Skip to main content
    • Aa
    • Aa

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

  • T. Kishi (a1), H. Y. Meltzer (a2), Y. Matsuda (a1) and N. Iwata (a1)

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.


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).


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).


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

Corresponding author
*Address for correspondence: T. Kishi, M.D., Ph.D., Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. (Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

J Angst (1998). Sexual problems in healthy and depressed persons. International Clinical Psychopharmacology 13 (Suppl. 6), S1S4.

BG Appelberg , EK Syvalahti , TE Koskinen , OP Mehtonen , TT Muhonen , HH Naukkarinen (2001). Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. Journal of Clinical Psychiatry 62, 448452.

S Aznar , Z Qian , R Shah , B Rahbek , GM Knudsen (2003). The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain. Brain Research 959, 5867.

RJ Bielski , L Cunningham , JP Horrigan , PD Londborg , WT Smith , K Weiss (2008). Gepirone extended-release in the treatment of adult outpatients with major depressive disorder: a double-blind, randomized, placebo-controlled, parallel-group study. Journal of Clinical Psychiatry 69, 571577.

M Bonierbale , C Lancon , J Tignol (2003). The ELIXIR study: evaluation of sexual dysfunction in 4557 depressed patients in France. Current Medical Research and Opinion 19, 114124.

LD Cohn , BJ Becker (2003). How meta-analysis increases statistical power. Psychological Methods 8, 243253.

R DerSimonian , N Laird (1986). Meta-analysis in clinical trials. Controlled Clinical Trials 7, 177188.

A Drago , C Crisafulli , A Sidoti , A Serretti (2011). The molecular interaction between the glutamatergic, noradrenergic, dopaminergic and serotoninergic systems informs a detailed genetic perspective on depressive phenotypes. Progress in Neurobiology 94, 418460.

LF Fabre , CS Brown , LC Smith , LR Derogatis (2011 a). Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women. Journal of Sexual Medicine 8, 14111419.

LF Fabre , AH Clayton , LC Smith , I Goldstein , LR Derogatis (2012). The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men. Journal of Sexual Medicine 9, 821829.

LF Fabre , LC Smith , LR DeRogatis (2011 b). Gepirone-ER treatment of low sexual desire associated with depression in women as measured by the DeRogatis Inventory of Sexual Function (DISF) fantasy/cognition (desire) domain – a post hoc analysis. Journal of Sexual Medicine 8, 25692581.

MT Fava , SD Tarqum , AA Nierenberg , LS Bleicher , TA Carter , PC Wedel , R Hen , FH Gage , C Barlow (2012). An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. Journal of Psychiatric Research 46, 15531563.

AD Feiger , JF Heiser , RK Shrivastava , KJ Weiss , WT Smith , JM Sitsen , M Gibertini (2003). Gepirone extended-release: new evidence for efficacy in the treatment of major depressive disorder. Journal of Clinical Psychiatry 64, 243249.

M Hamilton (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 23, 5662.

JP Higgins , SG Thompson , JJ Deeks , DG Altman (2003). Measuring inconsistency in meta-analyses. British Medical Journal 327, 557560.

I Hindmarch (2002). Beyond the monoamine hypothesis: mechanisms, molecules and methods. European Psychiatry 17 (Suppl. 3), 294299.

SW Jenkins , DS Robinson , LF Fabre Jr., JJ Andary , ME Messina , LA Reich (1990). Gepirone in the treatment of major depression. Journal of Clinical Psychopharmacology 10, 77S85S.

T Kishi , R Yoshimura , Y Fukuo , T Okochi , S Matsunaga , W Umene-Nakano , J Nakamura , A Serretti , CU Correll , JM Kane , N Iwata (2013). The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. European Archives of Psychiatry and Clinical Neuroscience 263, 105118.

T Kato (2007). Molecular genetics of bipolar disorder and depression. Psychiatry and Clinical Neurosciences 61, 319.

M Landen , G Bjorling , H Agren , T Fahlen (1998). A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. Journal of Clinical Psychiatry 59, 664668.

YD Lapierre , P Silverstone , RT Reesal , B Saxena , P Turner , D Bakish , J Plamondon , PM Vincent , RA Remick , C Kroft , R Payeur , D Rosales , R Lam , M Bologa (1998). A Canadian multicenter study of three fixed doses of controlled-release ipsapirone in outpatients with moderate to severe major depression. Journal of Clinical Psychopharmacology 18, 268273.

B Le Francois , M Czesak , D Steubl , PR Albert (2008). Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology 55, 977985.

