const {
  Document, Packer, Paragraph, TextRun, Table, TableRow, TableCell,
  HeadingLevel, AlignmentType, BorderStyle, WidthType, ShadingType,
  VerticalAlign, PageNumber, Header, Footer, PageBreak, TabStopType,
  TabStopPosition
} = require('docx');
const fs = require('fs');

// ─── Colour palette ─────────────────────────────────────────────────────────
const NAVY   = "1F3864";
const STEEL  = "2E74B5";
const TEAL   = "1F6B75";
const GOLD   = "C9A227";
const LTBLUE = "D6E4F0";
const LTGRN  = "D5F0E3";
const LTYEL  = "FFF8DC";
const WHITE  = "FFFFFF";
const LTGRAY = "F2F2F2";
const MIDGRAY= "D9D9D9";

// ─── Helpers ─────────────────────────────────────────────────────────────────
function heading1(text) {
  return new Paragraph({
    text,
    heading: HeadingLevel.HEADING_1,
    spacing: { before: 320, after: 160 },
    shading: { type: ShadingType.SOLID, color: NAVY, fill: NAVY },
    run: { color: WHITE, bold: true, size: 28 },
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}

function heading2(text) {
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    text,
    heading: HeadingLevel.HEADING_2,
    spacing: { before: 240, after: 120 },
    border: { bottom: { style: BorderStyle.SINGLE, size: 6, color: STEEL } },
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}

function heading3(text) {
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}

function body(text, opts = {}) {
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    spacing: { before: 80, after: 80 },
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}

function bullet(text, level = 0) {
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}

function boldBullet(label, detail) {
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}

function note(text) {
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    children: [new TextRun({ text: "Note: " + text, italics: true, size: 20, color: "555555" })],
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}

function hr() {
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    spacing: { before: 160, after: 160 },
  });
}

function pageBreak() {
  return new Paragraph({ children: [new PageBreak()] });
}

// ─── Table builder ───────────────────────────────────────────────────────────
function makeCell(text, opts = {}) {
  const { bold = false, bg = WHITE, color = "2C2C2C", width, colSpan = 1, vAlign = VerticalAlign.CENTER } = opts;
  return new TableCell({
    children: [new Paragraph({
      children: [new TextRun({ text, bold, size: opts.size || 20, color })],
      alignment: opts.align || AlignmentType.LEFT,
      spacing: { before: 60, after: 60 },
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    shading: { type: ShadingType.SOLID, color: bg, fill: bg },
    verticalAlign: vAlign,
    columnSpan: colSpan,
    width: width ? { size: width, type: WidthType.DXA } : undefined,
    margins: { top: 80, bottom: 80, left: 120, right: 120 },
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}

function headerCell(text, bg = NAVY, width) {
  return makeCell(text, { bold: true, bg, color: WHITE, size: 20, width });
}

function makeTable(rows, widths) {
  return new Table({
    width: { size: 100, type: WidthType.PERCENTAGE },
    rows: rows.map((cells, ri) => new TableRow({
      children: cells.map((c, ci) => c),
      tableHeader: ri === 0,
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      top:    { style: BorderStyle.SINGLE, size: 4, color: STEEL },
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      insideH:{ style: BorderStyle.SINGLE, size: 2, color: MIDGRAY },
      insideV:{ style: BorderStyle.SINGLE, size: 2, color: MIDGRAY },
    },
  });
}

// ─── Title page ──────────────────────────────────────────────────────────────
function makeTitlePage() {
  return [
    new Paragraph({ text: "", spacing: { before: 1200 } }),
    new Paragraph({
      alignment: AlignmentType.CENTER,
      children: [new TextRun({
        text: "AUTISM SPECTRUM DISORDER",
        bold: true, size: 48, color: NAVY, allCaps: true
      })],
      spacing: { before: 0, after: 200 },
    }),
    new Paragraph({
      alignment: AlignmentType.CENTER,
      children: [new TextRun({
        text: "Behavioral vs. Pharmacological Treatments",
        bold: true, size: 36, color: STEEL
      })],
      spacing: { before: 0, after: 200 },
    }),
    new Paragraph({
      alignment: AlignmentType.CENTER,
      children: [new TextRun({
        text: "A Comprehensive Comparison for Exam Revision",
        italics: true, size: 26, color: "555555"
      })],
      spacing: { before: 0, after: 600 },
    }),
    new Paragraph({
      alignment: AlignmentType.CENTER,
      border: {
        top: { style: BorderStyle.SINGLE, size: 8, color: GOLD },
        bottom: { style: BorderStyle.SINGLE, size: 8, color: GOLD },
      },
      shading: { type: ShadingType.SOLID, color: LTBLUE, fill: LTBLUE },
      children: [new TextRun({
        text: "Sources: Kaplan & Sadock's Synopsis of Psychiatry  |  Kaplan & Sadock's Comprehensive Textbook  |  PubMed 2024–2025",
        size: 18, italics: true, color: NAVY
      })],
      spacing: { before: 120, after: 120 },
    }),
    new Paragraph({ text: "", spacing: { before: 400 } }),
    new Paragraph({
      alignment: AlignmentType.CENTER,
      children: [new TextRun({ text: "June 2026", size: 22, color: "888888" })],
    }),
    pageBreak(),
  ];
}

