"mood disorders" AND "recent advances" AND treatment

"mood disorders" AND India AND clinical trial

recent advances mood disorders 2025 2026 new drugs neurobiology India clinical trials

"treatment-resistant depression" AND (ketamine OR esketamine OR psilocybin) AND advances

https://pmc.ncbi.nlm.nih.gov/articles/PMC12900052

depression India "clinical trial" OR "randomized" 2024 2025

India clinical trials depression bipolar disorder 2024 2025 NIMHANS AIIMS psychiatry research

"major depressive disorder" AND (neuromodulation OR "brain stimulation" OR TMS OR tDCS) AND advances

mkdir -p /home/daytona/workspace/mood-disorders-seminar && ls /home/daytona/work…

~/mood-disorders-seminar/generate_doc.js

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

// ─── HELPERS ────────────────────────────────────────────────────────────────
const H1 = (text) => new Paragraph({
  text, heading: HeadingLevel.HEADING_1,
  spacing: { before: 400, after: 200 }
});
const H2 = (text) => new Paragraph({
  text, heading: HeadingLevel.HEADING_2,
  spacing: { before: 300, after: 150 }
});
const H3 = (text) => new Paragraph({
  text, heading: HeadingLevel.HEADING_3,
  spacing: { before: 200, after: 100 }
});
const P = (text, bold=false, italic=false) => new Paragraph({
  children: [new TextRun({ text, bold, italics: italic, size: 22 })],
  spacing: { before: 60, after: 60 },
  indent: { left: 0 }
});
const BULLET = (text, level=0) => new Paragraph({
  children: [new TextRun({ text, size: 22 })],
  bullet: { level },
  spacing: { before: 40, after: 40 }
});
const EMPTY = () => new Paragraph({ children: [new TextRun({ text: '' })], spacing: { before: 60, after: 60 } });

// ─── TABLE HELPER ────────────────────────────────────────────────────────────
const makeTable = (headers, rows) => new Table({
  width: { size: 100, type: WidthType.PERCENTAGE },
  rows: [
    new TableRow({
      tableHeader: true,
      children: headers.map(h => new TableCell({
        shading: { fill: '1F4E79', type: ShadingType.CLEAR },
        children: [new Paragraph({ children: [new TextRun({ text: h, bold: true, color: 'FFFFFF', size: 20 })] })],
        verticalAlign: VerticalAlign.CENTER
      }))
    }),
    ...rows.map((row, ri) => new TableRow({
      children: row.map(cell => new TableCell({
        shading: { fill: ri % 2 === 0 ? 'D6E4F0' : 'FFFFFF', type: ShadingType.CLEAR },
        children: [new Paragraph({ children: [new TextRun({ text: cell, size: 20 })] })],
        verticalAlign: VerticalAlign.CENTER
      }))
    }))
  ]
});

// ─── DOCUMENT ────────────────────────────────────────────────────────────────
const doc = new Document({
  creator: 'Orris AI',
  title: 'Recent Advances in Mood Disorders - Seminar Notes',
  description: 'Detailed seminar notes for postgraduate residents on recent advances in mood disorders',
  styles: {
    default: {
      document: { run: { font: 'Calibri', size: 22 } }
    },
    paragraphStyles: [
      {
        id: 'Heading1', name: 'Heading 1', basedOn: 'Normal',
        run: { bold: true, size: 32, color: '1F4E79', font: 'Calibri Light' },
        paragraph: { spacing: { before: 400, after: 200 } }
      },
      {
        id: 'Heading2', name: 'Heading 2', basedOn: 'Normal',
        run: { bold: true, size: 26, color: '2E75B6', font: 'Calibri Light' },
        paragraph: { spacing: { before: 300, after: 150 } }
      },
      {
        id: 'Heading3', name: 'Heading 3', basedOn: 'Normal',
        run: { bold: true, size: 23, color: '1F4E79', font: 'Calibri' },
        paragraph: { spacing: { before: 200, after: 100 } }
      }
    ]
  },
  sections: [{
    properties: {
      page: { margin: { top: 1000, right: 1000, bottom: 1000, left: 1200 } }
    },
    headers: {
      default: new Header({
        children: [new Paragraph({
          children: [new TextRun({ text: 'Recent Advances in Mood Disorders | Seminar Notes for PG Residents', italics: true, color: '666666', size: 18 })],
          alignment: AlignmentType.RIGHT
        })]
      })
    },
    footers: {
      default: new Footer({
        children: [new Paragraph({
          children: [
            new TextRun({ text: 'Prepared by Orris AI  |  July 2026  |  Page ', size: 18, color: '666666' }),
            new TextRun({ children: [PageNumber.CURRENT], size: 18, color: '666666' }),
            new TextRun({ text: ' of ', size: 18, color: '666666' }),
            new TextRun({ children: [PageNumber.TOTAL_PAGES], size: 18, color: '666666' })
          ],
          alignment: AlignmentType.CENTER
        })]
      })
    },
    children: [

