Psychological Medicine

Original Articles

The different trajectories of antipsychotic response: antipsychotics versus placebo

T. R. Marquesa1, T. Arenovicha2, O. Agida2, G. Sajeeva2, B. Muthéna3, L. Chena4, B. J. Kinona4 and S. Kapura1 c1

a1 Institute of Psychiatry, King's College London, London, UK

a2 Centre for Addiction and Mental Health, Toronto, Canada

a3 Graduate School of Education and Information, UCLA, Los Angeles, CA, USA

a4 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA


Background 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.

Method 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.

Results 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.

Conclusions 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.

(Received April 09 2010)

(Revised September 13 2010)

(Accepted September 15 2010)

(Online publication October 20 2010)