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Modulating Neuroplasticity: Lessons Learned from Antidepressants and Emerging Novel Therapeutics

  • Depressive Disorders (K Cullen, Section Editor)
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Abstract

Purpose of review

Antidepressants share a common mechanism of action downstream of pharmacological drug targets. Rapid-acting antidepressants, such as ketamine, have highlighted the immense clinical potential of directly targeting neurotrophic signalling pathways. In turn, these neurotrophic mechanisms effectively reverse the deleterious effects of stress and other factors implicated in the aetiology of mood disorders at the cellular level. Treatments that target synaptic plasticity can restore functional synaptic connections in stress-sensitive neural circuits to improve mood regulation and cognitive function. Here, we describe the neurotrophic mechanisms of antidepressants and describe current and novel treatment modalities that can restore neural circuit function by directly engaging neuroplasticity.

Recent findings

The discovery of ketamine as a rapid modulator of synaptic plasticity with associated therapeutic actions for major depressive disorder and other psychiatric disorders has accelerated interest in the potential surrounding the direct targeting of neurotrophic pathways. Targets to the glutamatergic system currently seem to be the most promising area of novel drug discovery and development. Other systems such as the cholinergic and inflammatory systems are gaining traction as well. While cellular and animal studies have provided exquisite insights into the molecular mechanisms that influence plasticity, ongoing work demonstrating the therapeutic impact of targeting these mechanisms with neuromodulation, pharmacological, and/or behavioural interventions in human subjects is needed.

Summary

Targeting the neurobiological mechanisms that regulate neuroplasticity will be of relevance to a range of neurological and neuropsychiatric disorders beyond depression. However, the factors responsible for disrupting synaptic integrity across the disorders will vary. Consequently, the treatments targeting plasticity need to be optimally aligned to the specific pathophysiological context of the illness, which can vary even within a specific diagnostic category.

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References

  1. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. James SL, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018;392(10159):1789–858.

    Article  Google Scholar 

  3. Lampe L. Antidepressants: not just for depression. Aust Prescr. 2005;28(4):91–3.

    Article  Google Scholar 

  4. Wong J, et al. Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ. 2017;356:j603.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hindmarch I. Beyond the monoamine hypothesis: mechanisms, molecules and methods. Eur Psychiatry. 2002;17(Suppl 3):294–9.

    Article  PubMed  Google Scholar 

  6. Delgado PL. Depression: the case for a monoamine deficiency. J Clin Psychiatry. 2000;61(Suppl 6):7–11.

    CAS  PubMed  Google Scholar 

  7. Hyman SE, Nestler. Initiation and adaptation: a paradigm for understanding psychotropic drug action. (0002–953X (Print)).

  8. Bourin M, et al. Mechanism of action of antidepressants and therapeutic perspectives. Therapie. 2002;57(4):385–96.

    CAS  PubMed  Google Scholar 

  9. Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–4.

    Article  CAS  PubMed  Google Scholar 

  10. aan het Rot M, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67(2):139–45.

    Article  Google Scholar 

  11. Ballard ED, et al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 2014;58:161–6.

    Article  PubMed  Google Scholar 

  12. Zanos P, et al. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32(3):197–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Newport DJ, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950–66.

    Article  PubMed  Google Scholar 

  14. Zarate CA Jr, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153–5.

    Article  PubMed  Google Scholar 

  15. Wilkinson ST, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150–8.

    Article  PubMed  Google Scholar 

  16. Murrough JW, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiat. 2013;74(4):250–6.

    Article  CAS  PubMed  Google Scholar 

  17. Singh JB, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173(8):816–26.

    Article  PubMed  Google Scholar 

  18. Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol. 2013;16(9):2111–7.

    Article  CAS  PubMed  Google Scholar 

  19. Maeng S, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63(4):349–52.

    Article  CAS  PubMed  Google Scholar 

  20. Li N, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li N, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69(8):754–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu R-J, et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiat. 2012;71(11):996–1005.

