Ketamine-assisted psychotherapy (KAP) is the use of prescribed doses of ketamine, the drug, as an adjunct to psychotherapy sessions. KAP shows significant potential in treating mental disorders such as treatment-resistant depression (TRD), anxiety, obsessive–compulsive disorders (OCD), post-traumatic stress disorders (PTSD), and other conditions.[1] It can also be used for those experiencing substance abuse and physical pain. While it is primarily used as a veterinary anaesthetic, ketamine has also been found to have rapid analgesic and hallucinogenic effects,[2][3] which has sparked interest in its use as an antidepressant. Despite initial trials of its use in the treatment of mental disorders focussing primarily on its antidepressant effects, newer studies are attempting to harness its psychedelic effects to bring about altered states of consciousness, which will augment the adjunct psychotherapy. Ketamine's neuroplasticity-promoting effects strengthen the cognitive restructuring that takes place through traditional psychotherapy, thereby leading to long-lasting behavioural change.[4][5] KAP offers promising directions for research on new antidepressant alternatives, but is still not sufficiently defined or evaluated as a treatment combination.

Background

Ketamine is a short-acting, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.[2] It was discovered by Parke-Davis Labs and Dr. Calvin Lee Stevens in 1962 during research into derivatives of phencyclidine (PCP).[6] It was first used clinically as a veterinary anesthetic. The first dose of ketamine was administered to a human by Edward Domino in 1964. Soon after, Parke-Davis filed a patent for the utilization of the anesthetic.[7][8] With this patent, ketamine began to be used on the battlefield where it was considered the "buddy drug" because soldiers were able to administer it to one another.[9] Given its hallucinogenic properties, interest rapidly rose in the possibility of broader avenues of application, including within the field of psychiatry as a treatment for depression, substance use dependence, and more.[10] The US Food and Drug Administration (FDA) first approved the use of intranasal esketamine (Spravato)—an enantiomer of ketamine—for the use of ketamine-derived therapy for treatment-resistant depression, in 2019.[11] Ketamine is currently one of the two injected general anesthetics that the World Health Organisation includes in its Model List of Essential Medicines.

Rationale

Current antidepressant treatment is heavily limited by its delayed onset of efficacy, with noticeable effects only appearing over a period of months. The Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D) Trial[12] also found that patients had low response rates to alternative compounds after the failure of the first antidepressant.[2][13] Thus, a need for more rapid, yet prolonged, efficacy in treatment has stimulated further research on alternative treatment options.

Research evidence has found that the integrated use of psychotherapy and antidepressant medication to treat mental disorders, enhances the effects of both.[2][10][14] The combination of pharmacotherapy and psychotherapy has historically been efficacious in numerous instances, such as the pairing of psychotherapy with conventional antidepressants for mood and anxiety disorders, with naltrexone for alcohol and opioid dependence, and with bupropion for smoking cessation.[6] Ketamine offers a notable advantage as opposed to currently-approved antidepressants, as it has a rapid onset[15] (2–24 hours post-infusion)[16] of temporally limited, but sustained, antidepressant and analgesic effects (typically lasting 4–7 days).[2] Its dissociative, psychedelic effects could also provide patients with increased neuroplasticity and cognitive flexibility that would enable more effective participation in therapy sessions.[15] Therapy could, in turn, reinforce the effects and improvements facilitated by ketamine to provide longer-lasting treatment.[15][17] Supplementing ketamine use with cognitive behaviour therapy (CBT), in particular, has the potential to help patients reverse their inaccurate beliefs and maladaptive processing of information, that lead to depressive mental states.[18]

