Ketamine's Actions on Rumination Mechanisms as an Antidepressant

Depression is one of the leading causes of disease worldwide with detrimental personal, interpersonal and societal impact.The current treatments available for depression involve psychotherapy as well as antidepressant medication. SSRIs (Selective Serotonin Reuptake Inhibitors) are the primary antidepressant medications considered for depression due to their relatively mild side effects and broad effect on depression symptoms. However, other drug types are also available and include tricyclic antidepressants and monoamine oxidase inhibitors. Despite the variety of psychotherapeutic approaches and antidepressant medication, 20% of patients suffering from depression fail to respond to any pharmacological or psychological treatment.

Recently and in an effort to overcome the limitations of the current antidepressant treatments, ketamine has emerged as an effective antidepressant with especially promising results in treatment resistant depression as well as a rather effective antidepressant maintenance strategy.Ketamine is not a novel drug and has used safely and effectively as a dissociative anaesthetic since its introduction in the 1960s. It is commonly used in medicine for starting and maintaining general anaesthesia, sedation in intensive care as well as a painkiller and is also known for its recreational use.

Several studies investigating the antidepressant effects of ketamine have shown that a single ketamine infusion produced a significant decrease in depressive symptoms in treatment resistant patients. This decrease occurred within approximately 2 hours after the infusion and the antidepressant effects of the drug persisted, in some cases, for up to 3 days after the drug administration.

The mechanism by which ketamine exercises its antidepressant effect is unknown. However, recent research has implicated the intracellular mTOR pathway, a signalling system that controls the translation of synaptic proteins. At the molecular level, ketamine is an uncompetitive antagonist of the NMDA receptor and can disrupt memory formation and retrieval. Animal research has shown that ketamine administration leads to proactive interference of spatial memory representations whereas in humans ketamine can modulate hippocampal activity during simple episodic memory tests.

Rumination and anhedonia are two of the most prevalent symptoms of depression that also persist in remission and are not easily targeted by commonly prescribed antidepressants.

Ruminative patterns of thought mediate the relationship between the risk factors for the development of depression and onset of depression and could reinforce depressive symptoms in patients already suffering from the depression. According to the cognitive models of depression which try to identify and understand the factors that could maintain an episode of depression, rumination is associated with altered emotional and memory processing. The brain regions that are known to be involved in these processes include the amygdala, hippocampus and subgenual cingulate cortex, which are involved in emotional processing, the MPFC (medial prefrontal cortex), a brain area involved in representation of self, the ACC (anterior cingulate cortex) which is involved in the inhibition of emotional stimuli as well as the VLPFC (ventrolateral prefrontal cortex) and DLPFC (dorsolateral prefrontal cortex) which are involved in cognitive control. In depressed individuals, dysfunction of this memory system could lead to biased recall of autobiographical memories, greater rumination and often more severe episodes of depression. The NMDA receptor system, targeted by ketamine, plays a central role in memory formation processes in these brain regions.

Anhedonia is a complex construct that demonstrates as reduced motivation to work for rewards, reduced anticipatory pleasure, reduced consummatory pleasure and deficits in reinforcement learning. In the brain, the mesolimbic and mesocortical pathways mediate reward processing and are subserved by the neurotransmitter dopamine. In depression, several key brain ares that are part of those pathways, including the VTA, striatal areas and the thalamus, present with reduced function during the anticipation of rewards but also upon receipt of expected rewards. Ketamine, as an antidepressant, has been shown to significantly improve anhedonia as early as two hours after a single ketamine infusion. Moreover, ketamine 2h post administration was shown to significantly increase the metabolism of striatal areas, indicating that the drug might improve anhedonia by directly targeting brain areas important for reward processing.

This study aims to investigate the early antidepressant effects of ketamine, 2h after a single drug infusion. Autobiographical emotional memory recall - linked to rumination and reward processing - linked to anhedonia, will be examined using fMRI tasks in a sample of remitted depressed volunteers. If successful, this study will help better understand the mechanisms via which ketamine exerts its early antidepressant action and determine whether it could alter the activation of brain areas that are important for rumination and anhedonia in a way that would be beneficial to depression.