Histamine H-2 receptor antagonists in schizophrenia - Rationale for use and therapeutic potential

The serendipitous observation that famotidine, a competitive histamine H-2 receptor antagonist, administered as the sole medication to a patient with schizophrenia and coincidental peptic ulcer disease, was associated with a dramatic resolution of positive and negative symptoms, has stimulated the examination of a possible role for histamine in the pathophysiology of schizophrenia. It has been found that the terminal projections of histaminergic neurons originating in the posterior hypothalamus include regions implicated prominently in the pathophysiology of schizophrenia. Elevations of levels of histamine and its principal methylated metabolite in the CSF of patients with schizophrenia have been reported, and selective alterations of histamine receptor subtypes in autopsied brains from patients who had had schizophrenia support the possible existence of pathologically altered histaminergic neurotransmission. There are also some recent preliminary genetic-epidemiological data suggesting that patients with schizophrenia are more likely to possess an unusual allelic variant of the gene for the H-2 receptor. Conceivably, this variant results in altered 'coupling' of the receptor, a member of the superfamily of receptors with 7 transmembranous hydrophobic domains, to its guanine triphosphate-binding protein. Preliminary open-label clinical trials of famotidine as an adjuvant to antipsychotics in patients with schizophrenia have been encouraging and, therefore, support further exploration of H-2 receptor antagonists as possible adjunctive medications for schizophrenia.