apply. This statement is not aimed at guiding the therapeutic use of rTMS in any given condition or its application in any research paradigm, but rather is meant to apply broadly wherever rTMS is used.

rTMS has significant risks, most importantly that of producing epileptic seizures. The degree of risk varies with the dosing parameters and individual subject factors. Therefore, rTMS should be administered only under a licensed physician's orders (ie, by prescription or through some other mechanism that makes a physician directly responsible for its administration to the individual patient or research subject). Because rTMS has potential behavior-changing effects, undesirable side effects, and therapeutic impact, careful assessment of the risk and appropriateness of rTMS in each clinical or scientific context is critical and can only be made by, or in consultation with, a physician knowledgeable and experienced in the use of rTMS and fully trained in neurology, psychiatry, or another appropriate specialty.

In the last decades, increasing attention has been provided to socio-cultural and neurobiological factors involved in the psychopathology of feeding and eating disorders (FED), encouraging a multifactorial approach. In this framework, several authors stressed an association between FED and other kinds of psychiatric disorders from both a psychopathological and a neurobiological point of view. In particular, many promising contributions are focusing on the possible link between FED and autism spectrum disorder (ASD). Growing interest about this association rose from the frequently reported evidence of ASD-like traits amongst FED patients and abnormal eating behaviors amongst patients with ASD. This narrative review overview aims to summarize the most relevant findings about the overlap between different kinds of FED and the autism spectrum, taking into account the most recent hypotheses about the psychopathology of both these conditions. While most of the studies focused on anorexia nervosa, both ASD and autistic traits seem to be detectable also in other kinds of FED. In addition, the recently increased interest toward a dimensional approach to psychopathology led to progressively broadening the concept of ASD, focusing on its subthreshold and gender-specific manifestations and on its link with other psychiatric conditions, including FED. Globally the studies summarized here provide further support to theoretical models featuring a neurodevelopmental approach for mental disorders. In particular, FED have been conceptualized as a possible psychopathological trajectory of a neurodevelopmental alteration, toward which female gender would act as one of many predisposing factors.

Guidelines for treating various conditions can be helpful in setting practice standards, but the presence of several sets of guidelines from different countries, experts, and settings, written at different times, can also create confusion. Here we provide a “guideline of guidelines” for the treatment of schizophrenia, or “meta-guidelines,” which not only reconcile the various existing standards but also update them to include the use of several newer agents, most of which were marketed following the publication of existing standards.

Mixed affective states, defined as the coexistence of depressive and manic symptoms, are complex presentations of manic-depressive illness that represent a challenge for clinicians at the levels of diagnosis, classification, and pharmacological treatment. The evidence shows that patients with bipolar disorder who have manic/hypomanic or depressive episodes with mixed features tend to have a more severe form of bipolar disorder along with a worse course of illness and higher rates of comorbid conditions than those with non-mixed presentations. In the updated Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5), the definition of “mixed episode” has been removed, and subthreshold nonoverlapping symptoms of the opposite pole are captured using a “with mixed features” specifier applied to manic, hypomanic, and major depressive episodes. However, the list of symptoms proposed in the DSM–5 specifier has been widely criticized, because it includes typical manic symptoms (such as elevated mood and grandiosity) that are rare among patients with mixed depression, while excluding symptoms (such as irritability, psychomotor agitation, and distractibility) that are frequently reported in these patients. With the new classification, mixed depressive episodes are three times more common in bipolar II compared with unipolar depression, which partly contributes to the increased risk of suicide observed in bipolar depression compared to unipolar depression. Therefore, a specific diagnostic category would imply an increased diagnostic sensitivity, would help to foster early identification of symptoms and ensure specific treatment, as well as play a role in suicide prevention in this population.

Violent behavior associated with mental disorders is a common reason for admission to a psychiatric inpatient unit. Once hospitalized, patients may continue to be intermittently agitated and have persistent aggressive behaviors, preventing their discharge back into the community. Managing agitation quickly with effective pharmacological agents can avoid further escalation to aggression and violence. In the acute setting, this usually involves the parenteral use of antipsychotics, with or without benzodiazepines. Within the past decade, short-acting intramuscular formulations of second-generation antipsychotics have become available and provide a means to induce calm with a substantially lower risk of acute dystonia or akathisia compared with haloperidol. New alternative formulations that avoid injections include inhalation and sublingual administration. Longer-term management of persistent aggressive behavior by reducing the frequency and intensity of future episodes of agitation is more complex. In contrast to agitation associated with schizophrenia or bipolar mania, no agents have yet been approved by regulatory agencies for the treatment of persistent aggressive behavior. The strongest evidence supports the use of clozapine as an antihostility agent, followed by olanzapine. Adjunctive strategies with anticonvulsants and beta-adrenergic agents may also be worthwhile to consider.

