Temporal course of symptom domain improvement in schizophrenia: individual participant data analysis of six antipsychotic drug trials

BACKGROUND: The temporal course of antipsychotic drug action in schizophrenia remains poorly understood. We aimed to explore how different symptom domains of schizophrenia improve over time. Such knowledge has important implications for treatment decisions and for understanding the mechanisms of action of antipsychotic drugs. METHODS: We analysed individual patient data from an existing repository comprising six antipsychotic drug trials of 6-12 months' duration in patients with acute schizophrenia (n=2079; 1328 [64%] men, 751 [36%] women; 1577 [76%] White, 502 [24%] non-White; mean age 34·72 years [range 16-73]). We used descriptive statistics to examine improvement trajectories across five PANSS symptom domains according to an established five-factor model (positive symptoms, negative symptoms, hostility and excitement, anxiety and depression, and cognitive and disorganisation). Time-to-response analyses were conducted using a threshold of at least 50% symptom reduction to define response within each domain. We used path analysis to explore whether improvements in negative, positive, and cognitive symptoms were mediated by changes in other symptom domains. People with lived experience were not involved in the project. FINDINGS: All five symptom domains showed substantial improvements during the first weeks of treatment, which slowly plateaued from week 15 onwards. While the factors improved in parallel, some improved more than others. Within the first 6 months, on average, hostility and excitability symptoms decreased by 76% (95% CI -80·5 to -71·1) from baseline, positive symptoms by 64% (-68·0 to -60·5), anxiety and depression symptoms by 57% (-61·2 to -53·2), cognitive and disorganisation symptoms by 61% (-64·0 to -57·2), and negative symptoms by 50% (-53·9 to -46·4). Median time to response adjusted for baseline symptom severity, age, and sex, was 3 weeks (95% CI 3 to 3, restricted mean survival time [RMST] 6·60, SE 0·20)) for hostility and excitement and 4 weeks for positive symptoms (4 to 4, RMST 7·76, SE 0·20) and anxiety and depression symptoms (4 to 4, RMST 8·71, SE 0·22), compared with 8 weeks for negative symptoms (6 to 9, RMST 12·45, SE 0·25) and cognitive and disorganisation symptoms (6 to 9, RMST 12·06, SE 0·25). Exploratory investigations using path analysis suggested that only a small proportion of the improvement in negative symptoms was mediated by improvements in cognitive and disorganisation and anxiety and depression domains. INTERPRETATION: Clinicians should be aware of earlier attainment of substantial response of hostility and excitement, then positive symptoms, before substantial reductions in other domains. Treatment changes should not be made prematurely when negative and cognitive and disorganisation symptoms persist, as improvement in these domains lags behind. Researchers should consider these temporal patterns when investigating the mechanisms of action of antipsychotic drugs. FUNDING: None.