16: Antidepressants

Question 1

With regards to depression, list three sex differences.

Answer 1

10-25% of women versus 5-12% of men will become clinically depressed during their lifetime.

Women affected almost twice as often, probably due to hormonal changes.

Men are 4x more likely to commit suicide.

Question 2

What is the monoamine theory for depression?

Answer 2

Deficit of monoamines: NA, 5-HT, and DA in brain. Decreases concentration in the synaptic cleft, reduces neurotransmission in brain.

Question 3

What is the cortisol theory for depression?

Answer 3

Depressed patients have raised baseline cortisol concentration.

Question 4

Aside from medication, what are two methods for treating depression?

Answer 4

Electroconvulsive therapy - success rate of 78%, effective for severe depression and in cases where alternate methods do not provide relief.

Psychotherapy - learning about disorder, improving quality of life.

Question 5

Describe monoamine oxidase inhibitors (MAOIs). What were they initially developed for?

Answer 5

Phenelzine, tranylcypromine. Initially developed for tuberculosis.

Question 6

Describe tricyclic antidepressants (TCAs). What were they initially developed for?

Answer 6

Imipramine, amitriptyline; second-generation amoxapine, maprotiline. Initially developed as antipsychotics.

Question 7

MAOIs and TCAs are considered to be what generation of antidepressants? Why are they not commonly used?

Answer 7

First generation. Not commonly used due to drug/food interactions and side effect profile.

Question 8

What comprises selective 5-HT reuptake inhibitors (SSRIs)?

Answer 8

Fluoxetine, citalopram.

Question 9

What comprises selective NA reuptake inhibitors (SNRIs, NARIs)?

Answer 9

Reboxetine.

Question 10

What comprises mixed mechanism antidepressants (SSNRIs)? What neurotransmitters are targeted?

Answer 10

Venlafaxine (5-HT, NA, DA), bupropion (DA, NA).

Question 11

SSRIs, SNRIs, NARIs, and SSNRIs are considered to be what generation of antidepressants? Why are they more commonly used?

Answer 11

Second generation. Commonly used due to reduced side effects.

Question 12

Describe the three atypical antidepressants and their benefits.

Answer 12

Mianserine: presynaptic α2 blocker. Sedative, anxiolytic.

Tianepine: 5-HT reuptake. Few adverse drug effects.

Viloxazine: NE reuptake. Not cardiotoxic or cholinolytic.

Question 13

Describe the general pharmacology of antidepressants.

Answer 13

Similar absorption (SSRIs are slower), high protein binding (95%), extensive first-pass metabolism (inhibited by EtOH).

Question 14

What are the half-lives of MAOIs, TCAs, SSRIs?

Answer 14

MAOIs: 2-4h

TCAs: 24h

SSRIs: 15-20h

Question 15

How are fluoxetine and active metabolites distinct regarding their half-lives? What percent of the population are slow fluoxetine metabolizers?

Answer 15

Fluoxetine has half life of 6d, active metabolites 16d.

7% of the population are slow metabolizers.

Question 16

What is the main mechanism for all antidepressants?

Answer 16

All enhance monoamine levels in synapse (most block reuptake).

Question 17

What is the therapeutic antagonism for amitriptyline, nefazadone/terazodone. Agonist for buspirone?

Answer 17

Amitriptyline: 5-HT2 and NE alpha-2 antagonist.

Nefazadone/terazodone: 5-HT2A antagonist.

Buspirone: 5-HT1 agonist.

Question 18

TCAs produce what non-therapeutic antagonism? What are the side effects?

Answer 18

ACh muscarinic antagonism.

Side effects: dry mouth, blurred vision.

Question 19

What is the effect of SSRIs on SERT expression in the brain?

Answer 19

Single dose of 10 mg Citalopram significantly blocks SERT activity by 75%, reduced by 84% after 3 weeks of treatment.

Question 20

A study examining SSRI and TCA time lag in animals via novelty suppressed feeding found what?

Answer 20

After 5 days of oral administration, no effect on feeding latency. Effect shown only after 28 days.

Question 21

What are two explanations for the paradox in which antidepressants’ effect on monoamines is immediate, but the therapeutic effect takes 2-3 weeks?

Answer 21

Postsynaptic receptor downregulation and 5-HT autoreceptor downregulation.

Question 22

What effect do SSRIs have on 5-HT KO mice?

Answer 22

SSRIs don’t work.

Question 23

What effect does depression have on the hippocampus? What reduces antidepressant effect?

Answer 23

Hippocampus decreases in volume. Preventing hippocampal neurogenesis reduces antidepressant effect.

Question 24

In a brain imaging study on depressed patients, 5-HT1A receptors are reduced by how much in where?

Answer 24

42% in the raphe, 33% in the limbic structures, and 27% in the cortex.

Question 25

What receptors are needed for SSRIs to grow new neurons in the hippocampus and why?

Answer 25

Need 5-HT1A receptors in order for SSRIs to grow new neurons, since knock-outs don’t respond to SSRIs or agonists with new neurons.

Question 26

When zapped with X-rays, what area of the hippocampus prevented antidepressant behaviour? Did any other area yield effect?

Answer 26

Subgranular zone. No effect in other areas.

Question 27

In a study by Andreoli et al. (2002), which antidepressant measured yielded highest probability of response?

Answer 27

Reboxetine.

Question 28

List three side effects of MAOIs. Do they linger? What effect do they have on tyramine metabolism?

Answer 28

Weight gain, suppression of REM sleep, drug interactions. Linger ~2w after discontinuation.

Reduces tyramine metabolism, overdose potential leading to hypertension/stroke.

Question 29

How long should one wait between stopping MAOIs and starting an SSRI? Vice versa?

Answer 29

Wait at least two weeks between stopping MAOIs and starting an SSRI.

Wait at least five weeks after stopping an SSRI and starting an MAOI.

Question 30

TCAs may have what effect on bipolar affective disorder?

Answer 30

May cause a switch to manic behaviour.

Question 31

List six side effects of SSRIs.

Answer 31

Sexual dysfunction.
Nausea.
Headache.
Insomnia.
Reduction in REM sleep.
Serotonin syndrome.

Question 32

Why should changing treatments from an SSRI be cautiously managed?

Answer 32

Long half-life of fluoxetine and its metabolite.

Question 33

What herbal remedy is effective for milder depression and what is the recommended dose per day? Any side effects?

Answer 33

St. John’s Wort. 900-1800mg/day recommended.

Side effects: phototoxicity.

Question 34

What causes mania? How is it diagnosed? What percentage of the population suffers from bipolar depression?

Answer 34

Caused by an overproduction of neurotransmitters in the brain.

Diagnosed if elevated mood occurs with 3+ sx most of the day, nearly every day, for 1 week or longer.

1-2% of the population suffer from bipolar depression.

Question 35

What two mood stabilizers are used to treat bipolar affective disorder?

Answer 35

Lithium - most common, successful with ~60% of people.

Anticonvulsant drugs - given when lithium doesn’t work or is unsuitable.

Question 36

What are three other medications for treating bipolar affective disorder?

Answer 36

Antidepressants, neuroleptics, and benzodiazepines.