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Schizophrenia Research Program


A brief chronology of our research program

Our initial studies in the 1980's provided the first effective method for preventing  life-threatening water intoxication in schizophrenia(1). During this period we also characterized the nature of the abnormalities in antidiuretic hormone (vasopressin) regulation in these patients (polydipsic hyponatremic schizophrenics) (2).

 Our second phase studies demonstrated that recognized physiologic factors cannot account for these patients' enhanced secretion and action of  vasopressin (3,4), nor  for the further outpouring of vasopressin that occurs during psychotic episodes (5). We also demonstrated that  hypothalamic-pituitary-adrenal (HPA) axis feedback was diminished(6). The mechanism of abnormal HPA axis feedback in schizophrenia has been unclear, but the axis is controlled  by the same brain nuclei which regulate vasopressin release.

Early clues to the mechanism of these neuroendocrine changes were provided by our study showing that the anterior medial temporal lobe was smaller in polydipsic hyponatremic, than other, schizophrenic patients (7) and that this brain region regulates both vasopressin and HPA responses to psychological stress (in rodents) (8). Our third phase studies provided further evidence for this view: thus their anterior hippocampi, which lie within the anterior medial temporal lobe, are smaller (9), their HPA and vasopressin responses to psychological stress are greater (10), and  their hippocampal regulation of  HPA feedback is  impaired (11) relative to other schizophrenic patients and healthy controls.  Disruption of the neurodevelopment of this brain region, in what has proven to be the most robust animal model of schizophrenia, reproduces these changes(12); thus linking the structural and functional findings summarized above to the underlying mental disorder. Ongoing analysis of cognitive and affective data in these patients suggest they may also have intellectual and affective deficits arising from brain regions that are closely connected to the anterior hippocampus and implicated in schizophrenia. Throughout this time we have also  continued to test new methods of preventing water intoxication. In addition to modifications of our original methods which have been adopted world-wide (13), we have shown that clozapine has salutary effects (most likely by reducing water intake) (14), and more recently have joined other investigators around the world in demonstrating the efficacy of vasopressin antagonists (15).

Future Directions

Based on these findings we are putting forth the hypothesis that this subset of schizophrenic patients have anterior hippocampal pathology that  broadly disrupts their ability to manage psychological stress by disrupting functional connectivity with diverse limbic structures (16).
An increased vulnerability to psychological stress due to hippocampal pathology has been posited for many years to underlie schizophrenia, but with little empirical support. Furthermore, the concept that functional disconnections between the hippocampus and other limbic structures underlies schizophrenia has been espoused by many, but again with limited support. We believe this absence of evidence is in large part due to the heterogeneity of schizophrenia, an issue which other investigators have been reluctant to tackle given the obvious methodological challenges and previous failures associated with this strategy.  Preliminary evidence in support of the heterogeniety of the illness in respect to the current findings is provided by our recent studies showing that patients with normal water balance actually exhibit blunted HPA and vasopressin responses to psychological stress, and enhanced hippocampal mediated HPA feedback relative to schizophrenics with water imbalance as well as healthy controls.

Our current and planned studies will further characterize these patients and the extent that their symptoms can be associated with anterior hippocampal pathology. In particular, oxytocin is a neurohormone that is also regulated by the same nuclei which control vasopressin and HPA axis hormone release.  Deficits in oxytocin regulation have been linked to cognitive and affective deficits which appear to resemble those seen in polydipsic hyponatremic patients. We will also attempt to identify comparable changes in patients with diminished anterior hippocampal volume who have not yet manifested clinically significant water imbalance. This will link our work to the mainstream of current psychiatric research, and conclusively demonstrate the findings are not a consequence of  water imbalance, per se.  In addition, over the past several years we have begun  to probe the nature of impaired sensory processing in schizophrenia using a very simple model (i.e. prepulse inhibition of acoustic startle)which appears to involve the hippocampus and may reflect deficits in responding to novel (and therefore potentially psychologically stressful) stimuli (17).  Our hope is to use this information to begin linking changes in hippocampal regulation of stress responses to the neural circuitry associated with the cognitive dysfunction that is  clearly linked to core features of the mental illness.

