I don't think the SSRI effects are the primary goal. The appeal of esketamine is its rapid effect, the same thing being sought with DXM+bupropion (AXS-05). Studies with naltrexone and ketamine reduced the antidepressive effect, so maybe the mu opioid or sigma-1 are important. (https://www.cambridge.org/core/journals/cns-spectrums/articl...)
Interestingly, there's a small trial with just DMX (300mg - aka first/second plateau) to determine safety: https://clinicaltrials.gov/ct2/show/NCT04226352 The bupropion seems to be only useful for slowing the DXM->DXO to allow for lower doses. A full on 'robo-trip' may actually work as well as a full on ketamine trip.
I think there's an argument to be made that a working opioid system is central to the anti-depressant effect of any anti-depressant? I actually tried naltrexone for a condition related to depression and it made me feel much worse and unable to feel much pleasure in anything.
DMX is really a crappy drug with a half-life that is too long for frequent administration.
Interestingly, there's a small trial with just DMX (300mg - aka first/second plateau) to determine safety: https://clinicaltrials.gov/ct2/show/NCT04226352 The bupropion seems to be only useful for slowing the DXM->DXO to allow for lower doses. A full on 'robo-trip' may actually work as well as a full on ketamine trip.