Int J Clin Pharm (2014) 36:253–255 DOI 10.1007/s11096-013-9870-0
CASE REPORT
Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine Ellise D. Liew • Christopher P. Alderman
Received: 14 January 2013 / Accepted: 23 October 2013 / Published online: 15 November 2013 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2013
Abstract Objective To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with desvenlafaxine. Case summary A 57-yearold female with hyponatraemia. Her medications included desvenlafaxine, and symptoms included nausea, anxiety and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. Desvenlafaxine was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. Discussion SIADH has been widely reported with a range of antidepressants. This case report suggests that desvenlafaxine might cause clinically significant hyponatremia. Conclusions Clinicians should be aware of the potential for antidepressants to cause hyponatremia, and take appropriate corrective action where necessary. Keywords Desvenlafaxine Hyponatremia Syndrome of inappropriate anti-diuretic hormone secretion (SIADH)
E. D. Liew C. P. Alderman (&) C/o Pharmacy Department, Repatriation General Hospital, Daw Park, SA 5041, Australia e-mail: [email protected]; [email protected] C. P. Alderman Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
Impact of findings on practice • •
Like other antidepressants, desvenlafaxine appears to have the potential to cause SIADH. For patients with hyponatraemia during treatment with desvenlafaxine or other antidepressants, investigations including measurement of urinary electrolyte profile should be undertaken to exclude SIADH.
Introduction Hyponatraemia is an electrolyte disturbance commonly encountered amongst hospitalized patients, and although this clinical problem is particularly frequent amongst the elderly, can affect patients from all age groups [1]. One prospective study conducted over a 90-day period found that the daily incidence and prevalence of hyponatremia were 0.97 and 2.48 % respectively [2]. Research has also shown that an acute decrease in serum sodium concentrations to\120 mmol/L is associated with a higher mortality rate compared to hyponatremia with a chronic or slow progression [3]. Mild chronic hyponatremia is often asymptomatic and is not necessarily detected in the outpatient setting, but it is apparent that it is not entirely benign with respect to patient outcomes—for example, hyponatremia is associated with a higher incidence of falls [4]. It has been postulated that correction of serum sodium concentrations may actually have the potential to prevent a large number of hospitalizations [4]. Although there are many different causes, syndrome of inappropriate antidiuretic hormone (SIADH) secondary to treatment with psychotropic drugs is a clinically and epidemiologically important factor that may cause hyponatremia [5].
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Int J Clin Pharm (2014) 36:253–255
Case description
Discussion
A 57-year-old female presented to the emergency department with a history of two episodes of unconscious collapse within the last week, as well as symptoms of nausea, anxiety and confusion. She had been discharged that morning from another hospital after a 4 days admission for the investigation of these symptoms. During that admission there was a finding of significant hyponatremia (serum sodium 122 mmol/L) that resulted in a change in antihypertensive therapy from candesartan to amlodipine—this was associated with an increase in the serum sodium to 125 mmol/L. On the day of discharge she was advised to seek follow-up from her primary care physician to assess her blood pressure and electrolytes, and to consider cessation of desvenlafaxine if the hyponatremia persisted. She was reviewed as an outpatient on the day of discharge and her symptoms were erroneously attributed to worsening depression: she was consequently advised to increase her desvenlafaxine dosage from 50 mg daily to 100 mg daily. At this time she chose to present to a different hospital for further investigation. Her past medical history included hypertension, hypothyroidism, depression and anxiety. Medications on admission included desvenlafaxine (started approximately 4 months earlier), amlodipine, sodium valproate, thyroxine and inhaled tiotropium, salmeterol/fluticasone and inhaled albuterol as needed. On re-presentation to hospital her serum sodium was found to be 120 mmol/L and symptoms of poor concentration, lack of appetite, increased anxiety and poor sleep remained. She was admitted for management of the hyponatremia and later transferred to the care of the psychiatric team. Her serum osmolality on admission was 263 mosmol/kg with a urine osmolality of 410 mosmol/kg and urine sodium of 63 mmol/L, these findings being consistent with a likely diagnosis of SIADH. Desvenlafaxine was discontinued and fluid restriction at 800 mL for the first day and then 1,000 mL daily for the subsequent week was implemented. Other causes of hyponatremia were also investigated: the serum concentration of thyroid stimulating hormone was found to be 3.2 m IU/L and the serum cortisol was 636 nmol/L, both within reference ranges. After 4 days as an inpatient the serum sodium had increased to 128 mmol/L and after 7 days the fluid restriction was relaxed to 1,500 mL daily. On day 10 she was commenced on mirtazapine as an alternative antidepressant, and at this time the serum sodium was 140 mmol/ L and the fluid restriction was discontinued. During the subsequent inpatient stay for depression over the next 3 weeks the serum sodium ranged from 134 to 137 mmol/L despite treatment with mirtazapine.