    Article  CAS  PubMed  Google Scholar 

  23. Autry AE, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475(7354):91–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Laje G, et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiat. 2012;72(11):e27–8.

    Article  CAS  PubMed  Google Scholar 

  25. Murrough JW, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250–6.

    Article  CAS  PubMed  Google Scholar 

  26. Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol. 2013;4.

  27. Roy AV, 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(2):168–77.

    Article  CAS  PubMed  Google Scholar 

  28. Duman RS, et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4(5):409–18.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chaki S, Fukumoto K. Potential of glutamate-based drug discovery for next generation antidepressants. Pharmaceuticals. 2015;8(3):590–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ragguett R-M, et al. Rapastinel - an investigational NMDA-R modulator for major depressive disorder: evidence to date. Expert Opin Investig Drugs. 2019;28(2):113–9.

    Article  CAS  PubMed  Google Scholar 

  32. Moskal J, et al. The development of rapastinel (formerly GLYX-13); a rapid acting and long lasting antidepressant. Curr Neuropharmacol. 2016;15(1):47–56.

    Article  Google Scholar 

  33. Burgdorf J, et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013;38(5):729–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Burgdorf J, et al. Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats. Behav Brain Res. 2015;294:177–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rajagopal L, et al. GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behav Brain Res. 2016;299:105–10.

    Article  CAS  PubMed  Google Scholar 

  36. Moskal JR, et al. GLYX-13: A monoclonal antibody-derived peptide that acts as an N-methyl-d-aspartate receptor modulator. Neuropharmacology. 2005;49(7):1077–87.

    Article  CAS  PubMed  Google Scholar 

  37. Zanos P, et al. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J Pharmacol Exp Ther. 2015;355(1):76–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nguyen L, et al. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS ONE. 2014;9(2):e89985.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Stahl SM. Mechanism of action of dextromethorphan/quinidine: comparison with ketamine. CNS Spectr. 2013;18(5):225–7.

    Article  PubMed  Google Scholar 

  40. Pothula S, et al. Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons. Neuropsychopharmacology. 2021;46(4):799–808.

    Article  CAS  PubMed  Google Scholar 

  41. Agbo F, Bui KH, Zhou D. Population pharmacokinetic analysis of lanicemine (AZD6765), an NMDA channel blocker, in healthy subjects and patients with major depressive disorder. J Clin Pharm Ther. 2017;42(5):539–46.

    Article  CAS  PubMed  Google Scholar 

  42. Sanacora G, et al. Adjunctive lanicemine (AZD6765) in patients with major depressive disorder and history of inadequate response to antidepressants: a randomized, placebo-controlled study. Neuropsychopharmacology. 2017;42(4):844–53.

    Article  CAS  PubMed  Google Scholar 

  43. Poleszak E, et al. Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice. Metab Brain Dis. 2016;31(4):803–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dhir A. Investigational drugs for treating major depressive disorder. Expert Opin Investig Drugs. 2017;26(1):9–24.

    Article  CAS  PubMed  Google Scholar 

  45. Henter ID, de Sousa RT, Zarate CA Jr. Glutamatergic modulators in depression. Harv Rev Psychiatry. 2018;26(6):307.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Garner, R., et al., Preclinical pharmacology and pharmacokinetics of CERC-301, a GluN2B-selective N-methyl-D-aspartate receptor antagonist. Pharmacol Res Perspect. 2015;3(6).

  47. Beauregard M, Lévesque J, Bourgouin P. Neural correlates of conscious self-regulation of emotion. J Neurosci. 2001;21(18):RC165–RC165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li C-T, et al. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: a randomized controlled study. Hum Brain Mapp. 2016;37(3):1080–90.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008;33(1):88–109.

    Article  CAS  PubMed  Google Scholar 

  50. Nestler EJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13–25.

    Article  CAS  PubMed  Google Scholar 

  51. Duman RS. Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci. 2014;16(1):11–27.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116–27.

