Comparative Efficacy and Tolerability of Adjunctive Pharmacotherapies for Acute Bipolar Depression: A Systematic Review and Network Meta-analysis.

OBJECTIVE: We investigated the comparative efficacy and tolerability of augmentation strategies for bipolar depression. DATA SOURCES: We conducted a systematic review and network meta-analysis of 8 electronic databases for double-blind, randomized controlled trials of adjunctive pharmacotherapies for acute bipolar depression. DATA EXTRACTION AND SYNTHESIS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and applied the Cochrane risk of bias tool for study quality appraisal. Two reviewers independently abstracted data. We resolved all discrepancies by consensus. MAIN OUTCOMES AND MEASURES: Primary outcomes were response and completion of treatment. We estimated summary rate ratios (RRs) and standardized mean differences (SMDs) relative to placebo controls using frequentist random-effects network meta-analysis. RESULTS: We identified 69 trials meeting eligibility criteria (8,007 participants, 42.8 years, 58.0% female). Adjunctive racemic intravenous ketamine, coenzyme Q10, pramipexole, fluoxetine, and lamotrigine were more effective than placebo. Summary RRs for response ranged between 1.51 (95% confidence interval [CI], 1.11 to 2.06) for fluoxetine and 12.49 (95% CI, 3.06 to 50.93) for racemic intravenous ketamine. For completion of treatment, risperidone appeared less tolerable than placebo (RR = 0.59; 95% CI, 0.38 to 0.94), while fluoxetine seemed more tolerable than placebo (RR = 1.13; 95% CI, 1.02 to 1.24). None of the investigated agents were associated with increased treatment-emergent mood switches. CONCLUSIONS AND RELEVANCE: The evidence for augmentation strategies in bipolar depression is limited to a handful of agents. Fluoxetine appeared to have the most consistent evidence base for both efficacy and tolerability. There remains a need for additional research exploring novel treatment strategies for bipolar depression, particularly head-to-head studies.

Cannabinoids for the Neuropsychiatric Symptoms of Dementia: A Systematic Review and Meta-Analysis.

BACKGROUND: In 2016, the global number of individuals living with dementia was 43.8 million, representing a 117% increase from 1990-mainly due to increases in aging and population growth. Up to 90% of individuals with dementia experience neuropsychiatric symptoms (NPS). However, the limitations of current treatments for NPS have drivent he search for safer pharmacotherapies-including cannabinoids. AIM: To assess the efficacy and acceptability of cannabinoids for the treatment of NPS in individuals with dementia. DESIGN: Systematic review and meta-analysis of clinical trials. SETTING AND PARTICIPANTS: Of 6,902 papers, 9 were eligible (n = 205, 44% female, 78 ± 7 years, 85% Alzheimer disease). Trials were in North America and Europe and explored tetrahydrocannabinol (n = 3), dronabinol (n = 5), or nabilone (n = 1). MEASUREMENT: Titles/abstracts were independently screened by one reviewer and reviewed by a second. Full-text screening was by two reviewers with discrepancies resolved via a third reviewer. We extracted data on the standardized mean difference (SMD) for several NPS instruments, trial completion, and adverse events. Data were pooled using random-effects models. FINDINGS: Cannabinoids led to significant improvements across NPS instruments, including the Cohen Mansfield Agitation Inventory (SMD = -0.80; 95% confidence interval [CI], -1.45 to -0.16), the Neuropsychiatric Inventory (SMD = -0.61; CI, -1.07 to -0.15), and nocturnal actigraphy (SMD = -1.05; CI, -1.56 to -0.54h). Cannabinoids were well-tolerated, with an overall trial completion rate of 93% (193/205) and no serious treatment-related adverse events. Treatment efficacy was associated with baseline dementia severity and dose, but not dementia subtype, age, or sex. The overall study quality was rated as low. CONCLUSIONS: There is preliminary evidence for the efficacy and tolerability of cannabinoids as treatments for NPS. Population-based studies are needed to characterize their real-world effectiveness and acceptability.

Maintenance Pharmacological Treatment of Juvenile Bipolar Disorder: Review and Meta-Analyses.

