Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders - A comprehensive systematic review and meta-analysis.

OBJECTIVE: Antipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effect and safety of anti-inflammatory add-on treatment on psychotic disorders is lacking. METHOD: Multiple databases were searched up until February 2020. Only double-blinded, randomized, placebo-controlled clinical trials (RCTs) were included. Primary outcomes were change in total psychopathology and adverse events. Secondary outcomes included, amongst others, positive and negative symptoms, general psychopathology and cognitive domains. We performed random-effects meta-analyses estimating mean differences (MD) and standardized mean differences (SMD) for effect sizes. RESULTS: Seventy RCTs (N = 4104) were included, investigating either primarily anti-inflammatory drugs, i.e. drugs developed for immunomodulation, such as NSAIDs, minocycline and monoclonal antibodies (k = 15), or drugs with potential anti-inflammatory properties (k = 55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI = -5.93 to -3.20) points, corresponding to a SMD effect size of -0.29 (95%CI = -0.40 to -0.19). Trials on schizophrenia (MD = -6.80; 95%CI, -9.08 to -4.52) showed greater improvement (p < 0.01) than trials also including other psychotic disorders. However, primarily anti-inflammatory drugs (MD = 4.00; 95%CI = -7.19 to -0.80) were not superior (p = 0.69) to potential anti-inflammatory drugs (MD = 4.71; 95%CI = -6.26 to -3.17). Furthermore, meta-regression found that smaller studies showed significantly larger effect sizes than the larger studies (p = 0.0085), and only 2 studies had low risk of bias on all domains. Small but significant effects were found on negative symptoms (MD = -1.29), positive symptoms (MD = -0.53), general psychopathology (MD = -1.50) and working memory (SMD = 0.21). No differences were found regarding adverse events, but only 26 studies reported hereon. CONCLUSIONS: Anti-inflammatory add-on treatment to antipsychotics showed improvement of psychotic disorders; however, no superiority was found in primarily anti-inflammatory drugs, raising the question of the mechanism behind the effect, and treatment effect might be overestimated due to the large number of small studies.

Infections of the central nervous system as a risk factor for mental disorders and cognitive impairment: A nationwide register-based study.

BACKGROUND: CNS infections have been suggested as risk factors for cognitive decline and mental disorders; however, large-scale studies have been lacking regarding types and agents of CNS infections. METHODS: We utilized the unique personal registration number to create a cohort of 1,709,867 individuals born 1977-2010. CNS infection was exposure and data were analysed with 1) cox regression analyses estimating hazard ratios (HR) for developing mental disorders and 2) binomial regression estimating relative risk (RR) for completion of 9th grade including average grade score in a sub-cohort born 1988-1998. RESULTS: CNS infection increased the risk for developing mental disorders with a HR of 1.34 (95% CI 1.27-1.42). The highest risk observed was within the first 6 months after the CNS infection with a HR of 26.98 (95% CI 21.19-34.35). Viral CNS infections (HR 1.47, 95% CI 1.35-1.61) conferred a higher risk (p < 0.001) than bacterial (HR 1.24, 95% CI 1.15-1.35). Encephalitis (HR 1.64, 95% CI 1.41-1.90) conferred a higher risk (p < 0.001) than meningitis (HR 1.26, 95% CI 1.18-1.35). The risk was highest for organic mental disorders (HR 6.50, 95% CI 5.11-8.28) and disorders of intellectual development (HR 3.56, 95% CI 2.94-4.31), with a HR of 19.19 (95% CI 7.46-49.35) for profound disorder of intellectual development (IQ < 20). Furthermore, CNS infection decreased the RR of completing 9th grade of mandatory schooling (RR 0.89, 95% CI 0.88-0.91) and lowered average grade score for completers (p < 0.001). CONCLUSIONS: CNS infections increased the risk for mental disorders and decreased the likelihood of completing 9th grade, indicating long-term consequences of CNS infections.