Neuropsychological mechanisms of ketamine antidepressant effect

Thesis

Ketamine produces rapid (within hours) and sustained (up to 10 days) antidepressant effects that extend beyond its half-life. Although its molecular and cellular mechanisms are well characterised, the neuropsychological processes underlying its clinical effects in depression are less defined.

Animal studies suggest that ketamine reverses negative affective biases in negative memories without significantly impacting positive memories, differently from conventional antidepressants. Further, ketamine targets the lateral habenula, a small, evolutionarily conserved structure in the epithalamus that is key to the brain’s reward-punishment circuitry. Finally, emerging evidence suggests that ketamine has lasting effects on stress resilience.

This DPhil project investigates whether these neuropsychological mechanisms translate to humans. Two experimental medicine trials were conducted with participants randomised to receive either ketamine (0.5 mg/kg) or placebo via a 40-minute constant-rate infusion. In the first study, 70 healthy volunteers underwent a battery of assessments including questionnaires, computer-based tasks, and task-based 7 Tesla fMRI using a win-loss-shock Pavlovian paradigm designed to elicit habenula activation. The Emotional Battery Test was performed before and 24 hours post-infusion, and a stress-inducing paradigm was administered one week later to assess stress resilience. In the second study, 60 patients with treatment-resistant depression (TRD) were evaluated for negative biases in autobiographical memories (24 hours and 7-days post-infusion) and self-descriptive words (post-infusion).

Compared to placebo, ketamine significantly reduced negative biases for self-descriptive words in both healthy and depressed subjects, attenuated habenula response to aversive outcomes while engaging reward circuits (including the prefrontal cortex and anterior cingulate cortex) and diminished stress responses (as measured by heart rate variability) at 7 days in healthy volunteers. Interim analysis of the first 43 participants in the second study suggests that ketamine does not alter biases in autobiographical memories in TRD. Further research is needed to translate these effects clinically and further characterise the underlying neurobiological mechanisms of ketamine antidepressant effects.

Authors: Costi, S

• DOI: 10.5287/ora-wvydgvb7o
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: stress; depression; resilience; memory; emotional processing; habenula; ketamine
• Subjects: Experimental Medicine Study