Ketamine Treatment for Treatment-Resistant Depression: Efficacy and Mechanisms of Action This strategy may optimize the opportunities for change created by ketamine’s glutamate modulation, normalization of neural connectivity and coherence, and stimulation of synaptogenesis and neuroplasticity-and may be key to improving the quality and duration of ketamine’s therapeutic efficacy with TRD individuals. When this form of psychotherapy is timed to occur 24–48 h after paired ketamine-only sessions precision dosed to ensure high-entropy brain states and psychedelic experiences, it will coincide with the likely peak of dendritic spine growth and the therapeutic disruption of negative thoughts and beliefs induced by ketamine administration. While a variety of therapeutic approaches can be effective for TRD, treatments with trauma- and attachment-informed psychotherapy are designed specifically for the needs of this population (Dore et al., 2019 ). Developmental trauma and associated attachment injuries that occur during critical stages of child development are associated with treatment resistance in mental disorders including depression. TRD is a complex psychiatric disorder influenced by genetic, biological, and environmental factors that is typically, although not always, co-morbid with complex early childhood developmental stress and trauma (Chapman et al., 2004 Nemeroff, 1998 Palazidou, 2012 ). ![]() ![]() In particular, the consequences of chronic stress suffered in early childhood during critical periods of brain development and maturation are profound and may last a lifetime (Joseph, 1999 Schore, 2005 Siegel, 2006 ). Chronic stress influences depression and affective behavior, is associated with inflammation, and disrupts neuroplasticity, brain connectivity, interhemispheric excitatory homeostasis and associated cellular and molecular systems (Pittenger and Duman, 2008 ). The relationship between depression and stress, with its accompanying brain changes, has been well established over the last 20 years in both preclinical and clinical trials (Taylor et al., 2005 Stepanichev et al., 2014 Young et al., 2003 ). 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. 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. 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. 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. 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. ![]() 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. 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.
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