Neurobiology of mood disorders

1. Mood disorders
Neurobiology & functional brain circuits
Resource Person: Dr. Devrat Joshi
Presenter: Dr. Suman Prasad Adhikari
2nd year Resident
Department of Psychiatry
NAMS

2. Biological considerations
• Biological abnormalities are
reported in patients with mood
disorders
• May be of developmental in
origin
• Episodes may produce
neurobiological effects of
scarring---worsening subsequent
prognosis.

3. Martinowich et al, J Clin Invest, 2009; 119: 726-736.
Monoamine systems

4. Monoamine systems
SEROTONIN
Learning, reinforcement
Hedonic capacity
Motivation, concentration
Goal directed activity
Regulation of appetite,
body T, libido, metabolism
Regulation of Circadian
rhythm, sleep

5. Emotional memory
Behavioral sensitization to stress
MFB
Goal directed & reward seeking
NOR ADRENALINE
Interactwithsympatheticnervoussystemandadrenalmedulla
Hypothalamus

6. Nor epinephrine regulation of serotonin
Regulates serotonin by acting as a brake on serotonin release at alpha 2
receptors on axon terminals and as an accelerator of serotonin release at
alpha 1 receptors at the somatodendritic area
5HT2A

7. Classic monoamine hypothesis of depression
The monoamine hypothesis of depression states that if the "normal" amount of
monoamine neurotransmitter activity becomes reduced, depleted, or
dysfunctional for some reason, depression may ensue
Deficient monoamine--> depression

8. Monoamine receptor hypothesis of depression
Extends the classic monoamine hypothesis of depression, stating that deficient
activity of monoamine neurotransmitters causes up regulation of postsynaptic
monoamine neurotransmitter receptors, and that this leads to depression

9. Monoamine system Changes in depression
Serotonin Decrease in 5-HT1A receptor binding throughout cortical
and subcortical regions
Reduction in 5-HT reuptake sites
5-HT mediated endocrine responses blunted
Nor epinephrine Decreased MFB neurotransmission
Leading to:
anergia, anhedonia, and diminished libido
Dopamine Hypoactive D1 receptor
Increased binding of D2/D3 receptors in striatal regions
Consistently low CSF level of homovanilic acid(HVA)

12. acetylcholine
• Cholinergic neurons have
reciprocal relationship with all 3
monoamine systems
• Abnormal levels of choline,
found in autopsy of brain of
some depressed patients
• Cholinergic agonist can
exacerbate symptoms in
depression and reduce
symptoms in mania

13. Other neurotransmitters
• GABA have inhibitory effect on
ascending monoamine pathways
• Reductions in GABA observed in
plasma, CSF and brain areas in
depression
• GABA receptors up regulated by
antidepressants
• Some GABAergic medications
have weak antidepressant effects
• Excess glutamate- neurotoxic effects
• Drugs antagonizing NMDA receptors
(ketamine) may have antidepressant
effects
• Abnormalities in G-protein signalling/
second messenger system
dysregulation

14. Endocrine systems
• HPA Activity
• Thyroid Axis Activity
• Growth Hormone
• Prolactin

15. Decreased inhibitory 5-HT tone
Increased drive from NE, ACh or CRH
Decreased feedback inhibition from the
hippocampus
Hypercortisolemia
HPA activity
Elevated HPA activity as stress responses
has clearest links between depression
and biology of chronic stress
Alterednegativefeedback

16. PATHOPHYSIOLOGICAL BASIS OF MOOD
DISORDERS --2006 Elsevier
Glucocorticoid receptor theory of mood disorders
Increases LC activity
Decreased BDNF

18. HPA activity is found to be increased apparently in 20 to 40% of depressed
outpatients and 40 to 60% of inpatients
Laboratory evidence:
• Administration of dexamethasone (0.5 to 2.0 mg) :
non suppression of cortisol secretion at 8:00 AM the following morning or
is -indicative of impaired feedback inhibition
• Non suppression may implicate a loss of inhibitory hippocampal
glucocorticoid receptors more than increased CRH drive

20. Thyroid axis activity
• 5 to 10% depressed patients have
previously undetected hypothyroidism
• Reflected by :
 low levels of circulating thyroid
hormone,
 elevated basal TSH level,
 increased TSH response to TRH
• Often associated with elevated anti-
thyroid antibody levels
• 20 to 30% of depressed
patients have blunted TSH
response to TRH challenge
• Blunted TSH response is
evidence of an increased risk of
relapse
• blunted TSH response to TRH
does not normalize with
effective treatment

