The Consultant Pharmacist is published by the
American Society of Consultant Pharmacists.

Clinical Review
Hyponatremia Associated With Selective Serotonin Reuptake Inhibitors David R. P. Guay
Objective: To present a clinical review of hyponatremia caused by selective serotonin reuptake inhibitors (SSRIs).
Data Sources: A MEDLINE search was conducted to identify pertinent studies, case reports, letters, and reviews in the English language. All articles published from 1985 to 1999 were reviewed (medical subject headings [MeSH] terms: water- electrolyte imbalance, hyponatremia, inappropriate antidiuretic hormone [ADH] syndrome, selective serotonin reuptake inhibitors). Additional references were obtained from the bibliographies of these articles.
Study Selection: Human studies evaluating any aspect of SSRI association with hyponatremia.
Data Synthesis: Numerous clinical series and individual case reports have documented an association between SSRI use and hyponatremia. All SSRIs have been implicated. The syndrome of inappropriate ADH secretion has been the mechanism underlying many of these cases, based on serum and urine osmolality and sodium concentration data.
Conclusion: Hyponatremia associated with SSRI therapy is a rare but potentially serious adverse event. Elderly individuals may be at increased risk for hyponatremia associated with SSRI use. Further research is necessary to determine the true incidence of this adverse event, the relative risk in different age groups, and the risk associated with the individual SSRI agents.
Key Words: Selective serotonin reuptake inhibitors, Inappropriate antidiuretic hormone secretion, Hyponatremia, Adverse drug reactions, Fluoxetine, Fluvoxamine, Citalopram, Sertraline, Paroxetine.
Abbreviations: SSRI = selective serotonin reuptake inhibitor; ADH = antidiuretic hormone; SIADH = syndrome of inappropriate antidiuretic hormone; OR = odds ratio.
    Consult Pharm 2000;15:160-77.
The selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline are among the most widely prescribed drugs in the elderly. This has occurred principally for two reasons: the high rate of depression in the elderly population and the favorable safety and tolerability profile compared with other antidepressants. However, with such widespread use, low-frequency adverse events become more prevalent. This article reviews hyponatremia associated with SSRI use, one of the relatively infrequent adverse drug reactions of the class.

Normal Regulation of Water Balance

The regulation of water homeostasis involves osmoreceptors in the hypothalamus, which respond to changes in extracellular fluid osmolality, as well as baroreceptors in the carotid and stretch receptors in the left atrium, which respond to changes in arterial blood pressure and effective circulating volume, respectively. These receptors are activated under conditions that signal water deprivation, such as increased osmolality, decreased arterial blood pressure, or decreased circulating blood volume. They stimulate the release of antidiuretic hormone (ADH) and also enhance thirst. On the other hand, hypo-osmolality normally inhibits both ADH release and thirst. These mechanisms assure that serum osmolality is kept relatively constant.

ADH is synthesized in neurons within the supraoptic and paraventricular nuclei of the hypothalamus. Axons of these neurons project to the underlying posterior pituitary, where they release ADH into the peripheral circulation. In the kidney, vasopressin-2 (V2) receptors, mainly located on the cells of the collecting ducts, mediate the antidiuretic effect of ADH. These cells are relatively impermeable to water in the absence of ADH; the binding of ADH to the receptor initiates a sequence of steps that eventually increase the permeability of the luminal side to water so that the reabsorption of water is facilitated along a concentration gradient.

Although the reserve capacity of the neurohypophyseal-pituitary-renal axis is diminished markedly in old age, healthy elders retain the ability to maintain fluid-electrolyte homeostasis during usual stresses. However, when this decrement in reserve is superimposed on extremes of physiologic stress or during the course of numerous illnesses, clinical abnormalities in fluid-electrolyte balance can occur.

