Diminished Glucocorticoid Negative Feedback in Polydipsic Hyponatremic Schizophrenic Patients

Goldman, Michael; Wood, Gordoń; Goldman, Megan B.; Gavin, Michelle; Paul, Stacey; Zaheer, Suhaila; Fayyaz, Ghazala; Pilla, Ramani S.

doi:10.1210/jc.2006-1131

Cited by 24 publications

(34 citation statements)

References 31 publications

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“…Specifically, these patients do not exhibit the normal hippocampal-mediated constraint of pAVP and the HPA axis following stress (Goldman et al, 2007c) and exhibit blunted hippocampal-mediated glucocorticoid negative feedback (Goldman et al, 2007b;Tessner et al, 2007). Indeed, they also have smaller volumes of the hippocampal segment (i.e.…”

Section: Introductionmentioning

confidence: 93%

“…All but four patients were receiving haloperidol: one polydipsic and two hyponatremic patients were on risperidone, and one hyponatremic patient was taking ziprasadone. On separate occasions, fifteen of the 22 subjects completed an assessment of glucocorticoid feedback under conditions in which hippocampal influences are thought to predominate (Goldman et al, 2007b), 19 underwent a structural MRI scan, and 20 underwent testing of facial affect discrimination.…”

Section: Subjectsmentioning

confidence: 99%

“…Plasma adrenocorticotropin was sampled at 20 minute intervals from 40 minutes prior to the infusion until 90 minutes after it was completed. See Goldman et al 2007b for further details.…”

Section: 22mentioning

confidence: 99%

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Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits

Goldman

Marlow-O'Connor

Torres

et al. 2008

Schizophrenia Research

193

144

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Polydipsic hyponatremic schizophrenic patients (PHS) exhibit enhanced plasma arginine vasopressin (pAVP) and hypothalamic pituitary adrenal (HPA) axis responses to stress that appear attributable to anterior hippocampal dysfunction. Neuroanatomic and electrophysiologic studies indicate oxytocin activity in PHS patients should also be affected. Furthermore, oxytocin normally diminishes HPA responses to stress and facilitates cognitive and behavioral functions impaired in schizophrenia, suggesting that diminished oxytocin activity could contribute to this subsets' neuropsychiatric disorder. In the present study, we measured plasma oxytocin levels at intervals before and after stress induction in six polydipsic hyponatremic (PHS), four polydipsic normonatremic (PNS), five nonpolydipsic normonatremic schizophrenic (NNS) patients and seven healthy controls. Most of these subjects also completed studies measuring their medial temporal lobe volumes, their hippocampal-mediated HPA feedback and their ability to discriminate different facial emotions (an oxytocin-sensitive measure which is markedly impaired in schizophrenia). Results demonstrated that 1) plasma oxytocin levels were lower (p = .006) in hyponatremic patients relative to the other three groups, whose levels were similar and did not change. Oxytocin levels across all subjects were 2) inversely correlated with anterior hippocampal (p = .004) (but not posterior hippocampal or amygdala volumes), and 3) directly correlated with the integrity of hippocampal-mediated HPA feedback (p = .039). Finally, 4) oxytocin levels predicted schizophrenic patients' ability to correctly identify facial emotions (p = .004). These preliminary data provide further evidence that neuroendocrine dysfunction in PHS reflects anterior hippocampal pathology and contributes to a characteristic neuropsychiatric syndrome.

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Section: Introductionmentioning

confidence: 93%

Section: Subjectsmentioning

confidence: 99%

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Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits

Goldman

Marlow-O'Connor

Torres

et al. 2008

Schizophrenia Research

193

144

View full text Add to dashboard Cite

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“…Thus this segment of the hippocampus normally constrains AVP and ACTH responses to psychological stress (Herman et al, 1995(Herman et al, , 2005Mueller et al, 2004;Nettles et al, 2000); the findings in patients are recreated in an animal model of schizophrenia, which disrupts the neurodevelopment of this brain region (Mitchell and Goldman, 2004); and this subset of patients exhibits diminished anterior hippocampal volume (Goldman et al, 2005) as well as other impairments indicative of hippocampal-mediated neuroendocrine dysfunction (Goldman et al, 2006). Finally, our unpublished data demonstrate a significant association between anterior hippocampal volume and the cold pressor AVP response in hyponatremic polydipsic patients (r ¼ À0.825, p ¼ 0.022).…”

