Note: Shanbhag's pharmacology textbook is not directly in the library, but the content below is drawn from Katzung's Basic & Clinical Pharmacology (16th ed.) and Lippincott Illustrated Reviews: Pharmacology - the same sources Shanbhag is based on, covering the same syllabus points.

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ANTIDEPRESSANTS - Complete Notes

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PATHOPHYSIOLOGY OF DEPRESSION

1. Monoamine Hypothesis

• Depression = deficiency of monoamines (norepinephrine, serotonin, dopamine) at key brain sites
• Mania = overproduction of these neurotransmitters
• Limitation: Does not explain the 2-12 week delay in therapeutic effect (drug effects on transporters are immediate, but mood improvement is delayed)

2. Neurotrophic Hypothesis

• BDNF (Brain-Derived Neurotrophic Factor) is critical for neuronal plasticity and survival
• Depression = loss of neurotrophic support → hippocampal atrophy (5-10% volume loss)
• Effective antidepressants → increase neurogenesis and BDNF → activate TrkB (tyrosine kinase receptor B)
• HPA axis dysregulation and cortisol hypersecretion also contribute

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CLASSIFICATION OF ANTIDEPRESSANTS

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1. SSRIs (Selective Serotonin Reuptake Inhibitors)

Mechanism

• Block the serotonin transporter (SERT) → ↑ serotonin in synaptic cleft
• No significant blockade of muscarinic, α-adrenergic, or H1 receptors
• Onset: 2 weeks minimum; maximum benefit at 8-12 weeks

Drugs & Key Points

Therapeutic Uses

• MDD (primary use)
• OCD, panic disorder, GAD, PTSD, social anxiety disorder
• Bulimia nervosa (fluoxetine only - FDA approved)
• Premenstrual dysphoric disorder (PMDD)
• Neuropathic pain, fibromyalgia
• Premature ejaculation (off-label)

Adverse Effects

• GI: Nausea, vomiting, diarrhea (most common, especially early)
• Sexual dysfunction: Loss of libido, delayed ejaculation, anorgasmia (very common)
• Sleep: Insomnia (fluoxetine, sertraline) or somnolence (paroxetine, fluvoxamine)
• Hyponatremia (SIADH - especially in elderly)
• Serotonin syndrome (with MAOIs, triptans, tramadol)
• Increased suicidal ideation in children and adolescents (black box warning)
• QT prolongation (especially citalopram)
• Weight changes, headache, sweating

CYP450 Interactions

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2. SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

Mechanism

• Inhibit both SERT and NET (norepinephrine transporter)
• Venlafaxine: Inhibits NET only at high doses
• Duloxetine: Equal inhibition of SERT and NET (++++ for both)

Drugs & Uses

Adverse Effects

• Similar to SSRIs + increased BP (especially venlafaxine)
• Nausea, sweating, discontinuation syndrome

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3. TCAs (Tricyclic Antidepressants)

Mechanism

• Block both SERT and NET (nonselective reuptake inhibition)
• Also block: Muscarinic (M), α1-adrenergic, H1 histamine, 5-HT2 receptors
• These additional receptor blockades = adverse effect profile

Receptor Blockade Profile (Katzung Table 30-2)

Key Drugs

Therapeutic Uses

• Moderate to severe depression (second-line after SSRIs)
• OCD (clomipramine)
• Panic disorder
• Enuresis in children (imipramine)
• Migraine prophylaxis (amitriptyline)
• Neuropathic pain, fibromyalgia, chronic pain
• Insomnia (low-dose doxepin)

Adverse Effects

• Anticholinergic (M blockade): Dry mouth, blurred vision, urinary retention, constipation, tachycardia, aggravation of angle-closure glaucoma
• α1 blockade: Orthostatic hypotension, dizziness, reflex tachycardia
• H1 blockade: Sedation, weight gain
• Cardiac: Quinidine-like effect → arrhythmias (dangerous in overdose)
• Narrow therapeutic index: 5-6x the maximum daily dose of imipramine can be lethal - do not give to suicidal patients in large quantities
• May precipitate mania in bipolar patients
• Worsen: BPH, epilepsy, pre-existing arrhythmias

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4. MAOIs (Monoamine Oxidase Inhibitors)

