Showing papers in "Cns Spectrums in 2013"

Hot and cold cognition in depression.

Abstract: We discuss the importance of cognitive abnormalities in unipolar depression, drawing the distinction between "hot" (emotion-laden) and "cold" (emotion-independent) cognition. "Cold" cognitive impairments are present reliably in unipolar depression, underscored by their presence in the diagnostic criteria for major depressive episodes. There is good evidence that some "cold" cognitive abnormalities do not disappear completely upon remission, and that they predict poor response to antidepressant drug treatment. However, in many studies the degree of impairment is moderately related to symptoms. We suggest that "cold" cognitive deficits in unipolar depression may in part be explicable in terms of alterations in "hot" processing, particularly on tasks that utilize feedback, on which depressed patients have been reported to exhibit a "catastrophic response to perceived failure." Other abnormalities in "hot" cognition are commonly observed on tasks utilizing emotionally valenced stimuli, with numerous studies reporting mood-congruent processing biases in depression across a range of cognitive domains. Additionally, an emerging literature indicates reliable reward and punishment processing abnormalities in depression, which are especially relevant for hard-to-treat symptoms such as anhedonia. Both emotional and reward biases are strongly influenced by manipulations of the neurochemical systems targeted by antidepressant drugs. Such a pattern of "hot" and "cold" cognitive abnormalities is consistent with our cognitive neuropsychological model of depression, which proposes central roles for cognitive abnormalities in the generation, maintenance, and treatment of depressive symptoms. Future work should examine in greater detail the role that "hot" and "cold" cognitive processes play in mediating symptomatic improvement following pharmacological, psychological, and novel brain circuit-level interventions.

The efficacy of initial hydrocortisone administration at preventing posttraumatic distress in adult trauma patients: a randomized trial.

Abstract: INTRODUCTION: Secondary pharmacological interventions have shown promise at reducing the development of posttraumatic stress disorder symptoms (PTSS) in preclinical studies. The present study examined the preliminary efficacy of a 10-day low-dose (20 mg bid) course of hydrocortisone at preventing PTSS in traumatic injury victims. METHODS: Sixty-four traumatic injury patients (34% female) were randomly assigned in a double-blind protocol to receive either a 10-day course of hydrocortisone or placebo initiated within 12 hours of the trauma. One-month and 3-months posttrauma participants completed an interview to assess PTSS and self-report measures of depression and health-related quality of life. RESULTS: Hydrocortisone recipients reported fewer PTSD and depression symptoms, and had greater improvements in health-related quality of life during the first 3 months posttrauma than did placebo recipients. Hydrocortisone recipients who had never received prior mental health treatment had the lowest PTSD scores. CONCLUSION: Low-dose hydrocortisone may be a promising approach to the prevention of PTSD in acutely injured trauma patients, and may be particularly efficacious in acutely injured trauma victims without a history of significant psychopathology. Language: en

Defining anxious depression: a review of the literature

Abstract: The diagnosis of anxious depression is presently inconsistent. The many different definitions of anxious depression have complicated its diagnosis, leading to clinical confusion and inconsistencies in the literature. This article reviewed the extant literature in order to identify the varying definitions of anxious depression, which were then compared using Feighner's diagnostic criteria. Notably, these suggest a different clinical picture of patients with anxious depression. For instance, relying on The International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses yields a clinical picture of a comparatively mild or transient disorder; in contrast, using dimensional criteria such as DSM criteria combined with additional rating scales-most commonly the anxiety somatization factor score from the Hamilton Depression Rating Scale (HAM-D)-yields a more serious clinical picture. The evidence reviewed here suggests that defining anxious depression in a dimensional manner may be the most useful and clinically relevant way of differentiating it from other types of mood and anxiety disorders, and of highlighting the most clinically significant differences between patients with anxious depression versus depression or anxiety alone.

Quality of life in obsessive compulsive disorder.

