1932

Abstract

Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.

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2024-01-29
2024-10-13
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Literature Cited

  1. 1.
    Herrman H, Patel V, Kieling C et al. 2022. Time for united action on depression: a Lancet–World Psychiatric Association Commission. Lancet 399:9571022
    [Google Scholar]
  2. 2.
    Hirschfeld RM. 2000. History and evolution of the monoamine hypothesis of depression. J. Clin. Psychiatry 61:Suppl. 646
    [Google Scholar]
  3. 3.
    Machado-Vieira R, Baumann J, Wheeler-Castillo C et al. 2010. The timing of antidepressant effects: a comparison of diverse pharmacological and somatic treatments. Pharmaceuticals 3:1941
    [Google Scholar]
  4. 4.
    Cipriani A, Furukawa TA, Salanti G et al. 2018. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391:135766
    [Google Scholar]
  5. 5.
    Bergfeld IO, Mantione M, Figee M et al. 2018. Treatment-resistant depression and suicidality. J. Affect. Disord. 235:36267
    [Google Scholar]
  6. 6.
    Lavender E, Hirasawa-Fujita M, Domino EF. 2020. Ketamine's dose related multiple mechanisms of actions: dissociative anesthetic to rapid antidepressant. Behav. Brain Res. 390:112631
    [Google Scholar]
  7. 7.
    Berman RM, Cappiello A, Anand A et al. 2000. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47:35154
    [Google Scholar]
  8. 8.
    Zarate CA Jr., Singh JB, Carlson PJ et al. 2006. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63:85664
    [Google Scholar]
  9. 9.
    Yavi M, Lee H, Henter ID et al. 2022. Ketamine treatment for depression: a review. Discov. Mental Health 2:9
    [Google Scholar]
  10. 10.
    Phillips JL, Norris S, Talbot J et al. 2019. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am. J. Psychiatry 176:4019
    [Google Scholar]
  11. 11.
    aan het Rot M, Collins KA, Murrough JW et al. 2010. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol. Psychiatry 67:13945
    [Google Scholar]
  12. 12.
    Murrough JW, Perez AM, Pillemer S et al. 2013. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol. Psychiatry 74:25056
    [Google Scholar]
  13. 13.
    Zanos P, Moaddel R, Morris PJ et al. 2018. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol. Rev. 70:62160
    [Google Scholar]
  14. 14.
    Fava M, Freeman MP, Flynn M et al. 2020. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol. Psychiatry 25:1592603
    [Google Scholar]
  15. 15.
    Kim JW, Monteggia LM. 2020. Increasing doses of ketamine curtail antidepressant responses and suppress associated synaptic signaling pathways. Behav. Brain Res. 380:112378
    [Google Scholar]
  16. 16.
    Li N, Lee B, Liu RJ et al. 2010. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:95964
    [Google Scholar]
  17. 17.
    Miller OH, Yang L, Wang CC et al. 2014. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. eLife 3:e03581
    [Google Scholar]
  18. 18.
    Gerhard DM, Pothula S, Liu RJ et al. 2020. GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. J. Clin. Investig. 130:133649
    [Google Scholar]
  19. 19.
    Salahudeen MS, Wright CM, Peterson GM. 2020. Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review. Ther. Adv. Drug. Saf. 11:2042098620937899
    [Google Scholar]
  20. 20.
    Williams NR, Heifets BD, Blasey C et al. 2018. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am. J. Psychiatry 175:120515
    [Google Scholar]
  21. 21.
    Casarotto PC, Girych M, Fred SM et al. 2021. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell 184:1299313.e19
    [Google Scholar]
  22. 22.
    Zanos P, Moaddel R, Morris PJ et al. 2016. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:48186
    [Google Scholar]
  23. 23.
    MacDonald JF, Miljkovic Z, Pennefather P. 1987. Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. J. Neurophysiol. 58:25166
    [Google Scholar]
  24. 24.
    Kim JW, Suzuki K, Kavalali ET, Monteggia LM. 2023. Bridging rapid and sustained antidepressant effects of ketamine. Trends Mol. Med. 29:36475
    [Google Scholar]
  25. 25.
    Maeng S, Zarate CA Jr., Du J et al. 2008. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63:34952
    [Google Scholar]
  26. 26.
    Duman RS, Aghajanian GK, Sanacora G, Krystal JH. 2016. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22:23849
    [Google Scholar]
  27. 27.
    Kavalali ET, Monteggia LM. 2020. Targeting homeostatic synaptic plasticity for treatment of mood disorders. Neuron 106:71526
    [Google Scholar]
  28. 28.
    Homayoun H, Moghaddam B. 2007. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27:11496500
    [Google Scholar]
  29. 29.
