Ketamine-assisted psychotherapy

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. 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, 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. 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. It was discovered by Parke-Davis Labs and Dr. Calvin Lee Stevens in 1962 during research into derivatives of phencyclidine (PCP). 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. 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. 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. 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. 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 also found that patients had low response rates to alternative compounds after the failure of the first antidepressant. 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. 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. Ketamine offers a notable advantage as opposed to currently-approved antidepressants, as it has a rapid onset (2–24 hours post-infusion) of temporally limited, but sustained, antidepressant and analgesic effects (typically lasting 4–7 days). Its dissociative, psychedelic effects could also provide patients with increased neuroplasticity and cognitive flexibility that would enable more effective participation in therapy sessions. Therapy could, in turn, reinforce the effects and improvements facilitated by ketamine to provide longer-lasting treatment. 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.

Active mechanisms
There are several hypotheses as to the underlying neural and cognitive mechanisms responsible for the psychiatric effects of ketamine. 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. 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. 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. 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.

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. It has also been shown to have a moderate-to-large effect in reducing suicidality in some patients suffering from suicidal ideation, 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. 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.

The mode of ketamine administration is a crucial consideration in the use of KAP for depression. It employs a dosage escalation strategy 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. There is no notable difference in efficacy, however. 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.

Legality
The use of ketamine in the United States for any form of psychiatric treatment is not permitted by the FDA. Since 2010, ketamine has been prescribed off-label to patients with severe depression with the informed consent of patients. In 2019, the FDA 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.

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. 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) and functional analytic psychotherapy (FAP).