A number of examples of age-related changes in fluid-electrolyte homeostasis with aging exist. Reductions in blood volume/pressure are less likely to result in ADH release with increasing age. With water deprivation or hypertonic saline infusion, subjective measures of thirst and objective measures of drinking behavior are reduced in the elderly (this may be due to reduced renin-angiotensin levels and altered baroreceptor function with aging). The ability for urine concentration declines with aging, even when corrected for decreased glomerular filtration rate with age. Of importance, the modest age-related impairment in free water excretion may predispose elders to hyponatremia.1,2

Hyponatremia

Clinical signs and symptoms of hyponatremia usually do not occur until serum sodium falls below 130 mmol/L, and many individuals do not manifest signs and symptoms until the serum sodium falls below 125 mmol/L. In some cases, individuals will remain asymptomatic at even lower serum sodium concentrations if the decline in serum sodium has been gradual.

Early clinical signs and symptoms of hyponatremia include confusion, generalized weakness, decreased appetite, and general malaise, while later signs and symptoms, as serum sodium further declines, include headache, somnolence, coma, seizures, transient focal neurological signs, and abnormal electroencephalogram results. Table 1 illustrates the two major categories of geriatric hyponatremia: those with altered renal water excretion and those with normal renal water excretion.1

Table 1. Categories of Hyponatremia
Altered Renal Water ExcretionNormal Renal Water Excretion
“Effective” circulating volume depletionPrimary polydipsia
    (i.e., decreased tissue perfusion)Reset osmostat
Diuretics
  • “Effective” volume depletion
Renal impairment
  • Psychosis
Euvolemic states of ADH excess
  • Quadriplegia
  • SIADH
  • Malnutrition
  • Addison’s disease
  • Hypothyroidism
Decreased salt intake

Management involves elimination of the cause(s) if possible and, in mild cases, fluid restriction to less than or equal to 1,000 mL/day. In severe hyponatremia, the use of combined modalities such as fluid restriction, loop diuretic therapy (with electrolyte replacement), and hypertonic saline may be necessary. Hyponatremia should be corrected slowly (i.e., one-half of the way to “normal” over the first 24 hours) to avoid complications such as cerebral edema or central pontine demyelination. In cases in which the cause(s) cannot be eliminated, long-term therapy with fluid restriction or combined oral sodium chloride plus a loop diuretic, urea, demeclocycline, or lithium may be necessary.1,2

Brief Overview of the Syndrome of Inappropriate Antidiuretic Hormone

The syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by a reduced ability to excrete water, resulting in extracellular dilution leading to hyponatremia. SIADH may be due to an augmented renal response to ADH or excessive ADH secretion in the absence of normal osmotic or physiologic stimuli (e.g., hypotension, hypovolemia, serum hyperosmolality).

True SIADH occurs without edema, hypotension, azotemia, and dehydration. In addition to hyponatremia, reduction in serum chloride, blood urea nitrogen, creatinine, and uric acid concentrations may occur. On occasion, hypokalemia may occur as well. Serum osmolality falls, urine sodium concentration rises (over 20 mEq/L), and urine osmolality (over 100-150 mOsm/kg) exceeds serum osmolality. Diagnosis can also be made by measuring plasma or urine ADH concentrations and by performing a water-loading test.

There are a large number of etiologies of SIADH (Table 2). In addition, pseudohyponatremia caused by hyperglycemia, hypertriglyceridemia, and hyperproteinemia, and other causes of hyponatremia, such as adrenocortical insufficiency, congestive heart failure, hypothyroidism, cirrhosis, and psychogenic polydipsia, among others, need to be ruled out when considering the diagnosis of SIADH.1,2

Table 2. Causes of SIADH
Drugs
  • ADH and analogs
  • Vinca alkaloids
  • Cisplatin
  • Cyclophosphamide
  • Antidepressants
  • Antipsychotics
  • Carbamazepine
  • Monoamine oxidase inhibitors
  • Clofibrate
  • Chlorpropamide
  • Thiazide diuretics
  • Metformin
  • Opioids (morphine)

Central Nervous System Disorders

  • Delirium tremens
  • Head trauma
  • Subdural and subarachnoidal hemorrhage
  • Stroke
  • Infections
  • Hydrocephalus
Pulmonary Disease
  • Asthma
  • Pneumothorax
  • Chronic obstructive pulmonary disease
  • Pneumonia, empyema, tuberculosis

