(a) Several brain areas have been found to have abnormal activity or structure in patients with major depressive disorder (MDD) compared to healthy controls, including the prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, and orbitofrontal cortex. (b) Imaging studies have found both hypoactivity and hyperactivity in different areas, and treatment has been shown to help normalize some of these abnormalities. (c) The prefrontal cortex and limbic system including the hippocampus and amygdala appear to be particularly involved, and their structural and functional connections may contribute to MDD.

1. Dr salman kareem

2. 2

3. 1. Catecholamine Hypothesis
2. Serotonin Hypothesis
3. Adrenergic Cholinergic Balance
hypothesis
4. Serotonin nor epinephrine dichotomy
5. Opioid Hypothesis
6. Receptor down regulation hypothesis
7. GABA hypothesis

4. Widely known and acknowledged
Activity of catecholamines are high in
mania and diminshed levels in depression.
Higher urinary methoxy hydroxy phenyl
glycol

5. Nor epinephrine
• Manic patients – higher urinary MHPG levels than
depressed patients.
• Plasma MHPG levels are also high
• Plasma levels of cAMP is raised in mani and low
in depression.
• CSF MHPG is higher in mania.

6. Fusaric acid – inhibits enzyme dopamine β
hydroxylase ( converts DA NE) leading
to decrease in synthesis of NE
Clonidine reduces NE transmission by
direct action on presynaptic receptors and
thus improves manic symptom.
Propranolol posses anti manic properties.
action of venlafaxine – noradrenergic
effect.

7. Down regulation of b adrenergic receptors
and the clinical anti depressent response.
Reduction in the activity of alpha -2
adrenergic recpetors leading to decrease
in NE.

8. Dopamine
• Overactivity of dopamine plays important role in
pathogenesis of mania.
• Drugs and disease that reduce dopamine
concentraton lead to depression.
• CSF homvallinic acid is elevated in mania / switch
from depression to mania.

9.  L DOPA , amphetmanine preciptates mania
symptoms
Dopmaine recpetor agonists like
bromocriptine and piribedil precipitates mania
 Bupropion reduces the depression.
Various anti psychotic driugs
(chlorpromazine,haloperidol and pimozide )
have dopamine receptor blocking action
shown to have more effectiv ein it.

10. two new theories
Mesolimbic
dopamine
pathway be
dysfuntional
Dopamine D1
receptor hypoactive

11. Serotonin is the biogenic amine most
commonly associated with depression.
Pathophysiology of depression.
Normal or reduced levels of 5 HIAA , a
primary metabolite of serotonin in manic
patients.

12. Balance between the two
Depression a disease of cholinergic
preponderance and mania is a disease of
adrenergic preponderance
Anti catecholamine drugs (have central
and peripheral cholinomimetic activity).
Physostigmine – a cholinesterase inhibitor
causes dramatic decrease in the manic
and hypomanic symptoms.

13. A tri cyclic anti depressant is given only if
the patient has nor adrenergic or
serotonergic depression.
Assessed by presence of CSF MHPG.

14. Hypothesis that central opiod mechanism
control of expression of mood.
Positive evidence – I V endorophins
Negative – no action of methadone

15.  Inhibitory neurotransmitter
 Postulated to contribute to the etiology of
psychotic states.
Reduction have been observed in plasma ,
CSF and brain GABA levels in depression.
Sodium valproate inhibits the degradation of
GABA and reported improvement in acute
mania and effective in prophylaxis of bipolar
disorder.

16. Hypothalamic – pituitary adrenal axis
(HPA)
Midnight levels are increased in pts with
mood disorder.
50% manifest a decrease suppression of
cortisol secretion after administration of
dexamethasone.

18. Carrol Et al
1mg of DXM orally at 11pm
Plasma cortisol levels are determined at 8
am, 4pm amd 11 am.
Above 5μg/dl abnormal
Can be used to follow the response of
depressed person to treatment.
Normalization of DST not an indication to
stop antidepressent

19. FALSE POSITIVE FALSE NEGATIVE
 Cushings disease
 Estrogen
 Severe weight loss
 Drugs – phenytoin
barbiturates
 Uncontrolled Dm
 Gh grade fever
 A/c alcohol withdrawal
 Addisons disease
 Hypopitutarism
 Steroids
 benzodiazepines

20.  Hypothalamic Pituitary Adrenal Axis (HPA)
overactivity (elevated CRH and cortisol,
dexamethasone resistance) is present in many
patients with severe depression.
 Corticosteroids reduce hippocampal 5-HT1A
receptor sites in animal studies and may explain
reduced hippocampal damage in depression.
20

21. Release of thyroid secreting hormone is by
TRH , via anterior pituitary.
Release of TRH is influenced by limbic and
other brain areas.


