Background: Methamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence. Methods: A parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400 mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were p < 0.025 for primary outcomes and p < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257. Results: Participants (N = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo (n = 77) or NAC (n = 76). Both groups had a median (IQR) of 24 (15À28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean [SE] reduction of 7.3 [1.2]) days for placebo, 6.8 [1.2] for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4À4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6À7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or

Background and Hypothesis Despite the accepted link between childhood adversity (CA) and psychotic disorders, evidence on the relationship between CA and poor functional outcome remains less consistent and has never been reviewed quantitatively. The aim of this meta-analysis was to systematically examine the association between CA and functional outcomes in people with psychotic disorders. Study Design The study protocol was registered on the International Prospective Register of Systematic Reviews (CRD42021254201). A search was conducted across EMBASE, MEDLINE, PsycINFO, and Cochrane Libraries (CENTRAL) using search terms related to psychosis; CA (general, sexual abuse, physical abuse, emotional abuse, physical neglect, and emotional neglect); and functional outcomes (social, occupational, and general functioning [GF]). We conducted random-effects models, sensitivity and heterogeneity analyses, meta-regressions, and we assessed quality. Study Results Our meta-analysis comprised 35 studies, including 10 568 cases with psychosis. General CA was negatively associated with GF (28 studies; r = −0.109, 95%CI = −0.161 to −0.05, P &lt; .001), with greater effects in prospective data (10 studies; r = −0.151, 95% CI = −0.236 to −0.063, P = .001). General CA was also associated with social functioning (r = −0.062, 95% CI = −0.120 to −0.004, P = .018) but not occupational outcomes. All CA subtypes except sexual abuse were significantly associated with GF, with emotional and physical neglect showing the largest magnitudes of effect (ranging from r = −0.199 to r = −0.250). Conclusions This meta-analysis provides evidence for a negative association between general CA, specific subtypes, and general and social functional outcomes in people with psychosis.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD.Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors.Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions:The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.