Syndrome of inappropriate anti-diuretic hormone has been associated with the use of many psychotropic drugs, and case reports describe this form of electrolyte derangement for antidepressant medications including selective serotonin reuptake inhibitors, tricyclic antidepressants, irreversible monoamine oxidase inhibitors, moclobemide, reboxetine, mirtazapine, venlafaxine and duloxetine [6]. In addition to the case described here, there is also at least one other report (believed to be the first published) of SIADH that occurred after exposure to desvenlafaxine [7]. The mechanism of SIADH associated with antidepressants is not fully understood, but may involve direct or indirect stimulation of antidiuretic hormone secretion from the posterior pituitary gland in association with the neurohormonal effects noradrenaline and serotonin through alphaadrenergic and serotonin 5HT1c and 5HT2 receptors [6]. Other possibilities include that antidepressants might mimic the effect of antidiuretic hormone at the renal tuble, in the effects of these drugs (and others) might alter the responsiveness of the renal tubles to circulating antidiuretic hormone—without measure the serum concentration of Antidiuretic hormone, it is not possible to determine if this is the mechanism that causes hyponatraemia under these circumstances. Various approaches are used when dealing with a patient presenting with suspected antidepressant induced SIADH. In some cases, the most logical step involves cessation of therapy if clinically appropriate, but this will mean that an appropriate alternative treatment for the underlying psychiatric illness will need to be identified. The use of other approaches to the management of hyponatremia will be predicated upon other individual case factors such as the severity of hyponatraemia and associated clinical symptoms. If the hyponatremia is considered severe, for example if sodium is \120 mmol/L or if the patient remains symptomatic, correction of sodium levels by using a slow infusion of hypertonic saline at a conservative rate (to prevent cerebral osmotic demyelination) may be required. Mild/asymptomatic hyponatremia may be managed with ongoing monitoring of the serum sodium, and the use of fluid restriction. It is important to note that ongoing fluid restriction is often poorly tolerated by patients, and adherence to this approach in the ambulatory setting is often suboptimal. Drug treatment for SIADH using demeclocycline may be considered for chronic management: this approach is based upon inhibiting the effects of antidiuretic hormone on renal tubules, promoting the excretion of free water. Demeclocyline is only available in Australia on a restricted access basis via the Australian Special Access Scheme for
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Int J Clin Pharm (2014) 36:253–255
limited use of a non-registered product for specified patients. While selective vasopressin 2 receptor antagonists such as tolvaptan may also be effective by promoting aquaresis, this agent has only recently been registered for use in Australia and is not available for subsidised supply through the national medication reimbursement scheme. If further antidepressant therapy is required then an antidepressant from a different class should be considered and commenced cautiously with close monitoring. As newer antidepressants achieve more widespread uptake, the adverse effect profile associated with these drugs becomes more apparent.
Conclusion We report a case of significant hyponatremia with SIADH associated with the use of desvenlafaxine. The results of the investigations undertaken in this case support the possibility of a diagnosis of SIADH, and the temporal relationship between the discontinuation of desvenlafaxine and the resolution of hyponatremia lends support to the likelihood that this case represents a case of SIADH secondary to this relatively newly introduced psychotropic drug. Scoring using the widely accepted Naranjo Algorithm [8] suggests that in this case the likelihood that the SIADH observed is associated with the use of desvenlafaxine would be rated as a ‘‘probable’’ adverse drug reaction (score conservatively calculated = 5). We suggest that for
255
any patient treated with desvenlafaxine who presents with significant hyponatremia, the possibility of treatment-related SIADH should be considered. Conflicts of interest
None.
References 1. Shapiro DS, Sonnenblick M, Galperin I, Melkonyan L, Munter G. Severe hyponatremia in elderly hospitalized patients: prevalence, aetiology and outcome. Intern Med J. 2010;40:574–80. 2. Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med. 1985;102:164–8. 3. Movig KL, Leufkens HG, Lenderink AW, Van den Akker KG, Hodiamont PP, Goldschmidt HM, Egberts AC. Association between antidepressant drug use and hyponatremia: a case-control study. Br J Clin Pharmacol. 2002;53:363–9. 4. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119:71.e1–8. 5. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52:144–53. 6. Spigset O, Hedenmalm K. Hyponatremia in relation to treatment with antidepressants: a survey of reports in the World Health Organisation data base for spontaneous reporting of adverse drug reactions. Pharmacotherapy. 1997;17(2):348–52. 7. Lee GT, Leung JL. Syndrome of inappropriate secretion of antidiuretic hormone due to desvenlafaxine. Gen Hosp Psychiatry 2012; Jul 17 [Epub ahead of print]. 8. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45.