Abstract: Obsessive-compulsive disorder (OCD) has a profound impact with a high disease burden. In order to truly understand the scope of the effect OCD has on the patient population, one must take into account not only the relentless symptoms beleaguering the patients but also examine their overall ability to enjoy their life. Quality of life (QOL) assessments/improvements are becoming an increasingly important component of healthcare, especially in the mental health field. This review examines QOL in OCD, as well as the influence of comorbidities, and the impact that OCD treatment has on QOL. We searched MEDLINE/PUBMED and PsycINFO databases from 1980-2011 using keywords "obsessive compulsive disorder" OR "OCD" AND "quality of life" OR "QOL." Fifty-eight studies meeting specific selection criteria were ultimately included in this review. The results show that QOL in OCD is significantly impaired when compared to QOL in the general population and in patients with other psychiatric and medical disorders. Likewise, QOL in OCD also appears to be largely affected by comorbid conditions, which should be taken into account when developing a treatment plan. Furthermore, QOL in OCD has been shown to improve with medications and with both individual and group psychotherapy, albeit not to the levels enjoyed by community norms. QOL assessment in both clinical and research settings is important to examine the disease burden, to monitor treatment effectiveness, and to determine full recovery from OCD. Treatment providers should strive to not only reach symptom abatement, but also to assure that patients have regained satisfaction and functioning in their daily lives.

New insights into the mechanism of drug-induced dyskinesia.

Abstract: Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/ or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long term treatment with antipsychotic drugs. Dyskinesia is also induced with levodopa, a treatment for Parkinson's disease,and it occurs spontaneously as a symptom of Huntington's disease. Research on the pathogenesis of TD has focused on a dysfunction of either the dopaminergic or serotonergic system. However, recent evidence has suggested that we should focus on the possible damage of GABAergic medium spiny neurons (MSNs). MSNs are the first station in the corticostriato-thalamo-cortical circuit that regulates the amplitude and velocity of movements. Two pathways can be distinguished in this circuit: a direct pathway, which increases movements (hyperkinesia), and an indirect pathway,which decreases movements (hypokinesia). Both pathways are activated by glutamatergic corticostriatal neurons. Here,we discuss some evidence that supports the hypothesis that indirect pathway MSNs are damaged in dyskinesia.

Pharmacokinetics and pharmacodynamics of psychotropic drugs: effect of sex.

Abstract: Data on the specific effects of sex on pharmacokinetics, as well as tolerability, safety, and efficacy of psychotropic medications are still meager, mainly because only recently sex-related issues have attracted a certain degree of interest within the pharmacological domain. Therefore, with the present study, we aimed to provide a comprehensive review of the literature on this topic, through careful MEDLINE and PubMed searches of the years 1990-2012. Generally, data on pharmacokinetics are more consistent and numerous than those on pharmacodynamics. Sex-related differences have been reported for several parameters that influence pharmacokinetics, such as gastric acidity, intestinal motility, body weight and composition, blood volume, liver enzymes (mainly the cytochrome P450), or renal excretion, which may alter plasma drug levels. Sex-related peculiarities may also account for a different sensitivity of men and women to side effects and toxicity of psychotropic drugs. Further, some differences in drug response, mainly to antipsychotics and antidepressants, have been described. Further studies are, however, necessary to explore more thoroughly the impact of sex on the pharmacokinetics and pharmacodynamics of psychotropic drugs, in order to reach the most appropriate and tailored prescription for each patient.

“Meta-guidelines” for the management of patients with schizophrenia.

Abstract: 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.

A pooled analysis of six month comparative efficacy and tolerability in four randomized clinical trials: agomelatine versus escitalopram, fluoxetine, and sertraline.

