Search

Previous studies have evaluated the relationship between anhedonia and suicidality; however, to our knowledge, there has been no quantitative synthesis evaluating the foregoing association to date. Herein, this meta-analysis aims to provide a quantitative synthesis of the extant literature reporting on the association between levels of anhedonia across all dimensions (e.g., anticipatory, consummatory) amongst individuals endorsing suicidality. Online databases (i.e., PubMed, PsycINFO, Google Scholar) were searched from inception to 13 June 2022. Studies which assessed an aspect of suicidality (i.e., ideation, attempts) and a validated anhedonia scale were included. The risk of bias was assessed using the ROBINS-1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively synthesized using Pearson's r effect sizes via a random-effects meta-analysis. A total of 20 studies and 11,212 individuals were included in the final quantitative synthesis. Overall, results indicate that anhedonia has a significant and moderate correlation with suicidality in general and psychiatric populations (r = 0.31, p 0.001 and r = 0.32, p 0.001 respectively). Sub-analysis suggests a larger effect of anticipatory and consummatory interpersonal anhedonia (r = 0.40, p 0.001). The identification of increased levels of anhedonia in individuals with suicidality indicates that anhedonia may be a core risk factor for suicidal ideation and behaviours. Future studies should endeavour to develop a comprehensive risk assessment encompassing all domains of anhedonia which can be utilized in a primary care setting as a potential prevention strategy for suicidal behaviours and outcomes.

The use of antidepressants in the treatment of bipolar disorder (BD) has been one of the more enduring controversies in the field. Antidepressants continue to be one of the most widely used classes of psychotropic agents in BD and are still prominently featured in most treatment guidelines, despite the limited and inconsistent evidence supporting their safety and efficacy in the treatment and prevention of episodes of bipolar 1 depression. Herein, the authors review the clinical and meta-analytical evidence on the efficacy and safety of antidepressants in BD types 1 and 2. Clinicians should be aware of the potential risks and benefits of anti-depressants for patients with BD, as well as the scenarios and patients' characteristics that can affect treatment outcomes. [ Psychiatr Ann . 2023;53(2):63–67.]

Objectives Clinical staging is widely used in medicine to map disease progression, inform prognosis and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. Methods Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. Results Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthresholdhold stages, and to various clinical stages of BD as it is currently diagnosed. Conclusion The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

The emerging roles of ketamine and esketamine as effective rapid-acting antidepressants hold promise for patients suffering from treatment-resistant depression and/or major depressive disorder with suicidality. Practitioner familiarity with common tolerability/safety concerns along with pragmatic prevention and management strategies are needed to reduce patient burden and improve the acceptability and accessibility of these treatments. The most common treatment-emergent adverse events associated with ketamine/esketamine are dissociation, anxiety, nausea, increased blood pressure, and headache. The majority of side effects are mild, transient, dose dependent, and attenuate with subsequent treatments. Patient selection, baseline physical and psychiatric assessments, and an appropriate setting are critical first steps in the prevention and mitigation of adverse events. Patient education and supportive interventions play central roles in the prevention and management of select adverse events. Severe and/or clinically significant adverse effects may necessitate the judicious use of adjunctive medications. Moreover, practitioners must remain vigilant to the potential for abuse liability and long-term adverse events, for which there are insufficient data. This article succinctly reviews common treatment-emergent adverse events of ketamine and esketamine within the context of mood disorders, and provides practical suggestions for prevention and management at point-of-care.

