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

S. Alboni, R.M. Van DIjk, S. Poggini, G. Milior, M. Perrotta, T. Drenth, N. Brunello, D.P. Wolfer, C. Limatola, I. Amrein, F. Cirulli, L. Maggi, I. Branchi

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)552-561
Number of pages10
JournalMolecular Psychiatry
Issue number4
Publication statusPublished - 2017


  • brain derived neurotrophic factor
  • cyclic AMP responsive element binding protein
  • fluoxetine
  • serotonin uptake inhibitor
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • clinical practice
  • controlled study
  • depression
  • drug efficacy
  • endophenotype
  • excitatory postsynaptic potential
  • gene expression profiling
  • hippocampal CA1 region
  • immunohistochemistry
  • long term potentiation
  • male
  • molecular dynamics
  • mouse
  • nerve cell plasticity
  • neuromodulation
  • nonhuman
  • outcome assessment
  • prognosis
  • protein blood level
  • protein phosphorylation
  • real time polymerase chain reaction
  • RNA extraction
  • signal transduction
  • Western blotting
  • affect
  • animal
  • animal behavior
  • brain
  • C57BL mouse
  • Depressive Disorder, Major
  • drug effects
  • environment
  • hypophysis adrenal system
  • hypothalamus hypophysis system
  • metabolism
  • Affect
  • Animals
  • Behavior, Animal
  • Brain
  • Brain-Derived Neurotrophic Factor
  • CA1 Region, Hippocampal
  • Depression
  • Endophenotypes
  • Environment
  • Fluoxetine
  • Hypothalamo-Hypophyseal System
  • Long-Term Potentiation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pituitary-Adrenal System
  • Serotonin Uptake Inhibitors


Dive into the research topics of 'Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment'. Together they form a unique fingerprint.

Cite this