Depression
Depression is a serious illness and one of the leading causes of disability worldwide26,43,46. The World Health Organization estimates that globally 5% of adults suffer from depression15. The National Institute of Health reports that in the United States over 8% of the adult population, 21 million people, have suffered at least one major depressive episode42. There is no lab test or imaging study to diagnose depression the way we might diagnose a physical illness such as a heart attack or asthma. As a mental illness, depression can be more difficult to identify. Depression is a constellation of symptoms that includes, among others: feelings of sadness or emptiness, difficulty sleeping, rapid weight change, fatigue, lack of concentration, and an enduring sense of worthlessness or guilt5.
Despite the overwhelming number of people who battle depression daily, the field of mental health has struggled to provide adequate treatment. Prevailing research has shown that up to one-third of patients diagnosed with depression will not improve even after treatment with up to four different antidepressants59. This occurrence is called treatment resistant depression7. Treatment resistant depression is debilitating not only because of the hopelessness it contributes to, but also because depression and chronic stress have been shown to change the structure, function, and development of the brain1,12,20,61,65. Both chronic stress and depression lead to dysfunctional connections between and decreased size of some brain cells, alteration in the body’s stress hormone system, and changes in the shape and structure of the brain and its networks3,20,21.
Depression and Brain Networks
When multiple areas of the brain communicate and work together, this is called a brain network47,56. Different networks come online for different tasks and situations we encounter. Data from brain imaging shows that chronic stress and depression change the activity and communication of several brain networks23,39,40,55,65,69,75. The salience network (SAL), affective network (AN), cognitive control network (CCN), central executive network (CEN), and default mode network (DMN) are all affected by depression and chronic stress 10,30,74. Of particular interest for those suffering from symptoms of depression, the default mode network seems to become more active and larger in size than those without symptoms of depression11,23,40,48,61,65,69,75.
The default mode network is active when a person does not have a goal oriented task56. This network seems to be responsible for creating our inner monologue, remembering past experiences, and daydreaming23,55,68,75. In people who suffer from depression, their brain networks seem to favor rumination and self-critical introspection rather than processing, interacting, and interpreting outside information23,55,56,65,69,75. In this way, those who suffer from depression have an inner monologue that is more likely to be negative, self-critical, and ruminatively self-focused39,40.
Depression and Brain Receptors
For over 60 years theories of depression have focused on the monoaminergic system9,32,37. Enormous amounts of research have led to the development of SSRI’s and SNRI’s that act on that system. Yet these treatments are still hampered by limited effectiveness, slow onset, and bothersome side effects35,53,53. Recently, researchers have shifted their attention to look at medications that primarily affect a different system, the glutamate neurotransmitter system21,25. One of the more promising of these medications is ketamine.
In light of the cellular and network changes that occur in those suffering from depression and chronic stress, researchers began to target the glutamate neurotransmitter system with medications like ketamine. Ketamine binds to several different receptors in the brain including serotonin, dopamine, opioid, nicotinic and muscarinic receptors70,71. However, it seems its main neurochemical antidepressant activity occurs at the N-methyl-D-aspartate (NMDA) receptor71. Receptors are kind of like switches on the outside of a cell. When these switches are activated, a cascade of changes occur within cells. Sometimes these changes include release of molecules that can cause changes to other cells like stimulating growth or promoting communication.
Ketamine as Treatment for Depression
The activity of ketamine in the brain is very complicated. Ketamine interacts with many different receptors in different parts of the brain. One important interaction seems to be that ketamine turns off a cell that stops the activity of another cell; it essentially turns off the brake. This causes a cascade of transmitters, including glutamate, in specific areas of the brain. This cascade causes changes in brain cells that promote brain cell growth and the formation of new connections between brain cells. This creates “neuroplasticity,” the ability of the brain to change its structure and connectivity. Ketamine promotes neuroplasticity and actually reverses some of the detrimental changes caused by the symptoms of depression and chronic stress described above 2,3,6,12,19,20,24,34,35,41,71.
