Edema associated with quetiapine

Abstract

Background

Edema associated with quetiapine has been described in only one case report to date and represents a potentially serious adverse reaction.

Methods

We present a case series of three patients who developed bilateral leg edema following initiation of quetiapine.

Results

One of these patients had a recurrence of edema with subsequent rechallenge. Another patient developed quetiapine-induced edema following a prior episode of olanzapine-induced edema. All the cases present a compelling temporal relationship between the drug challenge and the adverse event.

Conclusions

Prompt recognition and intervention with discontinuation of the offending agent is important for this potentially serious, seemingly idiosyncratic, vascular complication.

Introduction

Quetiapine is a second-generation antipsychotic and is commonly prescribed for a broad range of psychiatric conditions with frequent off-label use (1, 2). Quetiapine’s mechanism of action is not fully elucidated though involves antagonism at serotonin type 1 (5-hydroxytryptamine [5-HT_1A]) and type 2 (5-HT_2A, 5-HT_2C) receptors with relatively weak antagonism at dopamine (D₁, D₂) receptors (3). In addition, quetiapine exhibits some α₁-adrenergic antagonism that may explain its cardiovascular side effects, like orthostatic hypotension (4). Bilateral leg edema has been infrequently described with several atypical antipsychotics, including case reports with olanzapine (5, 6), risperidone (7), and ziprasidone (8). Currently, there is only one published case report of peripheral edema related to quetiapine (9) and edema is not currently listed as a potential complication in the its prescribing information. Herein, we report three cases and four incidents of leg edema associated with quetiapine. Two cases involve a recurrence of edema with rechallenge, one following another agent. All patients had resolution of symptoms with medication discontinuation with or without additional symptomatic treatment.

Case report 1

A 59-year-old Caucasian female was admitted to psychiatry for manic psychosis with no active medical problems apart from chronic back pain. On admission, the patient was on lithium 1200 mg/day and clonazepam 1 mg/day. Quetiapine 150 mg/day was initiated. Eight days later, she developed 1+ bilateral leg edema accompanied by a rash and swollen joints. The rash subsequently resolved but the pitting edema worsened, despite treatment with furosemide, reaching midcalf and 2+ bilaterally. Quetiapine was eventually titrated to 500 mg/day over the course of 3 weeks for psychosis. Cardiac and pulmonary exam and blood pressure measurements were within normal limits. Laboratory work-up was unremarkable (thyroid stimulating hormone (TSH), albumin, electrolytes, blood urea nitrogen (BUN), creatinine, lithium, erythrocyte sedimentation rate, N-terminal fragment brain-type natriuretic peptide, complete blood count with differential, and urinalysis). One month after initiation of quetiapine, she was seen in the outpatient clinic with continued bilateral 2+ pitting leg edema. Patient expressed concern the quetiapine was causing the edema since she previously had edema following quetiapine initiation that resolved following discontinuation. Her psychiatrist primarily suspected lithium but obliged her request to decrease quetiapine from 500 mg to 300 mg/day. One week later, patient called to state edema had improved. Quetiapine was then discontinued with resolution and no recurrence of edema. No other medication changes were implemented.

Case report 2

A 44-year-old African-American female was admitted for transient cocaine-induced chest pain with myocardial infarction ruled-out by nuclear stress testing. Two days later, she was admitted to psychiatry for depression and suicidal ideation. Her past history was significant for asthma, hypertension, torn left meniscus, and carpal tunnel syndrome. Her medications were clonidine 0.2 mg/day, diltiazem 120 mg/day, aspirin 325 mg/day, ranitidine 150 mg/day, hydrochlorothiazide 25 mg/day, tramadol 100 mg/day, and as needed albuterol. On hospital day 2, she was started on trazodone 100 mg and quetiapine 50 mg nightly for insomnia and psychotic symptoms. On hospital day 4, she complained of bothersome leg edema that, on exam, was described as bilateral 2+ pitting edema up to the level of her mid-calves. Her blood pressure was normal, cardiac and pulmonary examinations were benign. A complete metabolic profile, including albumin and TSH, to determine etiology of her edema was within normal limits. To exclude allergic etiology, immunology testing consisting of C3, C4 and IgE were normal. Creatine kinase, troponins, electrocardiogram (ECG), and cardiac echocardiogram were further unremarkable. On hospital day 5, quetiapine was discontinued while trazodone continued. Her edema gradually resolved over the next two days.

Case report 3

A 38-year-old Caucasian female with history of fibromyalgia, pernicious anemia and prolonged QTc was admitted to psychiatry for psychosis and agitation. Concurrent medications included pregabalin 150 mg/day, baclofen 20 mg/day, vitamin B₁₂ injections, ibuprofen 800 mg as needed, and albuterol inhaler as needed. Risperidone 2 mg/day was added shortly after admission. On hospital day 5, risperidone was changed to quetiapine 200 mg/day. The next morning patient developed 1+ bilateral pitting edema in her legs and was complaining of dyspnea upon excretion. The edema quickly progressed to 2+ and reached her calves. Physical exam was otherwise unremarkable and vital signs were within normal limits. Medical work up was unrevealing and included ECG, trans-thoracic echocardiogram, urinalysis, liver transaminases, TSH, glucose, electrolytes, protein, creatinine, BUN, homocysteine, and vitamin B₁₂. The patient recalled she had similar edema when she previously took olanzapine, which improved following discontinuation and symptomatic treatment with furosemide. Quetiapine was thought potentially contributing and was quickly cross-tapered over two days to perphenazine 16 mg/day. Furosemide 20 mg/day was prescribed symptomatically for edema, which resolved over the course of approximately one week.

