🧠 Monoamine Hypothesis foundation

  • Core premise: depression linked to functional deficiency of monoamine neurotransmitters
    • Norepinephrine (NE)
    • Serotonin (5‑HT)
    • Dopamine (DA)
  • Key evidence: reserpine depletes monoamine stores & induces depressive symptoms
  • Acute drug effects: reuptake inhibition raises synaptic monoamine levels within hours
  • Clinical lag: therapeutic benefit typically requires 2–4 weeks of continuous treatment
    • Suggests downstream adaptive changes (receptor downregulation, neuroplasticity) are critical
  • Limitations of the hypothesis
    • Does not fully explain delayed onset
    • Does not account for all subtypes of depression
    • Other pathways (glutamate, BDNF, HPA axis) also contribute

💊 SSRIs first‑line

Representative agents
  • Fluoxetine
  • Sertraline
  • Paroxetine
  • Citalopram / Escitalopram
  • Fluvoxamine
Mechanism
  • Selectively block the serotonin transporter (SERT)
  • Inhibit presynaptic 5‑HT reuptake → increased synaptic serotonin
  • Minimal effect on NE or DA reuptake at therapeutic doses
Clinical uses
  • Major depressive disorder (MDD)
  • Obsessive‑compulsive disorder (OCD)
  • Generalized anxiety disorder (GAD) & panic disorder
  • Bulimia nervosa
  • Premenstrual dysphoric disorder (PMDD)
  • Post‑traumatic stress disorder (PTSD)
Adverse effects
  • Gastrointestinal: nausea, diarrhea, anorexia
  • Neuropsychiatric: anxiety, agitation, insomnia, bruxism
  • Sexual dysfunction: decreased libido, anorgasmia, erectile dysfunction
  • Weight changes: initial weight loss; long‑term weight gain possible
  • SIADH → hyponatremia (particularly in elderly)
  • QT prolongation (especially citalopram at higher doses)
  • Serotonin syndrome — potentially life‑threatening
  • Clinical triad: altered mental status, autonomic instability, neuromuscular excitation
  • Key triggers: SSRI + MAOI, SSRI + TCA, SSRI + meperidine, or overdose
  • Management: discontinue offending agents, supportive care, cyproheptadine (antidote)
Drug interactions
  • Cytochrome P450 inhibition (especially fluoxetine, fluvoxamine, paroxetine)
    • ↑ levels of benzodiazepines, TCAs, antipsychotics, warfarin
  • Citalopram/escitalopram have lower CYP interaction potential
  • Avoid concurrent use with MAOIs (washout period required)
  • High‑yield: SSRIs are first‑line for most depressive and anxiety disorders due to favorable safety profile
  • Discontinuation syndrome: fluvoxamine/paroxetine have shorter half‑lives → higher risk

🔬 TCAs older class

Representative agents
  • Amitriptyline
  • Imipramine
  • Clomipramine
  • Nortriptyline (secondary amine)
  • Desipramine
Mechanism
  • Non‑selective blockade of NE and 5‑HT reuptake transporters
  • Also block: muscarinic (M₁), histaminergic (H₁), and α₁‑adrenergic receptors
  • These off‑target actions account for many adverse effects
Clinical uses
  • Major depressive disorder
  • Neuropathic pain (e.g., diabetic neuropathy, postherpetic neuralgia)
  • Fibromyalgia
  • Prophylaxis of migraine
  • Nocturnal enuresis (imipramine)
  • OCD (clomipramine is especially effective)
Adverse effects
  • Anticholinergic: dry mouth, constipation, urinary retention, blurred vision, confusion
  • α₁‑blockade: orthostatic hypotension, reflex tachycardia
  • H₁‑blockade: sedation, weight gain
  • Cardiac: conduction delay (QRS widening), arrhythmias
  • Seizure threshold lowered (especially with overdose)
  • Overdose toxicity triad: coma, seizures, cardiotoxicity
  • Cardiotoxicity manifests as wide QRS, ventricular arrhythmias, hypotension
  • Treatment: sodium bicarbonate for QRS widening; avoid physostigmine
Drug interactions
  • MAOI co‑administration: hypertensive crisis or serotonin syndrome (avoid)
  • SSRI co‑administration: ↑ TCA levels (CYP inhibition) → toxicity risk
  • May antagonize antihypertensive effects of clonidine (α₂ agonist)
  • Additive anticholinergic effects with other anticholinergic agents
  • High‑yield: TCAs are highly effective but limited by side effects and overdose lethality
  • Nortriptyline and desipramine have fewer anticholinergic effects

