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Review
. 2025 Jun;45(2):e70023.
doi: 10.1002/npr2.70023.

Augmentation Therapy With Serotonin 5-HT1A Receptor Partial Agonists on Cognitive Function in Depressive Disorders: A Systematic Review of Randomized Controlled Studies

Risa Yamada  1   2 , Ayumu Wada  1   2 , Andrew Stickley  1 , Adrian Newman-Tancredi  3 , Tomiki Sumiyoshi  1   2
Affiliations
Review

Augmentation Therapy With Serotonin 5-HT1A Receptor Partial Agonists on Cognitive Function in Depressive Disorders: A Systematic Review of Randomized Controlled Studies

Risa Yamada et al. Neuropsychopharmacol Rep. 2025 Jun.

Abstract

Objective: The use of serotonin 5-HT1A receptor partial agonists (5-HT1A-PAs) as an add-on therapy has been associated with the enhancement of attention/processing speed in patients with schizophrenia. Also, 5-HT1A receptors have been shown to play a role in the pathophysiology of mood disorders. There is compelling evidence supporting that stimulation of 5-HT1A receptors accelerates antidepressant effects. Accordingly, this systematic review examines the ability of adjunctive treatment with 5-HT1A-PAs to improve cognitive function in patients with depressive symptoms.

Methods: A literature search using PubMed, the Cochrane Library, and Web of Science databases was performed from 1987 to January 2024 to identify randomized controlled trials (RCTs) corresponding to the following inclusion criteria: (1) RCTs, (2) human studies; studies that (3) targeted patients with a psychiatric disorder (except for schizophrenia or schizoaffective disorder), (4) evaluated the effect of cognitive functions, (5) were written in English.

Results: From the 80 studies initially screened, three met the inclusion criteria. Two of these studies dealt with vascular depression while one focused on major depressive disorder (MDD). In MDD, combined treatment with buspirone and melatonin was more efficacious in ameliorating subjective cognitive disturbances compared to the use of buspirone alone or the use of a placebo. Likewise, the combination of escitalopram-tandospirone was more advantageous than escitalopram alone for improving executive function and verbal fluency in patients with vascular depression.

Conclusions: Further studies with novel 5-HT1A receptor agonists are warranted to examine their potentially more robust benefits on cognitive performance in subjects suffering from mood deficits.

Keywords: 5‐HT1A receptor biased agonists; 5‐HT1A receptor partial agonists; azapirone derivative; cognitive impairment; depression.

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Conflict of interest statement

Dr. Sumiyoshi is an Editorial Board member of Neuropsychopharmacology Reports and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.

Figures

FIGURE 1
FIGURE 1
Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) study selection flowchart.
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References

    1. Bourne C., Aydemir Ö., Balanzá‐Martínez V., et al., “Neuropsychological Testing of Cognitive Impairment in Euthymic Bipolar Disorder: An Individual Patient Data Meta‐Analysis,” Acta Psychiatrica Scandinavica 128, no. 3 (2013): 149–162, 10.1111/acps.12133. - DOI - PubMed
    1. Keefe R. S., Silva S. G., Perkins D. O., and Lieberman J. A., “The Effects of Atypical Antipsychotic Drugs on Neurocognitive Impairment in Schizophrenia: A Review and Meta‐Analysis,” Schizophrenia Bulletin 25, no. 2 (1999): 201–222, 10.1093/oxfordjournals.schbul.a033374. - DOI - PubMed
    1. Lee R. S., Hermens D. F., Porter M. A., and Redoblado‐Hodge M. A., “A Meta‐Analysis of Cognitive Deficits in First‐Episode Major Depressive Disorder,” Journal of Affective Disorders 140, no. 2 (2012): 113–124, 10.1016/j.jad.2011.10.023. - DOI - PubMed
    1. Ibrahim H. M. and Tamminga C. A., “Treating Impaired Cognition in Schizophrenia,” Current Pharmaceutical Biotechnology 13, no. 8 (2012): 1587–1594, 10.2174/138920112800784772. - DOI - PubMed
    1. McCutcheon R. A., Keefe R. S. E., and McGuire P. K., “Cognitive Impairment in Schizophrenia: Aetiology, Pathophysiology, and Treatment,” Molecular Psychiatry 28, no. 5 (2023): 1902–1918, 10.1038/s41380-023-01949-9. - DOI - PMC - PubMed

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