Abstract: OBJECTIVE A pooled-analysis on the long-term outcome in four head-to-head studies: agomelatine versus fluoxetine, sertraline, and (twice) escitalopram. Method A meta-analytic approach was used. Hamilton Depression Rating Scale (HAM-D) scores, response and remission rates, Clinical Global Impression of Improvement (CGI-I) scores, response and remission rates, and completion rates/discontinuation rates due to adverse events were analyzed. RESULTS At the last post-baseline assessment on the 24-week treatment period, the final HAM-D-17 score was significantly lower in patients treated with agomelatine than in patients treated with selective serotonin reuptake inhibitors (SSRIs), as well in the total group of patients with severe depression (P = 0.014 and 0.040, respectively). HAM-D response rates at the end of 24 weeks were significantly higher in patients treated with agomelatine than in patients treated with SSRIs, as well in the total group of patients with severe depression (P = 0.031 and 0.048, respectively). HAM-D remission rates at the end of 24 weeks were numerically but not significantly higher in patients treated with agomelatine than in patients treated with SSRIs. Final CGI-I scores were significantly lower for agomelatine. CGI-I response as well as remission rates were numerically higher in patients treated with agomelatine, without statistical significance. The percentage of patients with at least one emergent adverse event leading to treatment discontinuation was 9.4% in patients treated with SSRIs and 6.6% in patients treated with agomelatine (P = 0.065). CONCLUSION The present pooled analysis shows that, from a clinical point of view, agomelatine is at least as efficacious as the investigated SSRIs with a trend to fewer discontinuations due to adverse events.

Psychopharmacology and psychotherapy for the treatment of adults with ADHD-a systematic review of available meta-analyses.

Abstract: UNLABELLED OBJECTIVE/INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) in adult life is a prevalent condition. We systematically reviewed the literature available by searching for meta-analyses assessing pharmacological and psychosocial interventions for adults with ADHD. METHODS Using wide-ranging search terms, we retrieved 191 titles from the PubMed and Cochrane databases. Two independent evaluators judged all abstracts. Only meta-analyses about the treatment of adults with ADHD were included. Information from meta-analyses found was systematically extracted by 3 independent evaluators. RESULTS Eight meta-analyses were identified. Results from those meta-analyses suggest that stimulants are effective in decreasing ADHD symptoms on a short-term basis with a medium to large effect size (ES). Short-acting stimulants might be superior to long-acting stimulants, but no data on difference in adherence are available for the comparison of these two types of formulation. Bupropion is superior to placebo but less effective than stimulants. No conclusions about the impact of psychosocial interventions can be drawn based on meta-analyses so far. Discussion The efficacy of stimulants in reducing ADHD symptoms for adults is well documented in meta-analyses, but there is a concerning lack of meta-analysis about other treatment interventions. CONCLUSION The available meta-analytic literature does not cover questions of essential clinical relevance for adults with ADHD.

Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses.

Abstract: IntroductionClozapine is considered the gold standard for the treatment of patients with treatment-resistant schizophrenia (TRS); however, randomized controlled trials (RCT) of olanzapine showed efficacy similar to clozapine in patients with TRS.MethodsA systematic review was conducted comparing clozapine with olanzapine in patients with TRS. Meta-analyses were performed for single outcome measures. Response to treatment was measured by the percentage of responders, or mean change or endpoint values of psychotic symptoms scales. Effect sizes were shown as relative risks (RR), or standardized mean differences, with 95% confidence intervals.FindingsSeven RCT were included, comprising 648 patients. Five meta-analyses were performed. Olanzapine and clozapine had similar effects on dropout rates (RR = 0.93, CI95% = 0.77–1.12), PANSS total endpoints (SMD = 0.21, CI95% = –0.04–0.46), and PANSS total mean changes (SMD = 0.08, CI95% = –0.01–0.027). Clozapine was superior to olanzapine for PANSS positive (SMD = 0.51, CI95% = 0.17–0.86) and negative (SMD = 0.50, CI95% = 0.16–0.85) subscales. There was a trend toward high doses of olanzapine producing higher effect sizes for this drug.ConclusionsThe results of this study suggest that clozapine is significantly more efficacious than olanzapine in improving positive and negative symptoms in TRS patients.