Studies have consistently demonstrated that ketamine safely, rapidly, and robustly decreases symptoms of depression4,8,13,16,31,50,51,53,57,63,72,73. Even a single infusion of ketamine seems to turn down the hyperactive default mode network in patients suffering from symptoms of depression and normalizes activity in other brain networks1,10,23,49,60–62,65,69. Additionally, ketamine has been shown to rapidly reduce suicidal ideation17,51,54,67,72 and also seems to normalize circadian rhythm, potentially improving sleep in those suffering from symptoms of depression22,35.
Of note, the majority of studies investigating ketamine as treatment for depression do not reference forms of therapy beyond ketamine administration in their protocols. The period of increased neuroplasticity after ketamine administration creates an advantageous milieu for psychotherapy14,24,29,33,36–38,45,64. Indeed, ketamine assisted therapy has been shown to bring a more long-lasting reduction in symptoms of not only depression, but also post-traumatic stress disorder (PTSD), anxiety, chronic pain disorders, and substance use disorder18,27,28,31,33,44,52,58,66.
Conclusion
The symptoms of depression are varied. The underlying causes of these symptoms are often complex. There are changes in the brains and bodies of people suffering from symptoms of depression. Ketamine seems to reverse some of the changes in the brain by promoting neuroplasticity. When ketamine is paired with therapy, these changes become much more transformative and long-lasting.
References:
1. Abdallah CG, Averill LA, Collins KA, et al. Ketamine Treatment and Global Brain Connectivity in Major Depression. Neuropsychopharmacology. 2017;42(6):1210-1219. doi:10.1038/npp.2016.186
2. Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics. Annu Rev Med. 2015;66(1):509-523. doi:10.1146/annurev-med-053013-062946
3. Abdallah CG, Sanacora G, Duman RS, Krystal JH. The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacol Ther. 2018;190:148-158. doi:10.1016/j.pharmthera.2018.05.010
4. Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. J Psychiatr Res. 2022;151:693-709. doi:10.1016/j.jpsychires.2022.04.037
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. DSM-5-TR. American Psychiatric Association Publishing; 2022. doi:10.1176/appi.books.9780890425787
6. Averill LA, Purohit P, Averill CL, Boesl MA, Krystal JH, Abdallah CG. Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies. Neurosci Lett. 2017;649:147-155. doi:10.1016/j.neulet.2016.11.064
7. Bergfeld IO, Mantione M, Figee M, Schuurman PR, Lok A, Denys D. Treatment-resistant depression and suicidality. J Affect Disord. 2018;235:362-367. doi:10.1016/j.jad.2018.04.016
8. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354. doi:10.1016/S0006-3223(99)00230-9
9. Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: Beyond monoamine hypothesis: Neural basis of major depressive disorder. Psychiatry Clin Neurosci. 2018;72(1):3-12. doi:10.1111/pcn.12604
10. Bonhomme V, Vanhaudenhuyse A, Demertzi A, et al. Resting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers. Anesthesiology. 2016;125(5):873-888. doi:10.1097/ALN.0000000000001275
11. Borserio BJ, Sharpley CF, Bitsika V, Sarmukadam K, Fourie PJ, Agnew LL. Default mode network activity in depression subtypes. Rev Neurosci. 2021;32(6):597-613. doi:10.1515/revneuro-2020-0132
12. Dai D, Lacadie CM, Holmes SE, et al. Ketamine Normalizes the Structural Alterations of Inferior Frontal Gyrus in Depression. Chronic Stress. 2020;4:247054702098068. doi:10.1177/2470547020980681
13. Dean RL, Hurducas C, Hawton K, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Common Mental Disorders Group, ed. Cochrane Database Syst Rev. 2021;2021(11). doi:10.1002/14651858.CD011612.pub3
