New antipsychotic drug development has created a class of medicines more effective and less toxic than Haloperidol and Fluphenazine of yesterday. But perhaps there is a place for the phased-out Dopamine2 receptor blockers after all.

A team of Israelis tested their hypothesis that a combined regimen of Clozapine and Sulpiride, a selective D2 blocker, would demonstrate a greater antipsychotic efficacy by enhancing the D2 blockade of Clozapine. The conclusion was that a subgroup of patients with chronic schizophrenia may substantially benefit from Sulpiride addition to Clozapine (British Journal of Psychiatry 171: pp. 569-573).

Twenty-eight people with schizophrenia, previously unresponsive to typical antipsychotics and only partially responsive to current treatment with Clozapine, received double-blind, 600 mg/day Sulpiride or placebo in addition to an ongoing Clozapine treatment. The clinical status was evaluated before, during, and at the end of 10 weeks of Sulpiride addition using the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms (SANS), and the Hamilton Rating Scale for Depression (HAM-D).

The participants were randomly allocated in a double-blind design to receive either Sulpiride (n = 16) or placebo (n= 12). Clozapine dosage remained unchanged throughout the entire study.

Baseline clinical status, as reflected by the BPRS, SAPS, SANS, and HAM-D scores at the beginning of the trial, was similar for the Sulpiride-Clozapine group and the control group. Significant differences between the groups were noted in magnitude of response to treatment. At the end of the 10-week trial, BPRS scores showed a mean reduction of 8.7 (19.8%) in the Clozapine-Sulpiride group but only 2.3 in the control group. No significant differences were found for the HAM-D scores.

The Clozapine-Sulpiride group was divisible based on magnitude of response. The degree of improvement in the responders ranged from 22.4 to 70.4% for the BPRS and 20.5 to 84.6% for the SAPS.

The researchers noted a strong trend of younger age associated with a more than 20% reduction in BPRS scores and also younger age and lower baseline SAPS scores associated with a more than 20% reduction in SAPS scores. No relevant factors were found regarding SANS score changes of more than 20%.

In the Clozapine-Sulpiride group, one patient had increased hypersalivation and another an aggravation of previously recorded tardive dyskinesia. No new extrapyramidal symptoms were recorded in the Clozapine-Sulpiride group, possibly due to the potent anticholinergic properties of Clozapine.

Some forensic hospitals have been describing, anecdotally, the benefits of combining clozapine with traditional antipsychotics in partially responding patients. The results of this study suggest that such practice, until now regarded as almost daring, may be legally defensible.