// ─── Section 1: Introduction ─────────────────────────────────────────────────
function makeSection1() {
  return [
    heading1("1. INTRODUCTION"),
    body("Autism Spectrum Disorder (ASD) is a neurodevelopmental condition defined by two core domains: persistent deficits in social communication/interaction, and restricted, repetitive patterns of behavior. No single treatment addresses all aspects of ASD. Management is therefore multimodal, combining behavioral, educational, and pharmacological strategies tailored to the individual's age, severity, cognitive level, and specific symptom profile."),
    new Paragraph({ spacing: { before: 120, after: 0 } }),
    note("No medication is approved for the core social communication deficits of ASD. Pharmacotherapy targets associated/comorbid symptoms only (e.g., irritability, hyperactivity, anxiety, sleep disturbance)."),
    new Paragraph({ spacing: { before: 120 } }),
    heading3("Quick Comparison Overview"),
    makeTable([
      [
        headerCell("Dimension", NAVY, 2200),
        headerCell("Behavioral Treatment", STEEL, 3200),
        headerCell("Pharmacological Treatment", TEAL, 3200),
      ],
      [
        makeCell("Primary target", { bg: LTBLUE, bold: true }),
        makeCell("Core ASD symptoms (social skills, communication, repetitive behaviors)"),
        makeCell("Associated symptoms (irritability, aggression, hyperactivity, anxiety, sleep)"),
      ],
      [
        makeCell("Evidence for core symptoms", { bg: LTBLUE, bold: true }),
        makeCell("Strong - multiple RCTs", { color: "1A7A3C", bold: true }),
        makeCell("None - no drug proven for core symptoms", { color: "8B0000", bold: true }),
      ],
      [
        makeCell("First-line?", { bg: LTBLUE, bold: true }),
        makeCell("YES - always first-line", { bold: true, color: "1A7A3C" }),
        makeCell("Adjunct only (add if behavioral insufficient)"),
      ],
      [
        makeCell("Side effects", { bg: LTBLUE, bold: true }),
        makeCell("None - safe at any age"),
        makeCell("Weight gain, sedation, EPS, metabolic effects (antipsychotics)"),
      ],
      [
        makeCell("Best age to start", { bg: LTBLUE, bold: true }),
        makeCell("As early as possible (18 months - 5 years optimal)"),
        makeCell("Usually school age; some medications from age 5-6"),
      ],
      [
        makeCell("Effect on prognosis", { bg: LTBLUE, bold: true }),
        makeCell("Can profoundly alter trajectory; some children no longer meet ASD criteria"),
        makeCell("Symptomatic relief; does not alter underlying disorder"),
      ],
      [
        makeCell("FDA-approved for ASD?", { bg: LTBLUE, bold: true }),
        makeCell("Not an FDA-regulated therapy"),
        makeCell("Risperidone (irritability, age 5+), Aripiprazole (irritability, age 6+)"),
      ],
    ]),
    new Paragraph({ spacing: { before: 200 } }),
  ];
}

// ─── Section 2: Behavioral ───────────────────────────────────────────────────
function makeSection2() {
  return [
    pageBreak(),
    heading1("2. BEHAVIORAL & PSYCHOSOCIAL TREATMENTS"),
    body("Behavioral interventions are the cornerstone of ASD management. They target the core features of the disorder and have the strongest evidence base, especially when started early. Below is a detailed breakdown of each approach."),
    new Paragraph({ spacing: { before: 80 } }),

    heading2("2.1 Applied Behavior Analysis (ABA) - UCLA/Lovaas Model"),
    boldBullet("Basis", "Behavioral learning principles - reinforcement, prompting, shaping, and extinction"),
    boldBullet("Intensity", "20-40 hours/week, one-to-one, structured setting"),
    boldBullet("Targets", "Specific social skills, language use, adaptive play behaviors, communication"),
    boldBullet("Method", "Discrete Trial Training (DTT): therapist presents stimulus, child responds, reward/correction follows; skills are broken into small steps"),
    boldBullet("Evidence", "5 RCTs in children aged 2-5 years showed significant gains in language acquisition, social interaction, and educational achievement vs. control groups"),
    boldBullet("Outcome", "In some cases leads to recovery - children no longer meet ASD criteria after intensive early intervention"),
    note("Lovaas (1987) original study: 47% of intensively treated children achieved normal intellectual and educational functioning vs. 2% of controls. Replication studies show smaller but consistent gains."),

