Psychopharmacology Masterclass

1. Mood Disorders (Depression & Related Conditions)

Selective Serotonin Reuptake Inhibitors (SSRIs)

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Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

  • Examples:
    Drug (Brand) Half-Life Active Metabolite CYP Metabolism SERT:NET Inhibition Ratio FDA Approvals
    Venlafaxine (Effexor) 5 hrs (IR), 11 hrs (XR) Desvenlafaxine (ODV) CYP2D6 (major), CYP3A4 30:1 (low dose) → 1:30 (high dose) MDD, GAD, Panic, Social Anxiety
    Desvenlafaxine (Pristiq) 11 hrs None UGT (glucuronidation) > CYP3A4 10:1 (fixed) MDD
    Duloxetine (Cymbalta) 12 hrs None CYP1A2 (major), CYP2D6 10:1 (fixed) MDD, GAD, Diabetic Neuropathy, Fibromyalgia, CMP
    Levomilnacipran (Fetzima) 12 hrs None CYP3A4 (minor) 1:2 (highest NE selectivity) MDD
  • Indication:
    • Core: MDD, GAD, Neuropathic Pain (Duloxetine), Fibromyalgia
    • Unique:
      • Venlafaxine: Vasomotor Menopause Symptoms (off-label), ADHD augmentation
      • Duloxetine: Stress Urinary Incontinence (EU approval), Chronic Musculoskeletal Pain
      • Desvenlafaxine: Preferred in renal impairment (non-CYP metabolism)
  • Mechanism:
    • Primary: Dual inhibition of SERT (serotonin transporter) and NET (norepinephrine transporter)
    • Secondary Effects:
      • Duloxetine: Weak inhibition of dopamine reuptake in prefrontal cortex (DAT inhibition at high doses)
      • Venlafaxine: ↑ PFC dopamine via NET blockade (dose-dependent)
    • Pain Modulation: NE enhances descending inhibitory pathways in dorsal horn (via α2 receptors)
  • Receptor Affinities (Beyond SERT/NET):
    Drug 5-HT2C α1-Adrenergic NMDA μ-Opioid Dopamine (DAT)
    Venlafaxine No Weak No No No
    Desvenlafaxine No No No No No
    Duloxetine Moderate No Weak Yes (Ki=230nM) Weak (>100mg)
    Levomilnacipran No No No No No
    • Clinical Implications:
      • Duloxetine’s μ-opioid affinity → analgesia in neuropathic pain
      • Venlafaxine’s α1 blockade → orthostatic hypotension (dose-dependent)
  • Side Effects:
    • Class-Wide:
      • Nausea (↑ 5-HT in area postrema), Hyperhidrosis (NE-mediated)
      • Hypertension (dose-dependent NE effect; monitor >150 mg venlafaxine)
      • Sexual Dysfunction (less than SSRIs due to NE offsetting 5-HT2C)
    • Drug-Specific:
      • Venlafaxine: Discontinuation syndrome (short t½), ↑ LDL cholesterol
      • Duloxetine: Hepatotoxicity (avoid in heavy alcohol use), ↓ gastric motility
      • Levomilnacipran: ↑ Heart rate (β1 agonism), activation (best for MDD with fatigue)
  • Contraindications:
    • Absolute:
      • MAOIs (serotonin syndrome risk; 14-day washout)
      • Uncontrolled narrow-angle glaucoma (SNRI-induced mydriasis)
    • Relative:
      • Duloxetine: Hepatic impairment (Child-Pugh B/C), severe CKD
      • Venlafaxine: Unstable hypertension, recent MI
  • Clinical Pearls:
    • Dosing Strategies:
      • Venlafaxine XR: Start 37.5 mg AM, ↑ by 75 mg q4-7d (max 375 mg)
      • Duloxetine: Start 30 mg AM for GI tolerance (↑ to 60 mg for pain)
      • Levomilnacipran: Only SNRI dosed BID (40-120 mg/day)
    • Switching from SSRIs: Cross-taper over 2 weeks (↓ SSRI while ↑ SNRI)
    • Overdose: Seizures (venlafaxine >2g), QTc prolongation (duloxetine >200mg)
  • Monitoring Guidelines:
    • Baseline: BP, LFTs (duloxetine), renal function (desvenlafaxine)
    • Follow-Up: BP q3mo (SNRIs), weight (venlafaxine), mood/anxiety scales
  • Black Box Warnings:
    • ↑ Suicidality in adolescents/young adults (age 18-24)
    • Venlafaxine: Neonatal withdrawal (3rd trimester use)
  • Mechanism-Based Drug Interactions:
    Interaction Risk Management
    SNRI + Triptans Serotonin syndrome Avoid or monitor closely
    Venlafaxine + CYP2D6 inhibitors (e.g., fluoxetine) ↑ Venlafaxine levels ↓ Venlafaxine dose by 50%
    Duloxetine + CYP1A2 inducers (e.g., tobacco) ↓ Duloxetine efficacy ↑ Dose if smoking initiated