Section: Model Of Enhanced Stress Vulnerabilitymentioning

confidence: 99%

“…About 20% of schizophrenic patients drink excessive amounts of water ('primary polydipsia') and about 20% of these retain enough of this excess water to produce a dilutional hyponatremia (de Leon et al, 1994). Furthermore, polydipsic patients with and without hyponatremia display impaired HPA axis negative feedback (Goldman et al, 1993) that is consistent with hippocampal pathology (Goldman et al, 2006). In addition, hyponatremic polydipsic (but not normonatremic polydipsic) patients exhibit an unexplained increase in AVP secretion that contributes to their water retention (Goldman et al, 1988(Goldman et al, , 1996.…”

Section: Introductionmentioning

confidence: 99%

Neuroendocrine Responses to a Cold Pressor Stimulus in Polydipsic Hyponatremic and in Matched Schizophrenic Patients

Goldman

Gnerlich

Hussain

2006

Neuropsychopharmacol

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Schizophrenia, many believe, reflects an enhanced vulnerability to psychological stress. Controlled exposure to stressors, however, has produced inconclusive results, particularly with regards to neurohormones. Some of the variability may be attributable to the nature and psychological significance of the stimulus and failure to control physiologic confounds. In addition, it is possible that the heterogeneity of schizophrenia is an important factor. In a carefully designed study and in a controlled setting, we measured the neuroendocrine response of eight polydipsic hyponatremic (PHS), seven polydipsic normonatremic (PNS), and nine nonpolydipsic normonatremic (NNS) (ie normal water balance) schizophrenic in-patients as well as 12 healthy controls (HC) to two different stressors: one of which appears to influence neuroendocrine secretion through its psychological (cold pressor) and the other (upright posture) through its systemic actions. Subjects in the three psychiatric groups were stabilized and acclimated to the research setting, and all received saline to normalize plasma osmolality. Following the cold pressor, plasma adrenocorticotropin and cortisol levels showed a more prolonged rise in PHS patients relative to PNS patients. NNS patients, in contrast, exhibited blunted responses relative to both of the polydipsic groups and the HC. Peak vasopressin responses were also greater in PHS and blunted in NNS patients. Responses to the postural stimulus were similar across patient groups. These findings provide a mechanism for life threatening water intoxication in schizophrenia; help to reconcile conflicting findings of stress responsiveness in schizophrenia; and potentially identify a discrete patient subset with enhanced vulnerability to psychological stress.

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Reduced anterior hippocampal formation volume in hyponatremic schizophrenic patients

et al. 2007

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Diminished hippocampal volume occurs in the anterior segment of some schizophrenic patients, and in the posterior segment in others. The significance of hippocampal pathology in general and these segmental differences in specific is not known. Several lines of evidence suggest anterior hippocampal pathology underlies the life-threatening hyponatremia seen in a subgroup of patients with schizophrenia; therefore our goal was to determine if this region was preferentially diminished in hyponatremic patients. We studied seven polydipsic hyponatremic, ten polydipsic normonatremic, and nine nonpolydipsic normonatremic schizophrenic inpatients, as well as 12 healthy controls. All underwent structural scanning on a high resolution (3.0 T) magnetic resonance imaging (MRI) scanner. Hippocampal formation, amygdala, and third ventricle volumes were manually traced in each subject. The hippocampus was divided at the posterior extent of the uncus, and all structural volumes were corrected for whole brain volume and other significant recognized factors (i.e., age, gender, height, parental education). Despite being overhydrated, anterior hippocampal formation volume was diminished in those with polydipsia and hyponatremia relative to each of the other three groups. Third ventricle volume was larger in this group than in healthy controls but similar to the two patient groups. Posterior hippocampal and amygdala volumes did not differ between groups. Other potential confounds (e.g., water imbalance) either had no effect or accentuated these differences. We conclude the anterior hippocampal formation is smaller in hyponatremic schizophrenic patients, thereby linking an important and objective clinical feature of schizophrenia to a neural pathway that can be investigated in animal models. The findings strengthen the hypothesis that anterior hippocampal formation pathology disrupts functional connectivity with other limbic structures in schizophrenia.

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Diminished Glucocorticoid Negative Feedback in Polydipsic Hyponatremic Schizophrenic Patients

Abstract: The marked impairment in glucocorticoid negative feedback in polydipsic hyponatremic schizophrenic patients is consistent with hippocampal mineralocorticoid dysfunction.

Cited by 24 publications

References 31 publications

Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits

Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits

Neuroendocrine Responses to a Cold Pressor Stimulus in Polydipsic Hyponatremic and in Matched Schizophrenic Patients

Reduced anterior hippocampal formation volume in hyponatremic schizophrenic patients

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