Transcriptome Analysis Identifies An ASD-Like Phenotype In Oligodendrocytes And Microglia From C58/J Amygdala That Is Dependent On Sex and Sociability.

Background: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. Methods: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. Results: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. Limitations: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its potential as an ASD therapeutic. Conclusions: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.

TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.

Sleep disruption precedes forebrain synaptic Tau burden and contributes to cognitive decline in a sex-dependent manner in the P301S Tau transgenic mouse model.

Background: Sleep is an essential process that supports brain health and cognitive function in part through the modification of neuronal synapses. Sleep disruption, and impaired synaptic processes, are common features in neurodegenerative diseases, including Alzheimer's disease (AD). However, the casual role of sleep disruption in disease progression is not clear. Neurofibrillary tangles, made from hyperphosphorylated and aggregated Tau protein, form one of the major hallmark pathologies seen in AD and contribute to cognitive decline, synapse loss and neuronal death.Tau has been shown to aggregate in synapses which may impair restorative synapse processes occurring during sleep. However, it remains unclear how sleep disruption and synaptic Tau pathology interact to drive cognitive decline. It is also unclear whether the sexes show differential vulnerability to the effects of sleep loss in the context of neurodegeneration. Methods: We used a piezoelectric home-cage monitoring system to measure sleep behavior in 3-11month-old transgenic hTau P301S Tauopathy model mice (PS19) and littermate controls of both sexes. Subcellular fractionation and Western blot was used to examine Tau pathology in mouse forebrain synapse fractions. To examine the role of sleep disruption in disease progression, mice were exposed to acute or chronic sleep disruption. The Morris water maze test was used to measure spatial learning and memory performance. Results: PS19 mice exhibited a selective loss of sleep during the dark phase, referred to as hyperarousal, as an early symptom with an onset of 3months in females and 6months in males. At 6months, forebrain synaptic Tau burden did not correlate with sleep measures and was not affected by acute or chronic sleep disruption. Chronic sleep disruption accelerated the onset of decline of hippocampal spatial memory in PS19 males, but not females. Conclusions: Dark phase hyperarousal is an early symptom in PS19 mice that precedes robust Tau aggregation. We find no evidence that sleep disruption is a direct driver of Tau pathology in the forebrain synapse. However, sleep disruption synergized with Tau pathology to accelerate the onset of cognitive decline in males. Despite the finding that hyperarousal appears earlier in females, female cognition was resilient to the effects of sleep disruption.

Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial.

Importance: The microbiota-gut-brain axis is a promising target for novel treatments for mood disorders, such as probiotics. However, few clinical trials have been conducted, and further safety and efficacy data are needed to support this treatment approach. Objective: To provide acceptability and tolerability data and estimates of intervention effect size for probiotics as adjunctive treatment for patients with major depressive disorder (MDD). Design, Setting, and Participants: In this single-center, double-blind, placebo-controlled pilot randomized clinical trial, adults aged 18 to 55 years with MDD taking antidepressant medication but having an incomplete response were studied. A random sample was recruited from primary and secondary care services and general advertising in London, United Kingdom. Data were collected between September 2019 and May 2022 and analyzed between July and September 2022. Intervention: Multistrain probiotic (8 billion colony-forming units per day) or placebo daily for 8 weeks added to ongoing antidepressant medication. Main Outcomes and Measures: The pilot outcomes of the trial were retention, acceptability, tolerability, and estimates of putative treatment effect on clinical symptoms (depression: Hamilton Depression Rating Scale [HAMD-17] and Inventory of Depressive Symptomatology [IDS] scores; anxiety: Hamilton Anxiety Rating Scale [HAMA] and General Anxiety Disorder [GAD-7] scores) to be used as indicators for a definitive trial. Results: Of 50 included participants, 49 received the intervention and were included in intent-to-treat analyses; of these, 39 (80%) were female, and the mean (SD) age was 31.7 (9.8) years. A total of 24 were randomized to probiotic and 25 to placebo. Attrition was 8% (1 in the probiotic group and 3 in the placebo group), adherence was 97.2%, and there were no serious adverse reactions. For the probiotic group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 11.00 (5.13) and 8.83 (4.28), respectively; IDS, 30.17 (11.98) and 25.04 (11.68); HAMA, 11.71 (5.86) and 8.17 (4.68); and GAD-7, 7.78 (4.12) and 7.63 (4.77). For the placebo group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 14.04 (3.70) and 11.09 (3.22), respectively; IDS, 33.82 (9.26) and 29.64 (9.31); HAMA, 14.70 (5.47) and 10.95 (4.48); and GAD-7, 10.91 (5.32) and 9.48 (5.18). Standardized effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive symptoms according to HAMD-17 scores (week 4: SES, 0.70; 95% CI, 0.01-0.98) and IDS Self Report scores (week 8: SES, 0.64; 95% CI, 0.03-0.87) as well as greater improvements in anxiety symptoms according to HAMA scores (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05), but not GAD-7 scores (week 4: SES, 0.57; 95% CI, -0.01 to 0.82; week 8: SES, 0.32; 95% CI, -0.19 to 0.65), compared with the placebo group. Conclusions and Relevance: The acceptability, tolerability, and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of probiotics as add-on treatment for people with MDD in a definitive efficacy trial. Trial Registration: ClinicalTrials.gov Identifier: NCT03893162.

