MDD-001
Major Depressive Disorder · HPA-BDNF-Neuroinflammation Engine · VIZASL v1
MEBICAL · EOSE Fleet · TRB-MEBICAL-HEALTH-DOMAIN-001 · Day 90 · Real data · Cited · Sorries marked
MEBICAL · PSYCH ← RESEARCH
HPA axis (hypothalamus→pituitary→adrenal)
BDNF dimer (shrinking)
Hippocampal volume loss
Cortisol cloud particles
γ₁ floor anchor
PHASES
RX
BIOMARKERS
EEG
NPs
Pathophysiology
HPA Axis Hyperactivation
Hypothalamus-pituitary-adrenal axis dysregulation. Cortisol chronically elevated. CRH-ACTH-cortisol cascade stuck in overdrive. Cortisol crosses BBB → glucocorticoid receptor (GR) activation → hippocampal neurotoxicity. Hippocampal volume reduced 5–10% in chronic MDD.
Nestler et al. 2002 Neuron (MDD neurobiology review)
BDNF Hypothesis
Brain-derived neurotrophic factor reduced in depression. BDNF supports hippocampal neurogenesis (dentate gyrus), synaptic plasticity. Antidepressants increase BDNF. The Castrén hypothesis: depression = BDNF deficiency syndrome. The correlation is strong but not established as causal.
Duman & Monteggia 2006 Biol Psychiatry · Castrén 2005 Trends Neurosci
Neuroinflammation Hypothesis
IL-6, TNF-α, CRP elevated in subset (~30%) of MDD. Neuroinflammation drives IDO pathway → tryptophan → kynurenine (not serotonin). Reduces serotonin precursor. Explains inflammatory subtype. Anti-inflammatory augmentation strategies in trials.
Raison et al. 2010 · Dantzer et al. 2008 Nat Rev Neurosci
Serotonin Hypothesis — SORRY: Overclaimed
Serotonin deficiency theory of depression = widely taught, widely overclaimed. Moncrieff et al. 2022: systematic review found NO consistent evidence of low serotonin in MDD. SSRIs work but the mechanism is NOT simply serotonin replenishment. The field got ahead of the evidence.
Moncrieff et al. 2022 Mol Psychiatry (systematic review — "chemical imbalance" myth critique)
Default Mode Network Hyperactivity
DMN (medial PFC, posterior cingulate, angular gyrus) overactive at rest in MDD. Self-referential rumination. DMN should suppress during tasks but fails to deactivate. Ketamine rapidly suppresses DMN overactivity, correlating with immediate antidepressant effect.
Sheline et al. 2009 PNAS · Hamilton et al. 2011
Pharmacological PROVEN
SSRIs — First-Line
Sertraline, escitalopram, fluoxetine. ~60% response rate in first episode. 4–6 weeks for full effect. Well-tolerated. Mechanism: SERT blockade → synaptic serotonin increase. Works, but not via serotonin deficiency reversal (see SORRY-1).
Cipriani et al. 2018 Lancet (large network meta-analysis of 21 antidepressants)
Ketamine / Esketamine FDA 2019
NMDA antagonist. Rapid antidepressant effect (hours, not weeks). FDA-approved esketamine (Spravato) intranasal for TRD. Mechanism: glutamate AMPA potentiation, BDNF release, DMN suppression. SORRY: durability — effect wanes 1–2 weeks, re-dosing required.
Murrough et al. 2013 Am J Psychiatry (ketamine RCT)
ECT — Most Effective for Severe/TRD
Electroconvulsive therapy. 70–90% response in severe/TRD MDD. Most effective treatment in psychiatry. Mechanism: UNKNOWN. Anticonvulsant theory, BDNF surge, HPA normalisation — all proposed, none proven. SORRY: we use the most effective treatment without knowing why it works.
UK ECT Review Group 2003 · Geddes et al. · SORRY: mechanism unknown
Psilocybin Phase 2/3
Carhart-Harris et al. 2021 NEJM: psilocybin non-inferior to escitalopram at 6 weeks. Phase 3 not complete. FDA Breakthrough Therapy designation. Mechanism: 5-HT2A agonism → default mode network disruption → ego dissolution → neuroplasticity.
Carhart-Harris et al. 2021 NEJM (psilocybin vs escitalopram) · Phase 3 ongoing
rTMS — FDA Cleared
Repetitive transcranial magnetic stimulation. Left DLPFC stimulation. FDA cleared for MDD (2008) and TRD. 4–6 week course. ~50% response in TRD. No anaesthesia. Mechanism: cortical excitability modulation. Deep TMS (H-coil) reaches deeper structures.
O'Reardon et al. 2007 Biol Psychiatry (pivotal trial)
Biomarker Status LARGEST GAP IN MEDICINE
No Validated Diagnostic Biomarker for MDD
SORRY: MDD is diagnosed entirely clinically (DSM-5 criteria). No blood test, no imaging biomarker, no EEG test confirms MDD. The biomarker gap in psychiatry is the largest in medicine. 30% treatment-resistant. No way to predict who will respond to which drug.
