Ketamine's Actions on Rumination Mechanisms as an Antidepressant
Condition: Remission in Depression
MeSH terms: Rumination Syndrome
Study type: Interventional

Summary: 
      Rumination and anhedonia are two of the most common characteristics of depression that
      persist during remission and are not easily targeted by commonly prescribed antidepressants.
      Ketamine, an NMDA receptor antagonist, has emerged within the last decade as a potent,
      fast-acting antidepressant that can significantly improve anhedonia as early as two hours
      after a single infusion. The brain mechanisms, however, by which ketamine exerts its
      antidepressant action remain largely unknown. The aim of this study is to examine the early
      antidepressant action of ketamine, 2h post infusion, in patients who remitted from depression
      using fMRI. Participants are scanned while performing a personalised, autobiographical,
      emotional memory task and a monetary reward task. Ketamine is expected to reduce the
      activation of limbic areas such as the amygdala during emotional memory recall. Increased
      activations after ketamine are expected in reward processing areas, including striatal
      regions.
    

Detailed description: 
      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.
    

Intervention name(s): Intravenous Infusion
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: A group of remitted depressed participants will receive an intravenous infusion of ketamine or an inactive placebo, in a double-blind, cross over design. A minimun of 1 week is required between the two study sessions.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science