Antidepressants

1. Describe the PATHOPHYSIOLOGY of depression

2. What is the Monoamine hypothesis

3. List the general prinicples of therapy

PATHOPHYSIOLOGY

• Reduced monoamine signaling in key mood circuits 

  • ↓ serotonin (5-HT) (mood, anxiety, sleep/appetite)

  • ↓ norepinephrine (NE) (energy, alertness, attention)

  • ↓ dopamine (DA) (reward, motivation, pleasure)

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MONOAMINE HYPOTHESIS

• Core idea: 

  • Depression linked to ↓ monoamine signaling

• Limitation: 

  • Hypothesis explains part, not all, of depression

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GENERAL PRINCIPLES OF THERAPY

• Delayed benefit

  • Improvement often begins after 2–6 weeks

• Early adverse effects

  • Side effects may appear before mood improves

• Stay consistent

  • Daily adherence supports treatment success

• Do not stop suddenly

  • Taper to reduce discontinuation symptoms

• Individualize therapy

  • Match drug choice to symptoms and comorbidities

Describe the different ANTIDEPRESSANT CLASSES and their MOA

ANTIDEPRESSANT CLASSES

• SSRIs

  • Target SERT → ↑ serotonin

• SNRIs

  • Target SERT + NET → ↑ 5-HT, NE

• TCAs

  • Target SERT + NET; 

  • also block M1, H1, α1

• MAOIs

  • Target MAO-A/MAO-B → ↓ monoamine breakdown

• Atypicals

  • NET/DAT, α2, 5-HT2, 5-HT1A

• Esketamine/Ketamine

  • Target NMDA receptor

Describe SSRIs

• AKA

• MOA

• Clinical Usage

• Describe the effect of SEXUAL DYSFUNCTION

  • MOA

  • Effect

  • Solution

• Members/AE

• Drugs Interactions

• CI

AKA:

• Selective Serotonin Reuptake Inhibitors (SSRIs)

MOA:

• Specifically inhibit serotonin reuptake

• Little blocking activity at 

  • Muscarinic receptor

  • α-adrenergic receptor

  • Histamine H1 receptor

Clinical Usage:

• First-line therapy in treating depression

  • Relatively safe in overdose

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Effect: SEXUAL DYSFUNCTION

• MOA:

  • increase serotonin & activate 5-HT₂ pathways ->  suppresses dopamine and NO signaling

• Effect:

  • ↓ libido, erectile dysfunction, delayed orgasm or ejaculation

• Solution:

  • Bupropion

    • MOA: Increases dopamine & NE , 

      • minimal serotonergic effect

---

Members/AE:

MEMTIP: Two Flus and a Parrot went into the City; C for Cardio

• Fluoxetine

  • Long half-life; fewer withdrawal problems

  • Important CYP2D6 inhibition

• Fluvoxamine

  • Strong CYP inhibitor

• Paroxetine

  • More anticholinergic, weight gain, sexual dysfunction, withdrawal

  • Important CYP2D6 inhibition

• Citalopram

  • Watch QT; dose-dependent prolongation concern

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DRUG INTERACTIONS

• MAOIs: Contraindicated → serotonin syndrome risk

• Other serotonergic drugs -> serotonin syndrome risk

  • Triptans, tramadol, linezolid, dextromethorphan, St. John’s wort

• NSAIDs/antiplatelets/anticoagulants: ↑ bleeding risk

• QT drugs + citalopram/escitalopram: Torsades risk

---

CONTRAINDICATIONS

• Bipolar disorder

  • may trigger mania

• Hyponatremia risk

  • Caution in elderly / SIADH-prone patients

• Pregnancy-specific caution

  • Paroxetine often avoided if possible

Describe SNRIs

• MOA

• Members

  • MEMTIP?

• Clinical Usage

  • MEMTIP:

• AE (8)

• Interactions

• CI

SNRIs

• MOA:

  • Inhibit SERT + NET → ↑ serotonin and norepinephrine in synapse

• Members: MEMTIP: Faxines, Xetines, Ciprans

  • Venlafaxine, 

  • desvenlafaxine, 

  • duloxetine, 

  • levomilnacipran

• Clinical Usage:

  • Duloxetine

    • MEMTIP: D for 2Ds

    • Depression + diabetic neuropathy/fibromyalgia

  • Venlafaxine

    • MEMTIP: DAPS

    • Depression, anxiety, panic, social anxiety

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ADVERSE EFFECTS

• GI effects: 

  • Nausea, constipation

• CNS effects: 

  • Insomnia, dizziness, headache

• Sexual dysfunction: 

• Hypertension 

• Autonomic:

  • Sweating

  • dry mouth

• Withdrawal risk: 

  • Discontinuation symptoms if abruptly

• Serotonin toxicity: 

• Hyponatremia: 

  • Possible, especially in older adults

---

DRUG INTERACTIONS

• MAOIs: 

  • Contraindicated → serotonin syndrome risk

• Serotonergic drugs: 

  • Tramadol, triptans, linezolid, dextromethorphan, St. John’s wort

• NSAIDs/anticoagulants/antiplatelets: 

  • ↑ bleeding risk

• Other BP-raising drugs: 

• Alcohol/CNS depressants: 

  • increase dizziness/sedation

• CYP interactions: 

  • Some SNRIs have hepatic metabolism interactions

  • Duloxetine: CYP-related interaction potential

---

CI:

• Uncontrolled hypertension

• Severe liver disease

  • Especially w/ duloxetine

• Narrow-angle glaucoma: 

• Bipolar disorder: 

  • May trigger mania

• Hyponatremia risk: 

  • Caution in elderly / SIADH- prone patients

• Abrupt discontinuation: 

  • Can lead to significant withdrawal

Describe TCAs

• MOA

• Members/Class

  • MEMTIP?

• Dif between Tertiary/Secondary Amines

• Clinical Usage

  • For Imipramine? Clomipramines? Doxepin?

• AE(8)

• Describe the relationship between H blockers and weight gain

• Drug Interactions (8)

• CI (8)

TCAs

• MOA:

  • Inhibit NET + SERT → ↑ norepinephrine & serotonin in synapse

  • Also Blocks:

    • M1, H1, α1 receptors

• Members/Class:

  • MEMTIP: Prada? Don’t Pty (pity) me

  • Tertiary Amines:

    • Amitriptyline, 

    • clomipramine, 

    • doxepin,

    • imipramine, 

    • Trimipramine

  •  Secondary amines

    • Desipramine, 

    • nortriptyline, 

    • protriptyline

• Difference between Tertiary and Secondary amines:

  • Tert:

    • Highly anticholinergic & strong serotonin & norepinephrine reuptake inhibitor

  • Secondary:

    • Less anticholinergic & more potent & more selective norepinephrine reuptake inhibitor

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Clinical Usage:

• Depression, neuropathic pain, migraine prevention

• Imipramine:

  • Enuresis

• Clomipramine:

  • OCD

• Doxepin:

  • Insomnia (low dose)

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ADVERSE EFFECTS

• • Anticholinergic (from M1 blockade): 

  • Dry mouth, constipation, urinary retention, blurred vision

• Sedation: 

  • H1 blockade

• Orthostasis: 

  • α1 blockade

• Cardiac toxicity: 

  • Conduction delay, arrhythmias, QT prolongation

• CNS toxicity: 

  • Confusion, tremor, seizures

• Weight gain: 

• Sexual dysfunction: 

• Overdose danger -> life-threatening

---

H1 BLOCKADE & WEIGHT GAIN

• MOA:

  • Increases appetite + Sedation 

• Specific Drugs:

  • TCAs

  • Mirtazapine

---

DRUG INTERACTIONS

• MAOIs: 

  • Contraindicated → serotonin syndrome / hypertensive risk

• Other serotonergic drugs: 

  • ↑ serotonin toxicity risk

• CNS depressants/alcohol: 

  • ↑ sedation and impairment

• Anticholinergics: 

  • Additive antimuscarinic toxicity

• QT-prolonging drugs: 

  • ↑ arrhythmia / torsades risk

• Antiarrhythmics: 

  • May worsen conduction abnormalities

• Sympathomimetics: 

  • Exaggerated cardiovascular effects possible

• CYP inhibitors: 

  • May ↑ TCA levels and toxicity

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CONTRAINDICATIONS

• Recent MI / serious heart disease: 

• Conduction abnormalities / arrhythmia

• Angle-closure glaucoma: 

• Urinary retention / BPH: 

• Seizure disorder: 

  • may lower threshold

• Suicidal overdose risk

• Elderly patients: 

  • Strong anticholinergic / fall risk

• Bipolar disorder: 

