Spotlight: Nonresponse to Ketamine in Treatment-Resistant Bipolar Depression (Kachlick, et al, 2025)

Evidence suggests that "IV racemic ketamine is more effective than IN esketamine in TRD; convergent preclinical and clinical findings support the hypothesis that arketamine plays a key role in this superiority and that ketamine’s antidepressant mechanisms extend beyond simple NMDAR antagonism."

"...evidence suggests that the use of serotonergic and non-serotonergic psychedelics (ketamine) for the treatment of SUD may provide advantages over traditional therapeutics, and these compounds may eventually become part of the next generation of treatments for SUD under specific circumstances."

"...mystical experiences were strongly related to immediate and sustained psychiatric benefits at the group level and on an individual, session-by-session basis across the six doses, providing mechanistic support for ketamine-psychotherapy pairings."

"Depression is increasingly conceptualized as a disorder of impaired synaptic plasticity and excitation-inhibition imbalance within corticolimbic circuits. Ketamine, brexanolone, zuranolone, offer complementary approaches to restore circuit function."

"Personality traits relate to baseline mental health severity but not short-term response to ketamine. Trauma history may predict greater benefit from treatment."

"Serotonergic psychedelics & ketamine appear to share common cellular mechanisms. They both recruit glutamatergic neurons to stimulate BDNF-trKB signaling, promoting synaptogenesis via the mTOR pathway. These changes may explain their efficacy in depression, anxiety, PTSD, & addiction."