84 - Database studies

Database studies

416 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Antidepressant-­induced hyponatraemia Most antidepressants have been associated with hyponatraemia. Onset is usually within 30 days of starting treatment.1–3 The effect appears not to be dose related,1,4 although some case reports suggest otherwise. The most likely mechanism of this adverse effect is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Risk of hospitalisation with hyponatraemia is elevated from 1 in 1,600 in the general population to 1 in 300 for those on any antidepressant.5 Hyponatraemia is a potentially serious adverse effect of antidepressants that demands careful monitoring,6 particularly in those patients at greatest risk. Hyponatraemia of all severities is associated with increased mortality.7 Which antidepressants? No antidepressant has been definitively shown not to be linked with hyponatraemia and almost all have a reported association.8 It has been suggested that serotonergic drugs are relatively more likely than noradrenergic drugs to cause hyponatraemia,9,10 although this is disputed.11 A 2024 meta-­analysis suggests that the risk may be highest with SNRIs, followed by SSRIs,12 and lowest with mirtazapine and trazodone. There are notably few reports for MAOIs,13,14 but all marketed antidepressants have some association with hyponatraemia, even more recently introduced drugs such as vortioxetine,15 desvenlafaxine16 and vilazodone.17 Older women who are frail and/or prescribed other medication known to reduce plasma sodium are at greatest risk.15,18 CYP2D6 poor metabolisers may be at increased risk of antidepressant-­induced hyponatraemia,19 although evidence is somewhat inconsistent.20 Database studies A 2018 French pharmacovigilance database study found an association of hyponatraemia with agomelatine, a drug not previously reported to cause hyponatraemia.21 Another database study using US Food and Drug Administration (FDA) data found the strongest association between hyponatraemia and antidepressants to be for mirtazapine, in contrast to most other reports,22 and a further French database study found the greatest risk to be with duloxetine.23 A 2022 Japanese study24 found that SSRIs and SNRIs caused, on average, a 1mmol/L fall in plasma sodium, an effect not seen with other antidepressants examined. The effect on sodium was directly linked to a drug’s binding affinity for the SERT transporter. The mean effect of antidepressants on sodium in this study suggests that clinical hyponatraemia might be an extreme of the normal distribution of effects rather than an idiosyncratic effect only seen in certain people. Extrapolating from incident report databases to estimate relative or absolute risk of hyponatraemia is fraught with difficulty. Problems include disproportionate reporting for antidepressants for which the adverse effect is considered to be rare, the inability to adjust for confounding by indication (drugs perceived to be of low risk are more likely to be prescribed to patients at already at high risk of hyponatraemia) and the impact of concomitant prescriptions. Table 3.14 provides a summary of the risk of hyponatraemia with antidepressants.

Depression and anxiety disorders CHAPTER 3 Monitoring1,27,28 All patients taking antidepressants should be informed of and observed for signs of hyponatraemia (dizziness, nausea, lethargy, confusion, cramps, seizures). The risk is highest in the first 4 weeks of starting antidepressants, and diminishes over time until by 3–6 months the risk is the same as for patients who do not take antidepressants.18 Consequently, in patients treated with antidepressants for several months or years, other causes should be assumed in the event of hyponatraemia. Serum sodium should be determined (at baseline and 2 and 4 weeks, and then 3-­monthly29) for those at high risk of drug-­induced hyponatraemia. This frequency of electrolyte monitoring may not identify all cases as serum sodium may drop precipitously.30 Box 3.4 lists high-risk factors for drug-­induced hyponatraemia. Table 3.14  Summary of risk of hyponatraemia with antidepressants5,12,24–26 Drug/drug group Risk of ↓Na Level of supporting evidence SNRIs High Strong SSRIs High Strong Tricyclics Moderate Strong MAOIs Low Weak NaSSas (mirtazapine, mianserin) Low Strong Trazodone Low Strong Bupropion Low Moderate Agomelatine Low Moderate MAOIs, monoamine oxidase inhibitors; NaSSas, noradrenergic and specific serotonergic antidepressants. Box 3.4  High-risk factors for drug-­induced hyponatraemia ■ ■Older age ■ ■Female sex ■ ■Major surgery ■ ■History of hyponatraemia or a low baseline sodium concentration ■ ■Co-­therapy with other drugs known to be associated with hyponatraemia (e.g. diuretics, NSAIDs, antipsychotics, carbamazepine, cancer chemotherapy, calcium antagonists, angiotensin-­converting enzyme inhibitors and laxatives) ■ ■Reduced renal function (glomerular filtration rate <50mL/minute) ■ ■Medical comorbidity (e.g. hypothyroidism, diabetes, chronic obstructive pulmonary disease (COPD), hypertension, head injury, congestive cardiac failure, cardiovascular accident, various cancers) ■ ■Low body weight Age is perhaps the most important risk factor, so for older people (especially women) monitoring is essential.27