Psychological Medicine

Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis

T. Kishia1 c1, H. Y. Meltzera2, Y. Matsudaa1 and N. Iwataa1

a1 Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

a2 Division of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA


Background A meta-analysis of the serotonin1A (5-HT1A) receptor partial agonist of the azapirone class as an anxiolytic drug for the treatment of major depressive disorder (MDD) has not previously been reported.

Method We carried out a systematic review of the literature available in PubMed, the Cochrane Library database and PsycINFO up to 12 October 2013, and conducted a meta-analysis of randomized controlled trials (RCTs) comparing 5-HT1A agonists with placebo and RCTs of 5-HT1A agonist augmentation therapies for MDD treatment. We calculated the risk ratio (RR), number needed to treat (NNT)/number needed to harm (NNH) and 95% confidence intervals (CIs).

Results Fifteen RCTs comparing 5-HT1A agonists with placebo (total n = 2469, four studies with buspirone, seven with gepirone, three with ipsapirone and one with zalospirone) were identified. Pooled 5-HT1A agonists had significantly more responders (RR 0.74, 95% CI 0.65–083, p < 0.00001, NNT = 6, 12 trials, n = 1816) than placebo. Pooled 5-HT1A agonists were superior to placebo in discontinuation due to inefficacy (RR 0.49, p = 0.02, NNH = 16, p = 0.03, 10 trials, n = 1494) but were inferior to placebo in discontinuation due to side-effects (RR 1.88, p < 0.0001, NNH = 17, p = 0.001, 13 trials, n = 2196). However, all-cause discontinuation was similar in both groups (RR 0.99, p = 0.85, 14 trials, n = 2402). Four 5-HT1A agonist augmentation studies were identified (total n = 365, three buspirone studies and one tandospirone study). There were no statistically significant effects of 5-HT1A agonist augmentation therapies on response rate (RR 0.98, p = 0.85, four trials, n = 341). 5-HT1A agonist-related side-effects including gastrointestinal symptoms, dizziness, insomnia, palpitation, paresthesia and sweating were greater than with placebo (p < 0.00001 to p = 0.03).

Conclusions Our results suggest that 5-HT1A agonist has a more beneficial effect on MDD than placebo, but has several side-effects.

(Received May 10 2013)

(Revised October 23 2013)

(Accepted October 26 2013)

(Online publication November 21 2013)

Key words

  • Buspirone;
  • gepirone;
  • ipsapirone;
  • major depressive disorder; meta-analysis;
  • serotonin1A receptor partial agonist;
  • zalospirone


c1 Address for correspondence: T. Kishi, M.D., Ph.D., Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. (Email: