Antidepressants may normalize brain tissue changes caused by chronic depression

An experimental study of individuals suffering from persistent depressive disorder found that treatment with the antidepressants duloxetine and desvenlafaxine normalized tissue microstructure in parts of the brain. Symptom severity mediated the treatment effects on tissue microstructure, suggesting that abnormal tissue at the start of the study might be a compensatory response of the brain to depression symptoms. The paper was published in NeuroImage: Clinical.

Persistent depressive disorder, formerly called dysthymia, is a chronic condition in which low mood and related symptoms persist for at least two years in adults. Symptoms may include low energy, poor concentration, hopelessness, low self-esteem, sleep disturbance, appetite changes, and reduced enjoyment or motivation.

These symptoms may be less intense than those of a major depressive episode, but their long duration can substantially impair work, relationships, and quality of life. Some people with persistent depressive disorder also experience superimposed episodes of major depression, sometimes informally called “double depression.” The mainstream treatments involve psychotherapy, medication, or a combination of both.

Study author Ravi Bansal, a researcher affiliated with the University of Southern California and Children’s Hospital Los Angeles, and colleagues note that previous studies have reported changes to the microstructure of different cortical and subcortical regions of the brain in individuals suffering from persistent depressive disorder. Studies have also noted that people who experience a reduction of depressive symptoms or remission in response to antidepressant medication also tend to see the structural changes associated with depression returning to normal.

These, for example, include increased volume of the amygdala and hippocampus and thickening of the limbic cortex region of the brain in people who experience a remission or have milder clinical symptoms after treatment. In contrast, the volume of these areas declines and the cortex thins in individuals who do not remit or have more severe symptoms.

The researchers conducted a study in which they tracked brain microstructure changes in individuals suffering from persistent depression and treated with two different antidepressant drugs: duloxetine and desvenlafaxine.

Participants in the duloxetine study were 57 individuals suffering from persistent depression recruited from the New York State Psychiatric Institute. They were randomly divided into two groups. One group of 29 participants was assigned to receive duloxetine (30-120 mg/day) for 10 weeks. The other group of 28 participants was assigned to receive a placebo for the same period.

Participants in the desvenlafaxine study were 61 individuals recruited from local clinics, psychiatric listservs, hospital bulletin boards, newspapers, and Craigslist in the same geographical area as the first study. They were also randomly divided into two groups. One group of 31 participants was assigned to receive desvenlafaxine (50mg at the start, increased to 100mg per day after week four if participants tolerated the lower dose and were still depressed), while the remaining 30 participants received a placebo.

The studies also included 35 healthy individuals as an additional control group. Their average age was about 40 years, and 22 of them were men. This group did not differ from patients in the two studies in either average age or gender.

Participants completed magnetic resonance imaging scans of their brains before and after the treatment. However, a substantial share of participants did not complete these brain imaging procedures. Because the number of participants who completed these procedures was relatively small in the end, the study authors merged data from these two studies and analyzed them jointly for overlapping effects.

Results showed that duloxetine and desvenlafaxine led to unique changes in brain tissue microstructure in the dorsal prefrontal cortex. The study also revealed overlapping medication effects. Duloxetine and desvenlafaxine both led to the normalization of tissue microstructure in the limbic system. In contrast, tissue microstructure in participants who received a placebo tended to continue deviating further away from values for healthy participants.

Further analyses showed that symptom severity mediated the treatment effects on tissue microstructure. In other words, the treatments led to a reduction of symptoms, which, in turn, led to the normalization of brain tissue microstructure. This suggests that abnormal tissue microstructure at the start of the study is at least partly a compensatory neuroplastic response of the brain helping patients manage symptoms.

“Medication may have reduced the need for compensatory response because it reduces symptom severity, whereas placebo sustains the need for compensation. The unique and common effects of duloxetine and desvenlafaxine on neurotransmitter systems are likely responsible for their spatially unique and common effects in altering tissue microstructure,” the study authors concluded.

The study contributes to the scientific understanding of the effects of antidepressant medication on brain microstructure. However, it should be noted that around one in every three participants failed to complete the study or provide the needed data. This substantial attrition rate might have affected the results. Study authors also note that patients who were acutely suicidal or who had other medical and psychiatric conditions were excluded from participation, thereby limiting the generalizability of the findings.

The paper, “Effects of antidepressant medications on brain tissue microstructure in persistent depressive disorder across two randomized controlled trials,” was authored by Ravi Bansal, David J. Hellerstein, Siddhant Sawardekar, Ying Chen, and Bradley S. Peterson.