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// ═══════════════════════════════════════════════════════════════════════════
// SLIDE 1: Title
// ═══════════════════════════════════════════════════════════════════════════
titleSlide("SSRIs: Selective Serotonin\nReuptake Inhibitors", "History • Mechanisms • Kinetics • Indications • Guidelines • Individual Drugs • Toxicity • Recent Advances");

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 1: HISTORY
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("History & Discovery", "01");

contentSlide("History of SSRIs", [
  { text:"1950s–60s: Monoamine Hypothesis of Depression", bold:true },
  { text:"Schildkraut (1965): proposed NE deficiency; Coppen (1967): proposed 5-HT deficiency as basis for depression", sub:true },
  { text:"1970s: Zimeldine — First SSRI", bold:true },
  { text:"Developed by Arvid Carlsson (Nobel Prize 2000); withdrawn 1983 due to Guillain-Barré syndrome", sub:true },
  { text:"1974: Fluoxetine Synthesized (Eli Lilly)", bold:true },
  { text:"Bryan Molloy & Klaus Schmiegel; approved FDA 1987 as Prozac — the 'blockbuster' antidepressant", sub:true },
  { text:"1990s–2000s: Expansion of SSRIs", bold:true },
  { text:"Fluvoxamine (1983 Europe), Paroxetine (1992), Sertraline (1991), Citalopram (1998), Escitalopram (2002)", sub:true },
  { text:"2000s–2020s: SSRI Revolution", bold:true },
  { text:"Most prescribed psychiatric drugs globally; over 13% of US adults use antidepressants; SSRIs surpassed TCAs as first-line therapy due to superior safety profile", sub:true },
], { fs:15 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 2: PSYCHOPHARMACOLOGY
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Psychopharmacology & Mechanism", "02");

contentSlide("Core Mechanism of Action", [
  { text:"Primary Action: SERT (Serotonin Transporter) Inhibition", bold:true },
  { text:"All 6 SSRIs share potent, selective blockade of the serotonin reuptake pump (SERT)", sub:true },
  { text:"Phase 1: Immediate SERT Blockade", bold:true },
  { text:"Increased synaptic 5-HT at somatodendritic autoreceptors (5-HT1A); negative feedback inhibits neuron firing — explains delayed onset", sub:true },
  { text:"Phase 2: Autoreceptor Desensitization (2–4 weeks)", bold:true },
  { text:"Sustained 5-HT elevation causes 5-HT1A somatodendritic autoreceptors to downregulate/desensitize → firing disinhibited", sub:true },
  { text:"Phase 3: Increased Axonal 5-HT Release", bold:true },
  { text:"With impulse flow restored, 5-HT levels rise at axon terminals → postsynaptic receptor activation", sub:true },
  { text:"Phase 4: Postsynaptic Receptor Adaptation + BDNF Upregulation", bold:true },
  { text:"Postsynaptic 5-HT receptors desensitize; BDNF increases → neuroplasticity, hippocampal neurogenesis, synaptic remodeling", sub:true },
], { fs:15 });

contentSlide("Why the Delay? — Therapeutic Onset", [
  "The 2–4 week lag to antidepressant effect is explained by the multi-step receptor adaptation sequence",
  "Immediate SERT blockade raises perisomatic (somatodendritic) 5-HT first, activating 5-HT1A autoreceptors that REDUCE neuron firing",
  "Only after autoreceptor desensitization does axonal 5-HT rise and therapeutic neuroplastic changes begin",
  "BDNF (Brain-Derived Neurotrophic Factor) upregulation and hippocampal neurogenesis are downstream effectors of antidepressant action",
  "Serotonin hypothesis of depression: 5-HT deficiency → upregulated postsynaptic receptors → emotional dysregulation",
  "Neurotrophic hypothesis: Chronic stress reduces BDNF → dendritic atrophy; SSRIs reverse this via 5-HT/cAMP/CREB pathway",
  "Neuroinflammatory model (recent): SSRIs may reduce IL-6, TNF-α, and microglial activation",
], { fs:16 });

contentSlide("Serotonin Receptor Pharmacodynamics", [
  { text:"5-HT1A (autoreceptors, hippocampus, raphe)", bold:true },
  { text:"Desensitization required for antidepressant onset; also mediates anxiolysis (buspirone partial agonist here)", sub:true },
  { text:"5-HT2A", bold:true },
  { text:"Blockade → anxiolytic, antipsychotic, sleep-promoting effects; fluoxetine notable 5-HT2C antagonist", sub:true },
  { text:"5-HT2C", bold:true },
  { text:"Fluoxetine 5-HT2C antagonism → weight loss, potential antidepressant/anti-binge effects", sub:true },
  { text:"5-HT3", bold:true },
  { text:"Activation → GI motility, nausea (explains GI side effects especially early); ondansetron blocks this", sub:true },
  { text:"5-HT4", bold:true },
  { text:"GI prokinetic, possibly cognition-related", sub:true },
  { text:"σ1 Receptor (Fluvoxamine)", bold:true },
  { text:"Fluvoxamine's unique σ1 binding → possible anti-anxiety, neuroprotective, and COVID-19 proposed benefits", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 3: PHARMACOKINETICS
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Pharmacokinetics", "03");