BACKGROUND: Guidelines for maintenance treatment of juvenile bipolar disorder rely heavily on evidence from adult studies and relatively brief trials in juveniles, leaving uncertainties about optimal long-term treatment. We aimed to systematically review long-term treatment trials for juvenile bipolar disorder. METHODS: We analyzed data recovered by a systematic literature search using the PRISMA guidelines statement, through 2018, for peer-reviewed reports on pharmacological treatments for juvenile bipolar disorder lasting ≥24 weeks. RESULTS: Of 13 reports with 16 trials of 9 treatments (18.8% were randomized and controlled), with 1773 subjects (94.4% BD-I; ages 6.9-15.1 years), lasting 11.7 (6-22) months. Pooled clinical response rates were 66.8% (CI: 64.4-69.1) with drugs vs 60.6% (53.0-66.7) in 3 placebo-control arms. Random-effects meta-analysis of 4 controlled trials yielded pooled odds ratio (OR) = 2.88 ([0.87-9.60], P = .08) for clinical response, and OR = 7.14 ([1.12-45.6], P = .04) for nonrecurrence. Apparent efficacy ranked: combined agents >anticonvulsants ≥lithium ≥antipsychotics. Factors favoring response ranked: more attention deficit/hyperactivity disorder, polytherapy, randomized controlled trial design, nonrecurrence vs response. Adverse events (incidence, 5.50%-28.5%) notably included cognitive dulling, weight-gain, and gastrointestinal symptoms; early dropout rates averaged 49.8%. CONCLUSIONS: Pharmacological treatments, including anticonvulsants, lithium, and second-generation antipsychotics, may reduce long-term morbidity in juvenile bipolar disorder. However, study number, quality, and effect magnitude were limited, leaving the status of scientific support for maintenance treatment for juvenile bipolar disorder inconclusive.

Transcranial Magnetic Stimulation of the Supplementary Motor Area in the Treatment of Obsessive-Compulsive Disorder: A Multi-Site Study.

Recently, strategies beyond pharmacological and psychological treatments have been developed for the management of obsessive-compulsive disorder (OCD). Specifically, repetitive transcranial magnetic stimulation (rTMS) has been employed as an adjunctive treatment in cases of treatment-refractory OCD. Here, we investigate six weeks of low frequency rTMS, applied bilaterally and simultaneously over the sensory motor area, in OCD patients in a randomized, double-blind placebo-controlled clinical trial. Twenty-two participants were randomly enrolled into the treatment (ACTIVE = 10) or placebo (SHAM = 12) groups. At each of seven visits (baseline; day 1 and weeks 2, 4, and 6 of treatment; and two and six weeks after treatment) the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was administered. At the end of the six weeks of rTMS, patients in the ACTIVE group showed a clinically significant decrease in Y-BOCS scores compared to both the baseline and the SHAM group. This effect was maintained six weeks following the end of rTMS treatment. Therefore, in this sample, rTMS appeared to significantly improve the OCD symptoms of the treated patients beyond the treatment window. More studies need to be conducted to determine the generalizability of these findings and to define the duration of rTMS' clinical effect on the Y-BOCS. Clinical Trial Registration Number (NCT) at www.clinicaltrials.gov: NCT00616486.

D1 dopamine receptor-mediated LTP at GABA synapses encodes motivation to self-administer cocaine in rats.

Enhanced motivation to take drugs is a central characteristic of addiction, yet the neural underpinning of this maladaptive behavior is still largely unknown. Here, we report a D1-like dopamine receptor (DRD1)-mediated long-term potentiation of GABAA-IPSCs (D1-LTPGABA) in the oval bed nucleus of the stria terminalis that was positively correlated with motivation to self-administer cocaine in rats. Likewise, in vivo intra-oval bed nucleus of the stria terminalis DRD1 pharmacological blockade reduced lever pressing for cocaine more effectively in rats showing enhanced motivation toward cocaine. D1-LTPGABA resulted from enhanced function and expression of G-protein-independent DRD1 coupled to c-Src tyrosine kinases and required local release of neurotensin. There was no D1-LTPGABA in rats that self-administered sucrose, in those with limited cocaine self-administration experience, or in those that received cocaine passively (yoked). Therefore, our study reveals a novel neurophysiological mechanism contributing to individual motivation to self-administer cocaine, a critical psychobiological element of compulsive drug use and addiction.

