To the Editor: Clozapine, an atypical antipsychotic drug, is the first-choice medication for treatment-refractory schizophrenia. However, clozapine can cause some adverse effects, such as agranulocytosis and sialorrhea, making it difficult for patients to continue with treatment. Otherwise, treatment options for patients who are resistant to clozapine are extremely limited. Herein, the authors report the case of a patient with refractory schizophrenia treated by amisulpride augmentation of clozapine who got significant improvement not only in his positive and negative symptoms but also the side effect of salivation. This case report might provide an alternative treatment for refractory schizophrenia.

A 53-year-old man with chronic, refractory schizophrenia was hospitalized because of his symptoms of hostility, aggression, insomnia, delusions, and auditory hallucinations, despite his medication with clozapine 200 mg per day. His initial laboratory studies revealed no remarkable findings. Clozapine was titrated to 350 mg per day for marked psychotic symptoms, but it seemed to be only slightly effective. Meanwhile, he complained of salivation worsening and wanted to discontinue clozapine treatment because of this adverse effect. We then added amisulpride 600 mg per day for augmentation of clozapine. Interestingly, there was a significant improvement in his auditory hallucinations, delusions, conceptual disorganization, and on the positive and negative syndrome scale (PANSS). Also, the adverse effect of sialorrhea was improved during the following days and nights.

Clozapine is used to treat severe schizophrenia symptoms in people who have not responded to or only partially responded to other antipsychotics. Sialorrhea is a common side effect leading to treatment noncompliance, occurring in about 31%–54% of patients receiving clozapine therapy.¹ Amisulpride, an atypical antipsychotic, possesses a higher selective binding to the D₂/D₃ dopamine receptor and a minimal effect on other receptors.² Clozapine produces moderate blocking of the D₂ dopamine receptors, whereas amisulpride is a potent antagonist of D₂ dopamine receptors. The efficacy of the combination may be due to the complementary receptor profile of the two drugs. In this report, amisulpride might be augmentative therapy for clozapine in patients who are not responsive to or only partially responsive to clozapine. Kreinin et al.³ reported a significant reduction in hypersalivation with addition of amisulpride to ongoing clozapine therapy. In our case, both daytime as well as nocturnal sialorrhea improved after the addition of amisulpride. However, the definite underlying mechanism is still unknown. In summary, our case suggested that amisulpride improve the antipsychotic effect of clozapine while improving the major adverse event of sialorrhea. Amisulpride augmentation of clozapine might be an optional approach to treatment-refractory schizophrenia.