Showing papers in "Cns Spectrums in 2019"

State of the science on mild cognitive impairment (MCI)

Abstract: Mild cognitive impairment (MCI) represents a transitional stage between healthy aging and dementia, and affects 10-15% of the population over the age of 65. The failure of drug trials in Alzheimer's disease (AD) treatment has shifted researchers' focus toward delaying progression from MCI to dementia, which would reduce the prevalence and costs of dementia profoundly. Diagnostic criteria for MCI increasingly emphasize the need for positive biomarkers to detect preclinical AD. The phenomenology of MCI comprises lower quality-of-life, greater symptoms of depression, and avoidant coping strategies including withdrawal from social engagement. Neurobiological features of MCI are hypoperfusion and hypometabolism in temporoparietal cortices, medial temporal lobe atrophy particularly in rhinal cortices, elevated tau and phosphorylated tau and decreased Aβ42 in cerebrospinal fluid, and brain Aβ42 deposition. Elevated tau can be identified in MCI, particularly in the entorhinal cortex, using positron emission tomography, and analysis of signal complexity using electroencephalography or magnetoencephalography holds promise as a biomarker. Assessment of MCI also relies on cognitive screening and neuropsychological assessment, but there is an urgent need for standardized cognitive tests to capitalize on recent discoveries in cognitive neuroscience that may lead to more sensitive measures of MCI. Cholinesterase inhibitors are frequently prescribed for MCI, despite the lack of evidence for their efficacy. Exercise and diet interventions hold promise for increasing reserve in MCI, and group psychoeducational programs teaching practical memory strategies appear effective. More work is needed to better understand the phenomenology and neurobiology of MCI, and how best to assess it and delay progression to dementia.

Cognitive impairment in major depressive disorder.

Abstract: Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.

Buying-shopping disorder—is there enough evidence to support its inclusion in ICD-11?

Abstract: The phenomenon of buying-shopping disorder (BSD) was described over 100 years ago. Definitions of BSD refer to extreme preoccupation with shopping and buying, to impulses to purchase that are experienced as irresistible, and to recurrent maladaptive buying excesses that lead to distress and impairments. Efforts to stop BSD episodes are unsuccessful, despite the awareness of repeated break-downs in self-regulation, experiences of post-purchase guilt and regret, comorbid psychiatric disorders, reduced quality of life, familial discord, work impairment, financial problems, and other negative consequences. A recent meta-analysis indicated an estimated point prevalence of BSD of 5%. In this narrative review, the authors offer a perspective to consider BSD as a mental health condition and to classify this disorder as a behavioral addiction, based on both research data and on long-standing clinical experience.

Neuroinflammation and cognition across psychiatric conditions.

Abstract: Cognitive impairments reported across psychiatric conditions (ie, major depressive disorder, bipolar disorder, schizophrenia, and posttraumatic stress disorder) strongly impair the quality of life of patients and the recovery of those conditions. There is therefore a great need for consideration for cognitive dysfunction in the management of psychiatric disorders. The redundant pattern of cognitive impairments across such conditions suggests possible shared mechanisms potentially leading to their development. Here, we review for the first time the possible role of inflammation in cognitive dysfunctions across psychiatric disorders. Raised inflammatory processes (microglia activation and elevated cytokine levels) across diagnoses could therefore disrupt neurobiological mechanisms regulating cognition, including Hebbian and homeostatic plasticity, neurogenesis, neurotrophic factor, the HPA axis, and the kynurenine pathway. This redundant association between elevated inflammation and cognitive alterations across psychiatric disorders hence suggests that a cross-disorder approach using pharmacological and nonpharmacological (ie, physical activity and nutrition) anti-inflammatory/immunomodulatory strategies should be considered in the management of cognition in psychiatry.

Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities.

Abstract: Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine's efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.

Cognitive impairment in substance use disorders.

Abstract: Cognitive impairments in substance use disorders have been extensively researched, especially since the advent of cognitive and computational neuroscience and neuroimaging methods in the last 20 years. Conceptually, altered cognitive function can be viewed as a hallmark feature of substance use disorders, with documented alterations in the well-known "executive" domains of attention, inhibition/regulation, working memory, and decision-making. Poor cognitive (sometimes referred to as "top-down") regulation of downstream motivational processes-whether appetitive (reward, incentive salience) or aversive (stress, negative affect)-is recognized as a fundamental impairment in addiction and a potentially important target for intervention. As addressed in this special issue, cognitive impairment is a transdiagnostic domain; thus, advances in the characterization and treatment of cognitive dysfunction in substance use disorders could have benefit across multiple psychiatric disorders. Toward this general goal, we summarize current findings in the abovementioned cognitive domains of substance use disorders, while suggesting a potentially useful expansion to include processes that both precede (precognition) and supersede (social cognition) what is usually thought of as strictly cognition. These additional two areas have received relatively less attention but phenomenologically and otherwise are important features of substance use disorders. The review concludes with suggestions for research and potential therapeutic targeting of both the familiar and this more comprehensive version of cognitive domains related to substance use disorders.

