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Cases that Test Your Skills


The patient who ‘spilled salt’

Mrs. V has psychotic depression and hyponatremia. Is beer drinking or diuretic use causing her low serum sodium? Or could it be something else?

Vol.07, No.06 / June 2008

HISTORY: ‘They’re out to get me’

Mrs. V, age 64, tells her primary care physician she has felt “bad” for 2 weeks. She complains of depressed mood, middle insomnia, diminished appetite, poor concentration, and poor energy. She denies suicidal thoughts but reports feeling alone, overwhelmed, and unable to manage her daily life.

Mrs. V is very concerned about losing her job because she cannot function at work. She believes her coworkers may be plotting to get her fired. The primary care physician refers Mrs. V to us to evaluate her mood.

According to her daughter, Mrs. V has had multiple psychiatric hospitalizations; the most recent occurred 2 years ago when she was admitted for paranoia and disorganized behavior. The daughter also mentions that her mother has a remote history of daily alcohol use, drinking until she was intoxicated. Mrs. V says she occasionally drinks beer and she scores 2 out of 4 on the CAGE questionnaire, which may indicate alcohol dependence.

During mental status examination, Mrs. V is alert and oriented to person, place, and date. She is pleasant and cooperative but shows apparent thought blocking and some tangentiality. She has substantial difficulty answering questions and articulating symptoms. Speech is slow in rate and rhythm. Mrs. V’s mood is severely depressed and her affect constricted.

She denies suicidal or homicidal ideations or visual or auditory hallucinations. Cognitive testing reveals mild deficits in recall memory and poor concentration. Her insight is limited and her judgment fair.

Her medical history includes hypertension, hyperlipidemia, coronary artery disease, cardiac catheterization, and hyponatremia. Her medication regimen consists of aripiprazole, 15 mg/d; diltiazem, 180 mg/d; atenolol, 25 mg/d; aspirin, 325 mg/d; atorvastatin, 10 mg/d; sertraline, 50 mg/d; and ibuprofen, 600 mg as needed for hip pain. She also reports taking diuretics in the past.

Vital signs include blood pressure, 125/95 mm Hg; respirations, 16/min; temperature, 98.2° F; and pulse rate, 72/min. Serum investigations reveal sodium, 119 mEq/L (normal range: 135 to 145 mEq/L) and random blood sugar, 160 mg/dL (normal range: 60 to 114 mg/dL).

The authors’ observations

The combination of major depression with psychosis and hyponatremia makes Mrs. V’s case challenging. Hyponatremia in psychiatric inpatients can prompt medical consultation, thus possibly halting or delaying psychiatric treatment.

Hyponatremia has been associated with the use of:

  • diuretics
  • selective serotonin reuptake inhibitors (SSRIs)
  • serotonin-norepinephrine reuptake inhibitors (SNRIs)
  • tricyclic antidepressants
  • calcium antagonists.

Elevated creatinine levels, chronic obstructive pulmonary disease, hypertension, systolic blood pressure, and diabetes also can lead to hyponatremia.

Among psychiatric inpatients, the risk of hyponatremia is doubled in women.1 It is unclear, however, if female gender is an independent risk factor for hyponatremia. Sharabi et al2 reported that patients of both sexes age >65 have a 9-fold greater risk of developing hyponatremia than younger counterparts.

In addition, hyponatremia risk during any antidepressant treatment is highest:

  • in the summer
  • during the first weeks of treatment
  • with concomitant drug use, especially with diuretics.3

The authors’ observations

To identify the cause of Mrs. V’s hyponatremia, we determine her volume status and measure serum osmolality.4 Next, we mea-sure urinary sodium and osmolality and assess her extracellular fluid status. We also evaluate her renal and adrenal function, which were within normal limits. Although Mrs. V reports fatigue and weakness, there is no evidence of dehydration.

Based on Mrs. V’s initial lab results (Table 1), we classify her hyponatremia as euvolemic, with high urine osmolarity (≥100 mOsm/L). That helps narrow our differential diagnosis to glucocorticoid deficiency, hypothyroidism, and SIADH (Table 2).5 We exclude psychogenic polydipsia, “tea and toast” syndrome, or beer potomania because they usually present as euvolemic hyponatremia with low urinary osmolality.

SSRI use in elderly persons has been associated with hyponatremia, which in some cases may be consistent with SIADH. Unfortunately, few psychiatrists are aware of this potentially fatal side effect.

