10/13 Basic Science of Depression, Anxiety - Alder Flashcards
anatomical correlates of depression/anxiety
4 areas involved
what things they affect
hippocampus and prefrontal cortex: cognitive abnormalities
- memory impairment
- hopelessness
- worthlessness
- guilt
amygdala
- anxiety and fear
- dysphoric emotions
nucleus accumbens
- anhedonia
- decreased motivation
hypothalamus
- neurovegetative sx (sleep, appetite, etc)
anatomical observations in depression
2 key groups of observations
are they causes or effects of dep?
- venricular enlargement, increased CSF, periventricular hyperintensity
- reduced volume in caudate and basal ganglia, hippocampus, frontal cortex, and gyrus rectus
- areas associated with limbic system!
cause or effect of depression??
- thin right lateral cortex seen in high-risk individuals, BUT is indep of whether they actually had hx of MDD/anx
- mediates attn and visuospatial memory → see deficiencies in these tasks
- thin left medial cortex correlates with MDD/anx!
- thick orbitofrontal and subgenual cortex in high risk group
neuronal activity correlates for depression
areas activated in depression
- thalamus, amygdala, ortibal/medial prefrontal cortex (incld subgenual cingulate cortex Cg25)
- mediate emotional and stress response
areas deactivated in depression
- anterior cingulate cortex
- implicated in attn and sensory processing
anatomical observations in PTSD
causes or effects?
study looking at combat exposed/unexposed co-twins
- broken down further into combat_PTSD/unexposed and combat_noPTSD /unexposed
observations:
cause
- smaller hippocampal volume may presidpose to PTSD
effect
- PTSD → smaller pregenual anterior cingulate cortex volume
neuronal activity correlates for OCD
clinical correlates for OCD (other disorders and why)
activated:
- head of caudate
- anterior cingulate gyrus
- orbitofrontal cortex
OCD relates to Tourette’s and Huntington’s disease
- same pathways affected → hyperactivity of motor fx
PANDAS
pediatric autoimmune neuropsychiatric disorders associated with Strep
- autoimmune attack against Strep bacteria goes awry → hits basal ganglia instead
- increased activity in caudate → OCD sx, tics, ADHD sx, anxiety changes
increasingly susceptible to future inf accompanied by same sx
neuronal activity correlates : panic disorder
fewer GABA receptors → increased activity
hypotheses of depression:
biogenic amine hypothesis
(monoamine hypothes9s)
been around since 1950s
monoamine hypothesis: depression represents decreased availability of either 5HT or NE or both
- 5HT: raphe nuclei → MFB → areas of brain
- NE: locus ceruleus → MFB → areas of brain/spinal cord
*connections between locus ceruleus and amygdala/hippocampus/frontal cortex may be involved in emotional learning
- can be strengthened in certain circumstances (you may not want this → negative emotional associations)
evidence for monoamine hypothesis
metabolic levels in csf, plasma, urine
depression
- decreased 5HT, DA, NE
mania
- increased DA
anxiety
- decreased GABA
- increased NE
- altered 5HT (USMLE says increased)
treatment-resistant depression
(TRD)
??
caveats to monoamine hypothesis
- treatments engineered for monoamine hypothesis dont always work! (TCAs, MAOIs, SSRIs/SNRIs)
* 30-46% of patients are treatment resistant
* approx 30% are respondant to tx, the rest are partial respondants - connection between locus ceruleus and hippocampus not always positive → increased monoamine transmission can strengthen memories of aversive life events
- long delay of efficacy of tx
* desensitization of presynaptic 5HT inhibitory autoreceptors (takes time)
* neuronal adaptation → gene expression, neurogenesis, synaptogenesis, survival
another theory of depression: HPA Axis Hypothesis
what is the HPA axis?