Mental imagery in psychiatry: Conceptual & clinical implications

Abstract: Mental imagery refers to the experience of perception in the absence of external sensory input. Deficits in the ability to generate mental imagery or to distinguish it from actual sensory perception are linked to neurocognitive conditions such as dementia and schizophrenia, respectively. However, the importance of mental imagery to psychiatry extends beyond neurocognitive impairment. Mental imagery has a stronger link to emotion than verbal-linguistic cognition, serving to maintain and amplify emotional states, with downstream impacts on motivation and behavior. As a result, anomalies in the occurrence of emotion-laden mental imagery has transdiagnostic significance for emotion, motivation, and behavioral dysfunction across mental disorders. This review aims to demonstrate the conceptual and clinical significance of mental imagery in psychiatry through examples of mood and anxiety disorders, self-harm and suicidality, and addiction. We contend that focusing on mental imagery assessment in research and clinical practice can increase our understanding of the cognitive basis of psychopathology in mental disorders, with the potential to drive the development of algorithms to aid treatment decision-making and inform transdiagnostic treatment innovation.

Reward systems and cognitions in Major Depressive Disorder

Abstract: A lack of motivation and anhedonia represent frequent and pervasive symptoms in depression, although with poor specificity. Historically described as a response bias, reward-related impairments in depression may account for the important aspects of the cognitive impairments associated with diagnosis of major depressive disorder. Reward processing is a broad psychological construct that can be parsed into 3 distinct components known as "reinforcement learning" (learning), "reward responsiveness" (liking), and "motivation to obtain a reward" (wanting). Depressed patients respond hyposensitively to reward and maladaptively to punishment: this pattern is related to a dysfunction in the frontostriatal systems modulated by the monoamine systems; seems to be observed in medicated and unmedicated patients with depression and in healthy individuals with high levels of anhedonia; and could be observed in patients with a history of depression, even when in full remission. Considered to be cognitive impairments, reward-related-impairments may also constitute part of an underlying neurobiological vulnerability to major depressive disorder (MDD). For example, the reward-related impairment is state dependent and, more or less, correlated with symptom severity in some studies but has also been proposed as being trait like, with endophenotype characteristics, possibly contributing to the persistence of the disease or treatment resistance. The 3 core aspects of reward processing have specific neurobiological correlates that involve the ventral and dorsal striatum, lateral habenula, ventral tegmental area, orbitofrontal cortex, anterior cingulate cortex, and ventromedial and dorsolateral prefrontal cortex. These structures underline the important role of the dopaminergic mesolimbic pathway, but glutamate and serotonin could also have an important role, at least in some aspects of reward-related impairments.

Neuronal underpinnings of cognitive impairment and - improvement in mood disorders

Abstract: Neuropsychiatric illnesses including mood disorders are accompanied by cognitive impairment, which impairs work capacity and quality of life However, there is a lack of treatment options that would lead to solid and lasting improvement of cognition This is partially due to the absence of valid and reliable neurocircuitry-based biomarkers for pro-cognitive effects This systematic review therefore examined the most consistent neural underpinnings of cognitive impairment and cognitive improvement in unipolar and bipolar disorders We identified 100 studies of the neuronal underpinnings of working memory and executive skills, learning and memory, attention, and implicit learning and 9 studies of the neuronal basis for cognitive improvements Impairments across several cognitive domains were consistently accompanied by abnormal activity in dorsal prefrontal (PFC) cognitive control regions-with the direction of this activity depending on patients' performance levels-and failure to suppress default mode network (DMN) activity Candidate cognition treatments seemed to enhance task-related dorsal PFC and temporo-parietal activity when performance increases were observed, and to reduce their activity when performance levels were unchanged These treatments also attenuated DMN hyper-activity In contrast, nonspecific cognitive improvement following symptom reduction was typically accompanied by decreased limbic reactivity and reversal of pre-treatment fronto-parietal hyper-activity Together, the findings highlight some common neural correlates of cognitive impairments and cognitive improvements Based on this evidence, studies are warranted to examine the reliability and predictive validity of target engagement in the identified neurocircuitries as a biomarker model of pro-cognitive effects

Cognition, social cognition, and Self-assessment in schizophrenia: prediction of different elements of everyday functional outcomes.

