The Pharmacological Management of Ketamine Use Disorder: A Systematic Review

Additional evidence suggests dysregulation of the hypothalamic-pituitary (HPA) axis, brain-derived neurotrophic factor (BDNF), vitamin D levels, and involvement of pro-inflammatory markers. Core symptoms include depressed mood or anhedonia, combined with neurovegetative symptoms such as sleep impairment, changes in appetite, feelings of worthlessness and guilt, and psychomotor retardation. Current first-line treatment options are antidepressants of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) class. Esketamine (Spravato) is an NMDA-receptor antagonist with additional AMPA-receptor agonist properties, which the FDA approved in 2019 to treat adult TRD in conjunction with an oral antidepressant.

Acute Dissociative Effects

One patient consistently had a SBP of 180 or greater at the last time point (40 minutes) of his second, third, and fourth infusions, which normalized within 30 minutes following treatment. During the first infusion, one patient transiently had a DBP of 110, which normalized within 30 minutes post-infusion. No patient had DBP values of 110 or greater during the second, third, or fourth infusions. Ketamine affects multiple neurotransmitter systems, including the opioidergic, monoaminergic, glutamatergic, and muscarinic systems, as well as substance P and sigma receptors.

More research is necessary to determine which palliative care patients would most benefit from ketamine and how to optimize their treatment. A recent study evaluated the efficacy of esketamine nasal spray (84 mg) administered twice a week versus placebo for four weeks in MDD patients with suicidal ideation in conjunction with standard care 43. A remission rate of 47% was observed in patients who received esketamine versus 37% in the placebo group. Adverse effects, including dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia, were mostly reported on intranasal dosing days and frequently resolved on the same day, highlighting the safety profile of repeated ketamine/esketamine dosing. Taken together, the evidence suggests that despite the growing research on maintenance treatment with ketamine and esketamine, further data from adequately powered randomized trials are needed to issue standardized clinical guidance.

Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript. Only very low-quality evidence of efficacy and tolerability was available for any pharmacological intervention in the treatment of ketamine use disorder. There were no randomized trials, and apart from one small controlled study with serious methodological concerns, all published articles were uncontrolled, with the majority of evidence confined to case reports.

• C.J.A.M. contributed to the conceptualisation, methodology, supervision, writing-original draft preparation, reviewing and editing.
• Additionally, included studies were heterogenous in terms of ketamine administration (dose, number, route of delivery), measurement of outcomes, length of follow-up, study design and setting, which reduces comparability.
• The dosage determines the application and resulting effects of the drug, leading to variations in the prescribing protocol.
• There is often an “efficacy-effectiveness” gap as new treatments move from research to clinical settings.28 Considerably less attention is paid to patients outside of research protocols compared to research subjects.

This is particularly important given that ketamine use for TRD is currently not approved by the FDA despite a significant body of evidence supporting its efficacy and safety. Interestingly, one recent study noted that, although six electroconvulsive therapy (ECT) sessions were superior to six ketamine sessions in treating TRD, both regimens were safe and effective in treating MDD 82. Furthermore, the approval of esketamine by both the FDA and the European Medicines Agency (EMA) highlights the utility of ketamine-like agents. Despite the preliminary nature of the evidence described above, a small number of studies have examined the promising effects of ketamine combined with psychotherapy for treating disorders other than depression, including alcohol, heroin, cocaine, and cannabis abuse 69–72. Ketamine was found to have benefits in treating substance addiction and dependence, increasing abstinence rates, reducing relapse rates, and decreasing cravings.

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Other than these events, the most common side effects in the first 24 hours were blurred vision, dry mouth, restlessness, fatigue, nausea/vomiting, poor coordination, and headache. Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD.

• In the first double-blind, placebo-controlled human study of ketamine for the treatment of MDD, seven patients received a single intravenous (IV) infusion of ketamine (0.5 mg/kg).
• Additionally, esketamine has the potential to cause severe cardiovascular and psychological adverse effects.
• Rehab insurance is a type of health insurance that covers the cost of addiction treatment, including inpatient and outpatient rehab programs, counseling sessions, and medication-assisted treatment.
• The variable action of ketamine’s enantiomers and respective metabolites on NMDA and AMPA receptors adds to the challenge of elucidating ketamine’s particular antidepressant effects 18, and additional downstream molecular and cellular pathways have been investigated to better understand ketamine’s rapid-acting antidepressant properties and its effects on promoting neuroplasticity 10.
• While those same regulations do not currently apply to ketamine administration when used as an off-label treatment for depression, FDA approval of ketamine for depression treatment would also likely require a REMS programme, placing similar logistical and economic barriers on ketamine administration.