    Article  CAS  PubMed  Google Scholar 

  53. Helm K, et al. Neuronal connectivity in major depressive disorder: a systematic review. Neuropsychiatr Dis Treat. 2018;14:2715–37.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Liberzon I, Krstov M, Young EA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology. 1997;22(6):443–53.

    Article  CAS  PubMed  Google Scholar 

  55. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23(5):477–501.

    Article  CAS  PubMed  Google Scholar 

  56. Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry. 2001;49(5):391–404.

    Article  CAS  PubMed  Google Scholar 

  57. Leonard BE, Wegener G. Inflammation, insulin resistance and neuroprogression in depression. Acta Neuropsychiatr. 2020;32(1):1–9.

    Article  PubMed  Google Scholar 

  58. Price JB, et al. Bioenergetics and synaptic plasticity as potential targets for individualizing treatment for depression. Neurosci Biobehav Rev. 2018;90:212–20.

    Article  PubMed  Google Scholar 

  59. Walker AJ, et al. Peripheral proinflammatory markers associated with ketamine response in a preclinical model of antidepressant-resistance. Behav Brain Res. 2015;293:198–202.

    Article  CAS  PubMed  Google Scholar 

  60. Lyra e Silva NDM, et al. Insulin resistance as a shared pathogenic mechanism between depression and type 2 diabetes. Front Psychiatry. 2019;10:57.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Penninx BWJH. Depression and cardiovascular disease: epidemiological evidence on their linking mechanisms. Neurosci Biobehav Rev. 2017;74(Pt B):277–86.

    Article  PubMed  Google Scholar 

  62. Duman RS. Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide. F1000Res. 2018;7.

  63. Perry BI, et al. Insulin resistance and obesity, and their association with depression in relatively young people: findings from a large UK birth cohort. Psychol Med. 2020;50(4):556–65.

    Article  CAS  PubMed  Google Scholar 

  64. Haroon E, Miller AH, Sanacora G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology. 2017;42(1):193–215.

    Article  CAS  PubMed  Google Scholar 

  65. Khairova RA, et al. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol. 2009;12(4):561–78.

    Article  CAS  PubMed  Google Scholar 

  66. Gold PW, Machado-Vieira R, Pavlatou MG. Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. Neural Plast. 2015;2015.

  67. Barbosa IG, et al. The immunology of bipolar disorder. NeuroImmunoModulation. 2014;21(2–3):117–22.

    Article  CAS  PubMed  Google Scholar 

  68. Majd M, et al. A randomized, double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in treatment of drug-naive depressed women: a pilot study. Iran J Pharm Res IJPR. 2015;14(3):891.

    CAS  PubMed  Google Scholar 

  69. Nery FG, et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol Clin Exp. 2008;23(2):87–94.

    Article  CAS  Google Scholar 

  70. Castrén E, Hen R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 2013;36(5):259–67.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Liu W, et al. The role of neural plasticity in depression: from hippocampus to prefrontal cortex. Neural Plast. 2017;2017:6871089.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Borczyk M, et al. Neuronal plasticity affects correlation between the size of dendritic spine and its postsynaptic density. Sci Rep. 2019;9(1):1693.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Okabe S. Molecular anatomy of the postsynaptic density. Mol Cell Neurosci. 2007;34(4):503–18.

    Article  CAS  PubMed  Google Scholar 

  74. Schikorski T, Stevens CF. Quantitative fine-structural analysis of olfactory cortical synapses. Proc Natl Acad Sci. 1999;96(7):4107–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nusser Z, Sieghart W, Somogyi P. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J Neurosci. 1998;18(5):1693–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Malenka RC, Bear MF. LTP and LTD. Neuron. 2004;44(1):5–21.

    Article  CAS  PubMed  Google Scholar 

  77. Citri A, Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 2008;33(1):18–41.

    Article  PubMed  Google Scholar 

  78. McEwen BS. Brain on stress: how the social environment gets under the skin. Proc Natl Acad Sci. 2012;109(Supplement_2):17180–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Barde Y-A. Trophic factors and neuronal survival. Neuron. 1989;2(6):1525–34.