    heading2("2.2 Early Start Denver Model (ESDM)"),
    boldBullet("Setting", "Naturalistic - home or play environment (not a formal therapy room)"),
    boldBullet("Age range", "12-48 months - the earliest evidence-based intervention available"),
    boldBullet("Approach", "Integrates ABA with developmental and relationship-based approaches"),
    boldBullet("Key components", "Joint attention, social reciprocity, imitation, symbolic play - all embedded in fun, child-directed activities"),
    boldBullet("Parent involvement", "Parents trained as co-therapists to deliver therapy throughout the day"),
    boldBullet("Evidence", "Rogers et al. RCT (2012): ESDM produced greater gains in cognition, language, and adaptive behavior than community treatment"),
    note("ESDM is particularly powerful because it capitalizes on the brain's neuroplasticity in the first years of life."),

    heading2("2.3 JASPER (Joint Attention, Symbolic Play, Engagement, and Regulation)"),
    boldBullet("Focus", "Expanding joint attention (sharing attention with another person toward an object/event) and symbolic play"),
    boldBullet("Setting", "Classroom and community settings; can be implemented by teachers and therapists"),
    boldBullet("Evidence", "RCT evidence for improvements in joint engagement, communication initiations, and play complexity"),
    boldBullet("Strength", "Targets the earliest social communication building blocks that underpin all later social development"),

    heading2("2.4 Speech and Language Therapy (SLT)"),
    boldBullet("Targets", "Verbal communication, pragmatic language (social use of language), non-verbal communication"),
    boldBullet("AAC devices", "Augmentative and Alternative Communication (AAC) - picture exchange (PECS), speech-generating devices for minimally verbal children"),
    boldBullet("PECS", "Picture Exchange Communication System - child hands therapist a picture to request items; builds functional communication without speech prerequisite"),
    boldBullet("Goals", "Increase spontaneous communication, reduce echolalia, improve conversational turn-taking"),

    heading2("2.5 Occupational Therapy (OT)"),
    boldBullet("Sensory Integration Therapy", "Addresses hyper/hyporeactivity to sensory stimuli through graded sensory exposure"),
    boldBullet("Fine motor skills", "Writing, self-care, scissors use"),
    boldBullet("ADL training", "Dressing, feeding, hygiene - critical for independence"),
    boldBullet("Evidence", "Evidence for sensory integration is moderate; ADL skill-building has strong functional benefit"),

    heading2("2.6 TEACCH (Treatment and Education of Autistic and Communication-Handicapped Children)"),
    boldBullet("Philosophy", "Accepts and accommodates ASD rather than aiming to normalize; builds on strengths"),
    boldBullet("Key tool", "Structured visual supports: visual schedules, workbins, clear physical organization of environment"),
    boldBullet("Setting", "Primarily school-based; now used internationally"),
    boldBullet("Benefit", "Reduces anxiety by making the environment predictable; exploits the visual-spatial strengths of ASD"),
    boldBullet("Suitable for", "All intellectual levels, especially non-verbal or low-functioning individuals"),

    heading2("2.7 Social Skills Training"),
    boldBullet("Format", "Group or individual sessions"),
    boldBullet("Targets", "Conversation initiation/maintenance, reading social cues, understanding unwritten rules, friendship building"),
    boldBullet("Programs", "PEERS (Program for the Education and Enrichment of Relational Skills) - RCT evidence in adolescents with ASD"),
    boldBullet("Best for", "School-age children and adolescents with average IQ and good verbal ability"),

    heading2("2.8 Cognitive Behavioral Therapy (CBT)"),
    boldBullet("Targets", "Anxiety, depression, OCD-like behaviors, anger management"),
    boldBullet("Adaptation for ASD", "More concrete, visual, structured; explicit teaching of emotional identification; reduced metaphor and abstract language"),
    boldBullet("Evidence", "Strong RCT evidence for anxiety in high-functioning ASD/Asperger profile"),
    boldBullet("Best for", "Adolescents and adults with IQ ≥70 and verbal language skills"),

    heading2("2.9 Parent Training and Psychoeducation"),
    boldBullet("Goal", "Train parents as co-therapists; generalize skills to home and daily life"),
    boldBullet("RUBI Curriculum", "Research Units in Behavioral Intervention - structured parent training RCT for disruptive behavior; showed significant reduction in noncompliance and tantrums"),
    boldBullet("Psychoeducation", "Understanding ASD, behavior management strategies, advocating for child in schools"),
    boldBullet("Support", "Parent support groups reduce caregiver burnout and improve family functioning"),
    boldBullet("Evidence", "Parent-mediated interventions show lasting improvements in child outcomes beyond the treatment period"),

    heading2("2.10 Educational Interventions"),
    boldBullet("IEP", "Individualized Education Program - legally mandated individualized plan in schools (in the USA and equivalent systems elsewhere)"),
    boldBullet("Placement options", "Full inclusion with support aide | Resource room | Self-contained special education | Specialized ASD school"),
    boldBullet("Transition planning", "Beginning at age 14-16: vocational training, independent living skills, post-secondary education planning"),
    new Paragraph({ spacing: { before: 120 } }),
    note("Early intensive behavioral intervention (20-40 hrs/week from age 2-4) is the ONLY treatment shown to substantially alter the developmental trajectory of ASD. Starting before age 3 yields the best outcomes."),
    new Paragraph({ spacing: { before: 120 } }),
  ];
}

