name: Major Depressive Disorder
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-17T21:53:14Z'
category: Complex
parents:
- Psychiatric Disease
- Mood Disorder
disease_term:
preferred_term: major depressive disorder
term:
id: MONDO:0002009
label: major depressive disorder
has_subtypes:
- name: Melancholic Depression
description: Characterized by anhedonia, psychomotor changes, and diurnal
variation.
- name: Atypical Depression
description: Features mood reactivity, hypersomnia, hyperphagia, and rejection
sensitivity.
- name: Psychotic Depression
description: Depression with hallucinations or delusions.
- name: Seasonal Affective Disorder
description: Depression recurring in winter months.
- name: Peripartum Depression
description: Depression during pregnancy or postpartum period.
pathophysiology:
- name: Monoamine Deficiency
description: >
Reduced serotonin, norepinephrine, and dopamine neurotransmission in
key brain circuits. While oversimplified, this remains a foundation
for antidepressant pharmacotherapy.
cell_types:
- preferred_term: Serotonergic Neuron
term:
id: CL:0000850
label: serotonergic neuron
- preferred_term: Dopaminergic Neuron
term:
id: CL:0000700
label: dopaminergic neuron
- preferred_term: Noradrenergic Neuron
term:
id: CL:0008025
label: noradrenergic neuron
biological_processes:
- preferred_term: Serotonin Signaling
term:
id: GO:0007210
label: serotonin receptor signaling pathway
- preferred_term: Dopamine Signaling
term:
id: GO:0007212
label: dopamine receptor signaling pathway
evidence:
- reference: PMID:38331979
supports: SUPPORT
snippet: "The currently widely accepted theories of MDD pathogenesis include the
neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA)
axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic
influence hypothesis"
explanation: This review confirms the neurotransmitter hypothesis as a
foundational theory of MDD pathogenesis, though it notes that multiple
hypotheses are needed to fully explain the disorder.
- reference: PMID:39150594
supports: SUPPORT
snippet: "MDD is especially burdensome as approved monoamine antidepressant treatments
have weeks-long delays before clinical benefit and low remission rates."
explanation: This highlights the clinical reality of monoamine-based
treatments, confirming their use while acknowledging their limitations in
achieving remission.
- reference: PMID:38474387
supports: SUPPORT
snippet: "neuroinflammation and gut dysbiosis induce alterations in tryptophan
metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related
mechanisms, and glutamate-mediated excitotoxicity."
explanation: This demonstrates how inflammatory mechanisms contribute to
decreased serotonin synthesis, supporting the monoamine deficiency theory
while connecting it to broader pathophysiological processes.
- name: HPA Axis Dysregulation
description: >
Hyperactivity of the hypothalamic-pituitary-adrenal axis leads to
elevated cortisol, which may contribute to hippocampal atrophy and
cognitive symptoms.
cell_types:
- preferred_term: Corticotroph
term:
id: CL:0002309
label: corticotroph
biological_processes:
- preferred_term: Cortisol Response
term:
id: GO:0071385
label: cellular response to glucocorticoid stimulus
evidence:
- reference: PMID:38331979
supports: SUPPORT
snippet: "The currently widely accepted theories of MDD pathogenesis include the
neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA)
axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic
influence hypothesis"
explanation: This review identifies the HPA axis hypothesis as one of the
widely accepted core pathophysiological mechanisms in MDD.
- name: Neuroplasticity Deficits
description: >
Reduced BDNF and impaired synaptic plasticity in prefrontal cortex
and hippocampus. Successful treatments restore neuroplasticity.
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: Synaptic Plasticity
term:
id: GO:0048167
label: regulation of synaptic plasticity
evidence:
- reference: PMID:38331979
supports: SUPPORT
snippet: "The currently widely accepted theories of MDD pathogenesis include the
neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA)
axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic
influence hypothesis"
explanation: This comprehensive review identifies the neuroplasticity
hypothesis as one of the core accepted mechanisms in MDD pathogenesis.
- reference: PMID:39150594
supports: SUPPORT
snippet: "This narrative review provides a high-level overview of glutamate signaling
in synaptogenesis and neural plasticity and the implications of glutamate dysregulation
in depression."
explanation: This demonstrates the link between glutamate signaling,
synaptogenesis, and neural plasticity deficits in depression, supporting
the neuroplasticity deficit mechanism.
- reference: PMID:38474387
supports: SUPPORT
snippet: "neuroinflammation and gut dysbiosis induce alterations in tryptophan
metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related
mechanisms, and glutamate-mediated excitotoxicity."
explanation: This shows how inflammatory processes lead to impairments in
neuroplasticity-related mechanisms, connecting inflammation to
neuroplasticity deficits in MDD.