    Article  CAS  PubMed  Google Scholar 

  80. Levi-Montalcini R, Cohen S. In vitro and in vivo effects of a nerve growth-stimulating agent isolated from snake venom. Proc Natl Acad Sci. 1956;42(9):695–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Castrén E, Rantamaki T. Neurotrophins in depression and antidepressant effects. in Novartis Foundation Symposium. 2008. Wiley Online Library.

  82. Racagni G, Popoli M. Cellular and molecular mechanisms in the long-term action of antidepressants. Dialogues Clin Neurosci. 2008;10(4):385–400.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Fava M, et al. A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients. Mol Psychiatry. 2016;21(10):1372–80.

    Article  CAS  PubMed  Google Scholar 

  84. Taupin P. Adult neural stem cells: the promise of the future. Neuropsychiatr Dis Treat. 2007;3(6):753–60.

    PubMed  PubMed Central  Google Scholar 

  85. McKay R. Stem cells in the central nervous system. Science. 1997;276(5309):66–71.

    Article  CAS  PubMed  Google Scholar 

  86. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10(9):1110–5.

    Article  CAS  PubMed  Google Scholar 

  87. Sheline YI, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93(9):3908–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004;161(11):1957–66.

    Article  PubMed  Google Scholar 

  89. Siuciak JA, et al. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav. 1997;56(1):131–7.

    Article  CAS  Google Scholar 

  90. Scharfman H, et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192(2):348–56.

    Article  CAS  PubMed  Google Scholar 

  91. Schmidt HD, Banasr M, Duman RS. Future antidepressant targets: neurotrophic factors and related signaling cascades. Drug Discov Today Ther Strateg. 2008;5(3):151–6.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Voleti B, et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiat. 2013;74(10):742–9.

    Article  CAS  PubMed  Google Scholar 

  93. Drevets WC, Zarate CA, Furey ML. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol Psychiat. 2013;73(12):1156–63.

    Article  CAS  PubMed  Google Scholar 

  94. Fuxe K, Borroto-Escuela DO. Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5. Expert Opin Investig Drugs. 2015;24(9):1247–60.

    Article  CAS  PubMed  Google Scholar 

  95. Ragguett R-M, et al. Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder. Expert Opin Drug Metab Toxicol. 2018;14(4):475–82.

    Article  PubMed  Google Scholar 

  96. Taylor TG, Manzella F. Kappa opioids, salvinorin A and major depressive disorder. Curr Neuropharmacol. 2016;14(2):165–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Haj-Mirzaian A, et al. Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors. Can J Physiol Pharmacol. 2016;94(6):599–612.

    Article  CAS  PubMed  Google Scholar 

  98. Shippenberg TS, Zapata A, Chefer VI. Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther. 2007;116(2):306–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhang H, et al. Central κ-opioid receptor-mediated antidepressant-like effects of nor-binaltorphimine: behavioral and BDNF mRNA expression studies. Eur J Pharmacol. 2007;570(1):89–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zan G-Y, et al. Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence. Behav Brain Res. 2015;291:334–41.

    Article  CAS  PubMed  Google Scholar 

  101. Lalanne L. et al. The kappa opioid receptor: from addiction to depression, and back. Front Psychiatry. 2014;5.

  102. Schmidt PJ, et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry. 2005;62(2):154–62.

    Article  CAS  PubMed  Google Scholar 

  103. Brown ES, Bobadilla L, Rush AJ. Ketoconazole in bipolar patients with depressive symptoms: a case series and literature review. Bipolar Disord. 2001;3(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  104. Jahn H, et al. Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry. 2004;61(12):1235–44.

    Article  CAS  PubMed  Google Scholar 

  105. Brown ES, et al. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014;39(12):2867–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Young AH, et al. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology. 2004;29(8):1538–45.

    Article  CAS  PubMed  Google Scholar 

  107. Blasey CM, et al. Efficacy and safety of mifepristone for the treatment of psychotic depression. J Clin Psychopharmacol. 2011;31(4):436–40.

