Understanding MDD Treatments
With Neuroplastic Effects
Neuroplastic changes have been observed with currently available treatments for depression.
Antidepressant Therapy (ADT)1,2
Monoaminergic ADTs have been shown to indirectly increase gene expression of
neuroprotective factors such as BDNF. An NMDA receptor antagonist has increased
BDNF and mTORC1 signaling, leading to new synapse formation in the PFC
Cognitive Behavioral Therapy (CBT)3
Decreased functional connectivity between the mPFC and ACC
has been observed following 12 weeks of CBT
Electroconvulsive Therapy (ECT)4,5
Following a course of ECT, increases in hippocampus and amygdala
volume, increase in peripheral BDNF levels, and modification in default
mode network connectivity have been observed
Transcranial Magnetic Stimulation (TMS)4,6
Left and right DLPFC targeting with TMS has been shown to enhance and
inhibit brain activity in these regions, consequently altering the cognitive
control network and potentially improving emotional regulation
Exercise7
Consistent physical activity has been observed to lead to a deactivation
pattern in the hippocampus and brain regions associated with the
default mode network during memory encoding processes
ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor; DLPFC, dorsolateral prefrontal cortex; mPFC, medial prefrontal cortex; mTORC1, mechanistic target
of rapamycin complex 1; NMDA, N-methyl-D-aspartate; PFC, prefrontal cortex.
1. Casarotto PC, et al. Cell. 2021;184(5):1299-1313.e19. 2. Duman RS, et al. Mol Psychiatry. 2019;24(12):1816-1832. 3. Yoshimura S, et al. J Affect Disord. 2017;208:610-614.
4. Wilkinson ST, et al. Biol Psychiatry. 2019;85(6):454-465. 5. Joshi SH, et al. Biol Psychiatry. 2016;79(4):282-292. 6. Zhang M, et al. Front Neurosci. 2021;15:695423.
7. Gourgouvelis J, et al. Neural Plast. 2017;2017:8305287.
Leveraging Neuroplasticity
in Investigational Treatments for MDD
Researchers are exploring whether it is possible to leverage neuroplasticity to develop
treatments for depression.
The first comprehensive application of the NIMH fast-fail approach investigated a κ-opioid receptor
(KOR) antagonist as a treatment for anhedonia in patients with a mood or anxiety disorder1
Their objective was to
improve reward-related
activation in the ventral
striatum through KOR
antagonism1
Patients were randomized 1:1 to treatment or control
Study Size
Treatment: n=45
Control: n=44
Treatment
8 weeks of double-blind treatment
While results are still exploratory, there were positive effects across 3 Research Domain
Criteria Initiative units of analysis: circuits, behavior, and self-report
In small proof-of-concept studies, researchers sought to adjust neural networks implicated in
mood and anxiety disorders using the Emotional Faces Memory Task (EFMT)2-4
Their objective was to
modulate hyperactivity in
the amygdala and improve
top-down emotional control
by the prefrontal cortex5
EFMT is a training exercise that combines cognition (via
N-back working memory task) and emotional processing
(via identifying emotions as part of working memory).5
In EFMT, patients identify whether emotional expressions
are the same as the one N faces back.5
N=2 example: Does this
emotion match the one
2 faces back?
Patients were randomized to treatment or control2,3
Pilot 1
Pilot 2
Study Size
EFMT: n=11
Control: n=10
EFMT: n=28
Control: n=23
Treatment
8 sessions on
a computer
over 4 weeks
18 sessions on
a computer
over 6 weeks
• A subset of patients from the EFMT arm of
Pilot 2 (n=14) had fMRI scans to study the
impact of EFMT on brain connectivity and
MDD symptoms4
While EFMT is still investigational, these proof-of-concept studies showed that following
treatment there were reductions in MDD symptoms as measured by the HAMD-17 total
score, increased effective connectivity from the right DLPFC to the amygdala, and decreased
effective connectivity from the left and right dACC to the amygdala4
dACC, dorsal anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; fMRI, functional
magnetic resonance imaging; HAMD-17, 17-item Hamilton Depression Rating Scale;
MDD, major depressive disorder; NIMH, National Institute of Mental Health.
1. Krystal AD, et al. Nat Med. 2020;26(5):760-768. 2. Iacoviello BM, et al. Depress Anxiety.
2014;31(8):699-706. 3. Iacoviello BM, et al. NPJ Digit Med. 2018;1:21. 4. Hoch MM, et al.
Chronic Stress (Thousand Oaks). 2019;3:2470547019877880. 5. Iacoviello BM, Charney DS.
Eur Psychiatry. 2015;30(1):75-81.
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