2. Neurobiology of Depression:
An Integrated View
Dr. Hani Hamed Dessoki, M.D.Psychiatry
Prof. Psychiatry
Chairman of Psychiatry Department
Beni Suef University
Supervisor of Psychiatry Department
El-Fayoum University
APA member
This information is provided in response to your request and is intended for your scientific and/or educational purpose
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3. Agenda
♦ Introduction
♦ Somatic depression
♦ Neurobiology of depression
♦ Different management
♦ Take home Message
♦ Future direction

4. Depression … the 21st Century
illness

5. ‫♦‬
‫♦‬
‫♦‬
‫♦‬
‫♦‬
‫المرض النفسي والعصبي الذي أصبح يصيب054 مليون إنسان فوق‬
‫سطح الرض.‬
‫وان الكتئاب وحده وصل الي041مليون انسان,‬
‫أما حالت القلق والخوف فقد وصلت في العالم الي002 مليون‬
‫انسان خائف وقلق..‬
‫ووصل الدمان في العالم أيضا الي031 مليون إنسان مدمن..‬
‫أما الرقام في مصر فإنها تؤكد وجود مليون و002 ألف إنسان مصري‬
‫يعاني عذاب الكتئاب.‬
‫جريدة الهرام، الخميس 22 من ذى القعدة 2341 هـ 02 اكتوبر 1102 السنة 631 العدد 80654‬

6. Depression
Samedi 9 novembre 2013

7. World Bank Reports
Year 2000
Anxiety Depression is
4th greatest health problem
Year 2020
Will be 2nd greatest health
problem causing disability
7

8. Challenges
By the year 2020,
depression is projected to
reach 2nd place of the
ranking of DALYs(WHO)
One DALY (disability-adjusted life
years) represents the loss of the
equivalent of one year of full health
By the year 2030,
depression is projected to reach 1st place
of the ranking of DALYs
10 Leading causes of burden of disease (DALYs), world 2004 and
2030

9. Challenges
Depressed patients
a 2 times greater overall mortality risk
than the general population
Direct causes
Indirect causes
(e.g. suicide)
(e.g. medical illness)

10. Economics of Depression —
U.S.A. Data - Total Annual Cost ~$44 Billion
Lost productivity—
55%
Suicide—17%
Outpatient care—
6%
Pharmaceuticals—
3%
Inpatient care—
19%
Greenberg PE, et al. J Clin Psychiatry. 1993;54:405-418.
U.S.
data.

11. Recognition of general practice
patients
Up to 50% of general practice
patients may have some
depressive symptoms.
Approximately 5% of these
will have major depression
defined by DSM-III-R
criteria.
Freeling and Tylee (1992); Regier et al (1988); Vazquez-Barquero et al (1987)

12. Prevalence of depression
5.8% of men
9.5% of
women
10-15% of
elderly ≥ 65
years
WHO - Fact Sheet N° 265,
December 2001

14. Depressed Patients Usually
Present with Physical Symptoms
69%
Presented
ONLY With
Physical
Symptoms
Other
N = 1146 patients with major depression
1. Simon GE, et al. N. Engl J Med. 1999;341(18):1329-1335.

15. Prevalence of Depression in
Chronic Disease
Alzheimer's disease
HIV
CAD
Stroke
MI
Diabetes
11%
12%
17%
23%
25%
27%
Cancer
Parkinson's disease
NHDS, NAMCS, NHAMCS
Sutor B, et al. Mayo Clin Proc. 1998;73(4):329-337; Jiang et al, CNS Drugs, 2002
42%
51%

16. Mechanisms of depression and
medical comorbidity
Primary medical
illness/condition
Neuroendocrine,
immune dysfunction,
inflammatory change
Premorbid coping
skills, cognitive set, and
personality traits
Social
supports
Pathologic
mood state
e.g., depression
Ellison et al. Mood Disorders in Later Life. Informa 2009

17. General practice patients and
recognised major depression
How do patients with major depression usually present in
primary care?
 Patients with major depression often present with predominantly physical
(somatic) symptoms such as:
• significant weight loss, or gain
• insomnia or hypersomnia
• agitation or retardation
• fatigue or loss of energy
 The presence of physical symptoms reduces the likelihood of diagnosis
by the GP.
 Many patients with major depression also have a physical illness.
Blacker and Clare (1987); Bridges et al (1991); Freeling et al (1985)

