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 o 2° amine TCA results in NE > 5-HT uptake 2° 3° 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, ↑t½, ↑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. John’s wort o Structure: prenyl group o Interactions: inductive effect on CYP3A4, CYP2C9, & p-glycoprotein transporter