Abstract: A growing body of research has shown that two domains of cognition, neurocognition and social cognition, predict different domains of real-world outcomes in people with schizophrenia. Social cognition has been shown to predict social outcomes but not non-social outcomes (e.g. living independently), and neurocognition provides minimal prediction of social outcomes (e.g. interpersonal relationships). The differing predictive value of neurocognition and social cognition has led to an exploration of potential factors that interact with cognition to influence everyday outcomes. Functional skills, negative symptoms, and self-assessment have shown particularly promising relationships with cognitive ability. Several consensus studies have pinpointed valid performance-based assessments. High-contact informant ratings have additionally been shown to be highly accurate. The emerging understanding of divergent patterns of predicting outcomes and reliable assessments present an opportunity to improve treatment targets and real-world outcomes for individuals with schizophrenia. In particular, a recently defined component of metacognition has shown particular promise. Introspective accuracy (IA) addresses how well individuals evaluate their own abilities. Emerging research has found that IA of neurocognitive ability better predicts everyday functional deficits than scores on performance-based measures of neurocognitive skills and has found that IA of social cognition accounts unique variance in real world disability above social cognitive abilities. Intriguingly, IA of neurocognition appears to preferentially predict non-social outcomes while IA of social cognition predicts social outcomes.

Assessment in Work Productivity and the Relationship with Cognitive Symptoms (AtWoRC): primary analysis from a Canadian open-label study of vortioxetine in patients with major depressive disorder (MDD).

Abstract: ObjectiveThe Assessment in Work Productivity and the Relationship with Cognitive Symptoms (AtWoRC) study aimed to assess the association between cognitive symptoms and work productivity in gainfully employed patients receiving vortioxetine for a major depressive episode (MDE).MethodsPatients diagnosed with major depressive disorder (MDD) and treated with vortioxetine independently of study enrollment were assessed over 52 weeks at visits that emulated a real-life setting. Patients were classified as those receiving vortioxetine as the first treatment for their current MDE (first treatment) or having shown inadequate response to a previous antidepressant (switch). The primary endpoint was the correlation between changes in patient-reported cognitive symptoms (20-item Perceived Deficits Questionnaire [PDQ-D-20]) and changes in work productivity loss (Work Limitations Questionnaire [WLQ]) at week 12. Additional assessments included changes in symptom and disease severity, cognitive performance, functioning, work loss, and safety.ResultsIn the week 12 primary analysis, 196 eligible patients at 26 Canadian sites were enrolled, received at least one treatment dose, and attended at least one postbaseline study visit. This analysis demonstrated a significant, strong correlation between PDQ-D-20 and WLQ productivity loss scores (r=0.634; p<0.001), and this correlation was significant in both first treatment and switch patients (p<0.001). A weaker correlation between Digit Symbol Substitution Test and WLQ scores was found (r=−0.244; p=0.003).ConclusionAt 12 weeks, improvements in cognitive dysfunction were significantly associated with improvements in workplace productivity in patients with MDD, suggesting a role for vortioxetine in functional recovery in MDD.

Overlapping dimensional phenotypes of impulsivity and compulsivity explain co-occurrence of addictive and related behaviors.

Abstract: ObjectiveImpulsivity and compulsivity have been implicated as important transdiagnostic dimensional phenotypes with potential relevance to addiction. We aimed to develop a model that conceptualizes these constructs as overlapping dimensional phenotypes and test whether different components of this model explain the co-occurrence of addictive and related behaviors.MethodsA large sample of adults (N = 487) was recruited through Amazon’s Mechanical Turk and completed self-report questionnaires measuring impulsivity, intolerance of uncertainty, obsessive beliefs, and the severity of 6 addictive and related behaviors. Hierarchical clustering was used to organize addictive behaviors into homogenous groups reflecting their co-occurrence. Structural equation modeling was used to evaluate fit of the hypothesized bifactor model of impulsivity and compulsivity and determine the proportion of variance explained in the co-occurrence of addictive and related behaviors by each component of the model.ResultsAddictive and related behaviors clustered into 2 distinct groups: Impulse-Control Problems, consisting of harmful alcohol use, pathological gambling, and compulsive buying, and Obsessive-Compulsive-Related Problems, consisting of obsessive-compulsive symptoms, binge eating, and internet addiction. The hypothesized bifactor model of impulsivity and compulsivity provided the best empirical fit, with 3 uncorrelated factors corresponding to a general Disinhibition dimension, and specific Impulsivity and Compulsivity dimensions. These dimensional phenotypes uniquely and additively explained 39.9% and 68.7% of the total variance in Impulse-Control Problems and Obsessive-Compulsive-Related Problems.ConclusionA model of impulsivity and compulsivity that represents these constructs as overlapping dimensional phenotypes has important implications for understanding addictive and related behaviors in terms of shared etiology, comorbidity, and potential transdiagnostic treatments.

