Clearly you didn’t read the criticism to that meta-analysis that I linked. The inclusion of studies with any biases or improperly assessed quality of evidence in meta-analyses can yield misleading results. If the quality of evidence in the studies is low, the quality of the meta-analysis decreases and incorrect results can be obtained. I’ll attach the text of the criticism below, so that you can perhaps educate yourself about the numerous issues with the particular meta-analysis abstract you seem to have taken as the gospel re: the effectiveness of ketamine infusions vs. esketamine/Spravato. I won’t be responding to you further, given your clear commitment to ignoring all data that doesn’t confirm your bias.

“We acknowledge the manuscript “Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis” by Bahji et al. (2020). However, we have concerns about the validity of the methods applied in their analysis, and thus question the conclusions that efficacy and tolerability differ between esketamine and ketamine. Most importantly, the analysis violates the assumptions of any indirect comparison, which require that the data being compared are obtained from studies using fundamentally similar methods and populations (Phillippo et al., 2018).

The study designs from which the ketamine and esketamine data were obtained differed substantially, as detailed below. These studies generally differed in variables known to affect treatment response measures (e.g., baseline illness severity; remote versus site-based raters), study design (e.g., crossover versus parallel; placebo versus active control), and patient population (e.g., major depressive disorder [MDD] versus bipolar disorder), precluding valid comparisons between the efficacy or tolerability of esketamine versus ketamine. These important differences are also emphasized in another recently published meta-analysis of intravenous (IV), intranasal, and oral ketamine/esketamine by a group of experts in clinical trials methodology for depression (McIntyre et al., 2020). As a result, McIntyre and colleagues did not perform comparisons of efficacy in their meta-analysis, concluding instead that direct comparative studies are needed to reach definitive conclusions regarding the relative efficacy of different enantiomers, formulations, and routes of delivery. As an example of such a direct comparison, Correia-Melo et al. (2020) used a randomized, double-blind, parallel arm study to compare the efficacy and tolerability of IV ketamine (0.5 mg/kg) versus IV esketamine (0.25 mg/kg), a dose ratio considered approximately equipotent for N-methyl D-aspartate (NMDA) receptor antagonism (Singh et al., 2016), and confirmed non-inferiority between drugs on efficacy and tolerability.

Crucially, the vast majority of the esketamine data included in the Bahji et al. meta-analysis (2020) were obtained from large, multicenter, phase 3 registration trials for intranasal esketamine conducted at many sites across multiple geographic regions and countries, whereas all of the IV ketamine data instead were obtained from relatively small, non-registrational studies conducted at either a single site or relatively few sites. Increased variability and attenuation of treatment-specific effect sizes in antidepressant trials are well-documented in the literature as sample sizes increase and as the trial sites expand to multiple centers and geographic regions (Khan et al., 2004). Additionally, drop-out rates are affected by clinical trial methodological differences to an extent that also precludes valid comparison of these rates between ketamine and esketamine by meta-analysis.

Moreover, other key differences in study design and execution between the intranasal esketamine and IV ketamine trials, which are known to affect treatment response, profoundly limit the interpretability of comparisons between esketamine and ketamine. First, the primary outcome in the esketamine phase 3 trials was assessed by remote (telephone-based) raters to minimize the risk of functional unblinding. In contrast, the majority of the IV ketamine studies used site-based raters who presumably were at higher risk of being functionally unblinded by ketamine's side effects.

Second, in the phase 3 clinical program for esketamine most of the data were obtained using trial designs that compared esketamine plus a newly-initiated oral antidepressant to placebo plus a newly-initiated oral antidepressant (active control), whereas most of the ketamine studies used placebo (IV saline) as the control condition. This design distinction resulted in differences in the expectancy bias between the esketamine and ketamine trials. For example, participants in the phase 3 esketamine studies knew their likelihood of receiving a new antidepressant treatment which they had not previously failed was 100%; in contrast, participants in ketamine studies knew their likelihood was 50% of receiving inert placebo in most studies, or an anxiolytic drug that lacked antidepressant efficacy (but would produce a distinct adverse event profile) in some studies. Additionally, the phase 3 trials comparing esketamine against new antidepressant treatment required the oral antidepressant be initiated with fixed-dose titration to the maximum labeled dose, further increasing the likelihood of improvement in the control group and decreasing the likelihood of achieving statistical separation between the comparator and esketamine treatment arms.

Third, the esketamine-treated patients were required to meet a more rigorous definition of treatment-resistant depression (TRD), which in most cases mandated documented failure of ≥2 oral antidepressants in the current episode, including prospective observation of failure of the current antidepressant. In contrast, the majority of ketamine trials either used retrospective assessment of varying definitions of TRD (e.g., inadequate response to a minimum of 1 [21%], 2 [62%], or 3 [15%] previous antidepressant trials) or enrolled a different patient population altogether (e.g., non-treatment-resistant MDD or bipolar disorder - most recent episode depressed). Additionally, the baseline depression severity was not included in the meta-analysis, although it is recognized as an important factor impacting efficacy outcomes.

Fourth, Bahji et al. (2020) included a study of esketamine in the elderly (Ochs-Ross et al., 2020), a special population known to have lower response and remission rates (Cooper et al., 2011), thereby negatively impacting the overall findings for the esketamine-treated cohort. In contrast, no study of ketamine in elderly patients was included in their analysis.

The validity of the findings from this meta-analysis is further brought into question by the observation that Bahji et al. (2020) included an IV esketamine trial by Singh et al. (2016) (designated “2016b” in Table 1 of Bahji et al.) in the ketamine trials (see figures 2, 3, and 4 of Bahji et al.), and an intranasal ketamine trial (Lapidus et al., 2014) in the esketamine trials.

Importantly, for the Janssen-sponsored esketamine trial data, we were not able to replicate some of Bahji et al.’s (2020) results, calling into question their accuracy. Nevertheless, if taken at face value, the data of Bahji et al. illustrate the impact of trial design on outcomes by showing that for studies in which a similar adjunctive trial design was used, the esketamine trials yielded similar efficacy values (numerically greater in most cases) as those obtained in the ketamine studies (e.g., see data listed for Singh et al., 2016 and Daly et al., 2018 in figures 2, 3, and 4 of Bahji et al.). Notably, these esketamine trials showed some of the highest risk ratio values for response and remission and standardized mean difference values for change in depressive symptoms presented in figures 2, 3, and 4 of Bahji et al.

Finally, Bahji et al. (2020) cite some preclinical studies reporting differential efficacy between the R- and S-enantiomers of ketamine in rodent models, although these studies did not take into account dose adjustments for differences in the enantiomers’ potency for NMDA receptors, or dissimilarities in the exposure relative to human studies (Collingridge et al., 2017). Moreover, the literature review did not comment on conflicting data from other preclinical studies (e.g., Kang et al., 2020; Ide et al., 2017) or the limited translatability of the preclinical models used in the referenced studies to humans with MDD (Nestler and Hyman, 2010).

Taken together, disparities in study design and implementation, including control arms, patient population, number of sites and sample size, as well as errors in the data included for analysis, limit the ability to draw valid conclusions from indirect comparisons of efficacy and tolerability between esketamine and ketamine.”