Brain circuit dysfunction in a distinct subset of chronic psychotic patients

Objective: To identify the mechanism of unexplained hyponatremia and primary polydipsia in schizophrenia and its relationship to the underlying psychiatric illness.

Methods: Briefly review previous studies that led to the conclusion the hyponatremia reflects altered hippocampal inhibition of peripheral neuroendocrine secretion. In greater detail, present the evidence supporting the hypothesis that circuit dysfunction associated with the hyponatremia and the polydipsia contributes to the underlying mental disorder.

Results: Polydipsic patients with and without hyponatremia exhibit enhanced neuroendocrine responses to psychological stress in proportion to structural deformations on their anterior hippocampus, amygdala and anterior hypothalamus. Nonpolydipsic patients exhibit blunted responses and deformations on other hippocampal and amygdala surfaces. The deformations in polydipsic patients are also proportional to diminished peripheral oxytocin levels and impaired facial affect recognition that is reversed by intranasal oxytocin. The anterior hippocampus is at the hub of a circuit that modulates neuroendocrine and other responses to psychological stress and is implicated in schizophrenia. Preliminary data indicate that other measures of stress reactivity are also enhanced in polydipsics and that the functional connectivity of the hippocampus with the other structures in this circuitry differs in schizophrenia patients with and without polydipsia.

Conclusion: Polydipsia may identify a subset of schizophrenia patients whose enhanced stress reactivity contributes to their mental illness. Stress reactivity may be a symptom dimension of chronic psychosis that arises from circuit dysfunction that can be modeled in animals. Hence polydipsia could be a biomarker that helps to clarify the pathophysiology and heterogeneity of psychosis as well as identify novel therapies. Clinical investigators should consider obtaining indices of water balance, as these may help them unravel and more concisely interpret their findings. Basic researchers should assess if the polydipsic subset is a patient group particularly suitable to test hypotheses arising from their translational studies.