More information on the Program

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10/26/06


  1. Goldman MB, and Luchins DJ:  Prevention of episodic water  intoxication with target weight procedure.  American Journal of Psychiatry, 144:365-366, 1987. PDF

  2. Goldman MB, Luchins DJ, Robertson GL:  Mechanisms of altered water  metabolism in psychotic patients with polydipsia and hyponatremia.  New England Journal of Medicine, 318:397-403, 1988. (abstract)

  3. Goldman MB, Robertson GL, Hedeker D:  Oropharyngeal regulation    of water  balance in polydipsic schizophrenics.  Clinical Endocrinology, 44:31-37, 1996. (abstract)

  4. Goldman MB, Robertson GL, Luchins DJ, Hedeker D.  The influence of poly dipsia on water excretion in hyponatremic polydipsic schizophrenic patients.Journal of Clinical Endocrinology and Metabolism, 81:1465-1470, 1996. (PDF)

  5. Goldman MB, Luchins DJ, Robertson GL, Hedeker D, Pandey GH:  Psychotic exacerbations and enhanced vasopressin in schizophrenics with hyponatremia and polydipsia.  Archives of General Psychiatry, 54: 443-449, 1997. (article)

  6. Goldman MB, Blake L, Marks RC:  Association of nonsuppression of cortisol on the DST with primary polydipsia in chronic schizophrenia.  American Journal of Psychiatry, 150:653-655, 1993. (PDF)

  7. Luchins DJ, Nettles  KW, Goldman MB. Anterior medial temporal lobe volumes in  polydipsic schizophrenic patients with and without hypo-osmolemia: A pilot study. Biological Psychiatry, 42: 767-770, 1997. (PDF)

  8. Nettles KW, Pesold  C, Goldman MB: Influence of the ventral hippocampal formation on antidiuretic hormone, hypothalamic-pituitary-adrenal axis, and behavioral responses to novel acoustic stress. Brain Research, 858:181-190, 2000. (PDF)

  9. Goldman MB, Torres IJ, Keedy S, Marlow-O’Connor M, Beenken B. Structural correlates of disturbed water balance in schizophrenia  (in review)

  10. Goldman MB, Hussain N, Gnerlich J. Neuroendocrine Responses to a Cold Pressor Stimulus in Polydipsic Hyponatremic and in Matched Schizophrenic Patients (in press neuropsychopharmacology).

  11. Goldman, MB, Hussain H, Wood G, Goldman MB, Gavin M, Weiss R, Paul S, Zaheer S, Fayyaz,G, R. Pilla. Diminished Glucocorticoid Negative Feedback  in Polydipsic Hyponatremic Schizophrenic Patients (in review)

  12.  Mitchell CP, Goldman MB. Neonatal lesions of the ventral hippocampal formation disrupt neuroendocrine  responses to auditory stress in the adult rat. Psychoneuroendocrinology 29: 1317-1325, 2004.(PDF)

  13. Goldman MB, Mitchell   CP: What is the Functional Significance of the Hippocampal Pathology in Schizophrenia? Schizophrenia Bulletin 30:367-392, 2004.

  14. Goldman MB, Luchins DJ, Robertson GL:  Treatment of hyponatremia secondary to water overload.  Lancet, i:328-329, 1989.

  15. Canuso C, Goldman MB:  Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome. Journal of Neuropsychiatry and Clinical Neurosciences, 11:86-90, 1999. (PDF)

  16.  Josiassen RC, Goldman M, Jessani M,  Czerwiec F, Orlandi C , for the Tolvaptan Investigators. Vasopressin V2-Receptor Blockade With Tolvaptan in Schizophrenic Patients With Hyponatremia: Results From a Double-Blind, Randomized Trial. International Congress on Schizophrenia Research, 2007.

  17. Goldman, MB, Heidinger L, Kulkarni K, Zhu DC, Chien A, McLaren DG,  Shah J, Coffey Jr. CE, Sharif S, Chen E, Uftring SJ, Small SL, Solodkin A, Pilla R.  Changes in the Amplitude and Timing of the Hemodynamic Response Associated with Prepulse Inhibition of Acoustic Startle Neuroimage 32:1375-1384, 2006. (PDF)




 


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