ADH-Producing Tumors
Carcinomas

  • Bronchogenic
  • Pancreatic
  • Prostatic
  • Duodenal
Thymoma
Lymphoma
Mesothelioma

Psychiatric Disorders

  • Psychosis

Endocrine Disorders

  • Exogenous (pituitary insufficiency therapy)

Psychotropic Drugs Associated With Hyponatremia

A large number of non-SSRI psychotropic drugs have been associated with hyponatremia (Table 3).3-11 In many of these reports, clear conclusions regarding the mechanism involved cannot be made due to lack of rechallenge or water-loading tests. In some cases, rechallenge was performed without the development of hyponatremia. However, a handful of cases within both therapeutic categories have been well documented and support the suspicion that non-SSRI antidepressants and antipsychotics can cause hyponatremia.

Table 3. Non-SSRI Psychotropic Drugs Associated With Hyponatremia
Antidepressants

Imipramine
Amitriptyline
Clomipramine
Desipramine
Lofepramine
Amoxapine
Doxepin
Dothiepin
Trazodone
Viloxazine
Phenelzine
Tranylcypromine
Venlafaxine

Antipsychotics

Chlorpromazine
Fluphenazine
Trifluoperazine
Thioridazine
Thiothixene
Haloperidol
Clozapine

Source: References 3–11.

Clinical Series of SSRI-Associated Hyponatremia

Until September 1995, the Adverse Drug Reactions Advisory Committee (Australia) received 33 reports of hyponatremia connected with the use of SSRIs, and seven of these included details of serum electrolyte and osmolality changes consistent with SIADH (Table 4). All but one patient was over 60 years old and most (76%) were women. The most common presenting symptoms were confusion, delirium or fluctuating consciousness (n = 6 each); somnolence (n = 5); convulsions, fatigue (n = 3 each); hallucinations, hypotension, urinary incontinence, and vomiting (n = 2 each). Other neurological signs were described as well, including agitation, anxiety, syncope, hypertonia, hyperreflexia, ataxia, nystagmus, and tremors. Of the patients, 26 made a full recovery, one died after a stroke, and six had not recovered at the time of publication.12

In a report published in 1996, the Canadian Adverse Drug Reaction Monitoring Program provided details on 15 reports of hyponatremia associated with SSRIs (12 with fluoxetine, two with fluvoxamine, one with paroxetine). The mean age of the affected individuals was 75 years (range 64–90 years). Of the individuals, 60% developed hyponatremia within 14 days of commencement of the SSRI. Only 20% of reports described symptoms, while 80% of reports recorded the serum sodium concentration (mean 120 mmol/l, range 106–125 mmol/l). Hyponatremia resulted in six hospitalizations and one emergency room visit. In 14 reports, the SSRI was discontinued and serum sodium concentration returned to normal within a few days. Ten individuals recovered fully, one became permanently disabled, one had not recovered at the time of publication, and two had an unknown outcome. Confounders were present in five cases: hypothyroidism in two patients, concurrent antipsychotic or diuretic use in one patient each, and recent history of antipsychotic use in one patient.13

Christe and Vogt described eight cases of SSRI-associated hyponatremia occurring in a 304-bed university geriatric hospital in Geneva, Switzerland, during the period 1996–97. Implicated drugs included citalopram (n = 5) and paroxetine (n = 3). Hyponatremia necessitated hospitalization in four cases. All affected individuals were women, with a median age of 86 years (range 78–89 years). Hyponatremia onset occurred 3–90 days after the commencement of SSRI therapy. All individuals were receiving therapeutic doses of SSRI (citalopram 10–30 mg/day, paroxetine 20 mg/day). Severe hyponatremia (serum sodium below 125 mmol/l) occurred in six cases, with a median plasma osmolality of 249 mmol/kg (range 229–261). Of the subjects, 75% complained of nausea, dizziness, diarrhea, and/or confusion. However, three subjects were receiving concurrent diuretic therapy, and two subjects had pulmonary comorbidities (pulmonary fibrosis, pneumonia). Hyponatremia resolved within 8–17 days after cessation of SSRI therapy and institution of fluid restriction (n = 5) or institution of fluid restriction alone for moderate hyponatremia (n = 2).14