⚡ SNRIs dual reuptake

Representative agents
  • Venlafaxine
  • Desvenlafaxine
  • Duloxetine
Mechanism
  • Inhibit both SERT and NET (norepinephrine transporter)
  • Dose‑dependent: at low doses primarily serotonergic; at higher doses noradrenergic effects emerge
  • Duloxetine has balanced inhibition at therapeutic doses
Clinical uses
  • Major depressive disorder
  • Generalized anxiety disorder (GAD)
  • Neuropathic pain (duloxetine specifically approved)
  • Chronic musculoskeletal pain
  • Diabetic peripheral neuropathy (duloxetine)
Adverse effects
  • Nausea, anorexia, dry mouth
  • Somnolence or insomnia
  • Dose‑dependent hypertension (venlafaxine)
  • SIADH → hyponatremia
  • Duloxetine: hepatotoxicity (monitor LFTs)
  • Sexual dysfunction (less than SSRIs but still present)
  • Discontinuation syndrome (especially venlafaxine due to short half‑life)
  • Serotonin syndrome risk with MAOIs, TCAs, meperidine, or other serotonergic agents
  • Hypertensive crisis with MAOI combination
  • High‑yield: SNRIs are useful when SSRIs are inadequate, especially with comorbid pain
  • Duloxetine is the only SNRI approved for diabetic neuropathy and fibromyalgia

⚠️ MAOIs last‑line

Representative agents
  • Phenelzine
  • Tranylcypromine
  • Isocarboxazid
  • Selegiline (selective MAO‑B, used in Parkinson's)
Mechanism
  • Irreversible inhibition of monoamine oxidase (MAO‑A and MAO‑B)
  • MAO‑A: metabolizes 5‑HT, NE, DA; MAO‑B: metabolizes DA, tyramine
  • Inhibition prevents intracellular degradation → ↑ monoamine stores
  • Irreversible binding → recovery requires new enzyme synthesis (weeks)
Clinical uses
  • Atypical depression (hypersomnia, hyperphagia, mood reactivity)
  • Treatment‑resistant depression
  • Social anxiety disorder
  • Panic disorder
Adverse effects
  • Orthostatic hypotension
  • Weight gain
  • Insomnia
  • Peripheral edema
  • Hepatotoxicity (especially phenelzine)
  • Hypertensive crisis — tyramine‑rich foods (aged cheese, cured meats, fermented products)
  • Tyramine causes massive NE release → severe hypertension, headache, arrhythmia, stroke
  • Management: phentolamine or nifedipine for acute hypertensive crisis
  • Serotonin syndrome — avoid SSRIs, TCAs, meperidine, dextromethorphan
  • Requires 2‑week washout when switching from MAOI to other antidepressants
  • High‑yield: MAOIs are effective but rarely first‑line due to dietary restrictions and interactions
  • Selegiline transdermal patch at low dose may avoid dietary tyramine restrictions

📌 Other Antidepressants atypical

Bupropion
  • Mechanism: inhibits DA and NE reuptake (weakly); no significant 5‑HT effect
  • Uses: MDD, seasonal affective disorder, smoking cessation (Zyban)
  • Advantage: low sexual dysfunction risk; less weight gain
  • Side effects: insomnia, anxiety, dry mouth, sweating
  • Contraindication: seizure disorder, eating disorders (lowers seizure threshold)
Mirtazapine
  • Mechanism: α₂‑adrenergic antagonist → ↑ NE and 5‑HT release
  • Potent H₁ antagonist → strong sedation
  • 5‑HT₂ and 5‑HT₃ antagonism reduces sexual dysfunction and GI side effects
  • Side effects: weight gain, increased appetite, somnolence, dizziness
  • Useful in depression with insomnia and poor appetite
Trazodone
  • Mechanism: 5‑HT₂ antagonism + weak 5‑HT reuptake inhibition
  • Commonly used at low doses for insomnia (off‑label)
  • Side effects: sedation, orthostatic hypotension, nausea
  • Notable: priapism (rare but serious; requires prompt treatment)
  • Cardiac: QT prolongation, arrhythmias (especially in overdose)
Vilazodone & Vortioxetine
  • Vilazodone: SSRI + 5‑HT₁A partial agonist
  • Vortioxetine: SSRI + 5‑HT₁A agonist + 5‑HT₃/5‑HT₇ antagonist
  • Both have lower sexual dysfunction rates than SSRIs
  • Side effects: nausea, headache, diarrhea
  • Clinical pearl: bupropion or mirtazapine are excellent alternatives when SSRIs cause sexual dysfunction
  • Mirtazapine + SSRI ("California rocket fuel") can be effective for refractory depression