A neuroscientific update on monoamine oxidase and its inhibitors

Abstract: The goal of this brief review is to explain the role of monoamine oxidase enzymes in the neurobiology, etiology, and presentation of psychiatric illnesses, primarily major depressive disorder. This article will initially focus on the basic science and function of the monoamine oxidase system and some proposed neuropsychiatric symptoms that may arise if this enzyme system is altered by genetic predisposition. These findings and theories will next be translationally discussed in regard to clinical application pertaining to enzyme inhibition and the treatment of major depressive and other psychiatric disorders.

Second messenger/signal transduction pathways in major mood disorders: Moving from membrane to mechanism of action, part I: Major depressive disorder

Abstract: The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [γ-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid-based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3β, and NFκB/ΔFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed.

A review of FDA-approved treatment options in bipolar depression.

Abstract: Objectives/IntroductionHerein we review the evidence supporting Food and Drug Administration (FDA) approved and emerging treatments for bipolar depression.MethodsA PubMed search of all English-language articles published up to July 2013 was conducted. The search terms were quetiapine, olanzapine-fluoxetine, olanzapine, lurasidone, ketamine, modafinil/armodafinil, and lamotrigine. The search was augmented with a manual review of relevant article reference lists, as well as posters presented at national and international meetings. Articles selected for review were based on the adequacy of sample size, the use of standardized diagnostic instruments, validated assessment measures, and overall manuscript quality.ResultsOlanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone are FDA-approved for the acute treatment of bipolar depression. Lurasidone is the most recently approved agent for bipolar depression. Olanzapine-fluoxetine combination and quetiapine are approved as single modality therapies while lurasidone is approved as a monotherapy and as an adjunct to lithium or divalproex. The overall effect size of the 3 treatments in mitigating depressive symptoms is similar. Clinically significant weight gain and metabolic disruption as well as sedation are significant limitations of OFC and quetiapine. The minimal propensity for weight gain as well as the metabolic neutrality of lurasidone in the bipolar population is a clinically significant advantage. Evidence also supports lamotrigine with compelling evidence as an adjunct to lithium and in recurrence prevention paradigm; suggested evidence also exists for ketamine and modafinil/armodafinil; notwithstanding, these treatments remain investigational.ConclusionRelatively few agents are FDA-approved for bipolar depression. The selection and sequencing of agents in bipolar depression should give primacy to those agents that are FDA-approved. Further refinement of the selection process will need to pay careful attention to the relative hazards of weight gain and metabolic disruption in this highly susceptible population. Other agents with differential mechanisms (eg, ketamine) offer a promising alternative in bipolar depression.

Cerebral basis of posttraumatic stress disorder following the Chernobyl disaster

Abstract: Background Whether posttraumatic stress disorder (PTSD) following radiation emergency has psychopathological, neurocognitive, and neurophysiological peculiarities is at issue. Objective The goal was to explore the features and cerebral basis of "radiation" PTSD in the survivors of the Chernobyl accident. Subjects and Methods The cross-sectional study included 241 people, 219 of whom have been diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, among them 115 clean-up workers of the Chernobyl accident (34 with acute radiation sickness), 76 evacuees from the Chernobyl exclusion zone, 28 veterans of the war in Afghanistan, and 22 healthy unexposed individuals. Psychometric examinations, neurocognitive assessments, computerized electroencephalography, and cerebral vascular Doppler were used. Results "Radiation" PTSD includes "flashforward" phenomena and anticipating stress (projection of fear and danger to the future); somatoform disorders (depression, trait and state anxiety); and neurocognitive deficit (impaired memory and attention, auditory-verbal memory and learning, proactive and retroactive interference, cerebellar and stem symptoms, intellectual changes). The intima-media component, thickness of common carotid arteries, and common and left internal carotid arteries stenosis rates are increased in the liquidators. Changes of bioelectrical brain activity as a decrease of beta- and theta-power, together with an increase of alpha-power, were found in the Chernobyl accident survivors with PTSD. Conclusions PTSD following radiation emergency is characterized by comorbidity of psychopathology, neurocognitive deficit, and cerebrovascular pathology with increased risk of cerebral atherosclerosis and stroke. The cerebral basis of this PTSD is proposed to be an abnormal communication between the pyramidal cells of the neocortex and the hippocampus, and deep brain structures. It is recommended that a system of emergency and long-term psychological and psychiatric care be organized for the survivors in Fukushima Daichi, Japan.

