SSRIs a 'Double-Edged Sword' in Major Depression?

Liam Davenport

October 19, 2018

BARCELONA, Spain – Use of selective serotonin reuptake inhibitors (SSRIs) appears to amplify the living environment of patients with major depressive disorder (MDD) in a dose-dependent manner, so that those in more positive situations are more likely to achieve remission compared with their counterparts living in less favorable conditions, new research shows.

Investigators led by Igor Branchi, PhD, Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy, explored the hypothesis that SSRIs may not "affect mood per se but [may amplify] the influence of living conditions on mood."

The clinical implications of the finding are "tricky," Branchi told Medscape Medical News. One potential implication may be that "patients living in adverse environments should not be treated with SSRIs because they may not benefit." However, he added, further study is needed before any firm conclusions can be drawn about the drugs' use in particular patient groups.

The findings were presented here at the 31st European College of Neuropsychopharmacology (ECNP) Congress.

Double-Edged Sword

SSRIs are the standard treatment for MDD. However, the investigators point out the efficacy of these agents is "variable and incomplete," with 60% to 70% of patients not achieving remission and 30% to 40% failing to show a significant response.

To better understand the mechanism of action of SSRIs with the aim of improving efficacy, a number of researchers have shown that serotonin enhances plasticity in the cortex.

Moreover, it has been shown that a polymorphism in the serotonin transporter gene regulatory region can affect the way in which individuals respond to the environment, with those homozygous for the long allele less vulnerable to adverse circumstances and those homozygous for the short allele highly susceptible.

This research led the current investigators to develop the hypothesis that neural plasticity associated with serotonin is a "double-edged sword" because increased levels lead to both greater vulnerability and an improved capacity to recover from MDD.

Specifically, Branchi noted that high serotonin levels increase plasticity in the brain, which enhances its ability to change an individual's behavioral habits. In a supportive environment, this results in a beneficial outcome, but in an adverse environment it can lead to worse outcomes.

In other words, he said, SSRIs simply amplify the impact of the environment on mood, but it is the nature of that environment that drives the direction of the change.

To test this hypothesis, Branchi and colleagues conducted a number of studies in preclinical models, but wanted to examine the hypothesis in a clinical population.

Using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the researchers compared the relative efficacy of different treatments for depression to identify predictors of remission.

STAR*D included 4000 patients aged 18 to 75 years who had a primary diagnosis of nonpsychotic MDD, had a score of 14 or higher on the Hamilton Rating Scale for Depression, and were being treated in specialty and primary care.

Sociodemographic characteristics were recorded at baseline and patients were assessed at weeks 0, 2, 4, 6, 9, and 12 using the Quick Inventory of Depressive Symptomatology - Self Report (QIDS16-SR).

An improvement in symptoms was defined as a reduction in QIDS16-SR scores by at least 1. Stationary patients were those with no change in scores and worsening symptoms were defined as an increase in scores of 1 or higher. Remission was defined as a score reduction of 5 or less.

Preliminary Analysis

In their first analysis, Branchi and colleagues looked at the initial 12 weeks of treatment with the SSRI citalopram during level 1 of the study, focusing on patients with an overlapping clinical history treated with citalopram 40 mg/day for 4 weeks and then 20 mg/day or 40 mg/day for 2 weeks.

This yielded a total of 357 patients treated with the lower dose between weeks 4 and 6, and 234 who received the higher dose during that period.

The results of this preliminary analysis, published last year, showed that for patients on the 20 mg/day dose of citalopram, there was no impact of employment, income, or education on the likelihood of a patient improving, being stationary, or worsening.

However, all of those factors had a significant impact on whether a patient was likely to improve among those given the higher 40 mg/day dose.

Unemployment had a five-fold impact on whether a patient was likely to experience an improvement in symptoms in this group, while income had a six-fold impact and educational level had a 37-fold effect (P < .05 for all).

A similar pattern was shown for remission, in which employment, income, and education had a two- to eight-fold impact on whether a patient was likely to go into remission when they were receiving the 40 mg/day dose of citalopram (P < .05). This effect was not seen with the lower dose.

For the current analysis, the researchers examined not just the 591 patients with overlapping clinical histories but all 4000 patients treated for 12 weeks with citalopram included in STAR*D to determine the correlation between the quality of patients' living environment and mood.

To do this, they conducted a principal component analysis of the QIDS16-SR scores to identify meaningful groups of symptoms. They also used canonical correlation analysis to select sociodemographic features that indicated socioeconomic status and symptoms, and examined the Pearson correlation between the canonical correlation coefficients and the dose level during treatment.

From this, the investigators selected ethnicity, education, income, unemployment, and insurance as markers of socioeconomic status, relating that to the indicative mood symptoms of core emotional, appetite/weight, and sleep/insomnia items from the questionnaire.

Dose-Dependent Effect

Results showed that the impact of the living environment on mood increased with increasing cumulative doses of citalopram, at an r value of 0.88 (P = .0000143), a finding that was highly significant.

Furthermore, receiver operating curve analysis showed that, in patients receiving low-dose citalopram, the environment was not able to predict remission at week 12 in responders (area under the curve [AUC], 0.54).

However, the environment was highly predictive of remission at 12 weeks among individuals being treated with high-dose citalopram (AUC, 0.81).

Branchi concluded that SSRIs amplify the influence of the environment on mood, that they do not have a "univocal" effect, with a permissive, rather than instructive, role.

He proposed a novel theoretical framework in which both biological and psychosocial factors are used as fundamental determinants of recovery from MDD.

Moreover, the role of SSRIs in plasticity should be viewed as a starting point for innovative and effective antidepressant strategies.

Branchi believes that the best approach would likely be to treat patients in adverse environments with SSRIs but also "give them the opportunity to better face their environment, for instance through psychotherapy or cognitive behavioral therapy, or something that allows them to be able to better face adversities."

Reinforcing his point, Branchi said "there are data in the literature showing that different forms of psychotherapeutic approaches in combination with antidepressants can be more effective than antidepressants alone."

These findings, the investigators note, provide a potential explanation for the variable efficacy of SSRIs and may lead to the development of personalized strategies aimed at enhancing the efficacy of these agents.

Findings "Make Clinical Sense"

Commenting on the findings for Medscape Medical News, Andreas Meyer-Lindenberg, MD, PhD, director, Central Institute of Mental Health, Mannheim, Germany, who cochaired the symposium and was not involved in the study, said the results "make clinical sense."

Meyer-Lindenberg explained that he had also studied the serotonin transporter gene and found that it mediates the effect of the environment on mood.

"So from that point of view, what he's observing in this reanalysis of these studies makes sense," he said.

"It would increase or decrease your gain, if you will, of the impact of the environment," he added.

Meyer-Lindenberg said the one aspect that requires further study is that of antidepressant withdrawal, which he underlined is a "heavy topic many people are discussing these days."

"I think his prediction would have to be that, as he withdraws antidepressants, there should be less of a gain effect of the environment," he said. "This is not what I think most clinicians observe during antidepressant withdrawal, but we didn't have this discussion."

The research was funded by the Italian Ministry of Health. None of the participants reported any relevant financial relationships.

31st European College of Neuropsychopharmacology (ECNP) Congress. Abstracts S.13.02 and P.543, presented October 8, 2018.

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