Investigating the effects of repeat ketamine exposure

: linking brain structural imaging changes to cellular alterations

Abstract

Ketamine has been used over the last 10-12 years as a surprisingly effective therapy for treatment resistant depression. This has led to the establishment of specialised ketamine treatment clinics in the United Kingdom and United States. However, treatment at these clinics is expensive and there is a concern that people suffering with depression will self-medicate with “street” ketamine and run the risk of using too high and too frequent doses. This might lead to detrimental changes in psychological wellbeing, brain functional activity, metabolism and brain structure; as has been observed in recreational ketamine users. There is a lack of evidence regarding the long-term effects and safety profile of ketamine exposure, and moreover the psychological and neurological changes observed in recreational ketamine users are likely confounded by additional psychotropic drug use. To investigate the long-term effects of ketamine, with and without these confounds, I conducted structural magnetic resonance imaging in both recreational ketamine users and mice (that received repeated doses of ketamine). In humans, repeat ketamine exposure induced decreases in brain volume in the frontal cortex, striatum and cerebellum. In mice, repeat ketamine exposure induced an increase in volume in the frontal cortex, which was associated with an increase in the amount of neurofilament and synaptophysin within the prefrontal cortex. I observed further decreases and increases in volume within the parietal, temporal and occipital cortices, striatum and cerebellum. Diffusion tensor imaging in mice revealed alterations in brain structure in the neuropil and corpus callosum, which partially replicates previously published changes observed in human ketamine users. These changes in the corpus callosum were associated with an increase in the amount of neurofilament and myelin basic protein. These data suggest remodelling of neural circuits under repeat ketamine exposure, the functional and behavioural consequences of which require further investigation.

Date of Award	1 Jul 2019
Original language	English
Awarding Institution	King's College London
Supervisor	Anthony Vernon (Supervisor) & James Stone (Supervisor)