SUMMARY  

• Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Careful consideration is advised prior to treatment of individuals with a history of substance use disorder.¹
• The phase 3 SPRAVATO trials excluded patients with a history of moderate or severe substance or alcohol use disorder, defined by DSM-5 criteria, within 6 months before the start of the screening/observational phase.^2-8
• The concomitant use of SPRAVATO and treatments for opioid dependence, such as methadone, buprenorphine, buprenorphine/naloxone, or naltrexone, were not studied in the clinical trial program for SPRAVATO.
• Esketamine (ESK), the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. However, the precise mechanism of action of ESK in major depressive disorder (MDD) is unknown. The antidepressant pharmacologic action of ESK is thought to be similar to ketamine.^9-13
• At the doses used in clinical practice, ESK’s primary antidepressant activity is not believed to directly involve mu-opioid receptor (MOR) stimulation,^14-17 nor is it believed to directly involve inhibition of serotonin, norepinephrine, or dopamine reuptake.^9-11
• A literature search did not yield data with SPRAVATO; however, there was limited information found for ketamine. A study evaluating pretreatment with naltrexone prior to intravenous ketamine suggested that ketamine’s acute antidepressant effect requires opioid system activation¹⁸; however, this result was not replicated in other studies:
  • One showed that naltrexone pretreatment did not appear to interfere with the antidepressant effects of ketamine.¹⁷
  • Another demonstrated that in patients receiving intravenous ketamine treatment, the antidepressant effect was similar between those who were receiving MOR agonists (buprenorphine, methadone) and those who were not receiving opioidergic drugs.¹⁹

Clinical data

Ketamine Data

Williams et al (2018 and 2019)^18,20 reported interim results of an analysis in 12 patients with treatment-resistant depression (TRD) who completed a double-blind, crossover study that evaluated whether opioid receptors play a role in the antidepressant effect of ketamine. Patients received oral naltrexone 50 mg or placebo 45 minutes prior to intravenous ketamine 0.5 mg/kg over 40 minutes. In the seven patients who met the prespecified response criterion (defined as a ≥50% reduction in the 17-item Hamilton Depression Rating Scale (HAM-D) score from baseline to day 1 with ketamine + placebo), reductions in the 17-item HAM-D score were significantly attenuated in the ketamine + naltrexone arms compared with the ketamine + placebo arm on day 1 (primary endpoint) and day 3, but not at days 5, 7, or 14.¹⁸ In a secondary endpoint analysis, the authors found that changes in suicidality, based on item 3 of the HAM-D, item 10 of the Montgomery-Asberg Depression Rating Scale (MADRS), and the Columbia Suicide Severity Rating Scale, were also significantly attenuated with the addition of naltrexone.²⁰ The authors suggested that ketamine’s acute antidepressant effect requires opioid system activation.^18,20

The interpretability of these findings is limited by the study design, including a lack of a control arm necessary to assess the effects of naltrexone alone or placebo alone (which is considered relevant since endogenous opioid peptide signaling of MOR have been associated with positive mood responses to placebo),²¹ possible carryover effects resulting from the crossover design, and a small final sample size due to early termination of the study resulting from ineffectiveness and “noxious” side effects (severe nausea and vomiting) for many patients receiving ketamine + naltrexone. In addition, the study did not specifically recruit for suicidal patients. The authors acknowledged a need to replicate the findings.^18,20

Yoon et al (2019)¹⁷ evaluated the use of naltrexone pretreatment with ketamine in patients with MDD and alcohol use disorder. This 8-week, open-label, pilot study included 5 patients who received injectable naltrexone (380 mg once as an extended-release formulation, 2-6 days prior to the first ketamine infusion) and repeated intravenous ketamine infusions (0.5 mg/kg once a week for 4 weeks for a total of 4 treatments). Clinical response, defined as a ≥50% improvement in the MADRS scores from baseline to 4 hours post-infusion, was met by 60% of patients after the initial ketamine dose and by 100% by the fourth dose. No serious side effects were reported. The authors concluded that naltrexone pretreatment does not appear to interfere with the antidepressant effects of ketamine.

Marton et al (2019)¹⁹ conducted a retrospective analysis of treatment outcome data of 40 veterans with TRD who were treated with up to 6 infusions of ketamine (0.5 mg/kg over 40 minutes) twice weekly for 3 weeks. During the treatment period, 7 patients received MOR agonists (buprenorphine [n=5], methadone [n=2]) for >12 months, 1 patient received long-acting injectable naltrexone, and 27 patients were not on opioidergic drugs. While the results demonstrated significant reductions (P<0.001) in Beck Depression Inventory-II scores over the 6 infusions of ketamine treatment, no difference was found between the MOR agonist and non-MOR agonist groups pre- and post-treatment. A similar antidepressant response was seen in the one patient receiving naltrexone.

Literature SearcH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 14 November 2024.