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

Ecological momentary assessment (EMA) for mental disorders, using application-based (app) technology capable of passive and ambient data collection, has been insufficiently evaluated and validated with rigorous, adequately-powered, high-quality studies. Herein, we sought to validate the mind.me application for the assessment of depressive symptoms in adults. Adults (ages 18–65) who self-identified as having clinically significant depressive symptoms [i.e. Patient Health Questionnaire 9 (PHQ-9) ≥ 5] utilized the mind.me app—a mobile phone technology that collects data passively and continuously, and is capable of integrating broad multimodal data [e.g., location variance (e.g. GPS), behavioural (e.g. social network activity), and communication data (e.g. SMS texting, phone calls)]. The primary outcome was predictive accuracy (i.e. convergent validity with depressive symptom measurement, as captured by the PHQ-9). 200 subjects were enrolled in the study (mean age 46 ± 12.71). The average PHQ-9 score was 12.8 ± 6.9. The predictive accuracy of the mind.me app was 0.91 ± 0.06. The sensitivity was 0.98 and the specificity was 0.93. The mind.me app was rated by 200 users as highly usable and informative to their illness. The mind.me app exhibits robust predictive accuracy in detecting depressive symptoms in adults with clinically relevant depressive symptoms. The mind.me app more specifically demonstrates convergence with the PHQ-9.

Intravenous (IV) ketamine has been shown to have rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD). Urological toxicity has been observed in chronic ketamine abusers as evidenced by dysuria, urgency, and hematuria. The foregoing observation provides the basis for evaluating whether ketamine-induced urological toxicity (KIUT) is associated with sub-anesthetic doses of ketamine (0.5-1.0 mg/kg) in adults with mood disorders. The overarching objective of this article is to identify potential mechanisms of KIUT which appears to be dose and frequency dependent. Available research indicates that high-frequency ketamine is associated with disruption of the urothelial barrier as well as direct ketamine toxicity (i.e., decreased expression of junction proteins) in KIUT of the bladder. Chronic and high-frequency ketamine use is also associated with bladder inflammation mediated via neurogenic and IgE inflammation. Other non-mutually exclusive causes are nerve hyperplasia, hypersensitivity, cell apoptosis, microvascular damage, and overexpression of carcinogenic genes. Notwithstanding the evidence of KIUT in ketamine abusers, there is no evidence that ketamine and/or esketamine treatment in adults with mood disorders is associated with KIUT. However, all patients receiving ketamine/esketamine for mood disorder treatment should be queried about genitourinary symptoms during acute and, where applicable, maintenance dosing.

Replicated evidence has documented cognitive deficits in populations with treatment-resistant depression (TRD). Approximately 40 % of patients with MDD present with impairment of one or more cognitive domains. As such, there is an unmet need to discover treatments that have pro-cognitive effects in TRD patients. Ketamine has demonstrated efficacy as a rapid-onset intervention for the treatment of depression. The objective of the current review was to assess the effects of ketamine on cognition in TRD patients. We systematically searched PubMed, Google Scholar and PsycINFO between database inception to March 24th, 2020. We identified five studies that evaluated cognition in TRD populations following ketamine treatment. All studies included a 0.5 mg/kg subanesthetic intravenous (IV) administration of ketamine. One study found significant improvements in complex (p = .008) and simple (p = .027) working memory and one study found improvements in visual learning memory following IV ketamine infusions (p = .014). Improvements in speed of processing and verbal learning memory were observed in anxious TRD participants only. Importantly, a subanesthetic dose of IV ketamine does not worsen cognitive function.

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.

Background Offspring of individuals with bipolar disorder (BD) are at greater risk for developing BD. Adiponectin (ADP), a hormone produced by adipocytes, plays a central role in energy homeostasis, insulin sensitivity and inflammatory response. ADP is negatively correlated with Body Mass Index (BMI) and is abnormal in patients with BD. Understanding the role of ADP among these offspring may help identify those likely to develop BD. The primary objective of this paper was to compare ADP levels among offspring of individuals with BD (symptomatic [SO], and asymptomatic [AO]) to offspring of healthy parents (HC). The role of ADP on cognition and ROI-based gray matter values in SO and AO offspring was secondarily assessed and compared to HC. Methods A cross-sectional study was conducted in China by the Guangzhou Brain Hospital in offspring of individuals with and without BD. Participants underwent neuropsychiatric and cognitive assessments, MRI scans and blood analyses. BMI z-scores (zBMI) were calculated adjusting for age and gender. Results Analyses included 117 participants (HC = 48, AO = 36, SO = 33). No significant differences were observed in plasma levels of ADP optical density (OD) among HC, AO and SO participants. No significant interaction effects on cognition were observed between symptomatic status and ADP OD, symptomatic status and BMI z-score, nor symptomatic status, zBMI and ADP OD. Multivariate tests revealed a significant interaction between offspring symptomatic status, ADP OD, and zBMI on gray matter volume in the right cerebellum (p = 0.05). Conclusion These findings suggest that an interaction exists between BMI and CNS structure.