Tricyclic Antidepressants (TCAs)

  • Examples:
    Drug (Brand) Class Half-Life Active Metabolite SERT:NET Inhibition Ratio Key FDA Approvals
    Amitriptyline (Elavil) Tertiary Amine 10-26 hrs Nortriptyline (active) 4:1 (SERT > NET) MDD, Migraine Prophylaxis
    Nortriptyline (Pamelor) Secondary Amine 18-44 hrs 10-OH-Nortriptyline (inactive) 1:10 (NET > SERT) MDD
    Imipramine (Tofranil) Tertiary Amine 6-18 hrs Desipramine (active) 2:1 (SERT > NET) MDD, Enuresis
    Desipramine (Norpramin) Secondary Amine 14-62 hrs 2-OH-Desipramine (weak) 1:50 (NET >> SERT) MDD
    Clomipramine (Anafranil) Tertiary Amine 20-30 hrs Desmethylclomipramine (weak) 200:1 (strongest SERT) OCD
    Doxepin (Sinequan) Tertiary Amine 8-24 hrs Nordoxepin (weak) 1:1 (balanced) MDD, Insomnia (low dose)
  • Indication:
    • Core: MDD, Neuropathic Pain (e.g., diabetic neuropathy), Migraine/Tension Headache Prophylaxis
    • Unique:
      • Clomipramine: First-line for OCD (highest SERT potency among TCAs)
      • Imipramine: Nocturnal Enuresis (pediatric, ≥6 years)
      • Doxepin: Insomnia (3-6 mg HS; H1 blockade)
      • Amitriptyline: Functional GI Disorders (IBS, cyclic vomiting)
  • Mechanism:
    • Primary: Inhibit SERT and NET → ↑ synaptic 5-HT/NE
    • Secondary Receptor Blockade:
      • Muscarinic (M1): Dry mouth, constipation (tertiary amines > secondary)
      • Histamine (H1): Sedation, weight gain
      • α1-Adrenergic: Orthostatic hypotension
      • Cardiac Fast Sodium Channels: QRS widening, arrhythmias (overdose)
    • Analgesic Mechanism: NE reuptake inhibition → ↑ descending inhibition in dorsal horn (via α2 receptors)
  • Receptor Affinities (Ki in nM):
    Drug SERT NET H1 M1 α1
    Amitriptyline 4.3 35 1.1 9.8 24
    Nortriptyline 18 4.4 10 37 55
    Clomipramine 0.28 38 31 36 38
    Desipramine 17.6 0.83 110 198 130
    Doxepin 68 29 0.24 83 24
    • Clinical Implications:
      • Amitriptyline: Most anticholinergic/sedating (↑ H1/M1 affinity)
      • Desipramine: "Cleanest" TCA (↑ NET selectivity, ↓ side effects)
      • Doxepin: Most potent H1 blockade → insomnia use at 3-6 mg
  • Side Effects:
    • Anticholinergic: Dry mouth, constipation, urinary retention, blurred vision (tertiary amines > secondary)