18. The association between
depression and medical illness
Depression is associated with disability caused by a variety of diseases.
Pulmonary
CN
S
Stroke
Alzheimer’s disease
Parkinson’s disease
Chronic obstructive pulmonary disease
Cardiac
Myocardial infarction
Rheumatic
Arthritis
Gurland et al (1988)

19. Cause or Effect?
Functional ability
Morbidity
Negative attitude
Depression
Medical illness
Neglect health
Biochemical changes

20. RECIPROCAL RELATIONSHIP
Pain
Depression

21. Chronic pain & depression
 Many factors can interfere with the
successful treatment of chronic pain
including undiagnosed diseases, mental
disorders,
emotional
distress,
personality traits, and personal beliefs.
 Depression is not simply a comorbid
condition but interacts with chronic pain
to increase morbidity and mortality.

22. Major Depressive Disorder (MDD)
♦ MDD can be a chronic, recurrent, and
progressive condition1
♦ MDD is associated with alterations in functional
and structural changes in the brain2
♦ MDD, stress, and pain are all associated with
similar suppression of neurotrophic factors and
compromised neuroplasticity2
♦ Remission, not response, is the ultimate goal
of treatment3,4
1.
2.
Kendler et al. Am J Psychiatry 2000;157(8):1243-51.
Maletic et al. Int J Clin Pract 2007;61(12):2030-40.
3.
4.
Keller et al. Arch Gen Psychiatry 1992;49(10):809-16.
APA. Am J Psychiatry 2000;157(4 suppl):1-45.

23. Depression
♦ Rate of recurrence after 1st episode is 50%.
♦ Rate of recurrence after 2nd episode is 70%.
♦ Rate of recurrence after 3rd episode is 80%.

24. Rates of Recovery Diminish with
Duration of Major Depressive Episode
100
% Recovery Rate
60
N = 431
54
40
20
16
11
6
1
0
6 Months
1 Year
2 Years
Recovery = 8 weeks of Psychiatric Status Rating (PSR) 1 or 2
Recovery = sustained remission
Keller et al. Arch Gen Psychiatry 1992;49(10):809-16.
4 Years
5 Years

25. Progression of Depression: Adverse
Effects of Each Successive Episode
10
Likelihood of recent life stress
precipitating depression
Risk (Odds Ratio) of depression
onset per month
Risk (Odds Ratio)
8
6
4
2
0
Female subjects only N = 2395
0
1
2
3
4
5
6
7-8
Number of Previous Depressive Episodes
Kendler et al. Am J Psychiatry 2000;157(8):1243-51.
9-11

26. Key Brain Areas Involved in
Regulation of Mood
♦ (A) Ventromedial prefrontal cortex (VMPFC)1
• Modulates pain and aggression, and sexual and
eating behaviors2
• Regulates autonomic and neuroendocrine response
B5
A5
♦ (B) Lateral orbital prefrontal cortex (LOPFC)3
• Activity is increased in depression, obsessivecompulsive disorder (OCD), post-traumatic stress
disorder (PTSD), and panic disorder
• Corrects and inhibits maladaptive, perseverative,
and emotional responses
♦ (C) Dorsolateral prefrontal cortex (DLPFC)4
C5
• Cognitive control, solving complex tasks, and
manipulation of information in working memory
• Hypoactivity of DLPFC in depression has been
associated with neuropsychological manifestation of
depression
Reprinted with permissions, from the Annual Review of Psychology,
Volume 53, © 2002 by Annual Reviews www.annualreviews.org
1. Ongür and Price. Cereb Cortex 2000;10(3):206-19.
2. Swanson. In: Handbook of Chemical Neuroanatomy;1987:1-124.
3. Drevets. Annu Rev Med 1998;49:341-61.
4. MacDonald et al. Science 2000;288(5472):1835-8.
5. Davidson et al. Annu Rev Psychol 2002;53:545-74.