    Moghaddam B, Adams B, Verma A, Daly D. 1997. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17:292127
    [Google Scholar]
  30. 30.
    Chowdhury GM, Zhang J, Thomas M et al. 2017. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol. Psychiatry 22:12026
    [Google Scholar]
  31. 31.
    Fukumoto K, Iijima M, Chaki S. 2016. The antidepressant effects of an mGlu2/3 receptor antagonist and ketamine require AMPA receptor stimulation in the mPFC and subsequent activation of the 5-HT neurons in the DRN. Neuropsychopharmacology 41:104656
    [Google Scholar]
  32. 32.
    Abdallah CG, De Feyter HM, Averill LA et al. 2018. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology 43:215460
    [Google Scholar]
  33. 33.
    Lepack AE, Fuchikami M, Dwyer JM et al. 2014. BDNF release is required for the behavioral actions of ketamine. Int. J. Neuropsychopharmacol. 18:pyu033 Erratum 2016. Int. J. Neuropsychopharmacol. 19:pyw031
    [Google Scholar]
  34. 34.
    Moda-Sava RN, Murdock MH, Parekh PK et al. 2019. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 364:eaat8078
    [Google Scholar]
  35. 35.
    Fuchikami M, Thomas A, Liu R et al. 2015. Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions. PNAS 112:810611
    [Google Scholar]
  36. 36.
    Ford N, Ludbrook G, Galletly C. 2015. Benzodiazepines may reduce the effectiveness of ketamine in the treatment of depression. Aust. N. Z. J. Psychiatry 49:1227
    [Google Scholar]
  37. 37.
    Frye MA, Blier P, Tye SJ. 2015. Concomitant benzodiazepine use attenuates ketamine response: implications for large scale study design and clinical development. J. Clin. Psychopharmacol. 35:33436
    [Google Scholar]
  38. 38.
    Albott CS, Shiroma PR, Cullen KR et al. 2017. The antidepressant effect of repeat dose intravenous ketamine is delayed by concurrent benzodiazepine use. J. Clin. Psychiatry 78:e3089
    [Google Scholar]
  39. 39.
    Anand A, Charney DS, Oren DA et al. 2000. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch. Gen. Psychiatry 57:27076
    [Google Scholar]
  40. 40.
    Mathew SJ, Murrough JW, aan het Rot M et al. 2010. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int. J. Neuropsychopharmacol. 13:7182
    [Google Scholar]
  41. 41.
    Niciu MJ, Luckenbaugh DA, Ionescu DF et al. 2014. Riluzole likely lacks antidepressant efficacy in ketamine non-responders. J. Psychiatr. Res. 58:19799
    [Google Scholar]
  42. 42.
    Cunningham MO, Jones RS. 2000. The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro. Neuropharmacology 39:213946
    [Google Scholar]
  43. 43.
    Doble A. 1996. The pharmacology and mechanism of action of riluzole. Neurology 47:S23341
    [Google Scholar]
  44. 44.
    Mitra-Ghosh T, Callisto SP, Lamba JK et al. 2020. PharmGKB summary: lamotrigine pathway, pharmacokinetics and pharmacodynamics. Pharmacogenet. Genom. 30:8190
    [Google Scholar]
  45. 45.
    Valentine GW, Mason GF, Gomez R et al. 2011. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS. Psychiatry Res. 191:12227
    [Google Scholar]
  46. 46.
    Averill LA, Averill CL, Gueorguieva R et al. 2022. mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression. J. Affect. Disord. 303:9197
    [Google Scholar]
  47. 47.
    Abdallah CG, Averill LA, Gueorguieva R et al. 2020. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology 45:99097
    [Google Scholar]
  48. 48.
    Cloughesy TF, Yoshimoto K, Nghiemphu P et al. 2008. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLOS Med. 5:e8
    [Google Scholar]
  49. 49.
    Gottschalk S, Cummins CL, Leibfritz D et al. 2011. Age and sex differences in the effects of the immunosuppressants cyclosporine, sirolimus and everolimus on rat brain metabolism. Neurotoxicology 32:5057
    [Google Scholar]
  50. 50.
    Barbosa AC, Kim MS, Ertunc M et al. 2008. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. PNAS 105:939196
    [Google Scholar]
  51. 51.
    Kim JW, Autry AE, Na ES et al. 2021. Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation. Nat. Neurosci. 24:11009
    [Google Scholar]
  52. 52.
    Bjorkholm C, Monteggia LM. 2016. BDNF—a key transducer of antidepressant effects. Neuropharmacology 102:7279
    [Google Scholar]
  53. 53.