contentSlide("Pharmacokinetics Overview", [
  { text:"Absorption", bold:true },
  { text:"All SSRIs: good oral bioavailability (generally >50%); food has minimal effect; paroxetine CR: improved tolerability", sub:true },
  { text:"Distribution", bold:true },
  { text:"High lipophilicity → large Vd (large volume of distribution); extensive CNS penetration; high plasma protein binding (>94%)", sub:true },
  { text:"Metabolism", bold:true },
  { text:"All hepatic, primarily CYP450 system; significant inter-individual variation based on CYP2D6 polymorphisms", sub:true },
  { text:"Half-Lives (clinically critical)", bold:true },
  { text:"Fluoxetine: 1–4 days (active metabolite norfluoxetine: 4–16 days) — longest, self-tapering", sub:true },
  { text:"Paroxetine: 20–24 hrs — shortest, highest discontinuation risk", sub:true },
  { text:"Sertraline: 26 hrs; Citalopram: 35 hrs; Escitalopram: 27–32 hrs; Fluvoxamine: 15–20 hrs", sub:true },
  { text:"Excretion", bold:true },
  { text:"Primarily renal (glucuronide conjugates); dose adjustment needed in severe hepatic/renal impairment", sub:true },
], { fs:14 });

contentSlide("CYP450 Drug Interactions", [
  { text:"Fluoxetine & Paroxetine — Potent CYP2D6 Inhibitors", bold:true },
  { text:"↑ levels of: TCAs, antipsychotics (haloperidol, risperidone), opioids (codeine → morphine conversion blocked), beta-blockers, tamoxifen (↓ efficacy)", sub:true },
  { text:"Fluoxetine — CYP3A4, CYP2C9, CYP2C19 inhibitor", bold:true },
  { text:"↑ levels of: benzodiazepines, warfarin, phenytoin; fluoxetine + MAOI → serotonin syndrome (washout 5 weeks required)", sub:true },
  { text:"Fluvoxamine — Potent CYP1A2 & CYP3A4 inhibitor", bold:true },
  { text:"↑ levels of: clozapine, olanzapine, theophylline, warfarin, cyclosporine, caffeine", sub:true },
  { text:"Sertraline, Citalopram, Escitalopram — Minimal CYP inhibition", bold:true },
  { text:"Safest for polypharmacy; escitalopram mildly inhibits CYP2D6 at high doses", sub:true },
  { text:"P-glycoprotein: most SSRIs are P-gp substrates — interactions with P-gp inhibitors (ritonavir)", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 4: INDICATIONS
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Indications & Guidelines", "04");

contentSlide("FDA-Approved Indications", [
  { text:"Major Depressive Disorder (MDD)", bold:true },
  { text:"All 6 SSRIs; first-line pharmacotherapy; superior safety/tolerability vs TCAs/MAOIs", sub:true },
  { text:"Anxiety Disorders", bold:true },
  { text:"GAD: escitalopram, paroxetine, sertraline; Panic Disorder: fluoxetine, paroxetine, sertraline; Social Anxiety: sertraline, paroxetine, fluvoxamine CR; PTSD: sertraline, paroxetine", sub:true },
  { text:"OCD", bold:true },
  { text:"Highest effective doses; fluoxetine, fluvoxamine, sertraline, paroxetine; 8–12 weeks for response", sub:true },
  { text:"PMDD (Premenstrual Dysphoric Disorder)", bold:true },
  { text:"Fluoxetine, sertraline, paroxetine; can be used continuously or luteal-phase only", sub:true },
  { text:"Bulimia Nervosa", bold:true },
  { text:"Fluoxetine 60 mg/day — only FDA-approved drug for bulimia", sub:true },
  { text:"Pediatric Use", bold:true },
  { text:"MDD in children ≥8: fluoxetine; MDD in adolescents: escitalopram; OCD in children ≥6: fluvoxamine, sertraline", sub:true },
], { fs:14 });

contentSlide("Off-Label Indications", [
  "Binge Eating Disorder (fluoxetine, sertraline)",
  "Body Dysmorphic Disorder",
  "Fibromyalgia (pain modulation via serotonergic pathways)",
  "Premature Ejaculation (paroxetine off-label; dapoxetine approved in some countries)",
  "Menopausal Vasomotor Symptoms (paroxetine 7.5 mg = Brisdelle, FDA-approved for hot flashes)",
  "Raynaud Phenomenon",
  "Autism Spectrum Disorder (repetitive behaviors — limited evidence)",
  "Irritable Bowel Syndrome (low-dose sertraline/fluoxetine — limited evidence)",
  "Neuropathic Pain (mixed evidence)",
  "Tourette's (augmentation)",
  "Trichotillomania / excoriation disorder",
  "Hypochondriasis / health anxiety",
], { fs:15 });

