July 3, 2013

Does Chronic Hyponatremia in Psychosis Really Matter?

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Richard C. Josiassen, PhD

Drexel University College of Medicine, Philadelphia, and Translational Neuroscience, LLC, Conshohocken, Pennsylvania


It has now been a little over a decade since vasopressin (V2) antagonists (known as “vaptans”) came on the scene as a new class of pharmaceuticals.1 Two of the vaptans (conivaptan & tolvaptan) have received FDA approval as the first therapeutic agents that effectively treat hyponatremia in a predictable, measurable, and efficient manner.2

As my colleagues and I stated in our recent review, hyponatremia (serum sodium concentration <136 mEq/L) is a potentially life-threatening medical comorbidity often seen in patients with schizophrenia. Prevalence rates have been pegged at 7% to 10% among institutionalized psychotic populations, and the condition is associated with increased morbidity and mortality.3 Therefore, as Peter Gross, MD, noted in an editorial, it is “… surprising … that physicians usually shrug their shoulders when confronted with a clinical case. What is the explanation for the apparent fact that physicians seem to do so little—and often in a misguided manner—about something that is as endemic as hyponatremia?”4(p559)

There are several explanations for this current situation.5 First, the manifestations of chronic hyponatremia (eg, headache, nausea, lethargy, restlessness, confusion) are nonspecific and overlap to a significant degree with psychotic symptoms. This makes it difficult if not impossible to unequivocally distinguish symptoms of hyponatremia from those of psychosis alone. Second, in the past, the few available treatments were generally considered suboptimal. Fluid restriction is the most common intervention, but the potential therapeutic benefits are often undermined in this population by poor patient compliance. I have noticed that, when fluid restriction fails to normalize serum sodium, further treatments (eg, sodium supplementation, loop diuretics, urea, demeclocycline) are seldom initiated. This is completely understandable: why waste time trying to treat a condition for which there are no good treatments! Third, the prevailing view has been that mild to moderate chronic hyponatremia is benign and asymptomatic. My colleagues and I commonly come across clinical lab reports showing serum sodium levels around 120 mEq/L characterized as “mild asymptomatic hyponatremia” with no further treatment recommended.

But things have changed. With vaptans, hyponatremia can be safely corrected in psychotic patients in only a few days.6 As a result, it is now possible to disentangle the clinical presentation to ascertain which symptoms are due to hyponatremia (if they subside) and which are related to psychosis itself. This is an important clinical development. With vaptans, it is also possible to examine the long-term consequences of hyponatremia under controlled conditions. This has resulted in a small but growing literature showing that even mild chronic hyponatremia is associated with gait and attentional impairment and an increased rate of falls and fractures, all of which would have a negative impact on long-term quality of life.

Vaptans have shed new light on the question of whether chronic hyponatremia in psychosis really matters. Many questions remain, such as the most appropriate way to use this new class of drugs in psychotic patients, the long-term treatment response rates, and whether sodium correction results in improved cognition, functional status, and quality of life. The vaptans have opened up new lines of clinical investigation aimed at treating this unmet need.

Financial disclosure:Dr Josiassen is a consultant for, has received grant/research support from, and is a member of the speakers/advisory boards for Otsuka and Cardiokine.


1. Robertson GL. Vaptans for the treatment of hyponatremia. Nat Rev Endocrinol. 2011;7(3):151–161. PubMed

2. Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 Suppl 1):S1–S21. PubMed

3. Josiassen RC, Filmyer DM, Geboy AG, et al. Reconsidering chronic hyponatremia in psychosis. J Clin Psychiatry. 2013;74(3):278–279. Full Text

4. Gross P. Hyponatremia now—a goldmine or a dead end? Adv Clin Exp Med. 2012;21(5)559–561. PubMed

5. Siegel AJ. Hyponatremia in psychiatric patients: update on evaluation and management. Harv Rev Psychiatry. 2008;16(1):13-24. PubMed

6. Josiassen RC, Goldman M, Jessani M, et al. Double-blind, placebo-controlled, multicenter trial of a vasopressin V2-receptor antagonist in patients with schizophrenia and hyponatremia. Biol Psychiatry. 2008;64(12):1097–1100. PubMed

Category: Medical Conditions , Psychosis , Schizophrenia
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8 thoughts on “Does Chronic Hyponatremia in Psychosis Really Matter?

  1. Central pontine myelinolysis matters, and while some adaptation to chronic hyponatraemia may occur, by glial absorption of interstitial fluid, the sequelae of intermittent confusion on confidence and coherence seen when sodium levels in low 120’s shpuld not be minimized.
  2. You are quite right — central pontine myelinolysis matters a great deal and so does cerebral edema. These are both potentially life-threatening medical emergencies. We are more focused on chronic and often mild hyponatremia. It has been our experience that this condition is generally dismissed by mental health professionals as benign. But new findings have suggested that the long-term effects of chronic, mild hyponatremia are not benign at all. Motor and gait disorders, falls leading to broken bones … possibly some cognitive impairment … investigators from a wide array of clinical disciplines are reporting these problems associated with chronic, mild hyponatremia.

    And now these problems are preventable. We think that their prevention should become a standard part of good clinical care.