22. 500 mg ofTRh is given in morning via IV
over 30 seconds.
Blood samples of TRH are collectedat
every 15 min intervals upto 15 min
including baseline (pre TRH push).
Maximal TRH difference is calculated from
baseline.
5-7 mg/ml is considered abnormal.

23. 3. Hypothalamic pituitary growyh hormone
axis
• CSF levels of somatostatin is decreased in
depressed patients.
• Abnormal positive growth hormone response to
TRh in depressed patients.
4. Hypothalamic pituitary prolactin axis
• Inconclusive
• Prolactin secretion is altered in nocturnal
secretion in depressed pts

24. 5. Melatonin
• Stimulated by nor adrenergic recpetors
• Secreted at night under the influence of
circadian rhythm.
• Decreased in depression.
6. Insulin tolerance test
• 44% of bipolar and 60% of unipolar have
blunted ITT
7. Vasopressin

25. Depression can interfere with
immunological competence
Severely depressed pts have reduced in
vitro lymphocyte response to mitogen
stimulation
Fewer natural killer T cell lymphocytes
Fewer suppressor t cells and few
circulating lymphocytes.

26. Sleep EEG in depressed pts shows
abnormalities
• Delayed sleep onset
• Shortened REM latency
• Incresed length of first REM sleep
• Abnormal delta sleep
Kindling -

27. Skin conductance – Found to be raised in
mania.

29. (a) Orbital prefrontal
cortex and
Ventromedial
prefrontal cortex
(b) Dorsolateral
prefrontal cortex
(c) Hippocampus and
Amygdala
(d) Anterior cingulate
cortex
Davidson et al, 2002, Annu.
Rev. Psychol.

30. Prefrontal
cortex2
Amygdala2
Hippocampus5
Anterior
cingulate cortex3
Nucleus accumbens4
Insular
cortex1
1. Kennedy SE, et al. Arch Gen Psychiatry. 2006;63:1199–1208. 2. Drevets WC. Curr Opin Neurobiol. 2001;11:240–249.
3. Whittle S, et al. Neurosci Biobehav Rev. 2006;30:511–525. 4. Schlaepfer TE, et al. Neuropsychopharmacology.
2008;33:368–377. 5. Gaughran F, et al. Brain Res Bull. 2006;70:221–227.

31. Areas of increased activation in patients with MDD at rest (red) and
decreased activation (blue) compared with controls
Increased activity: lateral orbital prefrontal cortex, ventromedial prefrontal cortex,
amygdala, thalamus, caudate
Decreased activity: dorsolateral prefrontal cortex (DLPFC), insula, pregenual and dorsal
anterior cingulate cortex (dACC), superior temporal gyrus
Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.

32. Total Hippocampal Volume ( mm3)
0 1000 2000 3000 4000
Days of Untreated Depression
6000
5500
5000
4500
4000
3500
3000
2500
Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.
R2=0.28; p=.0006
N=38

33. Atrophy of the Hippocampus in Depression
Normal Depression
Bremner JD, et al. Am J Psychiatry 2000;157(1):115-118.
Reprinted with permission from JD Bremner.

34. 800
700
600
500
400
300
200
100
0
*P=.02 vs comparison by ANOVA
Comparison subjects (N=20)
Major depression (N=15)
Orbitofrontal cortical (gyrus rectus)
volume (mm3)
*
MOFC
Image reprinted with permission from Elsevier
 Patients with MDD had 32% smaller MOFC (VMPFC) than controls
ANOVA=analysis of variance; MOFC=medial orbitofrontal cortices; VMPFC=ventromedial prefrontal cortex.
Bremner JD, et al. Biol Psychiatry. 2002;51:273–279.

35.  3-year prospective study comparing 38 patients with 30 healthy controls
 Significant decline in gray matter density was noted in hippocampus, amygdala,
anterior cingulate cortex, and dorsomedial prefrontal cortex
 Threshold was set at P<.001
Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165.

36.  Most brain imaging studies have shown abnormalities in these
key areas: amygdala, hippocampus, prefrontal cortex, anterior
cingulate cortex, and orbitofrontal cortex1–3
 Many studies have found prefrontal cortical hypoactivity at
baseline improved after treatment4
 Many studies have found limbic hyperactivity (especially
cingulate) at baseline normalized after treatment4
 More recent studies have focused on network relationships
(limbic, prefrontal) and dynamic changes over time2,4–6
 There is great heterogeneity among patients; scanning is not
predictive or individually diagnostic
1. Sheline YI. Biol Psychiatry. 2000;48:791–800. 2. Sheline YI. Biol Psychiatry. 2003;54:338–352. 3. Nestler EJ, et al.
Neuron. 2002;34:13–25. 4. Mayberg HS. Br Med Bull. 2003;65:193–207. 5. Fales CL, et al. Biol Psychiatry. 2008;63:
377–384. 6. Siegle GJ, et al. Biol Psychiatry. 2007;61:198–209.

39. "Depression is cancer of the emotions" (Lewis Wolpert)