In recent years there has been growing evidence of the involvement of the glutamate system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate receptor channel blocker, which has been shown to elicit a rapid and robust antidepressant response in subanesthetic dosages (0.5 mg/kg),1 has been of interest for treatment-resistant depression (TRD), particularly over the past decade. In March 2019, the US Food and Drug Administration (FDA) approved intranasal esketamine (the S-isomer of racemic ketamine) for TRD. There is little information available regarding ketamine's efficacy compared to other TRD treatments. We conducted a detailed search on PubMed for reported response (RES) and remission (REM) rates for non-ketamine and ketamine treatments for TRD. However, a meta-analysis was not conducted considering the limited scope of this article and because of different study designs, durations, and study drug dosages.
Although there is no overall agreement for the definition of TRD, the term is most commonly used when patients do not respond to at least two adequate antidepressant trials in their current depressive episode. This is the definition used in this article.
We conducted an extensive search on PubMed by using key words “treatment-resistant depression, antidepressant, ketamine, electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, neuromodulation.” A total of 415 studies were identified by title and abstracts, and 253 articles fulfilling criteria of sample size of 5 or more TRD participants and reporting RES and REM rates were selected for in-depth review. The mean RES and REM rates of studies are compared to the RES and REM rates reported with ketamine treatment studies. Lastly, illustrative graphs were created to demonstrate the efficacy of each treatment modality in terms of RES and REM rates and the differences between different modalities.
Studies of Treatment-Resistant Depression
Non-Ketamine Treatments for Treatment-Resistant Depression
For patients with TRD, combination medication treatments, augmentation strategies (eg, with atypical neuroleptics or lithium), and brain stimulation treatments (eg, transcranial magnetic stimulation [TMS], electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], and deep brain stimulation [DBS]) are available. Several studies have been conducted using different trial designs; a few have compared different therapeutic strategies with each other, and some metanalyses and reviews are available.2,3 We conducted analyses of average RES and REM rates of different modalities from various studies, and the results are shown in Figure 1. These mean RES and REM rates are compared below to the RES and REM rates reported with ketamine treatment studies.
Efficacy of other treatment modalities in treatment-resistant depression (TRD). Response and remission rates were obtained from each related study; mean values were calculated when there were several studies on each treatment modality. Short term refers to up to 6 weeks for rTMS, up to 12 months for DBS and VNS; long term refers to longer than 6 weeks for rTMS and longer than 12 months for DBS and VNS. AD, antidepressant; DB, double-blind; DBS, deep brain stimulation; ECT, electroconvulsive therapy; N, mean sample size or the range in which the sample size varies; NR, non-randomized; PC, placebo-controlled; OL, open-label; R, randomized; rTMS, repetitive transcranial magnetic stimulation; SC, sham-controlled; TBS, theta burst stimulation; TRD, treatment-resistant depression; VNS, vagus nerve stimulation.