Early Clinical Experiences of Esketamine Nasal Spray in the UK in Adults with Treatment-Resistant Major Depressive Disorder: Advisory Panel Recommendations.

Purpose: Treatment-resistant depression (TRD) is associated with profound morbidity for patients, placing a significant burden on those affected, the health service and wider society. Despite this, TRD remains chronically underserved in terms of viable treatment options. To address this gap, an advisory panel of psychiatrists and clinical researchers with experience in managing TRD convened to develop best practice statements on the use of esketamine nasal spray, one of the first TRD treatments to be licensed in 30 years. Methods: During a virtual meeting held on 12th November 2020, the advisory panel shared their experiences of using esketamine nasal spray in their clinical practice. The meeting focused on developing and refining recommendations for setting up and running an efficient esketamine nasal spray clinic for patients living with TRD. At the conclusion of the meeting, agreement was reached on all recommendation statements. Results: In setting up an esketamine nasal spray clinic, it is important to consider the logistical requirements involved and put measures in place to ensure it runs as efficiently as possible. Educating patients about the treatment and maintaining their well-being is paramount for preventing discontinuation. Putting in place checklists can be a useful strategy for ensuring treatment appointments run smoothly and safely. Conclusion: Providing additional treatment options for the management of TRD, such as esketamine nasal spray, is likely to be key to improving the long-term outcomes of this underserved patient population.

Neonatal Behavioral Screen for Mouse Models of Neurodevelopmental Disorders.

Behavioral phenotyping approaches for neonatal mice are important for investigating early alterations in brain development and function, relevant to neurodevelopmental disorders in humans. This chapter describes a behavioral screen that can provide an overall profile of function across the neonatal and preweaning period while also minimizing pup stress and disturbance of the maternal environment. Testing begins when mice are between 6 and 8 days in age, with additional evaluations at discrete time points until postnatal day (PD) 20-21, using tests for negative geotaxis, surface righting reflex, activity in an open field, acoustic startle responses and sensorimotor gating, and limb clasp.

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice.

BACKGROUND: Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3WT/ΔC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. METHODS: We recorded sleep behavior in developing Shank3ΔC/ΔC, Shank3WT/ΔC, and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3WT/ΔC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. RESULTS: Male and female Shank3ΔC/ΔC mice slept significantly less than wild-type and Shank3WT/ΔC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3WT/ΔC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3WT/ΔC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3WT/ΔC subjects had a significant reduction in risk aversion. CON Shank3WT/ΔC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. LIMITATIONS: This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. CONCLUSION: Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

Adolescent Binge Alcohol Enhances Early Alzheimer's Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation.