  • may trigger mania

Describe MAOIs

• MOA

  • Different types of MAOs

• Members/Class

• Clinical Usage

• AE (7)

• Drug interactions (4)

• CI (5)

MAOIs

• MOA:

  • inhibit monoamine breakdown → ↑ NE, 5- HT, and DA

  • Different Types:

    • MAO A: placenta, gut, & liver

      • Serotonin & norepinephrine

    • MAO B: brain, liver, and platelets

      • Phenylethylamine, methylhistamine, tryptamine

    • MAO A & B

      • Dopamine & tyramine

• Members: Class

  • Nonselective/irreversible

    • phenelzine,

    • tranylcypromine, 

    • Isocarboxazid

  • MAO-B selective/ Irreversible MAO B

    • selegiline, rasagiline 

      • (mainly for parkinson)

      • Selegiline = selective at low doses, nonselective at higher doses

      • Selegiline patch = lower tyramine interaction risk

  • Reversible/Selective MAO B

    • Safinamide

  • reversible MAO-A inhibitor

    • Moclobemide

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Clinical use: 

• treatment-resistant/atypical depression; 

• selected anxiety disorders

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ADVERSE EFFECTS

• Orthostatic hypotension: 

• Hypertensive crisis: 

  • w/ tyramine exposure

• Anticholinergic-like effects

• Serotonin syndrome: 

  • w/ serotonergic drug Combo

• Sexual dysfunction: 

• CNS effects: 

  • Insomnia, agitation, tremor

• Weight gain: 

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DRUG INTERACTIONS

• Tyramine-rich foods: 

  • ↑ hypertensive crisis risk

• Serotonin Drugs

• Sympathomimetics: 

  • Marked hypertension may occur

• Levodopa / stimulants: 

  • Excess catecholamine effects

• Clinical pearl: 

  • Respect washout periods

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CONTRAINDICATIONS

• Meperidine/tramadol/dextromethorphan:

• Uncontrolled hypertension: 

• Pheochromocytoma: 

• Severe liver disease: 

• Bipolar disorder: 

• Washout periods are essential

List the different mechanisms of the ATYPICAL ANTIDEPRESSANTS

• NDRI

  • Norepinephrine–Dopamine Reuptake Inhibitor

• NaSSA

  • Noradrenergic & Specific Serotonergic Antidepressant

• SARI

  • Serotonin Antagonist & Reuptake Inhibitor

• SPARI

  • Serotonin Partial Agonist– Reuptake Inhibitor

Describe BUPROPRION

• Class

• MOA

• Clinical Usage (4)

• Advantage

• AE (4)

• Avoid (2)

BUPROPRION

• Class: 

  • Norepinephrine-dopamine reuptake inhibitor (NDRI)

• MOA:

  • Targets NET + DAT -> ↑ NE and Dopa

• Clinical Usage:

  • Depression,

  • smoking cessation

  • Useful when fatigue or sexual side effects matter

• Advantage:

  • Minimal sexual dysfunction

  • weight-neutral or weight loss

• AE:

  • Insomnia, agitation, tremor

  • Major risks for Seizures

• Avoid:

  • Seizure disorders, eating disorders

Describe MIRTAZAPINE

• Class: 

• MOA:

• Clinical Usage:

• Advantage:(2)

• AE: (2)

MIRTAZAPINE

• Class: 

  • Noradrenergic and specific serotonergic antidepressant (NaSSA)

• MOA:

  • Targets: α2, 5-HT2/3, H1 -> Blocks α2 → ↑ NE and 5-HT release

• Clinical Usage:

  • Depression w/ Insomnia + poor appetite

• Advantage:

  • Less nausea from 5-HT3 blockade

  •  less sexual dysfunction than SSRIs

• AE:

  • Sedation

  • weight gain

Describe TRAZODONE

• Class

• MOA

• Clinical Usage (2)

• AE (3)

• Benefits (2)

TRAZODONE

• Class: 

  • Serotonin antagonist and reuptake inhibitor (SARI)

• MOA:

  • Targets: 5-HT2A, SERT, H1, α1 -> Blocks 5-HT2A; weakly inhibits SERT

• Clinical Usage:

  • Depression

  • Insomnia

• AE:

  • Priapism

    • α₁ blockade 

  • Sedation 

  • orthostatic hypotension

• Benefits:

  • Less sexual dysfunction than many SSRIs

  • Common low-dose sleep aid

Describe VILAZODONE

• Class: 

• MOA:

• Clinical Usage: (1)

• AEs: (3)

• Benefits: (2)

VILAZODONE

• Class: 

  • Serotonin partial agonist-reuptake inhibitor (SPARI)

• MOA:

  • Targets: SERT + 5-HT1A -> Inhibits SERT and partially agonizes 5-HT1A

• Clinical Usage:

  • MDD

• AEs:

  • Nausea, diarrhea, insomnia

• Benefits:

  • less sexual dysfunction in some patients

  • Take with food for better absorption

Describe VORTIOXETINE

• Class

• MOA

• Clinical Usage (1)

• AEs (3)

• Benefits (1)

VORTIOXETINE

• Class: 

  • Multimodal serotonergic antidepressant

• MOA:

  • Targets: SERT + multiple 5-HT receptors 

• Clinical Usage:

  • MDD

• AEs:

  • Nausea, headache, dizziness

• Benefits:

  • less sexual dysfunction in some patients

Describe KETAMINE

• Class: 

• MOA:

• Clinical Usage:

• Benefits:

• AEs: (3)

KETAMINE

• Class: 

  • Rapid-acting antidepressant / dissociative anesthetic

• MOA:

  •  Target NMDA receptor antagonist -> Modulates glutamate signaling; rapid synaptic effects

• Clinical Usage:

  • Treatment-resistant depression

• Benefits:

  • Can reduce depressive symptoms rapidly

• AEs:

  • Dissociation, sedation, dizziness

  • May increase blood pressure

  • Misuse/abuse potential

Describe the process of ANTIDEPRESSANT SWITCHING 

• SSRIs to SNRIs switching

• SSRIs to TCAs switching

• To MAOI: 

• From MAOI: 

ANTIDEPRESSANT SWITCHING 

• SSRIs to SNRIs switching

  • Taper SSRI first, then start SNRI cautiously

  • Cross-taper = serotonin risk

  • Fluoxetine needs extra washout

  • Monitor withdrawal and relapse

• SSRIs to TCAs switching

  • Taper SSRI first, then start TCA low

  • Cross-taper = serotonin risk

  • Fluoxetine needs extra washout

  • SSRIs may ↑ TCA levels

  • Monitor toxicity / ECG

• To MAOI: 

  • Stop old drug first

  • Usual washout: 14 days

  • Fluoxetine: 5 weeks

    • Risk of Serotonin syndrome from residual

• From MAOI: 

  • Wait 14 days

  • Do not overlap / cross-taper

  • Watch serotonin + hypertensive toxicity

1. Describe the symptoms of SEROTONIN SYNDROME (3,4,3)

2. Describe DISCONTINUATION SYNDROME

   • Highest risk:

   • Symptoms: 

     • MEMTIP?

   • Offending Drugs:  (2)

   • Prevention: 

SEROTONIN SYNDROME

• Mental status: 

  • Agitation,

  • confusion,

  • delirium

• Autonomic: 

  • Fever, 

  • diaphoresis, 

  • tachycardia, 

  • BP changes

• Neuromuscular: 

  • Hyperreflexia,

  • clonus,

  • tremor

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DISCONTINUATION SYNDROME

• Highest risk: Short half-life agents

• Symptoms: MEMTIP: DIIF

  • Dizziness, 

  • irritability, 

  • insomnia

  • flu-like feelings,

• Offending Drugs: 

  • Paroxetine 

  • venlafaxine

• Prevention: 

  • Taper gradually

  • Avoid abrupt discontinuation

How to Choose the right antidepressants

• Insomnia 

• Sexual dysfunction concern 

• Neuropathic pain 

• Overdose risk 

• Poor adherence 

What special populations should you be concerned about?

CHOOSING THE RIGHT ANTIDEPRESSANTS

• Insomnia 

  • mirtazapine, trazodone

• Sexual dysfunction concern 

  • bupropion

• Neuropathic pain 

  • duloxetine, some TCAs

• Overdose risk 

  • avoid TCAs

• Poor adherence 

  • fluoxetine may help

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SPECIAL POPULATIONS

• Elderly: 

  • Higher risk of hyponatremia, 

  • sedation, 

  • falls, 

  • anticholinergic harm.

• Bipolar disorder: 

  • trigger mania w/o mood stabilization.