Anesthesia<unk>  is a general anesthetic and is used for similar indications as ketamine. Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks. Depression<unk>  is approved under the brand name Spravato in the form of a nasal spray added to a conventional antidepressant as a therapy for treatment-resistant depression (TRD) as well as major depressive disorder (MDD) associated with suicidal ideation or behavior in adults in the United States. In the clinical trials that led to approval of<unk> , TRD was defined as MDD with inadequate response to at least two different conventional antidepressants. The nasal spray formulation of<unk>  used for depression delivers two sprays containing a total of 28 mg<unk>  and doses of 56 mg (2 devices) to 84 mg (3 devices) are used. The recommended dosage of Spravato is 56 mg on day 1, 56 or 84 mg twice per week during weeks 1 to 4, 56 or 84 mg once per week during weeks 5 to 8, and 56 or 84 mg every 2 weeks or once weekly during week 9 and thereafter. Dosing is individualized to the least frequent dosing necessary to maintain response or remission. Spravato is administered under the supervision of a healthcare provider and patients are monitored for at least 2 hours during each treatment session. Due to concerns about sedation, dissociation, and misuse,<unk>  is available for treatment of depression only from certified providers through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Spravato REMS. Five clinical studies of<unk>  for TRD (TRANSFORM-1, -2, and -3, and SUSTAIN-1 and -2) were submitted to and evaluated by the FDA when approval of<unk>  for treatment of TRD was sought by Janssen Pharmaceuticals. Of these five studies, three were short-term (4-week) efficacy studies (the TRANSFORM studies). Two of these three studies (TRANSFORM-1 and -3) did not find a statistically significant antidepressant effect of<unk>  relative to placebo. In the one positive short-term efficacy study (TRANSFORM-2), there was a 4.0-point difference between<unk>  and placebo on the Montgomery–Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment (P = 0.020). This scale ranges from 0 to 60 and the average score of the participants at the start of the study was about 37.0 in both the<unk>  and placebo groups. The total change in score after 4 weeks was –19.8 points in the<unk>  group and –15.8 points in the placebo group. This corresponded to a percentage change in MADRS score from baseline of –53.5% with<unk>  and –42.4% with placebo (a difference and reduction of depression score of –11.1% potentially attributable to the pharmacological action of<unk>  in these patient samples. Placebo showed 80.0% of the antidepressant effect of<unk>  for TRD in this study and hence approximately 20.0% of the antidepressant response was attributable to<unk> . In the two negative short-term efficacy trials that did not reach statistical significance (TRANSFORM-1 and -3), the differences in MADRS reductions between<unk>  and placebo were –3.2 (P = 0.088) and –3.6 (P = 0.059) after 4 weeks of treatment. Short-term antidepressant efficacy (as measured by change in MADRS total score from baseline over 4 weeks) with<unk>  nasal spray (56 or 84 mg) added to an existing oral antidepressant (n = 114) versus placebo nasal spray added to an existing oral antidepressant (n = 109) in people with treatment-resistant depression in the single positive efficacy trial. In two other short-term efficacy trials,<unk>  was not superior to placebo. The 4.0-point additional reduction in MADRS score with<unk>  over placebo in the single positive efficacy trial corresponds to less than "minimal improvement" and has been criticized as being below the threshold for clinically meaningful change. A difference of at least 6.5 points was originally suggested by the trial investigators to be a reasonable threshold for clinical significance. In other literature, MADRS reductions have been interpreted as "very much improved" corresponding to 27–28 points, "much improved" to 16–17 points, and "minimally improved" to 7–9 points. It has additionally been argued that the small advantage in scores with<unk>  may have been related to an enhanced placebo response in the<unk>  group due to functional unblinding caused by the psychoactive effects of<unk> . In other words, it is argued that the study was not truly a double-blind controlled trial. Dissociation was experienced as a side effect by a majority of participants who received<unk>  (61–75% with<unk>  and 5–12% with placebo; ~7-fold difference) and "severe" dissociation was experienced by 25%. Deblinding and expectancy