Table 4. ADRAC (Australia) Reports of Hyponatremia Associated With SSRI (September 1995)
 FluoxetineParoxetineSertraline
Reports of hyponatremia
(sole drug suspected)		18(14)8(6)7(4)
Female:male14:47:14:2
Age (years)
median
(range)		80
(69-91)		71.5
(40-86)		77
(68-86)
Dosage range (mg)10-402025-150
Onset (days)
median
(range)		30
(5-90)		6
(1-18)		6
(1-23)
Serum sodium range (mmol/l)117-123111-122112-122

Spigset and Hedenmalm performed a retrospective register study of the World Health Organization database for spontaneous reporting of adverse drug reactions (1963–93). Of the 668 reports of antidepressant-associated hyponatremia, 191 (28.6%) were secondary to use of SSRIs.15

Siegler et al. performed a case-controlled study of psychiatric inpatients in a tertiary care facility to look at risk factors for the development of hyponatremia. Of the cases of hyponatremia (serum sodium below 130 mmol/l), 64 were matched to control subjects (three control subjects per case). Significant associations were found with diuretic use (adjusted odds ratio [OR] = 8.2), fluoxetine use (OR = 21.4), tricyclic antidepressant use (OR = 4.9), calcium channel blocker use (OR = 4.0), female sex (OR = 4.0), increased serum creatinine (OR = 2.1), abnormal serum potassium (OR = 19.1), diabetes mellitus (OR = 4.4), hypertension (OR = 5.7), and chronic obstructive pulmonary disease (OR = 90.6).16

Bouman, Pinner and Johnson performed a retrospective case record study of an acute elderly psychiatric inpatient population in calendar year 1996 in a United Kingdom medical center. Of 32 individuals receiving SSRI therapy, four (12.5%) had symptomatic hyponatremia (confirmed SIADH), while four (12.5%) had asymptomatic hyponatremia. Of the eight individuals with hyponatremia, five were men (mean age 78.5 years [range 71-87 years]; mean nadir serum sodium concentration 125 mmol/l [range 111-133 mmol/l]). One patient continued SSRI therapy and began fluid restriction with close electrolyte monitoring, while seven patients had SSRI therapy discontinued. No factors could be identified that distinguished patients who developed severe hyponatremia (n = 4) from those who did not (n = 28).17

Strachan and Shepherd conducted a retrospective case record review of psychogeriatric hospital admissions over a one-year period. Of the 18 patients on fluoxetine (20–40 mg/day), five (28%) developed hyponatremia, and of the 37 patients on paroxetine (10–40 mg/day), eight (22%) developed hyponatremia. The mean nadir serum sodium concentration was 130 mmol/l (range 119–134 mmol/l). Of the patients, 13 were women, with a mean age of 76 years (range 70-83 years). Three, two, and one patient(s) were on concurrent diuretic, tricyclic antidepressant, and carbamazepine therapy, respectively. Therapy was discontinued in two symptomatic patients, two patients had asymptomatic hyponatremia and were left on SSRI therapy, and serum sodium concentration reverted to normal in nine patients who were left on SSRI therapy.18

Case Reports of SSRI-Associated Hyponatremia

Of the cases, 66 have been published in the English-language literature (Table 5),6,9,12,19-62 and 57 (86%) involved patients over 65 years of age (range 24–92 years). The mean nadir serum sodium concentration was 118 mmol/l (range 98–129 mmol/l). The mean time to onset of hyponatremia was 31 days (range 3–548 days), and time to recovery after drug discontinuation was 10 days (range 1–28 days). Concomitant illness or use of medications known to cause SIADH could be implicated in some of the cases. Many reports ruled out common causes of SIADH, such as pulmonary or cerebral pathology and renal, thyroid, or adrenal disease. These case reports were assessed for strength of association with the implicated SSRI using the algorithm of Naranjo et al.63 Possible, probable, and definite associations with SSRI use were found in 17%, 77%, and 6% of cases, respectively. In summary, the positive temporal association, the lack of alternative causes, and the reversal of hyponatremia after drug discontinuation offer good evidence of a causal relationship in the majority of these reports.

