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 olan- zapine 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 <[email protected]>.