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Ketamine for depression relapse prevention following electroconvulsive therapy: a randomised pilot trial with blood neuroplasticity biomarker evaluation

Major depressive disorder is a common debilitating illness that is the second leading contributor to the global burden of disease and has major socio-economic implications. Unfortunately, about 30% of patients do not respond to adequate trials of antidepressants and/or psychotherapies. About 60% of such treatment-resistant patients will remit with electroconvulsive therapy (ECT), which continues to be the most powerful treatment for severe, often life-threatening, depression. However, in a recent meta-analysis, we have reported that relapse rates are high following ECT, 27% after three months and 38% after six months. Indeed, such high relapse rates are seen for all patients with treatment-resistant depression, irrespective of what treatment they have received. A recent paradigm shift in treating depression and understanding its biology has been the finding that the competitive glutamate NMDA receptor antagonist ketamine has a robust rapid-onset (i.e. hours rather than weeks), though short-lived, antidepressant effect. Ketamine mediates these effects through rapid activation of neuroplasticity pathways involving mammalian target of rapamycin (mTOR) and brain derived neurotrophic factor signalling (BDNF) signalling, amongst others. The main objective of this study is to conduct a randomised pilot control trial (n=40) of a four-week course of once-weekly ketamine infusions for relapse prevention following ECT for severe depression in order to assess trial procedures that will inform a future definitive trial. At the same time, we will test the hypothesis that some pre-selected peripheral blood neuroplasticity biomarkers (e.g. BDNF, mTOR), known to be rapidly altered by ketamine, can act as predictive biomarkers for ketamine’s protective ability to reduce relapse rates over six months. We will similarly evaluate the role of telomerase, a key enzyme that regulates DNA telomere length and genomic stability and that also functions in neuroplasticity, as a biomarker for depression as well as response to ECT and ketamine.