Sleep architecture and cognitive changes in olanzapine-treated patients with depression: a double blind randomized placebo controlled trial.

BACKGROUND: Disturbance in sleep quality is a symptom of Major Depressive Disorder (MDD) and Bipolar Disorder (BD) and thus improving quality of sleep is an important aspect of successful treatment. Here, a prospective, double-blind, randomized, placebo-controlled study examined the effect of olanzapine (an atypical antipsychotic) augmentation therapy on sleep architecture, specifically slow wave sleep (SWS), in the treatment of depression. The effect of olanzapine augmentation therapy on other features of sleep (e.g., sleep continuity) and depression (e.g., illness severity and cognitive function) were also determined. METHODS: Patients currently experiencing a major depressive episode and who were on a stable medication were included. Sleep architecture was measured by overnight ambulatory polysomnography. Illness severity was determined using the Montgomery-Asberg Depression Rating Scale (MADRS). Cognitive function was examined using Cambridge Neuropsychological Test Automated Battery (CANTAB): Spatial Working Memory (SWM), Spatial Span (SSP), and Reaction Time (RTI) tasks. Polysomnographs, clinical measures and cognitive tests were administered at baseline, after 2-4 days of treatment and after 28-31 days of treatment. Twenty-five patients participated in the study (N = 10, N = 15 for placebo and olanzapine treated groups respectively). RESULTS: The primary objective of the study was to assess the objective (polysomnographic) changes in sleep quality, defined as changes in SWS, following olanzapine treatment for depression. Latency to but not duration of SWS was found to significantly differ between olanzapine- and placebo-treated participants (Hedge's g: 0.97, 0.13 respectively). A significant improvement in olanzapine-treated participants over placebo-treated participants was observed in secondary outcome measures, including sleep efficiency, total sleep time, and sleep latency. Secondary objectives assessed the subjective changes in sleep quality parameters and correlated them with measures of illness severity and changes in cognition. MADRS scores were significantly improved in olanzapine-treated participants over time but not more than placebo treatment. There was no significant difference between olanzapine- and placebo-treated participants in SWM, SSP or RTI tasks. CONCLUSIONS: Olanzapine augmentation treatment generally did not improve SWS but did improve sleep continuity and depression. Olanzapine may be one of few medications that improve sleep continuity, thus directly targeting symptoms of depression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00520507.

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

The use of transcranial direct current stimulation (tDCS) to reduce impulsivity and aggression in adults with mild intellectual developmental disabilities: the tDCS-RIADD randomised controlled trial protocol.

BACKGROUND: Challenging behaviours, in particular aggressive behaviours, are prevalent among people with intellectual developmental disabilities. Predictors of challenging behaviours are numerous, including past history of aggression, poor coping skills and impulsivity. Factors like motor or rapid-response impulsivity (RRI) have neurobiological underpinnings that may be amenable to change via neuromodulation using non-invasive brain stimulation techniques like transcranial direct current stimulation (tDCS). METHODS: This study aims to determine the efficacy of anodal tDCS in reducing RRI and incidents of aggression in people with intellectual developmental disabilities (IDD) in residential or hospital settings. Using a single blind, randomised, sham-controlled trial design, adults with IDD, with a history of impulsivity leading to aggression, will be randomised to receive either repetitive anodal or sham tDCS applied to the left dorsolateral prefrontal cortex. Outcome measures assessing impulsivity and aggression will be collected for up to 1 month following the last tDCS session. DISCUSSION: The results of this study may pave the way for developing targeted interventions for impulsivity and aggressive behaviours in people with IDD.