    Article  CAS  PubMed  Google Scholar 

  108. Carroll BJ, Rubin RT. Mifepristone in psychotic depression? Biol Psychiatry. 2008;63(1):e1.

    Article  PubMed  Google Scholar 

  109. DeBattista C, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiat. 2006;60(12):1343–9.

    Article  CAS  PubMed  Google Scholar 

  110. Belanoff JK, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiat. 2002;52(5):386–92.

    Article  CAS  PubMed  Google Scholar 

  111. Valiengo LL, et al. Plasma cortisol in first episode drug-naïve mania: differential levels in euphoric versus irritable mood. J Affect Disord. 2012;138(1–2):149–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhou J, et al. The effects of intramuscular administration of scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled trial. Ther Adv Psychopharmacol. 2020;10:204512532093855.

    Article  Google Scholar 

  113. Zhou J. et al. Scopolamine augmentation of a newly initiated escitalopram treatment for major depressive disorder: study protocol for a randomized controlled trial. Trials. 2019;20(1).

  114. Jaeschke G, et al. Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2, 5-dimethyl-1 H-imidazol-4-ylethynyl] pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases. J Med Chem. 2015;58(3):1358–71.

    Article  CAS  PubMed  Google Scholar 

  115. Lindemann L, et al. Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. J Pharmacol Exp Ther. 2015;353(1):213–33.

    Article  CAS  PubMed  Google Scholar 

  116. Guerini E, et al. A double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]-basimglurant and absolute bioavailability after oral administration and concomitant intravenous microdose administration of [13C6]-labeled basimglurant in humans. Xenobiotica. 2017;47(2):144–53.

    Article  CAS  PubMed  Google Scholar 

  117. Quiroz JA, et al. Efficacy and safety of basimglurant as adjunctive therapy for major depression: a randomized clinical trial. JAMA Psychiat. 2016;73(7):675–84.

    Article  Google Scholar 

  118. Thase ME, et al. Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder. Neuropsychopharmacology. 2019;44(13):2268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Fava M, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173(5):499–508.

    Article  PubMed  Google Scholar 

  120. Naganawa M, et al. Receptor occupancy of the -opioid antagonist LY2456302 measured with positron emission tomography and the novel radiotracer 11C-LY2795050. J Pharmacol Exp Ther. 2016;356(2):260–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lowe SL, et al. Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects. J Clin Pharmacol. 2014;54(9):968–78.

    Article  CAS  PubMed  Google Scholar 

  122. Jackson KJ, et al. Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice. Neuropharmacology. 2015;97:270–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Rorick-Kehn LM, et al. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology. 2014;77:131–44.

    Article  CAS  PubMed  Google Scholar 

  124. Skolnick P, et al. Antidepressant-like actions of DOV 21,947: a “triple” reuptake inhibitor. Eur J Pharmacol. 2003;461(2–3):99–104.

    Article  CAS  PubMed  Google Scholar 

  125. Golembiowska K, Kowalska M, Bymaster FP. Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity. Synapse. 2012;66(5):435–44.

    Article  CAS  PubMed  Google Scholar 

  126. Tran P, et al. Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Psychiatr Res. 2012;46(1):64–71.

    Article  PubMed  Google Scholar 

  127. Marks DM, Abramowitz JS, Spielmans GI. Concerns about data reporting and interpretation in “Efficacy and Tolerability of the Novel Triple Reuptake Inhibitor Amitifadine in the Treatment of Patients With Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial.” J Psychiatr Res. 2012;46(5):692–5.

    Article  PubMed  Google Scholar 

  128. Akhondzadeh S, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety. 2009;26(7):607–11.

    Article  CAS  PubMed  Google Scholar 

  129. Müller N, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11(7):680–4.

    Article  PubMed  Google Scholar 

  130. Andreazza AC, et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res. 2007;41(6):523–9.

    Article  PubMed  Google Scholar 

  131. Kuloglu M, et al. Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Funct. 2002;20(2):171–5.

    Article  CAS  PubMed  Google Scholar 

  132. Berk M et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. Efficiency of N-Acetylcysteine in MDD. 2014;75.

  133. Deepmala et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294–321.

  134. Lin KW, et al. Adjuvant pioglitazone for unremitted depression: clinical correlates of treatment response. Psychiatry Res. 2015;230(3):846–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sepanjnia K, et al. Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. Neuropsychopharmacology. 2012;37(9):2093–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zeinoddini A, et al. Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: a randomized, double-blind, placebo-controlled trial. Depress Anxiety. 2015;32(3):167–73.

