Lecture 11 - Depression and Treatment

Question 1

Describe the mechanism of action of 5HT.

Answer 1

5HT precursor is tryptophan. Tryptophan with TPH makes 5-HTP. 5-HTP combined with AADC makes 5HT.
5HT stored in vesicles so it can be release via exocytosis (also protects 5HT for metabolic enzymes in neurons).
Action potential comes down neuron and 5HT released into the synapse where it can act on 15 different subtypes.
Can also be retaken up into the vesicle by SERT.

Question 2

Describe TCAs.

Answer 2

Tricyclic antidepressants.
Inhibits 5HT and NA uptake.
Discovered when looking for new antihistamines so have the ability to act on histamine, muscarinic and adrenergic receptors so not selective and cause many side effects.
Want to get away from the tricyclic structure to prevent this as side effects immediate and the therapeutic effects take weeks which is not ideal.

Question 3

Describe SSRI, SNRI and NARI.

Answer 3

2nd generation antidepressants.
Lost affinity for the receptors that cause the side effects in TCAs due to no tricyclic structure but have the same antidepressant efficacy.
Side effects significantly reduced.
Side effects of SSRI = sexual dysfunction, gastrointestinal, can induce anxiety like symptoms early on.
They work by inhibiting 5HT reuptake into the presynaptic vesciles, so there is more 5HT in the synapse to then be taken up by the postsynapticc cleft.

Question 4

What antidepressants do not inhibit uptake?

Answer 4

Monoamine oxidase inhibitors (MAOIs) - if you block MAO then more 5HT is given to the vesicle and released into the synapse.

Question 5

Describe MAOIs.

Answer 5

2 isoforms - MAOa (breaks down 5HT and NA) and MAOb (breaks down DA).
New MAOIs selective for MAOa and are reversible so safer.

Question 6

Describe the MAOI and cheese effect.

Answer 6

Dietary amines can’t get broken down when on MAOIs so they stay in the blood stream. Need to be careful what is eaten (cheese).

Question 7

What are some atypical antidepressants?

Answer 7

Mirtazepine
Nefazodone
Mianserin
Have affinity for a range of MOA transporters and receptors.

Question 8

What are some possible explanations for the delayed onset of action of TCAs and SSRIs?

Answer 8

5HT increase acutely but produces its therapeutic effect by trophic action resulting in synaptic remodelling. SSRIs cause tropism and increase trophies factor in experimental animals.
Acute auto receptor activation restrains the ability of SSRIs to increase synaptic 5HT, emergence of therapeutic efficacy relates to auto receptor desensitisation.

Question 8

What are the types of drugs used to treat bipolar?

Answer 8

Antimanic agents - used for control of acute mania (sedatives, antipsychotics).
Mood stabilisers - used prophylactically to prevent the recurrence of manic or depressive episodes (lithium salts, anticonvulsants).

Question 9

Describe the auto receptor desensitisation hypothesis.

Answer 9

Acute auto receptor activation inhibits 5-HT neuronal activity.
Results in decreased 5HT release at the terminal and restrains the ability of SSRIs to increase synaptic 5HT.
Emergence of therapeutic efficacy relates to auto receptor desensitisation.