21. Other hormones
Growth hormone Characteristic secretory surge during the first few hours of sleep
Blunted GH response to Clonidine, an α2-receptor agonist
Blunted response to nonselective adrenergic agonists (Desipramine)
Decreased CSF somatostatin levels
Prolactin Blunted prolactin response to various 5-HT agonists

22. Decreased lymphocyte proliferation in response to mitogens
Decreased natural cell killer activity
Increased positive acute phase reactants
Increased cytokines levels(IL-1,IL-6)
Immune system

23. Impaired sleep continuity and
duration
Decreased stage 3 and 4 sleep
Decreased REM latency
Increased proportion of REM
sleep in the early part of the night
Sleep changes
Decreased REM latency may persist in recovered depressed patients and indicate a vulnerability to relapse

24. OFC
Brain circuits in Mood Disorders
DMPFC
VMPFC
DLPFC

25. Brain circuits in Mood Disorders
• Neuroimaging, lesion analysis and post
mortem methodologies
• Extensive interconnecting neural
networks are responsible
• Cortical-striatal-limbic circuits
Dorsomedial/DL Prefrontal Cortex
(DM/DL PFC)
(Cognition-decision making, planning)
VM PFC
(Emotion)
OFC
(Social)

26. The Dorsal “Cognitive” Circuit
• Receives input from DL and DM cortex
• DLPFC has top-down inhibitory control over amygdala
and other limbic tissue
• Hypometabolism of the dorsal PFC in both unipolar
and bipolar depression
• Global decreases in both GM and WM volume,
including areas of the DLPFC

27. Orbital Frontal Circuit
• Receives inputs from the OFC
• Projects to amygdala, hypothalamus, and brainstem
• Integrates limbic data with sensory input and provides
early analysis of reward or aversiveness of stimuli
• Data then processed by higher-level circuits (MPFC) to
guide behavior

28. • Lesions to OFC region manifests as :
- depression,
- mood instability and
- anxiety
• Has central role in self-regulation of emotion and social behavior
• Elevated metabolic activity or perfusion of the OFC in young to middle-
aged Unipolar acutely depressed subjects
• Potentially elevated OFC activity and tissue loss is consistent with the
operation of an excitotoxic process

29. Ventromedial “Emotion” Circuit
• Ventromedial prefrontal (ACC) plays a pivotal role in translating OFC-derived
valenced data into behavior
• More ventral and caudal to the SGPFC (24/25), BA 32pl is also an integral part of
the ventral “emotional” circuit
• Right-sided lesions produced anosognosic and manic symptomatology
• Emotional distress and depression often associated with left-hemisphere lesions

30. prefrontal cortex inhibits the amygdala
The mPFC, OFC, and ACC all inhibit amygdalar activity
When these structures are dysregulated, amygdalar activity is less modulated by the prefrontal cortex:
anxiety and emotional responses are less controlled; fear may be more easily aroused
OFC
AC
mPFC
A

31. OFC
AC
mPFC
A
Anticipatory
anxiety
Fear,
panic
Sym.
Arousal
Altered
NE, 5-HT, DA, Ach
release
Increased
CRH,
cortisol
BNST
Hypothalamus
NB, LC, VTA
PAG
Amygdala

32. Cortical and limbic connections
When prefrontal-striatal-thalamic processing is dysregulated, prefrontal function inhibition
of hippocampus/amygdala will be disconnected resulting in:
• abnormal function in the mPFC, ACC, and the OFC
• autonomic arousal, hypothalamic pituitary axis (HPA) activation
OFC
AC
mPFC
GABA
excitatory
inhibitory Amygdala Hippocampus

33. OFC
AC
mPFC
A
Anticipatory
anxiety
Fear,
panic
Sym.
Arousal
Altered
NE, 5-HT, DA, Ach
release
Increased
CRH,
cortisol
BNST
Hypothalamus
NB, LC, VTA
PAG
Amygdala
Hippocampus

