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Syndrome of inappropriate ADH secretion attributed to the serotonin re-uptake inhibitors, venlafaxine and paroxetine
The Netherlands
JOURNAL, OF MEDICINE Netherlands Journal of Medicine 50 (1997) 243-245
Brief report
Syndrome of inappropriate ADH secretion attributed to the serotonin re-uptake inhibitors, venlafaxine and paroxetine I.A. Meynaar a * , A.J. Peeters a, A.H Mulder a, J.P. Ottervanger b a Department b Netherlands
of Internal Medicine, Centre for Monitoring
Reinier de Graaf Gasthuis, R. de Graajiveg 3, 2625 AD De&, Netherla& of Adverse Reactions to Drags, PO Box 5406, 2280 HK Rijswijk, Netherland,v
Received 27 March 1996; revised 4 December 1996; accepted 11 December 1996
Abstract We report on 2 patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) which developed a few weeks after they had started treatment with venlafaxine and paroxetine, respectively. Due to the temporal relationship and the exclusion of other potential causes, a causal relationship between the use of the antidepressants and SIADH seems likely. Diagnostic criteria for SIADH and the role of drugs, especially serotonin re-uptake inhibitors, are discussed. 0 1997 Elsevier Science B.V. Keywords:
Venlafaxine;
Paroxetine;
SIADH;
Hyponatraemia;
Antidepressants
1. Introduction
2. Patient A
Selective serotonin re-uptake inhibitors (SSRIs) are a relatively new class of antidepressants, with little affinity for adrenergic, cholinergic or histaminergic receptors [ 11. In the late 1980s and the early 1990s a number of SSRIs were introduced, including fluoxetine, fluvoxamine, paroxetine and sertraline. Venlafaxine is a recently introduced SSRI that inhibits not only serotonin re-uptake but also noradrenaline re-uptake [2]. We report the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in 2 patients who had recently started the use of venlafaxine and paroxetine, respectively.
* Corresponding
author.
0300-2977/97/$17.00 8 PZI SO300-2977(97)00005-3
1997 Elsevier
Science
B.V.
All rights
reserved.
Patient A is a 65-year-old male who was referred to our hospital because of severe dizziness. Seven years previously a urethral stenosis had been dilated, whereafter he was advised to drink at least 2 litres of water daily to prevent cystitis. Two years later, he started sotalol240 mg per day for paroxysmal atria1 fibrillation. Ten weeks before admission fluoxetine 20 mg per day was prescribed by his general practitioner to treat a presumed depression. Four weeks later he was admitted to another hospital with atria1 fibrillation and oesophagitis. At that time, serum sodium concentration was 130 mmol/l. Fluoxetine therapy was discontinued because the indication was not clear, whereas omeprazole 20 mg/day and cisapride 80 mg/day were initiated. Cystitis was treated
244
LA. Meynaar
et al. /Netherlands
with noffloxacin 800 mg/day for 5 days. One week later he was discharged. One week before admission to our hospital the patient was given venlafaxine 75 mg/day by his general practitioner. Diuretics had never been prescribed to this patient. On admission to our hospital, apart from dizziness the patient reported no other complaints. At that time he was using sotalol, cisapride, omeprazol and venlafaxine. Physical examination revealed no abnormalities, in particular no oedema. His weight was 57.7 kg, his blood pressure llO/SO mmHg. Serum sodium concentration, however, was 114 mmol/l (normal 135-144), serum osmolality 248 mosm/l (normal 280-3001, urine volume 3140 ml/24 h with urine sodium excretion 239 mmo1/24 h and urine osmolality 640 mosm/l. Serum concentration of chloride, potassium and bicarbonate was 79 mmol/l (normal 55-105), 3.6 mmol/l (normal 3.6-4.8) and 26 mmol/l (normal 21-291, respectively. The concentration of antidiuretic hormone was not measured. Chest radiograph, chest computer tomography, urea, creatinine and haemoglobin concentrations, liver, thyroid and adrenal function tests were normal. Serum albumen was decreased (32 g/l, normal 3550). Measured creatinine clearance was 98 ml/mm. Electrocardiography showed atrial fibrillation. The patient was treated with additional sotalol and digoxin resulting in sinus rhythm. On the presumptive diagnosis of SIADH due to venlafaxine, this drug was discontinued and fluid intake was restricted to 1500 ml/24 h. Sodium concentration and osmolality of serum and urine returned to normal over a period of 2 weeks and remained normal after fluid restriction was stopped. At that time examination by a psychiatrist did not reveal a depression. The patient refused rechallenge with venlafaxine, but in view of the spontaneous recovery, and the absence of other causes, a causal relationship seems likely.