A considerable proportion of individuals report persistent, debilitating and disparate symptoms despite resolution of acute COVID-19 infection (i.e. long COVID). Numerous registered clinical trials investigating treatment of long COVID are expected to be completed in 2021-2022. The aim of this review is to provide a scope of the candidate treatments for long COVID. A synthesis of ongoing long COVID clinical trials can inform methodologic approaches for future studies and identify key research vistas.Scoping searches were conducted on multiple national and international clinical trial registries. Interventional trials testing treatments for long COVID were selected. The search timeline was from database inception to 28 July 2021.This scoping review included 59 clinical trial registration records from 22 countries with a total projected enrolment of 6718. Considerable heterogeneity was exhibited amongst component records with respect to the characterization of long COVID (i.e. name, symptoms- including frequency, intensity, trajectory and duration- mode of ascertainment, and definition of acute phase). In addition, the majority of proposed interventions were non-pharmacological and either targeted multiple long COVID symptoms simultaneously, or focussed on treatment of respiratory/pulmonary sequelae. Multiple interventions targeted inflammation, as well as tissue oxygenation and cellular recovery, and several interventions were repurposed from analogous conditions.The results of this scoping review investigating ongoing clinical trials testing candidate treatments for long COVID suggest that a greater degree of definitional stringency and homogeneity is needed insofar as the characterization of long COVID and inclusion/exclusion criteria.

Psychiatric and metabolic disorders are highly comorbid and the relationship between these disorders is bidirectional. The mechanisms underlying the association between psychiatric and metabolic disorders are presently unclear, which warrants investigation into the dynamics of the interplay between metabolism, substrate utilization, and energy expenditure in psychiatric populations, and how these constructs compare to those in healthy controls. Indirect calorimetry (IC) methods are a reliable, minimally invasive means for assessing metabolic rate and substrate utilization in humans. This review synthesizes the extant literature on the use of IC on resting metabolism in psychiatric populations to investigate the interaction between psychiatric and metabolic functioning. Consistently, resting energy expenditures and/or substrate utilization values were significantly different between psychiatric and healthy populations in the studies contained in this review. Furthermore, resting energy expenditure values were systematically overestimated when derived from predictive equations, compared to when measured by IC, in psychiatric populations. High heterogeneity between study populations (e.g., differing diagnoses and drug regimens) and methodologies (e.g., differing posture, time of day, and fasting status at measurement) impeded the synthesis of results. Standardized IC protocols would benefit this line of research by enabling meta-analyses, revealing trends within and between different psychiatric disorders.

Available studies have evaluated cognition in the unaffected relatives of bipolar disorder patients; however, to our knowledge, there has been no quantitative analysis evaluating the foregoing association. Herein, this meta-analysis aims to provide a quantitative synthesis of the extant literature reporting on the association between performance in cognitive domains (i.e., executive function, attention, learning and memory or global cognition) amongst unaffected individuals of probands with bipolar disorders.Online databases (i.e., PubMed, PsycINFO) and Google Scholar were searched from inception to 20 September 2021. Studies with unaffected, first-degree relatives of individuals with DSM-IV or DSM-5 defined bipolar disorders were included. The risk of bias was assessed using the ROBINS-1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively synthesized using Cohen's d effect sizes via a random-effects meta-analytic approach on JASP.A total of 15 studies were included in the final review. Overall, results indicate that cognitive performance across all domains is moderately impaired in unaffected relatives of individuals with bipolar disorders (d = 0.488). Sub-analysis suggests there is a higher level of impairment in executive functioning (d = 0.612).The identification of cognitive deficits in unaffected relatives of probands with bipolar disorders indicates that cognitive impairment is endophenotypic and a core disturbance in persons with bipolar disorders; future studies should endeavour to target cognition as a potential pre-emptive and prevention strategy of bipolar disorders.

