Showing papers in "Cns Spectrums in 2016"

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways.

Abstract: The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (ION Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased ON increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

Expanding the definition of addiction: DSM-5 vs. ICD-11.

Abstract: While considerable efforts have been made to understand the neurobiological basis of substance addiction, the potentially "addictive" qualities of repetitive behaviors, and whether such behaviors constitute "behavioral addictions," is relatively neglected. It has been suggested that some conditions, such as gambling disorder, compulsive stealing, compulsive buying, compulsive sexual behavior, and problem Internet use, have phenomenological and neurobiological parallels with substance use disorders. This review considers how the issue of "behavioral addictions" has been handled by latest revisions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD), leading to somewhat divergent approaches. We also consider key areas for future research in order to address optimal diagnostic classification and treatments for such repetitive, debilitating behaviors.

Neurodevelopmental Disorders (ASD and ADHD): DSM-5, ICD-10, and ICD-11

Abstract: Neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have undergone considerable diagnostic evolution in the past decade. In the United States, the current system in place is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), whereas worldwide, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) serves as a general medical system. This review will examine the differences in neurodevelopmental disorders between these two systems. First, we will review the important revisions made from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) to the DSM-5, with respect to ASD and ADHD. Next, we will cover the similarities and differences between ASD and ADHD classification in the DSM-5 and the ICD-10, and how these differences may have an effect on neurodevelopmental disorder diagnostics and classification. By examining the changes made for the DSM-5 in 2013, and critiquing the current ICD-10 system, we can help to anticipate and advise on the upcoming ICD-11, due to come online in 2017. Overall, this review serves to highlight the importance of progress towards complementary diagnostic classification systems, keeping in mind the difference in tradition and purpose of the DSM and the ICD, and that these systems are dynamic and changing as more is learned about neurodevelopmental disorders and their underlying etiology. Finally this review will discuss alternative diagnostic approaches, such as the Research Domain Criteria (RDoC) initiative, which links symptom domains to underlying biological and neurological mechanisms. The incorporation of new diagnostic directions could have a great effect on treatment development and insurance coverage for neurodevelopmental disorders worldwide.

Nonepileptic seizures: an updated review.

Abstract: Psychogenic nonepileptic seizures (PNES) are a functional neurological disorder/conversion disorder subtype, which are neurobehavioral conditions at the interface of neurology and psychiatry. Significant advancements over the past decade have been made in the diagnosis, management, and neurobiological understanding of PNES. This article reviews published PNES research focusing on semiologic features that distinguish PNES from epileptic seizures, consensus diagnostic criteria, the intersection of PNES and other comorbidities, neurobiological studies, evidence-based treatment interventions, and outcome studies. Epidemiology and healthcare utilization studies highlight a continued unmet medical need in the comprehensive care of PNES. Consensus guidelines for diagnostic certainty are based on clinical history, semiology of witnessed typical event(s), and EEG findings. While certain semiologic features may aid in the diagnosis of PNES, the gold standard remains capturing a typical event on video electroencephalography (EEG) showing the absence of epileptiform activity with history and semiology consistent with PNES. Medical-neurologic and psychiatric comorbidities are prevalent in PNES; these should be assessed in diagnostic evaluations and integrated into treatment interventions and prognostic considerations. Several studies, including a pilot, multicenter, randomized clinical trial, have now demonstrated that a cognitive behavioral therapy-informed psychotherapy is an efficacious treatment for PNES, and additional efforts are necessary to evaluate the utility of pharmacologic and other psychotherapy treatments. Neuroimaging studies, while requiring replication, suggest that PNES may occur in the context of alterations within and across sensorimotor, emotion regulation/processing, cognitive control, and multimodal integration brain systems. Future research could investigate similarities and differences between PNES and other somatic symptom disorders.

Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function.