Data Availability Statement

Only 2 databases were included, so there may be important studies not included in our review. The PRISMA extension for scoping reviews, however, does not routinely recommend quality appraisal in scoping reviews (17). In recent years, ketamine has also been pursued as a potential treatment for several other psychiatric diagnoses. Despite the small number of studies and the limited sample sizes, the preliminary results from some of these studies, reviewed below, are encouraging. Another paper in Lancet Psychiatry noted that clinical trials have avoided documenting—or even assessing for—dangerous effects. As with any novel use of a medication, it is important to investigate the potential harms from side effects.

Pain

In a secondary analysis, the researchers a potential case of acute ketamine withdrawal: clinical implications for the treatment of refractory depression american journal of psychiatry also investigated the effects of combining psychotherapy and ketamine, but the effect size failed to achieve statistical significance. In this context, ketamine may prove useful in both substance use abstinence and in the management of withdrawal symptoms. However, further research is warranted to better characterize the efficacy of ketamine use for these disorders. Results of individual studies included in the synthesis were presented in a separate table for each psychiatric diagnosis.

For instance, according to a recent paper in The British Journal of Psychiatry, there have been six four-week trials of esketamine. Five of those trials found the drug to be no better than placebo, while the last found a tiny statistically significant effect, which did not meet the criteria for clinical significance. Esketamine is currently FDA-indicated as an adjunctive treatment after two failed antidepressant trials. Despite this, the psychiatric community currently holds ketamine as a third-line treatment after augmentation has failed.Reference Lam, Kennedy, Adams, Bahji, Beaulieu and Bhat6 Thus, we believe that it is most appropriate to compare ketamine to other commonly utilised augmentation strategies for depression refractory to first-line therapy.

In contrast, another randomized, double-blind, placebo-controlled study of six repeated infusions versus a single IV ketamine infusion in patients with TRD found no significant difference in symptom remission at two weeks 41. In another double-blind, placebo-controlled study of 26 medicated outpatients with TRD and current, chronic suicidal ideation, six ketamine infusions (0.5 mg/kg over 45 min) administered over the course of three weeks did not outperform placebo 42. The variable action of ketamine’s enantiomers and respective metabolites on NMDA and AMPA receptors adds to the challenge of elucidating ketamine’s particular antidepressant effects 18, and additional downstream molecular and cellular pathways have been investigated to better understand ketamine’s rapid-acting antidepressant properties and its effects on promoting neuroplasticity 10. In preclinical animal model studies, the ketamine metabolites (2S,6S;2R,6R)-hydroxynorketamine (HNK) were found to be essential for its rapid antidepressant effects. In addition, the antidepressant effects of the (2R,6R)-HNK enantiomer were independent of the NMDA receptor, supporting the role of AMPA receptor activity in the potentiation of excitatory synapses in mood-relevant brain regions 11. In addition, both preclinical and clinical studies have demonstrated sex differences in the antidepressant efficacy and side effect profile of ketamine and its metabolites, further underscoring its pharmacokinetic complexity 19, 20.

This manuscript will review the clinical evidence for single-dose IV ketamine administration as well as intranasal esketamine for the treatment of MDD and TRD. A review of ketamine’s use for other psychiatric diagnoses, its potential adverse effects, and attempts to prolong its effects with combined therapy or repeated dosing will also be discussed. A wealth of evidence indicates the value of ketamine in treating severe pain, including conditions such as trauma, fractures, abdominal and flank pain, low back pain, and extremity pain. When used for pain management, sub-dissociative dosing, otherwise known as low-dose ketamine (LDK), is used either alone or as an adjunct to other pain relief medications.

Meta-analysis was not deemed appropriate because of the heterogeneity of dosage, number and methods of ketamine administrations, patient populations, study designs and outcome measures. The results were grouped according to patient population (MDD, bipolar disorder, suicidal ideation, generalised and social anxiety disorders, post-traumatic stress disorder, obsessive–compulsive disorders, substance use disorders and eating disorders) and by setting (ketamine in combination with ECT). In 2019, the FDA approved intranasal esketamine, the S-enantiomer of ketamine, in conjunction with oral antidepressants for the treatment of TRD in adults. In 2020, it was FDA-approved to treat adults with MDD and acute suicidal ideation or behavior. Due to concerns of possible adverse effects and potential abuse, esketamine was approved through a Risk Evaluation and Mitigation Strategy (REMS). Under this agreement, intranasal esketamine can be dispensed and administered only in a REMS-certified healthcare setting under medical supervision, and patients must be monitored for at least two hours following esketamine administration.

While those same regulations do not currently apply to ketamine administration when used as an off-label treatment for depression, FDA approval of ketamine for depression treatment would also likely require a REMS programme, placing similar logistical and economic barriers on ketamine administration. As with clozapine for schizophrenia, such data could inform treatment algorithms, and also promote improved coverage of ketamine by insurance carriers, thereby increasing accessibility. In a second trial, 176 adults in stable remission and 121 adults who were “stable responders” after 16 weeks of treatment with intranasal esketamine plus an oral antidepressant were randomized to either 1) continue taking the same regimen or 2) switch to intranasal placebo plus their oral antidepressant.