The use of psilocybin as treatment for major depressive disorder (MDD) has been examined as a promising alternative to traditional first-line options. We reviewed existing literature to provide a synthesis of the extant neuroimaging observations with psilocybin, and to identify putative therapeutic targets for target engagement studies with psilocybin, and potentially other psychedelics. We assessed neuroimaging observations with psilocybin among participants with MDD and healthy populations. A systematic search was conducted on PubMed, Google Scholar and PsycINFO from database inception to November 17th, 2021. The study quality (i.e., risk of bias) was assessed using the revised Cochrane risk-of-bias tool for randomized trials. A total of ten studies evaluated psilocybin in healthy populations and three studies assessed psilocybin in MDD participants using neuroimaging techniques. Following psilocybin administration, a decrease in amygdala activity and a reduction in depressive symptoms was observed in two studies. Changes in functional connectivity and activation of prefrontal limbic structures, specifically the ventral medial prefrontal cortex and amygdala, was seen in healthy populations. There was high heterogeneity in methodology (e.g., dosing schedule and imaging methods) amongst included studies. Longitudinal studies are needed to further elucidate psilocybin treatment for MDD, its long-term effects and the possibility of sustained therapeutic effects.

Metabolomics is defined as the study of the global metabolite profile in a system under a given set of conditions. The objective of this review is to comprehensively assess the literature on metabolomics in mood disorders and schizophrenia and provide data for mental health researchers about the challenges and potentials of metabolomics. The majority of studies in metabolomics in Psychiatry uses peripheral blood or urine. The most widely used analytical techniques in metabolomics research are nuclear magnetic resonance (NMR) and mass spectrometry (MS). They are multiparametric and provide extensive structural and conformational information on multiple chemical classes. NMR is useful in untargeted analysis, which focuses on biosignatures or 'metabolic fingerprints' of illnesses. MS targeted metabolomics approach focuses on the identification and quantification of selected metabolites known to be involved in a particular metabolic pathway. The available studies of metabolomics in Schizophrenia, Bipolar Disorder and Major Depressive Disorder suggest a potential in investigating metabolic pathways involved in these diseases' pathophysiology and response to treatment, as well as its potential in biomarkers identification.

Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry. The objectives of the current review are to comprehensively evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD. Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology. Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD. Orexin antagonists have been shown to treat insomnia effectively without disrupting normal sleep architecture in both preclinical (e.g., animal models) and clinical studies. Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence. Orexin antagonists have also been shown to possess antidepressant-like properties in some animal models of MDD. Extant evidence indicates that orexin-modulating treatments exert pleiotropic effects on multiple neural systems implicated in the phenomenology of mood disorders and suggests orexins as a promising target for investigation and intervention in mood disorders. To date, no human clinical trials evaluating the antidepressant effects of orexin antagonists in MDD have been completed. Given the promising results from preclinical studies, clinical trials are merited to evaluate the antidepressant effects of orexin antagonists in MDD.

Type 2 Diabetes Mellitus (T2DM) and Major Depressive Disorder (MDD) are leading causes of disability worldwide. Indeed, both are costly and burdensome diseases at both individual and socio-economic levels. Notably, there are similar pathophysiological elements, which might explain the overlap in phenotypic symptoms and the high rate of comorbidity. Brain insulin resistance is a shared metabolic abnormality amongst many individuals with T2DM and MDD. Patients with either or both diseases often exhibit disturbances in cognition and mood, as well as the presence of anhedonia-like symptoms. However, individuals with T2DM with high glycemic control have reduced cognitive and depressive symptom burden. Based on this evidence, it is possible that repurposing therapies approved for treating insulin resistance may be useful in treating cognitive and anhedonia symptoms in depression. The objective of this review is to discuss the relationship between brain insulin resistance and depression, as well as possible disease modifying therapeutic agents targeting insulin signalling.