14. DePierro J, Lepow L, Feder A, Yehuda R. Translating Molecular and Neuroendocrine Findings in Posttraumatic Stress Disorder and Resilience to Novel Therapies. Biol Psychiatry. 2019;86(6):454-463. doi:10.1016/j.biopsych.2019.07.009
15. Depressive disorder (depression). Accessed May 15, 2023. https://www.who.int/news-room/fact-sheets/detail/depression
16. Diazgranados N, Ibrahim L, Brutsche NE, et al. A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression. Arch Gen Psychiatry. 2010;67(8):793. doi:10.1001/archgenpsychiatry.2010.90
17. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid Resolution of Suicidal Ideation After a Single Infusion of an N -Methyl- D -Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder. J Clin Psychiatry. 2010;71(12):1605-1611. doi:10.4088/JCP.09m05327blu
18. Drozdz SJ, Goel A, McGarr MW, et al. Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature. J Pain Res. 2022;Volume 15:1691-1706. doi:10.2147/JPR.S360733
19. Du R, Han R, Niu K, et al. The Multivariate Effect of Ketamine on PTSD: Systematic Review and Meta-Analysis. Front Psychiatry. 2022;13:813103. doi:10.3389/fpsyt.2022.813103
20. Duman RS, Aghajanian GK. Synaptic Dysfunction in Depression: Potential Therapeutic Targets. Science. 2012;338(6103):68-72. doi:10.1126/science.1222939
21. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-249. doi:10.1038/nm.4050
22. Duncan WC, Slonena E, Hejazi NS, et al. Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine’s Rapid Antidepressant Properties. Biol Psychiatry. 2017;82(5):361-369. doi:10.1016/j.biopsych.2017.03.011
23. Evans JW, Szczepanik J, Brutsché N, Park LT, Nugent AC, Zarate CA. Default Mode Connectivity in Major Depressive Disorder Measured Up to 10 Days After Ketamine Administration. Biol Psychiatry. 2018;84(8):582-590. doi:10.1016/j.biopsych.2018.01.027
24. Feder A, Rutter SB, Schiller D, Charney DS. The emergence of ketamine as a novel treatment for posttraumatic stress disorder. In: Advances in Pharmacology. Vol 89. Elsevier; 2020:261-286. doi:10.1016/bs.apha.2020.05.004
25. Gerhard DM, Wohleb ES, Duman RS. Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity. Drug Discov Today. 2016;21(3):454-464. doi:10.1016/j.drudis.2016.01.016
26. Gore FM, Bloem PJ, Patton GC, et al. Global burden of disease in young people aged 10–24 years: a systematic analysis. The Lancet. 2011;377(9783):2093-2102. doi:10.1016/S0140-6736(11)60512-6
27. Grabski M, Borissova A, Marsh B, Morgan CJA, Curran HV. Ketamine as a mental health treatment: Are acute psychoactive effects associated with outcomes? A systematic review. Behav Brain Res. 2020;392:112629. doi:10.1016/j.bbr.2020.112629
28. Grabski M, McAndrew A, Lawn W, et al. Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder. Am J Psychiatry. 2022;179(2):152-162. doi:10.1176/appi.ajp.2021.21030277
29. Greenway KT, Garel N, Jerome L, Feduccia AA. Integrating psychotherapy and psychopharmacology: psychedelic-assisted psychotherapy and other combined treatments. Expert Rev Clin Pharmacol. 2020;13(6):655-670. doi:10.1080/17512433.2020.1772054
30. Gudayol-Ferré E, Peró-Cebollero M, González-Garrido AA, Guàrdia-Olmos J. Changes in brain connectivity related to the treatment of depression measured through fMRI: a systematic review. Front Hum Neurosci. 2015;9. doi:10.3389/fnhum.2015.00582
31. Hartberg J, Garrett-Walcott S, De Gioannis A. Impact of oral ketamine augmentation on hospital admissions in treatment-resistant depression and PTSD: a retrospective study. Psychopharmacology (Berl). 2018;235(2):393-398. doi:10.1007/s00213-017-4786-3