contentSlide("Treatment Guidelines", [
  { text:"APA (American Psychiatric Association)", bold:true },
  { text:"SSRIs = first-line for MDD, GAD, PD, SAD, PTSD, OCD; duration: 6–12 months after remission for first episode; >3 episodes or severe: indefinite maintenance", sub:true },
  { text:"NICE (UK)", bold:true },
  { text:"First-line: sertraline (best evidence/cost); treat for ≥6 months after remission; fluoxetine for younger patients and those at risk of discontinuation", sub:true },
  { text:"BAP (British Association for Psychopharmacology)", bold:true },
  { text:"Recommends 6–9 months maintenance; hyperbolic tapering for discontinuation", sub:true },
  { text:"WHO Essential Medicines", bold:true },
  { text:"Fluoxetine listed on WHO Model List of Essential Medicines", sub:true },
  { text:"CANMAT 2023 Guidelines", bold:true },
  { text:"SSRIs/SNRIs first-line for MDD; escitalopram and sertraline have best evidence for efficacy + tolerability balance", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 5: TITRATION & SWITCHING
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Dosing, Titration & Switching", "05");

contentSlide("Dosing Guide — All 6 SSRIs", [
  { text:"Fluoxetine (Prozac)", bold:true },
  { text:"Start: 10–20 mg/day → Target: 20 mg/day → Max: 80 mg/day (OCD); Bulimia: 60 mg/day", sub:true },
  { text:"Sertraline (Zoloft)", bold:true },
  { text:"Start: 25–50 mg/day → Target: 100 mg/day → Max: 200 mg/day; panic: start 25 mg", sub:true },
  { text:"Paroxetine (Paxil/Seroxat)", bold:true },
  { text:"Start: 10–20 mg/day → Target: 20–40 mg/day → Max: 60 mg (OCD); CR: 12.5–75 mg; PMDD: 7.5 mg", sub:true },
  { text:"Citalopram (Celexa)", bold:true },
  { text:"Start: 20 mg/day → Target: 20–40 mg/day → Max: 40 mg (FDA 2011 QTc warning; 20 mg in elderly/hepatic impairment)", sub:true },
  { text:"Escitalopram (Lexapro/Cipralex)", bold:true },
  { text:"Start: 10 mg/day → Target: 10–20 mg/day → Max: 20 mg; 10 mg max in elderly", sub:true },
  { text:"Fluvoxamine (Luvox)", bold:true },
  { text:"Start: 50 mg/day → Target: 150–200 mg/day → Max: 300 mg; OCD primary; CR formulation for SAD", sub:true },
], { fs:14 });

contentSlide("Titration Principles", [
  "Start low, go slow — especially in anxiety disorders (paradoxical early anxiogenesis)",
  "Therapeutic trial: minimum 4–6 weeks at target dose to assess response",
  "Full response assessment: 8–12 weeks",
  "Partial responders: increase dose before switching drug",
  "Dose escalation: every 2–4 weeks, monitor tolerability",
  "OCD requires higher doses and longer trials (8–12 weeks minimum)",
  "Pediatric dosing: start at half adult dose; titrate more slowly",
  "Elderly: 'Start half, go half' — 50% starting dose, maximum lower",
  "Hepatic impairment: reduce doses; fluoxetine has active metabolite, use caution",
  "Renal impairment: generally safe at standard doses; escitalopram and sertraline preferred",
  "Pregnancy: sertraline preferred (best data); discuss risk vs benefit; neonatal adaptation syndrome with late-pregnancy use",
], { fs:15 });

contentSlide("Switching Strategies", [
  { text:"Direct Switch (immediate switch)", bold:true },
  { text:"From one SSRI to another SSRI — generally safe; start new drug same day after stopping old one; cross-titration possible", sub:true },
  { text:"Cross-Taper (preferred for most switches)", bold:true },
  { text:"Gradually taper one drug while titrating the other; reduces discontinuation syndrome and relapse risk", sub:true },
  { text:"Washout Period", bold:true },
  { text:"Required before starting MAOI: 2 weeks washout for most SSRIs; 5 WEEKS for fluoxetine (long t½)", sub:true },
  { text:"MAOI-to-SSRI: 2-week washout required (regardless of SSRI type)", sub:true },
  { text:"SSRI → TCA: Use cross-titration; monitor TCA levels (paroxetine/fluoxetine raise TCA levels via CYP2D6)", sub:true },
  { text:"SSRI → SNRI: Direct switch or cross-taper; monitor for additive serotonergic effects", sub:true },
  { text:"SSRI → Novel agents (e.g., esketamine): Usually additive; maintain SSRI during initiation of esketamine", sub:true },
  { text:"Failed SSRI trial → Another SSRI: ~50% of SSRI non-responders respond to a second SSRI (STAR*D data)", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 6: SIDE EFFECTS
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Side Effects & Tolerability", "06");

