Lecture 10 - Pathophysiology of Mood Disorders Flashcards
What are the2 main bodies of evidence for neurobiological changes in mood disorders?
Monoamine pathology
Hypothalamic pituitary adrenal (HPA) axis
What are monoamine neurotransmitters?
5HT, NA, DA
All widely distribute din the forebrain.
Describe what implicated monoamines in mood disorders.
Drug used to treat hypertension (reserpine) had a high incidence of depression as a side effect.
Reserpine works by depleting MOA stores.
Drug used to treat TB (isoniazid) improved mood.
Isoniazid works by blocking the breakdown of MOA.
TCAs used to treat depression found to have an affinity for MOA transporters.
What is the monoamine theory of depression?
Depression is due to a decrease in the function of MOA neurotransmitters in the brain.
What was the monoamine theory of depression later refined to and why?
The 5HT theory of depression as depression is probably mainly due to 5HT dysfunction.
What is some evidence against the monoamine/5HT theory of depression?
Elevating MOAs acutely is not effective in treating depression - antidepressants take weeks to become effective.
No evidence for decrease MOA metabolites in the CSF of depressed patients - hard to get though so not very valid.
Giving a drug that increases MOA release does not give any antidepressant effects (even long term).
What is the evidence for 5HT dysfunction in mood disorders?
4 large bodies of evidence.
Tryptophan depletion
Endocrine responses to 5HT drugs
PET binding too transporters and receptors
5HT1A hypothermic responses
Describe tryptophan depletion.
Tryptophan hydroxyls = rate limiting enzyme in the synthesis of 5HT.
Tryptophan is the substrate and the enzyme is not saturated with this.
Manipulating tryptophan levels in this way in euthymic patients by depleting tryptophan causes a relapse of depressive symptoms.
So depletion of 5HT is associated with depression in some way.
Describe endocrine responses to 5HT drugs.
Number of hormones that are sensitive to 5HT and this can be exploited.
Endocrine responses to 5HT can be used as a marker of MOA receptor function.
Prolactin levels in the blood are sensitive to 5HT1A receptors, when a drug is given that increases 5HT can look at prolactin levels in the blood to see if they also increase as a marker of a particular 5HT receptor function.
Describe PET binding to transporters and receptors.
PET shows lowered 5HT transporter and receptors in different parts of the brain in depressed patients.
Particularly 5HT1A receptor (located in the cell body and postsynaptic parts of the brain) both the cell body and postsynaptic populations appear to be decreased.
Where is the 5HT1A receptor located?
Cell body region in the raphe nucleus where it acts as an auto receptor.
Also located postsynaptic to 5-HT neurons in the forebrain.
It seems that both these populations are lowered as indicated by PET studies.
Describe the 5HT1A hypothermic response.
Indirect evidence.
Found that if you give someone a 5HT1A receptor agonist there is a small drop in core body temperature and research studies found that this drop in temperature is attenuated.
Suggests some dysfunction in 5HT1A receptors.
What is the most compelling evidence for 5HT involvement in mood disorders?
Drugs that target 5HT can improve depressive symptoms and are effective.
Describe the HPA axis/cascade.
Comprised of the hypothalamus, the anterior pituitary and the adrenal cortex.
Controls the synthesis and release of cortisol.
CRH released from the hypothalamus that acts on the pituitary to secrete ACTH which acts on the adrenal glands to cause synthesis and release of cortisol.
What regulates the HPA axis?
A number of different systems.
Circadian clock - cortisol high in the morning, drops through the day.
Stress regulating activity.
Feedback regulation (negative feedback) which really does control the axis. Cortisol released feeds back onto the tissues of the axis and turns off activity.
