In a long-stay residential ward for patients with intellectual disability it was noticed that a large proportion of patients had hyponatraemia when their renal profile work-up was done as part of scheduled reviews. All the patients who had hyponatraemia were on carbamazepine and three of them were on a combination of a serotonin reuptake inhibitor (SSRI) and carbamazepine. One patient was severely symptomatic and was admitted with hyponatraemia related seizures to the Midland Regional Hospital, Portlaoise.

There were 28 patients – 46.4% (13) females and 53.6% (15) males – in our study group.

Carbamazepine is a commonly prescribed medication in psychiatry and produces side effects in 33-50% of patient.¹

Carbamazepine was prescribed for either problem behaviour and/or epilepsy.

The audit

Serum sodium level in the 12 months preceding the time of audit and the most recent serum sodium levels were checked for the 28 residents; the mean serum sodium levels were 137.7mmol/L (preceding audit) and 135.1mmol/L (most recent level). Hyponatraemia was taken as a serum sodium level of <135mmol/L and all blood tests were carried out in the biochemistry laboratory at the hospital.

Results

36% (10) of the residents were between 30-50 years old and 64% (18) were > 50 years old

39% (11) of residents had hyponatraemia at the start of the audit (in the preceding 12 months) and 61% (17) had normal values. Out of 11 patients who had hyponatraemia, 63.6% (7) were females and 36.4% (4) were males

The age range of the patients who had hyponatraemia was 42-73 years (mean age = 61.5 years), while the age range of patients with normal values was 38-69 years (mean age 56 years)

35.3% (6) of those with normal values were females and 64.7% (11) were males

Of the 11 patients who had hyponatraemia at the start of the audit (preceding 12 months), 72.7% (8) were on carbamazepine alone and 27.3% (3) were on both carbamazepine and SSRI. The mean serum sodium level was 130.7mmol/L, mean carbamazepine dose was 412mg/day and mean trough level was 10.7ug/ml (8-12ug/ml)

None of the patients on carbamazepine had normal values; 17.8% (5) patients on SSRIs had normal sodium levels with a mean serum sodium level of 138.3mmol/L.

We started reducing the dose of patients’ carbamazepine and also advised general practitioners who prescribed carbamazepine for patients with epilepsy to consider a change of medication as hyponatraemia is a known side effect of carbamazepine therapy.

12 months after audit

Eight patients remained on carbamazepine at reduced dose, five patients were still on SSRIs and three patients remained on both carbamazepine and SSRIs.

10.7% (3) of patients in total had hyponatraemia, 7.1% (2) on carbamazepine and 3.6% (1) of patients on both carbamazepine as well as SSRI; 17.9% (5) of patients on SSRI had normal values.

Findings

Hyponatraemia was found to be more common in women

Hyponatraemia was associated with higher mean age compared to patients with normal values

There was a good response overall to reduction in dose of carbamazepine resulting in normonatraemia.

Discussion

A retrospective chart review of all residents at a residential centre for people with intellectual disability (ID) was undertaken. All people receiving carbamazepine were identified, and the most recent serum sodium and carbamazepine levels were ascertained. All the people who were receiving carbamazepine, and had recorded serum sodium and carbamazepine levels from the previous two years were included as subjects (n = 53).

All people who were not receiving carbamazepine and had recorded serum sodium levels from the previous two years were included as controls (n =64).

Hyponatraemia was defined as a serum sodium level of < 135mmol/L. This is the value that has been used in comparable previous studies.^2,3

All blood tests were carried out at the same laboratory, which also defines 135mmol/L as the lower limit of the normal range for serum sodium. 

The carbamazepine blood levels were trough levels taken 12 hour after the administration of carbamazepine.

A checklist of symptoms of hyponatraemia was developed, based on clinical descriptions of the condition.⁴

A single investigator assessed all the subjects and controls through clinical observation and interviews with nursing staff. The checklist consisted of 25 items (see Table 1). 

Serum sodium levels were compared between the subject and control groups; the relationships between serum sodium level, sex, age, daily carbamazepine dose and serum carbamazepine level were also examined. There was no significant difference between the subject and control groups in terms of age or sex (see Table 2) and males outnumbered females in both groups. The mean age of the participants in the study was 42.18 years (range = 12-91 years).

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Literature review on hyponatraemia associated with carbamazepine therapy

The prevalence of hyponatraemia in patients with intellectual disability (ID) who were receiving carbamazepine and had had previous blood testing was 41.5%. This finding is considerably higher than the figures reported in other studies.

Lahr⁵ studied 60 patients with ID receiving carbamazepine and 61 age-matched controls. He found a 21.7% prevalence of hyponatraemia in the subject group and no hyponatraemia whatsoever in the control group.

In contrast, Kastner et al³ studied 40 patients with ID who were receiving carbamazepine and found a 5% prevalence of hyponatraemia in their sample.

In a general hospital population about 1% of patients develop hyponatraemia,⁶ whereas in psychiatric patients the prevalence has been reported to range from 3.3% to 12.2%.⁷

Estimates of the incidence of hyponatraemia with psychotropic medications could be confounded by other factors. Dubovsky et al⁸ reported that psychosis alone can cause hyponatraemia independent of drug therapy.

