graph LR
Sleep_disturbance["Sleep disturbance"]
Joint_instability_and_recurrent_soft_tissue_injury["Joint instability and recurrent soft-tissue injury"]
Candidate_extracellular_matrix_remodeling_abnormalities["Candidate extracellular matrix remodeling abnormalities"]
Myofibroblast_like_fibroblast_transition["Myofibroblast-like fibroblast transition"]
Chronic_pain["Chronic pain"]
Arthralgia["Arthralgia"]
Joint_dislocation["Joint dislocation"]
Joint_hypermobility["Joint hypermobility"]
Candidate_extracellular_matrix_remodeling_abnormalities --> Myofibroblast_like_fibroblast_transition
Joint_instability_and_recurrent_soft_tissue_injury --> Joint_dislocation
Joint_instability_and_recurrent_soft_tissue_injury --> Chronic_pain
Joint_instability_and_recurrent_soft_tissue_injury --> Arthralgia
Joint_hypermobility --> Joint_instability_and_recurrent_soft_tissue_injury
Chronic_pain --> Sleep_disturbance
style Sleep_disturbance fill:#fef3c7
style Joint_instability_and_recurrent_soft_tissue_injury fill:#dbeafe
style Candidate_extracellular_matrix_remodeling_abnormalities fill:#dbeafe
style Myofibroblast_like_fibroblast_transition fill:#dbeafe
style Chronic_pain fill:#fef3c7
style Arthralgia fill:#fef3c7
style Joint_dislocation fill:#fef3c7
style Joint_hypermobility fill:#fef3c7
graph LR
Monoamine_Deficiency["Monoamine Deficiency"]
IL1B["IL1B"]
Oligodendrocyte_Dysfunction_and_Demyelination["Oligodendrocyte Dysfunction and Demyelination"]
Neurogenic_Niche_Interferon_Signaling_Activation["Neurogenic Niche Interferon Signaling Activation"]
PENK+_GABAergic_Interneuron_Activation["PENK+ GABAergic Interneuron Activation"]
daf_2_insulin_receptor_loss_of_function_immobility_C._elegans["daf-2 insulin-receptor loss-of-function immobility C. elegans"]
Excitation_Inhibition_Imbalance["Excitation-Inhibition Imbalance"]
Transcranial_Magnetic_Stimulation["Transcranial Magnetic Stimulation"]
Ketamine_Esketamine["Ketamine/Esketamine"]
Serotonergic_neuron_p38alpha_MAPK_conditional_knockout_mouse_under_social_defeat["Serotonergic-neuron p38alpha MAPK conditional knockout mouse under social defeat"]
Neuroplasticity_Deficits["Neuroplasticity Deficits"]
Selective_Serotonin_Reuptake_Inhibitors_SSRIs["Selective Serotonin Reuptake Inhibitors (SSRIs)"]
Reference_Point_Dysregulation["Reference Point Dysregulation"]
C_511T["C-511T"]
Electroconvulsive_Therapy["Electroconvulsive Therapy"]
Neuroinflammation["Neuroinflammation"]
Astrocyte_specific_Fgf13_knockout_and_overexpression_mouse_under_chronic_stress["Astrocyte-specific Fgf13 knockout and overexpression mouse under chronic stress"]
Gsdmd_Casp1_and_astrocytic_Nlrp3_knockout_mice_under_chronic_mild_stress["Gsdmd, Casp1 and astrocytic Nlrp3 knockout mice under chronic mild stress"]
tph_1_serotonin_null_C._elegans["tph-1 serotonin-null C. elegans"]
Microglial_P2rx7_and_Il6_and_astrocytic_Il6ra_knockdown_mice_under_chronic_social_defeat_stress["Microglial P2rx7 and Il6 and astrocytic Il6ra knockdown mice under chronic social defeat stress"]
Lithium_Augmentation["Lithium Augmentation"]
Psilocybin_Assisted_Therapy["Psilocybin-Assisted Therapy"]
Stress_Responsive_Transcription_Factor_Reprogramming["Stress-Responsive Transcription Factor Reprogramming"]
Serotonin_Norepinephrine_Reuptake_Inhibitors_SNRIs["Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)"]
Stalled_Adult_Hippocampal_Neurogenesis["Stalled Adult Hippocampal Neurogenesis"]
Oligodendrocyte_Dysfunction_and_Demyelination --> Neuroplasticity_Deficits
Oligodendrocyte_Dysfunction_and_Demyelination --> Neuroinflammation
Stalled_Adult_Hippocampal_Neurogenesis --> Neuroplasticity_Deficits
Neurogenic_Niche_Interferon_Signaling_Activation --> Stalled_Adult_Hippocampal_Neurogenesis