    Autry AE, Adachi M, Nosyreva E et al. 2011. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:9195
    [Google Scholar]
  54. 54.
    Laje G, Lally N, Mathews D et al. 2012. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol. Psychiatry 72:e2728
    [Google Scholar]
  55. 55.
    Chen MH, Lin WC, Wu HJ et al. 2019. Antisuicidal effect, BDNF Val66Met polymorphism, and low-dose ketamine infusion: reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression (AKSTP-TRD). J. Affect. Disord. 251:16269
    [Google Scholar]
  56. 56.
    Herring BE, Nicoll RA. 2016. Long-term potentiation: from CaMKII to AMPA receptor trafficking. Annu. Rev. Physiol. 78:35165
    [Google Scholar]
  57. 57.
    Sutton MA, Ito HT, Cressy P et al. 2006. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell 125:78599
    [Google Scholar]
  58. 58.
    Proud CG. 2015. Regulation and roles of elongation factor 2 kinase. Biochem. Soc. Trans. 43:32832
    [Google Scholar]
  59. 59.
    Nosyreva E, Szabla K, Autry AE et al. 2013. Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J. Neurosci. 33:69907002
    [Google Scholar]
  60. 60.
    Suzuki K, Kim JW, Nosyreva E et al. 2021. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action. Cell Rep. 37:109918
    [Google Scholar]
  61. 61.
    Gideons ES, Kavalali ET, Monteggia LM. 2014. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. PNAS 111:864954
    [Google Scholar]
  62. 62.
    Zarate CA Jr., Singh JB, Quiroz JA et al. 2006. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am. J. Psychiatry 163:15355
    [Google Scholar]
  63. 63.
    Lenze EJ, Skidmore ER, Begley AE et al. 2012. Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int. J. Geriatr. Psychiatry 27:97480
    [Google Scholar]
  64. 64.
    Blanpied TA, Boeckman FA, Aizenman E, Johnson JW. 1997. Trapping channel block of NMDA-activated responses by amantadine and memantine. J. Neurophysiol. 77:30923
    [Google Scholar]
  65. 65.
    Yang Y, Cui Y, Sang K et al. 2018. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554:31722
    [Google Scholar]
  66. 66.
    Perez-Reyes E 2003. Molecular physiology of low-voltage-activated T-type calcium channels. Physiol. Rev. 83:11761
    [Google Scholar]
  67. 67.
    Zhang K, Jia G, Xia L et al. 2021. Efficacy of anticonvulsant ethosuximide for major depressive disorder: a randomized, placebo-control clinical trial. Eur. Arch. Psychiatry Clin. Neurosci. 271:48793
    [Google Scholar]
  68. 68.
    Newport DJ, Carpenter LL, McDonald WM et al. 2015. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am. J. Psychiatry 172:95066
    [Google Scholar]
  69. 69.
    Zhao X, Venkata SL, Moaddel R et al. 2012. Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression. Br. J. Clin. Pharmacol. 74:30414
    [Google Scholar]
  70. 70.
    Carreno FR, Donegan JJ, Boley AM et al. 2016. Activation of a ventral hippocampus–medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol. Psychiatry 21:1298308
    [Google Scholar]
  71. 71.
    Bagot RC, Cates HM, Purushothaman I et al. 2017. Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles. Biol. Psychiatry 81:28595
    [Google Scholar]
  72. 72.
    Lopez JP, Lucken MD, Brivio E et al. 2022. Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2. Neuron 110:228398.e9
    [Google Scholar]
  73. 73.
    Jentsch TJ. 2000. Neuronal KCNQ potassium channels: physiology and role in disease. Nat. Rev. Neurosci. 1:2130
    [Google Scholar]
  74. 74.
    Costi S, Morris LS, Kirkwood KA et al. 2021. Impact of the KCNQ2/3 channel opener ezogabine on reward circuit activity and clinical symptoms in depression: results from a randomized controlled trial. Am. J. Psychiatry 178:43746
    [Google Scholar]
  75. 75.
    Ma Z, Zang T, Birnbaum SG et al. 2017. TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response. Nat. Commun. 8:1668
    [Google Scholar]
  76. 76.
    Rawat R, Tunc-Ozcan E, McGuire TL et al. 2022. Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice. Nat. Commun. 13:2650
    [Google Scholar]
  77. 77.
    Soumier A, Carter RM, Schoenfeld TJ, Cameron HA. 2016. New hippocampal neurons mature rapidly in response to ketamine but are not required for its acute antidepressant effects on neophagia in rats. eNeuro 3:ENEURO.0116-15.2016
    [Google Scholar]
  78. 78.
    Sorrells SF, Paredes MF, Cebrian-Silla A et al. 2018. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555:37781
    [Google Scholar]
  79. 79.