// ─── Section 3: Pharmacological ─────────────────────────────────────────────
function makeSection3() {
  return [
    pageBreak(),
    heading1("3. PHARMACOLOGICAL TREATMENTS"),
    body("No medication is approved for the core features of ASD (social communication deficits or restricted/repetitive behaviors). Pharmacotherapy is used to manage associated symptoms that interfere with daily functioning and participation in behavioral therapy."),
    new Paragraph({ spacing: { before: 80 } }),

    heading2("3.1 FDA-Approved Medications for ASD"),
    body("Only two drugs carry FDA approval specifically for ASD (for irritability):"),
    new Paragraph({ spacing: { before: 60 } }),
    makeTable([
      [
        headerCell("Drug", NAVY, 1800),
        headerCell("Class", NAVY, 1600),
        headerCell("Dose Range", NAVY, 1600),
        headerCell("Target Symptoms", NAVY, 2000),
        headerCell("Key Adverse Effects", NAVY, 1600),
      ],
      [
        makeCell("Risperidone", { bg: LTBLUE, bold: true }),
        makeCell("Atypical antipsychotic (D2/5HT2A antagonist)"),
        makeCell("0.5-3 mg/day (age 5+)"),
        makeCell("Irritability, aggression, self-injurious behavior, tantrums"),
        makeCell("Weight gain +++, sedation, hyperprolactinemia, EPS, metabolic syndrome"),
      ],
      [
        makeCell("Aripiprazole", { bg: LTGRN, bold: true }),
        makeCell("Atypical antipsychotic (D2 partial agonist)"),
        makeCell("2-15 mg/day (age 6+)"),
        makeCell("Irritability, aggression, self-injurious behavior"),
        makeCell("Weight gain ++ (less than risperidone), akathisia, sedation, nausea"),
      ],
    ]),
    new Paragraph({ spacing: { before: 120 } }),
    note("Aripiprazole has a more favorable metabolic profile than risperidone and is preferred when weight gain or prolactin elevation is a concern."),
    new Paragraph({ spacing: { before: 120 } }),

    heading2("3.2 SSRIs (for Repetitive Behaviors, Anxiety, OCD-like symptoms)"),
    body("Serotonergic hypothesis: ~30% of children with ASD have elevated whole-blood serotonin (most replicated biological finding). SSRIs modulate serotonin and may reduce repetitive behaviors and anxiety."),
    new Paragraph({ spacing: { before: 60 } }),
    makeTable([
      [
        headerCell("Drug", STEEL, 1600),
        headerCell("Evidence", STEEL, 2800),
        headerCell("Dose in ASD", STEEL, 1600),
        headerCell("Precautions", STEEL, 2600),
      ],
      [
        makeCell("Fluoxetine", { bold: true }),
        makeCell("RCT showed improvement in repetitive behaviors; better evidence in adults than children"),
        makeCell("5-20 mg/day (start very low)"),
        makeCell("Activation/agitation, insomnia; children with ASD are highly sensitive to activating effects"),
      ],
      [
        makeCell("Fluvoxamine", { bold: true }),
        makeCell("RCT evidence in adults: reduction in repetitive behaviors and social relatedness improvement; limited/mixed evidence in children"),
        makeCell("50-200 mg/day adults"),
        makeCell("GI side effects, sedation; multiple drug interactions (CYP1A2)"),
      ],
      [
        makeCell("Sertraline", { bold: true }),
        makeCell("Used clinically; modest evidence; often preferred due to tolerability"),
        makeCell("12.5-50 mg/day children"),
        makeCell("Activation possible; generally well-tolerated"),
      ],
      [
        makeCell("Clomipramine (TCA)", { bold: true }),
        makeCell("Occasionally used; lacks RCT evidence; not first-line"),
        makeCell("25-150 mg/day"),
        makeCell("Cardiac (QTc prolongation), anticholinergic effects, seizure threshold lowering"),
      ],
    ]),
    new Paragraph({ spacing: { before: 120 } }),
    note("Children with ASD can paradoxically become more agitated, aggressive, or hyperactive on SSRIs - start at the lowest possible dose and increase slowly. Monitor carefully in the first 2-4 weeks."),
    new Paragraph({ spacing: { before: 120 } }),

