Antidepressant treatment outcome depends on the quality of the living environment: a pre-clinical investigation in mice

Abstract

Antidepressants represent the standard treatment for major depression. However, their efficacy is variable and incomplete. A growing number of studies suggest that the environment plays a major role in determining the efficacy of these drugs, specifically of selective serotonin reuptake inhibitors (SSRI). A recent hypothesis posits that the increase in serotonin levels induced by SSRI may not affect mood per se, but enhances neural plasticity and, consequently, renders the individual more susceptible to the influence of the environment. Thus, SSRI administration in a favorable environment would lead to a reduction of symptoms, while in a stressful environment might lead to a worse prognosis. To test this hypothesis, we treated C57BL/6 adult male mice with chronic fluoxetine while exposing them to either (i) an enriched environment, after exposure to a chronic stress period aimed at inducing a depression-like phenotype, or (ii) a stressful environment. Anhedonia, brain BDNF and circulating corticosterone levels, considered endophenotypes of depression, were investigated. Mice treated with fluoxetine in an enriched condition improved their depression-like phenotype compared to controls, displaying higher saccharin preference, higher brain BDNF levels and reduced corticosterone levels. By contrast, when chronic fluoxetine administration occurred in a stressful condition, mice showed a more distinct worsening of the depression-like profile, displaying a faster decrease of saccharin preference, lower brain BDNF levels and increased corticosterone levels. Our findings suggest that the effect of SSRI on depression-like phenotypes in mice is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Experimental design.

(A,B) Environmental switch protocols. (A) Fluoxetine treatment in an enriched condition after exposure to stress. (B) Fluoxetine treatment in a stressful condition, after exposure to enrichment. (C,D) Constant environment protocols. (C) Fluoxetine treatment in a stressful condition, after exposure to stress. (D) Fluoxetine treatment in an enriched condition, after exposure to enrichment.

Figure 2. Saccharin preference during fluoxetine treatment in an enriched condition after exposure to stress.

Stress exposure reduced saccharin preference in both groups of mice. Afterwards, fluoxetine-treated mice showed a significantly higher preference for the saccharin solution compared to control mice. # indicates p = 0.0120 and * indicates p = 0.0464, vs. vehicle group. Data are means ± S.E.M.

Figure 3. BDNF and corticosterone levels in mice in an enriched condition after exposure to stress.

Following the 21 days of recovery, fluoxetine mice showed a significant increase of hippocampal and hypothalamic BDNF levels as well as significantly more marked decrease in corticosterone levels compared to controls. * and ** indicate, respectively, p<0.05 and 0.01 vs. vehicle group. Delta (Δ) values were calculated comparing data obtained on the day before treatment and on last day of treatment. Data are means ± S.E.M.

Figure 4. Anhedonic profile during fluoxetine treatment in a stressful condition after exposure to enrichment.

When social stress was imposed during treatment, fluoxetine-treated mice showed a faster and more marked reduction of preference for the saccharin solution compared to control mice. # indicates p = 0.0199, * and ** indicate, respectively, p<0.05 and 0.01 vs. vehicle group. Data are means ± S.E.M.

Figure 5. BDNF and corticosterone levels in mice in a stressful conditions after exposure to enrichment.

Following social stress mice treated with fluoxetine showed reduced BDNF levels in both hippocampus and hypothalamus compared to control mice. Plasmatic corticosterone levels resulted increased in fluoxetine mice as shown by the statistically significant difference between levels before and after the treatment period. ** indicates p<0.01 vs. vehicle group. Delta (Δ) values were calculated comparing data obtained on the day before treatment and on last day of treatment. Data are means ± S.E.M.

Figure 6. Results of experiments investigating the effects of fluoxetine treatment in a constant environment.

(A,B,C,D) Fluoxetine treatment in a stressful condition, after exposure to stress. (A) Saccharin preference: exposure to stress before treatment significantly reduced saccharin preference. The following fluoxetine treatment administered in stressful conditions did not modify the anhedonic response. (B) Hippocampal and (C) hypothalamic BDNF levels: no difference between the two groups has been found. (D) Corticosterone levels. Fluoxetine mice showed a significant increase in corticosterone levels compared to vehicle. (E,F,G,H) Fluoxetine treatment in an enriched condition, after exposure to enrichment. (E) Saccharin preference: no difference between the two groups has been found. (F) Hippocampal and (G) hypothalamic BDNF levels: no difference between the two groups has been found. (H) Corticosterone levels: fluoxetine mice showed a significant decrease in corticosterone levels compared to vehicle. * indicates p<0.05 vs. vehicle group. # indicates p<0.01 vs. baseline level. Delta (Δ) values were calculated comparing data obtained on the day before treatment and on last day of treatment. Data are means ± S.E.M.