Pharmacotherapies for cannabis use disorder: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to determine the efficacy and acceptability of pharmacotherapies for cannabis use disorder (CUD). METHODS: We conducted a systematic review and frequentist network meta-analysis, searching five electronic databases for randomized placebo-controlled trials of individuals diagnosed with CUD receiving pharmacotherapy with or without concomitant psychotherapy. Primary outcomes were the reduction in cannabis use and retention in treatment. Secondary outcomes were adverse events, discontinuation due to adverse events, total abstinence, withdrawal symptoms, cravings, and CUD severity. We applied a frequentist, random-effects Network Meta-Analysis model to pool effect sizes across trials using standardized mean differences (SMD, g) and rate ratios (RR) with their 95% confidence intervals. RESULTS: We identified a total of 24 trials (n=1912, 74.9% male, mean age 30.2 years). Nabilone (d=-4.47 [-8.15; -0.79]), topiramate (d=-3.80 [-7.06; -0.54]), and fatty-acid amyl hydroxylase inhibitors (d=-2.30 [-4.75; 0.15]) reduced cannabis use relative to placebo. Dronabinol improved retention in treatment (RR=1.27 [1.02; 1.57]), while topiramate worsened treatment retention (RR=0.62 [0.42; 0.91]). Gabapentin reduced cannabis cravings (d=-2.42 [-3.53; -1.32], while vilazodone worsened craving severity (d=1.69 [0.71; 2.66]. Buspirone (RR=1.14 [1.00; 1.29]), venlafaxine (RR=1.78 [1.40; 2.26]), and topiramate (RR=9.10 [1.27; 65.11]) caused more adverse events, while topiramate caused more dropouts due to adverse events. CONCLUSIONS: Based on this review, some medications appeared to show promise for treating individual aspects of CUD. However, there is a lack of robust evidence to support any particular pharmacological treatment. There is a need for additional studies to expand the evidence base for CUD pharmacotherapy. While medication strategies may become an integral component for CUD treatment one day, psychosocial interventions should remain the first line given the limitations in the available evidence.

Subanesthetic ketamine infusions for suicide ideation in patients with bipolar and unipolar treatment refractory depression.

We evaluated the effects of repeated subanesthetic ketamine infusions on suicidal ideation (SI) in patients with major depression. 82 subjects with treatment-resistant unipolar and bipolar depression completed a two-site open-label case-series of repeated (up to four weeks) infusions of ketamine (0.5 mg/kg). Ketamine produced a significant reduction in SI as early as one hour (71.1%) and up to 1-week post-infusion (60.4%), accompanied by a reduction in overall depressive symptoms which were maintained until the 4th week. The observed anti-suicidal effect was independent of mood changes, as patients whose mood did not respond still exhibited significantly less SI than baseline.

Long-Term Treatment of Bipolar Disorder with Valproate: Updated Systematic Review and Meta-analyses.

LEARNING OBJECTIVE: After participating in this activity, learners should be better able to:• Evaluate the evidence regarding the effectiveness of long-term treatment of bipolar disorder with valproate. BACKGROUND: Prophylactic treatment is critical for bipolar disorder (BD) patients. Valproate is commonly used for this purpose but lacks regulatory approval and carries appreciable risks. METHODS: Systematic literature searching through June 2020 sought prospective trials lasting ≥12 months with adults diagnosed with BD to support comparisons of risk of new illness episodes with valproate versus placebo or other agents. RESULTS: Included were 13 reports involving 9240 subjects treated for an average of 29.1 months (range, 12-124) in 21 trials: 9 were blinded, randomized trials (RCTs) of valproate versus placebo (n = 3), lithium (5), or olanzapine (1); 2 were unblinded RCTs versus lithium (1) or quetiapine (1); and 10 were open-label trials versus lithium (5), quetiapine (2), carbamazepine (1), lamotrigine (1), or olanzapine (1). Random-effects meta-analysis found valproate superior to placebo in 3 trials (odds ratio [OR] = 0.42 [95% confidence level (CI), 0.30-0.60]; p < .0001). In 11 trials, protective effects with valproate and lithium were similar (OR = 1.20 [CI, 0.81-1.79]; p = .36), as well in 5 comparisons versus antipsychotics quetiapine and olanzapine (OR = 0.96 [CI, 0.66-1.40]; p = .84), and 2 versus other mood-stabilizing anticonvulsants (carbamazepine and lamotrigine) (OR = 1.30 [CI, 0.75-2.26]; p = .34). Valproate was nonsignificantly more effective versus new mania than depression (χ2 = 3.03; p = .08). CONCLUSIONS: Valproate was more effective than placebo in preventing new BD episodes of mania or depression, and not significantly different from lithium, second-generation antipsychotics, or other anticonvulsants. Overall benefits were nonsignificantly greater versus mania than bipolar depression.

