Differentiating the Effect of Medication and Illness on Brain Volume Reductions in First-Episode Psychosis: A Longitudinal, Randomized, Triple-blind, Placebo-controlled MRI study

Psychotic disorders are associated with reductions in brain volume, but the timing and causes of these reductions remain unclear. In particular, the effects of antipsychotic medication and illness have been difficult to disentangle due to a lack of prospective, longitudinal, randomized placebo-controlled designs. We conducted a triple-blind randomised placebo-controlled trial where 62 antipsychotic naive patients with first-episode psychosis (FEP) received either an atypical antipsychotic or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n=27) was also recruited. Structural MRI scans were obtained at baseline, 3-months and 12-months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum, such that patients receiving atypical antipsychotics showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. In patients, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity, consistent with a neuroprotective effect of atypical antipsychotics. We additionally found preliminary evidence for illness-related volume reductions in prefrontal cortices at 12 months and putative antipsychotic-related neurotoxicity in cerebellum at both 3-months and 12-months. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotics may be primarily mediated through their effects on the basal ganglia. Clinical Trial Registration ID #ACTRN12607000608460