SIADH occurs in association with reduced serum osmolality. It is characterized by:

  • hypotonic hyponatremia (serum sodium < 130 mEq/L)
  • inappropriately elevated urine osmolarity (>200 mOsm/L) relative to plasma osmolarity
  • elevated urine sodium (typically >20 mEq/L).4

We diagnose Mrs. V with SIADH because she has these lab findings in the absence of diuretic therapy; in the presence of euvolemia without edema; and in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function.

The key to the pathophysiology, signs, symptoms, and treatment of SIADH is understanding that the hyponatremia is a result of excess water and not a sodium deficiency. Hyponatremia’s signs and symptoms primarily are related to CNS dysfunction and correlate with how rapidly and severely the condition develops.

We monitor Mrs. V for anorexia, nausea, and malaise because they would be the earliest findings, followed by headache, irritability, confusion, muscle cramps, weakness, obtundation, seizures, and coma. These occur as osmotic fluid shifts and results in cerebral edema and increased intracranial pressure. When sodium concentration drops below 105 mEq/L, life-threatening complications are likely.

Table 1

Mrs. V’s laboratory results

 

 

Mrs. V’s results

 

Normal range

Before Tx

After Tx

Serum sodium (mEq/L)

135 to 145

119

127

Serum potassium (mEq/L)

3.5 to 5.0

3.6

3.8

Creatinine (mg/dL)

0.5 to 1.7

0.74

0.84

Glucose (mg/dL)

60 to 114

160

150

Osmolarity

Serum (measured; mOsm/L)

275 to 300

258

242

Urine (mOsm/L)

<150

257

180

Urine sodium (mEq/L)

20 to 40

48

42

Table 2

Mrs. V’s laboratory results

Hypovolemic hyponatremia

Euvolemic hyponatremia

Hypervolemic hyponatremia

Vomiting
Diarrhea
Laxative abuse
Renal disease
Nasogastric suction
Salt-wasting nephropathy
Addison’s disease

Normal urinary sodium
  Glucocorticoid deficiency
  Hypothyroidism
  Certain drugs
  SIADH

Congestive heart failure
Nephrotic syndrome
Cirrhosis

 

Low urinary osmolality
  Psychogenic polydipsia
  ‘Tea and toast’ syndrome
  Beer potomania

 

SIADH: syndrome of inappropriate antidiuretic hormone

Source: Reference 5

SSRIs and SIADH

Bouman et al6 estimated that the incidence of SSRI-induced SIADH in elderly patients is 12%. Liu et al7 described 706 cases of hyponatremia associated with SSRI use in unpublished reports. Fluoxetine was most commonly the cause (75.3% cases), followed by paroxetine (12.4%), sertraline (11.7%), and fluvoxamine (1.5%). Resuming the same drug resulted in hyponatremia in 16 of 24 of these cases (66.7%).

Kirby et al,8 however, found no clear advantages in different SSRIs’ propensity to cause hyponatremia. Seventy-one percent of patients treated with the SNRI venlafaxine developed hyponatremia, compared with 32% taking paroxetine and 29% receiving sertraline. It is unclear whether a specific SSRI or venlafaxine has a stronger association with hyponatremia than any other antidepressant.

Hyponatremia’s nonspecific symptoms and wide range of time to detection (1 to 253 days) suggest clinicians usually detect the condition by chance rather than specifically assessing for it.9

TREATMENT: Medication change?

Coordinating Mrs. V’s depression and hyponatremia treatment is critical. We propose discontinuing sertraline and treating Mrs. V’s symptoms with electroconvulsive therapy (ECT). She refuses ECT, stating “I don’t feel that bad. My father was treated with ECT and I am scared of it.”

We decide to switch to mirtazapine, a tetracyclic antidepressant. In a case report mirtazapine was successfully used in a similar patient.10 We continue to monitor Mrs. V’s serum sodium concentrations and emphasize the importance of complying with fluid restrictions, instructing her to limit her fluid intake to 250 to 500 mL (1 to 2 glasses) per day.

The authors’ observations

SSRI-induced hyponatremia can be transient or persistent and recurrent. The usual approach is to discontinue the SSRI and try a different antidepressant. Because hyponatremia has been associated with all SSRIs and SNRIs, it would be prudent to choose an alternate antidepressant agent outside these classes. If patients must continue taking an antidepressant that causes hyponatremia, avoid concurrent use of drugs that cause hyponatremia, restrict fluid intake, and consider adding a medication that prevents hyponatremia, such as demeclocycline or fludrocortisone.

SSRI-induced hyponatremia may resolve:

  • with SSRI discontinuation alone11
  • with fluid restriction and without discontinuation of the SSRI11
  • with drug discontinuation, fluid restriction, and sodium chloride and potassium supplementation.12

FOLLOW-UP: Analysis error?

