Psychosocial treatment with or without antipsychotic medication in first-episode psychosis: What have we learned from the STAGES trial about the risks and benefits?

Abstract

STAGES trial was a triple-blind noninferiority trial that investigated intensive psychosocial treatment with or without low-dose antipsychotics in young people with first-episode psychosis with a short duration of untreated psychosis, who were low-risk and had stable family support. Participants received cognitive behavioural case management combined with either low-dose risperidone/paliperidone or placebo. Only 7% of the screened individuals were included (N = 90), with just 30% completing the protocol, reflecting trial challenges. Both groups showed significant improvements in social and occupational functioning (primary outcome) and symptoms at 6 months, with placebo demonstrating noninferior outcomes. At 24 months, the groups did not significantly differ, though noninferiority could not be confirmed. Neuroimaging findings revealed that placebo recipients showed reduced basal ganglia volume and widespread cortical thinning relative to healthy controls, while antipsychotics increased basal ganglia volume and attenuated cortical thinning. This demonstrates that antipsychotics do not cause tissue loss early in treatment, and delaying medication may hasten illness-related brain volume loss. Metabolic analyses showed that antipsychotics contributed to greater weight gain and metabolic changes, though some risk existed without medication. Cognitive analyses revealed baseline illness-associated cognitive impairment, with verbal learning/memory decline over 6 months in the medication group only, suggesting early cognitive side effects. STAGES trial findings demonstrate that carefully selected low-risk first-episode psychosis patients can achieve clinical improvement through psychosocial interventions alone while minimising potential negative metabolic and cognitive effects. However, delaying medication may result in adverse structural brain changes. The results support integrated treatment and shared decision-making approaches that balance symptom management, functional recovery and preservation of physical, cognitive and brain health.