Ketamine mechanism as an antidepressant Flashcards
Why is there a dire need for anti-depressants
➢~7% of U.S. population suffer from major depressive disorder yearly
➢Leading cause of disability worldwide
~30% of patients do not respond to conventional antidepressants
➢800,000 deaths due to suicide yearly
- Standard antidepressants have a lag odf onset - 6-8 weeks,
need for new antidepressants that have a rapid onset (within hours) eg. electroconlusive therapy - has an effect in 30 mins
Ketamine use as an Anti-depressant.
- mode of action
- study example
- compared to other antagonists
- Ketamine is a NMDA antagonist
-In a study of 2000 depression patients, single infusion of ketamine had a robust decrease in depressive scores compared to placebo.
- had a sustained effect for 12 hours (much longer effect than SSRI’s)
- OTHER NMDAR antagonists (memantine) do not have the same effect as ketamine which has a
- rapid onset
- sustained action
does this mean that NMDAR inhibition may not be the mode of action of ketamine
What is evidence that NMDA receptor inhibition does not solely underlie the ketamine mechanism
(R)-ketamine - more potent inhibitor of NMDA
(S)-ketamine - less potent of NMDA
A study found that S-Ketamine was more effective in reversing depressive effects in mice even though it is a less potent inhibitor of NMDA.
Results:
1. Forced swim test:
S-Ketamine treated mice had a shorter period of mobility in the forced swim test than R-Ketamine treated mice.
- Learned helplessness test:
- Rats exposed to (electric shocks)- induce stress
- A door will open and measure escape failure
-Rats develop “learned helplessness” behavior.
-Antidepressant medication administered to some rats.
-Observe if medication reverses/helps learned helplessness.
- R-Ketamine treated mice had a lower rate of escape failures at lower doses compared to S-Ket.
….Therefore
NMDA antagonism is not the sole mechanism of Ketamine action
Describe the metabolism of ketamine
(+/-) ketamine is metabolised to
- norketamine (+/-)
- dehydronorketamine
Describe the metabolism of ketamine
Ketamine is rapidly metabolized by liver CYP450 into
- norketamine (+/-) (anaesthetic effect)
- dehydronorketamine (HNK) (does not cross the blood brain barrier)
-HNK is further metabolised into 6-HNK, 5-HNK, 4-HNK
Are the effects of ketamine due to metabolised HNK’s?
Study where (R,S)-ketamine molecule was taken and the 2 hydrogens were replaced with D2 - (R,S)-d2 ketamine. - Deuterated ketamine
(R,S)-d2 ketamine had a slower rate of metabolism compared to (R,S)-ketamine.
In the forced swim test:
(R,S)-d2 ketamine treated rats had a longer mobility time than (R,S) KET.
Inescapable shock test: (R,S)-d2 ketamine treated rats had greater escape failures than (R,S) KET treated rats.
therefore: Metabolism of ketamine to its HNK metabolites is critical
for its antidepressant-like actions
Give examples of rodent tests that shown the antidepressant effects of HNK
HNK exerts robust antidepressant-relevant
actions in rodent tests.
- Novelty suppressed feeding
-rats are deprived of food for a certain period, creating a state of hunger. They are then placed in an unfamiliar, brightly lit area with a food pellet in the center.
- Chronic administration of depressant Ketamine and HNK - reduced time taken to feed on pellet compared to untreated rats.
- Chronic CORT administration
-normally rats prefer sugar water compared to normal water.
chronic administration of cortisol (stress) decreases the preference of rats to drink sugar water (anhedonia)
- HNK reverses this anhedonic effect
3.Female urine preference
, male rodents are presented with two sources of odor: female rodent urine (from estrous females) and a control odor (e.g., water or male urine). A preference for the female urine over the control odor is considered indicative of a positive effect on mood and interest in social interactions. The administration of HNK may increase the preference for female urine, suggesting a potential antidepressant effect.
- chronic social preference
-the subject rodent is given the choice between spending time with a conspecific (another rodent of the same species) or alone in an isolated chamber.
- Antidepressant-like effects are observed if HNK-treated rodents display increased preference for social interaction, spending more time with the conspecific compared to untreated rodents.
Does HNK exhibit adverse effects as Ketamine is understood to exhibit in animal models
Ketamines adverse effects include motor incoordination.
-Rotating rod test: rotating rod - rat is able to balance
-HNK treated rats have no problem with motor incoordination.
HNK does not seem to exert ketamine-related side
effects (at least in animal models)
What is the evidence that HNK does not exhibit its effects by NMDA receptor antagonism
Drug discrimination paradigm showed that mice had greater preferance for Ketamine instead of HNK
40 days mice were trained to understand that on the left lever - saline pellet and the right side ketamine pellet
test day - on the ketamine lever we gave saline/ket/HNK
Greatest lever pressing for Ketamine but not HNK
Is NMDA receptor antagonism the reason for the subjective distinct effects of ketamine?
Another study
test day - on the ketamine lever we gave saline/ket/PCP
Both KET and PCP had similar high increased lever pressing
Compare the efficacy of Ketamine and HNK as NMDA receptor antagonists
-high levels of NMDA administration induce lethality
-NMDA antagonists HNK and Ketamine relieve this effect in vivo
Studies have found that huge doses of HNK are needed to block the NMDA receptor compared to Ketamine.
2R,6R)-HNK DOES NOT INHIBIT THE NMDAR TO EXERT
ITS ANTIDEPRESSANT-RELEVANT ACTIONS
What are the additional functions of HNK as an depressant
(2R,6R)-HNK acts presynaptically to enhance glutamatergic synaptic transmission (SC-CA1 pathway)
- important for synaptic plasticity and LTP
- Inc AMPA receptors presynaptically (study measured glutamate receptors in the hippocampus post HNK injection)
- HNK involves the action of the prefrontal cortex. In an EEG (measures neuron firing) - high frequency oscillations detected due to activation of the AMPA receptor in the ventral hippocampus.
Describe a study that shows that AMPA receptor action required for its depressant actions
rats were given an AMPA receptor antagonist prior HNK injection.
- Forced swim test: HNK produced a lower immobility time than rats treated with AMPA receptor antagonist.
What might regulate the
presynaptic actions of (2R,6R)-HNK?
Ketamine activates mGlu2R presynaptically- this prevents ketamine induced glutamate release
The expression of mGlu2R pre-synaptically is required for the antidepressant activity of HNK
Binding studies suggest that HNK does not functionally affect mGlu2R or mGlu3R
What is the proposed action of HNK action with mGlu2R
signaling
Convergent mechanism of HNK action with mGlu2R
signaling
- HNK enters the blood brain barrier
- HNK and GLU2R signalling pathways converge to induce an action potential presynaptically
- Increased levels of glutamate pre-synaptically
- Glutamate binds to AMPA and activates them
- Inc levels of BDNF release (responsible for synaptic plasticity)
- activates mTORC1 - triggers protein synynthesis
- AMPA deposits in the post synaptic cell membrane- this will make the synapse stronger
Newer studies suggest
Ketamine requires NMDA receptors to get activated to get ANTI depressent action
- phase 1 studies being conducted
