Pharmacology. 26/02/20
Antidepressants
1. Outline
What is depression?
3 key theories on the mechanism behind the pathology of depression
Pre-clinical models of depression
Antidepressant drugs and their ‘believed’ mechanism of action
- Monoamine uptake inhibitors
- Monoamine receptor antagonists
- Monoamine oxidase inhibitors (MAOI)
Bipolar disorder & it’s treatment
- Mechanism of action of lithium
2. Background
At some point in their lives 20% of people will become depressed.
Those with depression have a significantly worse survival rate from cancer and heart disease.
Excessive consumption of alcohol, associated with higher levels of depression... as well as suicide
and self har
3. Depression
Is an affective (mood) disorder.
- Heterogeneous, patients present with one or more core symptoms
Two types of depressive syndrome
- Unipolar – mood always goes in one direction
o Non-familial, associated with stressful life events (75%)
o Familial (endogenous depression), usually unrelated to life events (25%)
- Bipolar –depression alternates with mania
o Hereditary tendency –no susceptibility genes identified
o Affects 1-3% of population
4. Theories –monoamine theory schildkraut 1965
Depression caused by functional deficit of monoamine transmitters (NA/5-HT) at certain sites of
the brain
Evidence for
- reduced central serotonergic and/or noradrenergic activity
- reserpine depletes brain of NA/5-HT induces depression
- most antidepressant drugs ↑[amines] in brain
, Pharmacology. 26/02/20
Antidepressants
4. Theories –monoamine theory schildkraut 1965 2
Depression caused by functional deficit of monoamine transmitters (NA/5-HT) at certain sites of
the brain
Evidence against
- antidepressants have a rapid (hours) effect on ↑[amines], but ↑mood takes weeks to
develop
- have not robustly shown ↓[amines] in brain of patients
- cocaine blocks amine uptake, but no antidepressant effect
5. Theories -neuroendocrine
Often depression follows periods of stress
↑[cortisol] plasma of depressed patients
Negative feedback by cortisol desensitised
Corticotrophin-releasing hormone (CRH) in animals’ mimics depression
SSRIs ↑glucocorticoid receptors in hippocampus
ACTH = adrenocorticotrophic hormone
Hippocampus recognises we’re
under stress and it leads to the
release of CRH from the
hypothalamus. CRH binds to
receptors in the anterior
pituitary gland and leads to the
release of ACTH. ACTH binds to
receptors in the adrenal cortex
which releases cortisol this
system is known as HPA
(Hypothalamic pituitary
adrenal) access. Cortisol leads
to metabolic changes, fight-fly,
etc. we’re able to control via
negative feedback the levels of
cortisol. Glucocorticoid
receptors in anterior pituitary
and hypothalamus inhibits the
release of CRH or ACTH. People
with chronic stress
glucocorticoid receptors end
up being downregulated or
less sensitive therefore
negative feedback becomes
less effective. Hippocamps also has glucocorticoid receptors. Selective serotonin reuptake inhibitors can
increase our sensitivity to cortisol and restore the negative feedback loop and bring cortisol levels under
control.
Antidepressants
1. Outline
What is depression?
3 key theories on the mechanism behind the pathology of depression
Pre-clinical models of depression
Antidepressant drugs and their ‘believed’ mechanism of action
- Monoamine uptake inhibitors
- Monoamine receptor antagonists
- Monoamine oxidase inhibitors (MAOI)
Bipolar disorder & it’s treatment
- Mechanism of action of lithium
2. Background
At some point in their lives 20% of people will become depressed.
Those with depression have a significantly worse survival rate from cancer and heart disease.
Excessive consumption of alcohol, associated with higher levels of depression... as well as suicide
and self har
3. Depression
Is an affective (mood) disorder.
- Heterogeneous, patients present with one or more core symptoms
Two types of depressive syndrome
- Unipolar – mood always goes in one direction
o Non-familial, associated with stressful life events (75%)
o Familial (endogenous depression), usually unrelated to life events (25%)
- Bipolar –depression alternates with mania
o Hereditary tendency –no susceptibility genes identified
o Affects 1-3% of population
4. Theories –monoamine theory schildkraut 1965
Depression caused by functional deficit of monoamine transmitters (NA/5-HT) at certain sites of
the brain
Evidence for
- reduced central serotonergic and/or noradrenergic activity
- reserpine depletes brain of NA/5-HT induces depression
- most antidepressant drugs ↑[amines] in brain
, Pharmacology. 26/02/20
Antidepressants
4. Theories –monoamine theory schildkraut 1965 2
Depression caused by functional deficit of monoamine transmitters (NA/5-HT) at certain sites of
the brain
Evidence against
- antidepressants have a rapid (hours) effect on ↑[amines], but ↑mood takes weeks to
develop
- have not robustly shown ↓[amines] in brain of patients
- cocaine blocks amine uptake, but no antidepressant effect
5. Theories -neuroendocrine
Often depression follows periods of stress
↑[cortisol] plasma of depressed patients
Negative feedback by cortisol desensitised
Corticotrophin-releasing hormone (CRH) in animals’ mimics depression
SSRIs ↑glucocorticoid receptors in hippocampus
ACTH = adrenocorticotrophic hormone
Hippocampus recognises we’re
under stress and it leads to the
release of CRH from the
hypothalamus. CRH binds to
receptors in the anterior
pituitary gland and leads to the
release of ACTH. ACTH binds to
receptors in the adrenal cortex
which releases cortisol this
system is known as HPA
(Hypothalamic pituitary
adrenal) access. Cortisol leads
to metabolic changes, fight-fly,
etc. we’re able to control via
negative feedback the levels of
cortisol. Glucocorticoid
receptors in anterior pituitary
and hypothalamus inhibits the
release of CRH or ACTH. People
with chronic stress
glucocorticoid receptors end
up being downregulated or
less sensitive therefore
negative feedback becomes
less effective. Hippocamps also has glucocorticoid receptors. Selective serotonin reuptake inhibitors can
increase our sensitivity to cortisol and restore the negative feedback loop and bring cortisol levels under
control.
