Migraine/Depression

Question 1

Outline the synthesis of serotonin

Answer 1

Derived from Tryptophan

Tryptophan -> 5-hydroxytryptophan by tryptophan hydroxylase -> 5-Hydroxytryptamine by DOPA decarboxylase.

Question 2

List 3 locations where serotonin (5HT) is found in the body

Answer 2

1. GI tract (chromaffin cells)
2. Platelets
3. CNS

Question 3

List 4 functions of serotonin

Answer 3

1. Platelet aggregation
2. GI motility (excites ENS + GI smooth muscle)
3. Stimulation of peripheral nociceptors
4. Mood regulation

Question 4

List the 4 hypotheses governing anti-depressant medication use

Answer 4

1. Mono-amine hypothesis
2. Autoreceptor hypothesis
3. HPA -axis hypothesis
4. Neurogenesis hypothesis (BDNF)

Question 5

Outline the mono-amine hypothesis for + against

Answer 5

-> Postulates that depression is due to a reduction in mono-amines serotonin, noradrenalin, dopamine.
-> Drugs that decreased mono-amine levels by increasing their metabolism resulted in higher levels of depression.
-> Drugs that increased mono-amines by inhibiting their metabolism (MAOIs) resulted in improved mood.
-> However: Not everyone responds to anti-depressants suggesting a complex aetiology.
-> Difficult to get solid evidence in terms of mono-amine levels/ receptors.
-> The delayed anti-depressant effects of AD’s despite quick onset of side effects suggest that the anti-depressant effects are due to secondary effects and not due directly to the AD’s.

Question 6

outline the HPA-axis hypothesis

Answer 6

-> Suggests that HPA-axis dysregulation contributes to depression.
-> Dysregulation results in lack of negative feedback from excess cortisol levels, also results in elevated CRH + ACTH.
-> elevated CRH associated with depressive symptoms
-> Elevated cortisol associated with excitotoxicity in the hippocampus/frontal cortex through NMDA (glutamate) receptor activation.

Question 7

Outline the neurogenesis theory

Answer 7

Refers to role of BDNF
-BDNF levels found to be low in those with depression.
- BDNF’s normal role is neurogenesis/ encouraging synapse + neuronal development.
-Anti depressants thought to increase BDNF synthesis thereby promoting neurogenesis of the hypothalamus thereby offsetting depression.

Question 8

Outline the autoreceptor theory

Answer 8

Antidepressant’s cause densensitization of serotonin autoreceptor 5-HT1a.

-> These receptors normally function to inhibit serotonin release in response to negative feedback from high serotonin levels in synaptic cleft.
-> By desensitizing these receptors, the autoreceptors no longer respond to the negative feedback, and instead continue to release serotonin.

-> This could potentially explain why anti-depressant effects take weeks to kick in as autoreceptor desensitization occurs only after chronic exposure to the drugs.

Question 9

What is the criteria to be diagnosed with depression? What is the ICD10 scale.

Answer 9

2x core symptoms need to be present for atleast 2 weeks, most of the day, everyday.
These 2 symptoms are Anhedonia and/or feelings of persistent sadness/depression.

Question 10

List 4 depression subtypes

Answer 10

1. Recurrent depressive disorder
   - at least 2 episodes of depression.
2. Dysthymia/ Persistent depressive disorder
   - >2 years of continuous mild depression.
3. Psychotic depression
   - depression with psychosis; hallucinations/delusions.

4.Pre/post natal depression
- affects 7-10% of new mothers.

Question 11

What is meant by Cyclothymia?

Answer 11

Cyclothymia refers to unstable mood whereby there are fluctuations between depression and hypomania but not severe enough to be classed as Bipolar.

Question 12

Name 2 areas of the brain thought to be affected in depression and outline their normal role

Answer 12

Frontal cortex
-Behaviour and emotion.

Hippocampus
-Memories and emotions.

Question 13

What is the first line anti-depressant ? Give 4 examples of this group of AD’s

Answer 13

SSRIs - Selective Serotonin Reuptake inhibitors

-Fluoxetine
-Paroxetine
-Citalopram
-Sertraline.

Question 14

What anti-depressants are absolute contraindication for cardiovascular disease? Give 2 examples of this group.