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of quality of life outcome measures in clinical practice

Abstract: Background Transcranial magnetic stimulation (TMS) is an effective and safe therapy for major depressive disorder (MDD). This study assessed quality of life (QOL) and functional status outcomes for depressed patients after an acute course of TMS. Methods Forty-two, U.S.-based, clinical TMS practice sites treated 307 outpatients with a primary diagnosis of MDD and persistent symptoms despite prior adequate antidepressant pharmacotherapy. Treatment parameters were based on individual clinical considerations and followed the labeled procedures for use of the approved TMS device. Patient self-reported QOL outcomes included change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the EuroQol 5-Dimensions (EQ-5D) ratings from baseline to end of the acute treatment phase. Results Statistically significant improvement in functional status on a broad range of mental health and physical health domains was observed on the SF-36 following acute TMS treatment. Similarly, statistically significant improvement in patient-reported QOL was observed on all domains of the EQ-5D and on the General Health Perception and Health Index scores. Improvement on these measures was observed across the entire range of baseline depression symptom severity. Conclusion These data confirm that TMS is effective in the acute treatment of MDD in routine clinical practice settings. This symptom benefit is accompanied by statistically and clinically meaningful improvements in patient-reported QOL and functional status outcomes.

Mechanism of action of ketamine.

Abstract: Ketamine induces rapid-onset and short-duration improvement in depressive and suicidal symptoms in both treatment-resistant unipolar depression and bipolar depression, and also reduces chronic pain after short intravenous infusions. In order to develop long-acting oral agents with the same clinical effects, the pharmacologic mechanism of action must be understood, and the leading hypotheses are discussed here.

Long-term safety and tolerability of iloperidone: results from a 25-week, open-label extension trial.

Abstract: Introduction/ObjectiveLong-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone.MethodsPatients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion.ResultsA total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total.Discussion/ConclusionThis study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.

Prefrontal cortex, dopamine, and jealousy endophenotype.

Abstract: Jealousy is a complex emotion characterized by the perception of a threat of loss of something that the person values,particularly in reference to a relationship with a loved one, which includes affective, cognitive, and behavioral components. Neural systems and cognitive processes underlying jealousy are relatively unclear, and only a few neuroimaging studies have investigated them. The current article discusses recent empirical findings on delusional jealousy, which is the most severe form of this feeling, in neurodegenerative diseases. After reviewing empirical findings on neurological and psychiatric disorders with delusional jealousy, and after considering its high prevalence in patients with Parkinson's disease under dopamine agonist treatment, we propose a core neural network and core cognitive processes at the basis of (delusional) jealousy, characterizing this symptom as possible endophenotype. In any case,empirical investigation of the neural bases of jealousy is just beginning, and further studies are strongly needed to elucidate the biological roots of this complex emotion.

Alzheimer's disease drug development: translational neuroscience strategies.