Replicated clinical trials have demonstrated rapid and robust antidepressant effects with ketamine in treatment resistant mood disorders. Sex (biological) and gender differences in therapeutic effects for any new intervention is an important consideration, however, the differential efficacy, safety and tolerability of ketamine in males versus females remains underexplored. The objective of the present systematic review is to identify and qualitatively synthesize all published clinical studies relevant to the sex differential effects of ketamine for mood disorders. A systematic search of PubMed, Medline, and PsycInfo from inception until January 20, 2021, yielded 27 reports including 1715 patients (742 males and 973 females) that met inclusion criteria. Results from the vast majority of studies (88.8%) do not support significant sex differences in antidepressant response, tolerability or safety of ketamine. Nine (33.3%) of the reports included a bioanalytical component in the analysis and only one reported on sex differences. Evidence from the present review does not support clinically or statistically significant sex differences in therapeutic effects with ketamine. Nevertheless, future studies should continue to consider sex and biological sex differences in study design and data analytic plans.

OBJECTIVE To determine the effectiveness of intravenous (IV) ketamine on anxiety, irritability, agitation, and suicidality, in adults with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD). METHOD Adults (N = 201) with treatment-resistant MDD or BD received repeat-dose IV ketamine treatment at a community-based clinic. Mixed features were measured using symptoms of anxiety, irritability, and agitation (AIA), as measured by the Generalized Anxiety Disorder-7 (GAD-7) scale. The Quick Inventory for Depressive Symptomatology Self-Report-16 (QIDS-SR16 ) was used to measure overall treatment response, and the QIDS-SR16 suicidal ideation (SI) item was used to measure change in SI symptoms with ketamine treatment. The anxiety, irritability, and agitation items on the GAD-7 were used to assess effectiveness of IV ketamine in treating symptoms of mixed features. RESULTS In this retrospective analysis, 113 participants met AIA criteria. Participants with AIA experienced a significantly greater reduction in overall depressive symptoms (F(1, 558) = 9.49, P = .002), SI (F(1, 558) = 3.103, P = .079), anxiety (F(1, 198) = 5.52, P = .007), irritability (F(1, 198) = 28.35, P

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = −1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = −0.05, p = 0.003; and β = −0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

OBJECTIVES: The International Society for Bipolar Disorders Big Data Task Force assembled leading researchers in the field of bipolar disorder (BD), machine learning, and big data with extensive experience to evaluate the rationale of machine learning and big data analytics strategies for BD.METHOD: A task force was convened to examine and integrate findings from the scientific literature related to machine learning and big data based studies to clarify terminology and to describe challenges and potential applications in the field of BD. We also systematically searched PubMed, Embase, and Web of Science for articles published up to January 2019 that used machine learning in BD.RESULTS: The results suggested that big data analytics has the potential to provide risk calculators to aid in treatment decisions and predict clinical prognosis, including suicidality, for individual patients. This approach can advance diagnosis by enabling discovery of more relevant data-driven phenotypes, as well as by predicting transition to the disorder in high-risk unaffected subjects. We also discuss the most frequent challenges that big data analytics applications can face, such as heterogeneity, lack of external validation and replication of some studies, cost and non-stationary distribution of the data, and lack of appropriate funding.CONCLUSION: Machine learning-based studies, including atheoretical data-driven big data approaches, provide an opportunity to more accurately detect those who are at risk, parse-relevant phenotypes as well as inform treatment selection and prognosis. However, several methodological challenges need to be addressed in order to translate research findings to clinical settings.

