Are psychiatric disorders risk factors for COVID-19 susceptibility and severity? a two-sample, bidirectional, univariable, and multivariable Mendelian Randomization study

Observational studies have suggested bidirectional associations between psychiatric disorders and COVID-19 phenotypes, but results of such studies are inconsistent. Mendelian Randomization (MR) may overcome the limitations of observational studies, e.g., unmeasured confounding and uncertainties about cause and effect. We aimed to elucidate associations between neuropsychiatric disorders and COVID-19 susceptibility and severity. To that end, we applied a two-sample, bidirectional, univariable, and multivariable MR design to genetic data from genome-wide association studies (GWASs) of neuropsychiatric disorders and COVID-19 phenotypes (released in January 2021). In single-variable Generalized Summary MR analysis, the most significant and only Bonferroni-corrected significant result was found for genetic liability to BIP-SCZ (a combined GWAS of bipolar disorder and schizophrenia as cases vs. controls) increasing risk of COVID-19 (OR = 1.17, 95% CI, 1.06–1.28). However, we found a significant, positive genetic correlation between BIP-SCZ and COVID-19 of 0.295 and could not confirm causal or horizontally pleiotropic effects using another method. No genetic liabilities to COVID-19 phenotypes increased the risk of (neuro)psychiatric disorders. In multivariable MR using both neuropsychiatric and a range of other phenotypes, only genetic instruments of BMI remained causally associated with COVID-19. All sensitivity analyses confirmed the results. In conclusion, while genetic liability to bipolar disorder and schizophrenia combined slightly increased COVID-19 susceptibility in one univariable analysis, other MR and multivariable analyses could only confirm genetic underpinnings of BMI to be causally implicated in COVID-19 susceptibility. Thus, using MR we found no consistent proof of genetic liabilities to (neuro)psychiatric disorders contributing to COVID-19 liability or vice versa, which is in line with at least two observational studies. Previously reported positive associations between psychiatric disorders and COVID-19 by others may have resulted from statistical models incompletely capturing BMI as a continuous covariate

Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients with Schizophrenia

Background and Hypothesis Optimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland. Study Methods We studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias. Study Results Among the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6-0.9 DDD/day, and especially at 1.4-Peer reviewe

In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine

BACKGROUND: Although clozapine is often discontinued, there is a paucity of guidelines and evidence on treatment options after clozapine discontinuation. Moreover, it is currently unknown whether reinstating clozapine in patients formerly using clozapine should be avoided. AIMS: To compare the real-world effectiveness of antipsychotics after clozapine cessation. METHOD: From Finnish registry data (1995-2017), we identified 2250 patients with schizophrenia who had been using clozapine for ≥1 year before treatment cessation. The primary analysis consisted of adjusted within-individual analyses of psychiatric ward readmission owing to psychosis and treatment failure. Secondary analyses concerned between-individual mortality differences. RESULTS: Compared with no use of antipsychotics, risk of psychiatric ward readmission was lowest for reinitiation of clozapine (adjusted hazard ratio (aHR) 0.49; 95% CI 0.40-0.61; P < 0.0001), oral olanzapine (aHR 0.58; 95% CI 0.48-0.71; P < 0.0001) and antipsychotic polypharmacy (aHR 0.62; 95% CI 0.53-0.72; P < 0.0001). Risk of treatment failure was lowest for aripiprazole long acting injectable (aHR 0.42; 95% CI 0.27-0.65; P < 0.0001), reinitiation of clozapine (aHR 0.49; 95% CI 0.43-0.57; P < 0.0001) and oral olanzapine (aHR 0.69; 95% CI 0.61-0.77; P < 0.0001). Mortality risk was lowest for reinitiation of clozapine (aHR 0.18; 95% CI 0.09-0.36; P < 0.0001) and oral olanzapine (aHR 0.26; 95% CI 0.17-0.40; P < 0.0001). CONCLUSIONS: Clozapine and olanzapine are the most effective and safest treatment options in those discontinuing clozapine for undefined reasons. Clozapine should therefore be reconsidered in patients with schizophrenia who previously discontinued this compound

Event-related potentials and use of psychotropic medication in major psychiatric disorders

Background: Attention deficits measured using event-related potentials (ERPs) have been frequently reported in several major psychiatric disorders, e.g. mood disorder (MD), psychotic disorder (PD) and substance use disorder (SUD). However, comparisons between these specific categories are lacking. Here we investigated if electrophysiological parameters of basic information processing are associated with the above-mentioned categories of psychiatric disorders, or instead were associated with general psychopathology. Methods: 579 subjects with MD, PD or SUD and healthy controls (HC) were included. Participants were tested in a passive auditory and an active visual oddball paradigm to assess mismatch negativity (MMN), P3A and P3B amplitudes. Additionally, we examined associations between these measures and psychoactive medication treatments. Results: All patients had significantly lower P3B amplitudes compared to healthy controls, while only SUD patients had lower P3A amplitudes than MD, PD and HC. PD patients also produced significantly less MMN than both MD and SUD patients. Additionally, we found significantly higher P3B amplitude in HC compared to patients without psychopharmacological treatment and patients treated with two or more psychoactive compounds (polypharmacy), but no significant associations with medication on P3A and MMN amplitudes. Conclusions: Our results add to the theory that P3B deficits are associated with general psychopathology, whereas P3A and MMN deficits appear to be associated with substance abuse and psychotic disorders respectively

Persistence of Antipsychotic Use After Clozapine Discontinuation:A Real-World Study Across Antipsychotics

Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for >= 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P <0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients

The Direct and Long-Term Effects of Raloxifene as Adjunctive Treatment for Schizophrenia-Spectrum Disorders: A Double-Blind, Randomized Clinical Trial

BACKGROUND AND HYPOTHESIS: Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD. STUDY DESIGN: This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models. STUDY RESULTS: We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups. CONCLUSIONS: Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment