TCA antidepressants, tetracyclic and unicyclic, and MAOIs

Question 1

What is are the two main hypotheses about depression.

Answer 1

Amine hypothesis and the neurogenesis hypothesis

• The amine hypothesis of mood postulates that brain amines, particularly norepinephrine (NE) and serotonin (5-HT), are neurotransmitters in pathways that function in the expression of mood, and a functional decrease of these transmitters results in depression.
• Based on studies showing that many drugs capable of alleviating symptoms of major depressive disorders
  enhance the actions of the central nervous system (CNS) neurotransmitters 5-HT and NE.

Difficulties with this hypothesis include the facts that
(1) postmortem studies of patients do not reveal decreases in the brain levels of NE or 5-HT;
(2) although antidepressant drugs may cause changes in brain amine activity
within hours, clinical response requires weeks;
(3) most antidepressants ultimately cause a downregulation of amine receptors;
(4) bupropion has minimal effects on brain NE or 5-HT;
(5) Brain-derived neurotrophic factor (BDNF) is depressed in the brains of depressed patients.

Neurogenesis hypothesis
Depression is a result from impaired hippocampal neurogenesis. Explains the lag time.

Question 2

List the TCA antidepressants

Answer 2

Imipramine
Desipramine

Amitriptyline
Nortriptyline

Clomipramine
Trimipramine

Doxepin

Question 3

List the tetracyclic antidepressants

Answer 3

Maprotiline

Amoxapine

Question 4

What is the unicyclic AD

Answer 4

Buproprion

Question 5

What are the active metabolites of Imipramine and AMitryptyline

Answer 5

Impiramine –> Desipramine

Amitryptyline –> Nortriptyline.

Question 6

Actions of the TCAs

Answer 6

Main: inhibit NET and SERT

also:
anti-adrenergic alpha’s
anti-histamine
anti-muscarinic

Question 7

Actions of the Tetracyclic ADs

Answer 7

same, but Amoxapine also blocks D2 receptors.

Question 8

Which has the strongest anticholinergic actions?

Which has the least?

Answer 8

Amitryptyline

The secondary amines have the least

Desipramine
Nortryptyline

Question 9

What are the SEs of the TCAs

Answer 9

General SEs:

• sedation
• antimuscarinic
• orthostatic hypotension
• possible refractory hypotension
• Sexual dysfunction, decreased libido
• anorgasmia
• Impotence

Question 10

Treatment for TCA overdose

Answer 10

Sodium Bicarbonate i.v.

Increases pH, which decreases TCA ionization and inhibits its Na+ channel binding.

Question 11

What are the indications for TCAs

Answer 11

1st line for neuropathic or chronic pain syndromes

2nd line for SSRI/SNRI resistant:

• Major depressive disorder
• Panic disorder
• Phobias

Clomipramine 2nd line for SSRI resistant O.C.D.

Amitriptyline 2nd line for migraine prophylaxis.

Doxepine at low doses - H1 inhibition for insomnia.

Question 12

Indications for the tetracyclic ADs

Answer 12

Maprotiline -
same as the secondary amine TCAs, disipramine and nortriptyline

Amoxapine -
Also inhibits D2 and 5HT2, sometimes used off label as an atypical antipsychotic, otherwise classified as a regular TCA.

Question 13

Bupropions mechanism and indications

Answer 13

Inhibits NET and DAT.
Mild inhibition of nicotinic receptors

does not have ANY effect on serotonin receptors

Indications:

1) Antidepressant for people that couldn’t tolerate SSRI/SNRI side effects
- Bupropion has no sexual effects or weight gain

2) Quitting Smoking

Question 14

Buproprion SEs and contraindications

Answer 14

Can increase seizure risk

Contraindicated in anyone with any history of seizures

Also contraindicated in any patients with history of eating disorders, bc these are associated with seizures as well.

No other SEs, its used because it LACKS sexual or weight gain.

Question 15

List the NON-selective MAO-Is

Answer 15

Tranylcypromine

Phenelezine

Isocarboxazid

Question 16

Is Tranylcypromine reversible or irreversible

Answer 16

All the non-selective MAOIs are Irreversible.

Question 17

What are the MAO-B selective inhibitors

are they reversible or irreversible?

Answer 17

Selegeline
Rasageline
Safinamide.

They are all Irreversible.

Question 18

What is the reversible MAO inhibitor?

Is it selective?

Answer 18

Moclobeminde

Non-selective and reversible.

Question 19

Indications of the non-selective MAOIs

Answer 19

third line for MDD,
suggested to be more effective in atypical depression
- mdd with hyperphagia, hypersomnia, leaden paralysis.

third line for panic disorder and phobias.

Tranylcypromine
Phenelezine
Isocarboxazid

Question 20

Indications for the MAO-B inhibitors

Answer 20

Selegeline and Rasageline are used in parkinson’s to increase DA in the brain.

Question 21

SEs of MAOis

Answer 21

DELAYED Orthostatic hypotension, after 2-3 weeks, unclear why.

CNS excitation
Insomnia, hypomania, agitation
Convulsions

Weight loss or gain

Sexual dysfunction –> highest rates of this of all antideps

Serotonin syndrome, especially when given with SSRIs, absolutely contraindicated

Tryamine cheese reaction.
Hypertensive crisis, arrhythmias, strokes, AMI.