Long-term functioning outcomes are predicted by cognitive symptoms in working patients with major depressive disorder treated with vortioxetine: results from the AtWoRC study.

Abstract: ObjectiveAtWoRC (Assessment in Work productivity and the Relationship with Cognitive symptoms) was an interventional, open-label, Canadian study (NCT02332954) designed to assess the association between cognitive symptoms and workplace productivity in working patients with major depressive disorder (MDD) receiving vortioxetine.MethodsEligible patients with MDD received vortioxetine (10–20 mg/day) and were assessed over 52 weeks at visits emulating a real-life setting (n = 199). Partial correlation between changes in patient-reported cognitive symptoms (20-item Perceived Deficits Questionnaire–Depression; PDQ-D-20) and workplace productivity (Work Limitations Questionnaire; WLQ) was assessed at 12 and 52 weeks. Additional assessments included depression severity, cognitive performance, and patient-reported functioning. Structural equations model (SEM) analyses assessed causal relationships between changes in measures of cognition and functioning over time, adjusted for improvements in depressive symptoms.ResultsStatistically significant improvements in all outcomes from baseline to week 52 were seen in the overall population and both subgroups (first treatment and switch). Response and remission rates were 77% and 56%, respectively. Improvements in PDQ-D-20 and WLQ productivity loss scores at weeks 12 and 52 were significantly correlated. SEM analyses found patient-rated cognitive symptoms (PDQ-D-20) at weeks 12 and 26 were significantly predictive (p < 0.05) of patient-reported functioning (Sheehan Disability Scale) at the subsequent visit. Depression severity and objectively measured cognitive performance did not significantly predict functional outcomes at any timepoint.ConclusionThese results demonstrate the long-term benefits of vortioxetine treatment in working patients with MDD and emphasize the strong association between cognitive symptoms and functioning in a real-world setting.

Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity

Abstract: Although currently available antidepressants increase monoamine levels soon after the start of treatment, therapeutic benefits are often delayed by several weeks and the majority of patients with major depressive disorder fail to achieve an adequate response to first- or second-line therapies targeting monoamines. The recent approval of the NMDA (N-methyl-d-aspartate) antagonist esketamine given intranasally for treatment-resistant depression has reinforced the need for agents with rapid onset with alternate mechanisms of action. Dextromethorphan/bupropion, an investigational medicine currently in development, is one such candidate.

Drug-drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs.

Abstract: Psychotropic medications are frequently co-prescribed with antiretroviral therapy (ART), owing to a high prevalence of psychiatric illness within the population living with HIV, as well as a 7-fold increased risk of HIV infection among patients with psychiatric illness. While ART has been notoriously associated with a multitude of pharmacokinetic drug interactions involving the cytochrome P450 enzyme system, the magnitude and clinical impact of these interactions with psychotropics may range from negligible effects on plasma concentrations to life-threatening torsades de pointes or respiratory depression. This comprehensive review summarizes the currently available information regarding drug-drug interactions between antiretrovirals and pharmacologic agents utilized in the treatment of psychiatric disorders-antidepressants, stimulants, antipsychotics, anxiolytics, mood stabilizers, and treatments for opioid use disorder and alcohol use disorder-and provides recommendations for their management. Additionally, overlapping toxicities between antiretrovirals and the psychotropic classes are highlighted. Knowledge of the interaction and adverse effect potential of specific antiretrovirals and psychotropics will allow clinicians to make informed prescribing decisions to better promote the health and wellness of this high-risk population.

Binge eating disorder revisited: what's new, what's different, what's next.

Abstract: Binge eating disorder (BED) is the most common type of eating disorder. According to the most recent data available, the estimated lifetime prevalence of BED among US adults in the general population is 0.85% (men 0.42% and women 1.25%). Among psychiatric treatment populations, prevalence is several-fold higher. Although many people with BED are obese (BMI ≥ 30 kg/m2), roughly half are not. In the DSM-5, BED is defined by recurrent episodes of binge eating (eating in a discrete period of time, an amount of food larger than most people would eat in a similar amount of time under similar circumstances and a sense of lack of control over eating during the episode), occurring on average at least once a week for 3 months, and associated with marked distress. BED often goes unrecognized and thus untreated; in one study, 344 of 22,387 (1.5%) survey respondents met DSM-5 criteria for BED, but only 11 out of the 344 had ever been diagnosed with BED by a health-care provider. Psychiatric comorbidities are very common, with most adults with BED also experiencing anxiety disorders, mood disorders, impulse control disorders, or substance use disorders, suggesting that clinicians have patients in their practice with unrecognized BED. Multiple neurobiological explanations have been suggested for BED, including dysregulation in reward center and impulse control circuitry. Additionally, there is interplay between genetic influences and environmental stressors. Psychological treatments such as cognitive behavioral interventions have been recommended as first line and are supported by meta-analytic reviews; however, access to such treatments may be limited because of local availability and/or cost, and these treatments generally lead to little to no weight loss, although successfully eliminating binge eating can protect against future weight gain. Routine medication treatments for anxiety and depression do not necessarily ameliorate the symptoms of BED, but there are approved and emerging medication options, lisdexamfetamine and dasotraline, respectively, that specifically address the core drivers behind binge eating, namely obsessive thoughts and compulsive behaviors regarding food, resulting in marked decreases in binge eating behaviors as well as weight loss.