Answer 14

MAOI’s Mono-amine oxidase inhibitots

-Tranylcypromine
-Phenelzine

Use sertraline (SSRI) instead

Question 15

What is the “cheese” reaction in MAOI’s?

Answer 15

MAOI’s can reduce the first pass metabolism of tyramine, found in foods such as cheese/wine.

-> excess tyramine can cause acute rise in BP

Question 16

List 3 ADR’s for MAOIs

Answer 16

Hypotension
Hypoglycemia
GI upset

Question 17

List 3 ADRs of TCA’s

Answer 17

Postural hypotension (alpha 1 blocker)
Prolonged QT
Lowers seizure threshold

Question 18

List 2 TCA’s

Answer 18

Amitryptaline
Clomipramine

Question 19

List 3 ADR’s of SSRI

Answer 19

Nausea - 5HT stimulates CTZ

GI bleeding due to anti-platelet effects

Hyponatremia (increased ADH)

Sexual dysfunction
-reduced NO
-alpha blocker
-sedation

Question 20

List 2 SNRIS and 3 ADRs

Answer 20

1. Venlafaxine
2. Duloxetine

ADRS
-HTN
-Restlessness
-sweating
-sexual dysfunction

Question 21

What is meant by “Augmentation”? When is it used? List 2 common drugs for augementation

Answer 21

*Augmentation is the addition of another non-antidepressant drug to the patient’s treatment regimen in order to try enhance the overall therapeutic effect/Remission.

*Used in cases of refractory depression whereby patient has failed to achieve remission after atleast 2 different pharmacological AD options.

2 common drugs
- Lithium
-Tri-iodothyronine (T3)

Question 22

Outline how T3 hormone functions in depression managment

Answer 22

T4 is converted to T3 intracellularly within the CNS:
-> Can alter gene expression of those genes coding for the 5-HT1a/1b receptors
-> This can alter their sensitivity to serotonin thereby ultimately increasing serotonin neurotransmission in synpatic cleft.
-> inhibits the autoreceptor 5-HT1a and so it is no longer responding to negative feedback from high concentrations of serotonin in cleft.

Question 23

Management approach for mild depression?

Answer 23

NICE guidelines:

Anti-depressants not advocated.
Watchful waiting +/- CBT is advisable.

Question 24

What is management approach when prescribing anti-depressants?

Answer 24

Titrate drug slowly to therapeutic dose
Trials for 2 weeks then review patient again.
If effective: continue for 6 - 9 months.
If not: trials another drug.

AD’s will fail to achieve remission in 1 in 3 patients.

Question 25

How do Triptans i.e. sumatriptan help to alleviate migraine?

Answer 25

Sumatriptan is a 5-HT agonist, acting mainly at the 5HT1B/1D receptors of meningeal blood vessels and nerves.

Sumatriptan binds to these receptors which are GiPCR -> reduced activation of cAMP

5-HT1B Receptor: Activation of 5-HT1B receptors causes vasoconstriction of the dilated cranial blood vessels, which helps to alleviate the headache.

5-HT1D Receptor: Activation of 5-HT1D receptors inhibits the release of pro-inflammatory neuropeptides (such as CGRP) from trigeminal nerve endings, reducing neurogenic inflammation and pain.

Question 26

list 3 contraindications to Sumatriptan

Answer 26

Prinz metal angina due to vasoconstrictive affects

Coronary artery disease

MAO-A inhibitors -> Sumatriptan is metabolised by MAO-A so inhibition would reduce its clearance.

Question 27

list 3 prophylactic options for migraine

Answer 27

(1) Anticonvulsants
- Topiramate/Valproate
-> Sodium channel blockers in neurons
-> increase GABA-A activity
-> Decreases Glutamate activity
-> Overall reduces neuronal excitability -> prevents cortical spreading.

(2) Beta Blockers
- Propanolol
-> inhibits catecholamine release, nitric oxide release and neuronal excitability.
-> blocks the Beta-adrenergic receptors thereby preventing vasodilation of vessels.

(3) Botulinum toxin
-Cleaves synaptobrevin component of SNARE protein in pre-synaptic neuron.
- prevents release of neurotransmitter.