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CASE REPORT
Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine Ellise D. Liew • Christopher P. Alderman
Received: 14 January 2013 / Accepted: 23 October 2013 / Published online: 15 November 2013 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2013
Abstract Objective To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with desvenlafaxine. Case summary A 57-yearold female with hyponatraemia. Her medications included desvenlafaxine, and symptoms included nausea, anxiety and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. Desvenlafaxine was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. Discussion SIADH has been widely reported with a range of antidepressants. This case report suggests that desvenlafaxine might cause clinically significant hyponatremia. Conclusions Clinicians should be aware of the potential for antidepressants to cause hyponatremia, and take appropriate corrective action where necessary. Keywords Desvenlafaxine Hyponatremia Syndrome of inappropriate anti-diuretic hormone secretion (SIADH)
E. D. Liew C. P. Alderman (&) C/o Pharmacy Department, Repatriation General Hospital, Daw Park, SA 5041, Australia e-mail: [email protected]; [email protected] C. P. Alderman Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
Impact of findings on practice • •
Like other antidepressants, desvenlafaxine appears to have the potential to cause SIADH. For patients with hyponatraemia during treatment with desvenlafaxine or other antidepressants, investigations including measurement of urinary electrolyte profile should be undertaken to exclude SIADH.
Introduction Hyponatraemia is an electrolyte disturbance commonly encountered amongst hospitalized patients, and although this clinical problem is particularly frequent amongst the elderly, can affect patients from all age groups [1]. One prospective study conducted over a 90-day period found that the daily incidence and prevalence of hyponatremia were 0.97 and 2.48 % respectively [2]. Research has also shown that an acute decrease in serum sodium concentrations to\120 mmol/L is associated with a higher mortality rate compared to hyponatremia with a chronic or slow progression [3]. Mild chronic hyponatremia is often asymptomatic and is not necessarily detected in the outpatient setting, but it is apparent that it is not entirely benign with respect to patient outcomes—for example, hyponatremia is associated with a higher incidence of falls [4]. It has been postulated that correction of serum sodium concentrations may actually have the potential to prevent a large number of hospitalizations [4]. Although there are many different causes, syndrome of inappropriate antidiuretic hormone (SIADH) secondary to treatment with psychotropic drugs is a clinically and epidemiologically important factor that may cause hyponatremia [5].
123
254
Int J Clin Pharm (2014) 36:253–255
Case description
Discussion
A 57-year-old female presented to the emergency department with a history of two episodes of unconscious collapse within the last week, as well as symptoms of nausea, anxiety and confusion. She had been discharged that morning from another hospital after a 4 days admission for the investigation of these symptoms. During that admission there was a finding of significant hyponatremia (serum sodium 122 mmol/L) that resulted in a change in antihypertensive therapy from candesartan to amlodipine—this was associated with an increase in the serum sodium to 125 mmol/L. On the day of discharge she was advised to seek follow-up from her primary care physician to assess her blood pressure and electrolytes, and to consider cessation of desvenlafaxine if the hyponatremia persisted. She was reviewed as an outpatient on the day of discharge and her symptoms were erroneously attributed to worsening depression: she was consequently advised to increase her desvenlafaxine dosage from 50 mg daily to 100 mg daily. At this time she chose to present to a different hospital for further investigation. Her past medical history included hypertension, hypothyroidism, depression and anxiety. Medications on admission included desvenlafaxine (started approximately 4 months earlier), amlodipine, sodium valproate, thyroxine and inhaled tiotropium, salmeterol/fluticasone and inhaled albuterol as needed. On re-presentation to hospital her serum sodium was found to be 120 mmol/L and symptoms of poor concentration, lack of appetite, increased anxiety and poor sleep remained. She was admitted for management of the hyponatremia and later transferred to the care of the psychiatric team. Her serum osmolality on admission was 263 mosmol/kg with a urine osmolality of 410 mosmol/kg and urine sodium of 63 mmol/L, these findings being consistent with a likely diagnosis of SIADH. Desvenlafaxine was discontinued and fluid restriction at 800 mL for the first day and then 1,000 mL daily for the subsequent week was implemented. Other causes of hyponatremia were also investigated: the serum concentration of thyroid stimulating hormone was found to be 3.2 m IU/L and the serum cortisol was 636 nmol/L, both within reference ranges. After 4 days as an inpatient the serum sodium had increased to 128 mmol/L and after 7 days the fluid restriction was relaxed to 1,500 mL daily. On day 10 she was commenced on mirtazapine as an alternative antidepressant, and at this time the serum sodium was 140 mmol/ L and the fluid restriction was discontinued. During the subsequent inpatient stay for depression over the next 3 weeks the serum sodium ranged from 134 to 137 mmol/L despite treatment with mirtazapine.