⚖️ Lithium mood stabilizer

Overview
  • Gold standard for bipolar disorder maintenance
  • Reduces manic episodes and prevents depressive recurrences
  • Also has antisuicidal properties
  • Narrow therapeutic index: 0.6–1.2 mEq/L (acute mania); 0.6–0.8 mEq/L (maintenance)
Mechanism
  • Blocks inositol monophosphatase → depletes inositol → reduces PIP₂ recycling
  • Modulates second‑messenger systems (↓ cAMP, ↓ PKC activity)
  • Alters neurotransmitter release and receptor sensitivity
  • Neuroprotective effects via BDNF upregulation and inhibition of GSK‑3β
Adverse effects
  • Neurological: fine tremor, ataxia, dysarthria, confusion (correlate with serum levels)
  • Endocrine: hypothyroidism (goiter, ↓ T₄, ↑ TSH)
  • Renal: nephrogenic diabetes insipidus (polyuria, polydipsia)
  • GI: nausea, diarrhea, weight gain
  • Cardiac: ECG changes (T‑wave flattening/inversion)
  • Dermatologic: acne, psoriasis exacerbation
  • Teratogenicity: Ebstein anomaly — congenital tricuspid valve malformation
  • Risk during first trimester; avoid if possible; use alternative mood stabilizers in pregnancy
  • Lithium is contraindicated in first trimester when alternatives exist
Drug interactions & clearance
  • Eliminated unchanged via kidneys; 95% of clearance is renal
  • Drugs that reduce GFR or increase Na⁺ reabsorption ↓ lithium clearance → ↑ toxicity risk
    • NSAIDs (especially indomethacin)
    • ACE inhibitors & ARBs
    • Thiazide diuretics (loop diuretics have less effect)
  • Monitoring: serum lithium levels, renal function, thyroid function, ECG
  • High‑yield: lithium toxicity signs: coarse tremor, ataxia, confusion, seizures, coma
  • Management of toxicity: stop drug, IV fluids, hemodialysis in severe cases
  • Other bipolar agents: valproate, carbamazepine, lamotrigine, atypical antipsychotics

🎯 ADHD Agents stimulants & non‑stimulants

Methylphenidate
  • Mechanism: blocks DA and NE reuptake via DAT and NET
  • Available in immediate‑release and extended‑release formulations
  • First‑line for ADHD in children and adults
  • Side effects: insomnia, decreased appetite, weight loss, headache, jitteriness
  • Cardiovascular: ↑ HR, ↑ BP (monitor in patients with pre‑existing conditions)
  • Contraindications: glaucoma, severe anxiety, tics, MAOI use
Amphetamine salts
  • Mechanism: reverses DAT/NET → ↑ release of DA and NE; also inhibits reuptake
  • Includes: dextroamphetamine, lisdexamfetamine (prodrug), mixed amphetamine salts
  • Similar efficacy to methylphenidate
  • Side effects: insomnia, decreased appetite, agitation, cardiovascular effects
  • Higher abuse potential (schedule II controlled substance)
Atomoxetine
  • Mechanism: selective norepinephrine reuptake inhibitor (NET)
  • Non‑stimulant; schedule IV (lower abuse potential)
  • Onset: 1–2 weeks for therapeutic effect (unlike stimulants which work within hours)
  • Side effects: insomnia, fatigue, dry mouth, nausea, decreased appetite
  • Black box warning: increased risk of suicidal ideation in children/adolescents
  • Hepatotoxicity (rare but monitor LFTs)
  • Contraindications: MAOI use, narrow‑angle glaucoma
Other agents
  • Guanfacine & clonidine: α₂‑adrenergic agonists; used as adjuncts or in children with tics
  • Viloxazine: selective NE reuptake inhibitor; recently approved for ADHD
  • High‑yield: stimulants (methylphenidate, amphetamines) are first‑line; atomoxetine is alternative when stimulants are contraindicated or not tolerated
  • All ADHD medications require cardiovascular monitoring and growth assessment in children
Comparison of ADHD agents
Agent Mechanism Onset Abuse potential Key side effect
Methylphenidate DA/NE reuptake inhibition Hours Schedule II Insomnia, appetite suppression
Amphetamines DA/NE release + reuptake inhibition Hours Schedule II Agitation, cardiovascular
Atomoxetine NE reuptake inhibition 1–2 weeks Schedule IV Suicidal ideation (black box)
Guanfacine α₂‑agonist Weeks Not controlled Sedation, hypotension