development of hyponatremia can result from a number of different factors, but
one that has been associated in patients with schizophrenia is
polydipsia. In short, polydipsia is either a chronic or intermittent
ingestion of large volumes of water, which results in a dilution. It has
been estimated that approximately 20% of psychiatric inpatients (mainly schizophrenic
patients) will experience polydipsia with at least 5% of those experiencing
If severe enough, polydipsia induced hyponatremia can cause a number of
disturbances in the central nervous system (CNS) which include delirium,
ataxia, seizures, and death.1 Interestingly, antipsychotic therapies used
in the management of schizophrenia have been associated with causing this
condition. Those most commonly associated include the first generation or
typical antipsychotics and a few of the second generation or atypical
antipsychotics, with risperidone having several case reports suggesting it as a
causative agent or failure to improve the presence of polydipsia.2-5 On
the other hand, a few case reports have also suggested that risperidone has
been associated with improvements in polydipsia and hyponatremia.6,7 It
is not fully known if this improvement in symptoms of polydipsia with these few
cases were secondary to improved psychosis and/or related to the drug
concentrations present. It is also important to recognize that the
atypical antipsychotics, clozapine (Clozaril, FazaClo) and quetiapine
(Seroquel) in particular, have been associated with improving symptoms from
primary polydipsia seen in schizophrenic patients.4,8,9 Taking this
information all together, it would appear that some antipsychotics may cause or
prevent the improvement in polydipsia induced hyponatremia.
is the proposed mechanism by which risperidone could cause or worsen the risk
for developing polydipsia?
The physiologic process may be multifactorial, but some data
suggest that elevated dopamine levels can cause a resetting of the
osmoreceptors in the CNS.10 In addition, there is some evidence
suggesting that chronic antipsychotic therapy, could result in a neuroleptic-induced
dopamine supersensitivity effect within the hypothalamic-pituitary axis, which
has been associated with an increased peripheral response to angiotensin II.11
Increased sensitivity to angiotensin II is known to cause antidiuretic hormone
secretion and stimulate thirst. As such, it appears that dopamine can be
a modulator of thirst and that those antipsychotics associated with greater
degrees of dopamine inhibition may be more associated with polydipsia.12
Based on the differences in the pharmacodynamic profiles of the first
generation, or typical antipsychotics, compared to the second generation, or
atypical antipsychotics, as well as the differences within the atypical
antipsychotics, this might explain why risperidone could be associated with not
improving polydipsia or even worsening it.
the presence of a certain amount of drug concentration in the body influence
this potential risk?
There is also emerging data supporting that patients genetic polymorphisms to
the multi-drug resistant protein (MDR1; also known as P-glycoprotein (P-gp))
are at a greater risk for polydipsia induced hyponatremia.13 This is due
to increased cellular drug concentrations of antipsychotics that are known
substrates of P-gp. This is relevant given that risperidone is a known
substrate of P-gp.
it is pharmacologically plausible that risperidone could contribute to or
prevent the improvement of polydipsia through a multifactorial process.
It also appears that this risk is overall low, but should still remain in the
differential diagnosis for a patient with unexpected or unexplained develop of
- De Leon J, Verghese C, Tracy JI et al. Polydipsia and water
intoxication in psychiatric patients: a review of the epidemiological
literature. Biol Psychiatry 1994;35:408-19.
- Assal F, Chauchot F. [hyponatremia of therapeutic origin. Apropos of a case.] Encephale 1994;20:527-9.
- Whitten JR, Ruehter VL. Risperidone and hyponatremia: a case report. Ann Clin Psychiatry 1997;9:181-3.
- Bersani G, Pesaresi L, Orlandi V et al. Atypical antipsychotics
and polydipsia: a cause or a treatment? Hum Psychopharmacol
- Kawai N, Baba A, Suzuki T. Risperidone failed to improve
polydipsia-hyponatremia of the schizophrenic patients. Psychiatry Clin
- Landry P. Effect of risperidone on polydipsia and hyponatremia in schizophrenia. Can J Psychiatry 1995;40:566-7.
- Kern RS, Marshall BD, Kuehnel TG et al. Effects of risperidone
on polydipsia in chronic schizophrenia patients. J Clin
- Verghese C, Abraham G, Nair C et al. Absence of changes in
antidiuretic hormone, angiotensin II, and atrial natriuretic peptide
with clozapine treatment of polydipsia-hyponatremia: 2 case reports. J
Clin Psych 1998;59:415-9.
- Montgomery JH, Tekell JL. Adjunctive quetiapine treatment of the
polydipsia, intermittent hyponatremia, and psychosis syndrome: a case
report. J Clin Psychiatry 2003;64:339-41.
- Fraioli S, Cioli I, Nencini P. Amphetamine reinstates polydipsia
induced by chronic exposure to quinpirole, a dopaminergic D2 agonist, in
rats. Behav Brain Res 1997;89:199-215.
- de Leon J, Verghese C, Stanilla JK et al. Treatment of polydipsia
and hyponatremia in psychiatric patients; can clozapine be a new
option? Neuropsychopharmacology 1995;12:133-138.
- Hirayama T, Kita T, Ogawa Y et al. Effects of chronic treatment
with haloperidol on vasopressin release and behavioral changes by
osmotic stimulation of the supraoptic nucleus. Life Sci
- Shinkai T, De Luca V, Utsunomiya K et al. Functional
polymorphism of the human multidrug resistance gene (MDR1) and
polydipsia-hyponatremia in schizophrenia. Neuromolecular Med