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Richard C. Josiassen Ph.D.

Richard C. Josiassen Ph.D. Hyponatremia and Schizophrenia. Are Vaptans a Treatment Option?. Is Hyponatremia an Important Clinical Issue in the Overall Care of Individuals with Schizophrenia ? .

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Richard C. Josiassen Ph.D.

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  1. Richard C. Josiassen Ph.D.

  2. Hyponatremiaand Schizophrenia Are Vaptans a Treatment Option?

  3. Is Hyponatremia an Important Clinical Issue in the Overall Care of Individuals with Schizophrenia?

  4. Case Study J.C.64 years oldChronic schizophreniaHospitalized 37 yearsFirst hyponatremiadiagnosis ???Hx of multiple seizuresMuteSodium 118 – 125TremorsAggressive

  5. Targowla R (1923): Des troubles fonctionnel du rein dans les maladies mentales. L’excretion del’eau (Kidney malfunction and mental illness: water excretion). Bull Soc Med Hop Paris 47:1711-1715. • Hoskins RG (1933): Schizophrenia from the physiological point of view. Ann Intern Med 7:445-456. • Barahal HS (1938): Water intoxication in a mental case. Psychiat Quart 12:767-771.

  6. Three-Month Prevalence Rate • NSH Population(n = 328) 233 males 105 femalesMean Serum Sodium X = 139.3 SD = 2.87.9% HyponatremiaNo association with dose or class of anti-psychotic medication

  7. Symptoms of Hyponatremia Depend on: • Degree • Rapidity • Susceptibility age (young and old), CNS trauma, respiratory reserve, female gender

  8. Symptoms of Hyponatremia In the Context of Schizophrenia Normal 140 (mmol/L)  ??? 135  Lethargy, Apathy 130  Confusion  Agitation  Muscle Cramps  Hallucinations 120  Seizures  Coma  Pseudobulbar palsy 110  Hypothermia  Death 

  9. Symptoms of Hyponatremia Mostly CNS in nature: • Acute • Chronic

  10. Day 1104 mmol/LSeizuresComatoseDay 2121 mmol/LDay 3140 mmol/L Kurokawa et al (2004)

  11. Other morbidities include: •impaired cognition •impaired gait and balance leading to falls •pathologic fractures and osteoporosis (Siegel, 2008)

  12. Available Treatments for Hyponatremia Correct underlying disorder Diuretics Fluid Restriction Hypertonic Saline Off-label • Demeclocycline • Lithium carbonate • Urea • Clozapine

  13. A recent review identified more than 30 pharmacologic studies of agents thought to: reduce fluid intake (e.g. beta blockers, alpha adrenergic antagonists, angiotensin converting enzyme inhibitors) reduce stereotypic behaviors (e.g. opiod antagonists) increase water excretion (lithium, demeclocycline) directly increase plasma tonicity (e.g. salt, electrolyte containing beverages).

  14. “…the trials offer little useful datato the clinician” to guide effective management of polydipsia or hyponatremia. (Brooks & Ahmed, 2006)

  15. Vasopressin Antagonists V2 SpecificV1b/V2 non-specific OPC-41061 OPC-31260 - Otsuka (tolvaptan) - Otsuka VPA-985 YM-087 - Cardiokine (lixivaptan) - Yamanouchi (conivaptan) SR-121463 - Sanofi (satavaptan)

  16. “Double-Blind, Placebo-Controlled, Multicenter Trial of a Vasopressin V2-Receptor Antagonist in Patients With Schizophrenia and Hyponatremia” Richard C. Josiassen, PhD, Morris Goldman, MD, Meera Jessani, MD, Rita A. Shaughnessy, MD, PhD, Ala Albazzaz, MD, Jennifer Lee, John Ouyang, PhD, Cesare Orlandi, MD and Frank Czerwiec, MD, PhD Biological Psychiatry (in press)

  17. Demographic & BaselineCharacteristics Characteristic TolvaptanPlacebo p-value (n = 7) (n = 12) ______________________________________________________ n (%) n (%) Male 4 (57%) 11 (92%) ns Smoker 6 (86%) 10 (83%) ns Atypical neuroleptic 5(71%) 11(92%) ns Diagnosis Schizophrenia 5 (71%) 9 (75%) Schizoaffective 2 (28.6%) 2 (16.7%) Psychosis NOS -- 1 (8%)

  18. So, Is Hyponatremia an Important Issue in the Overall Care of Individuals with Schizophrenia?

  19. Case Study J.C.64 years oldChronic schizophreniaNormal Na for four years Living in the communityClinically stable and socially engaged

  20. ARTHUR P. NOYESRESEARCH FOUNDATION Richard C. Josiassen, PhD Rita A. Shaughnessy, MD, PhD Nina Skuban, MD Dawn M. Filmyer Margit Kacso Jessica L. Curtis Marice J. Davis Maurice D. Cornelius Naomi Finkel, RN Ann Marie Donohue, PhD Bruce McNeel Affiliated with the University of Pennsylvania

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