Abstract: The hippocampus plays an important role in emotional and cognitive processing, and both of these domains are affected in patients with major depressive disorder (MDD). Extensive preclinical research and the notion that modulation of serotonin (5-HT) neurotransmission plays a key role in the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) support the view that 5-HT is important for hippocampal function in normal and disease-like conditions. The hippocampus is densely innervated by serotonergic fibers, and the majority of 5-HT receptor subtypes are expressed there. Furthermore, hippocampal cells often co-express multiple 5-HT receptor subtypes that can have either complementary or opposing effects on cell function, adding to the complexity of 5-HT neurotransmission. Here we review the current knowledge of how 5-HT, through its various receptor subtypes, modulates hippocampal output and the activity of hippocampal pyramidal cells in rodents. In addition, we discuss the relevance of 5-HT modulation for cognitive processing in rodents and possible clinical implications of these results in patients with MDD. Finally, we review the data on how SSRIs and vortioxetine, an antidepressant with multimodal activity, affect hippocampal function, including cognitive processing, from both a preclinical and clinical perspective.

Comorbidity between neurological illness and psychiatric disorders

Abstract: Psychiatric disorders are common in many neurological disorders, including epilepsy, migraine, Alzheimer's disease, Parkinson's disease, essential tremor, and stroke. These comorbidities increase disease burden and may complicate the treatment of the combined disorders. Initial studies of the comorbidity of psychiatric and neurological disorders were cross-sectional, and time order of the associations was impossible to elucidate. More recent work has clarified time associations between psychiatric disorders and neurological disorders, particularly in epilepsy and stroke where epidemiological evidence suggests that there is a bidirectional relationship. This article takes an epidemiological approach to understanding these relationships and focuses mostly on epilepsy. Although, these relationships are understood in many neurological disorders, routine screening for psychiatric disorders in neurological disorders is infrequent, mostly due to the lack of partnerships between psychiatrists and neurologists and the paucity of neuropsychiatrists. Much more needs to be done to improve the detection and treatment of patients affected by neurological and psychiatric disorders. Understanding the scope of this overlap may inspire collaborations to improve the lives of people affected by both disorders.

Psychosis of epilepsy: a multifaceted neuropsychiatric disorder.

Abstract: Psychosis of epilepsy (POE) is a term applied to a group of psychotic disorders with a distinct phenomenology in which potential etiopathogenic mechanisms are believed to be closely related to a seizure disorder. POE can present as interictal psychotic episodes, which may often differ semiologically from primary schizophrenic disorder. They may present as ictal or postictal psychotic episodes and may be the expression of an iatrogenic process to pharmacologic and/or surgical interventions.Epilepsy and POE have a complex and bidirectional relation, as not only are patients with epilepsy at greater risk of developing a psychotic disorder, but patients with a primary psychotic disorder are also at greater risk of developing epilepsy. The prevalence of POE is more than 7 times higher than the frequency of primary schizophreniform disorders in the general population. While POE has been associated with focal epilepsy of temporal and frontal lobe origin, its etiology and pathophysiology of POE have yet to be established.The treatment of all forms of POE, with the exception of ictal psychotic episodes, requires the use of antipsychotic drugs, preferably the atypical antipsychotic agents with a very low or negligible potential to lower the seizure threshold (eg, risperidone, apiprazole), starting at a low dose with stepwise increments.

Mechanism of action of cariprazine.

Abstract: Cariprazine is a new therapeutic agent recently approved for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar disorder, and is under investigation for the treatment of both bipolar depression and major depressive disorder.

Patient-centered assessment of cognitive symptoms of depression.

Abstract: Objective To identify and explore concepts important to patients with cognitive symptoms of major depressive disorder (MDD) and adapt an existing patient-reported outcome (PRO) measure to assess these symptoms. Methods Four focus groups were conducted with MDD patients (n = 33) to elicit relevant concepts and determine whether one of several PRO scales could be used to assess cognitive symptoms of depression. Following selection and minor modification of the Perceived Deficits Questionnaire (PDQ), cognitive debriefing interviews were conducted with additional patients (n = 17) to further refine and adapt this measure for use in MDD. Minor revisions based on patient input yielded the PDQ for Depression (PDQ-D). Results Focus group participants reported a variety of cognitive symptoms that were classified into 7 general categories: lack of focus and clear thought, memory problems, difficulty with lexical access, difficulty with divided attention, difficulty with decision making, difficulty thinking quickly, and difficulty learning new things. Limitations in work productivity were the most commonly reported impacts of cognitive symptoms. While suggesting a few modifications, focus group participants reacted positively to the PDQ based on the breadth, specificity, and relevance of the items. Cognitive debriefing participants indicated that the modified PDQ items were generally easy to understand and relevant to their experiences with MDD. Conclusion Because cognitive symptoms are burdensome to patients with MDD, their assessment is important to optimize treatment outcomes. The PDQ-D has the potential to supplement existing assessment methods, providing unique information important for both comprehensive evaluation of individuals with MDD and evaluation of new treatments.

