The mechanism of life-threatening water imbalance in schizophrenia and its relationship to the underlying psychiatric illness

Impaired water excretion was noted to coincide with psychotic exacerbations in the first decades of the past century. In the ensuing decades, life-threatening water intoxication and elevated plasma levels of the antidiuretic hormone, arginine vasopressin (AVP) were reported in a subset of persons with schizophrenia. Subsequent studies demonstrated that the osmotic set point for AVP secretion was transiently reset in these patients by an unknown process and that this was further exacerbated by acute psychosis. More recent studies indicate that the AVP dysfunction is a manifestation of a hippocampal-mediated impairment in the regulation of both AVP and HPA axis responses to psychological, but not other types of, stimuli. Of potential significance, is that schizophrenic patients without water imbalance exhibit the opposite pattern of responses. Preliminary data indicate those with water imbalance also demonstrate a closely linked deficit in central oxytocin activity which may account for their diminished social function. These latter behavioral deficits are perhaps the most disabling and treatment resistant features of schizophrenia, which recent studies suggest, may respond to oxytocin agonists. Together these findings support the view that schizophrenia is a heterogeneous disorder, and provide novel biomarkers and approaches for exploring the pathophysiology and treatment of severe mental illness.