    Article  CAS  PubMed  Google Scholar 

  137. Colle R, et al. PPAR-γ Agonists for the treatment of major depression: a review. Pharmacopsychiatry. 2016;50(02):49–55.

    Article  PubMed  Google Scholar 

  138. Miskowiak KW, et al. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacology. 2014;39(6):1399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Banasr M, Duman RS. Keeping “trk” of antidepressant actions. Neuron. 2008;59(3):349–51.

    Article  CAS  PubMed  Google Scholar 

  140. Neis VB, et al. The involvement of PI3K/Akt/mTOR/GSK3β signaling pathways in the antidepressant-like effect of AZD6765. Pharmacol Biochem Behav. 2020;198:173020.

    Article  CAS  PubMed  Google Scholar 

  141. Hamer JA, et al. Brain insulin resistance: a treatment target for cognitive impairment and anhedonia in depression. Exp Neurol. 2019;315:1–8.

    Article  CAS  PubMed  Google Scholar 

  142. Zhou W, et al. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2014;29(7):419–23.

    Article  CAS  PubMed  Google Scholar 

  143. Zou XH, et al. Potential role of insulin on the pathogenesis of depression. Cell Proliferation. 2020;53(5):e12806.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Czéh B, Di Benedetto B. Antidepressants act directly on astrocytes: evidences and functional consequences. Eur Neuropsychopharmacol. 2013;23(3):171–85.

    Article  PubMed  Google Scholar 

  145. Gonçalves C-A, et al. Glycolysis-derived compounds from astrocytes that modulate synaptic communication. Front Neurosci. 2019;12:1035.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Kleinridders A, et al. Insulin action in brain regulates systemic metabolism and brain function. Diabetes. 2014;63(7):2232–43.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Nguyen TTL, et al. A review of brain insulin signaling in mood disorders: from biomarker to clinical target. Neurosci Biobehav Rev. 2018;92:7–15.

    Article  CAS  PubMed  Google Scholar 

  148. Chiu S-L, Cline HT. Insulin receptor signaling in the development of neuronal structure and function. Neural Dev. 2010;5:7.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Yokoyama K, et al. Relationship between hypothalamic–pituitary–adrenal axis dysregulation and insulin resistance in elderly patients with depression. Psychiatry Res. 2015;226(2):494–8.

    Article  CAS  PubMed  Google Scholar 

  150. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. McIntyre RS, et al. Should depressive syndromes be reclassified as “Metabolic Syndrome Type II”? Ann Clin Psychiatry. 2007;19(4):257–64.

    Article  PubMed  Google Scholar 

  152. Blázquez E, et al. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol. 2014;5:161.

    Article  Google Scholar 

  153. Lee C-C, Huang C-C, Hsu K-S. Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology. 2011;61(4):867–79.

    Article  CAS  PubMed  Google Scholar 

  154. Sripetchwandee J, Chattipakorn N, Chattipakorn SC. Links between obesity-induced brain insulin resistance, brain mitochondrial dysfunction, and dementia. Front Endocrinol. 2018;9:496.

    Article  Google Scholar 

  155. Sripetchwandee J, et al. DPP-4 inhibitor and PPARγ agonist restore the loss of CA1 dendritic spines in obese insulin-resistant rats. Arch Med Res. 2014;45(7):547–52.

    Article  CAS  PubMed  Google Scholar 

  156. Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008;11(8):1169–80.