    • Cardiac: Orthostatic hypotension (α1), QTc prolongation, torsades de pointes (overdose)
    • CNS: Sedation (H1), tremor (NE), seizure threshold ↓ (avoid in epilepsy)
    • Unique:
      • Clomipramine: ↑ Seizure risk (4% at >250 mg/day)
      • Imipramine: ↑ Risk of mania in bipolar depression
      • Doxepin: ↑ Sun sensitivity (phototoxicity)
  • Contraindications:
    • Absolute:
      • MAOIs (risk of serotonin syndrome; 14-day washout)
      • Acute MI, QTc >450 ms
      • Angle-closure glaucoma (M1 blockade → pupillary dilation)
    • Relative:
      • BPH/Urinary retention (tertiary amines)
      • Epilepsy (seizure threshold ↓)
      • Elderly (↑ fall risk from orthostasis/sedation)
  • Clinical Pearls:
    • Dosing:
      • Start low (e.g., 25 mg amitriptyline HS) → ↑ by 25 mg q3d (therapeutic range 75-150 mg/day)
      • Desipramine: Lower doses (50-150 mg/day) due to ↑ NE effects
      • Clomipramine: Start 25 mg HS (max 250 mg/day for OCD)
    • Therapeutic Drug Monitoring (TDM):
      • Amitriptyline + Nortriptyline: Total 100-300 ng/mL
      • Desipramine: 150-300 ng/mL
    • Overdose:
      • Lethal dose >1g (2g for tertiary amines); sodium bicarbonate for QRS >100 ms
      • ECG monitoring ×72 hrs (delayed arrhythmias)
  • Monitoring Guidelines:
    • Baseline: ECG (QTc), LFTs, renal function
    • Follow-Up: BP (orthostasis), weight, bowel regimen (constipation)
  • Black Box Warnings:
    • ↑ Suicidality in adolescents/young adults (age 18-24)
    • Overdose lethality (10-day supply max in suicidal patients)
  • Drug Interactions:
    Interaction Risk Management
    TCA + SSRI ↑ TCA levels (CYP2D6 inhibition) Avoid or ↓ TCA dose 50%
    TCA + Anticholinergics ↑ Anticholinergic toxicity Monitor for ileus/urinary retention
    TCA + Clonidine ↓ Clonidine efficacy (α2 antagonism) Avoid in hypertension
  • Receptor-Based Side Effect Profile:
    Receptor Effect Most Affected TCAs
    M1 Dry mouth, constipation Amitriptyline, Clomipramine
    H1 Sedation, weight gain Doxepin, Amitriptyline
    α1 Orthostatic hypotension Imipramine, Doxepin
    NET Tremor, insomnia Desipramine, Nortriptyline

Tricyclic Antidepressants (TCAs)

