Richard C. Josiassen Ph.D.

Hyponatremiaand Schizophrenia

Hyponatremiaand Schizophrenia

Are Vaptansa Treatment

Option?

Are Vaptansa Treatment

Option?

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

• Case Study J.C.

64 years oldChronic schizophrenia

Hospitalized 37 years

First hyponatremiadiagnosis ???

Hx of multiple seizuresMuteSodium 118 – 125TremorsAggressive

• 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.

Three-Month Prevalence Rate

• NSH Population(n = 328)

233 males105 females

Mean Serum SodiumX = 139.3SD = 2.8

7.9% Hyponatremia

No association with dose or class of anti-psychotic medication

Symptoms of Hyponatremia

Depend on:

• Degree

• Rapidity

• Susceptibility

age (young and old), CNS

trauma, respiratory reserve,

female gender

Symptoms of HyponatremiaIn 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

Symptoms of Hyponatremia

Mostly CNS in nature:

• Acute

• Chronic

Day 1104 mmol/LSeizuresComatose

Day 2121 mmol/L

Day 3140 mmol/L Kurokawa et al (2004)

Other morbidities include:• impaired cognition

• impaired gait and balance leading to falls

• pathologic fractures andosteoporosis

(Siegel, 2008)

Available Treatments for Hyponatremia

Correct underlying disorder

Diuretics

Fluid Restriction

Hypertonic Saline

Off-label

• Demeclocycline

• Lithium carbonate

• Urea

• Clozapine

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).

“…the trials offer little useful datato the clinician” to guide effective management of polydipsia or hyponatremia.

(Brooks & Ahmed, 2006)

Vasopressin Antagonists

V2 Specific V1b/V2 non-specific

OPC-41061 OPC-31260 - Otsuka (tolvaptan) - Otsuka

VPA-985 YM-087 - Cardiokine (lixivaptan) - Yamanouchi (conivaptan)

SR-121463 - Sanofi (satavaptan)

“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)

Demographic & BaselineCharacteristics

Characteristic Tolvaptan Placebo p-value(n = 7) (n = 12)

______________________________________________________n (%) n (%)

Male 4 (57%) 11 (92%) nsSmoker 6 (86%) 10 (83%) nsAtypical neuroleptic 5(71%) 11(92%)nsDiagnosis

Schizophrenia 5 (71%) 9 (75%)Schizoaffective 2 (28.6%) 2 (16.7%)Psychosis NOS -- 1 (8%)

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

• Case Study J.C.

64 years oldChronic schizophrenia

Normal Na for four years

Living in the community

Clinically stable and socially engaged

ARTHUR P. NOYESRESEARCH

FOUNDATIONRichard C. Josiassen, PhD

Rita A. Shaughnessy, MD, PhDNina Skuban, MDDawn M. Filmyer

Margit KacsoJessica L. CurtisMarice J. Davis

Maurice D. CorneliusNaomi Finkel, RN

Ann Marie Donohue, PhDBruce McNeel

Affiliated with the University of Pennsylvania