Ketamine Treatment for Treatment-Resistant Depression
Single-Dose Ketamine Studies of Fast Antidepressant Action (Within 24 Hours)
Single-dose, open-label ketamine studies reporting efficacy of ketamine in TRD with the efficacy end-point at the latest 24-hour period show mean RES and REM rates of 57.6% and 50%, respectively (standard error of mean [SEM] of ±7.4]).4–8 One single-dose ketamine infusion study comparing patients with TRD nonresponsive to ECT (n = 17) and patients with TRD who had not previously received ECT (n = 23) showed RES rate and REM rates of 100% and 0%, respectively.9
In randomized placebo-controlled trials with inactive placebo, lower RES and REM rates were seen. Overall, single-dose ketamine infusion compared to inactive placebo has been shown to have mean RES and REM rates for ketamine to be 44.5% and 29%, respectively [SEM ±17.1; n = 8, n = 17),1,10 whereas a single dose of intravenous (IV) esketamine showed mean RES rate to be 65.5% for different doses of esketamine (0.2 and 0.4 mg/kg) (n = 10 in each arm; SEM ±1.5).11 A single ketamine infusion as an adjunct to conventional antidepressants (n = 47 in ketamine groups), had a mean RES rate of 42.75% (SEM ±4.75).12 Another study that used oral ketamine showed an RES rate of 31.8% and an REM rate of 27.3% (n = 22).13
Moreover, when an active placebo such as midazolam was used, even lower RES and REM rates were seen, with single-dose IV ketamine showing mean RES and REM rates of 45.5% and 5%, respectively (SEM ±18.5), whereas active placebo RES rate was 14%. Only one of these studies reported an REM rate for single ketamine dose of 5%.14 In most of these studies, the efficacy difference between the combination of antidepressant and ketamine and the combination of antidepressant and active placebo was found to be statistically significant.14,15
Besides ketamine, there are not many other treatments that have been used as a single dose for treatment of TRD. An open-label study of psilocybin showed an REM rate of 67%.16 Nitrous oxide in a crossover study design showed much lower RES and REM rates of 20% and 15%, respectively.17
Serial Ketamine Infusion Studies
Open-label studies. Open-label studies of serial ketamine infusion in which IV ketamine was administered 2 to 7 days apart over a period of 2 to 3 weeks show a mean RES rate of 66.62% and REM rate of 45.2% (SEM ±8.81).14,15,18–21 Sample sizes differed in these studies, ranging between 10 and 47 participants in the ketamine arms.
Our review of other open-label, short-term (up to 6 weeks for repetitive TMS [rTMS] and up to 12 months for DBS and VNS) modalities such as antidepressant combinations, rTMS, VNS, DBS, and ECT for treatment of TRD showed RES and REM rates of 30% to 70% and 15% to 45%, respectively.2,3 Despite the differences in designs and duration of the trials, reported RES and REM rates for ECT treatment were comparable to that of serial ketamine infusion.
Randomized placebo-controlled studies. With inactive placebo, serial ketamine infusions administered twice weekly over 3 weeks (n = 13 in ketamine arm) showed lower RES and REM rates of 25% and 17%, respectively, for ketamine and 33% and 8%, respectively, for placebo.22 On the other hand, adjunctive serial ketamine infusions administered either twice (n = 18) or thrice weekly (n = 17) for 2 weeks showed higher mean RES and REM rates of 61.3% and 30.3%, respectively (SEM ±7.5).23 Mean RES and REM rates of adjunctive intranasal esketamine were 46.8% and 32%, respectively (SEM ±5.33) (Figure 2).24–26
Efficacy of ketamine and esketamine in treatment-resistant depression. Response and remission rates were obtained from each related study; mean values were calculated when there were several studies on each treatment modality. TRD: treatment-resistant depression, Adj, adjunctive; DB, double-blind; IN, intranasal; IV, intravenous; N, mean sample size or the range in which the sample size varies; NR, non-randomized; OL, open-label; PC, placebo-controlled; R, randomized.
These average rates are comparable to RES and REM rates for other short-term therapeutic modalities such as aripiprazole (39.5% and 31.1%), rTMS (38.2% and 24.9%), VNS (15.2% and 10%), and DBS (38% and 41%). In sham-controlled trials, ECT showed slightly higher RES rates of 58.5%, with REM rates not reported. In another study, scopolamine was shown to have much higher RES and REM rates of 67.2% and 55.5%, respectively, for recurrent depression, but the findings have not been replicated.2,3
Ketamine's Comparative Efficacy
Few meta-analyses or comparative studies of treatments for TRD have been conducted. A meta-analysis in 2017 compared the efficacy of medications, neuromodulation treatments (TMS and ECT), and ketamine in patients with TRD.2 Ketamine was considered to be superior to pharmacological and neuromodulation treatments at 2 weeks. At 2 weeks, ketamine, risperidone augmentation, and rTMS were found to be significantly more efficacious than placebo/sham treatment. The efficacy of quetiapine augmentation and ECT was also greater than placebo/sham treatment but less than that of ketamine, risperidone, and rTMS. At week 4, only rTMS was significantly superior to sham treatment; and at week 8, only pharmacological studies were reported (no ketamine, ECT, and TMS), which showed risperidone and quetiapine superiority, although the results were not statistically significant. The findings of this meta-analysis were limited by the number of different designs of the studies that were included, the variable durations and modes of administration of treatments, and by the fact that at the time of the metanalysis, data from serial ketamine infusions and nasal esketamine studies were not available. The data in Figure 1 and Figure 2 provide information keeping the study design, dosage, mode of administration, duration, and recent ketamine/esketamine studies in mind.