Efficacy and acceptability of cannabinoids for anxiety disorders in adults: A systematic review & meta-analysis.

OBJECTIVE: The aim of this study was to assess the efficacy and acceptability of cannabinoids for the treatment of anxiety disorders. METHODS: For this systematic review and meta-analysis, we searched for randomized trials utilizing cannabinoids for the treatment of adults with anxiety disorders. Primary outcomes were reduction in anxiety disorder symptoms, and study discontinuation due to adverse events. Evidence was synthesized as rate ratios (RRs) and as standardized mean differences (SMDs) using random-effects meta-analyses. RESULTS: A total of 14 eligible trials representing 1548 individuals (median age: 33 years; range: 28-44; 66% male) were identified. Cannabinoids reduced anxiety symptoms (SMD = -1.85, 95% CI: -2.61 to -1.09) without causing significant adverse events. Greater efficacy was observed among younger patients (p < 0.01) and with longer treatment (p < 0.01). However, publication bias was substantial, and after correction, the overall anxiolytic effect was not statistically significant. CONCLUSIONS: While cannabinoids may be of potential value in the treatment of anxiety disorders, the routine use of these treatments is not supported by the available evidence after correction for publication bias.

Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can develop following a traumatic experience. PTSD is associated with significant disability, a large economic burden, and despite the range of therapies to treat PTSD, response to antidepressants is limited. A growing body of clinical research suggests the efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in individuals with treatment-refractory PTSD. AIM: To assess the effectiveness and safety of MDMA-assisted psychotherapy for reducing symptoms of PTSD, a systematic review and meta-analysis was undertaken. METHODS: Six online databases were searched from inception to December 2018. Reference lists of relevant articles were manually searched as well as electronic sources of ongoing trials and conference proceedings. Researchers active in the subject were also contacted. Eligible studies included randomized and quasi-randomized clinical trials using MDMA-assisted psychotherapy for PTSD in comparison with other medications, placebo or no medication (supportive care). We used standard methodological procedures expected by the Cochrane Collaboration. Two authors assessed studies for inclusion and extracted data. Using random-effects meta-analysis with Cochrane's Review Manager 5.3, we obtained standardized mean differences [SMD] and rate ratios [RR] for reduction in PTSD symptomatology. RESULTS: A total of 5 trials met inclusion criteria, totaling 106 participants (average age: 35-40 years, 70% female). Studies were rated as moderate in quality. MDMA-assisted psychotherapy demonstrated a high rate of clinical response (RR = 3.47, 95% CI: 1.70, 7.06), remission (RR = 2.63, 95% CI: 1.37, 5.02), with a large effect size at reducing the symptoms of PTSD (SMD = 1.30, 95% CI: 0.66, 1.94). Available evidence indicates that MDMA was well-tolerated, with few serious adverse events reported across studies. CONCLUSIONS: MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD. However, future studies involving larger samples and longer durations of treatment and follow-up are warranted-and underway.

Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: A systematic review and network meta-analysis.

OBJECTIVE: We investigated the comparative efficacy and tolerability of pharmacological treatment strategies for the treatment of acute bipolar depression. DATA SOURCES: A systematic review and network meta-analysis was conducted by searching eight registries for published and unpublished, double-blind, randomized controlled trials of pharmacotherapies for the acute treatment of bipolar depression. DATA EXTRACTION AND SYNTHESIS: PRISMA guidelines were used for abstracting data, while the Cochrane Risk of Bias Tool was used to assess data quality. Data extraction was done independently by two reviewers, with discrepancies resolved by consensus. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: Primary outcomes were efficacy (response and remission rate) and acceptability (completion of treatment and dropouts due to adverse events). Summary odds ratios (ORs) were estimated using pairwise and network meta-analysis with random effects. RESULTS: Identified citations (4,404) included 50 trials comprising 11,448 participants. Escitalopram, phenelzine, moclobemide, carbamazepine, sertraline, lithium, paroxetine, aripiprazole, gabapentin and ziprasidone appear to be ineffective as compared to placebo in treatment of bipolar depression. Divalproex, olanzapine/fluoxetine, olanzapine, quetiapine, cariprazine, and lamotrigine, appear to be effective as compared to placebo in treatment of bipolar depression according to the network meta-analysis. Aripiprazole showed higher discontinuation rates versus placebo due to the appearance of any adverse event. Quetiapine was better than placebo at reducing treatment-emergent affective switches. For Bipolar I Disorder, cariprazine, fluoxetine, imipramine, lamotrigine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at response, while fluoxetine, imipramine, cariprazine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at remission. CONCLUSIONS AND RELEVANCE: These results could serve evidence-based practice and inform patients, physicians, guideline developers, and policymakers on the relative benefits of the different antidepressants, antipsychotics, and mood-stabilizing agents for the treatment of bipolar depression. REGISTRATION: PROSPERO (CRD42019122172).

