Trajectory patterns of positive, disorganized and negative dimension symptoms during antipsychotic treatment in drug-naive patients with first-episode psychosis have yet to be examined by using naturalistic data.

This pragmatic clinical trial randomized 161 drug-naive patients with a first episode of psychosis to olanzapine, risperidone or haloperidol. Patients were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and Positive Symptoms (SAPS) at baseline and at the end of weeks 1, 2, 3, 4 and 6 of antipsychotic treatment. Censored normal models of response trajectories were developed with three dimensions of the SAPS-SANS scores (positive, disorganized and negative) in order to identify the different response trajectories. Diagnosis, cannabis use, duration of untreated psychosis (DUP), smoking and antipsychotic class were examined as possible predictive variables.

Patients were classified in five groups according to the positive dimension, three groups according to the disorganized dimension and five groups according to the negative dimension. Longer DUPs and cannabis use were associated with higher scores and poorer responses in the positive dimension. Cannabis use was associated with higher scores and poorer responses in the disorganized dimension. Only schizophrenia diagnosis was associated with higher scores and poorer responses in the negative dimension.

Our results illustrate the heterogeneity of short-term response to antipsychotics in patients with a first episode of psychosis and highlight markedly different patterns of response in the positive, disorganized and negative dimensions. DUP, cannabis use and diagnosis appeared to have a prognostic value in predicting treatment response with different implications for each dimension.

It is generally accepted that antipsychotics are more effective than placebo. However, it remains unclear whether antipsychotics induce a pattern or trajectory of response that is distinct from placebo. We used a data-driven technique, called growth mixture modelling (GMM), to identify the different patterns of response observed in antipsychotic trials and to determine whether drug-treated and placebo-treated subjects show similar or distinct patterns of response.

We examined data on 420 patients with schizophrenia treated for 6 weeks in two double-blind placebo-controlled trials using haloperidol and olanzapine. We used GMM to identify the optimal number of response trajectories; to compare the trajectories in drug-treated versus placebo-treated patients; and to determine whether the trajectories for the different dimensions (positive versus negative symptoms) were identical or different.

Positive symptoms were found to respond along four distinct trajectories, with the two most common trajectories (‘Partial responder’ and ‘Responder’) accounting for 70% of the patients and seen proportionally in both drug- and placebo-treated. The most striking drug–placebo difference was in the ‘Dramatic responders’, seen only among the drug-treated. The response of negative symptoms was more modest and did not show such distinct trajectories.

Trajectory models of response, rather than the simple responder/non-responder dichotomy, provide a better statistical account of how antipsychotics work. The ‘Dramatic responders’ (those showing >70% response) were seen only among the drug-treated and make a significant contribution to the overall drug–placebo difference. Identifying and studying this subset may provide specific insight into antipsychotic action.