32. Hirschfeld RMA. History and Evolution of the Monoamine Hypothesis of Depression. J Clin Psychiatry. 2000;6(61):4-6.
33. Joneborg I, Lee Y, Di Vincenzo JD, et al. Active mechanisms of ketamine-assisted psychotherapy: A systematic review. J Affect Disord. 2022;315:105-112. doi:10.1016/j.jad.2022.07.030
34. Jumaili WA, Trivedi C, Chao T, Kubosumi A, Jain S. The safety and efficacy of ketamine NMDA receptor blocker as a therapeutic intervention for PTSD review of a randomized clinical trial. Behav Brain Res. 2022;424:113804. doi:10.1016/j.bbr.2022.113804
35. Kohtala S, Alitalo O, Rosenholm M, Rozov S, Rantamäki T. Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine. Pharmacol Ther. 2021;221:107741. doi:10.1016/j.pharmthera.2020.107741
36. Krediet E, Bostoen T, Breeksema J, van Schagen A, Passie T, Vermetten E. Reviewing the Potential of Psychedelics for the Treatment of PTSD. Int J Neuropsychopharmacol. 2020;23(6):385-400. doi:10.1093/ijnp/pyaa018
37. Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron. 2019;101(5):774-778. doi:10.1016/j.neuron.2019.02.005
38. Krystal JH, Charney DS, Duman RS. A New Rapid-Acting Antidepressant. Cell. 2020;181(1):7. doi:10.1016/j.cell.2020.02.033
39. Lemogne C, Delaveau P, Freton M, Guionnet S, Fossati P. Medial prefrontal cortex and the self in major depression. J Affect Disord. 2012;136(1-2):e1-e11. doi:10.1016/j.jad.2010.11.034
40. Lemogne C, Mayberg H, Bergouignan L, et al. Self-referential processing and the prefrontal cortex over the course of depression: A pilot study. J Affect Disord. 2010;124(1-2):196-201. doi:10.1016/j.jad.2009.11.003
41. Li N, Lee B, Liu RJ, et al. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science. 2010;329(5994):959-964. doi:10.1126/science.1190287
42. Major Depression. National Institute of Mental Health (NIMH). Accessed May 15, 2023. https://www.nimh.nih.gov/health/statistics/major-depression
43. Malhi GS, Mann JJ. Depression. The Lancet. 2018;392(10161):2299-2312. doi:10.1016/S0140-6736(18)31948-2
44. Marchi M, Magarini FM, Galli G, et al. The effect of ketamine on cognition, anxiety, and social functioning in adults with psychiatric disorders: A systematic review and meta-analysis. Front Neurosci. 2022;16:1011103. doi:10.3389/fnins.2022.1011103
45. Marguilho M, Figueiredo I, Castro-Rodrigues P. A unified model of ketamine’s dissociative and psychedelic properties. J Psychopharmacol (Oxf). 2023;37(1):14-32. doi:10.1177/02698811221140011
46. McCarron RM, Shapiro B, Rawles J, Luo J. Depression. Ann Intern Med. 2021;174(5):ITC65-ITC80. doi:10.7326/AITC202105180
47. Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011;15(10):483-506. doi:10.1016/j.tics.2011.08.003
48. Mueller F, Musso F, London M, de Boer P, Zacharias N, Winterer G. Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network. NeuroImage Clin. 2018;19:745-757. doi:10.1016/j.nicl.2018.05.037
49. Murrough JW, Collins KA, Fields J, et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry. 2015;5(2):e509-e509. doi:10.1038/tp.2015.10
50. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. Am J Psychiatry. 2013;170(10):1134-1142. doi:10.1176/appi.ajp.2013.13030392
51. Murrough JW, Perez AM, Pillemer S, et al. Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression. Biol Psychiatry. 2013;74(4):250-256. doi:10.1016/j.biopsych.2012.06.022
52. Pradhan B, Wainer I, Moaddel R, et al. Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy prolong the therapeutic effects of single ketamine infusion on post-traumatic stress disorder and comorbid depression: a pilot randomized, placebo-controlled, crossover clinical trial. Asia Pac J Clin Trials Nerv Syst Dis. 2017;2(3):80. doi:10.4103/2542-3932.211589