    heading2("3.3 Stimulants & ADHD Medications (for Hyperactivity, Inattention)"),
    body("ADHD is a common comorbidity in ASD. Stimulants work, but response rates are lower and adverse effects higher in ASD vs. ADHD without ASD."),
    new Paragraph({ spacing: { before: 60 } }),
    makeTable([
      [
        headerCell("Drug", TEAL, 1600),
        headerCell("Class", TEAL, 1600),
        headerCell("Evidence in ASD", TEAL, 2400),
        headerCell("Adverse Effects / Notes", TEAL, 2900),
      ],
      [
        makeCell("Methylphenidate", { bold: true }),
        makeCell("CNS stimulant"),
        makeCell("Moderate benefit for ADHD symptoms; lower response rate (~50% vs. ~75% in ADHD alone)"),
        makeCell("Irritability, social withdrawal, appetite suppression, insomnia - more common in ASD than in ADHD alone"),
      ],
      [
        makeCell("Guanfacine", { bold: true }),
        makeCell("Alpha-2A adrenergic agonist"),
        makeCell("RCT evidence for hyperactivity, impulsivity, inattention, tics, and aggression"),
        makeCell("Sedation, hypotension, bradycardia; better tolerability than stimulants in many ASD patients"),
      ],
      [
        makeCell("Clonidine", { bold: true }),
        makeCell("Alpha-2 adrenergic agonist"),
        makeCell("Used for hyperactivity, sleep disturbances, aggression"),
        makeCell("More sedation than guanfacine; rebound hypertension if stopped abruptly"),
      ],
      [
        makeCell("Atomoxetine", { bold: true }),
        makeCell("NRI (non-stimulant)"),
        makeCell("Some evidence for ADHD symptoms in ASD; good option if stimulants cause aggression"),
        makeCell("GI effects, mood changes; takes 4-6 weeks to work"),
      ],
    ]),
    new Paragraph({ spacing: { before: 120 } }),

    heading2("3.4 Mood Stabilizers / Anticonvulsants"),
    boldBullet("Valproate (Valproic acid)", "Used for mood instability, aggressive outbursts, and seizures (comorbid epilepsy in ~25% of ASD). Monitor LFTs, CBC, and blood levels."),
    boldBullet("Lamotrigine", "Limited evidence for behavioral improvement in ASD; primarily used for seizures."),
    boldBullet("Lithium", "Occasionally used in adolescents/adults with ASD + bipolar features; requires blood level monitoring."),
    note("Approximately 25% of children with ASD develop epilepsy; anticonvulsant choice should consider both seizure control and behavioral effects. Valproate and lamotrigine are generally preferred."),

    heading2("3.5 Melatonin (Sleep Disturbances)"),
    boldBullet("Indication", "Sleep-onset insomnia - extremely common in ASD (~80% prevalence)"),
    boldBullet("Mechanism", "Exogenous melatonin supplements the diminished pineal output seen in some children with ASD"),
    boldBullet("Dose", "0.5-5 mg, 30-60 minutes before bedtime"),
    boldBullet("Evidence", "Multiple RCTs confirm reduced sleep-onset latency and improved total sleep time"),
    boldBullet("Safety", "Excellent - safe for long-term use; no serious adverse effects reported in pediatric studies"),
    boldBullet("Status", "Best-supported CAM intervention; now considered near-mainstream"),

    heading2("3.6 Investigational / Emerging Agents"),
    makeTable([
      [
        headerCell("Drug", NAVY, 1800),
        headerCell("Mechanism", NAVY, 2000),
        headerCell("Current Evidence", NAVY, 2000),
        headerCell("Status", NAVY, 1800),
      ],
      [
        makeCell("Bumetanide", { bold: true }),
        makeCell("Loop diuretic; inhibits NKCC1 cotransporter - shifts GABA from excitatory to inhibitory in developing brain"),
        makeCell("Several studies showing improvements in communication and cognitive abilities; cytokine profiling may predict responders"),
        makeCell("Investigational; not approved for ASD", { color: "8B4513" }),
      ],
      [
        makeCell("Oxytocin", { bold: true }),
        makeCell("Neuropeptide promoting social bonding and trust"),
        makeCell("Initial studies promising; larger RCTs mixed/negative; intranasal route under study"),
        makeCell("Experimental", { color: "8B4513" }),
      ],
      [
        makeCell("Tetrahydrobiopterin", { bold: true }),
        makeCell("Coenzyme enhancing aromatic amino acid hydroxylases; increases monoamine synthesis"),
        makeCell("Post-hoc analysis showed improvement in social interaction; overall trial results not significant"),
        makeCell("Limited evidence", { color: "8B4513" }),
      ],
      [
        makeCell("Venlafaxine (low-dose)", { bold: true }),
        makeCell("SNRI"),
        makeCell("Case reports: 18.75 mg/day efficacious in adolescents with ASD + self-injurious behavior + hyperactivity over 6 months"),
        makeCell("Case reports only", { color: "8B4513" }),
      ],
      [
        makeCell("Naltrexone", { bold: true }),
        makeCell("Opioid receptor antagonist; theory - blocking endorphins reduces autistic symptoms"),
        makeCell("Multiple trials; results largely unsuccessful/equivocal"),
        makeCell("Not recommended", { color: "8B0000" }),
      ],
      [
        makeCell("Secretin", { bold: true }),
        makeCell("GI peptide hormone; purported neuromodulatory effects"),
        makeCell("Multiple RCTs: INEFFECTIVE"),
        makeCell("DISPROVEN - do not use", { bold: true, color: "8B0000" }),
      ],
    ]),
    new Paragraph({ spacing: { before: 200 } }),
  ];
}

