Optimized Clinical Strategies for Treatment-Resistant Depression: Integrating Ketamine Protocols with Trauma- and Attachment-Informed Psychotherapy

Abstract

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.

A unified model of ketamine’s dissociative and psychedelic properties

“…This synergy between acute changes in synaptic gain and sub-acute changes in neural plasticity also suggests that complementing the pharmacological treatment with psychotherapy may have additive benefits. Recently, Muscat et al (2022) proposed an integrative approach that aims to help improving the development of ketamine treatment protocols and clinical outcomes. The authors propose that preparation sessions, which should be based on a psychoeducational-based approach, may allow to increase efficacy and safety as the multiple levels of the beneficial actions of ketamine are extensively discussed.…”

“…A recently published trial of ketamine combined with mindfulness-based relapse prevention for alcohol use disorder demonstrated that treatment with three infusions of ketamine was associated with more days of abstinence from alcohol at 6-month follow-up ( Grabski et al, 2022 ). After reviewing these and other studies, Muscat et al (2022) have recently argued for the potential benefits of integrating ketamine protocols with psychotherapy.…”

Suicide prevention and ketamine: insights from computational modeling

“…Additionally, the absence of a lasting antidepressant or anti-suicidal impact of ketamine, especially in treatment-resistant populations, calls for strategies to extend these effects beyond repeated administration ( 136 , 137 ). Future research should investigate whether combining psychedelic-assisted therapy with ketamine infusions is necessary for the revision of negative beliefs, the acceptance of emotions, thoughts, and memories, and sustaining therapeutic effects ( 138 , 139 ). Computational models could be used to quantify long-term changes in cognitive processes associated with this combined therapeutic approach.…”

Inflammation and Treatment-Resistant Depression from Clinical to Animal Study: A Possible Link?

“…However, increased concentrations of inflammatory biomarkers have been found in individuals with depression compared to those without depression. Elevated concentrations of inflammatory markers may indicate a weak antidepressant response [ 8 , 9 ]. However, while approximately half of depressed patients show a sufficient response to antidepressants, around 15% show only a partial response to therapy.…”