3. Patient B Patient B is a 89-year-old female who was admitted to our hospital because of constipation and lethargy. Her medical history revealed the placement of an on-demand pacemaker, inguinal herniotomy and fracture of the left humerus. One week before admission she was seen by her general practitioner
Journal
of Medicine
50 (1997)
243-245
because of loss of appetite. Laboratory values at that time were normal with serum sodium concentration 132 mmol/l. The general practitioner made a diagnosis of vital depression and added paroxetine 10 mg daily to the long-standing medication consisting of temazepam 10 mg/day, azapropazone 900 mg/day, cetirizine 10 mg/day because of itching and flavoxate 200 mg/day because of urine incontinence. All these medications were taken until the day of admission. On admission, physical examination revealed moderate abdominal distension, normal peristalsis, no oedema, normal blood pressure and lethargy. Serum sodium concentration was 116 mmol/l, serum osmolality 250 mosm/l, urine volume 1675 ml/24 h, urine sodium excretion 97 mmo1/24 h, and urine osmolality 410 mosm/l. Measured creatinine clearance was 77 rnI/min. Serum concentration of chloride, potassium and bicarbonate was 86, 4.3 and 25 mmol/l, respectively. Serum ADH concentration was not measured. Chest radiograph, liver, adrenal and thyroid function tests were normal. A plain abdominal X-ray showed distension of the colon but no signs of ileus. Barium enema and ultrasound study of the upper abdomen were normal. On the presumptive diagnosis of SIADH due to paroxetine with lethargy and constipation caused by severe hyponatraemia, the patient was treated with intravenous saline infusion, whereas paroxetine was discontinued. Serum sodium concentration returned to normal, normal defaecation returned and lethargy disappeared in a few days. The clinical course was complicated by fever and urinary tract infection 6 days after admission. Escherichia coli was cultured from blood and urine. The patient was treated successfully with sulphamethoxazole 800 mg plus trimethoprim 160 mg twice daily. Fifteen days after admission the patient was discharged in good clinical condition. At that time examination by a psychiatrist did not reveal a depression. No rechallenge with paroxetine was performed because it was thought to be unethical.
4. Discussion Antidiuretic hormone (ADH) is produced by the pituitary gland in response to low blood pressure and hypovolaemia, and stimulates retention of water by
LA. Meynaar
et al./Netherlands
the kidneys. In the absence of ADH the kidneys produce maximally diluted urine. In the syndrome of inappropriate ADH secretion, ADH or an ADH-like substance stimulates retention of water in the absence of appropriate physiological stimuli. This results in hyponatraemia, probably by dilution but certainly by augmented natriuresis induced by natriuretic peptide in response to fluid retention [3]. Altered concentrations of aldosterone, prostaglandin and angiotensin II may also be of importance. Retention of water and augmented natriuresis results in the characteristic features of SIADH: hyponatraemia, low serum osmolality, high urine osmolality and urine sodium excretion which is inappropriately high with regard to serum sodium concentration. The diagnosis of SIADH can only be established in the absence of other potential causes of hyponatraemia such as the use of diuretics, hyper- or hypovolaemia, hypothyroidism or renal dysfunction. SIADH may be associated with ADH-producing tumours (especially small-cell lung carcinoma), pulmonary disease, central nervous system disorders and the use of several specific drugs. Although not definitely confirmed by measurements of ADH levels and rechallenge, both our patients seem to have developed SIADH due to venlafaxine and paroxetine, respectively. SIADH due to paroxetine has been reported previously [4,5], as well as SIADH due to several other SSRIs (e.g., fluoxetine, fluvoxamine and sertraline) [6] and other antidepressants (e.g., several tricyclics) [7]. To our knowledge, this is the first report of SIADH due to venlafaxine. The mechanism of this adverse drug reaction is not yet known.
