15 - Depression Flashcards
What is the requirements for a depression diagnosis?
5/9 of the symptoms in a 2 week period
What is the limbic system?
- Cortical border circling the brainstem
- Includes the amygdala, hippocampus, basal ganglia and cingulate gyrus with connects to the frontal cortex and hypothalamus
- Involved in emotions (subjective feelings - anger, fear, sadness, jealousy, embarrassment, joy)
Which system is associated with motivation?
Mesocorticolimbic dopamine system
Major depressive disorder is associated with increased activity in the ________ and decreased activity in the _______ of the brain compared to healthy controls
Major depressive disorder is associated with increased activity in the Limbic regions (amygdala) and decreased activity in the Striatum (regions involved with motivation) of the brain compared to healthy controls
Changes in brain activity reflect changes in _________ release and/or _______ response
Changes in brain activity reflect changes in neurotransmitter release and/or postsynaptic response
Neurotransmitters concentrated within the _________ region of the brain may be involved in mediating depression
Neurotransmitters concentrated within the limbic region of the brain may be involved in mediating depression
What is the Amine hypothesis of Depression?
The amine hypothesis of depression suggests that depression is due to the reduced functional activity of one or more brain amines (dopamine, norepinephrine, and serotonin).
What are the monoaminergic neurotransmitters?
- Dopamine
- Serotonin
- norepinephrine
What is the biosynthesis pathway for serotonin?
Tryptophan - converted to 5-HTP by tryptophan hydroxylase -> converted to serotinin by L-amino acid decarboxylase (AADC)
What is the catabolic pathway of serotonin?
Serotonin is broken down into 5-hydroxyindole acetic acid (5-HIAA) by MAO (Monoamine oxidase)
What is the biosynthesis pathway of Dopamine?
- Tyrosine is converted to L-DOPA by tyrosine hydroxylase (TH)
- L-DOPA is converted to Dopamine by L-amino acid decarboxylase (AADC)
What enzymes breakdown dopamine and what is the product?
MAO and COMT break dopamine into homovanillic acid (HVA)
What is the synthesis pathway of Noradrenaline (Norepinephrine)?
- Tyrosine is converted to L-DOPA by tyrosine hydroxylase (TH)
- L-DOPA is converted to dopamine by L-amino acid decarboxylase (AADC)
- Dopamine is converted to noradrenaline via dopamine Beta-hydroxylase (DBH)
What enzymes breakdown noradrenaline (norepinephrine) and what is the product?
PNMT and MAO
Product is adrenaline (epinephrine)
The monoaminergic neurotransmitters have a _________ role in the brain and are involved in ____, ______ and ______
The monoaminergic neurotransmitters have a modulatory role in the brain and are involved in mood, arousal, and attention
- alterations in these NT’s are associated with mood disorders (among other things)
- These NT’s include dopamine, norepinephrine and serotonin
What molecule is shown in the image?
Serotonin
What molecule is shown in the image?
Dopamine
What molecule is shown in the image?
Norepinephrine
What molecule is shown in the image?
Epinephrine
Fill in the blanks of the venn diagram
- Three functions of Norepinephrine
- Three fxns of Dopamine
- Four fxns of Serotonin
- Low Norepinephrine and Low Dopamine =________
- Low Norepinephrine and Low Serotonin = _______
- Low Serotonin and Low Dopamine = ________
Fill in the blanks of the venn diagram
- Three functions of Norepinephrine:
- Stress
- Energy
- arousal
- Three functions of Dopamine
- Motivation
- Salience
- Reward
- Four functions of Serotonin
- appetite
- anxiety
- well-being
- sleep
- Low Norepinephrine and Low Dopamine = Focus
- Low Norepinephrine and Low Serotonin = Depression
- Most antidepressants therefore target these two NT’s
- Low Serotonin and Low Dopamine = Learning
Depression results from inadequate _____________ (esp. _______ and _______) in the brain
Depression results from inadequate monoamine neurotransmission (esp. serotonin and norepinephrine) in the brain
What are three factors that could cause inadequate monoamine neurotransmission?
- less NT release
- fewer receptors
- impaired signal transduction
How was it decided that depression might be because of inadequate monoamine neurotransmission?
Through the use of the antihypertensive drug reserpine
- 15% of patients using this drug developed a syndrome indistinguishable from naturally occurring depression
- Discovered that reserpine depletes neurons of dopamine and norepinephrine transmitters
Why is it that ipronazid alleviated depression?