Neurogenic_Niche_Interferon_Signaling_Activation --> Neuroinflammation
Stress_Responsive_Transcription_Factor_Reprogramming --> Stalled_Adult_Hippocampal_Neurogenesis
Stress_Responsive_Transcription_Factor_Reprogramming --> Excitation_Inhibition_Imbalance
PENK+_GABAergic_Interneuron_Activation --> Excitation_Inhibition_Imbalance
Selective_Serotonin_Reuptake_Inhibitors_SSRIs --> Monoamine_Deficiency
Serotonin_Norepinephrine_Reuptake_Inhibitors_SNRIs --> Monoamine_Deficiency
Electroconvulsive_Therapy --> Neuroplasticity_Deficits
Ketamine_Esketamine --> Excitation_Inhibition_Imbalance
Transcranial_Magnetic_Stimulation --> Neuroplasticity_Deficits
Lithium_Augmentation --> Neuroplasticity_Deficits
Psilocybin_Assisted_Therapy --> Neuroplasticity_Deficits
tph_1_serotonin_null_C._elegans --> Monoamine_Deficiency
daf_2_insulin_receptor_loss_of_function_immobility_C._elegans --> Reference_Point_Dysregulation
Serotonergic_neuron_p38alpha_MAPK_conditional_knockout_mouse_under_social_defeat --> Monoamine_Deficiency
Astrocyte_specific_Fgf13_knockout_and_overexpression_mouse_under_chronic_stress --> Neuroinflammation
Gsdmd_Casp1_and_astrocytic_Nlrp3_knockout_mice_under_chronic_mild_stress --> Neuroinflammation
Microglial_P2rx7_and_Il6_and_astrocytic_Il6ra_knockdown_mice_under_chronic_social_defeat_stress --> Neuroinflammation
C_511T --> IL1B
style Monoamine_Deficiency fill:#dbeafe
style IL1B fill:#f3e8ff
style Oligodendrocyte_Dysfunction_and_Demyelination fill:#dbeafe
style Neurogenic_Niche_Interferon_Signaling_Activation fill:#dbeafe
style PENK+_GABAergic_Interneuron_Activation fill:#dbeafe
style daf_2_insulin_receptor_loss_of_function_immobility_C._elegans fill:#ede9fe
style Excitation_Inhibition_Imbalance fill:#dbeafe
style Transcranial_Magnetic_Stimulation fill:#fce7f3
style Ketamine_Esketamine fill:#fce7f3
style Serotonergic_neuron_p38alpha_MAPK_conditional_knockout_mouse_under_social_defeat fill:#ede9fe
style Neuroplasticity_Deficits fill:#dbeafe
style Selective_Serotonin_Reuptake_Inhibitors_SSRIs fill:#fce7f3
style Reference_Point_Dysregulation fill:#dbeafe
style C_511T fill:#f3e8ff
style Electroconvulsive_Therapy fill:#fce7f3
style Neuroinflammation fill:#dbeafe
style Astrocyte_specific_Fgf13_knockout_and_overexpression_mouse_under_chronic_stress fill:#ede9fe
style Gsdmd_Casp1_and_astrocytic_Nlrp3_knockout_mice_under_chronic_mild_stress fill:#ede9fe
style tph_1_serotonin_null_C._elegans fill:#ede9fe
style Microglial_P2rx7_and_Il6_and_astrocytic_Il6ra_knockdown_mice_under_chronic_social_defeat_stress fill:#ede9fe
style Lithium_Augmentation fill:#fce7f3
style Psilocybin_Assisted_Therapy fill:#fce7f3
style Stress_Responsive_Transcription_Factor_Reprogramming fill:#dbeafe
style Serotonin_Norepinephrine_Reuptake_Inhibitors_SNRIs fill:#fce7f3
style Stalled_Adult_Hippocampal_Neurogenesis fill:#dbeafe
name: com_Hypermobile_Ehlers-Danlos_Syndrome__Major_Depressive_Disorder
creation_date: '2026-09-18T02:40:05Z'
curation_status: CANDIDATE
notes: >-
Depression is a commonly reported hEDS comorbidity, though less
specifically studied than the anxiety/panic-disorder association. A large
propensity-matched cohort found a broad "depression" diagnostic category
in 18.7% of EDS patients versus matched controls (OR 1.3); this is a
broader depressive-disorder category rather than a figure specific to
major depressive disorder (see mapping_notes). A separate chart-review
cohort of adolescent/young adult hEDS patients found 30% of its
psychiatric-comorbidity subgroup (59% of the full cohort) reporting a
depression diagnosis. Directionality is UNKNOWN. No ICEES KG signal exists
for this pair: hEDS (MONDO:0007523) is not a node in the ICEES KG
snapshot at all (confirmed while curating the hEDS-POTS comorbidity
entry).
