Why don’t antidepressants work in some patients? Mouse study shows it may be down to your environment

Media Release: European College of Neuropsychopharmacology (ECNP)
“For the science and treatment of disorders of the brain”

Why don’t antidepressants work in some patients? Mouse study shows it may be down to your environment
For immediate release, Tues 20th September, Vienna

SSRI antidepressants (Selective Serotonin Reuptake Inhibitors, the best known being Prozactm) are amongst the most commonly taken medicines. However, there seems to be no way of knowing in advance whether or not SSRIs will work effectively. Now a group of European researchers has developed a new theory of SSRI action, and tested it in stressed mice. The results, which are presented at the ECNP conference in Vienna, shows why the circumstances we find ourselves in may influence whether an antidepressant works or not.
According to researcher, Silvia Poggini (Istituto Superiore di Sanità, Rome):
“There is no doubt that antidepressants work for many people, but for between 30 and 50% of depressed people, antidepressants don’t work. No-one knows why. This work may explain part of the reason”.
The researchers have proposed that simply increasing the levels of serotonin, by taking an SSRI, does not cause a recovery from depression, but puts the brain into a condition where change can take place – it increases the plasticity of the brain, making it more open to being changed. “In a certain way it seems that the SSRIs open the brain to being moved from a fixed state of unhappiness, to a condition where other circumstances can determine whether or not you recover” said Ms Poggini. According to the researchers, it is the environmental conditions you find yourselves in at the time of the treatment which determines whether you are likely to get better or worse.
To test this, they took a sample of mice which they subjected to stress for two weeks. They started treating the mice with the SSRI fluoxetine, and split the group. They continued to stress half (n=12) of the group of mice but the other half of the mice were subjected to a more comfortable environment. They then tested all the mice to measure the levels of the stress-related cytokines in the brain. Cytokines are protein-related molecules which aid cell to cell communication in the immune system.
They found that mice kept in a more comfortable environment showed an increase in the expression of pro-inflammatory cytokines and decreased anti-inflammatory-related genes, as well as showing fewer signs of depression, whereas those under continuous stress showed the opposite effect (i.e. a decrease in pro-inflammatory cytokines, and an increase in anti-inflammatory gene expression, with more signs of depression). The fluoxetine-treated mice exposed to the comfortable environment showed a 98% increase in the pro-inflammatory cytokines IL-1β while mice kept in a stressed environment and treated with fluoxetine showed a 30% decrease in the pro-inflammatory cytokines TNF-α.
This indicates that the environment determines the response to antidepressants. According to Silvia Poggini:
“This work indicates that simply taking an SSRI is probably not enough. To use an analogy, the SSRIs put you in the boat, but a rough sea can determine whether you will enjoy the trip. For an SSRI to work well, you may need to be in a favourable environment. This may mean that we have to consider how we can adapt our circumstances, and that antidepressant treatment would only be one tool to use against depression”.
She cautioned “Our studies have a number of limitations. First of all, we are not explaining the complete range of actions of SSRIs. It’s also an animal model, so clinical and epidemiological studies are needed to further test the validity of the hypothesis. Our results are preliminary and we strongly recommend that patients stick to the treatment prescribed by their doctors”.
Commenting, Dr Laurence Lanfumey (Centre de Psychiatrie et Neuroscience Inserm, Paris), Member of the ECNP Executive Committee, said:

“This original study is a nice model for combined behavioral and pharmacological treatments in depression- like disorders. The idea that environment could impact the output of a pharmacological treatment has been suggested for years, but this work brings direct biological evidences of such an interaction. Although the present work also raised several questions, this kind of experiment is important to do to bridge the gap between behavior and SSRIs efficacy”.
Note: For funding details, abstract, etc., see ’Notes for Editors’. A paper based on this work appeared in the peer-reviewed journal, Brain, Behaviour, and Immunity, 27 July 2016. See http://www.sciencedirect.com/science/article/pii/S088915911630349X
END
Notes for editors
Please mention the European College of Neuropsychopharmacology Congress in any stories which result from this press release.

Contacts
Silvia Poggini silviapoggini@gmail.com
Dr Laurence Lanfumey@inserm.fr laurence.lanfumey@inserm.fr
ECNP Press Officer, Tom Parkhill press@ecnp.eu tel +39 349 238 8191 (Italy)
The European College of Neuropsychopharmacology (ECNP)
The ECNP is an independent scientific association dedicated to the science and treatment of disorders of the brain. It is the largest non-institutional supporter of applied and translational neuroscience research and education in Europe. Website: www.ecnp.eu
The annual ECNP Congress takes place from 17th to 20th September in Vienna. It is Europe’s premier scientific meeting for disease-oriented brain research, annually attracting between 4,000 and 6,000 neuroscientists, psychiatrists, neurologists and psychologists from around the world. Congress website: http://www.ecnp-congress.eu/