Prevalence of Cannabis Withdrawal Symptoms Among People With Regular or Dependent Use of Cannabinoids: A Systematic Review and Meta-analysis.

Importance: Cannabis withdrawal syndrome (CWS)-a diagnostic indicator of cannabis use disorder-commonly occurs on cessation of heavy and prolonged cannabis use. To date, the prevalence of CWS syndrome has not been well described, nor have the factors potentially associated with CWS. Objectives: To estimate the prevalence of CWS among individuals with regular or dependent use of cannabinoids and identify factors associated with CWS. Data Sources: A search of literature from database inception to June 19, 2019, was performed using MEDLINE, Embase, PsycINFO, Web of Science, the Cumulative Index to Nursing and Allied Health Literature, ProQuest, Allied and Complementary Medicine, and Psychiatry online, supplemented by manual searches of reference lists of included articles. Study Selection: Articles were included if they (1) were published in English, (2) reported on individuals with regular use of cannabinoids or cannabis use disorder as a primary study group, (3) reported on the prevalence of CWS or CWS symptoms using a validated instrument, (4) reported the prevalence of CWS, and (5) used an observational study design (eg, cohort or cross-sectional). Data Extraction and Synthesis: All abstracts, full-text articles, and other sources were reviewed, with data extracted in duplicate. Cannabis withdrawal syndrome prevalence was estimated using a random-effects meta-analysis model, alongside stratification and meta-regression to characterize heterogeneity. Main Outcomes and Measures: Cannabis withdrawal syndrome prevalence was reported as a percentage with 95% CIs. Results: Of 3848 unique abstracts, 86 were selected for full-text review, and 47 studies, representing 23 518 participants, met all inclusion criteria. Of 23 518 participants included in the analysis, 16 839 were white (72%) and 14 387 were men (69%); median (SD) age was 29.9 (9.0) years. The overall pooled prevalence of CWS was 47% (6469 of 23 518) (95% CI, 41%-52%), with significant heterogeneity between estimates (I2 = 99.2%). When stratified by source, the prevalence of CWS was 17% (95% CI, 13%-21%) in population-based samples, 54% in outpatient samples (95% CI, 48%-59%), and 87% in inpatient samples (95% CI, 79%-94%), which were significantly different (P < .001). Concurrent cannabis (ß = 0.005, P < .001), tobacco (ß = 0.002, P = .02), and other substance use disorders (ß = 0.003, P = .05) were associated with a higher CWS prevalence, as was daily cannabis use (ß = 0.004, P < .001). Conclusions and Relevance: These findings suggest that cannabis withdrawal syndrome appears to be prevalent among regular users of cannabis. Clinicians should be aware of the prevalence of CWS in order to counsel patients and support individuals who are reducing their use of cannabis.

Mental, emotional, and behavioral effects of ketogenic diet for non-epileptic neuropsychiatric conditions.

Ketogenic diet (KD) is comprised of a distinct macronutrient combination: i.e. 90% fat, 8% of protein and 2% of carbohydrates, typically characterized as a high-fat low-carbohydrate diet. KD's efficacy was largely established for treatment resistant epilepsy in children, but its mental, emotional and behavioral effects remain largely unknown. Nevertheless, the efficacious effects of KD in childhood epilepsy provide rationale for repurposing this approach for other brain-based disorders. Consequently, clinicians and researchers should be aware of the evidence regarding efficacy, as well as the benefits and risks of adopting this diet. Results from animals and humans studies provide equivocal evidence across multiple domains of psychopathology. Conceptually, KD shows promise to serve as an efficacious treatment for mental disorders.

