Antidepressants Normalize the Default Mode Network in Patients With Dysthymia
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IMPORTANCE: The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brain's DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown. OBJECTIVE: To use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity. DESIGN: After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study. Enrollment occurred between 2007 and 2011. SETTING: University research institute. PARTICIPANTS: Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex. MAIN OUTCOME MEASURES: We used resting-state functional-connectivity MRI to measure the functional connectivity of the brain's DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity. RESULTS: Of the 41 subjects with DD, 32 completed the clinical trial and MRI scans, along with the 25 HC participants. At baseline, we found that the coherence of neural activity within the brain's DMN was greater in persons with DD compared with HC subjects. Following a 10-week clinical trial, we found that treatment with duloxetine, but not placebo, normalized DMN connectivity. CONCLUSIONS AND RELEVANCE: The baseline imaging findings are consistent with those found in patients with major depressive disorder and suggest that increased connectivity within the DMN may be important in the pathophysiology of both acute and chronic manifestations of depressive illness. The normalization of DMN connectivity following antidepressant treatment suggests an important causal pathway through which antidepressants may reduce depression.
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The results of studies examining the impact of antidepressant medication initiation on connectivity are heterogeneous.
“The results of studies examining the impact of ADM initiation on connectivity are heterogeneous28–39.”
From The relationship between resting-state functional connectivity, antidepressant discontinuation and depression relapse (2020) · cites this paper as [35]
The Results > Follow-up Scans (page unavailable) report that duloxetine reduced default-mode-network connectivity in patients with dysthymia, so this is a study of antidepressant treatment and connectivity. The paper supplies one result but does not establish that findings across the studies cited as a group are heterogeneous. (LLM, conf=0.82)
Experimental — accuracy not yet measuredEvidence suggests that CBT or medication can modify the cascade of responses to real or perceived threat - CBT by altering behavioral avoidance and information processing related to threat detection and coping, and medication by altering neurotransmitter levels that affect the function and structure of brain circuits.
“Evidence suggests that CBT or medication can modify the cascade of responses to real or perceived threat – CBT by altering behavioral avoidance and information processing related to threat detection and coping [56, 57], and medication by altering neurotransmitter levels that affect the function and structure of brain circuits [58–60].”
From A Sequential Multiple Assignment Randomized Trial (SMART) study of medication and CBT sequencing in the treatment of pediatric anxiety disorders (2021) · cites this paper as [60]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredWell-documented patterns of hyperconnectivity within the DMN in depression are sometimes normalized with antidepressant medication.
“given the well-documented patterns of hyperconnectivity within the DMN in depression (Kaiser et al., 2015) which are sometimes normalized with antidepressant medication (Posner et al., 2013).”
From Changes in functional connectivity following treatment with emotion regulation therapy (2019) · cites this paper as Posner et al., 2013
The few imaging studies combined with an RCT design have shown that SSRIs/SNRIs normalize pre-existing abnormalities in brain structure, function, and metabolism.
“The few imaging studies that have been combined with an RCT design to provide stronger causal inference of the effects of these medications have shown that they normalize pre-existing abnormalities in brain structure [59], function [60], and metabolism [123].”
From A Sequential Multiple Assignment Randomized Trial (SMART) study of medication and CBT sequencing in the treatment of pediatric anxiety disorders (2021) · cites this paper as [60]
It is highly probable that medication mechanisms are initiated by effects on altering neurotransmitter levels, which in turn affect the function and structure of brain circuits.
“It is highly probable, however, that those mechanisms are initiated by the effects that medication has on altering neurotransmitter levels, which in turn affect the function and structure of brain circuits [58–60].”
From A Sequential Multiple Assignment Randomized Trial (SMART) study of medication and CBT sequencing in the treatment of pediatric anxiety disorders (2021) · cites this paper as [60]
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Self-citationLangenecker, S. A., Klumpp, H., Peters, A. T., Crane, N. A., DelDonno, S. R., Bessette, K. L., Ajilore, O., Leow, A., Shankman, S. A., Walker, S. J., et al. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.07.001 · Cited by 11 · see citing works
- Authors
- Posner, J., Hellerstein, D. J., Gat, I., Mechling, A., Klahr, K., Wang, Z., McGrath, P. J., Stewart, J. W., & Peterson, B. S.
- Affiliations
- New York State Psychiatric Institute (US)
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2013-04-01
- Volume
- 70
- Issue
- 4
- Pages
- 373
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC3935731
- OpenAlex
- W2095139544
- Cited by
- 268
- References
- 48
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 15 · 2023: 12 · 2022: 18 · 2021: 50 · 2020: 18 · 2019: 21 · 2018: 15 · 2017: 15 · 2016: 22 · 2015: 25 · 2014: 21 · 2013: 8
- FWCI
- 13.84
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (K-02-74677)
- National Institute of Mental Health (K23MH091249)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- default mode network, dysthymia, functional connectivity, resting-state functional connectivity, duloxetine, antidepressant treatment, chronic depression, major depressive disorder, neural coherence
- MeSH terms
- Duloxetine Hydrochloride, Adult, Antidepressive Agents, Brain, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Nerve Net, Thiophenes, Case-Control Studies, Dysthymic Disorder, Functional Neuroimaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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