May 2009  << Back  

  Can't open the PDF? Click here for help.

 

 RESEARCH ARTICLE

3 case reports of edema associated with quetiapine

Hristina K. Koleva, MD

Department of Psychiatry, The University of Iowa Hospital and Clinics, Iowa City, IA, USA

Mark A. Erickson, BS

Medical Student, Roy A. and Lucille J. Carver College of Medicine, Iowa City, IA, USA

Erik R. Vanderlip, MD

Department of Psychiatry, The University of Iowa Hospital and Clinics, Iowa City, IA, USA

Janeta Tansey, MD, PhD

Department of Psychiatry, The University of Iowa Hospital and Clinics, Iowa City, IA, USA

Joseph Mac, PharmD

Department of Pharmaceutical Care, The University of Iowa Hospital and Clinics, Iowa City, IA, USA

Jess G. Fiedorowicz, MD, MS

Department of Psychiatry, The University of Iowa Hospital and Clinics, Iowa City, IA, USA

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 3 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 3 cases present a compelling temporal relationship between the drug challenge and the adverse event.

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

KEYWORDS: antipsychotics, cardiovascular, edema, quetiapine

ANNALS OF CLINICAL PSYCHIATRY 2009;21:77–80

  INTRODUCTION

Quetiapine is a second-generation antipsychotic that is commonly prescribed for a broad range of psychiatric conditions with frequent off-label use.1,2 Quetiapine’s mechanism of action, although not fully elucidated, involves antagonism at serotonin type 1 (5-hydroxytryptamine [5-HT1A]) and type 2 (5-HT2A, 5-HT2C) receptors with relatively weak antagonism at dopamine (D1, D2) receptors.3 In addition, quetiapine exhibits some alpha 1-adrenergic antagonism that may explain its cardiovascular side effects, such as orthostatic hypotension.4 Bilateral leg edema has been infrequently described with several atypical antipsychotics, including case reports with olanzapine, risperidone, and ziprasidone.5-8 Currently, there is only one published case report of peripheral edema related to quetiapine9 and edema is not currently listed as a potential complication in the package insert. Herein, we report 3 cases and 4 incidents of leg edema associated with quetiapine. Two cases involve a recurrence of edema with rechallenge, and the third following another agent. All patients had resolution of symptoms with medication discontinuation with or without additional symptomatic treatment.

  CASE REPORTS

Case report 1

A 59-year-old Caucasian woman was admitted to the psychiatry unit for manic psychosis, with no active medical problems other than chronic back pain. On admission, the patient was taking lithium 1200 mg/d and clonazepam 1 mg/d. Quetiapine 150 mg/d 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/d over the course of 3 weeks for psychosis. Cardiac and pulmonary exam and blood pressure measurements were within normal limits. Laboratory workup 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, the patient was seen in the outpatient clinic for continued bilateral 2+ pitting leg edema. She expressed concern that the quetiapine was causing the edema, since she previously had edema following quetiapine initiation that resolved following discontinuation. Her psychiatrist primarily suspected lithium as the cause of the edema but obliged her request to decrease quetiapine from 500 mg to 300 mg/d. One week later, the patient called to report that the 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 woman was admitted to the hospital for transient cocaine-induced chest pain with myocardial infarction ruled out by nuclear stress testing. Two days later, she was admitted to the psychiatry unit for depression and suicidal ideation. Her past history was significant for asthma, hypertension, a torn left meniscus, and carpal tunnel syndrome. Her medications were clonidine 0.2 mg/d, diltiazem 120 mg/d, aspirin 325 mg/d, ranitidine 150 mg/d, hydrochlorothiazide 25 mg/d, tramadol 100 mg/d, and as-needed albuterol inhaler. 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 her midcalves. Her blood pressure was normal and cardiac and pulmonary examinations were benign. A complete metabolic profile, including albumin and TSH, to determine the etiology of her edema was within normal limits. To exclude an allergic etiology, immunology testing consisting of C3, C4, and IgE was performed, with normal results. Creatine kinase, troponins, ECG, and cardiac echocardiogram were further unremarkable. On hospital day 5, quetiapine was discontinued and trazodone continued. Th e patient’s edema gradually resolved over the next 2 days.

Case report 3

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

  DISCUSSION

The cases reported here involve women ranging in age from 38 to 59 years, all of whom developed significant edema shortly after initiation of quetiapine (TABLE). 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 of quetiapine-associated edema, by Rozzini et al, described quetiapine-related peripheral edema in a 72-year-old man with Lewy body dementia.9

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 workups 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, and 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 resolution of edema were temporally correlated to changes in quetiapine use. In all 3 cases, edema followed incident use of quetiapine and resolved shortly after discontinuation. Furosemide was briefly given for symptomatic relief for only 1 of the cases, with no recurrence of edema thereafter.

Quetiapine doses ranged from 50 to 500 mg. With only 1 case report, a dose-dependent relationship between quetiapine and leg edema cannot clearly be established. In the case described by Rozzini et al,9 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 1 to 10 days in the cases presented. Time to resolution after drug discontinuation ranged from 2 days to 1 week.