This article reviews the theory, clinical application, and empirical findings on mindfulness–based cognitive therapy (MBCT) for mental health and addictive disorders. Expanding upon the research demonstrating the efficacy of cognitive-behavioral therapy (CBT) for addiction, this article develops and explores the rationale for combining mindfulness-based interventions with evidence-based CBTs in treating addictive disorders, with an emphasis on substance use disorders with co-occurring mood disorders.This article proposes that deficits in affect regulation — related to the behavioral and emotional effects of neurobiological changes that occur with longterm substance abuse — pose a unique set of challenges in early recovery. Prolonged use of addictive substances impairs the brain pathways to detach or maintain perspective in response to strong emotional states. In treating this affective dysregulation, which can contribute to the vulnerability to relapse in the early stages of recovery, the affect–regulation-specific focus of MBCT adds a valuable element to augment CBT for addiction. Summarizing magnetic resonance imaging and positron emission tomography findings on the effects of MBCT and the neurobiology of drug addiction, this article out-lines directions for further research on potential benefits of MBCT for the recovering individual. Finally, this article describes a structured protocol, developed at the Mount Sinai School of Medicine in New York City, which combines CBT with mindfulness-based intervention, for the treatment of affect-regulation issues specific to co-occurring addictive and mood disorders.

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Despite the large number of depressed patients who do not respond to first-line antidepressants, the evidence base of alternate strategies is quite thin. In this article, a simple 5-stage system for categorizing treatment-resistant depression (TRD) is described and the evidence pertaining to the major strategies currently utilized is summarized using four grades, ranging from D (case reports only) to A (multiple positive placebo-controlled trials). It is concluded that the level of evidence supporting many of the contemporary strategies used for TRD (eg, combinations of antidepressants and augmentation with medications such as pindolol, buspirone, or modafinil) is scanty at best. Even the fundamental question concerning “to augment or to switch” is not answerable with available data. It is noted that the best-documented treatments (ie, lithium augmentation, switching to a monoamine oxidase inhibitor, and electroconvulsive therapy) are among the least utilized. This state of affairs will improve with completion of the studies of Systematic Treatment Alternatives to Relieve Depression, a large multicenter study of difficult-to-treat depression funded by the National Institute of Mental Health. There is a need for greater collaboration among academicians and organizations, such as the American Psychiatric Association, the National Institute of Mental Health, and the pharmaceutical industry, to ensure that sufficient research is conducted so that clinician's choices for patients with TRD can be guided by empirical evidence.

Research on effective pharmacotherapy for body dysmorphic disorder (BDD) has rapidly increased in recent years, with emerging data consistently indicating that serotonin reuptake inhibitors (SRIs) are often efficacious for this disorder. Although data are limited, it appears that higher SRI doses and longer treatment trials than those used for many other psychiatric disorders are often needed to treat BDD effectively. Approaches to treatment-resistant BDD have received little investigation, but available data indicate that switching to another SRI and several SRI-augmentation strategies may be helpful. This article reviews the empirical literature on BDD and offers a recommended approach to the pharmacotherapy of this distressing and often disabling disorder.

Recently, findings on a wide range of auditory abnormalities among individuals with autism have been reported. To date, functional distinctions among these varied findings are poorly established. Such distinctions should be of interest to clinicians and researchers alike given their potential therapeutic and experimental applications. This review suggests three general trends among these findings as a starting point for future analyses. First, studies of auditory perception of linguistic and social auditory stimuli among individuals with autism generally have found impaired perception versus normal controls. Such findings may correlate with impaired language and communication skills and social isolation observed among individuals with autism. Second, studies of auditory perception of pitch and music among individuals with autism generally have found enhanced perception versus normal controls. These findings may correlate with the restrictive and highly focused behaviors observed among individuals with autism. Third, findings on the auditory perception of non-linguistic, non-musical stimuli among autism patients resist any generalized conclusions. Ultimately, as some researchers have already suggested, the distinction between impaired global processing and enhanced local processing may prove useful in making sense of apparently discordant findings on auditory abnormalities among individuals with autism.