  • Examples:
    Drug (Brand) Class Half-Life Active Metabolite SERT:NET Inhibition Ratio Key FDA Approvals
    Amitriptyline (Elavil) Tertiary Amine 10-26 hrs Nortriptyline (active) 4:1 (SERT > NET) MDD, Migraine Prophylaxis
    Nortriptyline (Pamelor) Secondary Amine 18-44 hrs 10-OH-Nortriptyline (inactive) 1:10 (NET > SERT) MDD
    Imipramine (Tofranil) Tertiary Amine 6-18 hrs Desipramine (active) 2:1 (SERT > NET) MDD, Enuresis
    Desipramine (Norpramin) Secondary Amine 14-62 hrs 2-OH-Desipramine (weak) 1:50 (NET >> SERT) MDD
    Clomipramine (Anafranil) Tertiary Amine 20-30 hrs Desmethylclomipramine (weak) 200:1 (strongest SERT) OCD
    Doxepin (Sinequan) Tertiary Amine 8-24 hrs Nordoxepin (weak) 1:1 (balanced) MDD, Insomnia (low dose)
  • Indication:
    • Core: MDD, Neuropathic Pain (e.g., diabetic neuropathy), Migraine/Tension Headache Prophylaxis
    • Unique:
      • Clomipramine: First-line for OCD (highest SERT potency among TCAs)
      • Imipramine: Nocturnal Enuresis (pediatric, ≥6 years)
      • Doxepin: Insomnia (3-6 mg HS; H1 blockade)
      • Amitriptyline: Functional GI Disorders (IBS, cyclic vomiting)
  • Mechanism:
    • Primary: Inhibit SERT and NET → ↑ synaptic 5-HT/NE
    • Secondary Receptor Blockade:
      • Muscarinic (M1): Dry mouth, constipation (tertiary amines > secondary)
      • Histamine (H1): Sedation, weight gain
      • α1-Adrenergic: Orthostatic hypotension
      • Cardiac Fast Sodium Channels: QRS widening, arrhythmias (overdose)
    • Analgesic Mechanism: NE reuptake inhibition → ↑ descending inhibition in dorsal horn (via α2 receptors)
  • Receptor Affinities (Ki in nM):
    Drug SERT NET H1 M1 α1
    Amitriptyline 4.3 35 1.1 9.8 24
    Nortriptyline 18 4.4 10 37 55
    Clomipramine 0.28 38 31 36 38
    Desipramine 17.6 0.83 110 198 130
    Doxepin 68 29 0.24 83 24
    • Clinical Implications:
      • Amitriptyline: Most anticholinergic/sedating (↑ H1/M1 affinity)
      • Desipramine: "Cleanest" TCA (↑ NET selectivity, ↓ side effects)
      • Doxepin: Most potent H1 blockade → insomnia use at 3-6 mg
  • Side Effects:
    • Anticholinergic: Dry mouth, constipation, urinary retention, blurred vision (tertiary amines > secondary)
    • Cardiac: Orthostatic hypotension (α1), QTc prolongation, torsades de pointes (overdose)
    • CNS: Sedation (H1), tremor (NE), seizure threshold ↓ (avoid in epilepsy)
    • Unique:
      • Clomipramine: ↑ Seizure risk (4% at >250 mg/day)
      • Imipramine: ↑ Risk of mania in bipolar depression
      • Doxepin: ↑ Sun sensitivity (phototoxicity)
  • Contraindications:
    • Absolute:
      • MAOIs (risk of serotonin syndrome; 14-day washout)
      • Acute MI, QTc >450 ms
      • Angle-closure glaucoma (M1 blockade → pupillary dilation)
    • Relative:
      • BPH/Urinary retention (tertiary amines)
      • Epilepsy (seizure threshold ↓)
      • Elderly (↑ fall risk from orthostasis/sedation)
  • Clinical Pearls:
    • Dosing:
      • Start low (e.g., 25 mg amitriptyline HS) → ↑ by 25 mg q3d (therapeutic range 75-150 mg/day)
      • Desipramine: Lower doses (50-150 mg/day) due to ↑ NE effects
      • Clomipramine: Start 25 mg HS (max 250 mg/day for OCD)
    • Therapeutic Drug Monitoring (TDM):
      • Amitriptyline + Nortriptyline: Total 100-300 ng/mL
      • Desipramine: 150-300 ng/mL
    • Overdose:
      • Lethal dose >1g (2g for tertiary amines); sodium bicarbonate for QRS >100 ms
      • ECG monitoring ×72 hrs (delayed arrhythmias)
  • Monitoring Guidelines:
    • Baseline: ECG (QTc), LFTs, renal function
    • Follow-Up: BP (orthostasis), weight, bowel regimen (constipation)
  • Black Box Warnings:
    • ↑ Suicidality in adolescents/young adults (age 18-24)
    • Overdose lethality (10-day supply max in suicidal patients)
  • Drug Interactions:
    Interaction Risk Management
    TCA + SSRI ↑ TCA levels (CYP2D6 inhibition) Avoid or ↓ TCA dose 50%
    TCA + Anticholinergics ↑ Anticholinergic toxicity Monitor for ileus/urinary retention
    TCA + Clonidine ↓ Clonidine efficacy (α2 antagonism) Avoid in hypertension
  • Receptor-Based Side Effect Profile:
    Receptor Effect Most Affected TCAs
    M1 Dry mouth, constipation Amitriptyline, Clomipramine
    H1 Sedation, weight gain Doxepin, Amitriptyline
    α1 Orthostatic hypotension Imipramine, Doxepin
    NET Tremor, insomnia Desipramine, Nortriptyline

