Neuroendocrinology and Stress Flashcards
The brain is key in the _________________ and ____________ to potential stressors
Interpretation
Response
What are the consequences of short-term, everyday stress?
▪️ Altered brain function
▪️ Adaptation to environmental challenges
What are the consequences of long-term stress?
▪️ Mal-adaptation
▪️ Psychiatric disorders
What are the key messengers for communication between the endocrine systems and the nervous system?
▪️ Hormones
▪️ Neurotransmitters
What are the key messengers used for communication between the immune system and the nervous/endocrine system?
Cytokines
What is the pituitary gland?
The master gland - produces hormones that control for many different processes, sending signals to other organs and glands to regulate function and homeostasis
What are the main pituitary hormones?
▪️ TSH
▪️ ACTH
▪️ FSH and LH
▪️ Growth hormone
▪️ Prolactin
▪️ Endorphins
What are hormones?
Chemical messengers, produced by glands, that are transported via blood to target organs to coordinate physiology and behaviour
What activities are regulated by hormones?
▪️ Digestion
▪️ Metabolism
▪️ Growth and development
▪️ Reproduction
▪️ Maintenance of body temperature
▪️ Cognitive function and mood etc
How do hormones relate to the circadian rhythm?
Secretion and action usually follows it
▪️ Follows the particular needs of the body at a particular time of day
▪️ Not always secreted in the same way throughout the day
How does transmission in the nervous system differ to the endocrine system?
▪️ Neurotransmitters
▪️ Rapid and brief duration
▪️ “wired”
▪️ Anatomical proximity
(Hormones as slower, have longer action, can go anywhere in the body)
What condition first led to the appreciation of psychiatric problems in patients with endocrine disorders?
Cushing’s syndrome:
▪️ Increased glucocorticoid secretion
▪️ Depression, irritability, loss of recent memory
How does stress relate to psychosis?
▪️ Stressful events associated with onset
▪️ Vulnerability stress model
▪️ Childhood trauma as a risk factor
How does stress relate to depression?
Adverse experience, especially during childhood, associated with significant increase in risk
What is the Hypothalamus-Pituitary-Adrenal (HPA) Axis?
In response to stress:
▪️ CRF stimulates pituitary gland to produce ACTH
▪️ ACTH stimulates adrenal gland to produce cortisol
▪️ Cortisol induces physiological changes supporting fight or flight response
▪️ Negative feedback loop - cortisol can feedback to pituitary and hypothalamus when too much to stop production
What are the two main types of corticosteroid receptor?
▪️ Mineralocorticoid receptor (type I/MR)
▪️ Glucocorticoid receptor (type II/GR)
What does the mineralocorticoid receptor do?
▪️ Binds endogenous glucocorticoids (e.g., cortisol) with HIGH AFFINITY (thus good even when levels are low)
▪️ Leads to regulation of circadian fluctuations of these hormones
What does the glucocorticoid receptor do?
▪️ Binds to endogenous glucocorticoids with LOWER AFFINITY
▪️ Leads to regulation of the response to stress when levels of glucocorticoids are high enough
What needs to detach from corticosteroid receptors before they can be activated?
HSP complex
What happens if the HSP complex does not detach from the corticosteroid receptor?
▪️ Translocation to the nucleus cannot occur
▪️ Receptors don’t get activated despite potentially very high levels of cortisol
Why might individuals with depression have increased levels of cortisol?
▪️ GR receptors not working properly
▪️ No negative feedback to the PG/HT to stop cortisol production
(Glucocorticoid resistance due to high levels)
How can you test for overproduction of cortisol/glucocorticoid resistance?
Dexamethasone Suppression Test
▪️ Potent synthetic glucocorticoid
▪️ Activates negative feedback, suppressing cortisol production in non-depressed people
▪️ If depressed/high cortisol, will have no effect staying high throughout the day, indicating negative feedback isn’t working
What can the low dose dexamethasone suppression test be used for?
Differentiating healthy individuals from those who produce too much cortisol
What can the high dose dexamethasone suppression test be used for?
Determining whether the abnormality is in the pituitary gland (i.e., Cushing’s disease)
Are HPA axis abnormalities as consequence of depression?
Possibly but there is also evidence that is PRECEDES depression, increasing risk of developing it
What are the consequences of sustained increased cortisol levels?
