This document provides an overview of the neurobiology of depression. It discusses the etiology of depression including genetic predisposition and adverse life experiences. It then examines various neurochemical and hormonal abnormalities associated with depression such as decreased serotonin, norepinephrine, dopamine, and BDNF. Brain regions involved like the prefrontal cortex, amygdala, and hippocampus are also outlined. Functional and structural changes in these regions are noted. Recent advances in deep brain stimulation and anti-inflammatory treatments are also summarized.

1. Continuing Medical Education On
Neurobiology of Depression
and recent updates

2. Neurobiology of Depression
and recent updates
Dr. Ahsan Aziz Sarkar
MD and FCPS Part 2 Trainee
Assistant Registrar, NIMH.

3. Etiology of depression
Genetic
Predisposition
Early Life
Experience
Adverse Life
Events

4. Etiology of depression
These three factors singly or in combination
can make ground for a depressive episode.
Presence of genetic predisposition diminishes
need for adverse childhood experience and
recent life stressors. (Kendler et al. 2001)
Life event is important for 1st episode but less
so for subsequent episodes.

5. Neurobiology in Depression

7. Neurochemical and hormonal
abnormalities in depression
Substrate Concentration/activ
ity
Note
Serotonin
Neurotransmission
Decreased Decrease
Tryptophan, 5-HT
receptor binding,
and receptor
uptake site
NA
Neurotransmission
Decreased Blunted NA
mediated endocrine
response
Dopamine Decreased Reward
BDNF Decreased Neurogenesis

8. Neurochemical and hormonal
abnormalities in depression
Serotonin pathway:
 Aversive processing to behavioral
inhibition
 Delay discounting
 Inhibition of chain of thought leads to
negative outcome (Cowen et al. 2015)
 Eating Behavior
 Sleep

9. Neurochemical and hormonal
abnormalities in depression
Role of NA in brain:
 Alertness, arousal, attention
 Enhance memory
BDNF (Also NGF and FGF-2)
Nerve growth, differentiation

10. Neurochemical and hormonal
abnormalities in depression
Substrate Concentration/activ
ity
Note
Cortisol and CRH Increased HPA Axis
Abnormality
Present in 50% of
cases
Pro-inflammatory
Cytokines
Increased Acute Phase
Proteins
IL-6 and TNF-alpha
Glutamate, GABA Decreased Glutamate in Ant.
Region; GABA in
Occipital Cortex

11. Neurochemical and hormonal
abnormalities in depression
Cortisol on brain:
Shrinkage and loss of dendrite.
Decreases level of BDNF specially in
Hippocampus.
Plasminogen activator (tPA), lipocalin 2,
corticotrophin-releasing factor (CRF), and
endocannabinoids.
Proteolytic and lipolytic effect.

12. Neurochemical and hormonal
abnormalities in depression
Cytokines (IL-6 and TNF-alpha):
 Increase tryptophan catabolism thus
lower serotonin level.
 INF treatment can cause depression
(Capuron et al., 2004).
 Depression that doesn’t respond to anti-
depressants has high cytokine level (Audet
et al., 2013).
Could have relapse predictive value.

13. Medial, Lateral and
Anterior view of PFC

14. DLPFC: 9, 46; VLPFC: 44, 45, 47 VMPFC: 14,
25, 32, 10 OFC: 11, 13, 14 MPFC: 10, 24, 25,
32

15. Brain Regions involved in depression
 DLPFC: Executive function (working memory,
planning, flexibility, decision making), Concrete
thinking, Social cognition, Conscious regulation
of emotion, inhibition, self-awareness and
reflection.
 VMPFC: Personal and Social decision making,
emotional regulation and
suppression(automatic), empathy, shame, guilt.
 OFC: Adaptive learning (expected reinforcer vs.
actual reinforcer)

16. Brain regions involved in depression

17. Brain regions involved in depression
 Limbic system: Motivation, emotion,
learning, emotional memory.
 Amygdala: Fear, conditioned fear, aggression,
anxiety, sexual behavior, flight fight response.
 Hippocampus: Memory, converting short
term memory into long term, learning

19. Functional and structural change in
brain
Region Volume Metabolic
Activity
Orbital/VMPFC Decreased Increased
DLPFC Decreased Decreased
Anterior
Cingulate Cortex
Decreased Decreased
Hippocampus Decreased -
Amygdala Decreased (?) -

21. Anhedonia
Anhedonia:
Decrease activity in Nucleus Accumbens
Low level of Dopamine (possibly
mediated by serotonin)
Increase activity in VMPFC and OFC
suppresses amygdala emotional processing

22. Appetite and weight change
Metabolic cue
Blunted by cortisol, IL-6 and TNF-alpha
Motivation cue
Deficits in activity of nucleus accumbens
Low dopamine release
Sugar releases dopamine in nucleus
accumbens

23. Insomnia and hypersomnia
NREM sleep
Increased GABA
Decreased Histamine
REM sleep
Decrease Noradrenaline and serotonin
Increase acetylcholine

24. Insomnia and hypersomnia
Hypersomnia
 Melatonin dysregulation (Melatonin
secretion depends on noradrenaline)
 Orexin deficiency.

25. Psychomotor retardation or agitation
Psychomotor retardation:
Decrease activity in DLPFC leads to poor
executive functioning and cognitive
slowness
Psychomotor agitation:
Noradrenaline and GABA mediated.
Overactive Amygdala.

26. Fatigue and loss of energy
Deficits in activity of nucleus accumbens.
TNF-alpha acting on hypothalamus.
Decrease BDNF concentration in brain.

27. Guilt and worthlessness
Self-conscious emotions.
Negative mood leads to negative bias.
Rumination.
Mediated by DLPFC, VMPFC and amygdala.

28. Concentration and decision
Impaired attention processing due to low
volume of anterior cingulate.
Indecisiveness from low volume and metabolic
activity of DLPFC.

29. Suicidal idea, thought, attempt
Low serotonin level in some cases.
Attentional bias indicates cingulate
dysfunction.
Poor problem solving ability indicates PFC
dysfunction.

30. Recent advance in treatment
Deep brain stimulation:
Subcallosal cingulate
Ventral striatum and Nucleus accumbens
BDNF targeted treatment:
Ketamine increases BDNF level.
Plant glycoside on trial.

31. Recent advance in treatment
Anti-inflammatory approach:
Celecoxib
Infliximab (TNF-alpha inhibitor)
Pioglitazone
Minocycline
Statins

32. Wrapping the session
Winston Churchill :
“All great men are products of difficult
childhood”
Victor Frankl quoted Nietzsche in ‘Man’s search
for Meaning’:
“He who has a why to live for can bear
almost any how”

33. Thank you