Active mechanisms

There are several hypotheses as to the underlying neural and cognitive mechanisms responsible for the psychiatric effects of ketamine.[2] Its mechanism of action is as an NMDA receptor antagonist. As such, glutamate modulation is a well-known effect, which is specifically believed to confer increased synaptic excitability. Notably, however, the effects of ketamine are now believed to be larger in scope than previously thought, ultimately leading to greater synaptogenesis and neuroplasticity.[18] As demonstrated in animal models, the administration of ketamine propagates signaling pathways surmised to augment neuroplasticity. Key among these are mammalian target of rapamycin (mTOR), glycogen synthase kinase-3 (GSK3), and elongation factor 2 (eEF2) kinase.[2] Ketamine has also demonstrated its ability to increase brain-derived neurotrophic factor (BDNF) levels within the brain in animal studies, which ameliorates the effects of acute and chronic stress.[19] The subsequent increase in both synaptic excitation and neuroplasticity is believed to precipitate the powerful and immediate symptom reduction ketamine elicits for a variety of conditions. It has additionally been theorized that ketamine disrupts the reconsolidation of dysfunctional memories and, through doing so, diminishes the burden of those associated with trauma, anxiety, substance use, and so on.[20]

An individual speaking with a psychotherapist.

Treatment-resistant depression

Efficacy in treatment

The use of ketamine as an antidepressant has mainly been studied for the treatment of treatment-resistant depression(TRD). Single-dose use has been found to have noticeable and rapid anti-depressive effects that tend to last up to a week, accompanied by acute side-effects that resolve spontaneously.[21] It has also been shown to have a moderate-to-large effect in reducing suicidality in some patients suffering from suicidal ideation,[3] with visible efficacy within two hours of administration. This is in sharp contrast with currently-approved treatment options, whose delayed onset poses an increased risk for suicidality in patients. However, this potency cannot currently be generalised for non-depressed patients experiencing suicidal ideation.

Protocol and administration

Repeated sessions of KAP have also been found to be an effective method for facilitating clinically-significant reduction in anxiety and depression, when conducted in private practice settings. Sessions may last up to three hours, with provisions for supervised recovery towards the end.[10] The time-to-relapse after ketamine treatment is typically 2–4 weeks, which is why a repeated dosage paradigm is used to increase KAP's efficacy on treatment-resistant depression. Currently only 20% of the 2,500 ketamine clinics in the United States offer KAP.[22]

The mode of ketamine administration is a crucial consideration in the use of KAP for depression. It employs a dosage escalation strategy[10] to achieve different levels of dissociative effects, depending on the amount of alteration of consciousness needed for treatment. Lower-dose sublingual administration is recommended for sessions that require active therapist-patient communication, and higher-dose intramuscular administration takes place when an inward focus is needed, with eye coverings and music provided.[14] There is no notable difference in efficacy, however.[23][14] Guidelines for the provision of psychotherapy are also variably defined, depending on the application, with it being delivered either simultaneously, or following the infusion of ketamine.[14]

Legality

The use of ketamine in the United States for any form of psychiatric treatment is not permitted by the FDA.[24] Since 2010, ketamine has been prescribed off-label to patients with severe depression with the informed consent of patients.[25] In 2019, the FDA it approved the use of esketamine (Spravato) as a nasal spray, in conjunction with an oral antidepressant, for treatment-resistant depression in adults. Potential risks associated with it include dissociation, sedation and abuse. Esketamine cannot be distributed outside of certified clinical settings.[11]

Limitations and future directions

KAP has the potential to show significant efficacy in the treatment of treatment-resistant depression and suicidality, among other mental disorders. But, extensive further research is needed for its effects and mechanisms of action to be properly understood. Currently, the lack of large, replicated clinical trials prevent existing results from being generalisable to the larger population. The current model of KAP also uses repeated administration of ketamine, the long-term side effects of which are not fully known yet. High doses of ketamine could also have potentially toxic effects in patients.[26] Given that existing studies only have short-term follow-up, the long-term safety of patients who undergo repeated dosing is, therefore, unknown. Future trials should be of larger scale, with repeated ketamine dosing, regular monitoring and follow-up. They should also focus on integrating ketamine with other forms of therapy, including, but not limited to motivational enhancement therapy (MET)[2] and functional analytic psychotherapy (FAP).[2]

