Selecting antidepressants according to a drug-by-environment interaction: a comparison of fluoxetine and minocycline effects in mice living either in enriched or stressful conditions.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder. It has been recently proposed that these drugs, by enhancing neural plasticity, amplify the influences of the living conditions on mood. Consequently, SSRI outcome depends on the quality of the environment, improving symptomatology mainly in individuals living in favorable conditions. In adverse conditions, drugs with a different mechanism of action might have higher efficacy. The antibiotic minocycline, with neuroprotective and anti-inflammatory properties, has been recently proposed as a novel potential antidepressant treatment. To explore the drug-by-environment interaction, we compared the effects on depressive-like behavior and neural plasticity of the SSRI fluoxetine and minocycline in enriched and stressful conditions. We first exposed C57BL/6 adult female mice to 14 days of chronic unpredictable mild stress to induce a depressive-like profile. Afterward, mice received vehicle, fluoxetine, or minocycline for 21 days, while exposed to either enriched or stressful conditions. During the first five days, fluoxetine led to an improvement in enrichment but not in stress. By contrast, minocycline led to an improvement in both conditions. After 21 days, all groups showed a significant improvement in enrichment while fluoxetine worsened the depressive like behavior in stress. The effects of the drugs on neural plasticity, measured as long-term potentiation, were also environment-dependent. Overall, we show that the environment affects fluoxetine but not minocycline outcome, indicating that the latter represents a potential alternative to SSRIs to treat depressed patients living in adverse conditions. From a translation perspective, our finding call for considering the drug-by-environment interaction to select the most effective pharmacological treatment.