Stress in Depression

Question 1

What is the hypothalamus-pituitary-adrenal cortex axis?

Answer 1

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

Question 2

What is the feedback regulation of cortisol?

Answer 2

cortisol provides negative feedback to both the hypothalamus and the anterior pituitary

Question 3

What is the physiological effect of fasting cortisol?

Answer 3

increases gluconeogenesis in the liver

modulates the immune system (shift from Th1 to Th2)

increases metabolism of fats, carbohydrates, and protein

Question 4

What is the physiological effect of cortisol in the stress response?

Answer 4

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

Question 5

What are the inputs to the HPA axis?

Answer 5

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

Question 6

What are glucocorticoids?

Answer 6

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

Question 7

What are glucocorticoid receptors?

Answer 7

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)

Question 8

What are the differences between glucocorticoid and mineralocorticoid receptors?

Answer 8

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

Question 9

Where are mineralocorticoid receptors located?

Answer 9

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

Question 10

Where are glucocorticoid receptors located?

Answer 10

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

Question 11

What are the chronic effects of cortisol?

Answer 11

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

Question 12

What hippocampal changes are seen in depression?

Answer 12

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

Question 13

What are external factors that impact the HPA axis?

Answer 13

acute sleep deprivation

caffeine

numerous social stressors

alcohol

all increased activity of the HPA axis in a cumulative manner

Question 14

How does the HPA axis relate to depression?

Answer 14

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

Question 15

How does depression alter the HPA axis?

Answer 15

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

Question 16

What is the Trier Social Stress test?

Answer 16

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

Question 17

What are the three stages of the Trier social stress test?

Answer 17

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)

Question 18

What are the typical results of the Trier social stress test?

Answer 18

normal: peaks at presentation, goes down with math

depression: stay at high level, doesn’t go down

Question 19

What is the dexamethasone challenge?

Answer 19

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)

Question 20

How do depressed patients react to the stress test and dexamethasone challenge?

Answer 20

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

Question 21

What are the glucocorticoid receptor deficits in depression?

Answer 21

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

Question 22

What is the genetic evidence for HPA model?

Answer 22

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)

Question 23

How do early life events impact the HPA?

Answer 23

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

Question 24

What are the connections between the HPA axis and monoamine?

Answer 24

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

Question 25

Is the HPA axis a risk factor for depression?

Answer 25

HPA axis hyperactivity is proposed to result from interactions in genetic and environmental factors leading to increased risk of depression

Question 26

How do antidepressants modify HPA axis hyperactivity?

Answer 26

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