Vaptans: A Potential New Approach for Treating Chronic Hyponatremia in Psychotic Patients

Josiassen, Richard C.; Curtis, Jessica; Shaughnessy, Rita A.; Filmyer, Dawn M.; Geboy, Alexander; Skuban, Nina; Czerwiec, Frank S.

doi:10.3371/csrp.6.1.3

Cited by 4 publications

(5 citation statements)

References 17 publications

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“…These studies also demonstrated that the resetting appeared to be ameliorated by habituation to the clinical environs (Goldman et al, 1996) and confirmed they were worsened by psychotic exacerbations (Figure 1) (Goldman et al, 1997). Recent trials with highly specific AVP antagonists substantiate the conclusion that the variability in the hyponatremia, and thus the resetting, is attributable to enhanced AVP activity (Jossiasen et al 2008, 2012). Together these findings provided a plausible physiologic explanation for the original observations linking acute psychosis to impaired water excretion and the life-threatening hyponatremia in hyponatremic polydipsic schizophrenic patients (Goldman, 2009).…”

Section: 0 Overview Of Impaired Water Excretion Water Intoxicationmentioning

confidence: 95%

Brain circuit dysfunction in a distinct subset of chronic psychotic patients

Goldman¹

2014

Schizophrenia Research

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Objective To identify the mechanism of unexplained hyponatremia and primary polydipsia in schizophrenia and its relationship to the underlying psychiatric illness. Methods Briefly review previous studies that led to the conclusion the hyponatremia reflects altered hippocampal inhibition of peripheral neuroendocrine secretion. In greater detail, present the evidence supporting the hypothesis that circuit dysfunction associated with the hyponatremia and the polydipsia contributes to the underlying mental disorder. Results Polydipsic patients with and without hyponatremia exhibit enhanced neuroendocrine responses to psychological stress in proportion to structural deformations on their anterior hippocampus, amygdala and anterior hypothalamus. Nonpolydipsic patients exhibit blunted responses and deformations on other hippocampal and amygdala surfaces. The deformations in polydipsic patients are also proportional to diminished peripheral oxytocin levels and impaired facial affect recognition that is reversed by intranasal oxytocin. The anterior hippocampus is at the hub of a circuit that modulates neuroendocrine and other responses to psychological stress and is implicated in schizophrenia. Preliminary data indicate other measures of stress reactivity are also enhanced in polydipsics and that the functional connectivity of the hippocampus with the other structures in this circuitry differs in schizophrenia patients with and without polydipsia. Conclusion Polydipsia may identify a subset of schizophrenia patients whose enhanced stress reactivity contributes to their mental illness. Stress reactivity may be a symptom dimension of chronic psychosis that arises from circuit dysfunction that can modeled in animals. Hence polydipsia could be a biomarker that helps to clarify the pathophysiology and heterogeneity of psychosis as well as identify novel therapies. Clinical investigators should consider obtaining indices of water balance, as these may help them unravel and more concisely interpret their findings. Basic researchers should assess if the polydipsic subset is a patient group particularly suitable to test hypotheses arising from their translational studies.

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Section: 0 Overview Of Impaired Water Excretion Water Intoxicationmentioning

confidence: 95%

Brain circuit dysfunction in a distinct subset of chronic psychotic patients

Goldman¹

2014

Schizophrenia Research

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Section: A New Treatment Optionmentioning

confidence: 99%

“…Discontinuation of vaptans usually results in a rapid decrease in serum sodium to baseline levels. [22][23][24] This suggests that the predisposing factor(s) for CHN in most of these cases is chronic, requiring long-term maintenance therapy-and maintenance treatment raises significant cost-benefit issues. Fortunately, tolvaptan is made available by the manufacturer through a patient assistance program, 29 although to date it has not been widely utilized for psychotic patients.…”

Section: Understanding the Risk Of Chronic Hyponatremia In Psychosismentioning

confidence: 99%

“…23 A multiyear study with psychotic patients confirmed that tolvaptan is effective and safe over long periods of time. 24 Another oral vaptan, lixivaptan, is effective and safe when used to treat CHN in psychotic patients 25,26 but is not yet FDA-approved.Vaptans are seldom used in psychiatric institutions. The available information regarding vaptans and psychosis comes almost entirely from pharmaceutical industry-sponsored clinical trials, and, as a result, little "real-world" experience has been reported.…”

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confidence: 99%

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Reconsidering Chronic Hyponatremia in Psychosis

