Default mode network functional connectivity following treatment with conventional antidepressants and (es)ketamine in major depressive disorder: A systematic review
Juliana Lima Constantino, Jesca E. de Jager, Jasper O. Nuninga, Jeanine Kamphuis, Robert A Schoevers, Jens H van Dalfsen
Psychiatry Research Neuroimaging September 17, 2026 DOI: 10.1016/j.pscychresns.2026.112333 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Adults with major depressive disorder across 19 included studies |
| Interventions | Conventional antidepressants Ketamine |
| Topics | Default mode network Depression Esketamine Ketamine |
| Key findings | Conventional antidepressants were associated with heterogeneous changes in default mode network resting-state functional connectivity, some of which related to clinical improvement, whereas ketamine was mostly associated with reductions in DMN rsFC, particularly DMN-limbic connectivity. The authors suggest the two agent classes show largely distinct patterns of DMN modulation and that differential DMN rsFC effects associate with clinical improvement. |
Abstract
Antidepressant treatments, including conventional antidepressants and (es)ketamine, may reverse default mode network (DMN) resting-state functional connectivity (rsFC) alterations related to major depressive disorder (MDD). Despite these agents having distinct initial action mechanisms, both likely share downstream effects that lead to structural and functional adaptations in MDD-related neural circuits. Examining the effects of these agents on DMN rsFC can provide insights into network-level effects, advance understanding of network-level mechanisms of treatment response, and generate hypotheses regarding potential neurobiological differences between MDD and treatment-resistant depression populations. A systematic search was performed to retrieve studies investigating changes in DMN rsFC following treatment with conventional antidepressants and (es)ketamine in MDD, including the association with clinical outcomes. Nineteen studies were included, 13 administered conventional antidepressants (N = 546), and six intravenous ketamine (N = 247). Conventional antidepressants were associated with heterogeneous changes in DMN rsFC, some of which related to clinical improvements. Conversely, ketamine mostly related with reductions in DMN rsFC, particularly in DMN-limbic connectivity. While interpretations of current findings are limited by heterogeneity in study populations, treatment regimens, and timing assessments, findings suggest that these agents exhibit mostly distinct patterns of DMN modulation, and that differential effects on DMN rsFC associate with clinical improvements.
Comparable studies
Other systematic reviews and meta-analyses on ketamine for depression, most cited first.
Citations in the library
Cites 22
- A default mode of brain function Proceedings of the National Academy of Sciences January 16, 2001
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Resting-State Functional Connectivity Reflects Structural Connectivity in the Default Mode Network Cerebral Cortex April 9, 2008
- 20 years of the default mode network: A review and synthesis Neuron May 10, 2023
- Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action PLoS One September 24, 2012
and 17 more in the library