LAUSR

TO THE EDITOR: We read with interest the article by Bonaventura et al. [1], who investigated the pharmacological properties of subanesthetic doses of ketamine enantiomers in rats and compared each enantiomer using rodent models of abuse liability. Consistent with the literature [2], the receptor affinity data of Bonaventura (Figure 1 [1]) showed that ketamine enantiomers are more potent for antagonizing N-methyl-D-aspartate receptors (NMDAR) than for activating mu-opioid receptors (MOR) and that (S)-ketamine is more potent than (R)-ketamine on both NMDAR and MOR. However, key elements of the study design limit the translation of their results to antidepressant treatment in humans (the only approved clinical indication for ketamine or its enantiomers in the subanesthetic dose range is the approved use of (S)-ketamine for reducing depressive symptoms in patients who manifest either treatment-resistant depression or major depressive disorder with acute suicidal ideation or behavior), and thus do not support some of the translational inferences which Bonaventura et al. draw from their data (see especially the “Clinical Implications” section of their Discussion). Most of the experiments conducted by Bonaventura et al. did not allow comparison between enantiomers at concentrations or doses that would be pharmacologically equipotent for antagonizing NMDAR receptors (see below) or for producing antidepressant effects in humans. The doses of (S)-ketamine tested in their rodent models (5–20mg/kg administered by single IP injection) exceed the human antidepressant doses of ketamine (0.5mg/kg, IV infused over 40min) or (S)-ketamine (0.2 or 0.25mg/kg, IV infused over 40min) [2]. Based on reported mouse [3] and human [4] plasma drug level data, these doses would have resulted in plasma levels substantially higher than those reached during antidepressant treatment in humans. Moreover, the dose range at which racemic ketamine produces anesthetic, analgesic, or antidepressant efficacy differs across these indications, and in each case the corresponding dose range for (S)-ketamine is lower than for ketamine [2]. The antidepressant dose-response relationship appears curvilinear for ketamine and (S)-ketamine, with optimal efficacy at ~0.5 mg/kg IV [5] and ~0.2 mg/kg IV [6], respectively. Results from a randomized, doubleblind study comparing ketamine (0.5 mg/kg) and (S)-esketamine (0.25 mg/kg) in treatment-resistant depression [7] further confirmed that a dose ratio of ~2:1 for ketamine versus (S)-ketamine achieves comparable antidepressant effects. The antidepressant efficacy of (R)-ketamine and the efficacy comparison of (R)-ketamine with ketamine or (S)-ketamine have not been assessed in a randomized, controlled trial (RCT). We previously reported that the estimated brain unbound levels of ketamine (0.5mg/kg, IV infusion) and (S)-ketamine (84mg, nasal spray) at their plasma Cmax are 1 and 0.4 μM, respectively [8]. The reported Ki-values of ketamine, (S)-ketamine, and (R)-ketamine for NMDAR are ~1, 0.5, and 2 μM, respectively [2]. The clinical antidepressant dose ratio of ~2:1 for ketamine versus (S)-ketamine is consistent with the ~2 fold higher Ki value for NMDAR of ketamine versus (S)-ketamine [2]. Notably, the Ki-values of ketamine, (S)-ketamine, and (R)-ketamine for human MOR are 42.1, 28.6, and 83.8 μM, respectively [9], so the clinical antidepressant dose ratio is also consistent with differences in the Ki-values of ketamine and (S)-ketamine for MOR. Nevertheless, the CNS side effects in humans (see below) and the difference between the estimated brain unbound drug level and Ki-values for MOR do not support pharmacodynamically meaningful engagement of MOR at antidepressant doses of ketamine and (S)-ketamine in humans. Given the NMDAR or MOR potency differences and the known antidepressant dose ratio of ketamine versus (S)-ketamine, the dose at which (R)-ketamine would be expected to produce antidepressant efficacy would be higher than for (S)-ketamine, in proportion to the ratio of their potencies for NMDAR (4-fold [2] to 6-fold [1]). Such a dose ratio must also be considered when contemplating potential clinical implications of these enantiomers’ relative potencies for MOR (approximately threefold based on the Ki [9] or EC50 [1] data). Therefore, while the authors concluded: “racemic ketamine’s abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer”, this statement overlooked the likelihood that if the (R)-enantiomer was used to treat depression, achieving an antidepressant effect putatively would depend on increasing the dose to achieve equipotency for NMDAR antagonism (which would also be the case if MOR stimulation played a role in the antidepressant mechanism), and that at such doses (R)-ketamine would show comparable abuse liability [10]. This point is supported by the one set of rodent abuse liability data reported by Bonaventura [1] that allowed comparison of doses equipotent for NMDAR antagonism: the pharmacodynamic effect on locomotor activity proved comparable between (S)-ketamine at 5mg/kg IP and (R)-ketamine at 20mg/kg IP (Figure 4 A of [1]). Crucially, the human literature also shows that the abuse liability of (S)and (R)-ketamine, as indexed by dissociation and other CNS adverse effects, are dose dependent and when the doses being compared for each enantiomer are set at equipotency for NMDAR antagonism, their abuse potential appears similar (e.g., Oye et al. [10]). Furthermore, Bonaventura [1] used 5–20mg/kg of (S)-ketamine doses IP in their PET, locomotor activity, and conditioned place preference studies. As mentioned earlier, these doses would have resulted in plasma levels substantially higher than those reached during antidepressant treatment in humans, along with greater NMDAR blockade and engagement of MOR and other targets. The higher exposures tested by Bonaventura [1] are particularly relevant for interpreting the functional studies of MOR engagement. Bonaventura [1] demonstrated functional engagement of MOR at 10 μM of (S)-ketamine using in vitro functional screening and [S]GTPγS autoradiography assays. In contrast, the estimated brain unbound concentration of (S)-ketamine at antidepressant