Subjects with schizophrenia have high risks of metabolic abnormalities and bioenergetic dysfunction. Acyl-carnitines involved in bioenergetic pathways provide potential biomarker targets for identifying early changes and onset characteristics in subjects with schizophrenia. We measured 29 acyl-carnitine levels within well-characterized plasma samples of adults with schizophrenia and healthy controls using liquid chromatography-mass spectrometry (LC-MS). Subjects with schizophrenia were measured at baseline and after 8 weeks of treatment. A total of 225 subjects with schizophrenia and 175 age- and gender-matched healthy controls were enrolled and 156 subjects completed the 8-week follow-up. With respect to plasma acyl-carnitines, the individuals with schizophrenia at baseline showed significantly higher levels of C4-OH (C3-DC) and C16:1, but lower concentrations of C3, C8, C10, C10:1, C10:2, C12, C14:1-OH, C14:2, and C14:2-OH when compared with healthy controls after controlling for age, sex, body mass index (BMI), smoking, and drinking. For the comparison between pretreatment and posttreatment subjects, all detected acyl-carnitines were significantly different between the two groups. Only the concentration of C3 and C4 were increased after selection by variable importance in projection (VIP) value >1.0 and false discovery rate (FDR) q value

Preclinical studies implicate insulin signaling as a modulator of dopamine transmission, but human data is currently limited. We hypothesize that changes in the expression of insulin receptor-related genes in the post-mortem brain tissue of patients with mood and psychotic disorders mediate the expression of dopamine regulation-related genes. From a database containing microarray data from the post-mortem dorsolateral prefrontal cortex (dlPFC) (healthy controls [HC]: n = 209; patients: n = 321) and hippocampus (HC: n = 180; patients: n = 196), we conducted a hypothesis-driven analysis through the a priori selection of 12 dopamine- and 3 insulin-related genes. Mediation and moderated mediation models, accounting for the role of body mass index (BMI), were used. In the dlPFC, expressions of insulin receptor- and dopamine regulation-related genes were moderated by BMI, with significantly lower expression in high BMI patients. In the hippocampus, there were significantly lower expressions of these genes, which were not moderated by BMI. Illnesses by BMI effects on expression of dopamine genes were fully mediated by expression of insulin receptor gene (INSR). Analysis of conditional indirect effects showed interactions between INSR and BMI, indicating significantly stronger indirect effects at higher BMI values. In the hippocampus we observed that expression of insulin receptor substrate 1 and 2 fully mediated the effects of illnesses on expression of dopamine genes. In conclusion, differential expression of dopamine-related genes was related to altered expression of insulin signaling genes. BMI had region-specific effects, supporting the hypothesis that metabolic systems are critical mediators of dopaminergic function.

Recent studies have demonstrated that antipsychotic drugs may activate mammalian target of rapamycin complex 1 (mTORC1) signaling in neurons. However, the relationship between mTORC1 signaling activation and currently prescribed antipsychotic drugs remains incompletely understood. The purpose of this study was to determine whether alterations in the level of mTORC1 signaling occur after rat primary hippocampal neurons are treated with olanzapine and haloperidol under toxic conditions. Additionally, we investigated whether these drugs affect dendritic outgrowth and synaptic protein expression through the mTORC1 signaling pathway. We measured changes in mTORC1-mediated and synaptic proteins by Western blotting assay under toxic conditions induced by B27 deprivation. Dendritic outgrowth was determined by a neurite assay. Olanzapine significantly increased the phosphorylated levels of mTORC1, its downstream effectors, and its upstream activators. The increased mTORC1 phosphorylation induced by olanzapine was significantly blocked by specific PI3K, MEK, or mTORC1 inhibitors. Olanzapine also increased dendritic outgrowth and synaptic proteins levels; all of these effects were blocked by rapamycin. However, haloperidol had none of these effects. We demonstrated that olanzapine, but not haloperidol, activated the mTORC1 signaling pathway and increased dendritic outgrowth and synaptic proteins by activating mTORC1 signaling in rat primary hippocampal neurons. These findings suggest that olanzapine affects neuroplasticity by activating mTORC1 signaling.

