Study protocol of a randomized, double-blind, placebo-controlled, multi-center trial to treat antipsychotic-induced weight gain: the Metformin-Lifestyle in antipsychotic users (MELIA) trial.

BACKGROUND: Antipsychotic-induced Weight Gain (AiWG) is a debilitating and common adverse effect of antipsychotics. AiWG negatively impacts life expectancy, quality of life, treatment adherence, likelihood of developing type-2 diabetes and readmission. Treatment of AiWG is currently challenging, and there is no consensus on the optimal management strategy. In this study, we aim to evaluate the use of metformin for the treatment of AiWG by comparing metformin with placebo in those receiving treatment as usual, which includes a lifestyle intervention. METHODS: In this randomized, double-blind, multicenter, placebo-controlled, pragmatic trial with a follow-up of 52 weeks, we aim to include 256 overweight participants (Body Mass Index (BMI) > 25 kg/m2) of at least 16 years of age. Patients are eligible if they have been diagnosed with schizophrenia spectrum disorder and if they have been using an antipsychotic for at least three months. Participants will be randomized with a 1:1 allocation to placebo or metformin, and will be treated for a total of 26 weeks. Metformin will be started at 500 mg b.i.d. and escalated to 1000 mg b.i.d. 2 weeks thereafter (up to a maximum of 2000 mg daily). In addition, all participants will undergo a lifestyle intervention as part of the usual treatment consisting of a combination of an exercise program and dietary consultations. The primary outcome measure is difference in body weight as a continuous trait between the two arms from treatment inception until 26 weeks of treatment, compared to baseline. Secondary outcome measures include: 1) Any element of metabolic syndrome (MetS); 2) Response, defined as ≥5% body weight loss at 26 weeks relative to treatment inception; 3) Quality of life; 4) General mental and physical health; and 5) Cost-effectiveness. Finally, we aim to assess whether genetic liability to BMI and MetS may help estimate the amount of weight reduction following initiation of metformin treatment. DISCUSSION: The pragmatic design of the current trial allows for a comparison of the efficacy and safety of metformin in combination with a lifestyle intervention in the treatment of AiWG, facilitating the development of guidelines on the interventions for this major health problem. TRIAL REGISTRATION: This trial was registered in the Netherlands Trial Register (NTR) at  https://www.trialregister.nl/trial/8440 as NTR NL8840 on March 8, 2020.

Clinical symptoms and psychosocial functioning in patients with schizophrenia spectrum disorders testing seropositive for anti-NMDAR antibodies: a case-control comparison with patients testing negative.

BACKGROUND: Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies. METHODS: In this case-control comparison, by combining new and existing studies, we included patients diagnosed with schizophrenia from four independent cohorts for whom anti-NMDAR serostatus had been assessed (or could be assessed by us) with live cell-based assays. Included cohorts were from the EULAST study (a trial conducted across 15 European countries and Israel), the OPTiMiSE study (an interventional study in Europe), and the PPiP1 and PPiP2 studies (conducted in the UK). Patients from these cohorts were analysed if they had complete Positive and Negative Syndrome Scale (PANSS) data. No participant had been diagnosed with autoimmune encephalitis or received treatment for this condition. After calculating the prevalence of serum anti-NMDAR antibodies, we examined possible differences in PANSS scores (negative, positive, and general symptom subscales, and total score) between anti-NMDAR-seropositive and anti-NMDAR-seronegative patients. Psychosocial functioning as measured by Personal Social Performance (PSP) score was also compared. All analyses were exploratory and no adjustment was done for multiple testing. People with lived experience were not involved in the conduct of this study. FINDINGS: We collected individual patient data from 1114 patients with schizophrenia across the four cohorts. The study population had a mean age of 28·6 years (SD 7·6) and comprised 382 (34·3%) women and 732 (65·7%) men, including patients of White (929 [83·4%]), Asian (54 [4·8%]), Black (68 [6·1%]), and other (62 [5·6%]) ethnicities. Overall, 41 (3·7%) participants (range 3·1-4·0% across cohorts) tested positive for serum anti-NMDAR antibodies. Lower symptom severity on the negative symptoms PANSS subscale was observed for anti-NMDAR-seropositive patients (mean score 15·8 [SD 6·4]) than for anti-NMDAR-seronegative patients (18·2 [6·8]; Cohen's d=0·36; p=0·026), as well as on the general symptoms PANSS subscale (32·9 [8·9] vs 36·1 [10·1]; d=0·33; p=0·029) and total PANSS score (65·5 [18·5] vs 72·6 [19·3]; d=0·37; p=0·013). Mean PSP score was better in anti-NMDAR-positive patients (62·0 [17·0]) than in anti-NMDAR-negative patients (53·5 [16·3]; d=0·52; p=0·014). INTERPRETATION: Serum NMDAR antibodies are present in 3-4% of patients with schizophrenia and are associated with relatively low severity of negative symptoms and relatively good psychosocial functioning. Thus, although the findings await replication in cohorts from other geographical regions, serum anti-NMDAR antibodies might be associated with a different form of psychotic illness. These findings could inform future prognostic and interventional studies examining whether anti-NMDAR antibodies are associated with a specific course of illness or with treatment response. FUNDING: None.

Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions.

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapine-associated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n = 698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4 % of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6 %), weight gain (69.3 %), and increased sleep necessity (65.9 %), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10 %). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being.

Clinical, Biochemical and Genetic Variables Associated With Metabolic Syndrome in Patients With Schizophrenia Spectrum Disorders Using Second-Generation Antipsychotics: A Systematic Review.

Background: Individuals with severe mental illness experience increased morbidity and mortality compared to the general population. Adverse effects of antipsychotics, including weight gain, may contribute to the development of metabolic syndrome (MetS), which is associated with increased risks of all-cause and cardiovascular disease mortality. We aim to provide a comprehensive overview of clinical, biochemical and genetic factors associated with MetS among patients with schizophrenia spectrum disorders using second-generation antipsychotics (SGA). Methods: A literature search was performed in Pubmed and Embase to identify all cohort studies, cross-sectional studies and clinical trials investigating associations with MetS in patients with schizophrenia spectrum disorders using SGAs. We extracted and enumerated clinical, biochemical and genetic factors reported to be associated with MetS. We defined factors associated with MetS as factors being reported as associated with MetS in two or more studies. Results: 58 studies were included in this review (n = 12,123). In total, 62 factors were found to be associated with increased risk of MetS. Thirty one out of 58 studies investigated factors that were reported as associated with MetS in two or more studies. With regard to clinical factors, we found gender, higher age, concomitant use of mood stabilizers, higher baseline and current BMI, earlier SGA exposure, higher dose, longer duration of treatment, psychosis and tobacco smoking to be significantly associated with MetS. Furthermore, the biochemical factors hypo-adiponectinemia, elevated levels of C-reactive protein (CRP) and higher white blood cell (WBC) count were identified as factors associated with MetS. Among pharmacogenetic factors, the rs1414334 C-allele of the HTR2C-gene was associated with MetS in patients using SGA. Conclusion: In this systematic review investigating clinical, biochemical and genetic factors associated with MetS in patients using SGAs we found that higher age, higher baseline BMI, higher current BMI and male as well as female gender were positively associated with MetS across all antipsychotics. This study may set the stage for the application of clinical, biochemical and genetic factors to predict the risk of developing MetS in patients using SGAs. Future research is needed to determine which patients using SGAs are at risk to develop MetS in clinical practice.

Impact of the first COVID-19 outbreak on mental health service utilisation at a Dutch mental health centre: retrospective observational study.

BACKGROUND: Previous studies into mental health service utilisation during the COVID-19 pandemic are limited to a few countries or specific type of service. In addition, data on changes in telepsychiatry are currently lacking. AIMS: We aimed to investigate whether the COVID-19 pandemic is associated with changes in mental health service utilisation, including telepsychiatry, and how these changes were distributed among patients with mental illness during the first COVID-19 outbreak. METHOD: This retrospective study obtained routinely assessed healthcare data from a large Dutch mental healthcare institute. Data from the second quarter of 2020 (the first COVID-19 outbreak period) were compared with the pre-pandemic period between January 2018 and March 2020. Time-series analyses were performed with the quasi-Poisson generalised linear model, to examine the effect of the COVID-19 lockdown and the overall trend of mental health service utilisation per communication modality and diagnostic category. RESULTS: We analysed 204 808 care contacts of 28 038 patients. The overall number of care contacts in the second quarter of 2020 remained the same as in the previous 2 years, because the number of video consultations significantly increased (B = 2.17, P = 0.488 × 10-3) as the number of face-to-face out-patient contacts significantly decreased (B = -0.98, P = 0.011). This was true for all different diagnostic categories, although this change was less pronounced in patients with psychotic disorders. CONCLUSIONS: Diminished face-to-face out-patient contacts were well-compensated by the substantial increase of video consultations during the first COVID-19 outbreak in The Netherlands. This increase was less pronounced for psychotic disorders. Further research should elucidate the need for disorder-specific digital mental healthcare delivery.