    Article  CAS  PubMed  Google Scholar 

  157. Levada OA, Troyan AS. Insulin-like growth factor-1: a possible marker for emotional and cognitive disturbances, and treatment effectiveness in major depressive disorder. Ann Gen Psychiatry. 2017;16:38.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Schmidt HD, Shelton RC, Duman RS. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology. 2011;36(12):2375–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Benedict C, et al. Intranasal insulin to improve memory function in humans. Neuroendocrinology. 2007;86(2):136–42.

    Article  CAS  PubMed  Google Scholar 

  160. Marks DR, et al. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci. 2009;29(20):6734–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. McIntyre RS, et al. A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord. 2012;14(7):697–706.

    Article  CAS  PubMed  Google Scholar 

  162. Cha DS, et al. A randomized, double-blind, placebo-controlled, crossover trial evaluating the effect of intranasal insulin on cognition and mood in individuals with treatment-resistant major depressive disorder. J Affect Disord. 2017;210:57–65.

    Article  CAS  PubMed  Google Scholar 

  163. Wang T, et al. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem. 2020;11(3):76.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Grillo C, et al. Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res. 2009;1296:35–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Pomytkin I, Pinelis V. Brain insulin resistance: focus on insulin receptor-mitochondria interactions. Life. 2021;11(3):262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Walker AJ, et al. Insulin-stimulated mTOR activation in peripheral blood mononuclear cells associated with early treatment response to lithium augmentation in rodent model of antidepressant-resistance. Transl Psychiatry. 2019;9(1):113.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Liu R-J, et al. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology. 2013;38(11):2268–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Cavaleiro C, et al. Memory and cognition-related neuroplasticity enhancement by transcranial direct current stimulation in rodents: a systematic review. Neural Plast. 2020;2020:4795267.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Jakobs M, et al. Cellular, molecular, and clinical mechanisms of action of deep brain stimulation—a systematic review on established indications and outlook on future developments. EMBO Mol Med. 2019;11(4):e9575.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Peruzzotti-Jametti L, et al. Safety and efficacy of transcranial direct current stimulation in acute experimental ischemic stroke. Stroke. 2013;44(11):3166–74.

    Article  PubMed  Google Scholar 

  171. Rueger MA, et al. Multi-session transcranial direct current stimulation (tDCS) elicits inflammatory and regenerative processes in the rat brain. PLoS ONE. 2012;7(8):e43776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. McCaig CD, Sangster L, Stewart R. Neurotrophins enhance electric field-directed growth cone guidance and directed nerve branching. Dev Dyn. 2000;217(3):299–308.

    Article  CAS  PubMed  Google Scholar 

  173. Pikhovych A, et al. Transcranial direct current stimulation modulates neurogenesis and microglia activation in the mouse brain. Stem Cells Int. 2016;2016:1–9.

    Article  Google Scholar 

  174. Tang A, Thickbroom G, Rodger J. Repetitive transcranial magnetic stimulation of the brain. Neuroscientist. 2017;23(1):82–94.

    Article  PubMed  Google Scholar 

  175. Miranda M et al. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci. 2019;13.

  176. Moretti J, Poh EZ, Rodger J. rTMS-induced changes in glutamatergic and dopaminergic systems: relevance to cocaine and methamphetamine use disorders. Front Neurosci. 2020;14:137.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Bambico FR, et al. Neuroplasticity-dependent and -independent mechanisms of chronic deep brain stimulation in stressed rats. Transl Psychiatry. 2015;5:e674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Belvederi Murri M et al. Physical exercise in major depression: reducing the mortality gap while improving clinical outcomes. Front Psychiatry. 2019;9.

  179. Phillips C. Brain-derived neurotrophic factor, depression, and physical activity: making the neuroplastic connection. Neural Plast. 2017;2017:7260130.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Gourgouvelis J, Yielder P, Murphy B. Exercise promotes neuroplasticity in both healthy and depressed brains: an fMRI pilot study. Neural Plast. 2017;2017:8305287.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Chen L. et al. Stereological study on the positive effect of running exercise on the capillaries in the hippocampus in a depression model. Front Neuroanat. 2017;11.