Mechanism of action of brexpiprazole: comparison with aripiprazole

Abstract: Brexpiprazole is a new therapeutic agent that was recently approved for the treatment of schizophrenia and for the adjunctive treatment of major depressive disorder. Brexpiprazole has features that both overlap and contrast with a related molecule, aripiprazole, and these features are discussed here.

Adult autism spectrum as a transnosographic dimension.

Abstract: Autism is usually diagnosed in childhood on the basis of early impairment in reciprocal communication and social interaction, stereotypic behaviors, late or poor language development, or intellectual retardation. However, subjects with mild forms of autism, with normal or aboveaverage intelligence,may reach high levels of functioning, developing in some cases excellent abilities in restricted areas, and may be undiagnosed until adulthood or misdiagnosed as having other mental disorders. Growing interest has been devoted in the last several years to the adult courses of these conditions, previously labelled as Asperger’s disorder (AD) and recently merged into the autism spectrum disorder (ASD) in the Fifth Edition of theDiagnostic and StatisticalManual ofMental Disorders (DSM-5), along with growing literature indicating that they are associated with high rates of comorbidity with anxiety, mood, psychotic, and traumaand stress-related disorders and with suicidal behaviors. While DSM-5made the attempt to fill the gaps between diagnostic categories by applying a spectrum approach to neurodevelopmental disorders, ASD diagnostic criteria may still be not sensitive enough to detect some adult forms with no intellectual or language disability and characterized by mild impairment in interpersonal and empathic functions, such as attuning and socialization, leading to isolation and social phobias. Individuals with such forms, lying at the boundaries of ASD, might be easily misdiagnosed as having a wide range of personality disorders (eg, schizoid, schizotypal, avoidant, dependent, borderline) or unspecified schizophrenia spectrum disorders and other psychotic disorders. Looking back at Asperger’s original descriptions, he focused on some stable autistic traits, often associated with special abilities, referring to Eugen Bleuler’s concept of autism as a fundamental symptom of schizophrenia and somehow recalling Jung’s “introvert” psychological type and Kretschmer’s “schizoid psychopathy.” Since entering the DSM in 1994, AD has lost the distinctiveness of Asperger’s first observations. Moreover, diagnostic criteria have mostly referred to the childhood course rather than to the adult clinical phenotype. From this perspective, there is no blame for dropping AD as a separate category in DSM-5. However, Asperger’s work should be revised within a coherent adult autism spectrum model that is currently supported by both clinical and neurobiological data. Consistent with Asperger’s intuition, it has been proposed that a neurodevelopmental deviation may represent the common vulnerability factor for most mental disorders (eg, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder), as suggested by their clinical overlap, familial co-aggregation, and shared genetic risk factors with ASD. Along with this hypothesis, genetic and environmental factors would act together to cause a neurodevelopmental deviation, the timing, severity, and anatomical location of which determine a gradient of neuroatypicality underlying different mental conditions. Somehow consistent with this hypothesis, it has been proposed that mental disorders should be reformulated as pathologies of the whole-brain organization, or “globalopathies,” rather than disturbances of a discrete neural network. If a global, brain-based physiopathologymust be hypothesized for psychiatric conditions, this might involve neurodevelopmental processes and the extent to which the brain is neuroatypic. This idea is also in line with some new and intriguing perspectives derived from neurobiological studies that have raised the hypothesis that schizophrenia could be considered a late-onset neurodevelopmental disorder, or the late stage of one, rather than an earlyonset neurodegenerative disease, as initially suggested by the Kraepelinian definition of dementia praecox. Interestingly, growing bodies of data indicate that ASD often remains unrecognized until adulthood, coming to clinical attention only when other mental disorders arise, *Address for correspondence: Liliana Dell'Osso, University of Pisa Department of Clinical and Experimental Medicine, Psychiatry Unit, via Roma 67, 56100 Pisa, Italy. (Email: liliana.dellosso@med.unipi.it) CNS Spectrums (2016), 21, 131–133. © Cambridge University Press 2015 doi:10.1017/S1092852915000450

Psychotic disorders in DSM-5 and ICD-11.