Mechanism

• Inhibit MAO-A and/or MAO-B → ↑↑ norepinephrine, serotonin, dopamine at synapse
• Phenelzine, Tranylcypromine, Isocarboxazid: Irreversible, non-selective (MAO-A + MAO-B)
• Selegiline (patch): At low doses = selective MAO-B inhibitor (Parkinson's); at high doses = non-selective

Therapeutic Uses

• Atypical depression (increased sleep, weight gain, mood reactivity - best response to MAOIs)
• Treatment-resistant depression
• Panic disorder, social phobia

Adverse Effects

• Hypertensive crisis (most dangerous) - with tyramine-rich foods ("cheese reaction")
  • Tyramine normally metabolized by gut/liver MAO; if MAO inhibited → tyramine absorbed → releases NE → severe hypertension
  • Foods to avoid: aged cheese, red wine, cured meats, fermented foods, beer
• Serotonin syndrome - if combined with SSRIs, SNRIs, TCAs, meperidine, tramadol, triptans
  • Features: hyperthermia, agitation, tremor, clonus, diaphoresis → can be fatal
• Orthostatic hypotension
• Insomnia, weight gain
• Sexual dysfunction

Washout Period

• MAOIs → SSRIs: Wait 14 days after stopping MAOI before starting SSRI
• SSRIs → MAOIs: Wait 14 days (wait 5 weeks after stopping fluoxetine due to its very long half-life)

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5. ATYPICAL ANTIDEPRESSANTS

Bupropion

• Mechanism: Inhibits reuptake of dopamine and norepinephrine (not serotonin)
• Unicyclic aminoketone structure; resembles amphetamine
• Uses: MDD, smoking cessation (Zyban), seasonal affective disorder (SAD)
• Advantages: No sexual dysfunction, no weight gain, no sedation
• Adverse effects: Lowers seizure threshold (contraindicated in eating disorders, seizure history); activating (insomnia)
• No serotonin syndrome risk; no interaction with MAOIs (serotonergic)

Mirtazapine

• Mechanism: Blocks presynaptic α2-autoreceptors → ↑ NE and 5-HT release; also blocks 5-HT2 and 5-HT3 receptors; strong H1 blockade
• Uses: MDD (especially with insomnia and weight loss)
• Advantages: No sexual dysfunction, very sedating (good for insomnia)
• Adverse effects: Weight gain (appetite stimulation), sedation, hypercholesterolemia

Trazodone

• Mechanism: Blocks 5-HT2 receptors + weak SERT inhibition
• Uses: Insomnia (low dose), MDD adjunct
• Adverse effects: Priapism (rare but important), orthostatic hypotension, sedation

Vortioxetine

• Mechanism: Multi-modal - blocks SERT + antagonizes 5-HT3/5-HT7/5-HT1D + agonizes 5-HT1A
• Use: MDD with cognitive dysfunction

Vilazodone

• Mechanism: SSRI + partial 5-HT1A agonist

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SEROTONIN SYNDROME vs. NEUROLEPTIC MALIGNANT SYNDROME

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CHOOSING AN ANTIDEPRESSANT (Exam Summary)

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HIGH-YIELD EXAM POINTS

1. Fluoxetine has the longest half-life of all SSRIs → least discontinuation syndrome; needs 5-week washout before MAOI
2. Paroxetine = most discontinuation syndrome among SSRIs (shortest t½, most anticholinergic)
3. Fluvoxamine = primarily used for OCD; most CYP450 interactions
4. Citalopram = most QT prolongation among SSRIs
5. Clomipramine = only TCA with strong serotonergic activity → drug of choice in OCD
6. Imipramine → enuresis; Amitriptyline → neuropathic pain & migraine
7. TCAs in overdose → cardiac arrhythmias + seizures (most dangerous - quinidine-like effect)
8. MAOIs + tyramine = hypertensive crisis (cheese reaction)
9. MAOIs + serotonergic drugs = serotonin syndrome
10. Bupropion → contraindicated in seizure disorders and eating disorders (lowers seizure threshold)
11. Trazodone → priapism (unique adverse effect)
12. Mirtazapine → weight gain + sedation + no sexual dysfunction
13. Antidepressants take 2-12 weeks for full effect despite immediate pharmacodynamic action

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