High prevalence of prediabetes and metabolic abnormalities in overweight or obese schizophrenia patients treated with clozapine or olanzapine.

Abstract: OBJECTIVE To assess the prevalence of prediabetes and metabolic abnormalities among overweight or obese clozapine- or olanzapine-treated schizophrenia patients, and to identify characteristics of the schizophrenia group with prediabetes. METHODS A cross-sectional study assessing the presence of prediabetes and metabolic abnormalities in schizophrenia clozapine- or olanzapine-treated patients with a body mass index (BMI) ≥27 kg/m2. Procedures were part of the screening process for a randomized, placebo-controlled trial evaluating liraglutide vs placebo for improving glucose tolerance. For comparison, an age-, sex-, and BMI-matched healthy control group without psychiatric illness and prediabetes was included. Prediabetes was defined as elevated fasting plasma glucose and/or impaired glucose tolerance and/or elevated glycated hemoglobin A1c. RESULTS Among 145 schizophrenia patients (age = 42.1 years; males = 59.3%) on clozapine or olanzapine (clozapine/olanzapine/both: 73.8%/24.1%/2.1%), prediabetes was present in 69.7% (101 out of 145). While schizophrenia patients with and without prediabetes did not differ regarding demographic, illness, or antipsychotic treatment variables, metabolic abnormalities (waist circumference: 116.7±13.7 vs 110.1±13.6 cm, P = 0.007; triglycerides: 2.3±1.4 vs 1.6±0.9 mmol/L, P = 0.0004) and metabolic syndrome (76.2% vs 40.9%, P<0.0001) were significantly more pronounced in schizophrenia patients with vs without prediabetes. The age-, sex-, and BMI-matched healthy controls had significantly better glucose tolerance compared to both groups of patients with schizophrenia. The healthy controls also had higher levels of high-density lipoprotein compared to patients with schizophrenia and prediabetes. CONCLUSION Prediabetes and metabolic abnormalities were highly prevalent among the clozapine- and olanzapine-treated patients with schizophrenia, putting these patients at great risk for later type 2 diabetes and cardiovascular disease. These results stress the importance of identifying and adequately treating prediabetes and metabolic abnormalities among clozapine- and olanzapine-treated patients with schizophrenia.

Expert Consensus on Screening and Assessment of Cognition in Psychiatry.

Abstract: During the past two decades, it has been amply documented that neuropsychiatric disorders (NPDs) disproportionately account for burden of illness attributable to chronic non-communicable medical disorders globally. It is also likely that human capital costs attributable to NPDs will disproportionately increase as a consequence of population aging and beneficial risk factor modification of other common and chronic medical disorders (e.g., cardiovascular disease). Notwithstanding the availability of multiple modalities of antidepressant treatment, relatively few studies in psychiatry have primarily sought to determine whether improving cognitive function in MDD improves patient reported outcomes (PROs) and/or is cost effective. The mediational relevance of cognition in MDD potentially extrapolates to all NPDs, indicating that screening for, measuring, preventing, and treating cognitive deficits in psychiatry is not only a primary therapeutic target, but also should be conceptualized as a transdiagnostic domain to be considered regardless of patient age and/or differential diagnosis.

Keeping up with the clinical advances: depression.

Abstract: Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.

Long-term safety and tolerability of aripiprazole lauroxil in patients with schizophrenia.

