Ketamine activity in treatment-resistant depression with history of early life stress
Dr Mario Juruena
Clinical Senior Lecturer in Translational Psychiatry
Dept Psychological Medicine, Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN)
King’s College London
Prof Mitul Mehta
Major depression is one of the major healthcare issues in the 21st century. Depression is associated with a growing economic burden and the pressing need for the determination of precise mechanisms leading to illness. Clinical guidelines recommend the use of antidepressant medication for the treatment of moderate to severe depression. However, around 30-50% of patients fail to obtain an optimal outcome to both first- and second-line treatments. This is therefore a common problem and an important issue for the NHS. Because of the high prevalence, recurrence rate of this disorder, and the limited efficacy of drug treatment, many researchers are trying to better understand the etiology and physiopathology of depression.
Studies indicate that Early Life Stress (ELS) aggravates the clinical course of depression and predicts poorer treatment outcomes. ELS has been significantly associated with adulthood Treatment-Resistant Depression (TRD). Notably, these patients have a history of childhood abuse and/or neglect and its hallmark is a pro-inflammatory phenotype.
We have taken as a starting point that an episode of depression can usefully be considered along three main dimensions: severity, chronicity, and risk of relapse. We need to identify why after the treatment of the 1st depressive episode, about 60% of patients will present a second depressive episode, and, on average, at least four depressive episodes during their lifetime; and why antidepressant medication in 30 to 50% of depressive subjects does not lead to full remission of depressive symptomatology. The most robust and consistent finding in a major depression so far has been its link to the abnormalities of the stress response system. The stress response system is a complex, multilevel mechanism largely dependent on feedback regulation. The suppression of the subgenual prefrontal cortex and the activation of the amygdala leads to the stimulation of the HPA axis. Reported evidence shows that during early childhood and adolescence, enduring changes in brain structure and function occur, affecting these regions, possibly explaining why the negative consequences of traumatic events are lasting and can remain over the person’s life. The HPA axis is activated in response to stressful events and disruptions in early life may have a significant role in abnormalities found in adult depression.
We need to understand the reason why ELS and childhood trauma are associated with dramatic increases in the risk factors for depression including increased vulnerability, worse clinical course, greater treatment resistance, and more suicide attempts. Stress and depression are highly associated comprising 50-70% of cases. Reported evidence shows that during early childhood and adolescence, enduring changes to brain structure and function occur, explaining why the negative consequences of traumatic events are lasting and can remain over the person’s life.
The fast-acting antidepressant, ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has emerged and can alleviate depressive symptoms. Neuroimaging studies suggest that ketamine can reverse some of the changes in brain function and connectivity observed in depression. When the drug effects were examined using an emotional processing task, decreased activations were identified for the medial frontal cortex, the posterior cingulate cortex, and the precuneus.
This project is designed to address the question of how ELS moderates the effects of ketamine in patients with TRD depression on different markers. The first marker is that of blood markers associated with synaptogenesis. The second is brain connectivity in the prefrontal-amygdala network associated with stress and HPA axis modulation. The third marker will be brain activity and connectivity changes the following ketamine during an emotional processing task. The project will involve up to 50 patients with TRD. Ketamine will be the active drug and midazolam will be the active placebo to reduce the automatic unblinding with ketamine to both the participant and experimenter. Patients will be randomised into the experiment if they meet the inclusion and exclusion criteria. Each study arm will involve multiple visits with three doses of ketamine being given in the active arm as more doses of ketamine are associated with a higher treatment response rate. The day after the final dose the study assessments will be conducted as this aligns with the average peak clinical response to ketamine treatment. After a washout period, participants will enter the second study arm and receive the drug they did not get the first time. The study assessments include neuroimaging, blood samples, questionnaires, electroencephalography clinical scales, and neuropsychological tests.
This project will fill the knowledge gap around the role of ELS and response to ketamine with a collection of markers known to be sensitive to depression and its treatment. However, no study to date has collected all these markers. The principle research question is then to explore the role of ELS in moderating markers of ketamine response.
Ketamine, Early Life Stress, Treatment Resistant depression, fMRI, Emotional Processing Task