// ─── Section 4: Head-to-Head Comparison ─────────────────────────────────────
function makeSection4() {
  return [
    pageBreak(),
    heading1("4. DETAILED HEAD-TO-HEAD COMPARISON"),
    new Paragraph({ spacing: { before: 80 } }),
    makeTable([
      [
        headerCell("Feature", NAVY, 2000),
        headerCell("Behavioral Treatments", STEEL, 3200),
        headerCell("Pharmacological Treatments", TEAL, 3200),
      ],
      [
        makeCell("Core social deficits", { bg: LTBLUE, bold: true }),
        makeCell("EFFECTIVE - ABA, ESDM, JASPER show RCT-proven improvements", { color: "1A7A3C", bold: false }),
        makeCell("NOT EFFECTIVE - no drug proven to treat core social deficits", { color: "8B0000" }),
      ],
      [
        makeCell("Repetitive behaviors", { bg: LTBLUE, bold: true }),
        makeCell("Behavioral interventions target ritualistic behaviors with moderate efficacy; habit reversal training also used"),
        makeCell("SSRIs (fluoxetine, fluvoxamine) have some evidence; not consistently effective"),
      ],
      [
        makeCell("Irritability / Aggression", { bg: LTBLUE, bold: true }),
        makeCell("Functional Behavior Analysis (FBA) + behavior intervention plan - highly effective if antecedents identified"),
        makeCell("Risperidone and Aripiprazole - FDA approved, large effect sizes in RCTs"),
      ],
      [
        makeCell("Hyperactivity / Inattention", { bg: LTBLUE, bold: true }),
        makeCell("Environmental structure, visual schedules, movement breaks reduce hyperactivity"),
        makeCell("Methylphenidate, guanfacine, atomoxetine - moderate effect in ASD+ADHD"),
      ],
      [
        makeCell("Anxiety", { bg: LTBLUE, bold: true }),
        makeCell("CBT adapted for ASD - strong RCT evidence for anxiety reduction"),
        makeCell("SSRIs - reasonable adjunct; start low, go slow"),
      ],
      [
        makeCell("Sleep disturbances", { bg: LTBLUE, bold: true }),
        makeCell("Sleep hygiene training, consistent routines, light management, visual bedtime schedules"),
        makeCell("Melatonin - efficacious, safe, well-supported by RCTs"),
      ],
      [
        makeCell("Communication deficits", { bg: LTBLUE, bold: true }),
        makeCell("Speech therapy, AAC, PECS, ESDM - all evidence-based approaches"),
        makeCell("No pharmacological treatment"),
      ],
      [
        makeCell("Safety profile", { bg: LTBLUE, bold: true }),
        makeCell("Excellent - no physical adverse effects; intensive hours can be tiring for child/family"),
        makeCell("Variable - antipsychotics carry metabolic, neurological, and cardiac risks"),
      ],
      [
        makeCell("Long-term effects", { bg: LTBLUE, bold: true }),
        makeCell("Skills acquired may be retained long-term; sustained neuroplastic changes documented"),
        makeCell("Symptom control continues while on medication; does not alter underlying disorder"),
      ],
      [
        makeCell("Cost / Accessibility", { bg: LTBLUE, bold: true }),
        makeCell("Expensive (ABA can cost $50,000-$80,000/year); requires trained therapists; not universally accessible"),
        makeCell("Relatively inexpensive and widely available"),
      ],
      [
        makeCell("Effect on prognosis", { bg: LTBLUE, bold: true }),
        makeCell("CAN alter developmental trajectory; early intensive intervention may lead to no longer meeting ASD criteria"),
        makeCell("Symptomatic relief; underlying ASD course unchanged"),
      ],
      [
        makeCell("When to use", { bg: LTBLUE, bold: true }),
        makeCell("ALWAYS - behavioral intervention is the universal foundation of ASD treatment"),
        makeCell("When behavioral interventions alone are insufficient to manage disruptive/dangerous symptoms"),
      ],
    ]),
    new Paragraph({ spacing: { before: 200 } }),
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}