HPA Axis Hypothesis
connection to anatomical/neuronal correlates of depression
hypothalamic-pitutary-adrenal axis hypothesis
problems in glucocorticoid release feedback mechanism → mood disorders
HPA axis:
- paraventricular nucleus releases CRF → pituitary releases ACTH → adrenal cortex releases glucocorticoids
- normally, glucocorticoids exert negative feedback on pathway at various levels
HPA axis theory:
something is wrong with negative feedback loop. either…
- dont have glucocorticoid receptors to detect high levels of glucocorticoids
- glucorticoid receptors are not functioning properly
recall:
- hippocampus inhibits this pathway
- amygdala activates this pathway
soooo…use the evidence!
- small hippocampus in depressed pt →→→ less negative feedback on HPA axis! → more glucocorticoids
- hyperactive amygdala in depressed pt →→→ more positive feedback on HPA axis! → more glucocorticoids
another theory of depression:
Neurotrophin Hypothesis
link to glucocorticoids and SSRIs
levels of growth factors (ex. BDNF: brain-derived neurotrophic factor) mediate neuroanatomical changes during stress and antidepressant tx
- BDNF enhances dendritic branching and synapse number
link to glucocorticoids/SSRIs:
- high conc of glucocorticoids inhibit expression of BDNF → retraction of dendritic branches and fewer synapses
- monoamines increase experssion of BDNF → incr dendritic branching and synapse number
implication: tx with monoamines can reduce effect of glucocorticoids (via BDNF)
phenomenon:
adult hippocampal neurogenesis (and depression)
factors enhancing and inhibiting neurogen
link to depression
neurogenesis in dentate gyrus of hippocampus
- one of two places where neurogen occurs in adults
factors that enhance neurogenesis
- neurotrophins, neuropeptides
- tx: antidepressants, DBS
- path: seizures
- lifestyle: exercise/running, learning
factors that inhibit neurogenesis
- stress
- drugs of abuse
link to depression:
- neurogen is required for antidepressant action
- lack of neurogen → depression-like behavior
evidence for HPA axis and BDNF hypothesis
what we know about depressed patiends and HPA axis
link between HPA axis and small hippocamp!
we know that…in depressed pt:
- hippocampus is smaller
- increased CRH levels (plus incr size of pituitary & adrenal cortex) → incr cortisol
- defect in negative feedback in HPA axis
- evidence: pts fail dexamethasone feedback test (no decrease in glucocorticoid production on dexamethasone admin)
putting it all together:
- stress activates HPA axis → glucocorticoids
* feedback mechanism is messed up → HPA axis keeps on going → more and more glucocorticoids - glucocorticoids → less BDNF → effects on hippocampus
* cause retraction of dendrites, neuronal atrophy → smaller hippocampus
atrophy of hippocampus leads to depressive disorder AND decreased HPA axis feedback → more glucocorticoids/less BDNF → VICIOUS CYCLE!!!
how we can reconcile effect of antidepressants with the HPA axis/BDNF hypothesis
why does this explain antidepressant effectiveness?
antidepressants…
- incr expression of glucocorticoid receptors → reboot negative feedback loop
- enhance gene expression of BDNF
- neurogenesis
- synaptogenesis
- neuronal survival
- →→→ may reverse effects of depression
if this hypothesis is true (and 5HT increase hypothesis is untrue), would better explain…
- why it takes weeks for effects to be seen!
- why it antidepressants dont work in everyone! (indirect mech)
interaction between neurotrophin and HPA Axis hypothesis
summary
ketamine as antidepressant for TRD
single low dose
- 63% of SSRI treatment-resistant patients respond to ketamine tx
- works within 2hr IV
- therapeutic response persists for 2wk!
faster than other tx
mechanism of action: epigenetic connection
(maltreatment & serotonin transporter)
stress → incr histone and DNA methylation → reduced transcription of genes involved in antidep effects (ex. BDNF)
- overall: incr methylation of antidep genes → incr likelihood of depression
histone acetylation → increased transcription of antidep genes
-
histone deacetylase (HDAC) inhibitors → inhibition of deacetylation (inhibiting deactivation of transcription = keeping transcription active) → act as antidepressants
evidence: in mice… - attentive mothering → methylation is removed
- inattentive mothering → methylation added
→→→ long term effects on stress reactivity and cognition
