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Letter to the Editor

Antidepressant Effects of Combined Mood Stabilizers May Account for High Placebo Response Rates

Takeshi Terao, MD, PhDa,*

Published: June 22, 2021

J Clin Psychiatry 2021;82(4):21lr13919

To cite: Terao T. Antidepressant effects of combined mood stabilizers may account for high placebo response rates. J Clin Psychiatry. 2021;82(4):21lr13919.
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© Copyright 2021 Physicians Postgraduate Press, Inc.

aDepartment of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan
*Corresponding author: Takeshi Terao, MD, PhD, Department of Neuropsychiatry, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-city, Oita, 879-5593, Japan (



See replies by Ghaemi and Goldberg, and article by Ghaemi et al

To the Editor: I read with much interest a recent JCP article in which Ghaemi et al1 reported that citalopram, added to standard mood stabilizers, does not have clinically meaningful benefits versus placebo for either acute or maintenance treatment of bipolar depression. In an editorial, Goldberg2 criticized the article because of the high placebo response rate, which was above 40%.

Although Ghaemi et al1 themselves attributed the high placebo response rate to nonpharmacologic reasons such as natural remission of bipolar depression, it should be noted that all patients (in both the placebo and citalopram groups) concurrently started taking mood stabilizers (lithium, divalproex, carbamazepine, or lamotrigine) or were already taking mood stabilizers for at least 4 weeks prior to study entry. Therefore, some patients in the placebo group began receiving not only a placebo but also a mood stabilizer. Thus, the antidepressant effect of the mood stabilizer might have contributed to these patients’ improvement. In addition, the other patients in the placebo group already receiving a mood stabilizer might have been asked to take medicine (ie, placebo and mood stabilizer) more regularly just before study entry, which probably led to the elevation of serum levels of the mood stabilizer, and thereby the antidepressant effect of the mood stabilizer might have contributed to their improvement.

In Ghaemi and colleagues’ study,1 the most commonly used mood stabilizer was lithium (24 of 60 patients in the citalopram group and 37 of 59 patients in the placebo group). The efficacy of lithium in the treatment of acute bipolar depression has been demonstrated in several previous studies.3,4 In any case, antidepressant effects of mood stabilizers as well as natural remission and/or true placebo effect could account for the high placebo response rate. If there had been a third group of patients receiving only a placebo in this study, the above possibilities could have been examined.

Published online: June 22, 2021.
Potential conflicts of interest: There were no conflicts of interest.
Funding/support: No funding was received.

Volume: 82

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