twoColSlide("Common Side Effects",
  "GI / Autonomic",
  [
    "Nausea (most common early; usually resolves in 1–2 weeks)",
    "Diarrhea, loose stools",
    "Dry mouth (paroxetine > others)",
    "Headache (early; usually transient)",
    "Sweating (especially paroxetine, venlafaxine)",
    "Appetite changes; weight gain (paroxetine > fluoxetine/sertraline)",
  ],
  "CNS",
  [
    "Initial anxiogenesis (first 1–2 weeks)",
    "Insomnia or somnolence (drug-dependent)",
    "Tremor, jitteriness",
    "Sedation: paroxetine, fluvoxamine > fluoxetine",
    "Activation: fluoxetine > others",
    "Cognitive effects: generally mild",
  ]
);

twoColSlide("Sexual Side Effects (Most Problematic)",
  "Prevalence & Mechanism",
  [
    "Occurs in 30–80% of patients — severely underreported",
    "All phases affected: desire, arousal, orgasm",
    "5-HT2A/2C stimulation → ↓ DA/NE in mesolimbic circuits → anhedonia, anorgasmia",
    "Most common: delayed orgasm/anorgasmia, decreased libido",
    "Sexual side effects rarely remit spontaneously",
    "Post-SSRI Sexual Dysfunction (PSSD): persists after discontinuation — emerging concern",
  ],
  "Management Strategies",
  [
    "Wait 2–4 weeks (often improves)",
    "Dose reduction (if clinically feasible)",
    "Switch to: bupropion, mirtazapine, vortioxetine (lower sexual SE rates)",
    "Drug holidays (short-term; not recommended for paroxetine)",
    "Add-on: bupropion, buspirone, sildenafil/tadalafil",
    "Add mirtazapine (5-HT3/2 antagonism offsets SSRI sexual SE)",
    "PSSD: no proven treatment; report to pharmacovigilance",
  ]
);

contentSlide("Other Important Side Effects", [
  { text:"Weight Gain", bold:true },
  { text:"Paroxetine > sertraline, citalopram > fluoxetine (may cause weight LOSS initially); mechanism: H1, 5-HT2C effects", sub:true },
  { text:"Hyponatremia (SIADH)", bold:true },
  { text:"Elderly at greatest risk; monitor Na+ levels; all SSRIs implicated; usually within first 2–8 weeks", sub:true },
  { text:"Bleeding Risk", bold:true },
  { text:"SSRIs inhibit platelet serotonin uptake → reduced platelet aggregation; increased GI bleeding especially with NSAIDs/aspirin; consider PPI co-prescription", sub:true },
  { text:"QTc Prolongation", bold:true },
  { text:"Citalopram (20 mg max in elderly, hepatic impairment); escitalopram (smaller risk); baseline ECG in high-risk patients", sub:true },
  { text:"Insomnia/Sedation", bold:true },
  { text:"Fluoxetine → activating → insomnia; paroxetine, fluvoxamine → sedating → morning dosing vs bedtime dosing", sub:true },
  { text:"Serotonin Syndrome (see toxicity section)", bold:true },
  { text:"Rarely from SSRI alone; risk increases with combinations (MAOI, tramadol, linezolid, triptans)", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 7: INDIVIDUAL DRUGS
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Individual Drug Profiles", "07");

drugSlide(
  "Fluoxetine (Prozac®)",
  "SERT inhibition + 5-HT2C antagonist + mild NRI (norepinephrine reuptake inhibition); 5-HT2C antagonism contributes to antidepressant, anti-binge, and possible weight-loss effects",
  "Start 10–20 mg/day → Target 20 mg → Max 80 mg (OCD), 60 mg (Bulimia). Weekly formulation (90 mg) available for maintenance.",
  "MDD (adults & ≥8 yrs), OCD (≥7 yrs), Bulimia Nervosa, Panic Disorder, PMDD, Depressive episodes in bipolar (Symbyax with olanzapine)",
  "Nausea, insomnia/activation, headache, weight neutral/loss initially; sexual dysfunction; rarely QTc (low risk)",
  "Longest t½ (norfluoxetine 4–16 days) → self-tapering, lowest discontinuation risk; potent CYP2D6 & 2C9/2C19 inhibitor; 5-week MAOI washout; only SSRI for bulimia and weekly formulation"
);

drugSlide(
  "Sertraline (Zoloft®)",
  "SERT inhibition (most selective); mild dopamine transporter (DAT) inhibition at high doses; minimal other receptor activity",
  "Start 25–50 mg/day → Target 100 mg → Max 200 mg/day. Panic: start 25 mg. OCD: up to 200 mg.",
  "MDD (adults & adolescents), OCD (≥6 yrs), Panic Disorder, PTSD, SAD (Social Anxiety), PMDD",
  "Nausea, diarrhea (more than others), sexual dysfunction, insomnia; weight neutral; mild activation",
  "Best overall tolerability and safety profile; preferred in pregnancy (most data); minimal CYP interactions; NICE first-line recommendation; mild DAT inhibition may add mild pro-dopaminergic effect"
);

drugSlide(
  "Paroxetine (Paxil® / Seroxat®)",
  "SERT inhibition + muscarinic anticholinergic + H1 antihistamine + NRI; most 'dirty' SSRI — most secondary receptor actions",
  "Start 10–20 mg → Target 20–40 mg → Max 60 mg (OCD). CR: 12.5–37.5 mg. PMDD: Brisdelle 7.5 mg. Elderly: max 40 mg.",
  "MDD, OCD, Panic Disorder, GAD, SAD, PTSD, PMDD; Brisdelle (7.5 mg) for vasomotor symptoms",
  "Most anticholinergic (dry mouth, constipation, blurred vision, urinary retention); weight gain; somnolence; highest sexual SE; most discontinuation syndrome risk",
  "Highest discontinuation syndrome (short t½ + no active metabolite); most weight gain; most sexual dysfunction; avoided in pregnancy (PPHN risk, cardiac defects); potent CYP2D6 inhibitor; only FDA-approved SSRI for GAD; PMDD low-dose formulation unique"
);

drugSlide(
  "Citalopram (Celexa®)",
  "SERT inhibition (racemic mixture: R+S enantiomers); R-enantiomer has antagonist hERG cardiac channel effects; S-enantiomer (escitalopram) is the active antidepressant enantiomer",
  "Start 20 mg/day → Target 20–40 mg → Max 40 mg (FDA 2011 QTc warning). Elderly/hepatic: MAX 20 mg. Check ECG if QTc concerns.",
  "MDD; off-label: OCD, panic disorder, anxiety, diabetic neuropathy",
  "Nausea, dry mouth, sedation, sexual dysfunction, sweating; QTc prolongation (dose-dependent — key safety issue)",
  "2011 FDA safety communication limiting max dose to 40 mg (20 mg in elderly/poor CYP2C19 metabolizers/hepatic impairment) due to QTc prolongation; avoid with other QTc-prolonging drugs; racemic mix means less pure than escitalopram"
);

drugSlide(
  "Escitalopram (Lexapro® / Cipralex®)",
  "Pure S-enantiomer of citalopram — binds SERT with higher affinity and selectivity; allosteric SERT binding site adds to potency; most selective SSRI with fewest off-target actions",
  "Start 10 mg/day → Target 10–20 mg → Max 20 mg/day. Elderly: Max 10 mg/day. Adolescents (12–17): 10 mg for MDD.",
  "MDD (adults + adolescents 12–17), GAD; off-label: OCD, SAD, panic disorder, PTSD",
  "Best tolerated SSRI; nausea (mild), sexual dysfunction, headache; mild QTc prolongation (less than citalopram); minimal CYP interactions",
  "Quintessential SSRI — highest selectivity, fewest drug interactions, best tolerability; meta-analyses show escitalopram among top for MDD efficacy+tolerability (Cipriani 2018 Lancet); allosteric site binding explains enhanced potency at lower doses vs citalopram"
);

drugSlide(
  "Fluvoxamine (Luvox®)",
  "SERT inhibition + unique sigma-1 (σ1) receptor agonist; σ1 binding → possible anxiolytic, anti-inflammatory, neuroprotective, anti-amnestic effects; melatonin receptor interactions",
  "Start 50 mg/day (single evening dose) → Target 100–300 mg/day → Max 300 mg. Doses >150 mg: split BD. CR capsules: 100–300 mg once daily.",
  "OCD (primary indication; adults & ≥8 yrs); SAD (CR formulation); off-label: MDD, PTSD, eating disorders, autism",
  "Most nausea (especially initial); somnolence; headache; sexual dysfunction; insomnia; significant drug interactions",
  "Most potent CYP1A2 + CYP3A4 inhibitor — major drug interactions (clozapine, olanzapine, warfarin, theophylline); σ1 agonism may explain unique anti-anxiety/anti-inflammatory properties; investigated for COVID-19 mortality reduction (TOGETHER trial — positive signal); lowest sexual SE compared to other SSRIs in some studies"
);

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 8: TOXICITY
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Toxicity & Overdose", "08");

contentSlide("SSRI Overdose & Toxicity", [
  { text:"Generally Safe in Overdose (compared to TCAs)", bold:true },
  { text:"Up to 30× daily dose rarely causes serious toxicity; unlike TCAs, do not cause lethal cardiac arrhythmias (except citalopram)", sub:true },
  { text:"Mild Toxicity (majority of cases)", bold:true },
  { text:"Nausea, vomiting, GI upset, somnolence, tachycardia, mild tremor, dizziness", sub:true },
  { text:"Moderate Toxicity", bold:true },
  { text:"Tachycardia, somnolence, prolonged vomiting; agitation", sub:true },
  { text:"Severe Toxicity", bold:true },
  { text:"Citalopram: QTc prolongation → torsades de pointes, dysrhythmias, seizures; severe with MAOI co-ingestion", sub:true },
  { text:"Serotonin Syndrome (most serious)", bold:true },
  { text:"Usually requires 2+ serotonergic agents (SSRI + MAOI, linezolid, tramadol, triptans, methylene blue, St. John's wort)", sub:true },
  { text:"Management", bold:true },
  { text:"Supportive care; activated charcoal if <2h; cardiac monitoring (citalopram); cyproheptadine for serotonin syndrome; benzodiazepines for agitation/seizures; ICU for severe cases", sub:true },
], { fs:14 });