Risk factors for the development of hyponatraemia in psychiatric patients are said to include old age, history of prior hyponatraemia, polydipsia and schizophrenia,⁹ smoking, an early onset of the psychiatric disorder (< 20 years), longer duration of psychiatric disease (> 10 years) and prolonged admission.⁷

Psychotropic-induced hyponatraemia may be expected to manifest itself within a few days of starting a new drug; occasionally it may occur much later.⁹

Treatment of hyponatraemia involves identification of the underlying cause, discontinuing the offending drug and correcting volume abnormalities. Several studies have attempted to identify risk factors for the occurrence of hyponatraemia during carbamazepine treatment. Uhde et al² studied the effects of carbamazepine in 12 patients and concluded that hyponatraemia in this population correlated positively with low baseline levels of serum sodium, high daily doses of carbamazepine and high serum carbamazepine levels.

Lahr⁵ also found significant correlations between serum carbamazepine level and serum sodium level in adults, and between serum sodium level and age.

Hyponatraemia can produce a wide variety of symptoms, may mimic depression or psychosis, and in the case of people with ID, may induce or aggravate challenging behaviours. It is known that severe, progressive hyponatraemia can produce significant clinical impairment, culminating in coma and death, but the clinical correlates of gradual-onset, mild hyponatraemia have not been well described.

Yassa et al¹⁰ studied the effects of carbamazepine in 20 patients with affective disorder; five patients (25%) developed hyponatraemia and three had clinical symptoms. These authors advised caution in prescribing carbamazepine to patients with low or borderline sodium levels.¹⁰

However, in a much larger study, Kalff et al¹¹ studied 674 patients with epilepsy who were receiving various antiepileptic drugs, including carbamazepine. None of the 28 patients (4.2%) with biochemical hyponatraemia had clinical symptoms and no special treatment was required.

In most of the studies, the checklist of clinical features of hyponatraemia did not correlate with serum sodium level and the implementation of the checklist depended on the assessment of non-specific clinical features because many of the signs and symptoms are present in other illnesses.

The absence of a detectable cluster of clinically significant signs and symptoms raises a question regarding the clinical importance of mild hyponatraemia.

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Recommendations 

Sodium levels should be checked in all psychiatric patients on admission and a baseline renal profile is advised prior to starting carbamazepine therapy.

All those at risk of hyponatraemia (eg. older people taking antidepressants) should have frequent sodium level determinations. 

Hyponatraemia should also be suspected whenever patients receiving psychotropic drugs show marked changes in their symptoms, significant increases in body weight, seizures or other symptoms of hyponatraemia (most commonly confusion).

Monthly renal profile is advised in those with low normal sodium levels at the start of therapy or after a dose change.

If sodium level falls below 125mmol/L at any point, medical referral is advised and a change of medication should be considered.

There is a strong need for prospective studies in this area with monitoring of baseline signs and symptoms, and long-term follow-up of clinical status.

Conclusion

Hyponatraemia is found in people with intellectual disability, but has greater prevalence in those being treated with carbamazepine. 

The risk factors for developing hyponatraemia during carbamazepine treatment include a high daily carbamazepine dose and a high serum carbamazepine level. 

There is no consistent relationship between serum sodium level, and age or sex. There is no consistent relationship between clinical status and mild hyponatraemia.

The majority of patients with hyponatraemia will respond to cessation of psychotropic drugs.

If long-term fluid restriction proves to be intolerable, and the offending drug cannot be withdrawn, demeclocycline (which is a drug that inhibits anti-diuretic hormone (ADH) at the kidneys) may be used to treat syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). 

References

1. Gandelman MS. Prog Neuropsychopharmacol Biol Psychiatry 1994: Review of Carbamazepine induced hypontraemia
2. Uhde TW, Post RM. Effects of carbamazepine on serum electrolytes: clinical and theoretical implications. J Clin Psychopharmacol 1983; (3):103-106
3. Kastner T, Friedman DL, Pond WS. Carbamazepine-induced hyponatremia in patients with mental retardation. Am J Mental Retardation 1992; 96:536-40
4. Lishman WA. Organic Psychiatry: The Psychological Consequences of Cerebral Disorder, 3rd edn. Blackwell Science, Oxford, 1999
5. Lahr MB. Hyponatremia during carbamazepine therapy. Clin Pharmacol Therapeu 1985; 37:693-696
6. Rutsky EA. Water electrolyte, mineral and acid base metabolism. In Merk Manual of Diagnosis and Therapy. Eds RB Berkow and AJ Fletcher 1992; 991-995
7. Ohsawa H, Kishimoto T, Hirai M et al. An epidemiological study on hyponatremia in psychiatric patients in mental hospitals in Nara Prefecture. Japanese J Psychiatr Neurol 1992 Dec; 46(4):883-889
8. Dubovsky SL, Grabon S, Berl T, Schrier RW. Syndrome of inappropriate secretion of antidiuretic hormone with exacerbated psychosis. Ann Intern Med 1973 Oct; 79(4):551-554
9. Thomas A, Verbalis JG. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion associated with drug therapy in psychiatric patients. CNS Drugs  Nov 1995, 4,(5): 357-369
10. Yassa R, Iskandar H, Nastase C, Camille Y. Carbamazepine and hyponatremia in patients with affective disorder. Am J Psychiatry 1988 Mar; 145(3):339-42
11. Kalff R, Houtkooper MA, Meyer WA et al. Carbamazepine and serum sodium levels. Epilepsia 1984; 25:390-397