Journal
of Medicine
50 (1997)
243-245
245
The risk of SIADH seems to be highest in the first weeks of treatment with antidepressants [7]. To date, it is not known how great the risk is of developing SIADH while using SSRIs. If SIADH develops and continued treatment with an antidepressant is necessary, a drug with a different pharmacological profile should be chosen, accompanied by regular monitoring of laboratory values. We recommend that serum sodium levels be measured in patients on SSRIs with symptoms such as weakness, lethargy, headache, anorexia, weight gain. confusion, constipation or convulsions.
References [l]
[2]
[3]
[4] [5] [6]
[7]
Finley PR. Selective serotonin reuptake inhibitors: pharmacologic profiles and potential therapeutic distinctions. Ann Pharmacother 1994;28:1359-1369. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995;49:280-294. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967:42:790806. Goddard C, Paton C. Hyponatraemia associated with paroxetine. Br Med J 1992;305:1332. Chua TP, Vong SK. Hyponatraemia associated with paroxetine [Letter]. Br Med J 1993;306:143. Ten Holt WL, Klaassen CHL, Schrijver G. Emstige hyponatriEmie, mogelijk door inadequate antidiuretisch-hormoonsecretie, bij gebruik van het antidepressivum fluoxetine. Ned Tijdschr Geneeskd 1994;138:1181-1183. Spigset 0, Hedenhalm K. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug Safety 1995:12:209--225.
JOURNAL, OF MEDICINE Netherlands Journal of Medicine 50 (1997) 243-245
Brief report
Syndrome of inappropriate ADH secretion attributed to the serotonin re-uptake inhibitors, venlafaxine and paroxetine I.A. Meynaar a * , A.J. Peeters a, A.H Mulder a, J.P. Ottervanger b a Department b Netherlands
of Internal Medicine, Centre for Monitoring
Reinier de Graaf Gasthuis, R. de Graajiveg 3, 2625 AD De&, Netherla& of Adverse Reactions to Drags, PO Box 5406, 2280 HK Rijswijk, Netherland,v
Received 27 March 1996; revised 4 December 1996; accepted 11 December 1996
Abstract We report on 2 patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) which developed a few weeks after they had started treatment with venlafaxine and paroxetine, respectively. Due to the temporal relationship and the exclusion of other potential causes, a causal relationship between the use of the antidepressants and SIADH seems likely. Diagnostic criteria for SIADH and the role of drugs, especially serotonin re-uptake inhibitors, are discussed. 0 1997 Elsevier Science B.V. Keywords:
Venlafaxine;
Paroxetine;
SIADH;
Hyponatraemia;
Antidepressants
1. Introduction
2. Patient A
Selective serotonin re-uptake inhibitors (SSRIs) are a relatively new class of antidepressants, with little affinity for adrenergic, cholinergic or histaminergic receptors [ 11. In the late 1980s and the early 1990s a number of SSRIs were introduced, including fluoxetine, fluvoxamine, paroxetine and sertraline. Venlafaxine is a recently introduced SSRI that inhibits not only serotonin re-uptake but also noradrenaline re-uptake [2]. We report the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in 2 patients who had recently started the use of venlafaxine and paroxetine, respectively.
* Corresponding
author.
0300-2977/97/$17.00 8 PZI SO300-2977(97)00005-3
1997 Elsevier
Science
B.V.