contentSlide("Serotonin Syndrome", [
  { text:"Clinical Triad (Hunter Criteria)", bold:true },
  { text:"1. Altered mental status (agitation, confusion, anxiety) | 2. Autonomic instability (tachycardia, hyperthermia, diaphoresis, labile BP) | 3. Neuromuscular abnormalities (tremor, myoclonus, hyperreflexia, clonus — KEY diagnostic feature)", sub:true },
  { text:"Common Precipitants", bold:true },
  { text:"SSRI + MAOI (most dangerous — never combine); SSRI + linezolid; SSRI + tramadol; SSRI + triptans (5-HT1B/D agonists); SSRI + dextromethorphan; SSRI + fentanyl/meperidine; SSRI + St John's Wort; SSRI + methylene blue; SSRI + metoclopramide", sub:true },
  { text:"Hunter Serotonin Toxicity Criteria (diagnosis)", bold:true },
  { text:"Serotonergic agent + (clonus with agitation/diaphoresis) OR (ocular clonus with agitation/diaphoresis) OR (tremor + hyperreflexia) OR (hypertonia + temp >38°C + ocular/inducible clonus)", sub:true },
  { text:"Management", bold:true },
  { text:"Discontinue all serotonergic agents; supportive care (fluids, cooling); benzodiazepines (1st line for agitation/rigidity); cyproheptadine (5-HT2A antagonist, 12 mg then 2 mg q2h up to 32 mg); severe: ICU, intubation if necessary", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 9: DISCONTINUATION
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Discontinuation Syndrome", "09");

contentSlide("SSRI Discontinuation Syndrome", [
  { text:"Onset: 1–3 days after stopping or significant dose reduction", bold:true },
  { text:"Symptoms — FINISH Mnemonic", bold:true },
  { text:"F — Flu-like symptoms (myalgia, fatigue, sweating, chills, headache)", sub:true },
  { text:"I — Insomnia (vivid dreams, disturbed sleep)", sub:true },
  { text:"N — Nausea, vomiting, diarrhea", sub:true },
  { text:"I — Imbalance (dizziness, ataxia, vertigo)", sub:true },
  { text:"S — Sensory disturbances (BRAIN ZAPS — paresthesias, electric shock sensations)", sub:true },
  { text:"H — Hyperarousal (anxiety, agitation, irritability, crying spells)", sub:true },
  { text:"High Risk Drugs", bold:true },
  { text:"Paroxetine > venlafaxine > fluvoxamine (short t½, no active metabolite)", sub:true },
  { text:"Low Risk", bold:true },
  { text:"Fluoxetine (t½ 4–16 days of active metabolite norfluoxetine — effectively self-tapers)", sub:true },
], { fs:14 });

contentSlide("Tapering & Management of Discontinuation", [
  { text:"Never abrupt stop — always taper (except fluoxetine which may allow shorter taper)", bold:true },
  "Hyperbolic Tapering (Horowitz & Taylor, Lancet Psychiatry 2019): preferred approach",
  "Standard taper: reduce by 25% every 2–4 weeks",
  "Slow taper (Maudsley guidelines): reduce by 10% of current dose every 4 weeks",
  "If severe symptoms on taper: return to previous dose and taper more slowly",
  "Fluoxetine switch: Switch to fluoxetine 10–20 mg (long t½) then taper fluoxetine slowly — useful for severe paroxetine discontinuation",
  "Duration of taper: proportional to duration of treatment and dose",
  { text:"Distinguish from relapse:", bold:true },
  { text:"Discontinuation: onset days 1–3 after stopping, resolves in 1–2 weeks with reinstatement; Relapse: onset weeks after stopping, may require reinstatement of treatment", sub:true },
  "Brain zaps: highly distressing; may persist for weeks-months (PSSD); management: reinstating drug briefly, gabapentin, omega-3 fatty acids (limited evidence)",
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 10: CONTRAINDICATIONS
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Contraindications & Special Populations", "10");