Abstract: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was published by the American Psychiatric Association (APA) in 2013, and the Work Group on the Classification of Psychotic disorders (WGPD), installed by the World Health Organization (WHO), is expected to publish the new chapter about schizophrenia and other primary psychotic disorders in 2017. We reviewed the available literature to summarize the major changes, innovations, and developments of both manuals. If available and possible, we outline the theoretical background behind these changes. Due to the fact that the development of ICD-11 has not yet been completed, the details about ICD-11 are still proposals under ongoing revision. In this ongoing process, they may be revised and therefore have to be seen as proposals. DSM-5 has eliminated schizophrenia subtypes and replaced them with a dimensional approach based on symptom assessments. ICD-11 will most likely go in a similar direction, as both manuals are planned to be more harmonized, although some differences will remain in details and the conceptual orientation. Next to these modifications, ICD-11 will provide a transsectional diagnostic criterion for schizoaffective disorders and a reorganization of acute and transient psychotic and delusional disorders. In this manuscript, we will compare the 2 classification systems.

Lamotrigine compared to placebo and other agents with antidepressant activity in patients with unipolar and bipolar depression: a comprehensive meta-analysis of efficacy and safety outcomes in short-term trials.

Abstract: Objectives To meta-analytically summarize lamotrigine’s effectiveness and safety in unipolar and bipolar depression. Methods We conducted systematic PubMed and SCOPUS reviews (last search =10/01/2015) of randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression. We performed a random-effects meta-analysis of depression ratings, response, remission, and adverse effects calculating standardized mean difference (SMD) and risk ratio (RR) ±95% confidence intervals (CIs). Results Eighteen studies (n=2152, duration=9.83 weeks) in patients with unipolar depression (studies=4, n=187; monotherapy vs lithium=1, augmentation of antidepressants vs placebo=3) or bipolar depression (studies=14, n=1965; monotherapy vs placebo=5, monotherapy vs lithium or olanzapine+fluoxetine=2, augmentation of antidepressants vs placebo=1, augmentation of mood stabilizers vs placebo=3, augmentation of mood stabilizers vs trancylpromine, citalopram, or inositol=3) were meta-analyzed. Lamotrigine’s efficacy for depressive symptoms did not differ significantly in monotherapy vs augmentation studies (vs. placebo: p=0.98, I2=0%; vs active agents: p=0.48, I2=0%) or in unipolar vs bipolar patients (vs placebo: p=0.60, I2=0%), allowing pooling of each placebo-controlled and active-controlled trials. Lamotrigine outperformed placebo regarding depressive symptoms (studies=11, n=713 vs n=696; SMD=–0.15, 95% CI=–0.27, –0.02, p=0.02, heterogeneity: p=0.24) and response (after removing one extreme outlier; RR=1.42, 95% CI=1.13–1.78; p=0.003, heterogeneity: p=0.08). Conversely, lamotrigine did not differ regarding efficacy on depressive symptoms, response, or remission from lithium, olanzapine+fluoxetine, citalopram, or inositol (studies=6, n=306 vs n=318, p-values=0.85–0.92). Adverse effects and all-cause/specific-cause discontinuation were similar across all comparisons. Conclusions Lamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects/discontinuations. Lamotrigine did not differ from lithium, olanzapine+fluoxetine, citalopram, or inositol.