Abstract: Objective Safety and tolerability of long-term treatment with the long-acting antipsychotic aripiprazole lauroxil (AL) were evaluated in patients with schizophrenia. Methods This was an international, multicenter, phase 3, 52-week safety study of 2 fixed doses of AL (441 mg or 882 mg intramuscular every 4 weeks). Safety endpoints included adverse events (AEs) and extrapyramidal symptoms (EPS) including akathisia, injection-site reactions (ISRs), and clinically relevant changes in metabolic and endocrine values. Results Of 478 patients entering this study, 236 (49%) continued from a previous 12-week, phase 3 efficacy study of AL, and 242 (51%) were newly enrolled. Overall, 77% and 23% of patients received AL 882 mg (N = 368) and 441 mg (N = 110), respectively. AEs occurred in 50.4% of patients; most were mild (28.7%) or moderate (18.2%). The most common AEs were insomnia (8.4%) and increased weight (5.0%). Akathisia was reported as an AE in 3.8% of the overall population, with higher rates in patients initiating AL on study entry than those continuing on AL. EPS-related AEs occurred in 9.4% of patients, and AEs related to metabolic parameters were reported in 4.6% of patients. Weight gain was minimal (0.8 kg), and no clinically relevant changes were observed for metabolic parameters. The overall incidence of ISRs was 3.8%; most were associated with the initial injections in patients receiving their first injection in this study. Conclusion Long-term treatment with AL is generally well tolerated, with a safety profile consistent with that of oral aripiprazole. It is a suitable option for patients with schizophrenia.

Practical considerations for managing breakthrough psychosis and symptomatic worsening in patients with schizophrenia on long-acting injectable antipsychotics.

Abstract: With more long-acting injectable (LAI) antipsychotics available for treating schizophrenia, each with variable durations of action (2 weeks to 3 months), it is important to have clear management strategies for patients developing breakthrough psychotic symptoms or experiencing symptomatic worsening on LAIs. However, no treatment guidelines or clinical practice pathways exist; health-care providers must rely on their own clinical judgment to manage these patients. This article provides practical recommendations-based on a framework of clinical, pharmacokinetic, and dosing considerations-to guide clinicians' decisions regarding management of breakthrough psychotic symptoms. Management options include ruling out/addressing medical illness or substance abuse/misuse as a contributing factor, addressing stressors, optimizing nonpharmacologic treatments, treating medical/psychiatric comorbidities, ensuring proper LAI administration technique, addressing missed LAI doses or lack of steady-state attainment, and increasing LAI dose directly or indirectly by shortening the injection interval (off-label). If these strategies do not work sufficiently with frequent monitoring, the LAI could be supplemented with a low dose of the corresponding oral formulation for fast symptom control (off-label). However, caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and oral antipsychotics (OAPs) are limited, especially over extended periods. If symptoms abate, therapy optimization could be continued and slow discontinuation of the OAP could be considered. For persistent/worsening symptoms, the OAP should be increased to optimum effective dose while intensifying the initial steps used before it was added. If this fails, switching the OAP or LAI could be considered. We believe that these strategies will help clinicians manage breakthrough psychotic symptoms during LAI treatment and improve overall outcomes among those who can benefit from LAIs.

Dysphagia characteristics in Huntington's disease patients: insights from the Fiberoptic Endoscopic Evaluation of Swallowing and the Swallowing Disturbances Questionnaire.

Abstract: BackgroundHuntington’s disease (HD) is a neurodegenerative disease characterized by increasing dysphagia as the disease progresses. Specific characteristics of the HD dysphagia are not well defined.ObjectiveTo characterize the swallowing disturbances of HD patients, to evaluate the feasibility of Fiberoptic Endoscopic Evaluation of Swallowing (FEES) in assessing dysphagia in HD patients, and to discern the relation between FEES findings and patients’ self-report on dysphagia symptoms and swallowing related quality of life (SWAL-QOL).MethodA retrospective case series in a tertiary referral center. All recruited HD patients underwent Bed Side Swallowing Evaluation (BSE), FEES, the Unified Huntington’s Disease Rating Scale (UHDRS), and the Montreal Cognitive Assessment (MoCA). All completed the Swallowing Disturbances Questionnaire (SDQ) and the SWAL-QOL questionnaire.ResultsFourteen HD patients were recruited. All were able to complete the FEES study. The FEES demonstrated delayed swallowing reflex, solid food residues, and pre/post swallowing spillage in most patients (50%, 53.5%, 83.3%, and 87.5%, respectively). The mean SDQ score was 13.2. Significant correlations were found between the SWAL-QOL fear of eating score; the SDQ oral, pharyngeal, and total scores; and the FEES parameters of pureed and solid food bolus flow time. Significant correlations were also found between the total UHDRS score, the volitional cough score, and the SWAL-QOL disease burden score.ConclusionHD patients exhibit prominent unique oropharyngeal dysphagia features that may serve as a marker of disease progression. The FEES and the SDQ are valuable tools for detecting these features in HD patients with swallowing disturbance.

A different aspect of the unexpected death of Mozart at the age of 35 years.