      // ─── COVER ─────────────────────────────────────────────────────────────
      new Paragraph({
        children: [new TextRun({ text: '', break: 3 })]
      }),
      new Paragraph({
        children: [new TextRun({ text: 'RECENT ADVANCES IN', bold: true, size: 40, color: '1F4E79', font: 'Calibri Light' })],
        alignment: AlignmentType.CENTER
      }),
      new Paragraph({
        children: [new TextRun({ text: 'MOOD DISORDERS', bold: true, size: 56, color: '2E75B6', font: 'Calibri Light' })],
        alignment: AlignmentType.CENTER
      }),
      EMPTY(),
      new Paragraph({
        children: [new TextRun({ text: 'Seminar Notes for Postgraduate Residents', italics: true, size: 26, color: '555555' })],
        alignment: AlignmentType.CENTER
      }),
      EMPTY(),
      new Paragraph({
        children: [new TextRun({ text: 'Covering: Neurobiology & Biomarkers  |  New Pharmacotherapy  |  Treatment-Resistant Depression', size: 21, color: '333333' })],
        alignment: AlignmentType.CENTER
      }),
      new Paragraph({
        children: [new TextRun({ text: 'Psychotherapy & Digital Tools  |  India-Specific Research', size: 21, color: '333333' })],
        alignment: AlignmentType.CENTER
      }),
      EMPTY(),
      new Paragraph({
        children: [new TextRun({ text: 'Prepared: July 2026', size: 20, color: '888888' })],
        alignment: AlignmentType.CENTER
      }),

      // ─── PAGE BREAK ───────────────────────────────────────────────────────
      new Paragraph({ children: [new PageBreak()] }),

      // ─── SECTION 1: OVERVIEW ──────────────────────────────────────────────
      H1('1. Overview of Mood Disorders'),
      P('Mood disorders are among the leading causes of disability worldwide (WHO, 2023). They comprise two broad categories:'),
      BULLET('Unipolar Depression - primarily Major Depressive Disorder (MDD), Persistent Depressive Disorder (PDD/dysthymia), Postpartum Depression (PPD)'),
      BULLET('Bipolar Spectrum - Bipolar I, Bipolar II, Cyclothymia, and Bipolar Disorder Not Otherwise Specified'),
      EMPTY(),
      P('In India, the NIMHANS National Mental Health Survey (2015-16) estimated that approximately 10.6% of Indian adults live with a diagnosable mental health disorder. Mood disorders (unipolar and bipolar combined) are among the top contributors to this burden. India has a severe treatment gap: fewer than 1 in 5 individuals with serious mental disorders receive any care.'),
      EMPTY(),

      // ─── SECTION 2: NEUROBIOLOGY ──────────────────────────────────────────
      H1('2. Recent Advances in Neurobiology & Biomarkers'),

      H2('2.1 Beyond the Monoamine Hypothesis'),
      P('The classical monoamine deficiency hypothesis (low serotonin/norepinephrine/dopamine) is now considered an oversimplification. Four major neuroscientific frameworks have emerged:'),

      H3('A. Glutamate-GABA Dysregulation'),
      BULLET('Reduced prefrontal glutamate signalling and impaired GABAergic interneuron function are consistently found in depression.'),
      BULLET('NMDA receptor hypofunction in cortical pyramidal neurons leads to reduced AMPA throughput and loss of synaptic plasticity.'),
      BULLET('This is the basis for ketamine/esketamine\'s rapid antidepressant mechanism: NMDA blockade on GABAergic interneurons triggers a glutamate surge, AMPA activation, BDNF release, and synaptogenesis.'),
      BULLET('Key citation: McIntyre RS & Jain R. "Glutamatergic Modulators for Major Depression from Theory to Clinical Use." CNS Drugs. 2024 Nov. [PMID: 39150594]'),

      H3('B. Neuroinflammation & the Inflammatory Subtype of MDD'),
      BULLET('Elevated pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, CRP) found in 30-40% of MDD patients - the "inflammatory subtype."'),
      BULLET('Microglia activation, kynurenine pathway dysregulation (IDO1 enzyme), and reduced tryptophan availability to serotonin synthesis.'),
      BULLET('Recent PubMed highlight: Miller AH. "Advancing an Inflammatory Subtype of Major Depression." Am J Psychiatry. 2025 Jun 1. [PMID: 40329642] - proposes biomarker-stratified treatment selection.'),
      BULLET('Neuroinflammation also drives white matter integrity loss in bipolar II depression (Cao Y et al., Brain Behav Immun, 2025 Aug. [PMID: 40199429]).'),

      H3('C. Neuroplasticity & BDNF'),
      BULLET('Brain-Derived Neurotrophic Factor (BDNF) levels are consistently reduced in MDD and normalize with effective antidepressant treatment.'),
      BULLET('Hippocampal volume loss in chronic depression (structural MRI evidence) is partly reversible.'),
      BULLET('The "synaptic plasticity hypothesis" - depression as a disorder of synaptogenesis - underpins the rationale for psychoplastogens (ketamine, psilocybin, MDMA).'),

