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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.


Hyponatremiaand Schizophrenia

Are Vaptans

a Treatment Option?


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


  • Case Study J.C.64 years oldChronic schizophreniaHospitalized 37 yearsFirst 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 femalesMean Serum SodiumX = 139.3SD = 2.87.9% HyponatremiaNo 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 Hyponatremia

In the Context of Schizophrenia

Normal140 (mmol/L) 

???135 

Lethargy, Apathy130 

Confusion 

Agitation 

Muscle Cramps 

Hallucinations120 

Seizures 

Coma 

Pseudobulbar palsy110 

Hypothermia 

Death 


Symptoms of Hyponatremia

Mostly CNS in nature:

• Acute

• Chronic


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


Other morbidities include:

•impaired cognition

•impaired gait and balance leading to falls

•pathologic fractures and

osteoporosis

(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 SpecificV1b/V2 non-specific

OPC-41061OPC-31260

- Otsuka (tolvaptan) - Otsuka

VPA-985YM-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

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%)


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


  • Case Study J.C.64 years oldChronic schizophreniaNormal Na for four years

    Living in the communityClinically stable and socially engaged


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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