Epidemiological studies suggest that heavy alcohol use early in life is associated with increased risk for Alzheimer's disease (AD). However, mechanisms connecting AD with alcohol use have not been identified. Both heavy alcohol use and AD feature increased proinflammatory signaling. Therefore, we hypothesized that adolescent binge ethanol would increase AD molecular and behavioral pathology in adulthood through proinflammatory signaling. The 3xTg-AD mouse model (APPSwe, tauP301, Psen1tm1Mpm) which features amyloid (Aß) and tau pathology beginning at 6-12 months underwent adolescent intermittent ethanol (AIE, 5 g/kg/d, i.g., P25-55) with assessment of AD pathologic mediators at P200. A second group of mice received AIE +/- minocycline (30 mg/kg/d, IP) followed by behavioral testing in adulthood. Behavioral testing and age of testing included: locomotor activity and exploration (27-28 weeks), novel object recognition (NORT, 28-30 weeks), 3-chamber sociability and social memory (29-31 weeks), prepulse inhibition (PPI, 30-32 weeks), Morris Water Maze with reversal (MWM, 31-35 weeks), and Piezo sleep monitoring (35-37 weeks). We found that AIE increased levels of neurotoxic Aß1-42 in adult female hippocampus as well as intraneuronal Aß1-42 in amygdala and entorhinal cortex. Phosphorylated tau at residue Thr181 (p-tau-181) was also increased in female hippocampus by AIE. Several proinflammatory genes were persistently increased by AIE in the female hippocampus, including IL-1ß, MCP-1, IL-6, and IFNα. Expression of these genes was strongly correlated with the levels of Aß1-42 and p-tau-181 in hippocampus. AIE caused persistent decreases in locomotor activity (open-field and NORT habituation) and increased anxiety-like behavior (thigmotaxis) while reducing memory retention. Treatment with the anti-inflammatory compound minocycline during AIE blocked persistent increases in Aß1-42 in amygdala and p-tau-181 in hippocampus, and prevented AIE-induced thigmotaxis and memory loss. Together, these data find that adolescent binge ethanol enhances AD molecular and behavioral pathology in adulthood through proinflammatory signaling. Blockade of proinflammatory signaling during ethanol exposure prevents ethanol-induced effects on pathologic accumulation of AD-associated proteins and persistent behavior changes relevant to human AD.

The Prevalence and Incidence of Irritable Bowel Syndrome and Inflammatory Bowel Disease in Depression and Bipolar Disorder: A Systematic Review and Meta-Analysis.

OBJECTIVE: The increased prevalence and incidence of affective disorders among patients with gastrointestinal disease have been well established. However, few studies have investigated the inverse relationship. We aimed to identify all pieces of evidence of the prevalence and incidence of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) in people with depression and bipolar disorder. METHODS: We conducted a systematic review of studies reporting the association between affective disorders (exposure) and IBS or IBD (outcome) in adults. Evidence was evaluated for quality using Joanna Briggs Institute Critical Appraisal tools. Where suitable data were available, meta-analyses were performed. RESULTS: We identified 18 studies that met the selection criteria, of which 11 provided data on IBS, 5 on IBD, and 2 on both. Overall, people with depression were significantly more likely to have comorbid IBS (risk ratio = 2.42, 95% confidence interval = 1.98-2.96) and to develop new-onset IBS (risk ratio = 1.90, 95% confidence interval = 1.41-2.56) compared with people without depression. They were also more likely to have and develop IBD, and among patients with IBD, significantly increased rates of depression were observed as early as 5 years before diagnosis. Bipolar disorder was not consistently associated with risk of either condition. CONCLUSIONS: People with depression are at an increased risk of both having and developing lower gastrointestinal disorders. These findings have important implications for how we understand, manage, and prevent this comorbidity in clinical practice. Further studies are needed to improve our understanding of the relationship between bipolar disorder and bowel disease as well as the role of psychotropic medication, particularly selective serotonin reuptake inhibitors.

Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration.

Neurologic disorders often disproportionately affect specific brain regions, and different apoptotic mechanisms may contribute to white matter pathology in leukodystrophies or gray matter pathology in poliodystrophies. We previously showed that neural progenitors that generate cerebellar gray matter depend on the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in these progenitors produces spontaneous apoptosis and cerebellar hypoplasia, while similar conditional deletion of Mcl-1 produces no phenotype. Here we show that, in contrast, postnatal oligodendrocytes depend on MCL-1. We found that brain-wide Mcl-1 deletion caused apoptosis specifically in mature oligodendrocytes while sparing astrocytes and oligodendrocyte precursors, resulting in impaired myelination and progressive white matter degeneration. Disabling apoptosis through co-deletion of Bax or Bak rescued white matter degeneration, implicating the intrinsic apoptotic pathway in Mcl-1-dependence. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mouse model of the leukodystrophy vanishing white matter disease (VWMD), suggesting the potential for MCL-1 deficiency to contribute to clinical neurologic disease. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 deficiency in white matter pathology, and suggest apoptosis inhibition as a leukodystrophy therapy.

Perturbations in Gut Microbiota Composition in Psychiatric Disorders: A Review and Meta-analysis.

