Valproate-Olanzapine-Nifedipine Interaction Related Pedal Edema

Letter-to-the Editor Taiwanese Journal of Psychiatry (Taipei) Vol. 28 No. 3 2014 • 181 •

Valproate-olanzapine-nifedipine Interaction Related Pedal Edema

Patient’s bilateral pedal pitting edema did not Case Report resolve spontaneously after discontinuing olanzapine until he received diuretics with furosemide A 45-year-old single male patient with bipo- 40 mg/day and spironolactone 75 mg/day on the lar I disorder was admitted to acute ward of our 21st day of pitting edema. He required further hospital due to depressive mood with irritability treatment, and had normal ﬁ ndings in physical ex- for more than one month. The ﬁ nding of physical amination and repeated laboratory tests. examination at admission revealed no bilateral pedal edema under long-term usage of valproate Comment 700 mg/day as mood stabilizer, nifedipine 30 mg/ day for essential hypertension, and allopurinol There have been some clinical reports to as- 100 mg/day for gouty arthritis before hospitaliza- sociate olanzapine treatment with bilateral lower tion. The results of laboratory tests for electro- extremity edema since 2000 [1]. Pre-clinical trials lytes, renal function, liver function, chest X-ray, of oral olanzapine (doses being equal or greater and electrocardiography were also within normal than 2.5 mg/day) have also reported peripheral limits. edema as a rare adverse event. The pathophysio- During this hospitalization, we added olan- logical mechanism of low extremity edema re- zapine 5 mg/day to control manic symptoms. Five mains unknown, although some mechanisms days later, he reported bilateral swelling over low- could be proposed, such as olanzapine’s blockage er legs and ankles, a bilateral 2+ pitting edema in of α1, M1, M3 and 5-HT2 receptors [2, 3]. The com- the legs and ankles without evidence of rash, skin bination of valproate and olanzapine related pedal thickening, local heat, or changes in pigmentation edema has been reported [3], although, valproate on physical examination. Results of renal function alone or in combination with other second-gener- test and serum uric acid level were normal. Eight ation (atypical) antipsychotics related edema has days after starting olanzapine therapy, we decided been observed, the drug-drug interactions re- to shift the olanzapine to aripiprazole and sug- mained uncovered [4]. gested an internist consultation on the following The most common adverse event reported day after his discharge. When the Naranjo algo- with osmotic controlled release oral delivery sys- rithm for drug-related adverse events was applied, tem (OROS) of nifedipine was peripheral edema it was found that the relationship of pedal edema which was dose-related and the frequency was observed in our case with the combination treat- 18% on nifedipine OROS mg/day versus 10% on ment of olanzapine, valproate, and nifedipine was placebo [Bayer HealthCare AG, Leverkusen, probable with score of 6. Germany]. Through blocking α1 receptors , nife-

Valproate-olanzapine-nifedipine 交互作用相關之足部水腫呂宇席、林清華、周立修 • 182 • Valproate-olanzapine-nifedipine Pedal Edema

dipine can induce vasodilatation and cause a pre- disposition to vasodilatation and edema [2]. In our References patient, long-term administration of valproate may predispose to edema formation, the addition 1. Yovtcheva SP, Yazel JJ: Olanzapine-induced bilateral of olanzapine may increase a vulnerability to ped- pedal edema: a case report. Gen Hosp Psychiatry al edema, and the synergistic interaction between 2000; 22: 290-1. olanzapine and nifedipine may take the responsi- 2. Brunton LL, Parker KL, Blumenthal DK, Buxton th bilities for the occurrence of bilateral pedal edema ILO: Goodman and Gilman’s Pharmacology, 11 ed. New York, NY: McGraw-Hill, 2005. through enhancing α1 blockade mechanism. 3. Yaluq I, Ozten E, Evren TA, Alemdar M, Cerit C: As valproate and olanzapine combination Bilateral pedal edema associated with olanzapine use provides synergistic mood-stabilizing, antidepres- in manic episode of bipolar disorder: report of two sant and antipsychotic effects in the management cases. Prog Neuropsychopharmacol Biol Psychiatry of bipolar disorder or other psychotic disorder, in 2007; 31: 1541-2. combination with other medications become more 4. Thomas V, Mifsud J: Interactions between valproic and more common in clinical practice. The case acid and quetiapine/olanzapine in the treatment of report described here suggests that caution may be bipolar disorder and the role of therapeutic drug warranted when giving the combination of nife- monitoring. J Pharm Pharmacol 2014; 66: 747-59. dipine and olanzapine treatment for patients with cardiovascular disease, and that bilateral pedal edema may occur, especially concurrent long- Yu-Shi Lu, M.D., term administration of valproate. Further clinical Ching-Hua Lin, M.D.,Ph.D., investigation and research concerning drug-in- Li-Shiu Chou, M.D., M.S.* duced pedal edema and second-generation anti- Kaohsiung Kai-Syuan Municipal Psychiatric psychotic-related drug-drug interaction need to be Hospital, Kaohsiung, Taiwan conducted. (All authors declare no potential Received: March 5, 2014; revised: April 10, conﬂict of interest in reporting this case.) 2014; accepted: May 17, 2014 *Corresponding author. No. 130, Kai-Syuan Second Road, Kaohsiung 802, Taiwan Email: Li-Shiu Chou