27. Key Brain Areas Involved in
Regulation of Mood (Cont.)
♦ (A) Amygdala: regulates cortical arousal
and neuroendocrine response to surprising
and ambiguous stimuli1
• Role in emotional learning and memory
• Activation of amygdala correlates with
degree of depression2
• Implicated in tendency to ruminate on
negative memories2
A6
♦ (B) Hippocampus: has a role in episodic,
contextual learning and memory3,4
• Rich in corticosteroid receptors5
• Regulatory feedback to hypothalamic-pituitaryadrenal axis
• Hippocampal dysfunction may be responsible
for inappropriate emotional responses
1. Davidson. Psychophysiology 2003;40(5):655-65.
2. Drevets. Curr Opin Neurobiol 2001;11(2):240-9.
3. Squire et al. In: The New Cognitive Neurosciences;2000:765-79.
B6
Reprinted with permissions, from the
Annual Review of Psychology,
Volume 53, © 2002 by Annual
Reviews www.annualreviews.org
4. Fanselow. Behav Brain Res 2000;110(1-2):73-81.
5. Reul and De Kloet. J Steroid Biochem 1986;24(1):269-72.
6. Davidson et al. Annu Rev Psychol 2002;53:545-74.

28. Serotonin (5-HT) and Norepinephrine
(NE) Pathways in the Human Brain1
Limbic System
Prefrontal
Cortex
Amygdala
Raphe Nuclei
(5-HT source)
Hippocampus
Locus
Coeruleus
(NE source)
Descending 5-HT
pathways
Descending
NE pathways
By permission of Oxford University Press, Inc. Page 209, figure 8.11 from “Biochemical Basis of Neuropharmacology” by Cooper Jack (2002)
1.Cooper et al. In: The Biochemical Basis of Neuropharmacology 2003.

29. Brain Atrophy in Depression?
Atrophy of the Hippocampus in Depression
Normal
Depression
Reprinted with permission from Bremner et al. Am J Psychiatry 2000
Bremner et al. Am J Psychiatry 2000;157(1):115-8.

30. Correlation Between Hippocampal Volume and
Duration of Untreated Depression*
Female Outpatients With Recurrent Depression in Remission
Total Hippocampal
Volume (mm3)
6000
R2 = .28
N = 38
5500
5000
4500
4000
3500
3000
0
1000
2000
3000
4000
Days of Untreated Depression
*p = .0006
*Significant inverse relationship between total hippocampal volume and the length of time depression
went untreated
Sheline et al. Am J Psychiatry 2003;160(8):1516-8.

31. Hippocampal Dysfunction Contributes to
Neuroendocrine Dysregulation
Reprinted from Neuron, 34(1), Nestler EJ, et al., “Neurobiology of Depression”, pp 13-25, (2002), with permission from Elsevier.
Nestler et al. Neuron 2002;34(1):13-25.

32. Major Depressive Disorder May
Have Systemic Consequences
Musselman DL, et al. Archives of General Psychiatry. 1998;55(7):580-592. Copyright © (1998), American Medical Association.
Musselman et al. Arch Gen Psychiatry 1998;55(7):580-92.

33. Brain-derived Neurotrophic Factor (BDNF),
Stress, and Neurogenesis in the Adult Brain
♦ Neurogenesis (the birth of new neurons) continues postnatally and
into adulthood
• BDNF is associated with production of new neurons and their growth and
development1
♦ The hippocampi appear to have important functions related to both
mood and memory
• Data suggest that neurogenesis occurs in the hippocampus 2
• Data from depressed patients have shown reduced hippocampal
volume3
♦ BDNF influences regulation of mood4 and perception of pain5
♦ BDNF is downregulated in MDD and increased with successful
antidepressant treatment4
♦ Both 5-HT and NE are believed to play roles in the modulation of
BDNF1
1. Duman et al. Arch Gen Psychiatry 1997;54(7):597-606.
2. Gould E. Neuropsychopharmacology 1999;21(2 suppl):46S-51S.
3. Sheline et al. Proc Natl Acad Sci USA 1996;93(9):3908-13.
4. Shimizu et al. Biol Psychiatry 2003;54(1):70-5.
5. Duric and McCarson. Neuroscience 2005;133(4):999-1006.

34. The Monoamine Hypothesis of Gene Action:
The Impact of Stress on BDNF
Preprinted with permissions from Cambridge University Press.
Stahl. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:187.

