1. Richard C. Josiassen Ph.D.

2. Hyponatremia and Schizophrenia Are Vaptans a Treatment Option? 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 old Chronic schizophrenia Hospitalized 37 years First hyponatremia diagnosis ??? Hx of multiple seizures Mute Sodium 118 – 125 Tremors Aggressive

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 females Mean Serum Sodium X = 139.3 SD = 2.8 7.9% Hyponatremia No 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 Normal140 (mmol/L)  ???135  Lethargy, Apathy130  Confusion  Agitation  Muscle Cramps  Hallucinations120  Seizures  Coma  Pseudobulbar palsy110  Hypothermia  Death 

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

10. Day 1 104 mmol/L Seizures Comatose Day 2 121 mmol/L Day 3 140 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 data to the clinician” to guide effective management of polydipsia or hyponatremia. (Brooks & Ahmed, 2006)

15. Vasopressin Antagonists V2 SpecificV1b/V2 non-specific OPC-41061OPC-31260 - Otsuka (tolvaptan) - Otsuka VPA-985YM-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 & Baseline Characteristics CharacteristicTolvaptanPlacebop-value (n = 7)(n = 12) ______________________________________________________ n (%)n (%) Male4 (57%)11 (92%)ns Smoker6 (86%)10 (83%)ns Atypical neuroleptic5(71%)11(92%)ns Diagnosis Schizophrenia5 (71%)9 (75%) Schizoaffective2 (28.6%)2 (16.7%) Psychosis NOS--1 (8%)

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

20. Case Study J.C. 64 years old Chronic schizophrenia Normal Na for four years Living in the community Clinically stable and socially engaged

21. ARTHUR P. NOYES RESEARCH 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