6.3 Antidepressants
Antidepressants treat major depressive disorder by modulating monoamine neurotransmitters (serotonin, norepinephrine, dopamine). Delayed onset (2-4 weeks) suggests neuroplastic mechanisms.
SSRIs - Selective Serotonin Reuptake Inhibitors
Mechanism
Selectively block SERT (serotonin transporter)
↑ Synaptic 5-HT concentration → enhanced serotonergic transmission
Common SSRIs
Fluoxetine (Prozac) - long t½, active metabolite
Sertraline (Zoloft) - dose-dependent DAT inhibition
Paroxetine (Paxil) - anticholinergic effects, short t½
Citalopram/Escitalopram (Celexa/Lexapro) - highly selective
Clinical Uses
Major depression, anxiety disorders, OCD, PTSD, panic disorder
First-line due to favorable safety profile
Adverse Effects
GI upset, sexual dysfunction (↓ libido, anorgasmia), insomnia/sedation
Serotonin syndrome: hyperthermia, rigidity, altered mental status (with MAOIs or other serotonergic drugs)
Withdrawal symptoms if abrupt discontinuation (especially paroxetine)
SNRIs - Serotonin-Norepinephrine Reuptake Inhibitors
Mechanism
Inhibit both SERT and NET (norepinephrine transporter)
Dual monoamine enhancement
Common SNRIs
Venlafaxine (Effexor) - dose-dependent: low = SSRI, high = SNRI
Duloxetine (Cymbalta) - also for neuropathic pain, fibromyalgia
Desvenlafaxine (Pristiq) - active metabolite of venlafaxine
Adverse Effects
Similar to SSRIs plus: ↑ BP (NE effect), ↑ HR, sweating
Monitor blood pressure, especially at higher doses
Tricyclic Antidepressants (TCAs)
Mechanism
Block SERT and NET (non-selective)
Also block: H₁, muscarinic, α₁-adrenergic receptors
Multi-target = effective but many side effects
Examples
Amitriptyline - sedating, pain management
Nortriptyline - less sedating metabolite
Imipramine - also for enuresis
Clomipramine - OCD (most serotonergic TCA)
Adverse Effects
Anticholinergic: dry mouth, blurred vision, urinary retention, constipation
Antihistaminic: sedation, weight gain
α₁-blockade: orthostatic hypotension
Toxicity
Cardiac: QT prolongation, arrhythmias (Na⁺ channel block)
Narrow therapeutic index—dangerous in overdose
CNS: seizures, confusion, coma
MAOIs - Monoamine Oxidase Inhibitors
Mechanism
Inhibit MAO-A and/or MAO-B enzymes
MAO-A: degrades 5-HT, NE, DA → antidepressant effect
MAO-B: degrades DA → used in Parkinson's (selegiline)
Examples
Phenelzine, tranylcypromine: irreversible, non-selective
Moclobemide: reversible MAO-A inhibitor (RIMA)
Selegiline: selective MAO-B at low doses
Hypertensive Crisis
Tyramine reaction: dietary tyramine (aged cheese, wine, cured meats) → ↑↑ NE release
Normally MAO-A metabolizes tyramine; inhibition → severe hypertension
Requires strict low-tyramine diet
Drug Interactions
Contraindicated with SSRIs, SNRIs, TCAs, meperidine → serotonin syndrome
Sympathomimetics (pseudoephedrine) → hypertensive crisis
Reserved for treatment-resistant depression due to interactions
Atypical Antidepressants
Bupropion (Wellbutrin)
Inhibits DA and NE reuptake (not 5-HT)
No sexual side effects—often added to SSRIs
Also for smoking cessation (Zyban)
Risk: Lowers seizure threshold
Mirtazapine (Remeron)
α₂-antagonist → ↑ NE and 5-HT release
5-HT₂, 5-HT₃, H₁ antagonist
Sedating, ↑ appetite, weight gain—useful in underweight/insomnia
Trazodone
5-HT₂ antagonist, weak SERT inhibitor
Highly sedating—often used off-label for insomnia
Risk: Priapism (rare but serious)
Vortioxetine (Trintellix)
SERT inhibitor + multiple 5-HT receptor modulation
May improve cognitive symptoms in depression