Syndrome of inappropriate anti-diuretic hormone has been associated with the use of many psychotropic drugs, and case reports describe this form of electrolyte derangement for antidepressant medications including selective serotonin reuptake inhibitors, tricyclic antidepressants, irreversible monoamine oxidase inhibitors, moclobemide, reboxetine, mirtazapine, venlafaxine and duloxetine [6]. In addition to the case described here, there is also at least one other report (believed to be the first published) of SIADH that occurred after exposure to desvenlafaxine [7]. The mechanism of SIADH associated with antidepressants is not fully understood, but may involve direct or indirect stimulation of antidiuretic hormone secretion from the posterior pituitary gland in association with the neurohormonal effects noradrenaline and serotonin through alphaadrenergic and serotonin 5HT1c and 5HT2 receptors [6]. Other possibilities include that antidepressants might mimic the effect of antidiuretic hormone at the renal tuble, in the effects of these drugs (and others) might alter the responsiveness of the renal tubles to circulating antidiuretic hormone—without measure the serum concentration of Antidiuretic hormone, it is not possible to determine if this is the mechanism that causes hyponatraemia under these circumstances. Various approaches are used when dealing with a patient presenting with suspected antidepressant induced SIADH. In some cases, the most logical step involves cessation of therapy if clinically appropriate, but this will mean that an appropriate alternative treatment for the underlying psychiatric illness will need to be identified. The use of other approaches to the management of hyponatremia will be predicated upon other individual case factors such as the severity of hyponatraemia and associated clinical symptoms. If the hyponatremia is considered severe, for example if sodium is \120 mmol/L or if the patient remains symptomatic, correction of sodium levels by using a slow infusion of hypertonic saline at a conservative rate (to prevent cerebral osmotic demyelination) may be required. Mild/asymptomatic hyponatremia may be managed with ongoing monitoring of the serum sodium, and the use of fluid restriction. It is important to note that ongoing fluid restriction is often poorly tolerated by patients, and adherence to this approach in the ambulatory setting is often suboptimal. Drug treatment for SIADH using demeclocycline may be considered for chronic management: this approach is based upon inhibiting the effects of antidiuretic hormone on renal tubules, promoting the excretion of free water. Demeclocyline is only available in Australia on a restricted access basis via the Australian Special Access Scheme for
123
Int J Clin Pharm (2014) 36:253–255
limited use of a non-registered product for specified patients. While selective vasopressin 2 receptor antagonists such as tolvaptan may also be effective by promoting aquaresis, this agent has only recently been registered for use in Australia and is not available for subsidised supply through the national medication reimbursement scheme. If further antidepressant therapy is required then an antidepressant from a different class should be considered and commenced cautiously with close monitoring. As newer antidepressants achieve more widespread uptake, the adverse effect profile associated with these drugs becomes more apparent.
Conclusion We report a case of significant hyponatremia with SIADH associated with the use of desvenlafaxine. The results of the investigations undertaken in this case support the possibility of a diagnosis of SIADH, and the temporal relationship between the discontinuation of desvenlafaxine and the resolution of hyponatremia lends support to the likelihood that this case represents a case of SIADH secondary to this relatively newly introduced psychotropic drug. Scoring using the widely accepted Naranjo Algorithm [8] suggests that in this case the likelihood that the SIADH observed is associated with the use of desvenlafaxine would be rated as a ‘‘probable’’ adverse drug reaction (score conservatively calculated = 5). We suggest that for
255
any patient treated with desvenlafaxine who presents with significant hyponatremia, the possibility of treatment-related SIADH should be considered. Conflicts of interest
None.
References 1. Shapiro DS, Sonnenblick M, Galperin I, Melkonyan L, Munter G. Severe hyponatremia in elderly hospitalized patients: prevalence, aetiology and outcome. Intern Med J. 2010;40:574–80. 2. Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med. 1985;102:164–8. 3. Movig KL, Leufkens HG, Lenderink AW, Van den Akker KG, Hodiamont PP, Goldschmidt HM, Egberts AC. Association between antidepressant drug use and hyponatremia: a case-control study. Br J Clin Pharmacol. 2002;53:363–9. 4. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119:71.e1–8. 5. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52:144–53. 6. Spigset O, Hedenmalm K. Hyponatremia in relation to treatment with antidepressants: a survey of reports in the World Health Organisation data base for spontaneous reporting of adverse drug reactions. Pharmacotherapy. 1997;17(2):348–52. 7. Lee GT, Leung JL. Syndrome of inappropriate secretion of antidiuretic hormone due to desvenlafaxine. Gen Hosp Psychiatry 2012; Jul 17 [Epub ahead of print]. 8. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45.
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