Pathophysiologic Process Likely Responsible for Persistent Depressive Disorder

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Investigators explored a link between elevated N-acetylaspartate concentrations and brain mechanisms in patients with persistent depressive disorder who were treated with duloxetine.

Persistent depressive disorder (PDD) does not appear to be the direct consequence of elevated N-acetylaspartate (NAA) concentrations, with a more fundamental pathophysiologic process likely causing the disorder and determining the severity of its symptoms. A 10-week, prospective, placebo-controlled, double-blind, randomized controlled study ( identifier: NCT00360724) was conducted to evaluate treatment with duloxetine in patients with PDD. Results of the study were published in the journal PLoS One.

The investigators sought to assess whether patients with PDD have abnormal levels of NAA and whether those levels become normalized after treatment with the antidepressant duloxetine. They also conducted a post hoc analysis of other important brain metabolites in order to better comprehend the cellular and physiologic determinants of changes in NAA levels.

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Proton magnetic resonance spectroscopic imaging (1H MRSI) data were acquired on a
3 Tesla (3T), magnetic resonance imaging (MRI) scanner from 41 patients with PDD at 2 time points: prior to the start of the study and at the end of the 10-week study. 1H MRSI data were also obtained once from 29 healthy controls (age, 37.7±11.2 years; 17 men). Patients were randomly assigned to treatment with the active medication (n=21) or placebo (n=20). Average patient age was 39.9±10.4 years; 22 were men.

Study results showed that patients had significantly higher baseline levels of NAA across white matter pathways and subcortical gray matter that was in direct proportion to the severity of symptoms of depression. Over the duration of the study, NAA concentrations declined in duloxetine-treated patients in the direction of healthy values, whereas levels in placebo-treated patients increased, deviating even farther from healthy values.

In addition, changes in NAA levels did not mediate the effects of duloxetine in decreasing symptom severity. Rather, changes in the severity of symptoms partially mediated the effects of the medication on NAA concentrations, particularly in the caudate nucleus and the putamen.

The investigators concluded that their findings suggest that although the use of duloxetine normalized NAA levels, it did so by modulating the severity of depressive symptoms. At baseline, NAA concentrations were significantly elevated across numerous regions of the brain in direct proportion to symptom severity, with the levels normalizing during treatment with the study medication. Based on mediation analyses, treatment reduced the severity of symptoms not by normalizing metabolite concentrations, but through other, as yet unidentified, brain mechanisms.


Bansal R, Hellerstein DJ, Sawardekar S, O’Neill J, Peterson BS. Effects of the antidepressant medication duloxetine on brain metabolites in persistent depressive disorder: a randomized, controlled trial. PLoS One. 2019;14(7):e0219679.