Mortality over a 20-year period in patients with primary polydipsia associated with schizophrenia: a retrospective study.

Primary polydipsia, excessive fluid intake without medical cause, is present in over 20% of seriously and persistently ill psychiatric inpatients. The long-term effects of primary polydipsia on longevity have not previously been examined. Inpatients in a psychiatric hospital were screened for polydipsia in 1985. Those identified to be polydipsic, the majority of whom suffered from schizophrenia, were re-evaluated in 2005 and compared with a control group of non-polydipsic patients. Chart reviews were conducted and follow-up data were obtained. Of 172 patients at the time of screening, 48 suffering from schizophrenia either had or went on to develop polydipsia; 42 non-polydipsic patients with schizophrenia from the original survey were randomly selected as controls. Primary polydipsia had a significant negative effect on longevity. The median age at death (age at which 50% of cases have died) was 59 years for polydipsic patients and 68 for non-polydipsic control patients. Adjusting for duration of schizophrenia, smoking, and diagnosis, a patient with polydipsia had a 74% greater chance of dying before a non-polydipsic patient (a hazard ratio of 2.84 [95% Confidence Interval (CI): 1.22-6.64]). Outcome was worst in patients with severe polydipsia: the median age at death was 57 years and a patient with severe polydipsia had a 75% greater chance of dying before a non-polydipsic patient (hazard ratio of 3.36 [95% CI: 1.31-8.60]). When polydipsia is associated with schizophrenia, mortality is increased in comparison to that in patients with schizophrenia who do not drink water to excess.

The Bed Nucleus of the Stria Terminalis, Homeostatic Satiety, and Compulsions: What Can We Learn From Polydipsia?

A compulsive phenotype characterizes several neuropsychiatric illnesses - including but not limited to - schizophrenia and obsessive compulsive disorder. Because of its perceived etiological heterogeneity, it is challenging to disentangle the specific neurophysiology that precipitates compulsive behaving. Using polydipsia (or non-regulatory water drinking), we describe candidate neural substrates of compulsivity. We further postulate that aberrant neuroplasticity within cortically projecting structures [i.e., the bed nucleus of the stria terminalis (BNST)] and circuits that encode homeostatic emotions (thirst, hunger, satiety, etc.) underlie compulsive drinking. By transducing an inaccurate signal that fails to represent true homeostatic state, cortical structures cannot select appropriate and adaptive actions. Additionally, augmented dopamine (DA) reactivity in striatal projections to and from the frontal cortex contribute to aberrant homeostatic signal propagation that ultimately biases cortex-dependent behavioral selection. Responding becomes rigid and corresponds with both erroneous, inflexible encoding in both bottom-up structures and in top-down pathways. How aberrant neuroplasticity in circuits that encode homeostatic emotion result in the genesis and maintenance of compulsive behaviors needs further investigation.

Estradiol potentiates inhibitory synaptic transmission in the oval bed nucleus of the striaterminalis of male and female rats.

17ß-Estradiol (E2) is a potent neuromodulator capable of producing changes in inhibitory synaptic transmission by either changing pre-synaptic GABA release or post-synaptic GABAA receptor function. Physiologically, E2 is important for energy homeostasis, influencing food consumption, body weight, adipose tissue metabolism and energy expenditure. E2 may influence energy homeostasis through estrogen receptor-rich regions such as the oval bed nucleus of the stria-terminalis (ovBNST). However, the neurophysiological effects of estradiol within the ovBNST remain largely unknown. Understanding how E2 affects inhibitory transmission may elucidate the ovBNST's contribution to energy homeostasis. Here, using brain slice electrophysiology, we saw that E2 produced a long-term potentiation (LTP) of GABAA synaptic transmission (LTPGABA) in the ovBNST in male rats. E2 acted on estrogen receptors α and G-protein coupled estrogen receptors (GPER), involved protein kinase activation and required an intact endocannabinoid system. The effects of E2 in males were sensitive to 24 h of food deprivation. In females, E2 was 100-fold more potent at producing LTPGABA ovBNST compared to male rats and involved all three known subtypes of estrogen receptors (ERα, ERß, and GPER). These results demonstrate that E2 is a potent neuromodulator of inhibitory synaptic transmission within the ovBNST of both sexes to potentially regulate energy homeostasis.