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.
Highlights
After a period of stress, which induces a depression-like phenotype, mice exposed to a favorable environment, such as enrichment, recovered when treated with FLX, displaying reduced anhedonia, higher brain BDNF levels and lower corticosterone levels compared to controls
FLX-treated mice showed a faster decrease of saccharin preference, already evident after two weeks of treatment, and had lower brain BDNF levels and increased corticosterone levels
A similar picture has been reported for the effects of selective serotonin reuptake inhibitors (SSRI) administered in a stressful condition on BDNF and corticosterone levels
Summary
Major depression is a chronic, recurring and potentially lifethreatening illness that affects up to 10% of the population across the globe. Recent publications have cast doubts about antidepressant efficacy [5,6,7], claiming that when a comprehensive analysis of all trials available is performed, their effects are not significantly different from placebo [8,9,10,11]. These studies have been widely criticized [12,13] and most psychiatrists believe that antidepressants work and prescribe them to patients [13].
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