Presynaptic Dopamine Capacity in Patients with Treatment Resistant Schizophrenia Taking Clozapine

Some patients with schizophrenia show poor response to first-line antipsychotic treatments and this is termed treatment resistant schizophrenia. The differential response to first-line antipsychotic drugs may reflect a different underlying neurobiology. Indeed, a previous study found dopamine synthesis capacity was significantly lower in patients with treatment resistant schizophrenia. However, in this study, the treatment resistant patients were highly symptomatic whilst the responsive patients showed no or minimal symptoms. The study could not distinguish whether this was a trait effect or reflected the difference in symptom levels. Thus we aimed to test whether dopaminergic function is altered in patients with a history of treatment resistance to first-line drugs relative to treatment responders when both groups are matched for symptom severity levels by recruiting treatment resistant patients currently showed low symptom severity with the clozapine treatment. Healthy controls(n=12), patients treated with clozapine(n=12) who had not responded to first-line antipsychotics and patients who had responded to first-line antipsychotics(n=12) were recruited. Participants were matched for age and sex, and symptomatic severity level in patient groups. Participants' dopamine synthesis capacity was measured by using [(18)F]DOPA PET. We found that patients treated with clozapine show lower dopamine synthesis capacity than patients who have responded to first-line treatment(Cohen's d=0.9191(whole striatum), 0.7781(Associative striatum), 1.0344(Limbic striatum), 1.0189(Sensorimotor striatum) in line with the hypothesis that the dopaminergic function is linked to treatment response. This suggests that a different neurobiology may underlie treatment resistant schizophrenia and that dopamine synthesis capacity may be a useful biomarker to predict treatment responsiveness.Neuropsychopharmacology accepted article preview online, 18 November 2016. doi:10.1038/npp.2016.258.