References

  1. ↑ Dolan, Eric W. (2023-04-19). "Ketamine shows promise in the treatment of depression in patients with borderline personality disorder". PsyPost. Retrieved 2023-04-20.
  2. 1 2 3 4 5 6 7 8 9 Drozdz, Sandra J; Goel, Akash; McGarr, Matthew W; Katz, Joel; Ritvo, Paul; Mattina, Gabriella F; Bhat, Venkat; Diep, Calvin; Ladha, Karim S (2022-12-31). "Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature". Journal of Pain Research. 15: 1691–1706. doi:10.2147/JPR.S360733. PMC 9207256. PMID 35734507.
  3. 1 2 Nowacka, Agata; Borczyk, Malgorzata (2019-10-05). "Ketamine applications beyond anesthesia – A literature review". European Journal of Pharmacology. 860: 172547. doi:10.1016/j.ejphar.2019.172547. ISSN 0014-2999. PMID 31348905. S2CID 198934018.
  4. ↑ Krystal, John H. (2007-10-15). "Neuroplasticity as a Target for the Pharmacotherapy of Psychiatric Disorders: New Opportunities for Synergy with Psychotherapy". Biological Psychiatry. 62 (8): 833–834. doi:10.1016/j.biopsych.2007.08.017. ISSN 0006-3223. PMID 17916459. S2CID 41034050.
  5. ↑ Greenway, Kyle T.; Garel, Nicolas; Jerome, Lisa; Feduccia, Allison A. (2020-06-02). "Integrating psychotherapy and psychopharmacology: psychedelic-assisted psychotherapy and other combined treatments". Expert Review of Clinical Pharmacology. 13 (6): 655–670. doi:10.1080/17512433.2020.1772054. ISSN 1751-2433. PMID 32478631. S2CID 219169886.
  6. 1 2 Mathai, David S.; Mora, Victoria; Garcia-Romeu, Albert (2022). "Toward Synergies of Ketamine and Psychotherapy". Frontiers in Psychology. 13: 868103. doi:10.3389/fpsyg.2022.868103. ISSN 1664-1078. PMC 8992793. PMID 35401323.
  7. ↑ "History of Ketamine". TD Consultancy. Retrieved 2023-12-05.
  8. ↑ Le Daré, B.; Pelletier, R.; Morel, I.; Gicquel, T. (January 2022). "[History of Ketamine: An ancient molecule that is still popular today]". Annales Pharmaceutiques Francaises. 80 (1): 1–8. doi:10.1016/j.pharma.2021.04.005. ISSN 0003-4509. PMID 33915159.
  9. ↑ Mercer, S. J. (2009). "'The Drug of War'--a historical review of the use of Ketamine in military conflicts". Journal of the Royal Naval Medical Service. 95 (3): 145–150. doi:10.1136/jrnms-95-145. ISSN 0035-9033. PMID 20180434.
  10. 1 2 3 4 Dore, Jennifer; Turnipseed, Brent; Dwyer, Shannon; Turnipseed, Andrea; Andries, Julane; Ascani, German; Monnette, Celeste; Huidekoper, Angela; Strauss, Nicole; Wolfson, Phil (2019-03-15). "Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy". Journal of Psychoactive Drugs. 51 (2): 189–198. doi:10.1080/02791072.2019.1587556. ISSN 0279-1072. PMID 30917760. S2CID 85543704.
  11. 1 2 Research, Center for Drug Evaluation and (2022-02-16). "FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray". FDA.
  12. ↑ Sinyor, Mark; Schaffer, Ayal; Levitt, Anthony (March 2010). "The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: A Review". The Canadian Journal of Psychiatry. 55 (3): 126–135. doi:10.1177/070674371005500303. ISSN 0706-7437. PMID 20370962. S2CID 19442084.
  13. ↑ Naughton, Marie; Clarke, Gerard; O′Leary, Olivia F.; Cryan, John F.; Dinan, Timothy G. (2014-03-01). "A review of ketamine in affective disorders: Current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action". Journal of Affective Disorders. 156: 24–35. doi:10.1016/j.jad.2013.11.014. ISSN 0165-0327. PMID 24388038.