Abstract: Alzheimer's disease (AD) is an urgent public health challenge that is rapidly approaching epidemic proportions. New therapies that defer or prevent the onset, delay the decline, or improve the symptoms are urgently needed. All phase 3 drug development programs for disease-modifying agents have failed thus far. New approaches to drug development are needed. Translational neuroscience focuses on the linkages between basic neuroscience and the development of new diagnostic and therapeutic products that will improve the lives of patients or prevent the occurrence of brain disorders. Translational neuroscience includes new preclinical models that may better predict human efficacy and safety, improved clinical trial designs and outcomes that will accelerate drug development, and the use of biomarkers to more rapidly provide information regarding the effects of drugs on the underlying disease biology. Early translational research is complemented by later stage translational approaches regarding how best to use evidence to impact clinical practice and to assess the influence of new treatments on the public health. Funding of translational research is evolving with an increased emphasis on academic and NIH involvement in drug development. Translational neuroscience provides a framework for advancing development of new therapies for AD patients.

Glutamate system as target for development of novel antidepressants

Abstract: Depression is a common psychiatric condition characterized by affective, cognitive, psychomotor, and neurovegetative symptoms that interfere with a person's ability to work, study, deal with interpersonal relationships, and enjoy once-pleasurable activities After the serendipitous discovery of the first antidepressants, for years the only pharmacodynamic mechanisms explored in the search of novel antidepressants were those related to the 3 main monoamines: serotonin, norepinephrine, and dopamine New-generation monoaminergic antidepressants, such as selective-serotonin and dual-acting serotonin/norepinephrine reuptake inhibitors, improved treatment and quality of life of depressed patients Nevertheless, there are still important clinical limitations: the long latency of onset of the antidepressant action; side effects, which can lead to early discontinuation; low rate of response; and high rate of relapse/recurrence Therefore, in the last several years, the focus of research has moved from monoamines toward other molecular mechanisms, including glutamatergic (Glu) neurotransmission This review provides a comprehensive overview of the current knowledge on the Glu system and on its relationships with mood disorders Up to now, N-methyl-D-aspartate (NMDA) receptor antagonists, in particular ketamine, provided the most promising results in preclinical studies and produced a consistent and rapid, although transient, antidepressant effect with a good tolerability profile in humans Although data are encouraging, more double-blind, randomized, placebo-controlled trials are needed to clarify the real potentiality of ketamine, and of the other Glu modulators, in the treatment of unipolar and bipolar depression

Incentive salience: novel treatment strategies for major depression.

Abstract: This article proposes that a recent shift in our understanding of dopamine function may support translational research to target deficits in positive emotions and reward processing in individuals with major depressive disorder (MDD). We review how dopamine functions to modulate approach behaviors in response to positive incentives, and we describe the incentive salience hypothesis, which posits that dopamine primarily modulates "wanting," or anticipatory reward, rather than "liking," or subjective pleasure. Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or "liking," it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it provides a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD.

Understanding depot antipsychotics: an illustrated guide to kinetics.

Abstract: Long-acting injectable (LAI) antipsychotics can have considerable advantages over oral medications for the management of patients with schizophrenia. Despite the high prevalence of treatment nonadherence with oral pharmacotherapy, LAI antipsychotics are significantly underutilized in this patient population. The availability of newer LAI antipsychotic preparations combined with a resurgent interest in the use of typical antipsychotics has rekindled awareness of the value of LAI medications. This article is intended to provide a visual understanding of the various kinetic profiles of LAI antipsychotics to facilitate initiation and greater use of these agents.

The last Diagnostic and Statistical Manual (DSM): replacing our symptom-based diagnoses with a brain circuit-based classification of mental illnesses.

Abstract: ISSUE:Current psychiatric diagnoses are defined “top-down” based upon clinical phenomenology, but may give way to defining mental illnesses “bottom-up” based upon genetic and molecular factors that regulate information processing in neuronal circuits, and that can be visualized with neuroimaging techniques.

A systematic review of the evidence for the treatment of acute depression in bipolar I disorder.

