Beyond rodents: A systematic review of antidepressant-like effects in Drosophila melanogaster as an alternative model in psychopharmacology

The development of antidepressants has traditionally relied on vertebrate models. Drosophila melanogaster offers a promising alternative approach, yet evidence of antidepressant-like effects is fragmented. The aim of this systematic review was to analyse the literature on the effects of antidepressants on D. melanogaster behaviours. A comprehensive search of a number of bibliographic databases (i.e. PubMed , Web of Science , Scopus and EMBASE ) was followed by a further screening of the retrieved articles (i.e. inclusion of studies on any D. melanogaster strain, sex, age, dose or outcome, tested in any behavioural assay; exclusion of reviews, studies on co-treatments and/or on non-prototypical antidepressants, and studies lacking control groups). This resulted in the final selection of 12 articles, comprising 146 studies. Most studies involved adult flies ( k = 131), males ( k = 56), fluoxetine treatment ( k = 109) and courtship outcomes ( k = 85). Some studies involved larvae ( k = 15), females ( k = 39), treatment with other antidepressants (citalopram, k = 12; desipramine, k = 6; amitriptyline, k = 2; imipramine, k = 2) and other outcomes (locomotion, k = 11; sucrose preference, k = 5; light preference, k = 2; aggression, k = 2; climbing, k = 1). Studies on larvae had, on average, larger sample sizes than studies on adult flies, resulting in more conclusive effect sizes. The effect sizes indicated that most studies presented inconclusive effects. However, sucrose preference, courtship and light preference were outcomes with conclusive findings, depending on the conditions (sex, treatment, stress), and thus these may represent more reliable indicators of antidepressant effects. However, the lack of consistency among studies precluded drawing any definitive conclusions on reliable indicators. In addition, incomplete reporting precluded an accurate risk-of-bias assessment. These findings highlight the need for standardisation and transparent reporting, in order to establish flies as a reproducible, ethically acceptable alternative to vertebrates in antidepressant research.