      H3('D. HPA Axis, Neurosteroids & Circadian Dysregulation'),
      BULLET('Hypercortisolaemia causes hippocampal glucocorticoid receptor downregulation, neuronal atrophy, and reduced neurogenesis.'),
      BULLET('Allopregnanolone (a GABA-A positive neurosteroid) is reduced in postpartum depression - the basis for brexanolone (Zulresso) and zuranolone (Zurzuvae).'),
      BULLET('Circadian rhythm disruption (suprachiasmatic nucleus dysfunction) is being studied as both a biomarker and treatment target in bipolar disorder.'),
      EMPTY(),

      H2('2.2 Emerging Biomarkers (2024-2026 Highlights)'),
      makeTable(
        ['Biomarker', 'Type', 'Clinical Relevance', 'Status (2026)'],
        [
          ['High-sensitivity CRP (hsCRP)', 'Inflammatory', 'Predicts poor response to SSRIs; may indicate benefit from anti-inflammatory adjuncts', 'Research use; entering clinical practice'],
          ['BDNF serum levels', 'Neuroplasticity', 'Low levels correlate with severity; may track treatment response', 'Research phase'],
          ['Kynurenine/tryptophan ratio', 'Metabolic/Inflammatory', 'Elevated in inflammatory-subtype MDD; links gut-brain axis to mood', 'Research phase'],
          ['Cortisol awakening response (CAR)', 'HPA axis', 'Dysregulated in MDD and bipolar; potential endophenotype marker', 'Research phase'],
          ['Pharmacogenomics (PGx) panel', 'Genetic', 'CYP2D6, CYP2C19 variants guide antidepressant selection; improves functional outcomes', 'FDA-cleared; expanding adoption (Fares-Otero et al., Eur Neuropsychopharmacol, 2025, PMID: 40889463)'],
          ['Inflammatory white matter changes on MRI', 'Neuroimaging', 'Linked to bipolar II depression severity and BMI; potential staging biomarker', 'Research phase'],
          ['EEG biomarkers (theta cordance)', 'Electrophysiological', 'Prefrontal theta cordance predicts antidepressant response before clinical improvement', 'Research phase']
        ]
      ),
      EMPTY(),

      // ─── SECTION 3: NEW PHARMACOTHERAPY ──────────────────────────────────
      new Paragraph({ children: [new PageBreak()] }),
      H1('3. Recent Advances in Pharmacotherapy'),

      H2('3.1 Approved Novel Agents (FDA/EMA, 2019-2025)'),
      makeTable(
        ['Drug', 'Mechanism', 'Indication', 'Key Trial'],
        [
          ['Esketamine (Spravato) IN', 'NMDA antagonist (S-enantiomer of ketamine)', 'TRD (2019); Acute suicidal ideation (2020)', 'TRANSFORM-2, SUSTAIN-2; also vs quetiapine (NEJM 2023)'],
          ['Brexanolone (Zulresso) IV', 'GABA-A PAM (neurosteroid allopregnanolone)', 'Postpartum Depression (2019)', 'Phase 3 RCT; 60-hour IV infusion'],
          ['Zuranolone (Zurzuvae) PO', 'GABA-A PAM (oral neurosteroid)', 'MDD + PPD (2023, FDA approved)', 'LANDSCAPE, NEST trials; 14-day oral course'],
          ['Lumateperone (Caplyta)', 'Multi-receptor (D1/D2, 5-HT2A, SERT)', 'Bipolar I+II depression (2021); MDD adjunct (ongoing)', 'Phase 3 data presented ACNP 2026 (Bhagwagar et al.)'],
          ['Seltorexant', 'Orexin-2 receptor antagonist (first-in-class)', 'MDD with insomnia symptoms (Phase 3)', 'Vs quetiapine XR as adjunct; Phase 3 ongoing (J&J, ACNP 2026)']
        ]
      ),
      EMPTY(),

      H2('3.2 Drugs Under Investigation (2024-2026 Pipeline)'),
      H3('Glutamatergic Agents'),
      BULLET('Dextromethorphan (DXM): NMDA antagonist being repurposed as adjunct to antidepressants. Indian RCT protocol published (Maji S et al., BMJ Open, 2024 Apr. [PMID: 38688675]) - Group Sequential Adaptive Design trial at AIIMS-type institution.'),
      BULLET('AUVELITY (d-amphetamine + bupropion): FDA-approved 2022 for MDD; uses bupropion to extend DXM half-life; oral glutamate modulator.'),
      BULLET('Azetukalner (Xenon Pharmaceuticals): Kv7 potassium channel modulator under Phase 3 for bipolar depression - novel mechanism to stabilize neuronal hyperexcitability without mania risk.'),