// ─── Section 5: CAM ──────────────────────────────────────────────────────────
function makeSection5() {
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    pageBreak(),
    heading1("5. COMPLEMENTARY & ALTERNATIVE MEDICINE (CAM)"),
    body("CAM approaches are widely used in ASD. It is important for clinicians to be aware of which are safe and potentially effective vs. which are ineffective or harmful."),
    new Paragraph({ spacing: { before: 80 } }),
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        headerCell("Intervention", NAVY, 2000),
        headerCell("Evidence", NAVY, 2400),
        headerCell("Safety", NAVY, 1600),
        headerCell("Recommendation", NAVY, 2500),
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      [
        makeCell("Melatonin", { bold: true }),
        makeCell("Efficacious - RCT evidence for sleep-onset latency"),
        makeCell("Safe", { color: "1A7A3C", bold: true }),
        makeCell("Recommend for sleep difficulties", { color: "1A7A3C" }),
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      [
        makeCell("Music therapy"),
        makeCell("Unknown; promotes communication and social expression"),
        makeCell("Safe", { color: "1A7A3C", bold: true }),
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      [
        makeCell("Yoga / Mindfulness"),
        makeCell("Unknown; promotes attention, reduces activity level"),
        makeCell("Safe", { color: "1A7A3C", bold: true }),
        makeCell("Reasonable adjunct"),
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      [
        makeCell("Physical exercise"),
        makeCell("2024 meta-analysis (PMID 38986177): significant improvement in social behavior, attention, motor skills"),
        makeCell("Safe", { color: "1A7A3C", bold: true }),
        makeCell("Recommend - evidence growing"),
      ],
      [
        makeCell("Vitamin C / Multivitamins"),
        makeCell("Unknown efficacy"),
        makeCell("Safe at normal doses"),
        makeCell("Not specifically recommended; no harm if nutritionally adequate"),
      ],
      [
        makeCell("Omega-3 fatty acids"),
        makeCell("Unknown; some positive signals in small studies"),
        makeCell("Safe", { color: "1A7A3C", bold: true }),
        makeCell("Reasonable; insufficient evidence to formally recommend"),
      ],
      [
        makeCell("Gluten/casein-free diet"),
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      ],
      [
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        makeCell("DO NOT USE - discredited", { bold: true, color: "8B0000" }),
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    new Paragraph({ spacing: { before: 200 } }),
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// ─── Section 6: Step-up algorithm ───────────────────────────────────────────
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    heading1("6. TREATMENT ALGORITHM - STEP-BY-STEP APPROACH"),
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    heading3("Step 1: Diagnosis and Assessment"),
    bullet("Confirm ASD diagnosis (DSM-5 criteria)"),
    bullet("Assess severity level (1, 2, or 3) for each domain"),
    bullet("Determine IQ and language level"),
    bullet("Screen for comorbidities: intellectual disability, ADHD, anxiety, epilepsy, sleep disorders"),
    bullet("Conduct Functional Behavior Assessment (FBA) if maladaptive behaviors present"),
    new Paragraph({ spacing: { before: 80 } }),

    heading3("Step 2: Initiate Behavioral Interventions (ALL children)"),
    bullet("Early intensive behavioral therapy (ABA/ESDM) for children under 5 - START IMMEDIATELY"),
    bullet("Speech and language therapy"),
    bullet("Occupational therapy as needed"),
    bullet("Enroll in appropriate educational program with IEP"),
    bullet("Begin parent training"),
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    heading3("Step 3: Address Associated Symptoms Behaviorally First"),
    bullet("Sleep: Sleep hygiene program + melatonin if behavioral strategies insufficient"),
    bullet("Anxiety: Adapted CBT before medication"),
    bullet("Hyperactivity: Structured environment, visual schedules, movement breaks"),
    bullet("Aggression: FBA to identify triggers + behavior intervention plan"),
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    heading3("Step 4: Add Pharmacotherapy if Behavioral Interventions Insufficient"),
    bullet("Irritability/aggression/self-injury: Risperidone or Aripiprazole (FDA-approved)"),
    bullet("Hyperactivity/ADHD: Methylphenidate or guanfacine"),
    bullet("Anxiety/OCD features: SSRI (start very low dose)"),
    bullet("Sleep: Melatonin"),
    bullet("Mood instability/seizures: Valproate or lamotrigine"),
    new Paragraph({ spacing: { before: 80 } }),