  14. 1 2 3 4 Walsh, Zach; Mollaahmetoglu, Ozden Merve; Rootman, Joseph; Golsof, Shannon; Keeler, Johanna; Marsh, Beth; Nutt, David J.; Morgan, Celia J. A. (January 2022). "Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review". BJPsych Open. 8 (1): e19. doi:10.1192/bjo.2021.1061. ISSN 2056-4724. PMC 8715255. PMID 35048815.
  15. 1 2 3 Hasler, Gregor (June 2020). "Toward specific ways to combine ketamine and psychotherapy in treating depression". CNS Spectrums. 25 (3): 445–447. doi:10.1017/S1092852919001007. ISSN 1092-8529. PMID 31213212. S2CID 195067658.
  16. ↑ Singh, Jaskaran B.; Fedgchin, Maggie; Daly, Ella J.; De Boer, Peter; Cooper, Kimberly; Lim, Pilar; Pinter, Christine; Murrough, James W.; Sanacora, Gerard; Shelton, Richard C.; Kurian, Benji; Winokur, Andrew; Fava, Maurizio; Manji, Husseini; Drevets, Wayne C. (August 2016). "A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression". American Journal of Psychiatry. 173 (8): 816–826. doi:10.1176/appi.ajp.2016.16010037. ISSN 0002-953X. PMID 27056608.
  17. ↑ Doblin, Richard E.; Christiansen, Merete; Jerome, Lisa; Burge, Brad (2019-03-15). "The Past and Future of Psychedelic Science: An Introduction to This Issue". Journal of Psychoactive Drugs. 51 (2): 93–97. doi:10.1080/02791072.2019.1606472. ISSN 0279-1072. PMID 31132970. S2CID 167220251.
  18. 1 2 Joneborg, Isak; Lee, Yena; Di Vincenzo, Joshua D.; Ceban, Felicia; Meshkat, Shakila; Lui, Leanna M. W.; Fancy, Farhan; Rosenblat, Joshua D.; McIntyre, Roger S. (2022-10-15). "Active mechanisms of ketamine-assisted psychotherapy: A systematic review". Journal of Affective Disorders. 315: 105–112. doi:10.1016/j.jad.2022.07.030. ISSN 0165-0327. PMID 35905796. S2CID 251141313.
  19. ↑ Du, Rui; Han, Ruili; Niu, Kun; Xu, Jiaqiao; Zhao, Zihou; Lu, Guofang; Shang, Yulong (2022). "The Multivariate Effect of Ketamine on PTSD: Systematic Review and Meta-Analysis". Frontiers in Psychiatry. 13: 813103. doi:10.3389/fpsyt.2022.813103. ISSN 1664-0640. PMC 8959757. PMID 35356723.
  20. ↑ Stein, Murray B.; Simon, Naomi M. (2021-02-01). "Ketamine for PTSD: Well, Isn't That Special". American Journal of Psychiatry. 178 (2): 116–118. doi:10.1176/appi.ajp.2020.20121677. ISSN 0002-953X. PMID 33517752. S2CID 231752701.
  21. ↑ Corriger, Alexandrine; Pickering, Gisèle (2019-12-31). "Ketamine and depression: a narrative review". Drug Design, Development and Therapy. 13: 3051–3067. doi:10.2147/DDDT.S221437. PMC 6717708. PMID 31695324.
  22. ↑ "About Healing Maps".
  23. ↑ Andrade, Chittaranjan (2017-08-23). "Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?". The Journal of Clinical Psychiatry. 78 (7): e852–e857. doi:10.4088/JCP.17f11738. ISSN 0160-6689. PMID 28749092.
  24. ↑ "FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders". FDA. 10 October 2023.
  25. ↑ "The legal psychedelic: Ketamine is a fast-acting treatment for depression (If you have the money)". Los Angeles Times. 28 February 2023.
  26. ↑ Short, Brooke; Fong, Joanna; Galvez, Veronica; Shelker, William; Loo, Colleen K (January 2018). "Side-effects associated with ketamine use in depression: a systematic review". The Lancet Psychiatry. 5 (1): 65–78. doi:10.1016/S2215-0366(17)30272-9. PMID 28757132.
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