The authors describe three patients with delusional unipolar depression whose delusional thinking worsened markedly following administration of tricyclic antidepressant drugs. The patients had met Research Diagnostic Criteria for major depressive episode and had no evidence of schizophrenia or mania. Since tricyclic antidepressants are known to exacerbate psychosis in schizophrenic patients, it is sometimes suggested that the exacerbation of psychotic thinking in depressed patients indicates schizophrenia. The authors suggest that such an exacerbation does not in itself indicate schizophrenia but may occur in patients with an affective disorder who are prone to depressive delusions. The authors discuss the use of antipsychotic medication in this patient group and present a neurochemical hypothesis to explain the interaction of the drug with the illness, which results in exacerbation of psychotic thinking.