The clinical inadequacy of the DSM-5 classification of somatic symptom and related disorders: an alternative trans-diagnostic model

Abstract: The Diagnostic and Statistical of Mental Disorders, Fifth Edition (DSM-5) somatic symptom and related disorders chapter has a limited clinical utility. In addition to the problems that the single diagnostic rubrics and the deletion of the diagnosis of hypochondriasis entail, there are 2 major ambiguities: (1) the use of the term "somatic symptoms" reflects an ill-defined concept of somatization and (2) abnormal illness behavior is included in all diagnostic rubrics, but it is never conceptually defined. In the present review of the literature, we will attempt to approach the clinical issue from a different angle, by introducing the trans-diagnostic viewpoint of illness behavior and propose an alternative clinimetric classification system, based on the Diagnostic Criteria for Psychosomatic Research.

Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder: a pooled analysis.

Abstract: Objective Antidepressants are frequently associated with treatment-emergent sexual dysfunction (TESD). Vortioxetine, which was approved for patients with major depressive disorder (MDD), has a receptor profile that suggests limited impact on sexual functioning. Methods Arizona Sexual Experiences Scale (ASEX) patient-level data were pooled from 7 short-term vortioxetine trials (6 in MDD, 1 in generalized anxiety disorder) and analyzed for incidence of TESD at any post-baseline visit in patients without sexual dysfunction at baseline (defined as ASEX total score ≥19; individual ASEX item score ≥5; or a score ≥4 on any 3 ASEX items). The primary objective was to confirm the non-inferiority of vortioxetine 5–20 mg/day to placebo on the incidence of TESD. Comparisons were based on the common risk difference (95% confidence interval). Additional analyses compared vortioxetine to duloxetine and duloxetine to placebo. A sensitivity analysis, defined as TESD at 2 consecutive post-baseline visits, was conducted. Results TESD incidence, relative to placebo, generally increased with vortioxetine dose with vortioxetine 5 mg non-inferior to placebo. Vortioxetine 10, 15, and 20 mg did not meet the non-inferiority criterion, but no dose had a significantly higher risk of developing TESD versus placebo. Changes in ASEX individual item scores supported the similarity of vortioxetine doses to placebo. Significantly higher TESD risk occurred with duloxetine 60 mg/day versus placebo and versus vortioxetine 5 or 10 mg. The sensitivity analysis was generally consistent with the primary analysis. Rates of spontaneously reported sexual adverse events were low. Conclusions Vortioxetine was associated with rates of TESD that were not significantly different from placebo in short-term clinical trials.

Mechanism of action of pimavanserin in Parkinson’s disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors

Abstract: 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.

Parkinson's disease psychosis as a serotonin-dopamine imbalance syndrome.

Abstract: Parkinson's disease psychosis (PDP) is theoretically a serotonin-dopamine imbalance syndrome due to disruption of the normal balance between the serotonergic and dopaminergic neurotransmitter systems in key brain circuits.

Psychopharmacological options for adult patients with anorexia nervosa.

Abstract: The aim of this review was to summarize evidence from research on psychopharmacological options for adult patients with anorexia nervosa (AN). Database searches of MEDLINE and PsycINFO (from January 1966 to January 2014) were performed, and original articles published as full papers, brief reports, case reports, or case series were included. Forty-one papers were screened in detail, and salient characteristics of pharmacological options for AN were summarized for drug classes. The body of evidence for the efficacy of pharmacotherapy in AN was unsatisfactory, the quality of observations was questionable (eg, the majority were not blinded), and sample size was often small. More trials are needed, while considering that nonresponse and nonremission are typical of patients with AN.

Addictive behaviors and personality traits in adolescents.

Abstract: Introduction Behavioral addictions refer to repeated dysfunctional behaviors that do not involve the ingestion of addictive substances. Studies on the association between behavioral addictions and personality traits have noted in individuals with problematic behaviors a high proclivity toward impulsivity and sensation-seeking and a low predisposition to harm avoidance. The majority of these studies have focused on adults, while far fewer have involved adolescents. Methods The study population was 109 high school students (age range 15-18 years) in Turin, Italy. Participants completed an assessment that comprised a demographic questionnaire and 3 self-report questionnaires: the Shorter PROMIS Questionnaire (SPQ), the Internet Addiction Test (IAT), and the Multidimensional Questionnaire for Adolescents (QMA). Results A gender-related difference in the risk of developing an addictive behavior was observed, with a significantly higher percentage of risk seen for several addiction tendencies among the males. Statistically significant correlations emerged between some personality determinants and certain addictive behaviors. Discussion The study pinpoints epidemiological indicators for the extent of this growing problem among adolescents. Conclusions The findings have implications for identifying protection factors and risk factors for addictive behaviors and related psychiatric disorders, and the development of primary prevention strategies derived from such factors.