Josiassen

Filmyer²,

Geboy³

et al. 2013

J. Clin. Psychiatry

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medical patients) showing that patients with CHN had an increased risk of death in the hospital, at 1 year, and at 5 years. These findings have obvious implications for quality of life and raise numerous questions. When does CHN become symptomatic in psychotic populations? Is the CNS of psychotic individuals unusually vulnerable to the consequences of CHN? When should CHN be treated with medications? What dosage and duration are appropriate? A New Treatment OptionVaptans have generated great expectation as a treatment option for CHN. 21 One US Food and Drug Administration (FDA)-approved vaptan, tolvaptan, is a selective vasopressin (V 2 ) receptor antagonist. 22 It works by blocking the effects of the pituitary hormone arginine vasopressin (AVP) on the V 2 receptors on the renal collecting duct cells. The Study of Ascending Levels of Tolvaptan (SALT) trial established short-term (30 days) efficacy of tolvaptan for elevating and maintaining serum sodium levels among patients with CHN of diverse etiologies. The SALT trial included a subgroup of psychotic patients with idiopathic CHN and demonstrated that short-term treatment with tolvaptan is effective and safe in this population as well. 23 A multiyear study with psychotic patients confirmed that tolvaptan is effective and safe over long periods of time. 24 Another oral vaptan, lixivaptan, is effective and safe when used to treat CHN in psychotic patients 25,26 but is not yet FDA-approved.Vaptans are seldom used in psychiatric institutions. The available information regarding vaptans and psychosis comes almost entirely from pharmaceutical industry-sponsored clinical trials, and, as a result, little "real-world" experience has been reported. The metric used to demonstrate vaptan efficacy has been serum sodium levels, which are thought to be of limited clinical value within the mental health context. There are no specific guidelines regarding treatment of CHN in psychotic populations, which means that clinicians need to rely solely on their clinical experience and good judgment on a case-by-case basis. Finally, the cost of tolvaptan ($250 per tablet) has raised significant cost-benefit considerations.Addendum: As this article was going to press, the authors were notified that 3 patients enrolled in a 3-year tolvaptan study and its extension trial of about 1,400 patients with autosomal dominant polycystic kidney disease (ADPKD) developed significant (> 3 × ULN) increases in serum alanine aminotransferase with concomitant, clinically significant (> 2 × ULN) increases in serum total bilirubin. Two of these cases were previously reported in the publication of the placebo-controlled study in ADPKD. 1 These patients were treated with doses between 60 and 120 mg/d. The maximum FDA-approved dose of tolvaptan in the US for the indication of euvolemic and hypervolemic hyponatremia is 60 mg/d. Tolvaptan is not currently approved for the treatment of ADPKD. Also, in published results from populations with other diseases treated with tolvaptan over multiple years, liver enzyme a...

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“…The mechanism appears to be attributable to psychosis lowering the osmotic set point for AVP secretion (Goldman et al, 1997) perhaps due to a stress diathesis that is associated with the underlying psychiatric illness (Goldman et al, 2007; Goldman, 2009; Goldman et al, 2011). The contribution of the elevated AVP to the hyponatremia is demonstrated by its rapid reversal with AVP antagonists (Josiassen et al, 2008; Josiassen et al, 2012). All classes of antipsychotic drugs are associated with hyponatremia (Mannesse et al, 2010), and currently there are no published guidelines to aid clinicians whether to increase or decrease antipsychotic medication.…”

Section: ) Introductionmentioning

confidence: 99%

A systematic review of the ability of urine concentration to distinguish antipsychotic- from psychosis-induced hyponatremia

Atsariyasing

Goldman

2014

Psychiatry Research

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Life-threatening hyponatremia in psychotic patients is common and typically is attributable to either antipsychotic medication or to acute psychosis in those with the polydipsia-hyponatremia syndrome. The preferred treatment for one situation may worsen the hyponatremia if caused by the other situation. Hence it is critical to distinguish between these two possibilities. Case reports and series were identified through electronic databases. 54 cases of hyponatremia without recognized causes in psychotic patients were divided into those with dilute (< plasma osmolality) or concentrated (> plasma osmolality) urine. The distribution of urine concentration and measures likely to be associated with psychotic illness and its treatment were compared in both groups. Naranjo’s scale was utilized to determine the probability hyponatremia was drug-induced. Urine osmolality fit a bimodal distribution (intersection 219 mOsm/Kg) better than a unimodal distribution. ‘Probable’ drug-induced cases occurred 6.8 (95%CI=1.6–28.9) times more often in those with concentrated urine. Acute psychotic exacerbations occurred 4.5 (95%CI=0.4–54.1) times more often in those with dilute urine. These findings, as well as several other trends in the data, indicate that measures of urine concentration can help distinguish between antipsychotic-induced and psychosis-induced hyponatremia.

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Vaptans: A Potential New Approach for Treating Chronic Hyponatremia in Psychotic Patients

Cited by 4 publications

References 17 publications

Brain circuit dysfunction in a distinct subset of chronic psychotic patients

Brain circuit dysfunction in a distinct subset of chronic psychotic patients

Reconsidering Chronic Hyponatremia in Psychosis

A systematic review of the ability of urine concentration to distinguish antipsychotic- from psychosis-induced hyponatremia

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