Antidepressant Treatment Outcome Depends on the Quality of the Living Environment: A Pre-Clinical Investigation in Mice

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 determine

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

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

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

It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions

Improving our understanding of sex-dependent mechanisms regulating healthspan through novel methodological approaches

Improving our understanding of sex-dependent mechanisms regulating healthspan through novel methodological approaches Alessandra Berry1, Carla Raggi1, Chiara Musillo1, Gaia De Cristofaro1, Igor Branchi1, Silvia Poggini1, Aurelia Viglione1, Francesca Cirulli1 1Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy A well-described clinical phenomenon is that females live longer but tend to experience greater levels of co-morbidity and disability than males, a condition that has been regarded as the “frailty paradox”. Frailty is a common condition associated with ageing relying on an increased vulnerability including decline of physical conditions in addition to metabolic and cognitive impairment. Notwithstanding this evidence, standardized measures of frailty in the ageing population (and in animal models) are still lacking. In the framework of the European project “Ageing with Elegans”, we sought to device a comprehensive protocol to assess frailty in both male and female mice. A frailty index was adapted from previously published protocols. Motor coordination and balance were assessed by means of the rotarod and beam walking tests, while muscle strength was measured using the grip strength test. Specific protocols were developed to measure cognitive performance, emotionality and motivation in the automated IntelliCage (TSE, Germany). This apparatus allows testing mice in their home-cage avoiding social isolation and the experimenter’s manipulation, markedly reducing the stress imposed by testing, a condition to which old animals are highly sensitive. Using this testing battery, we found that, despite females appeared in worst physical condition than males, they showed better performance in most of the above-described tasks, in agreement with the gender differences described in the human population. In conclusion, this protocol may be applied to better characterize the age-related frailty condition and to devise specific interventions. Support: H2020 AwE (grant N. 633589)

Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress

Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling - which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in the healthy brain - has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx3cr1 gene affects the brain's response to chronic stress. To this purpose, we housed Cx3cr1 knockout and wild-type adult mice in either control or stressful environments for 2weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron-microglia communication via the CX3CR1-CX3CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression

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

Combined Fluoxetine and Metformin Treatment Potentiates Antidepressant Efficacy Increasing IGF2 Expression in the Dorsal Hippocampus

An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available

Brain-immune crosstalk in the treatment of major depressive disorder

A growing number of studies are pointing out the need for a conceptual shift from a brain-centered to a body-inclusive approach in mental health research. In this perspective, the link between the immune and the nervous system, which are deeply interconnected and continuously interacting, is one of the most important novel theoretical framework to investigate the biological bases of major depressive disorder and, more in general, mental illness. Indeed, depressed patients show high levels of inflammatory markers, administration of pro-inflammatory drugs triggers a depressive symptomatology and antidepressant efficacy is reduced by excessive immune system activation. A number of molecular and cellular mechanisms have been hypothesized to act as a link between the immune and brain function, thus representing potential pharmacologically targetable processes for the development of novel and effective therapeutic strategies. These include the modulation of the kynurenine pathway, the crosstalk between metabolic and inflammatory processes, the imbalance in acquired immune responses, in particular T cell responses, and the interplay between neural plasticity and immune system activation. In the personalized medicine approach, the assessment and regulation of these processes have the potential to lead, respectively, to novel diagnostic approaches for the prediction of treatment outcome according to the patient's immunological profile, and to improved efficacy of antidepressant compounds through immune modulation

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

<p>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 <i>p</i> = 0.0120 and * indicates <i>p</i> = 0.0464, vs. vehicle group. Data are means ± S.E.M.</p

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

<p>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, <i>p</i><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.</p