Abstract Fluoxetine treatment affects the inflammatory response according to the quality of the living environment
S. Poggini1S. Alboni2 S. Garofalo3 G. Milior3,4 N. Brunello2 D.P. Wolfer5 C. Limatola3,6 L. Maggi3 I. Branchi1,5
1Istituto Superiore di Sanità, Department of Cell Biology and Neurosciences, Rome, Italy, 2University of Modena and Reggio Emilia, Department of Life Sciences, Modena, Italy, 3Sapienza University of Rome, Department of Physiology and Pharmacology, Rome, Italy, 4Institut du Cerveau et de la Moelleepiniere, Sorbonne Universites, Paris, France, 5University of Zurich, Istitute of Anatomy, Zurich, Switzerland,6IRCCS Neuromed, Pozzilli, Isernia, Italy
Aim of the study: It has been hypothesized that SSRIs, the most common treatment for major depression, affect mood through changes in immune function [1]. However, findings concerning the effects of SSRIs on inflammation are contradictory showing that these drugs act either as pro- or anti-inflammatory compounds [2]. Since previous studies showed that SSRI effects are moderated by the quality of the living environment [3] here we investigated whether the environment determines the effects of SSRI treatment on inflammation.
Methods: We treated C57BL/6 adult male mice with either fluoxetine or vehicle while exposing them to either an enriched or a stressful condition, following a chronic stress period aimed at inducing a depression-like phenotype. In the whole hippocampus, we assessed expression levels of IL-6, TNF-a, IL-1b and IFN-g, which are pro-inflammatory cytokines, and IL-4 and TGF-b, two anti-inflammatory cytokines. In isolated microglia, we performed RT-PCR analysis to assess the expression levels of a number of pro- and anti-inflammatory-related genes.
Results: As compared to vehicle, fluoxetine decreased TNF-a mRNA expression level in the stress condition (p = 0.0082, t = ˗3.075) but did not affect it in the enriched condition. Whereas IL-1b mRNA expression was increased by treatment in enrichment (p = 0.0008, t = 4.714) but not affected in stress. The change in IL-1b mRNA levels was paralleled by concordant modifications of IL-1b precursor and mature protein levels, fluoxetine-treated subjects showing a decrease in pro-IL-1b (p = 0.0281, t = ˗2.368) and an increase in mature IL-1b (p = 0.0460, t = 2.135) compared to vehicle. IFN-g expression levels were modified by fluoxetine as compared to vehicle only in the stressful condition, treated mice showing decreased mRNA levels compared to controls (p = 0.0109, t = ˗3.007).
RT-PCR analysis revealed that in microglia fluoxetine treatment administered in the enriched condition increased pro-inflammatory and decreased anti-inflammatory-related genes expression, in particular, iNOS (p = 0.041, t = ˗2.965), cd86 (p < 0.001, t = ˗6.399), IL-15 (p = 0.008, t = ˗3.925), IL-1b (p = 0.038, t = ˗2.675) and IL-23 (p < 0.001, t = ˗7.343) mRNA levels were increased, while arg-1 (p = 0.022, t = ˗3.059), ym-1 (p = 0.005, t = ˗5.547), IL-10 (p = 0.002, t = ˗5.201), IL-1ra (p = 0.025, t = ˗3.151) were reduced compared to vehicle. An opposite effect was found when fluoxetine treatment was administered in the stressful condition, specifically: Arg-1 (p = 0.007, t = ˗4.042), cd206 (p = 0.032, t = ˗2.783), ym-1 (p = 0.042, t = ˗2.961), TGF-b (p = 0.040, t = ˗2.605), socs3 (p = 0.031, t = ˗2.963), IL-10 (p = 0.006, t = ˗4.117), IL-1ra (p = 0.009, t = ˗3.752), fizz-1 (p = 0.022, t = ˗3.051) mRNA levels were increased, while iNOS (p = 0.005, t = ˗5.535), TNF-a (p = 0.018, t = ˗3.217), IL-1b (p = 0.008, t = ˗3.917), IL-6 (p = 0.026, t = ˗2.934) and IL-23 (p = 0.015, t = ˗3.366) levels were decreased compared to vehicle.
Conclusions: The present findings show that the effects of SSRIs on inflammation depend on the quality of the environment and provide a possible explanation for the inter-individual differences in SSRI action and effects. The increased understanding of the molecular mechanisms underlying this interplay may allow for more effective personalization of antidepressant treatment strategies based on the quality of the living environment of the depressed patient.
References
[1] Carvalho, L.A., Torre, J.P., Papadopoulos, A.S., Poon, L., Juruena, M.F., Markopoulou, K., Cleare, A.J., Pariante, C.M., 2013. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. Journal of affective disorders 148, 136–140.
[2] Horowitz, M.A., Wertz, J., Zhu, D., Cattaneo, A., Musaelyan, K., Nikkheslat, N., Thuret, S., Pariante, C.M., Zunszain, P.A., 2014 Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells. Int J Neuropsychopharmacol. Oct 31, 18(3).
Dr. Branchi’s research has been supported by the Italian Ministry of Health, RF-2011-02349921, “The role of the brain-adipocyte axis activity in potentiating antidepressant efficacy”.