SORRY: This is the fundamental challenge of psychiatric drug development
CRP elevationNeuroinflammation subtype marker. High CRP → poor SSRI response, better anti-inflammatory/immune approach. Not diagnostic. Subtype stratifier research only.
Cortisol awak. responseCAR: cortisol spike 30min after waking. Flattened in MDD. HPA dysregulation marker. Research use.
Sleep EEG REM latencyShortened REM latency (REM starts sooner in sleep) = most replicated biological finding in MDD. Research use only. STRONG
EEG in MDD
Alpha asymmetryReduced LEFT frontal alpha relative to right. Alpha inversely related to cortical activation. Less left frontal activation = approach motivation deficit. Approach/withdrawal model of frontal asymmetry. Davidson 1988 — research biomarker
Theta cordancePredicts antidepressant response (PREDICT study). Low prefrontal theta cordance after 1 week → poor response → switch earlier. Research paradigm. Cook et al. 2002
Sleep REM latency STRONGShortened REM latency in MDD EEG sleep study. First REM period earlier, longer, denser. Most replicated biological finding across MDD research.
DMN resting fMRIHyperactive default mode network at rest. Rumination correlate. Not technically EEG but resting-state oscillations overlap. Ketamine immediately suppresses.
Novel Patterns (8)
SORRYNP-MDD-001 · Serotonin deficiency hypothesis: no consistent evidence of low serotonin in MDD (Moncrieff 2022) — SSRIs work but mechanism is NOT serotonin replenishment
PROVENNP-MDD-002 · ECT most effective treatment in psychiatry (~80% response TRD) · mechanism completely unknown · "we don't know why the best treatment works"
PROVENNP-MDD-003 · HPA axis: cortisol → hippocampal GR activation → neurotoxicity → volume loss · first structural biomarker of depression · reversible with treatment
PROVENNP-MDD-004 · Ketamine: hours vs weeks for effect · NMDA antagonism → glutamate → BDNF → DMN suppression · fastest antidepressant mechanism known
EMERGINGNP-MDD-005 · Neuroinflammation subtype (high CRP): SSRIs don't work, anti-inflammatory approaches might · subtype stratification changes treatment algorithm
OPENNP-MDD-006 · Psilocybin: Phase 2 non-inferior to escitalopram · DMN disruption = ego dissolution = neuroplasticity window · Phase 3 results pending
OPENNP-MDD-007 · REM latency shortening: most replicated biological finding in MDD · still not used clinically · gap between research biomarker and clinical tool
SORRYNP-MDD-008 · No diagnostic biomarker · 30% TRD · ECT mechanism unknown · ketamine durability fails 1-2 weeks · serotonin myth still taught · psychiatry biomarker gap = largest in medicine
⚠ OPEN SORRIES · MDD-001
SORRY-1 · Serotonin hypothesis overclaimed
Moncrieff et al. 2022 Molecular Psychiatry: systematic umbrella review found no consistent evidence that serotonin levels or activity are reduced in people with depression. SSRIs work, but not by correcting a serotonin deficiency. The "chemical imbalance" story was marketing, not mechanism.

SORRY-2 · ECT mechanism unknown
Electroconvulsive therapy has 70–90% response rates in severe/TRD MDD, making it the most effective psychiatric treatment. The mechanism is completely unknown. Proposed theories include anticonvulsant effect, BDNF surge, HPA normalisation — none established.

SORRY-3 · Ketamine durability
Ketamine produces rapid antidepressant effects in hours but effects typically wane within 1–2 weeks without re-dosing. The maintenance protocol (frequency, duration) is not standardised. Dependency risk with chronic use unclear.

SORRY-4 · No diagnostic biomarker
MDD is diagnosed by clinical interview alone. No blood test, imaging finding, or EEG marker is validated for diagnosis. 30% of patients are treatment-resistant. No predictor of which drug will work for which patient exists.

SORRY-5 · Psilocybin Phase 3 incomplete
Phase 2 data is promising. Phase 3 trials are underway but not complete. Regulatory approval pending outcome. Cannot claim PROVEN status until Phase 3 complete.
MDD-001 · HPA-BDNF-NEUROINFLAMMATION · SEROTONIN MYTH · ECT BEST UNKNOWN MECHANISM · KETAMINE HOURS NOT WEEKS
γ₁ = 14.134725141734693