contentSlide("Contraindications", [
  { text:"Absolute Contraindications", bold:true },
  { text:"MAOIs (irreversible: phenelzine, tranylcypromine, isocarboxazid): risk of fatal serotonin syndrome; require 14-day washout (both directions); 5-week washout for fluoxetine before MAOI", sub:true },
  { text:"Methylene blue (MAO inhibitor): serotonin syndrome risk — avoid SSRIs peri-operatively if methylene blue planned", sub:true },
  { text:"Linezolid (antibacterial MAOI): contraindicated combination — serotonin syndrome; if urgent linezolid needed: stop SSRI", sub:true },
  { text:"Pimozide (QTc risk) + citalopram/escitalopram", sub:true },
  { text:"Relative Contraindications / Cautions", bold:true },
  { text:"Bipolar disorder (without mood stabilizer): risk of switching to mania/rapid cycling; use with caution — always add mood stabilizer first", sub:true },
  { text:"Bleeding risk: NSAIDs, anticoagulants, antiplatelet agents — consider GI protection (PPI)", sub:true },
  { text:"QTc >500 ms: avoid citalopram/escitalopram", sub:true },
  { text:"Seizure disorder: all SSRIs lower seizure threshold slightly; use lowest effective dose", sub:true },
  { text:"Angle-closure glaucoma: SSRIs can precipitate acute angle closure (mydriasis); paroxetine highest risk due to anticholinergic effects", sub:true },
  { text:"Hyponatremia (Na <130): risk of SIADH; monitor closely in elderly", sub:true },
], { fs:13 });

contentSlide("Special Populations", [
  { text:"Pregnancy", bold:true },
  { text:"Sertraline preferred (best safety data); paroxetine: avoid in 1st trimester (PPHN, cardiac septum defects — FDA category D); fluoxetine also commonly used; neonatal adaptation syndrome (NAS): irritability, respiratory distress — warn parents", sub:true },
  { text:"Breastfeeding", bold:true },
  { text:"Sertraline: very low milk transfer (preferred); paroxetine: acceptable; fluoxetine: higher milk transfer; avoid citalopram (higher milk levels)", sub:true },
  { text:"Elderly", bold:true },
  { text:"Use 50% starting dose; avoid paroxetine (anticholinergic, falls); avoid citalopram >20 mg/day; sertraline or escitalopram preferred; monitor Na+, falls risk, QTc", sub:true },
  { text:"Children & Adolescents", bold:true },
  { text:"FDA black box warning: increased suicidal ideation in <25 years — monitor closely first 4 weeks; fluoxetine: only FDA-approved for MDD in children ≥8; escitalopram: MDD ≥12 yrs", sub:true },
  { text:"Renal/Hepatic Impairment", bold:true },
  { text:"Hepatic: reduce doses, avoid in severe hepatic failure; sertraline and escitalopram most studied; renal: generally dose reduction only in severe CKD", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 11: EVIDENCE-BASED TRIALS
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Evidence-Based Trials", "11");

contentSlide("Landmark Clinical Trials", [
  { text:"STAR*D (2006) — N=3,671", bold:true },
  { text:"Sequential treatment for MDD; citalopram step 1: ~28% remission; each subsequent step: further ~20%; highlights treatment-resistant depression management strategy", sub:true },
  { text:"Cipriani et al. (Lancet 2018) — Network Meta-Analysis, N=116,477", bold:true },
  { text:"21 antidepressants vs placebo in MDD; escitalopram + mirtazapine = best efficacy-tolerability balance; all SSRIs superior to placebo; escitalopram/sertraline recommended as first-line", sub:true },
  { text:"TADS (2004) — Adolescent MDD", bold:true },
  { text:"Fluoxetine + CBT > fluoxetine alone > CBT alone > placebo; combination therapy gold standard for adolescent MDD", sub:true },
  { text:"Davidson et al. (2001) — Paroxetine CR in Social Anxiety", bold:true },
  { text:"Paroxetine CR demonstrated significant efficacy; established SSRIs as first-line for SAD", sub:true },
  { text:"OCD Collaborative Study Group — Fluvoxamine/Sertraline/Fluoxetine", bold:true },
  { text:"Multiple RCTs established SSRIs as first-line OCD treatment; response rates 40–60%; superior to placebo; higher doses required", sub:true },
], { fs:14 });

contentSlide("More Evidence & Meta-Analyses", [
  { text:"Cochrane Review: SSRIs for PTSD (2014 updated)", bold:true },
  { text:"Sertraline and paroxetine show consistent efficacy; SSRIs first-line pharmacotherapy for PTSD", sub:true },
  { text:"Guaiana et al. Cochrane (2023) — SSRIs for Panic Disorder", bold:true },
  { text:"Network meta-analysis: SSRIs effective for panic disorder; sertraline, paroxetine, fluoxetine all superior to placebo", sub:true },
  { text:"Kopcalic et al. Cochrane (2025) — SSRIs for GAD", bold:true },
  { text:"Antidepressants (mostly SSRIs) superior to placebo for GAD; effect sizes modest; escitalopram and paroxetine strongest evidence", sub:true },
  { text:"Yin et al. BMC Psychiatry (2023) — Escitalopram vs other antidepressants", bold:true },
  { text:"Escitalopram superior to many comparators; confirms Cipriani 2018 findings; recommended as a benchmark SSRI", sub:true },
  { text:"Horowitz & Taylor, Lancet Psychiatry (2019)", bold:true },
  { text:"Hyperbolic dose tapering prevents SSRI discontinuation syndrome; current guidance now adopted by Maudsley prescribing guidelines", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// SECTION 12: RECENT ADVANCES
// ═══════════════════════════════════════════════════════════════════════════
sectionHeader("Recent Advances (2020–2026)", "12");