      H3('Neuroactive Steroids & GABA Modulators'),
      BULLET('SAGE-324: Oral GABA-A PAM in development for essential tremor; potential mood applications.'),
      BULLET('Zuranolone continues to expand labelling and real-world data collection post-2023 approval.'),

      H3('Thyroid Hormone Receptor Agonists'),
      BULLET('Elunetirom (ABX-002) by Autobahn Therapeutics: Brain-targeted oral TRβ agonist. Novel approach - selective thyroid activity in neural circuits of depression without peripheral thyroid side effects.'),

      H3('Endoxifen - Indian Significance'),
      BULLET('Endoxifen, the active metabolite of tamoxifen, is being studied by Indian researchers as a novel mood stabilizer for bipolar disorder - particularly acute mania.'),
      BULLET('TIDE Trial (2026): International double-blind RCT of adjunctive trimetazidine for bipolar depression - includes Indian sites (Kim JH et al., BMC Psychiatry, 2026 Apr. [PMID: 41933313]).'),
      EMPTY(),

      H2('3.3 Psychedelics & Psychoplastogens'),
      P('This is the fastest-growing area in mood pharmacotherapy. Psychedelics act primarily via 5-HT2A receptor agonism, triggering neuroplasticity and the "psychoplastic" effect - rapid remodelling of dendritic spines.'),
      makeTable(
        ['Agent', 'Route', 'Mechanism', 'Evidence Level', 'PMID'],
        [
          ['Psilocybin', 'Oral, assisted therapy', '5-HT2A agonist; BDNF-mediated synaptogenesis', 'Phase 2/3 (COMP360 Phase 3 data 2025-26)', '39741440'],
          ['DT-120 (lysergide d-tartrate)', 'ODT (dissolving tablet)', '5-HT2A agonist', 'Phase 3 hit primary endpoints 2025-26 (Psychiatric Times Q2 2026)', 'Pipeline'],
          ['MDMA-assisted therapy', 'Oral with psychotherapy', '5-HT/DA/NE releaser; reduces amygdala fear response', 'Phase 3; R-MDMA (EMP-01) improved SAD outcomes', 'Pipeline'],
          ['DMT (N,N-dimethyltryptamine)', 'Vaporized (novel route)', '5-HT2A/1A agonist; ultra-rapid onset', 'Phase 2a: rapid & sustained antidepressant effect in TRD (Falchi-Carvalho, Neuropsychopharmacol, 2025)', '40258990'],
          ['BPL-003 (synthetic psychedelic)', 'Oral', '5-HT2A agonist', 'Phase 2a: rapid reductions in MADRS score in TRD on SSRIs (CNS Drugs 2026)', 'Pipeline']
        ]
      ),
      EMPTY(),
      P('Note for Indian context: Psychedelic-assisted therapies are not yet approved in India. Legal status, ethical framework, and healthcare infrastructure readiness are major barriers. However, academic research discussions are ongoing through NIMHANS and IPS.'),
      EMPTY(),

      // ─── SECTION 4: TRD ───────────────────────────────────────────────────
      new Paragraph({ children: [new PageBreak()] }),
      H1('4. Treatment-Resistant Depression (TRD) - Recent Advances'),

      H2('4.1 Definition'),
      P('TRD is defined as failure to achieve adequate response to at least two antidepressant trials of adequate dose and duration (typically ≥6 weeks each) in the current episode.'),
      P('Note: Some guidelines (CANMAT 2023 Update, Lam RW et al., Can J Psychiatry, 2024 [PMID: 38711351]) now distinguish "difficult-to-treat depression" (DTD) as a broader category including MDD with incomplete response or significant functional impairment.'),
      EMPTY(),

      H2('4.2 Ketamine / Esketamine'),
      BULLET('Ketamine (IV, 0.5 mg/kg over 40 min): Gold standard off-label treatment. Antidepressant effect within 2-24 hours, sustained ~1 week.'),
      BULLET('Mechanism: NMDA blockade on GABAergic interneurons → glutamate surge → AMPA activation → BDNF release → synaptogenesis.'),
      BULLET('30-60% of TRD patients respond to acute ketamine/esketamine trial.'),
      BULLET('Esketamine nasal spray (Spravato): FDA/EMA approved. 2023 landmark trial showed superiority over quetiapine augmentation for TRD over 32 weeks (NEJM 2023; Maudsley Guidelines, 15th ed.).'),
      BULLET('KADS Study (RCT, Br J Psychiatry 2023 [PMID: 38108319]): Repeated subcutaneous ketamine injections over 4 weeks were safe and effective for TRD.'),
      BULLET('Personalized use: Medeiros GC et al., Transl Psychiatry, 2024 [PMID: 39613748] - identifies predictors of ketamine response (younger age, higher BMI, no psychosis history).'),