34. Cortical and limbic connections:
role of monoamines

35. Dorsomedial/DL Prefrontal Cortex
(DM/DL PFC)
(Cognition-decision making, planning)
VM PFC
(Emotion)
OFC
(Social)
Striatum
Amygdala
Decreased reward/ goal directed behavior
Disinhibition of Amygdala
Bed nuclei of
striae
terminalis
Hypothalamus Nucleus basalis
VTA; LC
PAG
(Periaqueductal
gray)
Anticipatory
anxiety
Increased CRH
Increased Cortisol
Altered
Ach, DA, 5HT, NE release
Fear, panic, social
isolation
Functional
hypersensitivity

36. Kindling effect
• First discovered in 1967 by a scientist in Nova Scotia, named Graham Goddard –
somehow he had created epileptic rats
• First applied to Bipolar Disorder by Dr. Robert Post of the NIMH
• Like seizures, mood episodes can occur without obvious triggers, and have fairly
abrupt beginnings and endings
• Initial stress---mood episodes----episodes beget episodes—frequency increases/
worsens

37. DSM-IV symptoms of depression.

38. Matching depression symptoms to circuits
Functionality in each brain region is hypothetically associated with a different constellation of
symptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus;
HY, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal
cord; C,cerebellum.

39. diffuse DA reduction
NE dysfunction
Diffuse 5-HT reduction
NE dysfunction

40. Diffuse DA reduction
Diffuse 5-HT reduction
NE dysfunction

41. Diffuse DA reduction
Diffuse 5-HT reduction
NE dysfunction
Dysfunction of
subcortical circuits
Thalamus, BG,
striatum

42. Diffuse DA reduction
Diffuse 5-HT reduction
NE dysfunction
Decreased neuro-
transmission in MFB

43. Diffuse DA reduction
Diffuse 5-HT reduction
NE dysfunction

44. Diffuse DA reduction
Diffuse 5-HT reduction
NE dysfunction

45. Symptoms & circuits in mania

46. DSM-IV symptoms of mania.

47. Functionality in each brain region may be associated with a different constellation of symptoms.
PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; HY, hypothalamus;
A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum
Matching mania symptoms to circuits.

49. Note:-
Grandiosity, Flight of Ideas, Racing
thoughts are due to hyperactivity in
the nucleus accumbens
Regulated by 5HT & DA
Risk taking, pressured speech
(poor impulse control) due to
hyperactivity in OFC,DLPFC,VMPFC
Regulated by 5HT, DA & NE

50. (Cognitive symptoms)

51. uses of Neuroimaging in mood disorders
MRI
Reduced hippocampal volume in individual with MDD (Average 8% on left, 10% on right)
 Reduction in grey matter volume in PFC ventral to genu of corpus callosum
Findings remain inconclusive in regard to amygdala
(In adults -increased amygdala volume, reverse in children and adolescents)
MRS
Specific studies suggest that NAA may be reduced in the hippocampus of depressed
patients
Elevated choline levels in the basal ganglia of mood disorder subjects
White mater
changes
White matter hyperintensities (WMHs), especially of the deep frontal cortex and
BG- characteristic of UPD and BD
Increased white matter hyperintensities associated with
- late onset depressive disorder
- greater severity and poorer treatment response
- presence of vascular risk factors

52. uses of Neuroimaging in mood disorders
Postmortem study of UPD and BD showed volumetric reductions of :
- left nucleus accumbens,
- bilateral pallidum, and
- right putamen
Metabolic activity/perfusion elevated in manic or hypomanic as well as depressed samples
Enlargement of the BG nuclei - antipsychotic regimens for BD patients
Ventricular enlargement (mostly of the third or lateral ventricles) in UPD: In old or chronically depressed
samples with late-onset illness
Excitotoxic processes operating in medial-temporal or lateral-prefrontal cortical tissue could cause
ventricular enlargement
Decreased glial cell numbers(ACC)
Decreased neuronal size and density(ACC,PFC)
Decreased synaptic markers(PFC)

53. Summary
• Neuroimaging, lesion analysis, post-mortem analysis, drug analysis support the
role of neurobiology and brain circuitry
• Neurobiology extends further from neurotransmitters, secondary messengers to
the relevant genes
• Neurohumoroendocrinal connectivity is being established
• Brain areas and circuitry forming reciprocal connectivity of limbic-cortico-striato-
pallido-thalamic circuits

55. references
 Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 9th edition
 New Oxford Textbook of Psychiatry, 2nd edition
 Shorter Oxford Textbook of Psychiatry, 6th edition
 Stephan M. Stahl, Essential psychopharmacology; 4th edition
 Other Internet sources