Forgotten but not gone: new developments in the understanding and treatment of tardive dyskinesia.

Abstract: The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an important challenge due the persistent nature of its symptoms and resistance to numerous treatment modalities, including antipsychotic discontinuation. Recent insights on genetic risk factors and new concepts surrounding pathophysiology have spurred interest in the possibility of targeted treatment for TD. As will be reviewed in this article, the number of evidence-based strategies for TD treatment is small: only clonazepam, amantadine, ginkgo biloba extract, and the vesicular monoamine transporter 2 (VMAT2) inhibitor tetrabenazine have compelling data. Using new insights into the metabolism of tetrabenazine and the properties of its active metabolites, 2 modifications of tetrabenazine have been synthesized to improve the kinetic profile, and are currently involved in double-blind placebo controlled studies aimed at U.S. Food and Drug Administration (FDA) regulatory approval. The possible availability of these new agents, deuterated tetrabenazine and valbenazine, significantly widens the range of treatment choices for patients with TD. For clinicians with patients at risk for TD due to dopamine antagonist exposure, experience has shown that the problem of TD will be an ongoing issue in modern psychiatry, and that an appreciation of new developments in the pathophysiology of, risk factors for, and treatment of TD is crucial to managing this condition.

Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission.

Abstract: Previous work from this laboratory hypothesized that the multimodal antidepressant vortioxetine enhances cognitive function through a complex mechanism, using serotonergic (5-hydroxytryptamine, 5-HT) receptor actions to modulate gamma-butyric acid (GABA) and glutamate neurotransmission in key brain regions like the prefrontal cortex (PFC) and hippocampus. However, serotonergic receptors have circumscribed expression patterns, and therefore vortioxetine's effects on GABA and glutamate neurotransmission will probably be regionally selective. In this article, we attempt to develop a conceptual framework in which the effects of 5-HT, selective serotonin reuptake inhibitors (SSRIs), and vortioxetine on GABA and glutamate neurotransmission can be understood in the PFC and striatum-2 regions with roles in cognition and substantially different 5-HT receptor expression patterns. Thus, we review the anatomy of the neuronal microcircuitry in the PFC and striatum, anatomical data on 5-HT receptor expression within these microcircuits, and electrophysiological evidence on the effects of 5-HT on the behavior of each cell type. This analysis suggests that 5-HT and SSRIs will have markedly different effects within the PFC, where they will induce mixed effects on GABA and glutamate neurotransmission, compared to the striatum, where they will enhance GABAergic interneuron activity and drive down the activity of medium spiny neurons. Vortioxetine is expected to reduce GABAergic interneuron activity in the PFC and concomitantly increase cortical pyramidal neuron firing. However in the striatum, vortioxetine is expected to increase activity at GABAergic interneurons and have mixed excitatory and inhibitory effects in medium spiny neurons. Thus the conceptual framework developed here suggests that vortioxetine will have regionally selective effects on GABA and glutamate neurotransmission.

Dissociable brain correlates for depression, anxiety, dissociation, and somatization in depersonalization-derealization disorder

Abstract: Objective: The cerebral mechanisms of traits associated with depersonalization-derealization disorder (DPRD) remain poorly understood. Method: Happy and sad emotion expressions were presented to DPRD and non-referred control (NC) subjects in an implicit event-related functional magnetic resonance imaging (fMRI) design, and correlated with self report scales reflecting typical co-morbidities of DPRD: depression, dissociation, anxiety, somatization. Results: Significant differences between the slopes of the two groups were observed for somatization in the right temporal operculum (happy) and ventral striatum, bilaterally (sad). Discriminative regions for symptoms of depression were the right pulvinar (happy) and left amygdala (sad). For dissociation, discriminative regions were the left mesial inferior temporal gyrus (happy) and left supramarginal gyrus (sad). For state anxiety, discriminative regions were the left inferior frontal gyrus (happy) and parahippocampal gyrus (sad). For trait anxiety, discriminative regions were the right caudate head (happy) and left superior temporal gyrus (sad). Discussion: The ascertained brain regions are in line with previous findings for the respective traits. The findings suggest separate brain systems for each trait.