A study published in 2019 (but conducted in 2012) that compared the efficacy of ECT and ketamine head-to-head in 22 patients with TRD showed improvement by both treatments; the average Hamilton Depression Rating Scale scores decreased in both the ECT (from 26.1 ± 3.8 to 14.7 ± 3.3; n = 12) and ketamine arms (24.6 ± 2.4 to 16.4 ± 4.1; n = 10).27 However, these results were not statistically significant at any evaluation point of the study. According to the Wechsler Memory Scale, patients in the ketamine arm showed a trend of doing better cognitively, but this finding was not statistically significant.27
A review of ketamine efficacy studies in TRD shows that ketamine is an effective treatment for TRD. Due to a paucity of studies of direct comparison of ketamine/esketamine with other treatments of TRD, a determination cannot be made whether it is superior to other treatments. An analysis done for the purpose of this review suggests that its efficacy is comparable to other treatments for TRD; however, some of its properties such as its fast action and noninvasive ease of use (compared to ECT, VNS, or DBS) may make it particularly suitable for the treatment of TRD in certain settings.
Ketamine's fast efficacy in the first couple of weeks of starting treatment makes it similar to ECT treatment. It is important to note, however, that ketamine has been reported to be associated with fewer cognitive side effects. It would be reasonable to think that after medication combination and augmentation strategies and neuromodulation treatments such as TMS have failed, either ketamine or ECT can be administered for a rapid antidepressant effect. Given the invasive nature of VNS and DBS and the inconclusive data on their efficacy, these treatments should only be considered after ketamine/ECT treatments have failed. At this time, it is unclear whether ECT or ketamine would be more effective and for which type of patient. A large-scale, randomized, real-world trial is currently being conducted by the authors to compare ECT treatment with IV ketamine treatment.28
Per meta-analyses that compared ketamine and ECT head to head, ketamine was found to be as efficacious but did not cause the cognitive side effects associated with ECT, although the difference in cognitive side effects was not statistically significant. These results were in parallel with a recent randomized, double-blind, proof-of-concept pilot study conducted by the authors that compared ECT plus IV ketamine to ECT plus IV midazolam on alternate days in an interleaved fashion.29 The results showed that ketamine patients achieved remission faster with less cognitive complaints, although neither of these findings was statistically significant. One important detail to note is that in all of the study designs in which ketamine is compared to other treatments, patients remain on their current treatment regimens and, per the ketamine efficacy overview above, this design is when ketamine is most effective. Currently, there are no head-to-head comparisons of ketamine efficacy to that of other neuromodulation therapies such as rTMS, VNS, and DBS.
Ketamine or esketamine's role as an extended maintenance strategy for treating depression and preventing relapse is still unclear, although it is promising. In a recently published relapse prevention study, intranasal esketamine adjunct to antidepressants was found to decrease the risk of relapse by 51% among the patients who were in full remission and by 70% among those who achieved sustained response compared to antidepressant and placebo group.30 However, a limitation of this study was that an active placebo was not used. Moreover, maintenance ketamine was not compared with another treatment modality. Therefore, acute ketamine treatment is similar to ECT treatment in that after the rapid acute response, long-term treatment is still needed for relapse prevention. Whether maintenance ketamine has the same efficacy as maintenance ECT or is superior to other modalities will have to be determined in longer-term, head-to-head relapse-prevention trials.
The current literature supports ketamine being an effective and promising treatment for TRD, especially in the acute phase of the treatment when fast action is required. Future comparative studies and long-term efficacy and maintenance studies are needed to make a more definitive conclusion as to where it stands in the treatment algorithm for TRD.
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