All rights
reserved.
Patient A is a 65-year-old male who was referred to our hospital because of severe dizziness. Seven years previously a urethral stenosis had been dilated, whereafter he was advised to drink at least 2 litres of water daily to prevent cystitis. Two years later, he started sotalol240 mg per day for paroxysmal atria1 fibrillation. Ten weeks before admission fluoxetine 20 mg per day was prescribed by his general practitioner to treat a presumed depression. Four weeks later he was admitted to another hospital with atria1 fibrillation and oesophagitis. At that time, serum sodium concentration was 130 mmol/l. Fluoxetine therapy was discontinued because the indication was not clear, whereas omeprazole 20 mg/day and cisapride 80 mg/day were initiated. Cystitis was treated
244
LA. Meynaar
et al. /Netherlands
with noffloxacin 800 mg/day for 5 days. One week later he was discharged. One week before admission to our hospital the patient was given venlafaxine 75 mg/day by his general practitioner. Diuretics had never been prescribed to this patient. On admission to our hospital, apart from dizziness the patient reported no other complaints. At that time he was using sotalol, cisapride, omeprazol and venlafaxine. Physical examination revealed no abnormalities, in particular no oedema. His weight was 57.7 kg, his blood pressure llO/SO mmHg. Serum sodium concentration, however, was 114 mmol/l (normal 135-144), serum osmolality 248 mosm/l (normal 280-3001, urine volume 3140 ml/24 h with urine sodium excretion 239 mmo1/24 h and urine osmolality 640 mosm/l. Serum concentration of chloride, potassium and bicarbonate was 79 mmol/l (normal 55-105), 3.6 mmol/l (normal 3.6-4.8) and 26 mmol/l (normal 21-291, respectively. The concentration of antidiuretic hormone was not measured. Chest radiograph, chest computer tomography, urea, creatinine and haemoglobin concentrations, liver, thyroid and adrenal function tests were normal. Serum albumen was decreased (32 g/l, normal 3550). Measured creatinine clearance was 98 ml/mm. Electrocardiography showed atrial fibrillation. The patient was treated with additional sotalol and digoxin resulting in sinus rhythm. On the presumptive diagnosis of SIADH due to venlafaxine, this drug was discontinued and fluid intake was restricted to 1500 ml/24 h. Sodium concentration and osmolality of serum and urine returned to normal over a period of 2 weeks and remained normal after fluid restriction was stopped. At that time examination by a psychiatrist did not reveal a depression. The patient refused rechallenge with venlafaxine, but in view of the spontaneous recovery, and the absence of other causes, a causal relationship seems likely.
3. Patient B Patient B is a 89-year-old female who was admitted to our hospital because of constipation and lethargy. Her medical history revealed the placement of an on-demand pacemaker, inguinal herniotomy and fracture of the left humerus. One week before admission she was seen by her general practitioner
Journal
of Medicine
50 (1997)
243-245
because of loss of appetite. Laboratory values at that time were normal with serum sodium concentration 132 mmol/l. The general practitioner made a diagnosis of vital depression and added paroxetine 10 mg daily to the long-standing medication consisting of temazepam 10 mg/day, azapropazone 900 mg/day, cetirizine 10 mg/day because of itching and flavoxate 200 mg/day because of urine incontinence. All these medications were taken until the day of admission. On admission, physical examination revealed moderate abdominal distension, normal peristalsis, no oedema, normal blood pressure and lethargy. Serum sodium concentration was 116 mmol/l, serum osmolality 250 mosm/l, urine volume 1675 ml/24 h, urine sodium excretion 97 mmo1/24 h, and urine osmolality 410 mosm/l. Measured creatinine clearance was 77 rnI/min. Serum concentration of chloride, potassium and bicarbonate was 86, 4.3 and 25 mmol/l, respectively. Serum ADH concentration was not measured. Chest radiograph, liver, adrenal and thyroid function tests were normal. A plain abdominal X-ray showed distension of the colon but no signs of ileus. Barium enema and ultrasound study of the upper abdomen were normal. On the presumptive diagnosis of SIADH due to paroxetine with lethargy and constipation caused by severe hyponatraemia, the patient was treated with intravenous saline infusion, whereas paroxetine was discontinued. Serum sodium concentration returned to normal, normal defaecation returned and lethargy disappeared in a few days. The clinical course was complicated by fever and urinary tract infection 6 days after admission. Escherichia coli was cultured from blood and urine. The patient was treated successfully with sulphamethoxazole 800 mg plus trimethoprim 160 mg twice daily. Fifteen days after admission the patient was discharged in good clinical condition. At that time examination by a psychiatrist did not reveal a depression. No rechallenge with paroxetine was performed because it was thought to be unethical.
