Ketamine-Associated Change in Anhedonia and mTOR Expression in Treatment-Resistant Depression

Anhedonia is a core symptom of major depression increasingly recognized as a main driver of illlness morbidity and treatment resistance ( 1 Winer E.S. Nadorff M.R. Ellis T.E. Allen J.G. Herrera S. Salem T. Anhedonia predicts suicidal ideation in a large psychiatric inpatient sample. Psychiatry Res. 2014; 218: 124-128 Crossref PubMed Scopus (90) Google Scholar ). Immune dysfunction and insulin signaling dysregulation are causally associated with anhedonia and mediate metabolic homeostasis and neurotrophic and synaptic plasticity ( 2 Nguyen T.T.L. Chan L.C. Borreginne K. Kale R.P. Hu C. Tye S.J. A review of brain insulin signaling in mood disorders: From biomarker to clinical target. Neurosci Biobehav Rev. 2018; 92: 7-15 Crossref PubMed Scopus (19) Google Scholar , 3 Thomson A.W. Turnquist H.R. Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009; 9: 324-337 Crossref PubMed Scopus (665) Google Scholar , 4 Powell J.D. Pollizzi K.N. Heikamp E.B. Horton M.R. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012; 30: 39-68 Crossref PubMed Scopus (571) Google Scholar , 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; Google Scholar , 6 Bekhbat M. Treadway M.T. Goldsmith D.R. Woolwine B.J. Haroon E. Miller A.H. et al. 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 Crossref PubMed Scopus (30) Google Scholar , 7 Costi S. Morris L.S. Collins A. Fernandez N.F. Patel M. Xie H. et al. Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia. Transl Psychiatry. 2021; 11: 565 Crossref PubMed Scopus (10) Google Scholar ). The mechanistic target of rapamycin (mTOR) is a key regulator of immune cell responsivity ( 4 Powell J.D. Pollizzi K.N. Heikamp E.B. Horton M.R. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012; 30: 39-68 Crossref PubMed Scopus (571) Google Scholar ). 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 Nguyen T.T.L. Chan L.C. Borreginne K. Kale R.P. Hu C. Tye S.J. A review of brain insulin signaling in mood disorders: From biomarker to clinical target. Neurosci Biobehav Rev. 2018; 92: 7-15 Crossref PubMed Scopus (19) Google Scholar , 8 Li N. Lee B. Liu R.J. Banasr M. Dwyer J.M. Iwata M. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010; 329: 959-964 Crossref PubMed Scopus (2031) Google Scholar , 9 Walker A.J. Foley B.M. Sutor S.L. McGillivray J.A. Frye M.A. Tye S.J. Peripheral proinflammatory markers associated with ketamine response in a preclinical model of antidepressant-resistance. Behav Brain Res. 2015; 293: 198-202 Crossref PubMed Scopus (43) Google Scholar , 10 Roy A.V. Thai M. Klimes-Dougan B. Westlund Schreiner M. Mueller B.A. Albott C.S. et al. 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 Crossref PubMed Scopus (9) Google Scholar , 11 Tye S. Price J.B. Frye M. Cullen K.M. Bobo W. Impaired brain insulin signaling moderates antidepressant response to ketamine. ACNP 57th Annual Meeting: Poster Session I. Neuropsychopharmacology. 2018; 43: S135 Google Scholar ). Ketamine directly modulates these biological targets and has shown to reduce anhedonia ( 12 Lally N. Nugent A.C. Luckenbaugh D.A. Ameli R. Roiser J.P. Zarate C.A. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 2014; 4: e469 Crossref PubMed Scopus (173) Google Scholar , 13 Lally N. Nugent A.C. Luckenbaugh D.A. Niciu M.J. Roiser J.P. Zarate Jr., C.A. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol. 2015; 29: 596-607 Crossref PubMed Scopus (126) Google Scholar ); however, the biological mechanism underlying the antianhedonic effects remains under investigation.