      H2('4.3 Brain Stimulation Therapies'),
      makeTable(
        ['Modality', 'Recent Development (2024-2026)', 'Evidence', 'PMID'],
        [
          ['Repetitive TMS (rTMS)', 'Standard deep TMS (H1-coil) approved for MDD. Right DLPFC targeting for bipolar mania studied in Indian RCT.', 'Strong for MDD; Indian RCT for bipolar mania', 'Indian BD guideline 2026'],
          ['Accelerated iTBS (aiTBS)', 'Stanford SAINT protocol: 50 sessions/5 days; >70% remission in TRD. RCT in JAMA Psychiatry 2024 for bipolar depression.', 'Phase 2 RCT (Sheline YI et al., JAMA Psychiatry 2024)', '38985492'],
          ['Transcranial Direct Current Stimulation (tDCS)', 'Systematic review + meta-analysis (JAMA Netw Open 2025): tDCS effective for depression, scalable, low-cost - relevant for LMICs including India.', 'Meta-analysis 2025', '40531534'],
          ['Vagus Nerve Stimulation (VNS)', '1-year sham-controlled RCT (Brain Stimul 2025): VNS superior to sham in TRD over 12 months. FDA approved for chronic/recurrent TRD.', 'Level 1 RCT', '39706521'],
          ['ECT', 'Remains gold standard for severe/psychotic depression, active suicidal ideation. Ketamine may enhance ECT effect. Broadly available in India.', 'Established', 'Multiple'],
          ['Deep Brain Stimulation (DBS)', 'Subcallosal cingulate (SCC25), VCVS targets under investigation. Individualized programming with imaging-guided lead placement emerging.', 'Phase 2/open-label', 'Pipeline']
        ]
      ),
      EMPTY(),

      H2('4.4 Pharmacogenomics-Guided Treatment (PGx)'),
      P('A major 2025 systematic review and meta-analysis (Fares-Otero NE et al., Eur Neuropsychopharmacol, 2025 Nov. [PMID: 40889463]) confirmed that PGx-guided antidepressant selection significantly improves functional outcomes and quality of life in affective disorders. Genes of interest include:'),
      BULLET('CYP2D6 - metabolizes most TCAs, paroxetine, fluoxetine, venlafaxine, aripiprazole'),
      BULLET('CYP2C19 - metabolizes citalopram, escitalopram, sertraline, diazepam'),
      BULLET('SLC6A4 (serotonin transporter gene, 5-HTTLPR) - modifies SSRI response and stress reactivity'),
      BULLET('COMT - dopamine metabolism; relevant for fatigue, anhedonia, and cognitive symptoms'),
      P('PGx panels are becoming commercially available in Indian tertiary centres (e.g., Strand Life Sciences, Mapmygenome).'),
      EMPTY(),

      // ─── SECTION 5: PSYCHOTHERAPY & DIGITAL ──────────────────────────────
      new Paragraph({ children: [new PageBreak()] }),
      H1('5. Advances in Psychotherapy & Digital Mental Health'),

      H2('5.1 Evidence-Based Psychotherapies - New Developments'),
      makeTable(
        ['Therapy', 'Recent Advance', 'Relevance'],
        [
          ['Cognitive Behavioural Therapy (CBT)', 'Digital delivery (iCBT) via smartphone proven equivalent to therapist-led CBT for mild-moderate depression in multiple RCTs (2023-25)', 'High scalability for India'],
          ['Behavioural Activation (BA)', 'Task-sharing model: lay counsellors deliver BA; MANAS/VISHRAM trials in India prove effectiveness in primary care', 'Critical for India\'s treatment gap'],
          ['Mindfulness-Based Cognitive Therapy (MBCT)', 'Standard of care for preventing depression relapse (3+ prior episodes); equivalent to maintenance antidepressants in recent meta-analyses', 'Growing evidence base'],
          ['Heartfulness Meditation', 'RCT (Philip ST et al., Medicine Baltimore, 2025 [PMID: 41305815]): Heartfulness meditation altered neuroendocrine profiles (stress hormones) in Indian participants - evidence base for yoga/meditation-based interventions', 'India-specific evidence'],
          ['Interpersonal Therapy (IPT)', 'Modified IPT for postpartum depression in LMICs showing strong efficacy; PACT trial in India ongoing', 'Relevant for perinatal psychiatry'],
          ['Collaborative Care Model', 'ARTEMIS trial: Intervention for depression & suicide among adolescents in Indian slums (Mukherjee A et al., BMJ Open 2024 [PMID: 38772584])', 'India - community level']
        ]
      ),
      EMPTY(),