Abstract: In this article, we examined evidence for the acute treatment of depression in bipolar I disorder, focusing on double-blind, placebo-controlled studies with a definite primary outcome measure and published in peer review journals. Quetiapine and olanzapine/fluoxetine are currently approved by the FDA for the treatment of bipolar depression, and a number of additional agents (including other atypical antipsychotics, mood stabilizers, antidepressants, and novel compounds) have been studied with varying degrees of efficacy. The medication with the most evidence for efficacy in bipolar depression is quetiapine, with five studies showing positive efficacy compared to placebo. In contrast, five studies of lamotrigine were negative, although meta-analyses of the pooled have found some treatment effects. Two studies of olanzapine and olanzapine/fluoxetine and three small studies of divalproex showed significant efficacy in treating bipolar depression. Two studies of aripiprazole found no differences compared to placebo. Early research on lithium in bipolar depression had significant methodological flaws, and only one study of lithium met our primary search criteria. To better understand the role of antidepressants, we also examined studies of antidepressants as adjunctive treatment of bipolar depression in participants taking mood stabilizers or atypical antipsychotics. These studies reported mixed results for a variety of antidepressants, but the majority found no differences compared to placebo. Other studies of adjunctive treatment were also discussed. There has been one positive adjunctive study each of lamotrigine, omega-3 fatty acids, modafinil, and armodafinil, while there was one negative trial each of omega-3 fatty acids, ziprasidone, and levetiracetam.

Role of α1 adrenergic antagonism in the mechanism of action of iloperidone: reducing extrapyramidal symptoms.

Abstract: 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.

Second messenger/signal transduction pathways in major mood disorders: moving from membrane to mechanism of action, part II: bipolar disorder.

Abstract: In this second of two articles on second messenger/signal transduction cascades in major mood disorders, we will review the evidence in support of intracellular dysfunction and its rectification in the etiopathogenesis and treatment of bipolar disorder (BD). The importance of these cascades is highlighted by lithium's (the gold standard in BD psychopharmacology) ability to inhibit multiple critical loci in second messenger/signal transduction cascades including protein kinase C (involved in the IP3/PIP2 pathway) and GSK-3β (canonically identified in the Wnt/Fz/Dvl/GSK-3β cascade). As a result, and like major depressive disorder (MDD), more recent pathophysiological studies and rational therapeutic targets have been directed at these and other intracellular mediators. Even in the past decade, intracellular dysfunction in numerous neuroprotective/apoptotic cascades appears important in the pathophysiology and may be a future target for pharmacological interventions of BD.

A factor analytic study in bipolar depression, and response to lamotrigine

Abstract: Objective There have been no previous factor analytic studies of the Hamilton Depression Rating Scale (HDRS) in samples with bipolar I depression, and no investigations of the utility of any derived factors in determining treatment response in this condition. This study aimed to identify and compare factors of a 31-item version of the HDRS (HDRS-31) in large samples of patients with bipolar depression and Major Depressive Disorder (MDD), then examine the responsiveness of such factors to lamotrigine compared with placebo in the bipolar depressed sample. Methods This multivariate analytical study was performed on 2 large depressed samples (one bipolar and the other MDD) that had been recruited for separate, contemporaneous, double-blind placebo-controlled trials of lamotrigine. The 2 studies had similar designs and assessment tools, the major measures being the Montgomery-Asberg Depression Rating Scale (MADRS) and HDRS-31. To identify the constructs underlying the scale, exploratory factor analyses were conducted using HDRS-31 baseline scores. Treatment responsiveness in the bipolar depressed sample-as indicated by improvement in the total MADRS and HDRS-31, as well as HDRS factors-were examined using both a mixed-effects analysis and individual time-point t-tests. Results Seven factors of the HDRS-31 were identified: I-"depressive cognitions," II-"psychomotor retardation," III-"insomnia," IV-"hypersomnia," V-"appetite and weight change," VI-"anxiety," and VII-"anergia." A significant therapeutic effect of lamotrigine in bipolar depression was found for the "depressive cognitions" factor (from week 3) and "psychomotor retardation" (from week 4). Conclusion This study has identified 7 factors of the HDRS in a large sample of patients with bipolar depression. The results suggest that that the clinical benefits of lamotrigine in acute bipolar depression are primarily upon depressive cognitions and psychomotor slowing.

