Haloperidol in combination with clozapine in treatment-refractory patients with schizophrenia

Objectives: Clozapine is an antipsychotic widely used in treatment-resistant schizophrenia. However, about 40−70% of patients with treatment-refractory schizophrenia are also clozapine non-responders. While lacking clear evidence based on doubleblind, placebo-controlled trials, in clinical practice clozapine is often combined with an adjunctive antipsychotic. To date, there are only 4 double-blind, placebo-controlled trial evaluating combination strategies of clozapine with other antipsychotics, 2 of which finding positive effects. All antipsychotics act on dopamine receptors, clozapine having a relatively low affinity to dopamine D2 receptors. The purpose of this trial was to assess the effects of 4 mg/d haloperidol in addition to existing clozapine therapy on dopamine D2 receptor occupancy and psychopathology in a double-blind, placebo-controlled manner. Preliminary data will be presented. Methods: Treatment-resistant patients with schizophrenia as defined by resistant to 2 adequate trials with 2 different antipsychotics and to a trial with clozapine during a minimum of 6−8 weeks in adequate dosage were included in the study. 10 patients gave informed consent to participation, while 6 patients completed the study. Patients were randomized to either placebo or 4 mg/d haloperidol in addition to their existing clozapine therapy. Before and after 10 weeks [123I]IBZM SPECT scans were performed for selective measurement of dopamine D2 receptors. Regions of interest (ROI) were drawn manually in areas corresponding to the striatum and the cerebellum. A ratio was calculated between the average count-rates in the striata (S) and the cerebellum (C) (S/C-ratio) and compared to an agecorrected control value obtained in a historic, healthy control group. PANSS ratings were assessed at baseline, at each weekly visit and after 10 weeks. The study was performed in accordance with the Declaration of Helsinki. Results: Patients had a mean age of 32.5 years in each group. Mean clozapine dose was 450 mg/d (SD 70.7) in the haloperidolgroup and 500 mg/d (SD 81.6) in the placebo-group. Under clozapine monotherapy (i.e. both groups before, placebo-group also after randomization) mean D2 receptor occupancy was 23.8% (SD 11.4) (n = 13 [123I] IBZM-SPECT). D2 receptor occupancies increased from 21.2% (SD 17.1) at baseline to 65.3% (SD 22.6) after 10 weeks in the haloperidol-group (n = 2). In the placebogroup occupancies were from 22.8% (SD 8.44) to 21.0% (SD 14) (n = 4). Regarding psychopathology, no significant improvement was found: in the haloperidol-group mean PANSS total scores were 86 (SD 4.2) at baseline and 87 (SD 19.8) after 10 weeks, in the placebo-group 96.25 (SD 30.3) versus 75.7 (SD 29.2). Conclusion: We found a clear increase in D2 receptor occupancy after 10 weeks of combination of 4 mg/d haloperidol to existing clozapine therapy. There was no clinical correlation with changes in PANSS scores. Whether this is due to small sample size or lack of efficacy of increase of D2 blockade in treatment-resistant schizophrenia should be assessed in further double-blind, placebo-controlled combination trials in clozapine non-responders.