- name: Neuroinflammation
description: >
Elevated inflammatory cytokines (IL-6, TNF-alpha, CRP) observed in
depression. Inflammation may contribute to monoamine depletion and
neuroplasticity deficits.
cell_types:
- preferred_term: Microglia
term:
id: CL:0000129
label: microglial cell
evidence:
- reference: PMID:38331979
supports: SUPPORT
snippet: "The currently widely accepted theories of MDD pathogenesis include the
neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA)
axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic
influence hypothesis"
explanation: This review identifies the cytokine hypothesis as one of the
widely accepted theories of MDD pathogenesis, supporting the role of
inflammatory mechanisms.
- reference: PMID:38474387
supports: SUPPORT
snippet: "The involvement of central and peripheral inflammation in the pathogenesis
and prognosis of major depressive disorder (MDD) has been demonstrated. The
increase of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, and
TNF-α) in individuals with depression may elicit neuroinflammatory processes
and peripheral inflammation"
explanation: This provides direct evidence for elevated pro-inflammatory
cytokines in MDD and their role in eliciting neuroinflammatory processes.
- reference: PMID:38474387
supports: SUPPORT
snippet: "mechanisms that, in turn, can contribute to gut microbiota dysbiosis.
Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan
metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related
mechanisms, and glutamate-mediated excitotoxicity."
explanation: This demonstrates how neuroinflammation contributes to both
monoamine depletion (decreased serotonin) and neuroplasticity deficits,
confirming the description's mechanistic links.
- reference: PMID:20015486
supports: SUPPORT
snippet: This meta-analysis reports significantly higher concentrations of
the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects
compared with control subjects.
explanation: Meta-analysis evidence shows elevated proinflammatory cytokines
in major depression, supporting neuroinflammatory mechanisms.
- name: Mitochondrial Dysfunction
description: >
Impaired mitochondrial respiration and cellular energy metabolism contribute to
MDD pathophysiology. Patient-derived cells show decreased mitochondrial function,
altered membrane potential, and disrupted calcium homeostasis.
evidence:
- reference: PMID:38256041
supports: SUPPORT
snippet: "The link between mitochondria and major depressive disorder (MDD) is
increasingly evident, underscored both by mitochondria's involvement in many
mechanisms identified in depression and the high prevalence of MDD in individuals
with mitochondrial disorders."
explanation: This establishes the connection between mitochondrial
dysfunction and MDD, noting both mechanistic involvement and
epidemiological evidence.
- reference: PMID:38256041
supports: SUPPORT
snippet: "Similarities were observed between the Mito patient and a broader MDD
cohort, including decreased respiration and mitochondrial function."
explanation: This provides direct evidence from patient-derived cells
showing decreased mitochondrial respiration and function in MDD patients.
- reference: PMID:38256041
supports: SUPPORT
snippet: "the Non-R patient's data offered a new perspective on MDD, suggesting
a detrimental imbalance in mitochondrial and cellular processes, rather than
simply reduced functions."
explanation: This suggests that mitochondrial dysfunction in MDD may involve
complex imbalances beyond simple reduction, including altered respiratory
rates and calcium homeostasis.
phenotypes:
- name: Depressed Mood
category: Psychiatric
frequency: VERY_FREQUENT
diagnostic: true
phenotype_term:
preferred_term: Depression
term:
id: HP:0000716
label: Depression
- name: Anhedonia
category: Psychiatric
frequency: VERY_FREQUENT
diagnostic: true
notes: Loss of interest or pleasure
phenotype_term:
preferred_term: Anhedonia
term:
id: HP:0012154
label: Anhedonia
- name: Sleep Disturbance
category: Sleep
frequency: VERY_FREQUENT
notes: Insomnia or hypersomnia
phenotype_term:
preferred_term: Sleep Disturbance
term:
id: HP:0002360
label: Sleep disturbance
- name: Fatigue
category: Systemic
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- name: Poor Appetite
category: Systemic
frequency: FREQUENT
notes: Decreased or increased appetite
phenotype_term:
preferred_term: Poor Appetite
term:
id: HP:0004396
label: Poor appetite
- name: Concentration Difficulties
category: Cognitive
frequency: FREQUENT
phenotype_term:
preferred_term: Cognitive Impairment
term:
id: HP:0100543
label: Cognitive impairment
- name: Psychomotor Changes
category: Neurological
frequency: OCCASIONAL
notes: Retardation or agitation
phenotype_term:
preferred_term: Psychomotor Abnormality
term:
id: HP:0001266
label: Choreoathetosis
biochemical:
- name: Cortisol
presence: Elevated
context: HPA axis hyperactivity
evidence:
- reference: PMID:38331979
supports: SUPPORT
snippet: "The currently widely accepted theories of MDD pathogenesis include the
neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA)
axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic
influence hypothesis"
explanation: The HPA axis hypothesis supports elevated cortisol as a key
biochemical feature of MDD.
