Antidepressants II Flashcards
Neurobiology of depression: altered neuroendocrine stress pathway and neurotrophic hypothesis
(explain both and issues with both)
- looks at role of stress in depression and altered HPA axis, stress affects hippocampal neurons and there is decreased hippocampal volumes in depression
- antidepressants increase BDNF and stress decreases it
issues with:
- altered stress pathway = only subset of patients have decreased hippocampal volume and this is also seen in other diseases
- BDNF deficiency not specific to depression and we also can’t actually directly measure synaptic loss (no assay)
How physiological stress affects the brain
Chronic stress and sustained activation of HPA increases glucocorticoids and changes gene expression
- new gene expression profile affects cell function and depressive state
- GCs cause decrease in BDNF and reduced BDNF decreases neurogenesis and causes dendrite retraction (reversed with AD treatment)
more glucocorticoids also seen in other diseases though
Brain changes in depression
PFC and Cingulate Cortex
- reduced volume; reduced number of glia; reduced neuron size
- impaired connectivity
Hippocampus
- no hippocampal cell loss but size decreases; decreased neuropil
- impaired connectivity
^^ both above can be reversed with AD treatment
Amygdala
- glial density reduction
- no neuron density changes
- strengthened connectivity
cytoarchitecture
the structural arrangement of neurons within the central nervous system
Ablating GABA neurons and astroglia can result in
chronic stress-like behavioural deficits
which isomer of ketamine used for treatment of refractory depression
S-ketamine
Ketamine
- NMDA receptor antagonist
- dissociative anesthetic
- used to model SZ
- antidepressant effects within 2 hours when given IV in-patient clinic
- produces an increase in spine density in cingulate cortex by activating mTOR pathway
- GABAergic and glutamatergic alterations considered as key upstream mediators of ketamine effects
Ketamine anesthetic vs antidepressant doses
anesthetic high doses -> reduces glutamate
antidepressant doses -> transitory glutamate surge that is needed for anti-depressant effects
Ketamine disinhibition hypothesis
Ketamine antagonizes NMDARs on GABA terminals that synapse on Glutamatergic neurons
- the GABA neurons that would inhibit the glut Ns are inhibited so the glut neurons are then disinhibited
Riluzole
Thought to act similarly on brain circuitry to ketamine (synaptogenesis) Anti-glutamatergic drug approved for lateral sclerosis
- blocks voltage dependent Na+ channels
- reduces synaptic Glu release
- increases glial Glu uptake
- increases BDNF, GDNF, NGF
- increases synaptogenesis
negative/inconclusive results in double blind placebo trials for AD
Cannabis and depression: clinical use
thought that cannabis can be used in secondary depressions (from cancer, HIV, glaucoma, etc)
- CBD could be useful for anxiety (cannabidiol not THC)
- Cannabis use more than once a month increases risk of depression episodes, risk of suicide, and chances of not responding to AD
Scopolamine
Thought to act similarly on brain circuitry to ketamine (synaptogenesis) anticholinergic drug used to treat motion sickness and post-op nausea
- used as an anesthetic
- primary active component of night shade plant family known to have psychoactive action and hallucinogenic effects
negative/inconclusive results in double blind placebo trials for AD
three varieties of cannabis
- cannabis sativa
- cannabis indica
- cannabis ruderalis
Number of compounds in cannabis
400 compounds, 70 of which are psychoactive
functional effects of cannabis
(cognitive, behavioural, perceptual)
cognitive - decrease attention, concentration and short-term memory
behavioural - decreased movement, increased/decreased talkativeness
perceptual - altered pain, visual, and time perception
