Tricyclic + atypical antidepressants

Category: signaling

Overview

Antidepressant classes outside the SSRI / SNRI / MAOI groupings. TCAs (tricyclic antidepressants — amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin) inhibit both SERT + NET (varying ratios) plus block H1 + muscarinic + α1 (the "dirty" pharmacology that drives sedation + dry mouth + orthostasis). Therapeutic-index narrow: lethal in overdose (Na+-channel block + QT prolongation + anticholinergic toxidrome). Atypicals: mirtazapine (α2 + 5-HT2A/2C + H1 antagonist — sedation + appetite); bupropion (NRI + DRI — smoking cessation + ADHD); vilazodone (SERT + 5-HT1A partial); vortioxetine (covered in serotonin); agomelatine (MT1/MT2 agonist + 5-HT2C antagonist — EU only); trazodone (SARI — 5-HT2A antagonist + α1 + H1 — sleep aid at low doses, antidepressant at high); dapoxetine (short-acting SSRI for PE only).

Organ Systems

• nervous

Pathway Steps

1. monoamine-reuptake-blockade-or-receptor-modulation → synaptic-monoamine-elevation — via mixed SERT/NET inhibition + receptor antagonism — multi-target profile. Tricyclics (amitriptyline) and atypical/multimodal antidepressants raise synaptic monoamines by blocking serotonin/norepinephrine reuptake and/or modulating receptors (mirtazapine’s α2 antagonism, vortioxetine’s multimodal 5-HT actions). TCAs’ added antihistamine, anticholinergic, and sodium-channel effects explain their sedation and dangerous overdose toxicity.

Known Modulators

• amitriptyline (inhibitor) — SERT + NET + H1 + M1 + α1 + Na channel. sedating TCA; chronic pain + migraine prophylaxis + insomnia at low doses; depression at high; overdose-lethal narrow TI
• nortriptyline (inhibitor) — NET > SERT + H1/M1/α1. amitriptyline's active metabolite; cleaner profile than parent; lower anticholinergic load; therapeutic drug monitoring
• imipramine (inhibitor) — SERT + NET + H1 + M1. first TCA (1957); depression + childhood enuresis (peripheral anticholinergic on bladder)
• desipramine (inhibitor) — NET > SERT. imipramine's NE-selective metabolite; cleanest TCA profile; ADHD + neuropathic pain off-label; CYP2D6 substrate (DDI authored — quinidine/terbinafine)
• clomipramine (inhibitor) — SERT > NET (most serotonergic TCA). OCD; SSRI-like serotonergic activity; canine OCD label (Clomicalm)
• doxepin (inhibitor) — SERT + H1 (potent) + NET + α1. antidepressant + chronic urticaria + insomnia at low dose (3-6 mg Silenor — H1 antagonism); CYP2D6 substrate
• doxepin low dose (inhibitor) — H1 (selective at low dose). Silenor 3-6 mg insomnia; pure H1 antagonist at this dose; no anticholinergic side effects
• mirtazapine (inhibitor) — α2 + 5-HT2A/2C + 5-HT3 + H1. tetracyclic; sedation + appetite stimulation; minimal sexual side effects vs SSRIs; weight gain
• bupropion (inhibitor) — NET + DAT (NDRI). NDRI; depression + smoking cessation (Zyban) + ADHD off-label; minimal sexual side effects; seizure risk at high doses (eating disorders contraindicated)
• vilazodone (inhibitor) — SERT + 5-HT1A partial agonist (SPARI). serotonin partial-agonist reuptake inhibitor; modest GI side effects; lower sexual side effects vs SSRIs
• agomelatine (activator) — MT1 + MT2 + 5-HT2C antagonist. EU-only antidepressant (Valdoxan); melatonin + serotonin hybrid; LFT monitoring (hepatotoxicity)
• trazodone (inhibitor) — SARI — 5-HT2A + α1 + H1. antidepressant high-dose; sleep aid low-dose (50-100 mg); priapism rare (α1 mechanism)
• dapoxetine (inhibitor) — SERT (short-acting). on-demand SSRI for premature ejaculation; t½ ~1h prevents chronic antidepressant exposure
• desvenlafaxine (inhibitor) — SERT + NET (venlafaxine's active metabolite). pre-formed active metabolite of venlafaxine; cleaner CYP2D6 dependence
• tranylcypromine (inhibitor) — MAO-A + MAO-B (irreversible non-selective). irreversible MAOI; treatment-resistant depression; tyramine + serotonergic DDI risk → dietary restrictions
• moclobemide (inhibitor) — MAO-A (reversible, RIMA). reversible MAO-A inhibitor; cleaner DDI profile; tyramine reaction much less prominent; not FDA-approved (EU/Canada Rx)
• methylene blue (inhibitor) — MAO-A inhibitor + guanylate cyclase + electron donor. IV methemoglobinemia rescue + ifosfamide-encephalopathy + cyanide; serotonin-syndrome with SSRIs (MAOI activity)
• viloxazine (inhibitor) — NRI (Qelbree, non-stimulant ADHD). NRI ADHD; less hepatotoxicity than atomoxetine; CYP1A2 inhibitor
• lurasidone (inhibitor) — 5-HT2A + D2 antagonist (atypical AP). atypical AP for schizophrenia + bipolar depression; food requirement (>350 cal) for absorption; minimal weight gain

References

• PMID 17471183
• PMID 26062986