    Lucassen PJ, Fitzsimons CP, Salta E, Maletic-Savatic M. 2020. Adult neurogenesis, human after all (again): classic, optimized, and future approaches. Behav. Brain Res. 381:112458
    [Google Scholar]
  80. 80.
    Fava M, Johe K, Ereshefsky L et al. 2016. A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients. Mol. Psychiatry 21:137280
    [Google Scholar]
  81. 81.
    Papakostas GI, Johe K, Hand H et al. 2020. A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder. Mol. Psychiatry 25:156979
    [Google Scholar]
  82. 82.
    Yang C, Shirayama Y, Zhang JC et al. 2015. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl. Psychiatry 5:e632
    [Google Scholar]
  83. 83.
    Suzuki K, Nosyreva E, Hunt KW et al. 2017. Effects of a ketamine metabolite on synaptic NMDAR function. Nature 546:E13
    [Google Scholar]
  84. 84.
    da Fonseca Pacheco D, Lima Romero TR, Gama Duarte ID. 2014. Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Res. 1562:6975
    [Google Scholar]
  85. 85.
    Klein ME, Chandra J, Sheriff S, Malinow R. 2020. Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents. PNAS 117:265662
    [Google Scholar]
  86. 86.
    Yoon G, Petrakis IL, Krystal JH. 2019. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder. JAMA Psychiatry 76:33738
    [Google Scholar]
  87. 87.
    Marton T, Barnes DE, Wallace A, Woolley JD. 2019. Concurrent use of buprenorphine, methadone, or naltrexone does not inhibit ketamine's antidepressant activity. Biol. Psychiatry 85:e7576
    [Google Scholar]
  88. 88.
    Bond C, LaForge KS, Tian M et al. 1998. Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity: possible implications for opiate addiction. PNAS 95:960813
    [Google Scholar]
  89. 89.
    Huang P, Chen C, Mague SD et al. 2012. A common single nucleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and protein stability. Biochem. J. 441:37986
    [Google Scholar]
  90. 90.
    Saad Z, Hibar D, Fedgchin M et al. 2020. Effects of mu-opiate receptor gene polymorphism rs1799971 (A118G) on the antidepressant and dissociation responses in esketamine nasal spray clinical trials. Int. J. Neuropsychopharmacol. 23:54958
    [Google Scholar]
  91. 91.
    Harraz MM, Tyagi R, Cortes P, Snyder SH. 2016. Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol. Psychiatry 21:31319
    [Google Scholar]
  92. 92.
    Vogt MA, Vogel AS, Pfeiffer N et al. 2015. Role of the nitric oxide donor sodium nitroprusside in the antidepressant effect of ketamine in mice. Eur. Neuropsychopharmacol. 25:184852
    [Google Scholar]
  93. 93.
    Bevilacqua L, Charney A, Pierce CR et al. 2021. Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: a randomized controlled trial. J. Psychopharmacol. 35:12427
    [Google Scholar]
  94. 94.
    Belujon P, Grace AA. 2014. Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity. Biol. Psychiatry 76:92736
    [Google Scholar]
  95. 95.
    Wu M, Minkowicz S, Dumrongprechachan V et al. 2021. Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions. eLife 10:e64041
    [Google Scholar]
  96. 96.
    Gigliucci V, O'Dowd G, Casey S et al. 2013. Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology 228:15766
    [Google Scholar]
  97. 97.
    Lopez-Gil X, Jimenez-Sanchez L, Campa L et al. 2019. Role of serotonin and noradrenaline in the rapid antidepressant action of ketamine. ACS Chem. Neurosci. 10:331826
    [Google Scholar]
  98. 98.
    Krystal JH, D'Souza DC, Karper LP et al. 1999. Interactive effects of subanesthetic ketamine and haloperidol in healthy humans. Psychopharmacology 145:193204
    [Google Scholar]
  99. 99.
    Pham TH, Mendez-David I, Defaix C et al. 2017. Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice. Neuropharmacology 112:198209
    [Google Scholar]
  100. 100.
    Bel N, Artigas F. 1992. Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur. J. Pharmacol. 229:1013
    [Google Scholar]
  101. 101.
    Quitkin FM, Rabkin JD, Markowitz JM et al. 1987. Use of pattern analysis to identify true drug response. A replication. Arch. Gen. Psychiatry 44:25964
    [Google Scholar]
  102. 102.
    Tiger M, Veldman ER, Ekman CJ et al. 2020. A randomized placebo-controlled PET study of ketamine's effect on serotonin1B receptor binding in patients with SSRI-resistant depression. Transl. Psychiatry 10:159
    [Google Scholar]
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