Major depressive disorder and bipolar disorder are highly prevalent and disabling conditions. Cognition is considered a core domain of their psychopathology and a principle mediator of psychosocial impairment, disproportionately accounting for overall illness-associated costs. There are few interventions with replicated evidence of efficacy in treating cognitive deficits in mood disorders. Evidence also indicates that cognitive deficits are associated with obesity and involve significant impairment across multiple domains. Conversely, weight-loss interventions, such as physical exercise and bariatric surgery, have been shown to beneficially affect cognitive function. This convergent phenomenology suggests that currently available agents that target metabolic systems may also be capable of mitigating deficits in cognitive functions, and are, therefore, candidates for repurposing. The incretin glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors (GLP-1R) are widely expressed in the central nervous system. Activation of GLP-1R leads to facilitation of glucose utilization and antiapoptotic effects in various organs. Pre-clinical trials have demonstrated significant neuroprotective effects of GLP-1, including protection from cell death, promotion of neuronal differentiation and proliferation; and facilitation of long-term potentiation. Liraglutide is a GLP-1R agonist that has been approved for the treatment of type 2 diabetes mellitus and obesity. Convergent preclinical and clinical evidence, including a proof-of-concept pilot study from group, has suggested that liraglutide may improve objective measures of cognitive function in adults with mood disorders. The safety and availability of GLP-1R agonists indicate that they are promising candidates for repurposing, and that they may be viable therapeutic options for mood disorders. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

This study (registered with PROSPERO, CRD42018085967) compares the efficacy (i.e. pro-cognitive effects) and acceptability of antidiabetic agents for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials comparing antidiabetic agents with placebo and/or another active antidiabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4855) evaluating the effects of 6 different antidiabetic drugs (i.e. intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with antidiabetic agents compared with placebo. Pioglitazone 15 to 30 mg demonstrated the greatest efficacy compared to placebo in network meta-analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro-cognitive class effect of antidiabetic agents in AD/MCI. Other antidiabetic agents should also be investigated in future studies.

Approximately 0.35-1% of the general population is afflicted with psychotic depression at some time in their life. Psychotic depression is a subtype of major depressive disorder characterized by mood congruent hallucinations and/or delusions. Patients with psychotic depression often represent the most severe cases, with high relapse and mortality rate. Although treatment guidelines recommend a combination of antidepressants and antipsychotics or electroconvulsive therapy, most patients subsequently relapse due to treatment resistance. Furthermore, with the concern of antipsychotic drug's side effects (e.g., tardive dyskinesia), there is a need for an alternative pharmacotherapy for psychotic depression. Recently, several case studies demonstrated that treatment with ketamine not only ameliorated mood, but also improved psychotic symptoms in patients with treatment-resistant depression and psychotic features. However, the safety of ketamine in these patients is controversial since ketamine is known to induce psychotomimetic and dissociative effects. Additionally, the efficacy and safety of ketamine in patients with psychotic depression has not been established as most clinical trials have excluded these persons due to the theorized risk of aggravating psychotic symptoms. Notwithstanding, it is not established empirically that ketamine treatment in psychotic depression would predictably amplify psychotic symptoms and/or overall illness presentation. Future trials evaluating ketamine in depression should include patients with psychotic features to inform whether ketamine is safe and effective in this subpopulation.

The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.

AIM This study aimed to compare plasma copeptin levels, the c-terminal of provasopressin, between individuals with bipolar disorder (BD) and healthy controls and to assess the relation between copeptin and metabolic parameters. METHODS We measured plasma levels of copeptin in individuals with BD (n = 55) and healthy controls (n = 21). Information related to psychiatric/medical history, as well as to metabolic comorbidities and laboratorial parameters was also captured. Insulin resistance and β-cell function in basal state were calculated from fasting plasma glucose and C-peptide using the HOMA2 calculator. Impaired glucose metabolism was defined as pre-diabetes or type 2 diabetes mellitus. Copeptin, adiponectin, and leptin plasma levels were determined by enzyme-linked immunosorbent assay. RESULTS Plasma copeptin levels were lower in individuals with BD, relative to healthy controls (P

