Anti-depressants

Question 1

What pharmacological evidence supports the monoamine theory of depression?

Answer 1

Effects of drugs in depressed patients: 1. TCAs block NA, 5-HT re-uptake - increase mood 2. MAO inhibitors increase NA, 5-HT stores - increase mood 3. a-methyltyrosine and methyldopa inhibit NA synthesis - reduce mood 4. Reserpine inhibits NA, 5-HT storage - reduces mood 5. ECT ? increases CNS responses to NA, 5-HT - increases mood

Question 2

What pharmacological evidence doesn’t support the monoamine theory of depression?

Answer 2

Effects of drugs in depressed patients: 1. Amphetamine (releases NA and blocks re-uptake) and cocaine (inhibits NA reuptake) - no effect 2. Tryptophan (increases 5-HT synthesis) - questionable effects on mood 3. Methysergide (5-HT antagonist) - no effect 4. a/B antagonists (block actions of NA) - mood slightly decreased w/B 5. L-dopa (increases NA synthesis) - no effect 6. Iprindole (no effect on amine metabolism) - increases mood

Question 3

What is the monoamine theory of depression?

Answer 3

• Depression = functional deficit of central NA and/or 5-HT transmission - Down-regulation of a2, B, 5-HT receptors

Question 4

How do TCAs work?

Answer 4

• Neuronal monoamine re-uptake inhibitors - Other receptor actions - a2 (block presynaptic -ve fb), mAchRs, histamine, 5-HT - Delayed down-regulation of B-adrenoceptors and 5-HT2 receptors

Question 5

What are the side effects of TCAs?

Answer 5

Therapeutic dosage: - Atropine-like effects (esp amitriptyline) - parasymp effects - Postural hypotension (VMC) - Sedation (H1 antagonism) Acute toxicity (o.d): - CNS: excitement, delirium, seizures, coma - Resp depression - CVS: cardiac dysrhythmias, ventricular fibrillation, sudden death - Attempted suicide

Question 6

How do monoamine oxidase inhibitors work?

Answer 6

• Most are non-selective - MAO-A: NA, 5-HT - MAO-B: DA - Irreversible inhibition tf long d.o.a. - Rapid effects: cytoplasmic NA, 5-HT - Delayed effects: clinical response, down-regulation of B-adrenoceptors, 5-HT2 receptors - Inhibit other enzymes

Question 7

What are the side effects of MAOIs?

Answer 7

• Atropine-like effects (less than TCAs) - Postural hypotension - Sedation (seizures od) - Weight gain - Hepatotoxicity

Question 8

How do SSRIs work?

Answer 8

Selective 5-HT re-uptake inhibition

Question 9

What are the side effects of SSRIs?

Answer 9

Fewer than TCAs and MAOIs Nausea, diarrhoea, insomnia, loss of libido

Question 10

Why should fluoxetine (SSRI) not be coadministered with TCAs?

Answer 10

Fluoxetine competes with TCAs for hepatic enzymes Could accumulate to toxic levels

Question 11

What are the proposed mechanisms underlying the delayed therapeutic effects of antidepressants?

Answer 11

• Their secondary adaptive changes are important - Down-regulation of B and a2-adrenoceptors and 5-HT2 receptors - How this is related to therapeutic effect is unclear