      H2('5.2 Digital Mental Health Tools'),
      P('Digital mental health is the most rapidly scaling space in global psychiatry:'),
      BULLET('Smartphone apps (e.g., Wysa, Youper, iCall, Vandrevala Foundation app in India): Provide CBT-based modules, mood tracking, crisis helplines.'),
      BULLET('Chatbot-delivered therapy: Woebot (CBT-based), Wysa (Indian origin, AIML-powered) - validated in RCTs for mild-moderate depression.'),
      BULLET('OptimizeD Trial (India, 2025-ongoing): Phase III RCT comparing Healthy Activity Programme (HAP psychotherapy) vs antidepressant medication in primary care, Bhopal, Madhya Pradesh. Uses PEERS smartphone app for supervision/quality assurance. (Sangath/AIIMS/HMS collaboration, Springer BMC Psychiatry 2025).'),
      BULLET('Telepsychiatry: Post-COVID accelerated adoption in India; DMHP and iCall telepsychiatry services now provide coverage in underserved districts.'),
      BULLET('AI-driven mood monitoring: Passive sensing (phone usage, GPS, accelerometry) for prodromal mood episode detection in bipolar disorder - research phase.'),
      BULLET('PEERS app (India): Smartphone-based supervision platform for task-sharing psychological therapies in rural India - validated by Sangath.'),
      EMPTY(),

      H2('5.3 Adjunctive Non-Pharmacological Approaches'),
      BULLET('Ashwagandha (Withania somnifera): RCT (Kale S et al., J Psychoactive Drugs, 2026 [PMID: 39498904]) showed safety and efficacy for cognition, energy, and mood - evidence for Ayurvedic adjuncts.'),
      BULLET('Creatine monohydrate: Pilot RCT (Sherpa NN et al., Eur Neuropsychopharmacol, 2025 [PMID: 39488067]) - add-on to CBT in under-resourced area; feasible & promising for energy metabolism in depression.'),
      BULLET('Aerobic exercise: Grade A evidence as monotherapy for mild depression and adjunct for moderate-severe; 30-45 min moderate aerobic activity 3-5x/week.'),
      BULLET('Chronotherapy: Sleep deprivation, bright light therapy, and sleep phase advance - emerging adjuncts for bipolar depression; rapid but transient effects when used alone.'),
      EMPTY(),

      // ─── SECTION 6: INDIA ─────────────────────────────────────────────────
      new Paragraph({ children: [new PageBreak()] }),
      H1('6. India-Specific Research & Trials'),

      H2('6.1 Landmark Indian Guidelines (2026)'),
      P('The Indian Journal of Psychiatry published updated Clinical Practice Guidelines for the Management of Bipolar Disorder in 2026 (Multi-institutional, led by JIPMER, NIMHANS, AIIMS). Key India-specific highlights:'),
      BULLET('First consolidated Indian guideline for BD integrating DSM-5/ICD-11 criteria, Indian data, and treatment preferences.'),
      BULLET('Lithium remains first-line maintenance in India despite monitoring concerns; valproate widely used but metabolic risk acknowledged.'),
      BULLET('Olanzapine and risperidone commonly used for maintenance mania in India; antipsychotics now recognized as viable maintenance alternative to mood stabilizers.'),
      BULLET('Ketamine/esketamine: Recognized for TRBD; Indian ketamine data reviewed - few India-based studies but consistent with international literature.'),
      BULLET('Endoxifen (tamoxifen metabolite) studied in acute mania at Indian centres.'),
      BULLET('rTMS: Indian sham-controlled RCT - adjunctive high-frequency rTMS over right DLPFC superior for bipolar mania.'),
      BULLET('No Indian data on DSM-5 defined mixed states/presentations yet - acknowledged gap.'),
      EMPTY(),

      H2('6.2 Ongoing/Recent Indian Clinical Trials'),
      makeTable(
        ['Trial / Study', 'Institution', 'Topic', 'Status/PMID'],
        [
          ['Dextromethorphan as adjunct in MDD', 'AIIMS Bhubaneswar (Maji S, Mohapatra D)', 'Repurposing DXM as NMDA antagonist adjunct for MDD; Group Sequential Adaptive RCT protocol', 'Protocol published BMJ Open 2024 [PMID: 38688675]'],
          ['Bupropion for T2DM + Depression self-care', 'AIIMS Jodhpur (Shamim MA et al.)', 'Bupropion cross-over RCT for glycaemic control in comorbid T2DM and depression', 'Protocol published BMJ Open 2024 [PMID: 38834315]'],
          ['ARTEMIS Trial - Adolescent Depression in Slums', 'PHFI / NIMHANS (Mukherjee A et al.)', 'Community intervention for depression and suicide prevention in urban slum adolescents; cluster RCT', 'Process evaluation published BMJ Open 2024 [PMID: 38772584]'],
          ['OptimizeD Trial - HAP vs ADM in Primary Care', 'Sangath/AIIMS/HMS - Bhopal, MP', 'Phase III RCT: Healthy Activity Programme (psychotherapy) vs antidepressant medication in rural primary care', 'Ongoing 2025 [Springer BMC Psychiatry 2025]'],
          ['Heartfulness Meditation RCT', 'Indian-based (Philip ST, Thimmapuram J)', 'Neuroendocrine profile changes with Heartfulness meditation; mood and stress outcomes', 'Published Medicine (Baltimore) 2025 [PMID: 41305815]'],
          ['Kushal Maa - mHealth for Perinatal Mental Health', 'Multi-site India (El Ayadi AM et al.)', 'Group-based mHealth education & social support for maternal depression and neonatal outcomes', 'Protocol published BMJ Open 2025 [PMID: 40578858]'],
          ['TIDE Trial - Trimetazidine for Bipolar Depression', 'International incl. India (Reddy PV - NIMHANS)', 'Double-blind RCT: adjunctive trimetazidine for bipolar depression; mitochondrial/metabolic mechanism', 'Protocol published BMC Psychiatry 2026 [PMID: 41933313]'],
          ['BiD-CoIN Study', 'Multi-centre India (Grover S, Avasthi A et al.)', 'Course & outcome study of Bipolar I vs II disorder in India; comparative clinical profiles', 'Published Indian J Psychiatry 2024'],
          ['NIMHANS Bipolar Registry', 'NIMHANS Bengaluru', 'Longitudinal registry of BD patients; pharmacoepidemiology and outcomes in India', 'Ongoing'],
          ['Ashwagandha RCT for Mood', 'Indian industry-academic collaboration', 'Safety & efficacy of Ashwagandha root extract for cognition, energy, and mood', 'Published J Psychoactive Drugs 2026 [PMID: 39498904]']
        ]
      ),
      EMPTY(),