Relationship between olfactory function and social cognition in euthymic bipolar patients

Abstract: Objective/Introduction There is a close functional and neuroanatomical relationship between olfactory ability and emotional processing. The present study seeks to explore the association between olfactory ability and social cognition, especially facial emotion perception, in euthymic bipolar patients. Methods Thirty-nine euthymic outpatients meeting DSM-IV-TR criteria for bipolar disorder and 40 healthy volunteers matched on socio-demographic criteria were recruited. Both groups were assessed at one time point with the University of Pennsylvania Smell Identification Test (UPSIT), the Emotion Recognition Test, and The Faux Pas Recognition Test, as well as measures of general cognition and functioning. Results The bipolar patients showed a significant impairment in olfactory identification (UPSIT) and social cognition measures compared to healthy controls. Analyses revealed significant relationships between olfactory identification and facial emotion recognition, theory of mind, general cognition, and a trend-level relationship with functioning. Controlling for age and cigarettes smoked, relationships remained significant between olfactory function and facial emotion recognition. Conclusion There is a deficit of olfactory identification in euthymic patients with bipolar disorder that is correlated with a deficit in both verbal and non-verbal measures of social cognition.

Anhedonia and cognitive function in adults with MDD: results from the International Mood Disorders Collaborative Project.

Abstract: Background Cognitive dysfunction is common in major depressive disorder (MDD) and a critical determinant of health outcome. Anhedonia is a criterion item toward the diagnosis of a major depressive episode (MDE) and a well-characterized domain in MDD. We sought to determine the extent to which variability in self-reported cognitive function correlates with anhedonia. Method A post hoc analysis was conducted using data from (N=369) participants with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR)-defined diagnosis of MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. The IMDCP is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Canada, and the Cleveland Clinic, Cleveland, Ohio. Measures of cognitive function, anhedonia, and depression severity were analyzed using linear regression equations. Results A total of 369 adults with DSM-IV-TR-defined MDD were included in this analysis. Self-rated cognitive impairment [ie, as measured by the Adult ADHD Self-Report Scale (ASRS)] was significantly correlated with a proxy measure of anhedonia (r=0.131, p=0.012). Moreover, total depression symptom severity, as measured by the total Montgomery-Asberg Depression Rating Scale (MADRS) score, was also significantly correlated with self-rated measures of cognitive dysfunction (r=0.147, p=0.005). The association between anhedonia and self-rated cognitive dysfunction remained significant after adjusting for illness severity (r=0.162, p=0.007). Conclusions These preliminary results provide empirical data for the testable hypothesis that anhedonia and self-reported cognitive function in MDD are correlated yet dissociable domains. The foregoing observation supports the hypothesis of overlapping yet discrete neurobiological substrates for these domains.

Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.

Abstract: This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

Bipolar and related disorders in DSM-5 and ICD-10.

Abstract: Bipolar disorders are a group of psychiatric disorders with profound negative impact on affected patients. Even if their symptomatology has long been recognized, diagnostic criteria have changed over time and diagnosis often remains difficult. The Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), issued in May 2013, comprises several changes regarding the diagnosis of bipolar disorders compared to the previous edition. Diagnostic categories and criteria for bipolar disorders show some concordance with the internationally also widely used Tenth Edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). However, there are also major differences that are worth highlighting. The aim of the following text is to depict and discuss those.