35. Pain and Stress Lower BDNF Gene
Expression in Animal Models
Changes in Hippocampal BDNF Synthesis
8
8
6
6
4
4
*
2
0
Acute and Chronic Pain
Pg BDNF mRNA/ng β-actin
mRNA
Pg BDNF mRNA/ng β-actin
mRNA
Acute and Chronic Stress
Control
*
Acute
Stress
Chronic
Stress
2
0
*
*
*
6h
24h
10-Day
CFA
*
Control 2:45h
Formalin
*p<.05 compared to control
Duric and McCarson. Neuroscience 2005;133(4):999-1006.

36. Major Depressive Disorder:
The Consequences
♦ Structural changes in the hippocampus and
prefrontal cortex often accompany MDD1
♦ MDD may be associated with diminished
neurotrophic support, resulting in impaired
neuroplasticity, neurogenesis, and cellular
resilience2
♦ Cerebral areas affected by MDD have significant
noradrenergic and serotonergic innervation 2
1.
2.
Sheline. Biol Psychiatry 2000;48(8):791-800.
Manji et al. Nat Med 2001;7(5):541-7.

37. Antidepressants:
The Importance of Serotonin and
Norepinephrine in the Treatment
of Depression

38. Beyond Synapse: 5-HT and NE Aid BDNF
Synthesis (Preclinical Evidence)
┴ = inhibitory
1.
2.
Manji et al. Biol Psychiatry 2003;53(8):707-42.
Tsankova et al. Nat Neurosci 2006;9(4):519-25.

39. Successful Antidepressant Treatment
can be Associated with BDNF Increase
35
Plasma BDNF (ng/mL)
30
25
20
*
15
10
5
(n = 50)
(n = 16)
(n = 17)
Control
Depressedtreatment-naïve
Depressed-treated
0
*p<.01 vs. control or treated
Mixed group of antidepressants used for treatment
HAMD17 = 27.8±10.2 and 18.8±11.4 for untreated and treated groups respectively
Shimizu et al. Biol Psychiatry 2003;54(1):70-5.

40. Network Hypothesis of Depression
Reprinted from Neuron, 34(1), Nestler EJ, et al., “Neurobiology of Depression”, pp 13-25, (2002), with permission from Elsevier.
Nestler et al. Neuron 2002;34(1):13-25.

41. Summary:
BDNF, Depression, and Antidepressants
♦ BDNF is downregulated in MDD and increased
with antidepressant treatment1,2
♦ BDNF has a hypothetical neurotrophic effect that
influences regulation of mood2 and perception of
pain3 in clinical and animal studies
♦ 5-HT and/or NE are believed to play roles in the
modulation of BDNF1
♦ Increase in BDNF promotes the 3 Ns
• Neuroplasticity, neurogenesis, and neuroprotection
(cellular resilience)1
1.
2.
3.
Duman et al. Arch Gen Psychiatry 1997;54(7):597-606.
Shimizu et al. Biol Psychiatry 2003;54(1):70-5.
Duric and McCarson. Neuroscience 2005;133(4):999-1006.

42. Remission, Not Response, is the
Goal of Treatment of Depression

43. Regional Blood Flow Abnormalities
in Patients with Depression
Ventrolateral
PFC
Amygdala
Medial Orbital
0
2.0
t-value
4.5
0
2.0
t-value
4.0
Patients with depression had increased blood flow in amygdala and left
medial and lateral orbital cortex, extending to ventrolateral PFC
Drevets et al. J Neurosci 1992;12(9):3628-41.

44. Hippocampal Volume (mm3)
Structural Difference in the Hippocampus of
Remitted vs. Nonremitted Patients
Remitted, left
hippocampus
Remitted, right
hippocampus
4.5
Nonremitted, left
hippocampus
Nonremitted, right
hippocampus
4.0
3.5
3.0
Remitted
(N = 18)
Nonremitted
(N = 12)
Left
Hemisphere
Frodl et al. J Clin Psychiatry 2004;65(4):492-9.
Remitted Nonremitted
(N = 18)
(N = 12)
Right
Hemisphere

45. Summary:
Restoring Homeostasis and Harmony
♦ Continuous antidepressant use may be associated with
increased 5-HT and/or NE in the prefrontal cortex and
limbic system1
♦ Effective antidepressant treatment may be associated with
decreased activity in the VMPFC, hippocampus and amygdala,
and increased activity in the DLPFC1,2
♦ Changes in activity may correlate with symptomatic
improvement in MDD: decrease in sadness, anxiety,
psychomotor retardation, and fatigue as well as improvement in
cognitive functioning1,2
♦ Activation of 5-HT and/or NE may help restore adaptive
homeostasis by modulating balance between excitatory and
inhibitory inputs in key brain areas, and by optimizing
neuroplasticity, neurogenesis, and neuroprotection2,3
1.
2.
3.
Mayberg et al. Biol Psychiatry 2000;48(8):830-43.
Brody et al. Biol Psychiatry 2001;50(3):171-8.
Duman. Neuromolecular Med 2004;5(1):11-25.