Discussion

The cases reported here involve females ranging in age from 30 to 59-years-old, all of whom developed significant edema shortly after the initiation of quetiapine (Table 1). In all cases patients reported the leg edema to be quite bothersome and distressing. This is the first description of quetiapine-associated edema in middle-aged female patients. The only previous report by Rozzini et al. describes quetiapine-related peripheral edema in a 72-year-old man with Lewy Body dementia (9).

Table 1.

Demographic characteristics, medications, doses, and timeline of three presented cases with quetiapine-induced edema. Two cases previously experienced edema with a similar agent.

Case #	Age	Gender	Agent / Dose	Time to Onset	Rate of Resolution	Edema on prior challenge
1	59	Female	Quetiapine 150 mg	< 10 days	1 week	Quetiapine
2	44	Female	Quetiapine 50 mg	4 days	2 days	None
3	38	Female	Quetiapine 200 mg	1 day	1 week	Olanzapine

The temporal relationship between initiation of the medication and the appearance of edema supports the impression of an adverse reaction to quetiapine. Extensive cardiovascular and metabolic work-up further failed to reveal alternative explanations. One potential limitation of our case series is the prevalent use of medications with known associations with edema (lithium in case 1, a calcium channel blocker in case 2, nonsteroidal anti-inflammatory drugs in cases 2 and 3) (10). However, no changes in these medications were implemented around the time of edema formation and resolution; and the onset and offsets of edema were temporally correlated to changes in quetiapine. In all three cases, edema followed incident use of quetiapine and resolved shortly after discontinuation. Furosemide was briefly given for symptomatic relief for only one of the cases with no recurrence of edema thereafter.

Quetiapine doses ranged from 50 to 500 mg. With only one case report, a dose-dependent relationship between quetiapine and leg edema cannot clearly be established. In the case described by Rozzini et al. (2005) a dose increase from 100 mg to 150 mg quetiapine daily was followed the next day by bilateral leg edema. Case 1 in our report describes symptomatic improvement when the dose was decreased but not discontinued, perhaps suggesting a dose-response relationship. Time to appearance of leg edema after initiation of the offending drug varied from one day up to ten days in the presented cases. Time to resolution after drug discontinuation ranged from two days to one week.

Quetiapine is an antagonist for several neurotransmitter receptors, including serotonin 5-HT_1A and 5-HT₂, dopamine D₁ and D₂, histamine H₁, and α₁- and α₂- adrenergic receptors (3). While potential mechanisms for antipsychotic-induced edema remain speculative, prior study has suggested a relationship between dopaminergic antagonism and idiopathic edema (11–13). Through a variety of receptor subtypes, dopamine may effect natriuresis, epithelial fluid resorption, vascular smooth muscle relaxation, and the renin-angiotensin system (14, 15). Given that quetiapine is considered a comparatively weak dopaminergic antagonist (16), a different mechanism may seem more plausible. Notably, quetiapine exhibits 5-HT₂ antagonism. Some authors speculate 5-HT₂ receptor blockade may account for olanzapine-induced leg edema through increase in cyclic adenosine monophosphate levels that can ultimately lead to vascular smooth muscle relaxation (5, 17). Alternatively, α₁-adrenergic blocking activity of atypical antipsychotics has been thought to explain cardiovascular side effects like orthostatic hypertension, dizziness and reflex tachycardia (4). Alpha-adrenergic-mediated peripheral vasodilation has also been proposed as a potential mechanism for olanzapine-induced edema (5, 17). Since quetiapine and olanzapine demonstrate similar affinity to the α₁-adrenergic receptor (4) and share similar propensities for orthostatic hypertension, an analogous mechanism for quetiapine-induced edema could be proposed.

An allergic reaction could pose an alternative explanation for drug-induced edema. This was concluded to be the most plausible explanation for ziprasidone-induced edema in a case report where edema was associated with elevation of IgE, C3 and C4. Indeed, the abrupt onset of edema in our cases may hint at a possible allergic mechanism. In case 2, however, IgE, C3 and C4 levels were all normal.

Two cases (1 and 3) demonstrated an on-off-on-off phenomenon with re-challenge, one following prior edema with quetiapine, another following olanzapine. The presence of an on-off-on-off relationship provides a more compelling cause-and-effect argument for quetiapine-induced edema than previously reported. Interestingly, case 1 presented with quetiapine-associated edema after similar symptoms with olanzapine. The recurrence with rechallenge also suggests that prior reactions may pose a risk factor, even with another, albeit similar, antipsychotic.

This case series is the first to report multiple cases of quetiapine-associated leg edema and edema with rechallenge. The mechanism of quetiapine-induced edema remains uncertain though likely parallels that of other second-generation antipsychotics. Further clinical observation and research is needed to clarify the characteristics, risk factors, dose-dependence, and potential mechanisms of quetiapine-associated edema. We hope our report will alert physicians to this potential vascular complication to promote prompt recognition and intervention.