  182. Liu PZ, Nusslock R. Exercise-mediated neurogenesis in the hippocampus via BDNF. Front Neurosci. 2018;12:52.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Blumenthal JA, et al. Effects of exercise training on older patients with major depression. Arch Intern Med. 1999;159(19):2349–56.

    Article  CAS  PubMed  Google Scholar 

  184. Babyak M, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med. 2000;62(5):633–8.

    Article  CAS  PubMed  Google Scholar 

  185. Alqahtani DA, et al. Factors underlying suboptimal diagnostic performance in physicians under time pressure. Med Educ. 2018;52(12):1288–98.

    Article  PubMed  Google Scholar 

  186. Chang Y-K, et al. Exercise modality is differentially associated with neurocognition in older adults. Neural Plast. 2017;2017:3480413.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Siqueira CC, et al. Antidepressant efficacy of adjunctive aerobic activity and associated biomarkers in major depression: a 4-week, randomized, single-blind, controlled clinical trial. PLOS ONE. 2016;11(5):e0154195.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Davis AK et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2020.

  189. Mithoefer MCP, Grob CSP, Brewerton TDP. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry. 2016;3(5):481–8.

    Article  PubMed  Google Scholar 

  190. Baumeister D, et al. Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles. Ther Adv Psychopharmacol. 2014;4(4):156–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ly C, et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 2018;23(11):3170–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Bouso JC, et al. MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. J Psychoactive Drugs. 2008;40(3):225–36.

    Article  PubMed  Google Scholar 

  193. Carhart-Harris RL, Goodwin GM. The therapeutic potential of psychedelic drugs: past, present, and future. Neuropsychopharmacology. 2017;42(11):2105–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Roseman L, et al. Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression. Neuropharmacology. 2018;142:263–9.

    Article  CAS  PubMed  Google Scholar 

  195. Jefsen OH et al. Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. J Psychopharmacol. 2020;269881120959614.

  196. Albensi BC. Transcription Factors CREB and NF-κB: Involvement in Synaptic Plasticity and Memory Formation. 2012: Bentham Science Publishers. 141.

  197. González-Maeso J, et al. Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53(3):439–52.

    Article  PubMed  Google Scholar 

  198. Hibicke M, et al. Psychedelics, but not ketamine, produce persistent antidepressant-like effects in a rodent experimental system for the study of depression. ACS Chem Neurosci. 2020;11(6):864–71.

    Article  CAS  PubMed  Google Scholar 

  199. Kadriu B, et al. Ketamine and serotonergic psychedelics: common mechanisms underlying the effects of rapid-acting antidepressants. Int J Neuropsychopharmacol. 2021;24(1):8–21.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

All figures were created with Biorender.com.

Funding

The authors thank the Nicol Foundation for funding to support this work. CY was supported by an Asia Pacific Centre for Neuromodulation Scholarship.

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Authors and Affiliations

  1. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

    Clarissa Yates BSc & Susannah J. Tye PhD

  2. Cousins Center for Psychoneuroimmunology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

    Jennifer L. Kruse MD

  3. Jane and Terry Semel Institute for Neuroscience and Human Behavior At UCLA, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, Los Angeles, CA, USA

    Jennifer L. Kruse MD

  4. Department of Neurosurgery Research, Mayo Clinic, Rochester, MN, 55905, USA

    J. Blair Price PhD

  5. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, 4072, Australia

    Avril A. B. Robertson PhD

  6. Department of Psychiatry and Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, USA

    Susannah J. Tye PhD

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  1. Clarissa Yates BSc
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  2. Jennifer L. Kruse MD
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  3. J. Blair Price PhD
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Correspondence to Susannah J. Tye PhD.

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Yates, C., Kruse, J.L., Price, J.B. et al. Modulating Neuroplasticity: Lessons Learned from Antidepressants and Emerging Novel Therapeutics. Curr Treat Options Psych 8, 229–257 (2021). https://doi.org/10.1007/s40501-021-00249-9

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