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
neurotransmitter and neuropeptide hypothesis
neural circuitry of mood involves multiple neurotransmitters and neuropeptides (not just 5HT and NE)
- reduced GABAergic neurotransmission → depression
- GABA levels reduced in csf and plasma
- fewer GABAergic neurons in depression
- GABA agonists → antidep effects
- antideps affect GABAergic fx
- reduced glu neurotransmission → depression
- glu levels as well as synthetic enzymes and transporters reduced in prefrontal cortex in depression
- ketamine (inhibits NMDA receptors, increases AMPA_gluR1 receptors) → strong antidep effects
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
immune/cytokine hypothesis
evidence for it
incr stress has same effect as incr infl, inf, immunotx →→→ incr cytokines
- direct effect on neurons?
- activate HPA axis
- increased CRF release → depression
- altered monoamine pathways
evidence:
- patients with autoimmune diseases or who are treated with recombinant interferon…often → depression
- blocking cytokine pathways in mice → antidep-like phenotype!
- antideps have anti-infl effects
heritability of mood disorders
high prevalence of mood disorders among individuals who are closely genetically related
- depression: 2-5x higher
- bipolar disorder: 25x higher
- anx disorders: 3-5x higher
genetics of mood disorders
candidate genes
gene influence on mood disorders is polygenic in nature
- location has begun to be better understood
- regular disorders: 18q, 12q
- early onset: 15q25-q26
monoamine hypothesis: risk factors
- 5-HT transporter promoter (for SERT or 5TT)
- 5HT1A receptor
- TPH2
HPA Axis hypothesis: protective factors
- CHR recpetor 1
- GC cochaperone FKBP5
neurotrophin hypothesis
- BDNF
- C281A protective
- Val66Met risk
environmental influences on mood disorders
- stress
- estrogen
- mood disorders in general: F > M
- estrogen levels
- reduced in depressed women
- linked to changes in HPA axis
- estrogen receptors can be found in hoppocampus and amygdala
- elevated estrogen can enhance synaptogenesis in the hippocampus (poss through induction of BDNF)
- exercise and enriched environment
- increase neurogenesis
- can have antidep effects
- maternal care
- tactile stim → incr glucocorticoid receptor expression
- long term effect: better response to stress as an adult
epigenetics
interaction between genetics and environment
5HT transporter (moves serotonin from synaptic cleft back into presyn cell) has two forms: short and long
in cases of no maltreatment as a child, makes no diff if you have short or long form → equal chances of depression
however, with maltreatment as a child, short transporter → 2x chance of depression
implication: some connection between mistreatment and serotonin transporter affecting ability to stave off depression as an adult
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
new treatment approaches: phamacological approaches to diff hypotheses
monoamine hypothesis
HPA axis hypothesis
neurotrophin hypothesis
neurotransmission hypothesis
immune hypothesis
epigenetic mechs
- monoamine hypothesis → 5HT receptor agonists (vilazodone)
- HPA axis hypothesis → CRH receptor antagonists
- neurotrophin hypothesis → BDNF receptor agonist and antagonists
- neurotransmission hypothesis → sub-anesthetic doses of ketamine
- immune hypothesis → IL1beta antagonist
- epigenetic mechs → HDAC inhibitors
traditional non-pharma tx:
ECT
electroconvulsive therapy
- induce grand mal seizure:
- incr sensitivity and number of 5HT receptors
- incr neurogenesis
- used for antidep non-responders, suicidal, or elderly pt
MAJOR SIDE EFFECT: retrograde amnesia
new non-pharma tx:
DBS
deep brain stimulation for OCD and MDD
- subgenual cingulate cortex (Cg25) (MDD)
- VTA/NAc (OCD)
- anterior limb of internal capsule (OCD)
possible mechanisms for inhibition include:
- activation of GABA neurons
- synaptic failure induced by high freq stimulation
- interruption of cortical inputs
caveats: control of timing, possible that there are better targets
alternates being looked into on basis of less invasive stimulation
- vagus nerve stim
- repetitive transcranial magnetic stim
- magnetic seizure tx