Monoamine Oxidase Inhibitors (MAOIs)

  • Examples:
    Drug (Brand) Selectivity Irreversible? Half-Life Formulation FDA Approvals
    Phenelzine (Nardil) MAO-A/B Yes 1.5-4 hrs (11-day enzyme recovery) Oral Depression
    Tranylcypromine (Parnate) MAO-A/B Yes 2.5-3.2 hrs (10-day enzyme recovery) Oral Depression
    Selegiline (Emsam) MAO-B (low dose), MAO-A/B (high dose) Yes 10 hrs (oral), 18-25 hrs (transdermal) Oral, Transdermal Depression (patch), Parkinson’s
    Isocarboxazid (Marplan) MAO-A/B Yes 36 hrs Oral Depression
    Moclobemide (Aurorix) MAO-A (reversible) No 1-2 hrs Oral Depression (not FDA-approved)
  • Indication:
    • Core:
      • Treatment-resistant depression (TRD), Atypical Depression (reactive mood, hypersomnia)
      • Parkinson’s Disease (selegiline ≥10 mg/day)
    • Off-label:
      • Social Anxiety Disorder (moclobemide), Bipolar Depression (with caution)
      • Neuropathic Pain (MAOIs ↑ NE/5-HT in descending pathways)
  • Mechanism:
    • Primary: Inhibit MAO enzymes → ↑ synaptic serotonin, NE, dopamine, and trace amines (e.g., phenethylamine).
    • Enzyme Dynamics:
      • MAO-A: Metabolizes 5-HT, NE, dopamine (gut, liver, brain).
      • MAO-B: Metabolizes dopamine, phenethylamine (CNS, platelets).
      • Irreversible Inhibition: Permanent until new enzymes synthesized (2 weeks).
    • Secondary Effects:
      • Phenelzine: ↑ GABA via inhibition of GABA transaminase.
      • Tranylcypromine: Weak amphetamine-like properties (↑ NE release).
  • Tyramine Interaction (Hypertensive Crisis):
    Risk Level Tyramine Content Examples MAOI Risk
    High >6 mg/serving Aged cheeses, cured meats, tap beer, soy sauce ↑↑↑ (SBP >180 mmHg)
    Moderate 2-6 mg/serving Avocados, sauerkraut, red wine ↑↑
    Low <2 mg/serving Fresh meat, pasteurized beer, most fruits Safe with transdermal MAOIs
    • Emsam Patch: Tyramine restrictions lifted at 6 mg/24h dose (no MAO-A inhibition in gut).
  • Side Effects:
    • Common:
      • Orthostatic hypotension (α1 blockade from accumulated NE metabolites)
      • Insomnia (SEA >80%), weight gain (phenelzine), sexual dysfunction
    • Serious:
      • Hypertensive crisis (tyramine), serotonin syndrome (with SSRIs), hepatotoxicity (isocarboxazid)
      • Peripheral neuropathy (phenelzine-induced pyridoxine deficiency)
  • Contraindications:
    • Absolute:
      • Concurrent serotonergic agents (SSRIs, SNRIs, TCAs, triptans, meperidine)
      • Pheochromocytoma (↑ catecholamine release risk)
      • Severe hepatic impairment (moclobemide, isocarboxazid)
    • Relative:
      • Epilepsy (↓ seizure threshold), CHF (fluid retention)
      • Elective surgery (discontinue 10 days prior due to anesthetic interactions)
  • Clinical Pearls:
    • Washout Periods:
      • SSRIs → MAOI: 2-5 weeks (5 weeks for fluoxetine)
      • MAOI → SSRI: 2 weeks (enzyme regeneration)
    • Hypertensive Crisis Management:
      • Immediate sublingual nifedipine 10 mg or IV phentolamine
      • Avoid β-blockers (unopposed α1 → ↑ BP)
    • Dosing:
      • Start phenelzine 15 mg AM → ↑ by 15 mg q3d (target 45-90 mg/day)
      • Emsam patch: 6 mg/24h (no diet) → 9-12 mg/24h (diet required)
  • Monitoring:
    • Baseline: LFTs, BP (orthostasis), tyramine education
    • Follow-Up: BP q2wks, weight, mood logs
  • Black Box Warnings:
    • Hypertensive crisis (tyramine), suicidality in young adults
  • Drug Interactions:
    Interaction Risk Management
    MAOI + Dextromethorphan Serotonin syndrome Absolute contraindication
    MAOI + Sympathomimetics (e.g., pseudoephedrine) Hypertensive crisis Avoid
    MAOI + Buspirone ↑ Serotonin Avoid
  • Mechanism-Based Efficacy in Atypical Depression:
    • ↑ Dopamine/NE reverses symptoms like hypersomnia, leaden paralysis, rejection sensitivity.
    • MAOIs are 70-80% effective vs 50% for SSRIs in atypical depression.
  • Overdose Management:
    • Symptoms: Hyperthermia, rigidity, hypertensive crisis, seizures
    • Treatment:
      • IV fluids, cooling blankets
      • Benzodiazepines for seizures
      • Nitroprusside for hypertension
  • Special Populations:
    • Elderly: ↑ Orthostasis risk; avoid tranylcypromine (stimulating).
    • Pregnancy: Class C (risk of fetal hypotension); Emsam preferred (lower systemic exposure).