  3. It is necessary for all psychiatrists to be well aware of management of this condition and early detection and prevention is essential
  4. Even though I have no experiences with the use of vaptans, some questions keep bothering me.
    Vaptans would correct sodium levels, which is fine, but what happens next? How long the treatment with vaptans should last? Should it last a few days or the treatment should be chronic. Plus what would be the cost chronic vaptan therapy?(1)
    Furthermore, while some authors have emphasized that euvolemic hyponatremia is associated with water retention, and not with salt depletion (2), others have emphasized the importance of depletion of cations and anions (3). Anyway, clinicians should be aware that during hyponatremia, cells must lose K + ions and anions. Anions are dominantly organic molecules with some of them being neurotransmitters as well (glycine, γ-aminobutyric acid, glutamate and aspartate).
    Thus, assumptions that changes in cognitive functioning of “asymptomatic” persons with euvolemic hyponatremia may be associated with intracellular changes seem logical (4). Yet, can the use of vaptans normalize intracellular contents? The answer to that could be positive, but the issue as such is not addressed enough so far.
    Several reports suggested the beneficial effect of clozapine in patients with polydipsia or water intoxication, not only in those diagnosed with schizophrenia (e.g. 5-7). As per my personal experience clozapine may be the good choice. However, can the use of vaptans be a better option with usually severely disturbed patients?
    A few years ago, a hypothesis that in some of these patients, polydipsia and hyponatremia are consequences of patients’ adjustment to a prolonged intake of an insufficient diet, dominantly poor in potassium was put forward (8). In my opinion, clinicians shoud have an accurate information on patients’ food intake.
    1. Gross PA, Wagner A, Decaux G. Vaptans are not the mainstay of treatment in hypernatremia: perhaps not yet. Kidney Int. 2011 Sep;80(6):594-600.
    2. Gross P. Hyponatremia now—a goldmine or a dead end? Adv Clin Exp Med. 2012;21(5)559–561.
    3. Verbalis JG. Whole-body volume regulation and escape from antidiuresis. Am J Med 119 (7 Suppl 1): S21-29, 2006.

    4. Margetić B, Aukst-Margetić B. Comments on “Hyponatremia-induced change in mood mimicking late-onset bipolar disorder”. Gen Hosp Psychiatry. 2011 May-Jun;33(3):e9-10.

    5. Henderson DC, Goff DC. Clozapine for polydipsia and hyponatremia in chronic schizophrenics. Biol Psychiatry 1994;36:768–70.

    6. de Leon J, Verghese C, Stanilla JK, Lawrence T, Simpson GM. Treatment of polydipsia and hyponatremia in psychiatric patients. Can clozapine be a new option? Neuropsychopharmacology 1995;12:133–8.

    7. Margetić B, Aukst-Margetić B, Zarković-Palijan T. Successful treatment of polydipsia, water intoxication, and delusional jealousy in an alcohol dependent patient with clozapine. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Sep 30;30(7):1347-9

    8. Margetić B, Aukst-Margetić B. A different hypothesis on hyponatremia in psychiatric patients: treatment implications and experiences. World J Biol Psychiatry. 2009;10(4 Pt 2):677-81

  5. Branimir,

    You have asked some very good questions. I will try to answer some of them. First, you asked how long vaptan treatment should last. We only have experience with psychotic patients, but I think our observations hold in other groups as well. All the published data shows that serum sodium is corrected very briskly, but once the drug is discontinued the serum sodium levels go back to baseline. That suggests that the treatment will be long term. But how long is long term? There are no studies I know on this topic, but I can tell you that we did have two psychotic subjects whose serum sodium remained normal when the drug was discontinued after 6 months. My guess is that the various causal factors of hyponatremia will have different response profiles. And, yes the vaptans are very expensive at this point.
    You brought up the intracellular changes as a consequences of chronic hyponatremia. Joseph Verbalis has done the most elegant work in this area in my opinion, and it certainly seems that the depletion of these intracellular contents has negative consequences. (See Verbalis, J. G. (2010). Brain volume regulation in response to
    changes in osmolality. Neuroscience, 168, 862–870. and Verbalis, J. G. & Gullans, S. R. (1991). Hyponatremia causes large sustained reductions in brain content of multiple organic
    osmolytes in rats. Brain Research, 567, 274–282.).
    As for clozapine, there is some published data and we have some clinical experience in this area as well. It seems that clozapine’s effect in this area has to do more with reduced fluid consumption, not water excretion. So in cases where polydipsia is the underlying cause it seems helpful. At one of the local state hospitals, a couple of the physicians use clozapine in cases of polyldipsia, and it does seem to reduce the number of episodes of polydipsia.
    As for food intake, I remember reading the Margetic paper but I haven’t seen any follow-up. If you have I would enjoy reading it.
    If you want to stay in touch would you send me your full name and email address — I’d be glad to share some other ideas.

  6. I just wanted to let people know that there is a syndrome called reset osmostat syndrome in which there is hyponatremia whish is different than low sodium from SIADH
  7. It is an important topic often come across in clinical practice while dealing with adult and more so with geriatric psychiatric patients.Apart from psychotics I came across Hyponitraemia in treatment resistant depressive disorders,chronic Benzodizepine use/abuse/dependence.We had been treating them with Na salt replacement along with clinical syndrom management.Only few cases were placed on vaptan with encouraging results. It is bit early for me to comment on Vaptan.
  8. Does anyone know of a recent study on the effects of a structured diet with patients suffering from psychotic conditions? Many in-patients don’t adhere to diets well during their stay and once out on their own may have horrible diets. Also, what’s the effect of long term tobacco use and alcohol use on these particular patients? Finally, there is the issue of restful sleep, not just deadening nerves to put a person in a long term stupor. What is the collective effect of these in developing hyponatremia?

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