Sex differences in depression and antidepressant response in humans are modestly studied and results are controversial. Experimental studies using animal models may provide insights that could be useful in clinical trials.

The objective is to summarize findings from preclinical studies on sex differences and suggest how such preclinical research might be of use in clinical research.

Specifically it is aimed to summarize evidence for both sexes in relation to the phenotype of depression, its endophenotype and the antidepressant response.

A selection of experimental studies on sex differences in stress and antidepressant response was performed and their findings were linked to potential confounders or methodological issues that might obscure the results of clinical trials.

In preclinical studies, behavioral indices and models are adjusted for both sexes, in order to properly identify sex differences in primary outcomes. This is not routinely happening in clinical studies when using depression rating scales, which is the analogue of behavioral indices. Moreover, preclinical studies show sex differences at the baseline behavioral response and underlying mechanisms that often converge following antidepressant treatment. This is also a neglected issue in human studies. Finally, preclinical research suggests that when researching on potential biomarkers for depression and antidepressant response sex should be an important factor to consider.

Cautious exploitation of findings on sex differences from preclinical research could improve the design and quality of clinical studies for disease biomarkers and novel antidepressants and facilitate the drug development in a gender aware manner.

NK has received honoraria and travel support from Janssen-Cilag, Lundbeck, Sanofi-Aventis, Medochemie Generics and Elpen S.A. CD has received honoraria from Janssen-Cilag and travel support from Boehringer Ingelheim. None of those is relevant to this study.