Selective serotonin reuptake inhibitors are a widely used type of antidepressant. However, their efficacy in the treatment of depression has long been debated. While there is currently no method of knowing ahead of treatment whether this type of medication will work effectively, researchers have found what may influence its success.

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Study findings reveal that the environment a person is subjected to may determine their response to antidepressants.

Selective serotonin reuptake inhibitors (SSRIs) can help manage the symptoms of moderate to severe depression, as well as other mental health conditions, such as generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder (PTSD).

SSRIs are suggested to work by increasing levels of serotonin in the brain. Serotonin is a neurotransmitter, which is a chemical messenger that carries signals between nerve cells and the brain. A rise in serotonin levels can improve symptoms and make people more responsive to psychotherapy.

“There is no doubt that antidepressants work for many people, but for between 30 percent and 50 percent of depressed people, antidepressants don’t work,” says Silvia Poggini, of Istituto Superiore di Sanità in Rome, Italy. “No one knows why. This work may explain part of the reason,” she adds.

Poggini and a team of European researchers have developed a new theory of how SSRIs control depression and have tested the principle in stressed mice. They presented their findings at the European College of Neuropsychopharmacology (ECNP) conference in Vienna.

The team has proposed that recovery from depression does not occur solely from increasing levels of serotonin with SSRIs. They suggest instead that the increased serotonin levels put the brain into a condition where change can take place by increasing the plasticity of the brain and making it more susceptible to change.

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.”

Silvia Poggini

The researchers indicate that the environmental conditions people find themselves in at the time of antidepressant treatment may determine whether they are likely to get better or worse.

Poggini and colleagues tested their hypothesis on mice that been subjected to an enriched or stressful condition for 2 weeks. Following the stressful period aimed at inducing depression-like characteristics, all the mice were treated with the SSRI fluoxetine.

The mice were then split into two groups, half of which continued to be stressed and the other half subjected to a more comfortable environment.

Measures of stress-related cytokines – protein-related molecules that aid cell-to-cell communication in the immune system – were analyzed in the brains of all the mice.

Results indicated that compared with the stressed mice, the mice that were kept in a more comfortable environment presented increased expression of pro-inflammatory cytokines and decreased anti-inflammatory-related genes, as well as showing fewer signs of depression.

In contrast, the stressed mice showed decreased pro-inflammatory cytokines and increased anti-inflammatory gene expression, with more signs of depression.

The mice exposed to the comfortable environment had a 98 percent increase in the pro-inflammatory cytokines IL-1β, and the mice subjected to a continually stressed environment had a 30 percent decrease in the pro-inflammatory cytokines TNF-α.

These findings show that the environment determines the response to antidepressants, says 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 favorable 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 continues.

Poggini cautions that there are some study limitations, including that the research does not explain the complete range of actions of SSRIs. The current study is an animal model, and further studies are required to test the hypothesis in humans.

“Our results are preliminary, and we strongly recommend that patients stick to the treatment prescribed by their doctors,” advises Poggini.

“This original study is a nice model for combined behavioral and pharmacological treatments in depression-like disorders,” comments Dr. Laurence Lanfumey, of the Centre de Psychiatrie et Neuroscience Inserm, Paris, and member of the ECNP Executive Committee.

The idea that environment could impact the output of a pharmacological treatment has been suggested for years, but this work brings direct biological evidence of such an interaction.”

Dr. Laurence Lanfumey

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,” Lanfumey concludes.

Read about how most antidepressants are ineffective for children and teens.