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The Mechanism for Risperidone (Risperdal) Induced Hyponatremia in Some Patients Being Treated for Schizophrenia

Summary:

  • Approximately 20% of psychiatric inpatients (mainly schizophrenic patients) will experience polydipsia with at least 5% of those experiencing water intoxication.
  • Antipsychotic therapy used in the management of schizophrenia has been associated with causing this condition.
  • Antipsychotic associated polydipsia has been linked to the effect that elevated dopamine levels can cause a resetting of the osmoreceptors in the CNS, neuroleptic-induced dopamine supersensitivity effect within the hypothalamic-pituitary axis (which has been associated with an increased peripheral response to angiotensin II), and increased sensitivity to angiotensin II is known to cause antidiuretic hormone secretion and stimulate thirst.
  • Therefore, it is pharmacologically plausible that risperidone could contribute to or fail to improve the presence of polydipsia through a multifactorial process.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
August 2015

Explanation

  • The 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 water intoxication.1

    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. 

    What 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. 

    Does 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. 

    Therefore, 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 hyponatremia.

    References:

    1. 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.  
    2. Assal F, Chauchot F.  [hyponatremia of therapeutic origin. Apropos of a case.]  Encephale 1994;20:527-9.  
    3. Whitten JR, Ruehter VL.  Risperidone and hyponatremia: a case report.  Ann Clin Psychiatry  1997;9:181-3.  
    4. Bersani G, Pesaresi L, Orlandi V et al.  Atypical antipsychotics and polydipsia: a cause or a treatment?  Hum Psychopharmacol  2007;22:103-7.  
    5. Kawai N, Baba A, Suzuki T.  Risperidone failed to improve polydipsia-hyponatremia of the schizophrenic patients.  Psychiatry Clin Neurosci  2002;56:107-10.  
    6. Landry P. Effect of risperidone on polydipsia and hyponatremia in schizophrenia.  Can J Psychiatry  1995;40:566-7.  
    7. Kern RS, Marshall BD, Kuehnel TG et al.  Effects of risperidone on polydipsia in chronic schizophrenia patients.  J Clin Psychopharmacol  1997;17:432-5. 
    8. 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.  
    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.  
    10. 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.  
    11. 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.  
    12. 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 2001;69:2147-2156.  
    13. 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 2008;10:362-7.

MESH Terms & Keywords

  • Atypical Antipsychotic, Risperidone, Risperdal, Risperidone Induced Hyponatremia, Schizophrenia