CHEMISTRY of ANTIDEPRESSANTS

Biological basis of depression: imbalance/deficiency of 5-HT and NE + relationship with DA

Fate of 5-HT & NE: 1. Reuptake for reuse, 2. Metabolism into inactive metabolites
Role of antidepressants: block these two fates from occurring in order to 5-HT or NE available in synapse

Tricyclic Antidepressants (TCAs)

MOA: block the reuptake of both 5-HT & NE

Drugs: imipramine, amitriptyline, amoxapine
Structure: tricyclic ring structures
o 2 phenyl rings in a 6-7-6 ring system
o Tricyclic skeletons: dihydrodibenzazepine (imipramine), dibenzcycloheptadiene (amitriptyline),
dibenzocycloheptatriene (protryptiline)
Development of antidepressants
o Conversion of antipsychotic antidepressant
(Chlorpromazine TCA forerunner)
o Difference: replacing the -S of the antipsychotic with an ethylene bridge causes a lack of coplanarity in
the antidepressant
2 vs. 3 amine TCAs
3
2
o 2 amine TCA results in NE > 5-HT uptake
o 3 amine TCA results in 5-HT > NE uptake

TCA metabolism
o Side chain demethylation
o Ring hydroxylation + glucuronidation (on C2)
o Ring hydroxylation + glucuronidation (on aromatic rings)
o Epoxide formation
o Imipramine metabolism: mediated by CYP450

Monoamine Oxidase Inhibitors (MAOIs)

MOA: block the breakdown of 5-HT & NE by blocking the enzyme that metabolizes them, monoamine oxidase
Drugs: phenelzine (hydrazine), isocarboxizid (hydrazide), tranylcypromine (amphetamine analog)
o Irreversible, nonselective
o Phenelzine & isocarboxazid: very reactive, liver toxic
Side effects
o Tyramine effect
Severe SE from irreversible/nonselective MAOIs
Result: life threatening hypertensive crisis
These MAOIs are nonselective, therefore targeting both MAO-A and MAO-B

MAO-A: intestinal & brain enzymes

MAO-B: hepatic enzymes
Because intestinal MAO-A is inhibited, so is the metabolism of tyramine (which is contained in
some foods), resulting in a build up to a toxic level, eventually causing a hypertensive crisis
o Anticholinergic effects
Less pronounced than TCAs
In particular, dry mouth & constipation
o Hepatocellular damage
Phenelzine: due to its hydrazine moiety
Reversible, selective MAO: meclobemide
o Non-hydrazine
o Reversible: does not inhibit MAO-B no anticholinergic, CV, or tyramine effects

Selective Serotonin Reuptake Inhibitors (SSRIs)

First line therapy for Major Depressive Disorders

MOA: blocks the reuptake of 5-HT
Drugs: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa),
escitalopram (Lexapro)
o Fluoxetine (Prozac)
Structure: trifluoronated methyl CF3 in para position
Racemate: S-isomer makes it more selective for 5-HT transporters (SERT) than NE transporters
Metabolism: via CYP2D6 & CYP3A4 to metabolite norfluoxetine
Norfluoxetine: = potency, t, SERT selectivity
Drug-drug interactions: both fluoxetine & norfluoxetine inhibit CYP2D6, norfluoxetine
also inhibits CYP3A4
o Paroxetine (Paxil)
Compared to fluoxetine, has SERT selectivity, therefore also anticholinergic SE
Structure: trans orientation important for SERT binding
Interactions: CYP2D6 inhibitor and NO synthase inhibitor
o Sertraline (Zoloft)
High SERT selectivity
Structure: 1S,4S stereocenters important for selectivity
SE: no anticholinergic SE
Metabolism: N-demethylation via CYP2D6/2C9 to active metabolite norsertraline
Interactions: weak inhibitor of CYP2D6
o Fluvoxamine (Luvox)
Indication: OCD only
Interactions: strong inhibitor of CYP1A2, CYP3A4, as well as a lot of drug-food interactions
o Escitalopram (Lexapro)
Predecessor: citalopram (Celexa), which was a racemate
Escitalopram is the isolated S-enantiomer of citalopram, making it 2x as effective
Metabolism: extensive hepatic metabolism via CYP 3A4/CYP2C19

Selective Noradrenaline Reuptake Inhibitors (NARIs)

MOA: blocks reuptake of NE only

Drugs: maprotiline, reboxetine, atomoxetine
o Maprotiline
Structure: similar to TCAs but has 4 rings (1 bicyclic ring)
Metabolism: similar to TCA
SE: strong antihistaminic action (sedative), weak anticholinergic action
o Reboxetine
Interactions: only antidepressant with no activity on CYP450
Not FDA approved in North America
o Atomoxetine
Indication: ADHD, also good for mild depression
First non-stimulant treatment for ADHD
Metabolism: via CYP2D6

Selective 5-HT/NE Reuptake Inhibitors (SNRIs)

MOA: blocks both 5-HT and NE reuptake (dual action!)

Drugs: venlaxafine (Effexor), duloxetine (Cymbalta)
o Venlaxafine (Effexor)
SE: lacks typical TCA side effects (no antimuscarinic or antihistaminergic)
Racemate: both enantiomers have similar activity
Metabolism: extensively via CYP2D6 to active metabolite
o Duloxetine (Cymbalta)
SE: also none significant
Metabolism: via CYP2D6 AND CYP1A2
Interactions: moderate inhibitor of CYP2D6

Atypicals

Drugs: bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone, trazadone (Desyrel), venlafaxine, duloxetine

Herbal Supplements

St. Johns wort

o Structure: prenyl group
o Interactions: inductive effect on CYP3A4, CYP2C9, & p-glycoprotein transporter