confounds are problems with studies of hallucinogens for psychiatric indications in general. The FDA normally requires at least two positive short-term efficacy studies for approval of antidepressants, but this requirement was loosened for<unk>  and a relapse-prevention trial was allowed to fill the place of the second efficacy trial instead. This is the first time that the FDA is known to have made such an exception and the decision has been criticized as lowering regulatory standards. In the relapse-prevention trial (SUSTAIN-2), the rate of depression relapse was significantly lower with<unk>  continued than with it discontinued and replaced with placebo in<unk> -treated stable responders and remitters (51% rate reduction in remitters and 70% reduction in responders). Short-term antidepressant efficacy (as measured by change in MADRS total score from baseline over 4 weeks) with<unk>  nasal spray (84 mg twice weekly) added to an existing oral antidepressant (n = 177–225) versus placebo nasal spray added to an existing oral antidepressant (n = 175–225) in people with major depressive disorder and suicidality in one of the two positive efficacy trials. Findings were similar in the other positive short-term efficacy trial.<unk>  was approved for the treatment of MDD with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week) phase 3 trials (ASPIRE-1 and -2) of<unk>  nasal spray added to a conventional antidepressant. The primary efficacy measure was reduction in MADRS total score after 24 hours following the first dose of<unk> . In both trials, MADRS scores were significantly reduced with<unk>  relative to placebo at 24 hours. The mean MADRS scores at baseline were 39.4 to 41.3 in all groups and the MADRS reductions at 24 hours were –15.9 and –16.0 with<unk>  and –12.0 and –12.2 with placebo, resulting in mean differences between<unk>  and placebo of –3.8 and –3.9. The secondary efficacy measure in the trials was change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) 24 hours after the first dose of<unk> . The CGI-SS-r is a single-item scale with scores ranging from 0 to 6.<unk>  was not significantly effective in reducing suicidality relative to placebo on this measure either at 24 hours or after 25 days. At 24 hours, CGI-SS-r scores were changed by –1.5 with<unk>  and –1.3 with placebo, giving a non-significant mean difference between<unk>  and placebo of –0.20. Hence, while efficacious in reducing depressive symptoms in people with depression and suicidality, antisuicidal effects of<unk>  in such individuals have not been demonstrated. Expectations were initially very high for ketamine and<unk>  for treatment of depression based on early small-scale clinical studies, with discovery of the rapid and ostensibly robust antidepressant effects of ketamine described by some authors as "the most important advance in the field of psychiatry in the past half century". According to a 2018 review, ketamine showed more than double the antidepressant effect size over placebo of conventional antidepressants in the treatment of depression based on the preliminary evidence available at the time (Cohen's d = 1.3–1.7 for ketamine, Cohen's d = 0.8 for midazolam (active placebo), and Cohen's d = 0.53–0.81 for conventional antidepressants). However, the efficacy of ketamine/esketamine for depression declined dramatically as studies became larger and more methodologically rigorous. The effectiveness of<unk>  for the indication of TRD is described as "modest" and is similar in magnitude to that of other antidepressants for treatment of MDD. The comparative effectiveness of ketamine and<unk>  in the treatment of depression has not been adequately characterized. A 2021 meta-analysis reported that ketamine was similarly effective to<unk>  in terms of antidepressant effect size ( for depression score of –1.1 vs. –1.2) but more effective than<unk>  in terms of response and remission rates ( = 3.01 vs. RR = 1.38 for response and RR = 3.70 vs. RR = 1.47 for remission). However, this meta-analysis involved largely non-directly-comparative studies with dissimilar research designs and patient populations. Only a single clinical trial has directly compared ketamine and<unk>  for depression as of May 2021. This study reported similar antidepressant efficacy as well as tolerability and psychotomimetic effects between the two agents. However, the study was small and underpowered, and more research is still needed to better-characterize the comparative antidepressant effects of ketamine and<unk> .
Esketamine
Ketamine
Eptazocine
Naloxone
Pentazocine
Remifentanil
Pethidine
Fentanyl