Brain circuit dysfunction in a distinct subset of chronic psychotic patients

Abstract

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 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 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.

Reduction in the volume of the front part of the hippocampus in schizophrenics with hyponatremia on hospital admission

“…The findings may partially replicate other morphometric research findings, where a two-sided decrease in the volume of the front part of the hippocampi in comparison with schizophrenics with no polydipsia [26,28,29] was found in patients with schizophrenia, polydipsia and transient hyponatremia. In those studies, the atrophy was two-sided and related to the front parts of the hippocampi, i.e.…”

“…Uzyskane wyniki mogą stanowić częściowe powtó-rzenie wyników innych badań morfometrycznych, w któ-rych u chorych ze schizofrenią, polidypsją i przemijającą hiponatremią wykazano obustronne zmniejszenie obję-tości przedniej części hipokampów w porównaniu z chorymi na schizofrenię bez polidypsji [26,28,29]. W tych pracach zanik był obustronny i dotyczył przednich czę-ści hipokampów, tzn.…”

The role of oxytocin in the pathogenesis and treatment of schizophrenia

“…Authors of subsequent studies emphasize that disturbances in the regulation of the oxytocynergic system are associated with the pathophysiology of psychotic disorders [47,56]. It was found that patients diagnosed with schizophrenia had reduced blood plasma oxytocin concentration.This is particularly evident in patients with the PIP-syndrome: psychosis-intermittent hyponatremiapolydipsia) [56,57].…”

“…Autorzy kolejnych badań podkreślają, iż zaburzenia w regulacji systemu oksytocynergicznego wiążą się z patofizjologią zaburzeń psychotycznych [47,56]. Stwierdzono, iż pacjenci z rozpoznaniem schizofrenii mają obniżone stężenie oksytocyny w osoczu krwi.Jest to szczególnie widoczne u pacjentów z towarzyszącym zespołem psychoza-hiponatremia-polidypsja(PIP-syndrome: psychosis-intermittenthyponatremia-polydipsia) [56,57].…”

The Neurocircuitry of fluid satiation

“…Fluid satiation is a key homeostatic signal which limits the amount of fluid ingested and prevents the potentially lethal consequences of overhydration, such as severe hyponatremia and cerebral edema, which can occur in patients with psychogenic polydipsia (Goldman ). Tight control of fluid homeostasis is vital for maintaining cell size which is required for proper cell functioning; and for maintaining stable blood volume and pressure, which are necessary for transporting essential nutrients and oxygen around the body (Leib et al.…”