The evolution of various pharmacological therapies for schizophrenia has given rise to several pharmacological models for the neuroreceptor targets of antipsychotics and the influence of various neuroreceptors on specific symptoms and side effects.

Experience in clinical practice affirms clozapine's position as the treatment of choice for patients with treatment-refractory schizophrenia. Unlike clozapine, risperidone has a more targeted profile of neurotransmitter binding, with particular predilection for dopamine and serotonin receptors. Risperidone is, to date, the most extensively documented clozapine augmentation agent.

The aim was to evaluate clinical efficacy, safety and tolerability of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia.

In a randomized, double-blind, placebo-controlled 8-week trial, 10 patients unresponsive or partially responsive to 300mg/day of clozapine monotherapy (n=5) received a steady dose of 450mg/day clozapine combined with or up to 4mg/day of risperidone (n=5). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS) and Clinical Global Impression (CGI) improvement scale.

From baseline to week 4 and week 8, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine monotherapy group. Clozapine/risperidone treatment did not induce additional weight gain or agranulocytosis compared with clozapine monotherapy treatment.

Clozapine augmentation with risperidone appears to be well tolerated, safe and may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.