SHORT COMMUNICATION Differential effects of diazepam, tandospirone, and paroxetine on plasma brain-derived neurotrophic factor level under mental stress Ai Tamaji 1,2 , Kunihiro Iwamoto 1 *, Yukiko Kawamura 2 , Masahiro Takahashi 3 , Kazutoshi Ebe 4 , Naoko Kawano 1 , Shohko Kunimoto 1 , Branko Aleksic 1 , Yukihiro Noda 2 and Norio Ozaki 1 1 Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan 2 Division of Clinical Science and Neuropsychopharmacology, Graduate School of Pharmacy, Meijyo University, Nagoya, Aichi, Japan 3 Department of Psychiatry, Graduate School of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan 4 Toyota Central R&D Labs., Inc., Nagakute, Aichi, Japan Objectives Serum brain-derived neurotrophic factor (BDNF) levels are reduced in depressed patients, and successful antidepressant treatment leads to increases in BDNF levels. However, little is known about how psychotropic drugs affect the mechanism of the human response to mental stress. We investigated the influence of psychotropic drugs on plasma BDNF levels under mental stress using a driving simulator (DS) task. Methods Fourteen healthy male volunteers received one of four drugs, diazepam (5 mg), tandospirone (20 mg), paroxetine (10 mg), and matched placebo, in a double-blind, crossover manner. Subjects were asked to perform the DS task 4 h post-dosing. Plasma BDNF levels were measured before and after the DS task. Results Plasma BDNF levels under the placebo, diazepam, and tandospirone conditions significantly decreased after the DS task compared with before the task. Conversely, no significant differences in plasma BDNF levels were detected under the paroxetine condition. Conclusion As these three psychotropic drugs have differential effects on plasma BDNF levels under mental stress after 4 h post-dosing, antidepressants, unlike anxiolytics, might have a prompt positive effect on the mental stress response. Copyright © 2012 John Wiley & Sons, Ltd. key words —antidepressant; anxiolytic drug; brain-derived neurotrophic factor; mental stress INTRODUCTION Stress is common in everyday life and is believed to affect happiness, health, and cognition (Caspi et al., 2003). A role for brain-derived neurotrophic factor (BDNF) in the effects of stress and the response to antidepressant treatment is supported by studies demonstrating opposing regulation of this neurotrophic factor (Charmey, 2004). BDNF, the most abundant neurotrophin in the brain, enhances the growth and maintenance of several neuronal systems and serves as a neurotransmitter modulator (Shimizu et al., 2003). BDNF is present in blood and can pass through the blood–brain barrier carried by a high-capacity, saturable transport system (Pan et al., 1998). Although the source and function of blood BDNF remains unknown, recent reports have shown that more than 99% of blood BDNF proteins are stored in platelets and can be released in serum (Radka et al., 1996) and that blood levels of BDNF might in part reflect BDNF levels in the brain (Karege et al., 2002, Mitoma et al., 2008). The “neurotrophin hypothesis of depression” is based largely on two observations: a decrease in hippocampal BDNF levels is correlated with stress-induced depres- sive behavior, and antidepressant treatment enhances the expression of BDNF (Martinowich et al., 2007). Recent studies suggested that serum BDNF levels are reduced in depression (Sen et al., 2008, aan het Rot et al., 2009). Antidepressants are thought to upregulate the expression of BDNF and its receptor and to promote adult neurogenesis, which might be the core pharmaco- logical effect of antidepressants (Martinowich and Lu, 2008); successful antidepressant treatment leads to an increase in plasma BDNF levels (Lee and Kim, 2008). *Correspondence to: K. Iwamoto, Department of Psychiatry, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466–8550, Japan. Tel: +81 52 744 2282; Fax: +81 52 744 2293. E-mail: iwamoto@med.nagoya-u.ac.jp Received 16 November 2011 Accepted 26 January 2012 Copyright © 2012 John Wiley & Sons, Ltd. human psychopharmacology Hum. Psychopharmacol Clin Exp (2012) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2220