    heading3("Step 5: Monitor and Review"),
    bullet("Monitor medication side effects: weight, metabolic panel, ECG if indicated"),
    bullet("Reassess behavioral therapy goals every 3-6 months"),
    bullet("Aim to reduce medication dose once behaviors stabilized"),
    bullet("Transition planning from adolescence onward"),
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    note("Behavioral interventions should NEVER be stopped when pharmacotherapy is added. Medication + behavioral therapy together produces better outcomes than either alone."),
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  ];
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// ─── Section 7: Exam Key Points ─────────────────────────────────────────────
function makeSection7() {
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    heading1("7. HIGH-YIELD EXAM KEY POINTS"),
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    makeTable([
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      [makeCell("1", { bg: LTYEL, bold: true }), makeCell("No drug is approved or proven for the CORE features of ASD (social communication deficits / restricted-repetitive behaviors)", { bold: true })],
      [makeCell("2", { bg: LTYEL, bold: true }), makeCell("The ONLY two FDA-approved drugs for ASD are Risperidone (age 5+) and Aripiprazole (age 6+) - BOTH for irritability only")],
      [makeCell("3", { bg: LTYEL, bold: true }), makeCell("Behavioral interventions (ABA, ESDM) are the ONLY treatments shown to alter the developmental trajectory of ASD")],
      [makeCell("4", { bg: LTYEL, bold: true }), makeCell("Elevated whole-blood serotonin (~30% of ASD patients) is the most replicated biological finding in ASD - rationale for SSRIs")],
      [makeCell("5", { bg: LTYEL, bold: true }), makeCell("SECRETIN is INEFFECTIVE - proven by multiple RCTs. A common exam trap.")],
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      [makeCell("7", { bg: LTYEL, bold: true }), makeCell("Children with ASD are MORE sensitive to SSRI activating effects than children without ASD - start at the LOWEST possible dose")],
      [makeCell("8", { bg: LTYEL, bold: true }), makeCell("Stimulants (methylphenidate) have LOWER response rates and MORE adverse effects in ASD vs. pure ADHD")],
      [makeCell("9", { bg: LTYEL, bold: true }), makeCell("~25% of ASD children develop epilepsy - screening and anticonvulsant management essential")],
      [makeCell("10", { bg: LTYEL, bold: true }), makeCell("Best prognosis predictors: IQ >70 + communicative language by age 5-7 + early intensive behavioral intervention")],
      [makeCell("11", { bg: LTYEL, bold: true }), makeCell("Aripiprazole preferred over risperidone when weight gain or hyperprolactinemia is a concern")],
      [makeCell("12", { bg: LTYEL, bold: true }), makeCell("Bumetanide (loop diuretic) is an emerging investigational treatment - acts on NKCC1 cotransporter, shifts GABA to inhibitory")],
      [makeCell("13", { bg: LTYEL, bold: true }), makeCell("Physical exercise (2024 meta-analysis) shows significant improvement in ASD symptoms - growing evidence base")],
      [makeCell("14", { bg: LTYEL, bold: true }), makeCell("Behavioral therapy + pharmacotherapy TOGETHER produces better outcomes than either alone for comorbid symptoms")],
      [makeCell("15", { bg: LTYEL, bold: true }), makeCell("DSM-5 ASD has TWO domains: A) Social communication/interaction deficits  B) Restricted, repetitive behaviors - symptoms needed from BOTH")],
    ]),
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    makeTable([
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        headerCell("Drug(s) of Choice", NAVY, 2200),
        headerCell("FDA Approved for ASD?", NAVY, 1800),
        headerCell("Watch For", NAVY, 2400),
      ],
      [makeCell("Irritability / Aggression"), makeCell("Risperidone, Aripiprazole", { bold: true }), makeCell("YES", { color: "1A7A3C", bold: true }), makeCell("Weight gain, metabolic syndrome, EPS")],
      [makeCell("Repetitive behaviors"), makeCell("Fluoxetine, Fluvoxamine"), makeCell("No"), makeCell("Agitation, activation syndrome")],
      [makeCell("Hyperactivity / Inattention"), makeCell("Methylphenidate, Guanfacine"), makeCell("No"), makeCell("Irritability, appetite loss (MPH); sedation (guanfacine)")],
      [makeCell("Anxiety"), makeCell("SSRIs (sertraline, fluoxetine)"), makeCell("No"), makeCell("Activation, GI effects")],
      [makeCell("Sleep"), makeCell("Melatonin"), makeCell("No (but widely recommended)"), makeCell("Minimal - very safe")],
      [makeCell("Mood instability / Seizures"), makeCell("Valproate, Lamotrigine"), makeCell("No"), makeCell("LFTs, weight (VPA), rash (lamotrigine)")],
      [makeCell("SNRI option (severe SIB)"), makeCell("Venlafaxine low-dose"), makeCell("No"), makeCell("Case report evidence only")],
      [makeCell("AVOID"), makeCell("Secretin, Fenfluramine, Naltrexone (routine use)", { bold: true, color: "8B0000" }), makeCell("N/A"), makeCell("Proven ineffective")],
    ]),
    new Paragraph({ spacing: { before: 200 } }),
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// ─── References ──────────────────────────────────────────────────────────────
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    bullet("Kaplan & Sadock's Synopsis of Psychiatry, 11th Ed. (9781975145569) - Chapter 2.3: Autism Spectrum Disorder"),
    bullet("Kaplan & Sadock's Comprehensive Textbook of Psychiatry, 10th Ed. (9781975175733)"),
    bullet("Katzung's Basic and Clinical Pharmacology, 16th Ed. (9781260463309)"),
    bullet("Frye RE et al. Biomarkers of mitochondrial dysfunction in ASD. Neurobiol Dis. 2024 Jul. [PMID: 38703861]"),
    bullet("Wu Y et al. Effect of physical exercise therapy on ASD: systematic review and meta-analysis. Psychiatry Res. 2024 Sep. [PMID: 38986177]"),
    bullet("GBD 2021 Autism Spectrum Collaborators. Global epidemiology and health burden of the autism spectrum. Lancet Psychiatry. 2025 Feb. [PMID: 39709974]"),
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