53. Price RB, Kissel N, Baumeister A, et al. International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators. Mol Psychiatry. 2022;27(12):5096-5112. doi:10.1038/s41380-022-01757-7
54. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant Depression. Biol Psychiatry. 2009;66(5):522-526. doi:10.1016/j.biopsych.2009.04.029
55. Raichle ME. The Brain’s Default Mode Network. Annu Rev Neurosci. 2015;38(1):433-447. doi:10.1146/annurev-neuro-071013-014030
56. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci. 2001;98(2):676-682. doi:10.1073/pnas.98.2.676
57. aan het Rot M, Collins KA, Murrough JW, et al. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression. Biol Psychiatry. 2010;67(2):139-145. doi:10.1016/j.biopsych.2009.08.038
58. Rothberg RL, Azhari N, Haug NA, Dakwar E. Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial. J Psychopharmacol (Oxf). 2021;35(2):150-158. doi:10.1177/0269881120970879
59. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. FOCUS. 2008;6(1):128-142. doi:10.1176/foc.6.1.foc128
60. Scheidegger M, Henning A, Walter M, et al. Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation: Amygdalo-Hippocampal Reactivity and Ketamine Administration. Hum Brain Mapp. 2016;37(5):1941-1952. doi:10.1002/hbm.23148
61. Scheidegger M, Walter M, Lehmann M, et al. Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action. Sensi SL, ed. PLoS ONE. 2012;7(9):e44799. doi:10.1371/journal.pone.0044799
62. Sheline YI, Price JL, Yan Z, Mintun MA. Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc Natl Acad Sci. 2010;107(24):11020-11025. doi:10.1073/pnas.1000446107
63. Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Published online 2013.
64. Stein MB, Simon NM. Ketamine for PTSD: Well, Isn’t That Special. Am J Psychiatry. 2021;178(2):116-118. doi:10.1176/appi.ajp.2020.20121677
65. Wade BSC, Loureiro J, Sahib A, et al. Anterior default mode network and posterior insular connectivity is predictive of depressive symptom reduction following serial ketamine infusion. Psychol Med. 2022;52(12):2376-2386. doi:10.1017/S0033291722001313
66. Walsh Z, Mollaahmetoglu OM, Rootman J, et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych Open. 2022;8(1):e19. doi:10.1192/bjo.2021.1061
67. Wilkinson ST, Ballard ED, Bloch MH, 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):150-158. doi:10.1176/appi.ajp.2017.17040472
68. Yeshurun Y, Nguyen M, Hasson U. The default mode network: where the idiosyncratic self meets the shared social world. Nat Rev Neurosci. 2021;22(3):181-192. doi:10.1038/s41583-020-00420-w
69. Zacharias N, Musso F, Müller F, et al. Ketamine effects on default mode network activity and vigilance: A randomized, placebo‐controlled crossover simultaneous fMRI/EEG study. Hum Brain Mapp. 2020;41(1):107-119. doi:10.1002/hbm.24791
70. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801-811. doi:10.1038/mp.2017.255
71. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Witkin JM, ed. Pharmacol Rev. 2018;70(3):621-660. doi:10.1124/pr.117.015198
72. Zarate CA, Brutsche NE, Ibrahim L, et al. Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biol Psychiatry. 2012;71(11):939-946. doi:10.1016/j.biopsych.2011.12.010
73. Zarate CA, Singh JB, Carlson PJ, et al. A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Arch Gen Psychiatry. 2006;63(8):856. doi:10.1001/archpsyc.63.8.856
74. Zheng H, Xu L, Xie F, et al. The Altered Triple Networks Interaction in Depression under Resting State Based on Graph Theory. BioMed Res Int. 2015;2015:1-8. doi:10.1155/2015/386326
75. Zhou HX, Chen X, Shen YQ, et al. Rumination and the default mode network: Meta-analysis of brain imaging studies and implications for depression. NeuroImage. 2020;206:116287. doi:10.1016/j.neuroimage.2019.116287