Limbic and motor circuits involved in symmetry behavior in Tourette's syndrome

Abstract: OBJECTIVE The need for symmetry and ordering objects related to a "just right"-feeling is a common symptom in Tourette's syndrome (TS) and resembles symmetry behavior in obsessive-compulsive disorder, but its pathophysiology is unknown. We used a symptom provocation paradigm to investigate the neural correlates of symmetry behavior in TS and hypothesized the involvement of frontal-striatal and limbic brain areas. METHODS Pictures of asymmetrically and symmetrically arranged objects were presented in randomized blocks (4 blocks of each condition) to 14 patients with TS and 10 matched healthy controls (HC). A H2 15O positron emission tomography scan was acquired during each stimulus block, resulting in 8 scans per subject. After each scan, state anxiety and symmetry behavior (the urge to rearrange objects) were measured using a visual analogue scale. RESULTS During the asymmetry condition, TS patients showed increased regional cerebral blood flow (rCBF) in the anterior cingulate cortex, supplementary motor area, and inferior frontal cortex, whereas HC showed increased rCBF in the visual cortex, primary motor cortex, and dorsal prefrontal cortex. Symmetry ratings during provocation correlated positively with orbitofrontal activation in the TS group and sensorimotor activation in the HC group, and negatively with dorsal prefrontal activity in HC. CONCLUSIONS Results suggest that both motor and limbic circuits are involved in symmetry behavior in TS. Motor activity may relate to an urge to move or perform tics, and limbic activation may indicate that asymmetry stimuli are salient for TS patients. In contrast, symmetry provocation in HC resulted in activation of brain regions implicated in sensorimotor function and cognitive control.

Is there an association between cortical thickness, age of onset, and duration of illness in schizophrenia?

Abstract: Objective Several studies have shown cortical volume loss in frontotemporal regions in schizophrenia patients, and it is known that these reductions may be associated with disease symptoms and cognitive deficits. The aim of this study was to investigate possible cortical thickness correlations in frontotemporal regions in relation to age at onset and duration of illness. Methods One hundred forty-eight schizophrenia patients (97 males; age and SD 36.30 ± 10.06) and 87 (57 males; age and SD 36.48 ± 10.10) age-matched healthy subjects underwent a brain MRI scan. Cortical segmentation and surface statistical analysis were performed using the FreeSurfer software package. Results were corrected for multiple comparisons using the Monte Carlo method considering a cluster-corrected Type I Error of 5%. Results Compared to controls, schizophrenia patients presented significant cortical thinning in the frontotemporal, parietal, and occipital cortices. No correlation between prefrontal cortex thickness and duration of illness in patients with schizophrenia or between frontotemporal cortical thickness and age at onset was found. However, a significant interaction between age and diagnosis was observed on frontal cortical thickness with patients presenting a thinner cortex than expected for age. Conclusion Although there was no correlation between age of onset and duration of illness with brain volume, our findings suggest that there is an accelerated cortical loss in schizophrenia, thus reinforcing the progressive processes of the disease.

Twisting the night away: a review of the neurobiology, genetics, diagnosis, and treatment of shift work disorder

Abstract: Although not all individuals who work outside of standard daytime hours develop physical and psychiatric issues, there is a substantial portion of shift workers who develop shift work disorder Shift work disorder is due to a misalignment between an individual's endogenous circadian rhythms and environmental stimuli, and can have potentially serious consequences to an individual's health and quality of life This article reviews the neurobiological and genetic underpinnings of shift work disorder, and describes how desynchronization of the molecular clock may lead to both physical and psychiatric illnesses Diagnostic tools and treatment guidelines to address the circadian misalignment, excessive sleepiness, and insomnia experienced by patients with shift work disorder are also discussed