      H2('6.3 India-Specific Epidemiology Highlights (2025)'),
      BULLET('NIMHANS NMHS (2015-16): ~10.6% adults with diagnosable mental disorder; depressive disorders ~2.7%, bipolar disorder ~0.1%.'),
      BULLET('India accounts for ~36.6% of global disability from depression in South East Asia (WHO data).'),
      BULLET('Suicide: India contributes approximately 17% of global suicides; agricultural workers, students, and young women (15-39 years) are highest-risk groups.'),
      BULLET('Treatment gap: 80%+ for mental disorders in rural India. DMHP (District Mental Health Programme) aims to bridge primary care gap.'),
      BULLET('Government of India Mental Health Policy 2014 and National Mental Health Programme - scaled up through National Health Mission from 2023 onward.'),
      EMPTY(),

      // ─── SECTION 7: RAPID SUMMARY / GIST ─────────────────────────────────
      new Paragraph({ children: [new PageBreak()] }),
      H1('7. Quick-Reference Gist for Exam & Seminar'),

      H2('7.1 Top "What\'s New" Points - Must Know for 2026'),
      makeTable(
        ['Category', 'Key New Point'],
        [
          ['Neurobiology', 'Shift from monoamine deficiency to Glutamate/GABA, Neuroinflammation, BDNF-Neuroplasticity, HPA-Neurosteroid models'],
          ['New drug class', 'Neurosteroids (GABA-A PAMs): brexanolone (PPD), zuranolone (MDD+PPD) - first entirely new class since atypical antipsychotics'],
          ['TRD breakthrough', 'Esketamine nasal spray (Spravato) - only FDA-approved drug for TRD + suicidal ideation; ketamine broadly accepted off-label'],
          ['Psychedelics', 'Psilocybin Phase 3 (COMP360); DT-120 hit Phase 3 endpoints; DMT Phase 2a positive - psychoplastogens redefine TRD possibilities'],
          ['Brain stimulation', 'Accelerated iTBS (Stanford SAINT): >70% TRD remission in 5 days; VNS FDA-approved for chronic TRD; tDCS scalable for LMICs'],
          ['Pharmacogenomics', 'PGx-guided antidepressant selection: Meta-analysis 2025 confirms improved functional outcomes'],
          ['Digital health', 'iCBT equivalent to face-to-face; Wysa (Indian) validated; OptimizeD trial running in Bhopal'],
          ['India-specific', 'BD CPG 2026 (Indian), TIDE trial (trimetazidine at NIMHANS), ARTEMIS (adolescent slum depression), Dextromethorphan RCT (AIIMS)'],
          ['Failed 2025 trials', 'KOR antagonists (J&J, Neumora): Multiple kappa-opioid receptor antagonist Phase 3 trials failed - highlights CNS drug development challenges'],
          ['Bipolar advances', 'Lumateperone approved for bipolar depression; azetukalner (Kv7 modulator) in pipeline; theta-burst stimulation meta-analysis 2025']
        ]
      ),
      EMPTY(),

      H2('7.2 Mnemonic - GREAT Advances'),
      BULLET('G - Glutamate modulators (ketamine, esketamine, DXM, AMPA potentiators)'),
      BULLET('R - Rapid-acting antidepressants (ketamine: 2-24 hours) and Receptor-targeted (orexin, PGx)'),
      BULLET('E - Esketamine (Spravato) + ECT refinements + Electrostimulation (aiTBS, VNS, tDCS)'),
      BULLET('A - Affective neuroscience - neuroplasticity, BDNF, neuroinflammation biomarkers'),
      BULLET('T - Technology/Digital (iCBT, telepsychiatry, AI sensing, apps) + TRD new definitions'),
      EMPTY(),