46. What Happens if Remission is Not
Achieved?
% of Patients Who Relapsed (2-Year Follow-up Study)
100
% of Patients
90
80
*
67.6%
70
60
50
40
30
15.2%
20
10
(n = 71)
0
Patients Not in
Remission
*p<.0001
Pintor et al. J Affect Disord 2003;73(3):237-44.
(n = 112)
Patients in
Remission

47. Functional Benefits of Remission
Work Composite Scale of
the Social Adjustment
Scale-SR (Mean ± SD)
4
3
*
**
2
1
*
(n = 482)
(n = 202)
(n = 122)
(n = 299)
Normal
Remission
Response
Nonresponse
*p≤.05 vs. nonresponse
**p≤.05 vs. response
Only remitters function at levels comparable to healthy people
Miller et al. J Clin Psychiatry 1998;59(11):608-19.

48. Take Home Message
♦ Inadequately treated depression may have a progressive
course and result in structural changes in the brain
♦ Activation of NE and/or 5-HT pathways may lead to an
increase in BDNF, resulting in neuroprotective benefits and
restoration of neuroplasticity and neurogenesis
♦ It is important to choose an effective treatment first because
failure to achieve remission may lead to more frequent
relapses and future failures in treatment response1
1.
Oswald et al. Eur Neuropsychopharmacol 2005;15(suppl 3):S326-7.

49. Future Directions

50. TODAY….
diagnosis
trials and errors
effective treatment
TOMORROW….
tailor made

51. Future of Behavioral Health has
Arrived
♦ Patients with depression and anxiety are frustrated with drug
treatments because of poor response (up to 5 trials).
♦ Also, some of these medications increase anxiety, resistance to
treatment, insomnia, and sexual dysfunction.
♦ Sometimes they may quit medications.
♦ It is better to choose psychotropic medications based on the
individual genetic characteristics, metabolizing pathways leading to
better medication tolerance.
♦ This give the patient the confidence to continue treatment.
♦ Test can done by a simple cheek swab (Assure Rx- GeneSightRx).

53. Cells Show Signs of Faster Aging After
Depression
Study found structures called telomeres were shorter in people with the condition
By Brenda Goodman
HealthDay Reporter
TUESDAY, Nov. 12 (HealthDay News) -- The cells of people who have had depression
may age more quickly, a new study suggests.
Dutch researchers compared cell structures called telomeres in more than 2,400 people
with and without depression.
Like the plastic tips at the ends of shoelaces, telomeres cap the ends of chromosomes to
protect the cell's DNA from damage. Telomeres get a bit shorter each time a cell
divides, so they are useful markers for aging.
The researchers found that the telomeres of people who had ever been depressed were
significantly shorter -- about 83 to 84 base pairs of DNA shorter, on average -- than
those of people who had never suffered from depression.
The results remained even after researchers accounted for a host of lifestyle factors that
can also damage DNA, such as heavy drinking and cigarette smoking.
Since people naturally lose about 14 to 20 base pairs of DNA in the telomeres each year,
the researchers said the difference represents about four to six years of advanced
aging.

54. Telomeres

55. A telomere
♦ A telomere is a region of repetitive nucleotide sequences at
each end of a chromatid, which protects the end of the
chromosome from deterioration or from fusion with
neighboring chromosomes. Its name is derived from the
Greek nouns telos (τέλος) 'end' and merοs (μέρος, root: μερ-)
'part.' Telomere regions deter the degradation of genes near
the ends of chromosomes by allowing chromosome ends to
shorten, which necessarily occurs during
chromosome replication.
♦ Without telomeres, the genomes would progressively lose
information and be truncated after cell division because the
synthesis of Okazaki fragments requires RNA primers
attaching ahead on the lagging strand.
♦ Over time, due to each cell division, the telomere ends
become shorter.