Importance: Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers. However, no attempts have been made to evaluate the specificity of these across the range of psychiatric conditions. Objective: To conduct an umbrella and updated meta-analysis of gut microbiota alterations in general adult psychiatric populations and perform a within- and between-diagnostic comparison. Data Sources: Cochrane Library, PubMed, PsycINFO, and Embase were searched up to February 2, 2021, for systematic reviews, meta-analyses, and original evidence. Study Selection: A total of 59 case-control studies evaluating diversity or abundance of gut microbes in adult populations with major depressive disorder, bipolar disorder, psychosis and schizophrenia, anorexia nervosa, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, or attention-deficit/hyperactivity disorder were included. Data Extraction and Synthesis: Between-group comparisons of relative abundance of gut microbes and beta diversity indices were extracted and summarized qualitatively. Random-effects meta-analyses on standardized mean difference (SMD) were performed for alpha diversity indices. Main Outcomes and Measures: Alpha and beta diversity and relative abundance of gut microbes. Results: A total of 34 studies provided data and were included in alpha diversity meta-analyses (n = 1519 patients, n = 1429 control participants). Significant decrease in microbial richness in patients compared with control participants were found (observed species SMD = -0.26; 95% CI, -0.47 to -0.06; Chao1 SMD = -0.5; 95% CI, -0.79 to -0.21); however, this was consistently decreased only in bipolar disorder when individual diagnoses were examined. There was a small decrease in phylogenetic diversity (SMD = -0.24; 95% CI, -0.47 to -0.001) and no significant differences in Shannon and Simpson indices. Differences in beta diversity were consistently observed only for major depressive disorder and psychosis and schizophrenia. Regarding relative abundance, little evidence of disorder specificity was found. Instead, a transdiagnostic pattern of microbiota signatures was found. Depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were consistently shared between major depressive disorder, bipolar disorder, psychosis and schizophrenia, and anxiety, suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while pro-inflammatory genera are enriched. The confounding associations of region and medication were also evaluated. Conclusions and Relevance: This systematic review and meta-analysis found that gut microbiota perturbations were associated with a transdiagnostic pattern with a depletion of certain anti-inflammatory butyrate-producing bacteria and an enrichment of pro-inflammatory bacteria in patients with depression, bipolar disorder, schizophrenia, and anxiety.

Updated Review and Meta-Analysis of Probiotics for the Treatment of Clinical Depression: Adjunctive vs. Stand-Alone Treatment.

Recent years have seen a rapid increase in the use of gut microbiota-targeting interventions, such as probiotics, for the treatment of psychiatric disorders. The objective of this update review was to evaluate all randomised controlled clinical trial evidence on the efficacy of probiotics for clinical depression. Cochrane guidelines for updated reviews were followed. By searching PubMed and Web of Science databases, we identified 546 new records since our previous review. A total of seven studies met selection criteria, capturing 404 people with depression. A random effects meta-analysis using treatment type (stand-alone vs. adjunctive) as subgroup was performed. The results demonstrated that probiotics are effective in reducing depressive symptoms when administered in addition to antidepressants (SMD = 0.83, 95%CI 0.49-1.17), however, they do not seem to offer significant benefits when used as stand-alone treatment (SMD = -0.02, 95%CI -0.34-0.30). Potential mechanisms of action may be via increases in brain-derived neurotrophic factor (BDNF) and decreases in C-reactive protein (CRP), although limited evidence is available at present. This review offers stronger evidence to support the clinical use of probiotics in depressed populations and provides an insight into the mode of administration more likely to yield antidepressant effects.

Loss of α7 nicotinic acetylcholine receptors in GABAergic neurons causes sex-dependent decreases in radial glia-like cell quantity and impairments in cognitive and social behavior.

The dentate gyrus (DG) is a unique brain structure in that neurons can be generated postnatally and integrated within existing circuitry throughout life. The maturation process of these newly generated neurons (granule cells) is modulated by nicotinic acetylcholine receptors (nAChRs) through a variety of mechanisms such as neural stem pool proliferation, cell survival, signal modulation, and dendritic integration. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, predominantly the α7 subtype, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined histological and behavioral effects of knocking out α7 nAChRs in GABAergic neurons. Deletion of α7 nAChRs resulted in a reduction of radial glia-like cells within the subgranular zone of the DG and a concomitant trend towards decreased immature neurons, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition and spatial learning. Overall, these findings suggest α7 nAChRs expressed in GABAergic neurons play an important role in regulating the adult neural stem cell pool and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.

Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis.

