Anhedonia is a core symptom of major depression increasingly recognized as a main
driver of illlness morbidity and treatment resistance (
1
). Immune dysfunction and insulin signaling dysregulation are causally associated
with anhedonia and mediate metabolic homeostasis and neurotrophic and synaptic plasticity
(
2
,
3
,
4
,
5
,
- Bekhbat M.
- Li Z.
- Mehta N.D.
- Treadway M.T.
- Lucido M.J.
- Woolwine B.J.
- et al.
Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic
targets in depression with high inflammation: Evidence from a dopamine challenge study
[published online ahead of print Aug 4].
Mol Psychiatry. 2022;
6
,
7
). The mechanistic target of rapamycin (mTOR) is a key regulator of immune cell responsivity
(
4
). Preclinical models have shown that ketamine activates neurotrophic signaling downstream
of brain-derived neurotrophic factor and insulin to modulate mTOR and enhance structural
plasticity (
2
,
8
,
9
,
10
,
11
). Ketamine directly modulates these biological targets and has shown to reduce anhedonia
(
12
,
13
); however, the biological mechanism underlying the antianhedonic effects remains
under investigation.To read this article in full you will need to make a payment
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References
- Anhedonia predicts suicidal ideation in a large psychiatric inpatient sample.Psychiatry Res. 2014; 218: 124-128
- A review of brain insulin signaling in mood disorders: From biomarker to clinical target.Neurosci Biobehav Rev. 2018; 92: 7-15
- Immunoregulatory functions of mTOR inhibition.Nat Rev Immunol. 2009; 9: 324-337
- Regulation of immune responses by mTOR.Annu Rev Immunol. 2012; 30: 39-68
- Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: Evidence from a dopamine challenge study [published online ahead of print Aug 4].Mol Psychiatry. 2022;
- Gene signatures in peripheral blood immune cells related to insulin resistance and low tyrosine metabolism define a sub-type of depression with high CRP and anhedonia.Brain Behav Immun. 2020; 88: 161-165
- Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia.Transl Psychiatry. 2021; 11: 565
- mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010; 329: 959-964
- Peripheral proinflammatory markers associated with ketamine response in a preclinical model of antidepressant-resistance.Behav Brain Res. 2015; 293: 198-202
- Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression.J Psychopharmacol. 2021; 35: 168-177
- Impaired brain insulin signaling moderates antidepressant response to ketamine. ACNP 57th Annual Meeting: Poster Session I.Neuropsychopharmacology. 2018; 43: S135
- Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.Transl Psychiatry. 2014; 4: e469
- Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.J Psychopharmacol. 2015; 29: 596-607
- Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions.J Affect Disord. 2018; 236: 291-297
- Continuation phase intravenous ketamine in adults with treatment-resistant depression.J Affect Disord. 2016; 206: 300-304
- The PHQ-9: Validity of a brief depression severity measure.J Gen Intern Med. 2001; 16: 606-613
- Mapping depression rating scale phenotypes onto research domain criteria (RDoC) to inform biological research in mood disorders.J Affect Disord. 2018; 238: 1-7
- Depression symptom dimensions as predictors of antidepressant treatment outcome: Replicable evidence for interest-activity symptoms.Psychol Med. 2012; 42: 967-980
- Clinical relevance of depressive symptom improvement in bipolar I depressed patients.J Affect Disord. 2006; 92: 261-266
- A new depression scale designed to be sensitive to change.Br J Psychiatry. 1979; 134: 382-389
- GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine.Neuropsychopharmacology. 2013; 38: 2268-2277
- Mechanisms of ketamine action as an antidepressant.Mol Psychiatry. 2018; 23: 801-811
- Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.Neuropsychopharmacology. 2020; 45: 990-997
- mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression.J Affect Disord. 2022; 303: 91-97
Article info
Publication history
Published online: January 25, 2023
Accepted:
October 17,
2022
Received in revised form:
October 14,
2022
Received:
September 26,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Society of Biological Psychiatry.