▪️ HPA axis alterations correlate with impaired cognitive function in depression
▪️ More common and more pronounced in severely depressed patients with melancholic and/or psychotic features
▪️ Damaging to brain and neurogenesis?
How does chronic stress affect neuroplasticity in rats?
▪️ Dendrites become shorter in CA3 (hippocampus)
▪️ BUT reversible within several weeks
Why might HPA axis dysfunction increase risk or psychosis?
Glucocorticoids increase dopaminergic activity in the mesolimbic system
What stress/HPA-related changes are evident in both depression and psychosis?
▪️ Enlarged pituitary gland
▪️ Cortisol hypersecretion
▪️ Dexamethasone non-suppression
BUT not as consistent in psychosis - greater heterogeneity?
How does treatment with antipsychotics affect cortisol levels in FEP?
It decreases it to the level of healthy controls throughout the day
BUT does not appear to normalise cortisol awakening response (less of a natural increase on awakening)
What is the relationship between cortisol levels and hippocampal volume in FEP?
Moderate negative relationship
Increased cortisol = decreased left hippocampal volume
How does cortisol response to Social Stress Test differ in depression and psychosis from healthy controls?
▪️ No difference in cortisol peak response in depression
▪️ Lower peak response in psychosis - blunted?
How does HPA axis activity differ in psychosis to controls?
▪️ Increased cortisol during the day
▪️ Decreased awakening cortisol
▪️ Decreased cortisol response to stress
How does HPA axis activity differ in depression to controls?
▪️ Increased cortisol during the day
▪️ Increased/equal awakening cortisol
▪️ Equal cortisol response to stress
Can cortisol activity predict response to treatment for FEP?
Possibly - non responders had lowest cortisol awakening response
What is the immune system?
▪️ Host defence system
▪️ Protects against disease
▪️ Distinguished pathogens from own healthy tissue
How does psychological stress impact wound healing?
Disrupts immune function thus impairing wound healing
Study found mouth wound 3 days before exam healed ~40% slower than during summer holiday
How does the HPA axis affect inflammation and immune response?
▪️ Modulates release of cytokines
▪️ Cytokines alter monoamine metabolism, increased excitotoxicity, and decrease production of trophic factors
▪️ Cortisol = immunosuppressant
What is the relationship between depression and immune activation?
Patients show raised inflammatory markers (proinflammatory cytokines), even before development of depression
(e.g., TNF-alpha, IL-6)
Glucocorticoid resistance due to high levels so cortisol doesn’t suppress as it should
Is there increased inflammation in psychosis?
Yes - elevated levels of pro-inflammatory cytokines (IL1-beta, IL-6, TFG-beta) in both schizophrenia and FEP
How does stress affect inflammation in psychosis?
▪️ Significantly increased levels of TNF-alpha, CRP, and IL-6 in those with childhood trauma
▪️ Significantly increased levels of C reactive protein in those with sexual abuse
What is interleukin-6?
One of the main inflammatory cytokines in the brain, marking inflammation
How does inflammation relate to hippocampal volume in FEP?
Greater inflammation (greater IL-6 expression) = smaller HC volume at onset of psychosis
(significant but weak negative correlation)
Can inflammation predict treatment response in FEP?
▪️ Non responders has significantly elevated IL-6
▪️ Responders still elevated compared to controls but not by a lot
(Similar in depression!)
What is the main issues with anti-inflammatory treatments for psychiatric disorders?
▪️ A certain degree of inflammation may be beneficial and neuroprotective
▪️ Should we only target those with increased inflammation?
What did the trial of infliximab (TNF-alpha antagonist) for treatment resistant depression find?
▪️ Placebo better overall
▪️ Those with higher levels of CROP had most benefit
▪️ Thus may only be beneficial to those with inflammation, may be harmful otherwise?
What did the MINDEP clinical trial investigate?
Minocycline in addition to antidepressant for treatment-resistant depression
What is minocycline and why was it chosen for the MINDEP trial?
It is a tetracycline antibiotic that can cross the BBB
What did the MINDEP trial find?
▪️ Overall no difference to placebo
▪️ BUT when divided by baseline CRP, those with higher baseline inflammation showed significant improvement in symptoms
(Important to understand threshold for treatment benefit e.g., CRP >3? )
