Antidepressant Effects Thwarted by Stressful Environments


A new study, about to be published in the journal Brain, Behavior, and Immunity, investigates the role a stressful environment plays in antidepressant effectiveness. The results of this study, conducted on mice to examine brain inflammation, indicate that SSRIs such as fluoxetine (Prozac) may only be effective for those who live relatively unstressed lives. Indeed, those with stressful lives may actually find their symptoms worsened by the use of such antidepressant medications.

A stressful environment can mitigate the effectiveness of antidepressants, a new study suggests.
A stressful environment can mitigate the effectiveness of antidepressants, a new study suggests.

Since the simplistic serotonin imbalance theory of depression has fallen out of favor, other neurological theories have taken its place in the attempt to find a medical intervention for depression. One current theory involves an immune response in the brain. In previous studies, SSRIs were found to decrease inflammatory responses in the brain, which was theorized to be part of the mechanism of their antidepressant effect.

However, attempts to replicate these studies were inconsistent. Some researchers found pro-inflammatory responses in the brain, while others found anti-inflammatory responses. Because of this, it is unclear whether pro- or anti-inflammatory responses are associated with antidepressant effects.

Given these contradictory results, researchers have hypothesized that the degree of inflammatory response caused by SSRI use is dependent on another factor, the environment. ‚ÄúThe increase in serotonin levels induced by SSRIs enhances neural plasticity, rendering individuals more susceptible to environmental conditions,‚ÄĚ write the researchers, led by Silvia Alboni at the University of Modena and Reggio Emilia, Modena, Italy.

In this study, researchers attempted to discover whether antidepressant medications were more or less effective due to differences in environmental stress. Mice were exposed to stressful situations for 14 days to induce symptoms theorized to mimic human depressive symptoms. The mice were then separated into a stressful condition, an enriched condition, and a standard condition, and in each condition, half were given the SSRI fluoxetine (trade name Prozac).

The results were striking. The antidepressant appeared to increase susceptibility to environmental effects. The mice placed in enriched conditions experienced the pro-inflammatory effect theorized to be helpful, while the mice were continuing to experience stressful conditions experienced an anti-inflammatory effect, which the researchers hypothesized could be even more damaging than no treatment.

There are significant limitations to this study. For instance, it is unclear whether mice that were stressed using puffs of air, doors that were unpredictable, and being placed in a cage with other mice can be considered an appropriate parallel to human depressive symptoms or stressful human situations. It is also unclear whether this inflammatory effect on a microcellular level relates to any change in a person’s experience of depressive symptoms.

However, these results confirm the growing body of literature that indicates that antidepressant drugs may only be effective for individuals who are living relatively unstressed lives. This finding calls into question the effectiveness of these medications for those who need appropriate treatment most‚ÄĒthose who have particularly taxing occupations, who live in poverty, who are homeless, who are facing an abusive partner, or who deal with racism on a daily basis, for instance. Indeed, if antidepressants increase susceptibility to stress, as this study indicates, then these drugs may even be less effective than no treatment for most people with depression.



Alboni, S., Poggini, S., Garofalo, S., Milior, G., El Hajj, H., Lecours, C., . . . Branchi, I. (2016). Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment. Brain Behav. Immun. (Abstract)


  1. Wow. This makes a lot of sense to me. People I’ve seen fail on antidepressants often have chaotic lives. The success stories I can think of are in people who have more comfortable, settled lives. As for the drugs making one more “susceptible to environmental effects,” I can easily see that, too, from personal experience.

    I’d love to think that this will mean more psychosocial approaches to various forms of distress, but…I’m not so sure, at least…not so much in the US. Not yet. Society isn’t there yet. Maybe in 10+/- years?

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      • wow. I really…don’t…have..words.

        Szasz, later on in his career, wrote a book about this sort of thing…Psychiatry The Art of Lies or something like that. There’s also an older book I’ve seen but not read…Whores of the Court, something to that effect.

        On the other hand, shrinks sometimes (often?) go after people dealing with criminal charges. I seem to recall Andrea Yate’s shrink falsely accusing her of making things up based on a Law and Order episode. Something like that, anyway.

        Psychiatrists seem to fancy themselves experts…on everything. Raising children, relationships, morality, etc. They are the High Priests and Priestesses of the secular belief system. Psychologists, counselors, etc. generally function as lesser priests and priestesses serving the same religion.

        I get the impression that a shrink is a shrink is a shrink. The exceptions seem to prove the rule. My best guess is that every psychiatrist has something like this in his or her past. This dude may have just pushed it too far.

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  2. When Dr Christiaan Bernard first began heart transplants many years ago, I heard a story about some boys from another school, regarding a heart transplant trial they claimed they carried out on two mice (that they managed to catch).

    According to the boys, they removed both hearts from both mice and exchanged them. And the result was that one mouse died on the spot, but the other mouse leapt to its feet and ran off. Nobody believed them, but it was a good story!

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