Objectives To examine the role of pain on cognitive function in adults with major depressive disorder (MDD). Methods Adults (18–65) with a Diagnostic and Statistical Manual – Fifth Edition (DSM-5)-defined diagnosis of MDD experiencing a current major depressive episode (MDE) were enrolled (nMDD = 100). All subjects with MDD were matched in age, sex, and years of education to healthy controls (HC) (nHC = 100) for comparison. Cognitive function was assessed using the recently validated THINC-integrated tool (THINC-it), which comprises variants of the choice reaction time (i.e., THINC-it: Spotter), One-Back (i.e., THINC-it: Symbol Check), Digit Symbol Substitution Test (i.e., THINC-it: Codebreaker), Trail Making Test – Part B (i.e., THINC-it: Trails), as well as the Perceived Deficits Questionnaire for Depression – 5-item (i.e., THINC-it: PDQ-5-D). A global index of objective cognitive function was computed using objective measures from the THINC-it, while self-rated cognitive deficits were measured using the PDQ-5-D. Pain was measured using a Visual Analogue Scale (VAS). Regression analyses evaluated the role of pain in predicting objective and subjective cognitive function. Results A significant between-group differences on the VAS was observed (p < 0.001), with individuals with MDD reporting higher pain severity as evidenced by higher scores on the VAS than HC. Significant interaction effects were observed between self -rated cognitive deficits and pain ratings (p < 0.001) on objective cognitive performance (after adjusting for MADRS total score), suggesting that pain moderates the association between self-rated and objective cognitive function. Conclusions Results indicated that pain is associated with increased self-rated and objective cognitive deficits in adults with MDD. Implications The study herein provides preliminary evidence demonstrating that adults with MDD reporting pain symptomatology and poorer subjective cognitive function is predictive of poorer objective cognitive performance. THINC-it is capable of detecting cognitive dysfunction amongst adults with MDD and pain.

Background The burden of illness associated with bipolar disorder (BD) warrants early pre-emption/prevention. Prediction models limited to psychiatric phenomenology have insufficient predictive power. Herein, we aimed to evaluate whether the presence of overweight/obesity is associated with greater cognitive decline in individuals at high risk (HR) or ultra high risk (UHR) for BD. Methods We conducted a retrospective analysis to investigate the moderational role of body mass index (BMI) on measures of cognitive function. Subjects between the ages of 8 and 28 years with a positive family history of BD were compared to age-matched controls with a negative family history of BD. Subjects with at least one biological parent with bipolar I/II disorder were further stratified into UHR or HR status by the presence or absence, respectively, of subthreshold hypomanic, major depressive, attenuated psychotic, and/or attention-deficit/hyperactivity disorder symptoms. Results A total of 36 individuals at HR for BD, 33 individuals at UHR for BD, and 48 age-matched controls were included in the analysis. Higher BMI was significantly associated with lower performance on measures of processing speed (i.e. Brief Assessment of Cognition in Schizophrenia−symbol coding: r=−.186, P=.047) and attention/vigilance (i.e. Continuous Performance Test−Identical Pairs: r=−.257, P=.006). There were trends for negative correlations between BMI and measures of working memory (i.e. Wechsler Memory Scale-III Spatial Span: r=−0.177, P=.059) and overall cognitive function (i.e. Measurement and Treatment Research to Improve Cognition in Schizophrenia composite score: r=−.157, P=.097). Negative associations between BMI and cognitive performance were significantly stronger in the UHR group than in the HR group, when compared to controls. Conclusions Individuals at varying degrees of risk for BD exhibit greater cognitive impairment as a function of co-existing overweight/obesity. Prediction models for BD may be substantively informed by including information related to overweight/obesity and, perhaps, other general medical conditions that share pathology with BD. Our findings herein, as well as the salutary effects of bariatric surgery on measures of cognitive function in obese populations, provide the rationale for hypothesizing that mitigating excess weight in individuals at elevated risk for BD may forestall or prevent declaration of illness.