Quetiapine is an antagonist for several neurotransmitter receptors, including serotonin 5-HT1A and 5-HT2, dopamine D1 and D2, histamine H1, and alpha 1-and alpha 2-adrenergic receptors.3 Although 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 reninangiotensin 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 that 5-HT2 receptor blockade may account for olanzapine-induced leg edema through an increase in cyclic adenosine monophosphate levels that can ultimately lead to vascular smooth muscle relaxation.5,17 Alternatively, alpha 1-adrenergic blocking activity of atypical antipsychotics has been thought to explain such cardiovascular side effects as orthostatic hypotension, 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 alpha 1-adrenergic receptor4 and share similar propensities for orthostatic hypotension, an analogous mechanism for quetiapine-induced edema could be proposed.

An allergic reaction could pose an alternative explanation for drug-induced edema. This was considered the most plausible explanation for ziprasidone-induced edema in a case report in which edema was associated with elevation of IgE, C3, and C4.8 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 rechallenge, 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 3 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, although it likely parallels that of other second-generation antipsychotics. Further clinical observation and research are 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.


TABLE

Quetiapine-induced edema: Demographic characteristics, medications, doses, and timeline in 3 cases*

Case no. Age Gender Agent, dose Time to onset Rate of resolution Edema on prior challenge
1 59 Female Quetiapine, 150 mg <10 d 1 wk Quetiapine
2 44 Female Quetiapine, 50 mg 4 d 2 d None
3 38 Female Quetiapine, 200 mg 1 d 1 wk Olanzapine
*Two cases previously experienced edema with a similar agent.

ACKNOWLEDGEMENTS: The authors would like to thank Rami Assi, Vicki Kijewski, and Robert E. Smith for their assistance.

DISCLOSURES: Drs. Koleva, Vanderlip, Tansey, and Mac and Mr. Erickson report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Fiedorowicz is supported by L30 MH075180-02, the Nellie Ball Trust Research Fund, and a NARSAD Young Investigator Award. He has also received research support for participating in a colleague’s investigator-initiated study with Eli Lilly and Company.

    REFERENCES

  1. Goren JL, Levin GM. Quetiapine, an atypical anti-psychotic. Pharmacotherapy. 1998;18:1183–1194.
  2. Philip NS, Mello K, Carpenter LL, et al. Patterns of quetiapine use in psychiatric inpatients: an examination of off-label use. Ann Clin Psychiatry. 2008;20:15–20.
  3. McEvoy G. AHFS drug information. Bethesda, MD: American Society of Health-System Pharmacists, Inc.; 2008.
  4. Richelson E. Preclinical pharmacology of neuroleptics: focus on new generation compounds. J Clin Psychiatry. 1996;57(suppl 11):4–11.
  5. Yalug I, Ozten E, Evren Tufan A, et al. Bilateral pedal edema associated with olanzapine use in manic episode of bipolar disorder: report of two cases. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1541–1542.
  6. Yovtcheva SP, Yazel JJ. Olanzapine-induced bilateral pedal edema: a case report. Gen Hosp Psychiatry. 2000;22:290–291.
  7. Ravasia S. Risperidone-induced edema. Can J Psychiatry. 2001;46:453–454.
  8. Ku HL, Su TP, Chou YH. Ziprasidone-associated pedal edema in the treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:963–964.
  9. Rozzini L, Ghianda D, Vicini Chilovi B, et al. Peripheral oedema related to quetiapine therapy: a case report. Drugs Aging. 2005;22:183–184.
  10. Ely JW, Osheroff JA, Chambliss ML, et al. Approach to leg edema of unclear etiology. J Am Board Fam Med. 2006;19:148–160.
  11. Franco K, Tamburrino M, Campbell N, et al. Dopaminergic activity and idiopathic edema. Hosp Community Psychiatry. 1991;42:309–310.
  12. Norbiato G, Bevilacqua M, Raggi U, et al. Effect of metoclopramide, a dopaminergic inhibitor, on renin and aldosterone in idiopathic edema: possible therapeutic approach with levodopa and carbidopa. J Clin Endocrinol Metab. 1979;48:37–42.
  13. Dent RG, Edwards OM. Bromocriptine-responsive form of idiopathic oedema. Lancet. 1979;2:355–356.
  14. Adir Y, Sznajder JI. Regulation of lung edema clearance by dopamine. Isr Med Assoc J. 2003;5:47–50.
  15. Zeng C, Zhang M, Asico LD, et al. The dopaminergic system in hypertension. Clin Sci (Lond). 2007;112:583–597.
  16. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008;13:27–35.
  17. Ng B, Postlethwaite A, Rollnik J. Peripheral oedema in patients taking olanzapine. Int Clin Psychopharmacol. 2003;18:57–59.

CORRESPONDENCE: Hristina K. Koleva, MD The University of Iowa Hospitals and Clinics 200 Hawkins Drive Iowa City, IA 52242-1009 USA. E-MAIL: hristina-koleva@uiowa.edu