There is consistent evidence that mood disorders often co-occur with anxiety disorders, however, the strength of the association of these two broad groups of disorders has been challenging to summarize across different studies. The aim was to conduct a metaanalysis of publications reporting on the pairwise comorbidity between mood and anxiety disorders after sorting into comparable study types. We searched MEDLINE, Embase, CINAHL, Web of Science, and the grey literature for publications between 1980 and 2017 regardless of geographical locations and languages. We meta-analyzed estimates from original articles after sorting by: (a) broad or narrow diagnostic criteria, (b) study time-frame, and (c) estimates with or without covariate adjustments. Over 43 000 unique studies were identified through electronic searches, of which 391 were selected for fulltext review. Finally, 171 studies were eligible for inclusion, including 53 articles from additional snowball searching. In general, regardless of variations in diagnosis type, study time-frame, temporal order, or use of adjustments, there was substantial comorbidity between mood and anxiety disorders. Based on the entire 90 separate meta-analyses, the median OR was 6.1 (range 1.5-18.7). Of these estimates, all 90 were above 1, and 87 were significantly greater than 1 (i.e., the 95% confidence intervals did not include 1). Fourteen of the 90 pooled estimates had ORs that were greater than 10. This systematic review found robust and consistent evidence of comorbidity between broadly defined mood and anxiety disorders. Clinicians should be vigilant for the prompt identification and treatment of this common type of comorbidity.
Background: There is limited evidence on interventions to minimise weight gain at clozapine commencement. We compared the effect of adjunctive metformin versus placebo at clozapine initiation. Methods: People with schizophrenia commencing on clozapine were randomised to either metformin or placebo for 24 weeks. The primary outcome was difference in the change of body weight. Secondary outcomes included comparative rates of weight gain of more than 5%, overall weight gain/loss, and differences in metabolic and psychosis outcomes. Results: The study was closed prematurely in March 2020 due to COVID-19 restrictions. Ten participants were randomised to each of the metformin and placebo groups. Eight metformin group and five placebo group participants completed the trial and were included in the analysis. The study was insufficiently powered to detect difference between the metformin and placebo groups for the primary outcome of change in weight (0.09 kg vs 2.88 kg, p = 0.231). In terms of secondary outcomes, people in the metformin group were significantly less likely to gain >5% of their body weight (12.5% vs 80%, p = 0.015) and were more likely to lose weight (37.5% vs 0% p = 0.024) compared to placebo. There was no difference between the groups in terms of adverse drug reactions (ADRs). Conclusion: While limited by the forced premature closure of the trial due to COVID19, the findings from this randomised controlled trial are promising. Clozapine and metformin co-commencement may be a promising treatment to prevent clozapine-associated weight gain, especially given the low rates of ADRs associated with metformin. This supports the consideration of use of metformin to prevent weight gain in people initiated on clozapine; however, further studies are needed to confirm this finding. Trial registration: ACTRN12617001547336
Background: People with schizophrenia have a 15–20-year reduction in life expectancy, driven in part by the metabolic effects of antipsychotics. Clozapine is associated with the highest rates of weight gain. As clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), identifying treatments to ameliorate clozapine-induced weight gain (CIWG) is urgently needed to reduce this morality gap. Methods: We retrospectively analysed digital health records of patients with TRS aged 18–65 newly initiated on clozapine at four tertiary hospitals in south-east Queensland from 1 March 2017 to 30 June 2019. Our primary outcome was the effect of metformin on change in percentage bodyweight at 12 months after clozapine initiation, with secondary outcome being proportion with >5% or >7% bodyweight change. We also explored impact on bodyweight change of other variables including sex, tobacco smoking, type 2 diabetes (T2DM), age, clozapine level and dose and clozapine/norclozapine ratio. Results: Among 90 patients initiated on clozapine, metformin use ( n = 48) was associated with a smaller increase in percentage bodyweight (1.32% versus 5.95%, p = 0.031), lower rates of >7% gain in bodyweight (37.8% versus 63.0%, p = 0.025) but not >5% gain in bodyweight. Age below the median (32.0 years) was associated with greater bodyweight gain (5.55% versus 1.22%, p = 0.046). Sex, tobacco smoking, T2DM, clozapine dose and level and clozapine/norclozapine ratio were not associated with differences in change in bodyweight. Conclusion: In this small retrospective cohort study, use of metformin within 12-months of clozapine initiation was associated with a statistically and clinically significant reduction in CIWG. Although there is increasing evidence for the role of metformin to ameliorate bodyweight gain at time of clozapine initiation, our findings need replication and testing in a randomised controlled trial before recommending metformin co-commencement with clozapine as standard clinical practice.
Cognitive impairment in psychosis is one of the strongest predictors of functional decline. Problems with decision-making processes, such as goal-directed action and reversal learning, can reflect cortico-striatal dysfunction. The heterogenous symptoms and neurobiology observed in those with psychosis suggests that specific cognitive phenotypes may reflect differing causative mechanisms. As such, decision-making performance could identify subgroups of individuals with more severe cortico-striatal dysfunction and help to predict their functional decline. The present work evaluated the relationship between goal-directed action, reversal learning, and symptom profiles in those with psychosis. We assessed decision-making processes in healthy controls (N = 34) and those with persistent psychosis (N = 45), subclassifying subjects based on intact/impaired goal-directed action. Compared with healthy controls (<20%), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. Impaired decision-making also was associated with reduced levels of grandiosity and increased problems with abstract thinking. These findings suggest that prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis. Moreover, these impairments would have significant functional implications in terms of planning and abstract thinking.
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