Despite modifications to Mrs. V’s diet, her fasting serum glucose level remains >100. She is diagnosed with diabetes mellitus type 2 and treated with metformin. We continue mirtazapine, which has successfully controlled Mrs. V’s depressive symptoms. Her serum sodium levels start normalizing.

The authors’ observations

In patients with serum hyperglycemia— such as Mrs. V—correct laboratory analysis yields low serum sodium levels, but these levels do not reflect a true hypo-osmotic state. Accumulation of extracellular glucose induces a shift of free water from the intracellular space to the extracellular space. For each 100 mg/dL increase above normal serum glucose concentration, serum sodium concentration is diluted by a factor of 1.6 mEq/L. Systemic osmolarity is normal or increased, but not decreased as would be the case in true (hypo-osmotic) hyponatremia.

Related resources

  • Siegel AJ. Hyponatremia in psychiatric patients: update on evaluation and management. Harv Rev Psychiatry 2008;16(1):13-24.
  • Atalay A, Turhan N, Aki OE. A challenging case of syndrome of inappropriate secretion of antidiuretic hormone in an elderly patient secondary to quetiapine. South Med J 2007;100(8):832-3.

Drug brand name

  • Aripiprazole • Abilify
  • Atenolol • Tenormin
  • Atorvastatin • Lipitor
  • Demeclocycline • Declomycin, Declostatin, others
  • Diltiazem • Cardizem, Dilacor, others
  • Fludrocortisone • Florinef
  • Fluvoxamine • Luvox
  • Ibuprofen • Advil, Motrin, others
  • Metformin • Glucophage, Diabex, others
  • Mirtazapine • Remeron
  • Paroxetine • Paxil
  • Sertraline • Zoloft
  • Venlafaxine • Effexor

Disclosures

Dr. Romanowicz reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.

Dr. Wilson receives research support from the National Institute of Mental Health, the Veterans Administration, the State of Nebraska, Health Futures Foundation, Inc., AstraZeneca, Dainippon Sumitomo Pharma, Eli Lilly and Company, and Pfizer Inc. and serves as a consultant to the Substance Abuse and Mental Health Services Administration and the State of Nebraska.

Reference

1. Siegler EL, Tamres D, Berlin JA, et al. Risk factors for the development of hyponatremia in psychiatric inpatients. Arch Intern Med 1995;155(9):953-7.

2. Sharabi Y, Illan R, Kamari Y, et al. Diuretic induced hyponatraemia in elderly hypertensive women. J Hum Hypertens 2002;16(9):631-5.

3. Rosner MH. Severe hyponatremia associated with the combined use of thiazide diuretics and selective serotonin reuptake inhibitors. Am J Med Sci 2004;327(2):109-11.

4. Buff DD, Markowitz S. Hyponatremia in the psychiatric patient: a review of diagnostic and management strategies. Psychiatr Ann 2003;33(5):318-25.

5. Levitan A. Hyponatremia: how to recognize the cause promptly—and avoid treatment pitfalls. Consultant 2003;43(7):861-70.

6. Bouman WP, Pinner G, Johnson H. Incidence of selective serotonin reuptake inhibitor (SSRI) induced hyponatraemia due to the syndrome of inappropriate antidiuretic hormone (SIADH) secretion in the elderly. Int J Geriatr Psychiatry 1998;13(1):12-5

7. Liu BA, Mittmann N, Knowles SR, et al. Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports. CMAJ 1996;155(5):519-27

8. Kirby D, Ames D. Hyponatraemia and selective serotonin re-uptake inhibitors in elderly patients. Int J Geriatr Psychiatry 2001;16(5):484-93

9. Kirchner V, Silver LE, Kelly CA. Selective serotonin reuptake inhibitors and hyponatraemia: review and proposed mechanisms in the elderly. J Psychopharmacol 1998;12(4):396-400.

10. Jagsch C, Marksteiner J, Seiringer E, Windhager E. Successful mirtazapine treatment of an 81-year-old patient with syndrome of inappropriate antidiuretic hormone secretion. Pharmacopsychiatry 2007;40(3):129-31.

11. Bigaillon C, El Jahiri Y, Garcia C, et al. Inappropriate ADH secretion-induced hyponatremia and associated with paroxetine use. Rev Med Interne 2007;28(9):642-4.

12. Blacksten JV, Birt JA. Syndrome of inappropriate secretion of antidiuretic hormone secondary to fluoxetine. Ann Pharmacother 1993;27(6):723-4.

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