4. Discussion Antidiuretic hormone (ADH) is produced by the pituitary gland in response to low blood pressure and hypovolaemia, and stimulates retention of water by
LA. Meynaar
et al./Netherlands
the kidneys. In the absence of ADH the kidneys produce maximally diluted urine. In the syndrome of inappropriate ADH secretion, ADH or an ADH-like substance stimulates retention of water in the absence of appropriate physiological stimuli. This results in hyponatraemia, probably by dilution but certainly by augmented natriuresis induced by natriuretic peptide in response to fluid retention [3]. Altered concentrations of aldosterone, prostaglandin and angiotensin II may also be of importance. Retention of water and augmented natriuresis results in the characteristic features of SIADH: hyponatraemia, low serum osmolality, high urine osmolality and urine sodium excretion which is inappropriately high with regard to serum sodium concentration. The diagnosis of SIADH can only be established in the absence of other potential causes of hyponatraemia such as the use of diuretics, hyper- or hypovolaemia, hypothyroidism or renal dysfunction. SIADH may be associated with ADH-producing tumours (especially small-cell lung carcinoma), pulmonary disease, central nervous system disorders and the use of several specific drugs. Although not definitely confirmed by measurements of ADH levels and rechallenge, both our patients seem to have developed SIADH due to venlafaxine and paroxetine, respectively. SIADH due to paroxetine has been reported previously [4,5], as well as SIADH due to several other SSRIs (e.g., fluoxetine, fluvoxamine and sertraline) [6] and other antidepressants (e.g., several tricyclics) [7]. To our knowledge, this is the first report of SIADH due to venlafaxine. The mechanism of this adverse drug reaction is not yet known.
Journal
of Medicine
50 (1997)
243-245
245
The risk of SIADH seems to be highest in the first weeks of treatment with antidepressants [7]. To date, it is not known how great the risk is of developing SIADH while using SSRIs. If SIADH develops and continued treatment with an antidepressant is necessary, a drug with a different pharmacological profile should be chosen, accompanied by regular monitoring of laboratory values. We recommend that serum sodium levels be measured in patients on SSRIs with symptoms such as weakness, lethargy, headache, anorexia, weight gain. confusion, constipation or convulsions.
References [l]
[2]
[3]
[4] [5] [6]
[7]
Finley PR. Selective serotonin reuptake inhibitors: pharmacologic profiles and potential therapeutic distinctions. Ann Pharmacother 1994;28:1359-1369. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995;49:280-294. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967:42:790806. Goddard C, Paton C. Hyponatraemia associated with paroxetine. Br Med J 1992;305:1332. Chua TP, Vong SK. Hyponatraemia associated with paroxetine [Letter]. Br Med J 1993;306:143. Ten Holt WL, Klaassen CHL, Schrijver G. Emstige hyponatriEmie, mogelijk door inadequate antidiuretisch-hormoonsecretie, bij gebruik van het antidepressivum fluoxetine. Ned Tijdschr Geneeskd 1994;138:1181-1183. Spigset 0, Hedenhalm K. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug Safety 1995:12:209--225.