Ipronazid inhibited Monoamine oxidase (MAO) which is the enzyme responsible for the breakdown of monoamines = increased synaptic [monoamine NT’s]
What are 3 problems with the amine hypothesis of Depression?
- Drugs that restore monoaminergic levels are only moderately effective in 30-50% of patients
- Inconclusive evidence that serotonin and noradrenergic systems are disrupted in depression
- Antidepressants take several weeks before clinical effect is seen, despite immediate effects on synaptic NT levels
- could suggest downstream effects are more important
What is the glutamatergic hypothesis of depression?
Suggests that depression is associated with reduction in glutamatergic signaling in the cortex
- loss of glutamatergic signaling impacts both excitatory and inhibitory function leading to reduced signal to noise
Loss of glutamatergic signaling can impact long-term ______, ______ production, _______ formation and ___________
Loss of glutamatergic signaling can impact long-term potentiation, neurotrophic production (BDNF), synapse formation and gene transcription (Brain remodeling)
What is the effect of Monoamine antidepressants?
Increase synaptic levels of monoamine NT’s (particularly norepinephrine and serotonin)
What enzyme is involved in the breakdown of all three monoamine nt’s?
MAO (Monoamine oxidase)
What is an example of an MAO inhibitor and how does it treat depression?
MAO inhibitors block amine NT breakdown (particularly serotonin and noradrenaline/norepinephrine) which results in an increase in synaptic levels of those NT’s
eg: ipronazid
What drugs need to be taken with a low tyramine diet?
MAO inhibitors
(can lead to hypertension = Tyramine Cheese Reaction)
MAO inhibitors must be taken with a low _______ diet
MAO inhibitors must be taken with a low tyramine diet
What is the tyramine cheese reaction?
An acute attack of hypertension that can occur in a person taking a monoamine oxidase inhibitor (MAOI) drug who eats cheese, caused by an interaction of the MAOI with tyramine, formed in ripe cheese when bacteria provide an enzyme that reacts with the amino acid tyrosine in the cheese
- Tyramine is also degraded by MAO
- inhibition of MAO = buildup of tyramine
- Tyramine binds to adrenergic receptors on blood vessels in the heart
- acute hypertension reaction
How do selective reuptake inhibitors work and what is an example?
Eg Fluoxetine
- Inhibit the serotonin (SET) or noradrenaline (NET) transporters (which move NT’s from the synapse back into the intracellular space)
- inhibition of these transporters leads to an increase in the concentration of NT’s in the synapse
Drugs that are selective for SET are called:
Selective Serotonin Reuptake Inhibitors (SSRI’s)
Drugs that inhibit both NET and SET are called:
Serotonin-norepinephrine reuptake inhibitors (SNRI’s)
What are three limitations of monoamine antidepressants?
- Drugs that restore monoaminergic levels are only moderately effective in 30-50% of patients
- MAOIs, SSRIs and SNRIs take several weeks before clinical effect is seen, despite immediate effects on the synaptic NT levels
- MAOIs, SSRIs and SNRIs affect serotonin and noradrenaline levels throughout the body
- side effects such as nausea, indigestion, dizziness, dry mouth, weight loss etc (because 90% of Serotonin is in GIT)
What is Ketamine?
Glutamate antidepressant
- noncompetitive NMDA receptor antagonist
- dissociative anesthetic with hallucinogenic properties
- recently been demonstrated to have potential as an antidepressant
Depression is associated with reduction in ________ signaling in the cortex. How does ketamine combat this?
Depression is associated with reduction in glutamateric signaling in the cortex. How does ketamine combat this?
- Ketamine causes a transient burst of glutamate resulting from blockage of NMDA receptors on GABA interneurons
- glutamate burst causes synaptic remodeling and resetting of glutamate and GABA systems
- Other downstream signaling effects:
- BDNF release, gene transcription = long term effects
What are the limitations of ketamine?
- very narrow therapeutic index
- fatal at high doses
- Anesthetic at moderate doses
- hallucinogenic at low dose
- antidepressant at very low dose
- must be administered intravenously within a hospital setting
Drugs that target the ________ associated with synaptic ______ may be a more effective/selective treatment for depression.
Example?
Drugs that target the downstream signaling events associated with synaptic remodeling may be a more effective/selective treatment for depression.
Example?
- decreased secondary messenger such as inositol, cAMP and CREB have been reported in brains of patients with major depression at autopsy
- Rolipram a phosphodiesterase inhibitor that increases cAMP may be good for depression
