Stressful Environment May Counteract Antidepressant Efficacy

Liam Davenport

September 23, 2016

VIENNA — A stressful environment may counteract the effect antidepressant medications, new research suggests.

An animal study conducted by investigators at the Istituto Superiore di Sanità in Rome, Italy, supports previous research in humans that showed that depressed individuals with a high-status occupation are less likely to respond to antidepressant therapy.

Silvia Poggini, a PhD student in the Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, showed that the effect of fluoxetine (multiple brands) on inflammatory markers in the hippocampus was completely reversed in mice that were placed in a stressful environment. This was not the case with those that were not subjected to stress.

While emphasizing that the results are preliminary, Poggini said the research "indicates that simply taking an SSRI [selective serotonin reuptake inhibitor] 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."

The findings were presented here at the 29th European College of Neuropsychopharmacology (ECNP) Congress.

Direct Biological Evidence

In another study that lends credence to this theory, Austrian researchers found that a high occupational level (OL), in which there are high levels of responsibility and stress, influences antidepressant efficacy.

Investigators at the Medical University of Vienna found that individuals with a high OL were significantly more likely to be resistant to antidepressant therapy and significantly less likely to be currently in remission from depression than their counterparts with a middle or low OL.

Siegfried Kasper, MD, who led the study, believes that "a number of factors" may explain these results.

"For example, there may be specific working environment demands and stressors; people may find it difficult to accept or cope with illness, or to continue with medication; or there may be other factors, related, for example, to cognitive, personality, and behavioral differences," he said.

Poggini told Medscape Medical News that it is difficult for patients to change their environment, "but maybe with cognitive-behavioral therapy they can change their approach to their environment."

In cases of patients who do not respond to antidepressant therapy, "our suggestion is to [combine] antidepressant treatment with psychotherapy, and only in this way may the antidepressant help improve the depressive symptoms."

In the first study, which was published in the July issue of Brain, Behavior, and Immunity, Poggini and colleagues exposed C57BL/6 adult male mice to a 14-day period of chronic stress to induce a depressionlike phenotype. The mice were then randomly allocated to receive fluoxetine or vehicle for 21 days, during which they were exposed to either a stressful or an enriched condition.

The animals' behavior was assessed throughout the treatment period. In addition, expression of the proinflammatory cytokines interleukin (IL)–6, IL-1b, tumor necrosis factor (TNF)–alpha, and interferon (IFN)–gamma, as well as the anti-inflammatory cytokines IL-4 and transforming growth factor (TGF)-beta, in the hippocampus was measured at the end of the 21 days.

Fluoxetine significantly decreased TNF-alpha and IFN-gamma mRNA expression in the stress condition compared with the vehicle but had no effect in the enrichment condition, whereas the drug had the opposite effect on IL-1b mRNA expression, significantly increasing it in the enrichment condition but having no effect in the stress condition.

Reverse transcription polymerase chain reaction analysis in microglia revealed that fluoxetine increased proinflammatory gene expression, including expression of iNOS, CD86, IL- 15, IL-1b and IL-23 genes, and decreased anti-inflammatory gene expression, including expression of arg-1, ym-1, IL-10, and IL-1ra in the enriched condition compared with the vehicle. When fluoxetine was administered during the stress condition, it had the opposite effect.

"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 Poginini.

Laurence Lanfumey, PhD, Centre de Psychiatrie et Neuroscience Inserm, Paris, and Member of the ECNP Executive Committee, who was not involved in the study, described it as a "nice model for combined behavioral and pharmacological treatments in depressionlike 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," he added.

"Although the present work also raised several questions, this kind of experiment is important to do to bridge the gap between behavior and SSRI efficacy."

The second study, which was published in the August issue of European Neuropsychopharmacology, involved 654 individuals with major depression who had undergone at least one adequate antidepressant trial and who were stratified into high, middle, and low OLs.

Dr Kasper and colleagues excluded individuals who were unemployed, students, lived off stock market investments, and were invalid or infirm, as well as those with a diagnosis of bipolar disorder or schizophrenia spectrum disorder.

The mean age of the participants was 49 years, and 65.6% were women. Of the participants, 336 had a high OL, 161 had a middle OL, and 157 had a low OL. Those with a high OL were significantly younger and had a significantly higher educational level than those with a middle or low OL (P < .001 for both).

Logistic regression analysis revealed that individuals with a high OL were more likely to be treatment resistant to antidepressant therapy, at 55.9% vs 40.2% of those with a middle OL and 44.3% of those with a low OL (P = .009). Moreover, participants with a high OL were less likely than those with a middle or low OL to be currently in remission, at 13.7% vs 25.5% and 23.6%, respectively (P = .02).

A high OL was also associated with an increase in the mean number of failed antidepressant treatments per patient, at 1.5 vs 1.4 and 1.1 for middle- and low-OL individuals, respectively (P = .003).

Combination Therapy Best

Commenting on these findings, Eduard Vieta, MD, PhD, chair of the Department of Psychiatry and Psychology at the University of Barcelona Hospital Clinic, Spain, and treasurer of the ECNP, said that the results of the study "might sound counterintuitive.

"But people with highly demanding jobs are subject to a lot of stress, and when they breakdown with depression, it may be particularly difficult to cope."

Nevertheless, Dr Vieta noted that an "alternative explanation, which cannot be ruled out, given the naturalistic design of the study, is that high-status-job patients may be more prone to request psychosocial treatments without the support of pharmacotherapy.

"The ideal treatment of depression is, in general, the combination of both pharmacotherapy and psychotherapy."

The first study was supported by the Italian Ministry of Health. The second study was funded by the Expert Platform on Mental Health Focus on Depression. The authors have disclosed no relevant financial relationships.

29th European College of Neuropsychopharmacology (ECNP) Congress. Abstracts P.2.e.012 and P.2.f.024. Presented September 20, 2016.


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