Glu and MDD

Question 1

Percentage of the population affected by MDD?

Answer 1

15-20%

Question 2

Monoaminergic therapy

Answer 2

Changed little over last 5o years
Reuptake inhibitors or MAOIs
Latency period of 2-4 weeks in which suicide risk increases and compliance problems arise
<50% of patients ever become symptom free and 33% of patients completely monoamine treatment resistant

Question 3

Ketamine’s antidepressant profile

Answer 3

Infusion at sub-anaesthetic dose rapidly reduces depression in treatment resistant patients, effect within 2 hours and lasts over a week, no lag and a single dose has a long lasting effect

Question 4

Human imaging and post-mortem studies of MDD

Answer 4

Lower brain volume, neurones smaller in size and lower in density, loss of dendritic spines

Question 5

Animal models of MDD (chronic stress)

Answer 5

Reduction in dendritic branch length, reduction in spine numbers (in rat medial PFC)

Question 6

Underlying changes in human imaging and post-mortem studies in MDD

Answer 6

Decreased AMPA GluA2 and GluA3, increase EC Glu in patients diagnosed with major depression

Question 7

Underlying changes in animal models of MDD (chronic stress)

Answer 7

Decrease in AMPA-R and NMDA-R mediated synaptic responses, increase inhibition and a further decrease in excitation and decrease in synaptic Glu release, decreased Glu uptake so increased EC Glu

Question 8

Acute dose of ketamine reverse synaptic loss

Answer 8

In rat cortex layer V cells: decrease in number of spines following 21 days of CUS, subsequent acute ketamine treatment returns number of spines to control after 1 day (on day 21)

Question 9

Acute dose of ketamine induces synaptogenesis

Answer 9

In rat cortex layer V cells:

increases number of spines and head diameters on tufted dendrites after 24 hours

Question 10

Evidence for ketamine’s potential mechanisms

Answer 10

Mimicked by MK-801 –> NR2B containing NMDA-Rs?
Blocked by NBQX –> mediated by downstream activation of AMPA/KA-Rs?
Phosphorylation of mTOR –> protein translation and synthesis (antidepressant action, synaptogenesis, increased GluA1 inhibited by rapamycin)? (links between AMPA-R and mTOR- required for release of BDNF/TrKB signalling?)
Increased GluA1 –> AMPA-R trafficking and insertion?
Targeting of eEF2 –> decreased phosphorylation and increased translation of BDNF
Overall parallels with monoamine antidepressants which increase AMPA-Rs