The separation of adult separation anxiety disorder

Abstract: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) categorization of mental disorders places "separation anxiety disorder" within the broad group of anxiety disorders, and its diagnosis no longer rests on establishing an onset during childhood or adolescence. In previous editions of DSM, it was included within the disorders usually first diagnosed in infancy, childhood, or adolescence, with the requirement for an onset of symptoms before the age of 18 years: symptomatic adults could only receive a retrospective diagnosis, based on establishing this early onset. The new position of separation anxiety disorder is based upon the findings of epidemiological studies that revealed the unexpectedly high prevalence of the condition in adults, often in individuals with an onset of symptoms after the teenage years; its prominent place within the DSM-5 group of anxiety disorders should encourage further research into its epidemiology, etiology, and treatment. This review examines the clinical features and boundaries of the condition, and offers guidance on how it can be distinguished from other anxiety disorders and other mental disorders in which "separation anxiety" may be apparent.

Long-term safety and effectiveness of lurasidone in schizophrenia: a 22-month, open-label extension study.

Abstract: Objective To evaluate the safety and effectiveness of lurasidone in the long-term treatment of patients with schizophrenia. Methods Patients who completed a 6-week, double-blind (DB), placebo-controlled trial continued in a 22-month, open-label (OL) study during which they received once-daily, flexible-doses of lurasidone, 40–120 mg. Change in the Positive and Negative Syndrome Scale (PANSS) was analyzed using both observed case (OC) and last observation carried forward (LOCF) analyses. Results Of the 251 patients who entered the OL extension, 51.4% completed 6 months, 36.7% completed 12 months, and 26.7% completed 22 months of OL treatment. Treatment with lurasidone was associated with a mean change from DB baseline, in weight of +0.4 kg at Month 12 (n=99), and +0.8 kg at Month 24 (n=67; OC analyses). Median change from DB baseline to Month 12 and Month 24, respectively, was -1.0 and -9.0 mg/dL for total cholesterol; 0.0 and -1.0 mg/dL for LDL; +1.0 and -11.0 mg/dL for triglycerides; and 0.0 and +0.1/% for HbA1c (OC analyses). The mean PANSS total score was 96.5 at DB baseline and 69.5 at OL baseline. The mean change from DB baseline in the PANSS total score at Month 24 was -43.6 (OC) and -28.4 (LOCF). Thirty-seven patients (14.7%) discontinued due to an adverse event (AE) during OL treatment. Three AEs occurred in ≥10% of patients: schizophrenia (12.4%), akathisia (10.8%), and somnolence (10.8%); and 19.2% reported at least one movement disorder–related AE. Discontinuations due to AEs occurred in 14.8% of patients. Conclusions In this 22-month, open-label extension study, treatment with lurasidone was associated with minimal effects on weight, glucose, lipids, and prolactin. Patients demonstrated sustained improvement in the PANSS total score for up to 24 months of lurasidone treatment.

Recognizing and treating pseudobulbar affect.

Abstract: Pseudobulbar affect, thought by many to be a relatively newly described condition, is in fact a very old one, described as early as the 19th century. It refers to those who experience inappropriate affect, disconnected from internal state, or mood, generally thought to be the result of an upper motor neuron injury or illness. One possible explanation for this condition's relative obscurity is the dearth of treatment options; clinical medicine is not typically in the habit of identifying conditions that cannot be modified. Now, however, there is good evidence for the treatment of pseudobulbar affect, and even a therapy approved for use by the U.S. Food and Drug Administration (FDA). As a result, appropriate identification and subsequent management of pseudobulbar affect is more important than ever. This article purports to summarize the origins of pseudobulbar affect, most current hypotheses as to its physiopathology, clinical identification, and evidence for management.

Obsessive compulsive and related disorders: comparing DSM-5 and ICD-11.

Abstract: Obsessive-compulsive disorder (OCD) has been recognized as mainly characterized by compulsivity rather than anxiety and, therefore, was removed from the anxiety disorders chapter and given its own in both the American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the Beta Draft Version of the 11th revision of the World Health Organization (WHO) International Classification of Diseases (ICD-11). This revised clustering is based on increasing evidence of common affected neurocircuits between disorders, differently from previous classification systems based on interrater agreement. In this article, we focus on the classification of obsessive-compulsive and related disorders (OCRDs), examining the differences in approach adopted by these 2 nosological systems, with particular attention to the proposed changes in the forthcoming ICD-11. At this stage, notable differences in the ICD classification are emerging from the previous revision, apparently converging toward a reformulation of OCRDs that is closer to the DSM-5.