S Leucht , C Corves , D Arbter , RR Engel , C Li , JM Davis (2009 a). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 3141.

S Leucht , K Komossa , C Rummel-Kluge , C Corves , H Hunger , F Schmid , C Asenjo Lobos , S Schwarz , JM Davis (2009 b). A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. American Journal of Psychiatry 166, 152163.

GK Matheson , DM Pfeifer , MB Weiberg , C Michel (1994). The effects of azapirones on serotonin1A neurons of the dorsal raphe. General Pharmacology 25, 675683.

PJ McGrath , JW Stewart , FM Quitkin , S Wager , SW Jenkins , DG Archibald , JC Stringfellow , DS Robinson (1994). Gepirone treatment of atypical depression: preliminary evidence of serotonergic involvement. Journal of Clinical Psychopharmacology 14, 347352.

D Moher , A Liberati , J Tetzlaff , DG Altman ; PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. British Medical Journal 339, b2535.

JL Moll , CS Brown (2011). The use of monoamine pharmacological agents in the treatment of sexual dysfunction: evidence in the literature. Journal of Sexual Medicine 8, 956970.

SA Montgomery , M Asberg (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.

A Newman-Tancredi , MS Kleven (2011). Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties. Psychopharmacology (Berlin) 216, 451473.

E Onder , U Tural (2003). Faster response in depressive patients treated with fluoxetine alone than in combination with buspirone. Journal of Affective Disorders 76, 223227.

C Pinto , RP Souza , D Lioult , M Semeralul , JL Kennedy , JJ Warsh , AH Wong , VD Luca (2011). Parent of origin effect and allelic expression imbalance of the serotonin transporter in bipolar disorder and suicidal behaviour. European Archives of Psychiatry and Clinical Neuroscience 261, 533538.

M Pompili , G Serafini , M Innamorati , AM Moller-Leimkuhler , G Giupponi , P Girardi , R Tatarelli , D Lester (2010). The hypothalamic-pituitary-adrenal axis and serotonin abnormalities: a selective overview for the implications of suicide prevention. European Archives of Psychiatry and Clinical Neuroscience 260, 583600.

J Prins , B Olivier , SM Korte (2011). Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited. Expert Opinion on Investigational Drugs 20, 11071130.

K Rickels , A Derivan , N Kunz , A Pallay , E Schweizer (1996). Zalospirone in major depression: a placebo-controlled multicenter study. Journal of Clinical Psychopharmacology 16, 212217.

DS Robinson , JM Sitsen , M Gibertini (2003). A review of the efficacy and tolerability of immediate-release and extended-release formulations of gepirone. Clinical Therapeutics 25, 16181633.

J Savitz , I Lucki , WC Drevets (2009). 5-HT(1A) receptor function in major depressive disorder. Progress in Neurobiology 88, 1731.

E Schweizer , K Rickels , H Hassman , F Garcia-Espana (1998). Buspirone and imipramine for the treatment of major depression in the elderly. Journal of Clinical Psychiatry 59, 175183.

SM Stahl , L Kaiser , J Roeschen , JM Keppel Hesselink , J Orazem (1998). Effectiveness of ipsapirone, a 5-HT-1A partial agonist, in major depressive disorder: support for the role of 5-HT-1A receptors in the mechanism of action of serotonergic antidepressants. International Journal of Neuropsychopharmacology 1, 1118.

H Tanaka , T Tatsuno , H Shimizu , A Hirose , Y Kumasaka , M Nakamura (1995). Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain. General Pharmacology 26, 17651772.

PM Whitaker-Azmitia , M Druse , P Walker , JM Lauder (1996). Serotonin as a developmental signal. Behavioural Brain Research 73, 1929.

K Yamada , G Yagi , S Kanba (2003). Clinical efficacy of tandospirone augmentation in patients with major depressive disorder: a randomized controlled trial. Psychiatry and Clinical Neurosciences 57, 183187.

K Zuideveld , J Rusic-Pavletic , H Maas , L Peletier , P Van der Graaf , M Danhof (2002). Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats. Journal of Pharmacology and Experimental Therapeutics 303, 11301137.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Materials

Kishi et al. Supplementary Material

 Word (225 KB)
225 KB
Supplementary Materials

Kishi et al. Supplementary Material

 Word (138 KB)
138 KB


Altmetric attention score

Full text views

Total number of HTML views: 4
Total number of PDF views: 30 *
Loading metrics...

Abstract views

Total abstract views: 290 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 28th June 2017. This data will be updated every 24 hours.