Stress in Depression Flashcards
What is the hypothalamus-pituitary-adrenal cortex axis?
HPA axis is the (neuro)endocrine system responsible stress response
the HPA axis hypothesis of depression posits that persistently increased cortisol due to HPA axis hyperactivity leads to depression
What is the feedback regulation of cortisol?
cortisol provides negative feedback to both the hypothalamus and the anterior pituitary
What is the physiological effect of fasting cortisol?
increases gluconeogenesis in the liver
modulates the immune system (shift from Th1 to Th2)
increases metabolism of fats, carbohydrates, and protein
What is the physiological effect of cortisol in the stress response?
increased blood glucose, water reabsorption, blood pressure
increased activity in the amygdala and hippocampus for emotional learning, increased cortical frontal areas for planning and control
What are the inputs to the HPA axis?
the hypothalamus receives bi-directional (afferent and efferent) projections from: hippocampus (via the fornix), cortex (via the forebrain and septum), amygdala, brainstem tegmentum (including locus coeruleus)
the hypothalamus is connected to the limbic system through the Papez circuit/medial limbic circuit
What are glucocorticoids?
steroid hormones derived from cholesterol
cortisol (humans) and corticosterone (rodents) are lipophilic and freely diffuse into cells
receptors for glucocorticoids reside in the cytoplasm of cells
What are glucocorticoid receptors?
cytoplasmic GR are inactivated (in the resting state) by binding to chaperone proteins (heat-shock proteins 70, 90, and FKBP52)
cortisol enters the cell and binds GR, displacing the chaperones
the bound complex (2 GR and 2 cortisol) translocate to the nucleus and bind glucocorticoid-response elements (GRE) in DNA
GRE induces expression of genes such as IkB (an anti-inflammatory protein that inhibits NFkB)
What are the differences between glucocorticoid and mineralocorticoid receptors?
MR have high homology to GR and signal in the same manner
MR and GR vary in tissue and cell expression as well as affinity for cortisol
GR binds cortisol with a low affinity (increased binding at high cortisol)
MR binds cortisol with a high affinity (increased binding at low cortisol)
MR is proposed to contribute to negative feedback on the HPA axis during normal circadian rhythms
Where are mineralocorticoid receptors located?
MR are highly expressed in the hippocampus where it is proposed they affect tonic inhibitory (GABAergic) projections to the hypothalamic PVN
MR are thus implicated in feedback regulation of the HPA in “normal” conditions
Where are glucocorticoid receptors located?
GR are widely expressed in the CNS but strongest in the hypothalamus
GR are activated at higher cortisol levels and are proposed to control feedback during the recovery from stress response
What are the chronic effects of cortisol?
impairment of explicit memory
associated with decreased verbal memory, visuospatial and working memory
reduced hippocampal volume
reduced cell survival and increased apoptosis in the hippocampus
decreased neurogenesis in CA1, CA3, and denudate gyrus of hippocampus
What hippocampal changes are seen in depression?
changes in hippocampal structure and function are seen in depression
neurogenic model of depression puts forward a causal role for degeneration of hippocampal neurons in the pathogenesis of depression (animal model work)
cortisol –> increased damage to hippocampus –> depression
What are external factors that impact the HPA axis?
acute sleep deprivation
caffeine
numerous social stressors
alcohol
all increased activity of the HPA axis in a cumulative manner
How does the HPA axis relate to depression?
a significant proportion of depressed patients have high secretion of cortisol
24-hour urinary free cortisol
elevated plasma and CSF cortisol
flattening of circadian cortisol cycles are observed
How does depression alter the HPA axis?
a significant proportion of depressed patients have enlarged pituitary and adrenal glands
elevated ACTH is often observed
depressed patients show enhanced response to social stressors and lack of response to dexamethasone challenge
What is the Trier Social Stress test?
standardized laboratory stress test on humans
subject is fitted with IV for blood sampling and heart rate monitor and escorted into a room with 3 judges, video and audio recording
the test has 3 stages, 5 minutes each
serum levels of cortisol, ACTH, prolactin and human growth hormone are measured over time
What are the three stages of the Trier social stress test?
stage 1 (anticipation): assigned to prepare a 5 minute presentation typically on pretext of a job interview, paper and pen provided then unexpectedly confiscated at the end of the 5 minute period
stage 2 (presentation): judges remain silent and unreactive for the full 5 minutes, if the subject finishes early they are instructed to keep talking until the full period is complete
stage 3 (mental arithmetic): subject instructed to count backwards from 1022 in steps of 13, on any mistake subjects must restart (5 minute limit)
What are the typical results of the Trier social stress test?
normal: peaks at presentation, goes down with math
depression: stay at high level, doesn’t go down
What is the dexamethasone challenge?
exogenous steroid that is highly specific for GR
single oral does (high or low)
normal controls show rapid negative feedback on the HPA axis, sustained reduction in serum ACTH and cortisol for 24 hours
depressed patients have a reduced or absent response (sustained ACTH and cortisol levels)
How do depressed patients react to the stress test and dexamethasone challenge?
depressed patients have an enhanced response to social stress (Trier test) but a muted response to feedback inhibition (dexamethasone challenge)
HPA axis is easily induced and remains chronically elevated
failure of dexamethasone challenge indicates an insensitivity of GR signalling
suggests impaired negative feedback to the HPA axis
What are the glucocorticoid receptor deficits in depression?
GR function and expression in the hypothalamus and pituitary have been shown to be deficient in depressed patients
decreased expression of GR, increased sequestration of GR in the nucleus (cortisol can’t access), epigenetic changes in regulatory elements for GR
decreased availability of cortisol in the brain
altered activity or expression of the multidrug-resistance P-glycoprotein, responsible for cortisol transport at the blood-brain-barrier
What is the genetic evidence for HPA model?
polymorphisms predicting clinical response to antidepressants: GR gene, FKBP5 gene (GR associated HSP) and multidrug resistance P glycoprotein (membrane steroid transporter - efflux of steroids from cells)
polymorphisms associated with increased cortisol in depressed patients: MR gene (two identified polymorphisms)
How do early life events impact the HPA?
in humans enhanced HPA axis activity has been associated with childhood physical or sexual abuse (even in non-depressed)
animal studies such as neonatal maternal separation elicits HPA axis changes that persists into adulthood
What are the connections between the HPA axis and monoamine?
serotonergic systems are modifiable by early life events
a polymorphism in the 5-HT transporter interacts with stressful life events to predict risk of MDD as well as suicidality: especially MDD vs single MDE
neonatal maternal deprivation in rodents was found to alter alpha1-adrenoreceptors on serotonergic neurons of the dorsal raphe nucleus and 5-HT1A receptors in the frontal cortex
Is the HPA axis a risk factor for depression?
HPA axis hyperactivity is proposed to result from interactions in genetic and environmental factors leading to increased risk of depression
How do antidepressants modify HPA axis hyperactivity?
antidepressant treatment is correlated with normalizing activity of the HPA axis
AD treatment decreases cortisol levels and increases responsiveness to dexamethasone challenge
AD increases expression and function of GR in animal models and patients
GR agonists and antagonists are being explored as possible adjuvant therapeutics