      // ─── REFERENCES ───────────────────────────────────────────────────────
      new Paragraph({ children: [new PageBreak()] }),
      H1('8. Key References'),
      P('Sources consulted for this document:', true),
      EMPTY(),
      BULLET('Kaplan & Sadock\'s Comprehensive Textbook of Psychiatry, 11th Edition.'),
      BULLET('Maudsley Prescribing Guidelines in Psychiatry, 15th Edition, 2024.'),
      BULLET('Katzung\'s Basic and Clinical Pharmacology, 16th Edition.'),
      BULLET('Eric Kandel PRINCIPLES OF NEURAL SCIENCE, 6th Edition.'),
      EMPTY(),
      BULLET('Fares-Otero NE et al. PGx-guided antidepressant treatment - meta-analysis. Eur Neuropsychopharmacol. 2025. PMID: 40889463'),
      BULLET('Loo C et al. KADS study - Subcutaneous ketamine for TRD. Br J Psychiatry. 2023. PMID: 38108319'),
      BULLET('McIntyre RS & Jain R. Glutamatergic modulators for MDD. CNS Drugs. 2024. PMID: 39150594'),
      BULLET('Medeiros GC et al. Personalized use of ketamine/esketamine. Transl Psychiatry. 2024. PMID: 39613748'),
      BULLET('Singh B, Swartz HA et al. Bipolar disorder. Lancet. 2025. PMID: 40712624'),
      BULLET('Richardson E et al. Transformative Therapies for Depression. Annu Rev Med. 2025. PMID: 39527720'),
      BULLET('Hoyer D. Psychedelics, entactogens, psychoplastogens for depression. Br J Pharmacol. 2026. PMID: 40518133'),
      BULLET('Aaronson ST et al. Single-dose psilocybin for TRD - Open label trial. Am J Psychiatry. 2025. PMID: 39741440'),
      BULLET('Falchi-Carvalho M et al. Vaporized DMT Phase 2a for TRD. Neuropsychopharmacology. 2025. PMID: 40258990'),
      BULLET('Conway CR et al. VNS in TRD - 1-year sham-controlled RCT. Brain Stimul. 2025. PMID: 39706521'),
      BULLET('Sheline YI et al. Accelerated iTBS for bipolar depression RCT. JAMA Psychiatry. 2024. PMID: 38985492'),
      BULLET('Ren C et al. Transcranial electrical stimulation in depression - meta-analysis. JAMA Netw Open. 2025. PMID: 40531534'),
      BULLET('Lam RW et al. CANMAT 2023 update on MDD management. Can J Psychiatry. 2024. PMID: 38711351'),
      BULLET('Miller AH. Advancing an inflammatory subtype of major depression. Am J Psychiatry. 2025. PMID: 40329642'),
      BULLET('Maji S et al. Dextromethorphan adjunct in MDD - RCT protocol. BMJ Open. 2024. PMID: 38688675'),
      BULLET('Mukherjee A et al. ARTEMIS trial process evaluation - adolescent depression in India. BMJ Open. 2024. PMID: 38772584'),
      BULLET('Philip ST et al. Heartfulness meditation RCT - neuroendocrine profiles. Medicine (Baltimore). 2025. PMID: 41305815'),
      BULLET('Kim JH et al. TIDE trial - trimetazidine for bipolar depression protocol. BMC Psychiatry. 2026. PMID: 41933313'),
      BULLET('Grover S, Avasthi A et al. BiD-CoIN study. Indian J Psychiatry. 2024.'),
      BULLET('Clinical Practice Guidelines for Bipolar Disorder - Indian Journal of Psychiatry 2026 (JIPMER/NIMHANS/AIIMS). PMC12900052.'),
      BULLET('Psychiatric Times Q2 2026 Pipeline Review - www.psychiatrictimes.com'),
      EMPTY(),
      new Paragraph({
        children: [new TextRun({ text: 'Document ends. Prepared by Orris AI for PG Resident Seminar, July 2026.', italics: true, color: '888888', size: 18 })],
        alignment: AlignmentType.CENTER
      })
    ]
  }]
});

Packer.toBuffer(doc).then(buf => {
  fs.writeFileSync('/home/daytona/workspace/mood-disorders-seminar/Recent_Advances_Mood_Disorders.docx', buf);
  console.log('Document created successfully!');
}).catch(err => {
  console.error('Error:', err);
  process.exit(1);
});

cd /home/daytona/workspace/mood-disorders-seminar && node generate_doc.js 2>&1

python3 /home/daytona/skills/docx/scripts/office/validate.py /home/daytona/works…

ls -lh /home/daytona/workspace/mood-disorders-seminar/ && python3 -c "import zip…