Abstract: The cause of the early death of Wolfgang Amadeus Mozart (1756–1791) at the age of 35 has been the source of much discussion in the medical community. Investigators attributed to Mozart nearly 150 different medical diagnoses. However, the neurosurgical aspect of the early death of Mozart has yet to be well-analyzed, and this subject was investigated herein. The key words “Mozart” and “Mozart’s death” were searched in PubMed as well as the libraries of universities. The main source was the archive and website of Internationale Stiftung MOZARTEUM/Salzburg ( www.mozarteum.at ) and the cranium stored in the Internationale Stiftung Mozarteum in Salzburg/Austria. The linear fracture of the cranium is important, since it shows the neurosurgical aspect of the early death of Mozart. Mozart’s disease was most likely a neurotraumatologic one. His fracture likely occurred several months before his death, as evidenced by signs of healing. Intense headaches and declining musical performance in his last year may have been influenced by intracranial hemorrhage induced by the linear fracture. His final disease therefore may have been chronic postconcussion syndrome depending on chronic calcified epidural hematoma.

Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder.

Abstract: Objective Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia. Methods We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented. Results We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10-1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=-1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in β-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone-mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6). Conclusions No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions.

Duration of untreated illness in a cross-diagnostic sample of obsessive-compulsive disorder, panic disorder, and social anxiety disorder.

Abstract: ObjectiveIn this study, we compared duration of untreated illness (DUI) in obsessive-compulsive disorder (OCD), panic disorder (PD), and social anxiety disorder (SAD) patients and investigated its correlates, both within specific diagnoses and across the whole sample.MethodsEighty-eight patients (33 OCD, 24 SAD, and 31 PD) had their diagnosis confirmed by the Mini International Neuropsychiatric Interview, were assessed for treatment-seeking variables, and were evaluated with instruments aimed at quantifying transdiagnostic features (i.e., the Cause subscale of the Illness Perception Questionnaire–Mental Health and the Anxiety Sensitivity Index–Revised) and severity of illness (i.e., Beck Depression and Anxiety Inventories, the Dimensional Obsessive-Compulsive Scale, the Panic and Agoraphobia Scale, and the Social Phobia Inventory).ResultsThe only differences between groups with short ( 2 years) DUI were greater fear of public display of anxiety in the first group and greater social avoidance in the second group. The DUI was significantly different between groups that sought treatment after the onset of illness, with OCD patients having longer DUI than PD patients and shorter DUI than SAD patients. Further, DUI correlated negatively with the perception of OCD being caused by stress and positively with severity of panic-related disability in SAD patients, but not in PD or OCD patients.ConclusionThere was substantial delay in treatment seeking among the anxiety and obsessive-compulsive disorder patients, particularly those with OCD or SAD. Perception of stress as a cause of OCD prompted treatment seeking, while severity of panic symptoms delayed treatment seeking.

Altered brain functional networks in Internet gaming disorder: independent component and graph theoretical analysis under a probability discounting task

Abstract: ObjectivesInternet gaming disorder (IGD) is becoming a matter of concern around the world. However, the neural mechanism underlying IGD remains unclear. The purpose of this paper is to explore the differences between the neuronal network of IGD participants and that of recreational Internet game users (RGU).MethodsImaging and behavioral data were collected from 18 IGD participants and 20 RGU under a probability discounting task. The independent component analysis (ICA) and graph theoretical analysis (GTA) were used to analyze the data.ResultsBehavioral results showed the IGD participants, compared to RGU, prefer risky options to the fixed ones and spent less time in making risky decisions. In imaging results, the ICA analysis revealed that the IGD participants showed stronger functional connectivity (FC) in reward circuits and executive control network, as well as lower FC in anterior salience network (ASN) than RGU; for the GTA results, the IGD participants showed impaired FC in reward circuits and ASN when compared with RGU.ConclusionsThese results suggest that IGD participants were more sensitive to rewards, and they were more impulsive in decision-making as they could not control their impulsivity effectively. This might explain why IGD participants cannot stop their gaming behaviors even when facing severe negative consequences.

Cognitive emotional processing across mood disorders.

Abstract: While impairments in cognitive emotional processing are key to the experience of mood disorders, little is understood of their shared and distinct features across major depressive disorder (MDD) and bipolar disorder (BD). In this review, we discuss the similarities and differences in abnormal emotional processing associated with mood disorders across the cognitive domains of perception, attention, memory, and reward processing, with a particular focus on how these impairments relate to the clinical profile of the disorders. We consider behavioral and neuroimaging evidence, especially that of the growing consensus surrounding mood-congruent biases in cognition, in combination with state- and trait-related characteristics in an attempt to provide a more comprehensive and translational overview of mood disorders. Special consideration is given to the shared phenomenon of mood instability and its role as a potential transdiagnostic marker across the prodrome and maintenance of mood disorders.

