Abstract
To the Editor
Although listed on the product information as among the common (occurring in 1–10%) side effects of quetiapine (AstraZeneca Australia, 2011), only a handful of cases of peripheral oedema associated with its use have been reported. Most of these reports have occurred while patients have been on treatment with a combination of medications (Chen et al., 2009; Koleva et al., 2009).We report another case of quetiapine-induced pedal oedema. This case highlights the importance of specific enquiry in eliciting side effects that may not be volunteered by patients and the importance of carefully considering drug interactions when prescribing psychotropic medication in polypharmacy situations.
Ms KM is a 45-year-old woman with a long history of difficult-to-treat depression, well-controlled hypothyroidism, chronic back pain, asthma and dyslipidaemia. She presented to hospital with ongoing symptoms of depression. At the time of admission she was on treatment with venlafaxine 300 mg/day, plain lithium 650 mg/day, sodium valproate 2.5 g/day, diazepam 7.5 mg/day, thyroxine 50 µg/day, morphine 600 mg/day and rosuvastatin 10 mg/day. She acknowledged heavy nicotine and cannabis use. Lithium was ceased on day 1. Valproate was tapered in preparation for electroconvulsive therapy (ECT). She was started on quetiapine fumarate 200 mg/day on day 4. She reported pedal oedema 12 h after initiation of therapy with quetiapine. This progressively worsened to bilateral pitting pedal oedema extending up to the knees (grade 3) over the next 4 days. Valproate and venlafaxine were ceased on day 7 with no effect. Quetiapine was ceased on day 8 with relief within 24 h and complete resolution in 48 h. There was no history or symptoms suggestive of hepatic, cardiac or renal dysfunction. Physical examination was unremarkable.
Electrocardiogram, chest radiograph, full blood examination, liver and thyroid function tests, electrolytes, urea and creatinine were normal. She subsequently tolerated treatment with olanzapine without event.
The close temporal correlation between quetiapine use and oedema implicates quetiapine as the most likely causal agent. Pedal oedema is a known side effect of lithium, valproate and morphine. The lithium had been ceased 4 days prior to symptom onset. Valproate had been reduced significantly by the time of onset and the oedema continued to worsen beyond the cessation of valproate. This patient had used the former combination of medications uneventfully for several years.
The combination of valproate with quetiapine may have predisposed this patient to developing oedema. It has been shown that co-medication with valproate can increase the plasma concentration of quetiapine by 77%, thus increasing the risk of developing adverse effects (Aichhorn et al., 2006). This highlights the need to consider drug interactions when prescribing quetiapine.
Several possible mechanisms have been postulated in the causation of oedema by quetiapine. Firstly, quetiapine antagonizes alpha-1 (α1) adrenergic receptors, resulting in peripheral vasodilation, increased capillary hydrostatic pressure and, consequently, transudation of fluid into the interstitial space. Secondly, by blocking 5-hydroxytryptamine 2 (5-HT2) receptors, there could be an increase in intracellular cyclic adenosine monophosphate levels, ultimately causing smooth muscle relaxation. This has been proposed as the potential mechanism for oedema caused by another atypical antipsychotic, olanzapine (Ng et al., 2003). Thirdly, blockade of muscarinic-1 (M1), histaminergic-1 (H1) and serotonin (5-HT2) receptors by quetiapine may inhibit the increase of inositol triphosphate that is required to mobilize intracellular calcium stores for smooth muscle contraction, resulting in smooth muscle relaxation, vasodilation and oedema (Chen et al., 2009). Finally, an allergic reaction mediated by immunoglobulin E (IgE) has been proposed as the cause of quetiapine-induced oedema, however, in other cases of quetiapine-induced oedema, immunoglobulin levels have been normal (Chen et al., 2009; Koleva et al., 2009).
Quetiapine has become increasingly popular in Australia for a variety of on- and off-label conditions (Hollingworth et al., 2010). The discrepancy between expected reports of pedal oedema and documented events suggests that milder cases of pedal oedema are probably going unrecognized as complications of quetiapine use. This highlights the need for specific enquiry and a comprehensive physical examination as part of regular reviews for patients with mental illnesses.