- name: BDNF
presence: Decreased
context: Reduced neuroplasticity marker
evidence:
- reference: PMID:38474387
supports: SUPPORT
snippet: "neuroinflammation and gut dysbiosis induce alterations in tryptophan
metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related
mechanisms, and glutamate-mediated excitotoxicity."
explanation: This demonstrates how neuroplasticity-related mechanisms are
impaired in MDD, which is consistent with decreased BDNF as a
neuroplasticity marker.
- name: Inflammatory Markers
presence: Elevated
context: IL-6, CRP, TNF-alpha
evidence:
- reference: PMID:38474387
supports: SUPPORT
snippet: "The increase of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6,
IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory
processes and peripheral inflammation"
explanation: This directly confirms elevated inflammatory cytokines
including IL-6 and TNF-α in MDD patients.
genetic:
- name: SLC6A4
association: Risk Factor
notes: Serotonin transporter gene
- name: BDNF
association: Risk Factor
notes: Val66Met polymorphism
- name: FKBP5
association: Risk Factor
notes: HPA axis regulation
- name: HTR2A
association: Risk Factor
notes: Serotonin receptor gene
environmental:
- name: Childhood Trauma
notes: Strong risk factor for adult depression
- name: Chronic Stress
notes: Major precipitant
evidence:
- reference: PMID:38331979
supports: SUPPORT
snippet: "The currently widely accepted theories of MDD pathogenesis include the
neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA)
axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic
influence hypothesis"
explanation: The HPA axis hypothesis directly relates to stress response
dysregulation, supporting chronic stress as a major environmental
precipitant of MDD.
- name: Social Isolation
notes: Risk factor and consequence
- name: Substance Abuse
notes: Bidirectional relationship
treatments:
- name: Selective Serotonin Reuptake Inhibitors (SSRIs)
description: First-line pharmacotherapy (sertraline, escitalopram,
fluoxetine).
evidence:
- reference: PMID:39150594
supports: SUPPORT
snippet: "MDD is especially burdensome as approved monoamine antidepressant treatments
have weeks-long delays before clinical benefit and low remission rates."
explanation: This confirms the clinical use of monoamine antidepressants
while acknowledging their limitations in terms of delayed benefit and
incomplete remission.
- name: Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
description: Venlafaxine, duloxetine for depression with pain or fatigue.
- name: Cognitive Behavioral Therapy
description: Evidence-based psychotherapy, comparable efficacy to medications.
- name: Electroconvulsive Therapy
description: Most effective treatment for severe or treatment-resistant
depression.
- name: Ketamine/Esketamine
description: Rapid-acting treatment for treatment-resistant depression.
evidence:
- reference: PMID:39150594
supports: SUPPORT
snippet: "Nasal administration of esketamine (Spravato®) was approved by the US
Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant
depression and in 2020 for adults with MDD with acute suicidal ideation or behavior."
explanation: This confirms FDA approval of esketamine for
treatment-resistant depression and acute suicidal ideation/behavior in
MDD.
- reference: PMID:39150594
supports: SUPPORT
snippet: "Based on this preclinical evidence implicating glutamate in depression
and the rapid improvement of depression with ketamine treatment in a proof-of-concept
trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated."
explanation: This explains the mechanistic basis for ketamine's rapid-acting
antidepressant effects through NMDA receptor antagonism and glutamate
modulation.
- reference: PMID:39150594
supports: SUPPORT
snippet: "Oral combination dextromethorphan-bupropion (AXS-05, Auvelity® extended-release
tablet) was FDA approved in 2022 for the treatment of MDD in adults."
explanation: This documents the approval of another glutamatergic modulator
for MDD treatment, expanding treatment options beyond esketamine.
- name: Transcranial Magnetic Stimulation
description: Non-invasive neuromodulation for treatment-resistant depression.
- name: Behavioral Activation
description: Increasing engagement in rewarding activities.
classifications:
harrisons_chapter:
- classification_value: psychiatric disorder
datasets:
references:
- reference: DOI:10.1007/s40263-024-01114-y
title: Glutamatergic Modulators for Major Depression from Theory to Clinical
Use
findings: []
- reference: DOI:10.1038/s41392-024-01738-y
title: 'Major depressive disorder: hypothesis, mechanism, prevention and treatment'
findings: []
- reference: DOI:10.1101/2025.05.03.25326369
title: 'Multi-omics insights in major depressive disorder: Dysfunction of Neurons'
findings: []
- reference: DOI:10.3390/cells13050423
title: 'Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology
to Potential Pharmacological Targets'
findings: []
- reference: DOI:10.3390/ijms25020963
title: 'Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and
Astrocytes Derived from Case Study Patients: Insights into Major Depression as
a Mitochondria-Associated Disease'
findings: []
- reference: DOI:10.3390/ijtm4010010
title: 'Advancements Exploring Major Depressive Disorder: Insights on Oxidative
Stress, Serotonin Metabolism, BDNF, HPA Axis Dysfunction, and Pharmacotherapy
Advances'
findings: []