disease_a:
slug: Hypermobile_Ehlers-Danlos_Syndrome
preferred_term: Ehlers-Danlos syndrome, hypermobility type
term:
id: MONDO:0007523
label: Ehlers-Danlos syndrome, hypermobility type
disease_b:
slug: Major_Depressive_Disorder
preferred_term: major depressive disorder
term:
id: MONDO:0002009
label: major depressive disorder
directionality: UNKNOWN
hypotheses:
- description: >-
Hypothesis: depression in hEDS is largely secondary to the disease's
chronic pain, multisystem symptom burden, disability, and diagnostic
odyssey, though the same "neurovisceral phenotype" mechanism proposed for
anxiety (altered interoceptive/autonomic signaling and amygdala/insular
reactivity) may also predispose to mood symptoms rather than depression
being purely a reactive consequence of chronic illness.
evidence:
- reference: PMID:37761523
reference_title: "Exploring Comorbidities in Adolescent and Young Adults with Hypermobile Ehlers-Danlos Syndrome with and without a Surgical History: A Preliminary Investigation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Over half (59%) of the sample had documented psychiatric comorbidities, with the maximum number of reported psychiatric comorbidities being 4 for one patient. The mean number of psychiatric comorbidities was 1.2 (SD = 1.2). Of the 59% of the total sample of individuals reporting psychiatric comorbidities, 47% reported a diagnosis of anxiety and 30% reported a diagnosis of depression."
explanation: >-
A chart-review cohort of adolescent/young adult hEDS patients
documents a 30% depression diagnosis rate alongside a high overall
psychiatric comorbidity burden.
pathophysiology:
- name: Chronic-pain-associated mood dysregulation
description: >-
Sustained chronic pain, multisystem symptom burden, and disability
from hEDS are proposed to contribute to depressive symptoms, with a
possible additional contribution from the same altered
interoceptive/autonomic signaling implicated in hEDS-associated
anxiety.
biological_processes:
- preferred_term: sensory perception of pain
term:
id: GO:0019233
label: sensory perception of pain
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0007523
signal_disorder_b_id: MONDO:0002009
population: >-
TriNetX research network, retrospective propensity-matched analysis
(2005-2023), 59,128 matched pairs of EDS patients (excluding Marfan
syndrome) versus controls.
mapping_notes: >-
The cohort study reports a broad "depression" diagnostic category rather
than major depressive disorder specifically; recorded here against MDD
as the closest existing dismech disorder entry.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 18.7
notes: Depression (broad diagnostic category) prevalence in the EDS cohort.
- metric_type: OR
metric_value: 1.3
metric_ci_lower: 1.2
metric_ci_upper: 1.3
p_value: 0.001
notes: Odds ratio for depression in EDS versus propensity-matched controls. Reported by the source as p < 0.001, an upper bound, not a point estimate.
evidence:
- reference: PMID:41432355
reference_title: "Comprehensive Risk Profile of Gastrointestinal and Extra Articular Comorbidities in Ehlers-Danlos Syndrome: A Propensity-Matched Analysis of 118,256 Individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Psychiatric conditions showed heightened prevalence of anxiety (26.1%, OR 1.8, 95% CI 1.7-1.8, p < 0.001) and depression (18.7%, OR 1.3, 95% CI 1.2-1.3, p < 0.001)."
explanation: A large propensity-matched cohort quantifies elevated depression prevalence and odds ratio in EDS patients.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0007523
signal_disorder_b_id: MONDO:0002009
population: >-
Retrospective chart review of 100 adolescent and young adult hEDS
patients at a single pediatric hospital.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 30.0
notes: >-
Proportion of the psychiatric-comorbidity subgroup (59% of the
cohort) reporting a diagnosis of depression -- not a full-cohort
figure. The snippet's own denominator is that subgroup, so the
implied full-cohort rate would be lower (~30% of 59%, i.e. roughly
18%), which this record does not separately assert.
evidence:
- reference: PMID:37761523
reference_title: "Exploring Comorbidities in Adolescent and Young Adults with Hypermobile Ehlers-Danlos Syndrome with and without a Surgical History: A Preliminary Investigation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the 59% of the total sample of individuals reporting psychiatric comorbidities, 47% reported a diagnosis of anxiety and 30% reported a diagnosis of depression."
explanation: An independent smaller cohort corroborates a substantial depression diagnosis rate in hEDS patients.