| Summary: | Strategically timed trauma- and attachment-informed psychotherapy to address underlying emotional wounds, paired with ketamine administered in precision-calibrated doses to ensure high-entropy brain states, may be key to improving the quality and duration of ketamine’s therapeutic efficacy for treatment-resistant depression. This approach optimizes the opportunities for change created by ketamine’s known effects as a rapid antidepressant that stimulates synaptogenesis, normalizes neural connectivity and coherence, enhances neuroplasticity, reduces inflammation, and induces high-entropy brain states with associated subjective psychedelic experiences. Ketamine, a non-selective N-methyl-D-aspartate (NMDA) receptor antagonist is a safe, effective, fast-acting dissociative anesthetic that, as a standalone treatment, also exhibits rapid sustained antidepressant effects, even in many patients with treatment-resistant depression. A prior history of developmental trauma and attachment injuries are known primary factors in the etiology of treatment resistance in depression and other mental disorders. Thus, the adjunct of targeted psychotherapy attuned to trauma and attachment injuries may enhance and prolong ketamine efficacy and provide an opportunity for lasting therapeutic change. Psychotherapy engagement during repeated ketamine sessions for patient safety and integration of altered states, paired with separate individualized psychotherapy-only sessions timed 24–48 h post ketamine induction, takes advantage of peak ketamine-induced dendritic spine growth in the prefrontal cortex and limbic system, and normalized network connectivity across brain structures. This strategically timed paired-session approach also exploits the therapeutic potential created by precision-calibrated ketamine-linked high-entropy brain states and associated psychedelic experiences that are posited to disrupt overly rigid maladaptive thoughts, behaviors, and disturbing memories associated with treatment-resistant depression; paired sessions also support integration of the felt sense of happiness and connectivity associated with psychedelic experiences.
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