Most interventions for treatment-resistant depression (TRD) are added as augmenters. We aimed to determine the relative effectiveness of augmentation treatments for TRD. This systematic review and network meta-analysis (NMA) sought all randomized trials of pharmacological and psychological augmentation interventions for adults meeting the most common clinical criteria for TRD. The NMA compared the intervention effectiveness of depressive symptoms for TRD augmentation. Of 36 included trials, 27 were suitable for inclusion in NMA, and no psychological trials could be included in the absence of a common comparator. Antipsychotics (13 trials), mood stabilizers (three trials), NMDA-targeting medications (five trials), and other mechanisms (3 trials) were compared against placebo. NMDA treatments were markedly superior to placebo (ES = 0.91, 95% CI 0.67 to 1.16) and head-to-head NMA suggested that NMDA therapies had the highest chance of being an effective treatment option compared to other pharmacological classes. This study provides the most comprehensive evidence of augmenters' effectiveness for TRD, and our GRADE recommendations can be used to guide guidelines to optimize treatment choices. Although conclusions are limited by paucity of, and heterogeneity between, trials as well as inconsistent reports of treatment safety. This work supports the use of NMDA-targeting medications such as ketamine.

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in individuals with AS are common, debilitating, and often drug resistant. Thus, there is an unmet need for better treatment options. Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has shown antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here, we show that acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS. However, neither acute CBD nor a 2-week-long course of CBD administered immediately after a kindling protocol could halt the proepileptogenic plasticity observed in AS model mice. CBD had a dose-dependent sedative effect but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including the delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. We believe our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS and will thus help guide the rational development of CBD as a treatment for AS.

Gut feeling: randomized controlled trials of probiotics for the treatment of clinical depression: Systematic review and meta-analysis.

BACKGROUND: Recently the gut microbiota has attracted significant interest in psychiatric research due to the observed bidirectional gut-brain communication. A growing body of evidence from preclinical work has suggested that probiotics may be effective in reducing stress and anxiety and alleviating low mood. It is unclear to what extent these effects are seen in clinical populations. We aimed to identify all published evidence on the efficacy of probiotics as treatment for depression in clinically depressed populations. METHODS: Randomized controlled trials of patients with depression where probiotics were used as supplementary or standalone treatment were considered eligible. A literature search with the terms (probiotic* OR bacteria OR Lactobacillus OR Bifidobacterium) AND depress* was performed in PubMed and Web of Science. Data on study population characteristics, treatment effectiveness, tolerability and risk of bias were extracted from eligible studies. A random effects model was used for meta-analyses. RESULTS: Only three studies met inclusion criteria (229 individuals randomized), two of which administered probiotics as a supplementary treatment to antidepressants and one as a standalone treatment. Upon removal of the latter study from the meta-analysis due to clinical heterogeneity, there was an overall positive effect of probiotics on depressive symptoms (standardized mean difference = 1.371, 95% confidence interval 0.130-2.613). CONCLUSIONS: There is limited evidence for the efficacy of probiotics in depression at present, although there may be a beneficial effect of probiotics on depressive symptoms when administered in addition to antidepressants. Further studies are required to investigate this and explore potential mechanisms.

Inter-α-inhibitor deficiency in the mouse is associated with alterations in anxiety-like behavior, exploration and social approach.

In recent years, several genome-wide association studies have identified candidate regions for genetic susceptibility in major mood disorders. Most notable are regions in a locus in chromosome 3p21, encompassing the genes NEK4-ITIH1-ITIH3-ITIH4. Three of these genes represent heavy chains of the composite protein inter-α-inhibitor (IαI). In order to further establish associations of these genes with mood disorders, we evaluated behavioral phenotypes in mice deficient in either Ambp/bikunin, which is necessary for functional ITIH1 and ITIH3 complexes, or in Itih4, the gene encoding the heavy chain Itih4. We found that loss of Itih4 had no effect on the behaviors tested, but loss of Ambp/bikunin led to increased anxiety-like behavior in the light/dark and open field tests and reduced exploratory activity in the elevated plus maze, light/dark preference and open field tests. Ambp/bikunin knockout mice also exhibited a sex-dependent exaggeration of acoustic startle responses, alterations in social approach during a three-chamber choice test, and an elevated fear conditioning response. These results provide experimental support for the role of ITIH1/ITIH3 in the development of mood disorders.

Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism.

Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate oxytocin receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4-9) and OT(5-9). While OT(5-9) failed to affect social deficits, the metabolite OT(4-9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4-9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD.

Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis.

BACKGROUND: Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD. METHOD: Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions. RESULTS: Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25-1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23-1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81-1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.80-1.30) and psychological (ES = 1.43, 95% CI 0.50-2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66-0.91) and psychological control (ES = 0.94, 95% CI 0.36-1.52). CONCLUSIONS: Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.