A systematic review on neuropsychological function in bipolar disorders type I and II and subthreshold bipolar disorders—something to think about

Abstract: Neuropsychological dysfunction is a well-established finding in individuals with bipolar disorder type I (BP-I), even during euthymic periods; however, it is less clear whether this also pertains to bipolar disorder type II (BP-II) or those with subthreshold states (SBP; subthreshold bipolar disorder), such as bipolar not otherwise specified (BP-NOS). Herein, we compare the literature regarding neuropsychological performance in BP-II vs BP-I to determine the extent of relative impairment, and we present and review all related studies on cognition in SBP. After systematically searching PubMed, Medline, PsycINFO, and The Cochrane Library, we found 17 papers that comprise all the published studies relevant for this review. The areas that are consistently found to be impaired in BP are executive function, verbal memory, visual spatial working memory, and attention. More studies than not show no significant difference between BP-I and BP-II, particularly in euthymic samples. Preliminary evidence suggests that patients experiencing major depressive episodes who also meet criteria for SBP show similar profiles to BP-II; however, these results pertain only to a depressed sample. SBP were found to perform significantly better than both MDD and healthy controls in a euthymic sample. A consensus on mood state, patient selection, and neuropsychological testing needs to be agreed on for future research. Furthermore, no studies have used the most recent DSM-5 criteria for SBP; future studies should address this. Finally, the underlying bases of cognitive dysfunction in these diagnostic groups need to be further investigated. We suggest recommendations on all of the above current research challenges.

Unconjugated bilirubin and schizophrenia: a systematic review

Abstract: Schizophrenia is a complex syndrome of unknown etiology and difficult to manage. Unconjugated bilirubin has been researched as a potential biological marker of this syndrome. The objective of this review article was to gather the studies published to date on the relationship between this molecule and schizophrenia. Broad inclusion criteria have been used (PRISMA) to include as many relevant studies as possible. Fourteen studies were selected: 3 analyzed the effects of unconjugated hyperbilirubinemia in animal models; 6 demonstrated an increased incidence of schizophrenia in patients with increased unconjugated bilirubin; 2 reported an increased incidence of the disease in patients with decreased unconjugated bilirubin; and 3 linked an increased incidence of schizophrenia with an increased excretion of the oxidative product of bilirubin, the so-called biopyrrins. Because of apparently contradictory reported results, the hypothesis that the relationship between schizophrenia and unconjugated bilirubin was not linear and that there was an inflammatory dysfunction explaining this was considered. The 2 most accepted models for the pathophysiology of schizophrenia are described, and the possible role of the molecule in each is clarified. The bilirubin buffer system and its role in antioxidant defense was explored. The average levels of unconjugated bilirubin in patients with schizophrenia, schizoaffective disorder, and bipolar disorder were also compared, having been hypothesized that these diseases could be different points of a same pathological spectrum. Finally, it was concluded that unconjugated bilirubin is a promising molecule that could be used as a possible biological marker for schizophrenia, and the necessity of subsequent efforts for its research was considered.

A study on the correlates of habit-, reward-, and fear-related motivations in alcohol use disorder.

Abstract: OBJECTIVE We assessed self-reported drives for alcohol use and their impact on clinical features of alcohol use disorder (AUD) patients. Our prediction was that, in contrast to "affectively" (reward or fear) driven drinking, "habitual" drinking would be associated with worse clinical features in relation to alcohol use and higher occurrence of associated psychiatric symptoms. METHODS Fifty-eight Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol abuse patients were assessed with a comprehensive battery of reward- and fear-based behavioral tendencies. An 18-item self-report instrument (the Habit, Reward and Fear Scale; HRFS) was employed to quantify affective (fear or reward) and non-affective (habitual) motivations for alcohol use. To characterize clinical and demographic measures associated with habit, reward, and fear, we conducted a partial least squares analysis. RESULTS Habitual alcohol use was significantly associated with the severity of alcohol dependence reflected across a range of domains and with lower number of detoxifications across multiple settings. In contrast, reward-driven alcohol use was associated with a single domain of alcohol dependence, reward-related behavioral tendencies, and lower number of detoxifications. CONCLUSION These results seem to be consistent with a shift from goal-directed to habit-driven alcohol use with severity and progression of addiction, complementing preclinical work and informing biological models of addiction. Both reward-related and habit-driven alcohol use were associated with lower number of detoxifications, perhaps stemming from more benign course for the reward-related and lack of treatment engagement for the habit-related alcohol abuse group. Future work should further explore the role of habit in this and other addictive disorders, and in obsessive-compulsive related disorders.