Mirtazapine-associated peripheral oedema

Mirtazapine is a specific serotonergic and noradrenergic antidepressant with a unique psychopharmacological mechanism. While sedation and weight gain are commonly reported, peripheral oedema has rarely been documented despite its alpha-2 receptor antagonism action. We describe two patients with mirtazapine-associated peripheral oedema.

A 74-year-old woman was admitted due to psychotic depression with catatonic features. Medications on admission included lorazepam, clonazepam, venlafaxine and thyroxine. Co-morbid diagnoses included breast cancer in remission and hypothyroidism. Venlafaxine was ceased due to patient refusal and inefficacy. Benzodiazepines were ceased in preparation for electroconvulsive therapy. Mirtazapine was commenced on day 7 and titrated to 60 mg by day 19. Aripiprazole was commenced on day 15 and increased to 10 mg by day 20. Bilateral pitting oedema of the lower limbs was noted on day 26. Clinical examination was otherwise unremarkable. Pathology investigations, sonography, chest x-ray and trans-thoracic echocardiogram were normal. Aripiprazole was ceased secondary to extra-pyramidal side effects. Diuresis with frusemide 80 mg twice-daily did not improve the peripheral oedema. Cross titration of mirtazapine to sertraline was undertaken, resulting in complete resolution of oedema within 1 week. Diuresis was ceased with no recurrence of oedema.

A 70-year-old woman presented with deterioration in mood and melancholic features. Co-morbid conditions included controlled hypertension and fibromyalgia. Mirtazapine was commenced and titrated to 30 mg by day 5. Peripheral oedema of the lower limbs and mouth ulcers were noted days after commencing 30 mg dosage of mirtazapine. Clinical examination was otherwise unremarkable. Pathology investigations, sonography, chest x-ray and trans-thoracic echocardiogram were normal. Long-term medications taken by the patient included duloxetine, diazepam, aspirin, valsartan, hydrochlorothiazide, tramadol and oxycodone. Subsequently, agomelatine was introduced while mirtazapine was decreased. A complete resolution of oedema and mouth ulcerations occurred following mirtazapine cessation.

The diagnosis of mirtazapine-associated peripheral oedema was initially felt unlikely as dermatological reactions to mirtazapine have been rarely reported. However, after exclusion of more common aetiologies, a diagnosis of mirtazapine-associated peripheral oedema was made. A full resolution of oedema following cessation of mirtazapine and a Naranjo score of 6 in both our cases suggest a ‘probable’ adverse drug reaction (ADR). Only two other cases have described a ‘probable’ association of peripheral oedema with mirtazapine (Kutscher et al., 2001; Saddichha, 2014).

The mechanism of mirtazapine-associated peripheral oedema is unknown. Although medical conditions and other medications are known to produce peripheral oedema, they are unlikely in our cases. Immune-mediated processes have been attributed to peripheral oedema (Mitkov et al., 2013). Given that mouth ulcerations were observed in one patient, an autoimmune mechanism may be considered. Interestingly, all reported cases of mirtazapine-associated peripheral oedema have occurred at a dosage of 30 mg/day or greater (Kutscher et al., 2001; Saddichha, 2014). Rapid titration of mirtazapine was observed in our first case and may also be a contributory factor in the development of peripheral oedema.

To our knowledge, this is the first report to describe mirtazapine-associated peripheral oedema in the geriatric psychiatric population. The occurrence in two patients within 1 year in a single Australian institution may suggest an under-recognition in clinical practice of mirtazapine-associated peripheral oedema. ADR can be associated with morbidity and hinder compliance. We present these two cases to increase awareness of this potential ADR and to facilitate earlier recognition and optimal management.