Mechanism of SSRI-Associated Hyponatremia

The mechanism of SSRI-associated hyponatremia is unclear. Serotonin (5-HT)-mediated effects on 5-HT2 and 5-HT1C receptors have been shown to induce ADH release.64,65 In addition, norepinephrine induces ADH release via stimulation of a1 adrenergic receptors.66,67 As SSRIs certainly inhibit 5-HT reuptake and also inhibit norepinephrine reuptake (to varying degrees), this may contribute to the hyponatremic potential of these agents (via induction of SIADH). Hyponatremia associated with these agents may also be a manifestation of drug-drug interactions. As these agents are known to inhibit a number of cytochrome P450 isoenzymes,68 they may interact with other drugs known to cause hyponatremia and potentiate their effects.

Management of SSRI-Associated Hyponatremia

A suggested flow chart for the treatment of psychotropic drug–associated hyponatremia is presented in Figure 1.3 Severe symptomatic hyponatremia is a medical emergency and requires prompt treatment with intravenous saline. Acute-onset hyponatremia requires intravenous 3% sodium chloride with loop diuretic coadministration. In acute hyponatremia, the recommended correction rate of serum sodium is 1–2 mmol/L per hour, while in chronic hyponatremia, the recommended rate is 0.5 mmol/l per hour. In mild hyponatremia, water restriction alone is often sufficient (less than or equal to 1,000 mL/day).

After the initial hyponatremia has resolved, consideration needs to be given to performing a water-loading test and/or drug rechallenge. The water-loading test should be postponed until the suspected drug has been eliminated from the body. Typically, the water-loading test is performed by giving a water load of 20 mL/kg body weight to drink over 15–20 minutes. Thereafter, urine is collected for five hours, and volume and osmolality are measured. Normally, more than 80% of the load is excreted over five hours, and urine osmolality falls below 100 mmol/kg. In patients with SIADH, frequently less than 40% of the load has been excreted by five hours, and urine is not diluted to hypotonic levels.

Consideration of drug rechallenge may be reasonable if the suspected drug is the only one to which the patient has favorably responded. However, frequent serum and urine electrolyte and osmolality monitoring is necessary during rechallenge, and the performance of a second water-loading test while the patient is on the suspected drug is recommended. If results of the second water-loading test are normal, treatment can be continued; if not, the agent should be changed.

If drug therapy is absolutely necessary with an offending agent, a number of long-term management strategies may prove useful.3 These include fluid restriction (to 250–1,000 mL/day), oral sodium chloride 6–82 mg/day plus loop diuretic, oral urea 30–60 g/day, oral demeclocycline 900–1,200 mg/day initially titrated to a maintenance dose of 300–900 mg/day, and lithium.

Conclusion

Hyponatremia associated with SSRI use is a rare but potentially serious adverse event. Considering the structural heterogeneity of the SSRIs, this adverse event is not likely related to chemical structure. It would be an overreaction to monitor serum electrolytes routinely in all patients undergoing SSRI therapy. However, since patients with hyponatremia may have nonspecific symptoms that mimic depression, any change in disease course should alert the clinician to the possibility of hyponatremia. Unexplained symptoms such as confusion or lethargy, particularly in the first few weeks of SSRI therapy in an elderly individual, especially one receiving other drugs associated with hyponatremia (e.g., diuretics), would mandate measurement of serum sodium concentration. Most reports suggest that SSRI-associated hyponatremia recurs upon rechallenge, even if a different SSRI is prescribed.

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David R. P. Guay, PharmD, FCP, FCCP, FASCP, CGP, is Professor, Institute for the Study of Geriatric Pharmacotherapy, College of Pharmacy, University of Minnesota, Minneapolis, and Clinical Specialist, PartneringCare Senior Services, Health Partners, Minneapolis, Minnesota.

Address for Correspondence: David R. P. Guay, PharmD, College of Pharmacy, Weaver-Densford Hall 7-115C, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455. E-mail:guayx001@tc.umn.edu

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