Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment

Abstract

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic–pituitary–adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype 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.

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

“…The results concerning the neural and behavioral response to fluoxetine treatment displayed in the different environmental conditions by the experimental subjects used in this study have been published elsewhere (Alboni et al, 2016). These show that the exposure to 14 days of stress before treatment induced a depression-like phenotype and the neurobehavioral profile was affected by treatment according to the quality of the environment.…”

“…It is worth noting that, in order to assess the effects of treatment in individuals showing a depression-like phenotype, we administered fluoxetine to mice previously exposed to chronic stress. Such pre-exposure activates the hypothalamic-pituitary-adrenal axis, increasing corticosterone levels (Alboni et al, 2016;Milior et al, 2015), and likely affects the interaction among the drug, the brain and immune system, making the results not applicable to different circumstances. However, this procedure has been chosen because it reproduces the clinical condition of patients who, before receiving the treatment, already show depressive symptoms and have high levels of cortisol (Juruena et al, 2009).…”

“…Recently, a number of preclinical studies have identified the living environment as a key moderator of the outcome of SSRI treatment (Alboni et al, 2016;Branchi, 2011;Branchi et al, 2013). In particular, since the increase in serotonin levels induced by SSRIs enhances neural plasticity, rendering individuals more susceptible to environmental conditions, the outcome of SSRI administration is not univocal but depends on the quality of the environment.…”

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

“…106 Indeed, evidence suggests that environmental enrichment is necessary for the antidepressant-like effect of fluoxetine in mice, and that this effect is mediated through increased hippocampal BDNF and decreased corticosterone levels. 107 Increasing evidence supports a role for SSRIs in the enhancement of synaptic plasticity, 108 and repeated treatment in mice can reactivate cortical plasticity after monocular deprivation 109 and restore behavior in a fear extinction paradigm. 110 Likewise in humans, if administered early enough, chronic fluoxetine treatment can improve motor deficits in stroke patients.…”

Chance of response to an antidepressant: what should we say to the patient?

“…Actually, repeated individual cross-over testing would be required to eliminate several sources of variance and determine the real response rate. Recently, it could be demonstrated that even in mice the response rate under treatment with selective serotonin reuptake inhibitors was significantly dependent on the circumstances of the environment 8 . In everyday practice, key predictors of the individual response rate are in fact the "health care system" and the variable "doctor" 7 .…”