2 Neuroscience2.11 Integrated neurobiology of syndromes and states

2.11.7 Major depressive disorders

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Written by Resident Doctor Committee · Published

Genetic and environmental risk

  • Heritability of depression is roughly 35 to 40%, spread across many small genetic effects.

  • Childhood adversity predicts earlier onset and recurrence, and loss, humiliation or entrapment can precipitate an episode.

Negative valence circuitry

Structure

Finding

Clinical correlate

Amygdala

Hyperactive to negative faces and words, slow to habituate: the most consistent functional neuroimaging finding

Negative bias, threat sensitivity

Subgenual anterior cingulate

Activity tracks severity and normalises with treatment

Sustained sadness; deep brain stimulation target

Rostral anterior cingulate

Pretreatment activity predicts response

Conflict monitoring

Medial prefrontal cortex

Reduced connectivity with amygdala

Appraising emotional significance

Look at the dark sad face bars: the amygdala responds more to sad than to neutral faces in both depressed groups but not in healthy controls, and the coronal slice places the difference in both amygdalae, the most consistent functional neuroimaging finding in depression. Klug M, Enneking V, Borgers T, et al. Persistence of amygdala hyperactivity to subliminal negative emotion processing in the long-term course of depression. Molecular Psychiatry 2024, Fig. 1A and 1B, CC BY 4.0

  • High-frequency repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression is delivered over the left dorsolateral prefrontal cortex.

Default mode network and rumination

  • The default mode network is overconnected and poorly suppressed in major depressive disorder.

  • Its midline hubs, the medial prefrontal and posterior cingulate cortex, stay active when an external task should switch them down, and this sustains rumination.

  • Mindfulness-based cognitive therapy aims to reduce repetitive negative thinking and recurrence.

Reward and anhedonia

  • Anhedonia goes with altered ventral striatal responses during reward anticipation and learning.

Neurochemistry

  • Depression is not a universal monoamine shortage: monoamines change rapidly, but full clinical benefit develops more slowly.

  • Ketamine acts rapidly, probably through glutamate and brain-derived neurotrophic factor signalling.

Stress, sleep and inflammation

  • Severe, melancholic or psychotic depression can involve raised cortisol with reduced feedback sensitivity.

  • Sleep shows shortened rapid eye movement (REM) latency, increased REM density and reduced slow-wave sleep.

  • Inflammatory markers are raised in a subgroup, and interferon can induce depression.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.