contentSlide("Recent Advances in SSRI Research", [
  { text:"Post-SSRI Sexual Dysfunction (PSSD)", bold:true },
  { text:"EMA (2019) required label update; persists months-years after stopping; possible epigenetic mechanism; no proven treatment yet; major pharmacovigilance concern", sub:true },
  { text:"Fluvoxamine & COVID-19", bold:true },
  { text:"TOGETHER trial (Brazil, 2021): fluvoxamine reduced hospitalization risk in early COVID-19 by 32%; σ1 receptor agonism + anti-inflammatory mechanism proposed; not yet standard of care", sub:true },
  { text:"Neuroinflammation Hypothesis", bold:true },
  { text:"SSRIs reduce IL-6, TNF-α, microglial activation — may explain broader benefits in inflammatory depression subtypes; implications for treatment selection", sub:true },
  { text:"Precision Pharmacotherapy / Pharmacogenomics", bold:true },
  { text:"CYP2D6/2C19 genetic testing guides SSRI selection; FDA, CPIC guidelines support gene-guided prescribing; reduces trial-and-error; commercial panels available (GeneSight, etc.)", sub:true },
  { text:"Escitalopram Allosteric Mechanism", bold:true },
  { text:"Structural studies (X-ray crystallography) revealed escitalopram binds both primary and allosteric sites of SERT → superior sustained effect vs citalopram; R-enantiomer of citalopram antagonizes S-enantiomer's allosteric binding", sub:true },
], { fs:14 });

contentSlide("Emerging Therapies & SSRI Comparisons", [
  { text:"Vortioxetine (Trintellix) — Multimodal Antidepressant", bold:true },
  { text:"SERT inhibitor + 5-HT1A agonist + 5-HT3/7/1D antagonist + 5-HT1B partial agonist; superior procognitive effects; fewer sexual side effects than SSRIs", sub:true },
  { text:"Vilazodone (Viibryd)", bold:true },
  { text:"SSRI + 5-HT1A partial agonist (SPARI); lower sexual SE; less weight gain; fewer GI effects with food", sub:true },
  { text:"Esketamine (Spravato) — 2025 Monotherapy Approval", bold:true },
  { text:"NMDA antagonist; approved January 2025 as monotherapy for treatment-resistant depression; rapid-onset (24 hrs); often combined with SSRIs in clinical practice", sub:true },
  { text:"Zuranolone (Zurzuvae)", bold:true },
  { text:"GABA-A positive allosteric modulator; first oral neurosteroid for MDD (FDA 2023); rapid-acting 2-week course; not a substitute for SSRIs in maintenance", sub:true },
  { text:"Digital Biomarkers & AI-guided SSRI Selection", bold:true },
  { text:"Machine learning models predicting SSRI response; EEG biomarkers (cordance) predicting antidepressant response; microbiome-serotonin axis research ongoing", sub:true },
], { fs:14 });

// ═══════════════════════════════════════════════════════════════════════════
// FINAL SLIDE
// ═══════════════════════════════════════════════════════════════════════════
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    "6 SSRIs — shared SERT mechanism, distinct secondary profiles",
    "Delayed onset (2–4 wks): receptor adaptation + BDNF",
    "First-line for MDD, anxiety, OCD, PTSD, PMDD, bulimia",
    "Escitalopram/sertraline: best efficacy-tolerability balance",
    "Titrate slowly, especially in anxiety; full trial 8–12 wks",
    "Key SE: sexual dysfunction, weight gain, QTc (citalopram)",
    "Taper hyperbolicly; fluoxetine self-tapers (long t½)",
    "MAOI combo → serotonin syndrome (absolute CI)",
    "PSSD, σ1 research, COVID-19 (fluvoxamine) — emerging",
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    { text:"• Stahl SM. Essential Psychopharmacology, 5th ed. Cambridge University Press, 2021\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Maudsley Prescribing Guidelines in Psychiatry, 15th ed. 2023\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Cipriani A, et al. Lancet. 2018;391(10128):1357-1366\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• STAR*D Team. Am J Psychiatry. 2006;163(11):1905-1917\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Horowitz MA & Taylor D. Lancet Psychiatry. 2019;6(6):538-546\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Guaiana G, et al. Cochrane Database Syst Rev. 2023 (PMID:38014714)\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Kopcalic K, et al. Cochrane Database Syst Rev. 2025 (PMID:39880377)\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Yin J, et al. BMC Psychiatry. 2023 (PMID:38001423)\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Kaplan & Sadock's Synopsis of Psychiatry, 12th ed.\n", options:{fontSize:12, color:C.white, breakLine:true} },
    { text:"• Lippincott Illustrated Reviews: Pharmacology, 8th ed.", options:{fontSize:12, color:C.white} },
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  sl.addText("Orris Medical Education  •  SSRIs Comprehensive Guide  •  May 2026", { x:0.3, y:6.9, w:12.7, h:0.45, fontSize:13, color:C.white, align:"center", fontFace:"Calibri" });
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