Importance: Several lines of evidence suggest that adjunctive therapies influences the course of schizophrenia. Design and intervention: We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline. The primary outcome was PANSS-positive score. The other 8-week randomized, placebo-controlled trial among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5 who received a 200-μg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment. Results and conclusions: While there is a sound theoretical basis for an anti-inflammatory hypothesis in schizophrenia, we conclude that our studies and meta-analysis failed to find a statistically significant improvement of adjunctive aspirin therapy in comparison to placebo in schizophrenia. The results in trial with estradiol suggest that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years.