Reversible Inhibitors of Monoamine Oxidase A (RIMAs)

  • Examples: Moclobemide (Aurorix, Manerix), Brofaromine (experimental)
  • Indication: MDD, Social Anxiety Disorder
  • Mechanism: Reversible inhibition of MAO-A → ↑ serotonin, norepinephrine
  • Receptors: MAO-A
  • Effects: Antidepressant, anxiolytic
  • Side Effects: Insomnia, nausea, headache
  • Contraindications: Concurrent MAOIs, severe liver disease

Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)

  • Examples: Mirtazapine (Remeron)
  • Indication: MDD, Insomnia, Appetite Stimulation
  • Mechanism: Blocks α2 autoreceptors → ↑ norepinephrine and serotonin; also blocks 5-HT2/5-HT3 and H1 receptors
  • Receptors: α2, 5-HT2, 5-HT3, H1
  • Effects: Antidepressant, sedative, appetite stimulation
  • Side Effects: Sedation, weight gain, dry mouth
  • Contraindications: Concurrent MAOIs

2. Bipolar Disorder

Mood Stabilizers

3. Psychotic Disorders (Schizophrenia, Schizoaffective)

First-Generation (Typical) Antipsychotics

Second-Generation (Atypical) Antipsychotics

4. ADHD & Stimulant Medications

Stimulants

Non-Stimulants

5. Anxiety Disorders (GAD, Panic, Social Anxiety)

Benzodiazepines

SSRIs/SNRIs (First-Line for Chronic Anxiety)

Buspirone (5-HT1A Partial Agonist)

6. Insomnia & Sedative-Hypnotics

Non-Benzodiazepine "Z-Drugs"

Melatonin Receptor Agonists

7. Dementia & Cognitive Enhancers

Acetylcholinesterase Inhibitors (AChEIs)

NMDA Receptor Antagonists