Dealing with treatment resistance to clozapine : characteristics of treatment response in schizophrenia
Background: Clozapine, the treatment of choice in treatment-resistant schizophrenia, is not effective in up to half of patients. Aims of this thesis were: to verify whether clozapine augmentation with amisulpride, an atypical antipsychotic with preferential affinity at doparninergic D2-like receptors, is clinically effective; to test the prediction that changes in D2-like receptor availability might explain that improvement; to explore clinical and receptor availability characteristics of good clozapine responders. Methods: Study 1: Thirty-three patients with schizophrenia, partially or non-responsive to clozapine, had augmentation with amisulpride using an open label design. Study 2: Ten patients recruited from study 1 underwent 123I_IBZM SPET scans at baseline and after 10-12 weeks on amisulpride augmentation, to assess striatal D2-like receptor binding potential. Ten matched controls had one 123I-IBZM scan. Scanning was carried out using a Picker Prism 3000XP triple headed SPET camera. Study 3: Ten "good" responders to clozapine monotherapy were matched to patients in study 2 and had one 123I-IBZM scan. Results: Study 1: Twenty-eight subjects (85%) completed 6 months' augmentation. There was a statistically significant improvement from baseline in clinical rating scales and no change in side-effects. 71% and 32% of patients showed a 20% and 50% reduction in BPRS respectively. Study 2: Patients had mean striatal D2-like receptor occupancy of 47% at baseline, which increased with amisulpride augmentation to 59%. Study 3: Clozapine responders were on much lower doses of clozapine (331 mg/day) with lower s-clozapine levels (0.26 ng/L). Their D2-like occupancy was 45%. Conclusion: The augmentation led to substantial improvement in both positive and negative symptoms and was well tolerated. It raised D2-like binding to likely "threshold levels" for response. Some patients require both the broad receptor occupancy profile of clozapine and a higher degree of D2-like receptor occupancy than can be provided by clozapine alone.