Clozapine-resistant psychosis, smoking, and caffeine: managing the neglected effects of substances that our patients consume every day.

More than 30% of patients with psychotic disorders who are refractory to antipsychotic treatment also fail to respond to clozapine. Despite the high prevalence of smoking and caffeine use in the psychiatric population, these habits are usually overlooked as factors contributing to antipsychotic treatment failure. We describe 2 male patients with severe treatment-resistant psychosis, one with schizophrenia and the other with bipolar affective disorder-both of whom smoked heavily, and the latter also consumed enormous amounts of caffeine-whose symptoms were refractory to clozapine. Both patients experienced a major, sustained amelioration of their psychotic symptoms when clozapine treatment was recommenced under supervision in the inpatient setting and the pharmacological interactions between clozapine, smoking, and caffeine were considered. Therapeutic strategies included gradual increases in daily doses of clozapine, monitoring clozapine plasma levels, using single daily doses of clozapine at night, and augmenting clozapine treatment with low doses of amisulpride, a selective antagonist at the dopamine D2 and D3 receptors. Smoking and excessive caffeine use are associated with poor therapeutic responses to clozapine and should be considered in the pharmacological management of treatment-refractory psychosis, regardless of the primary diagnosis.