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

Neurobiology of Depression:Neurobiology of Depression:An Integrated ViewAn Integrated View

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AgendaAgenda

Introduction Somatic depression Neurobiology of depression Different management Take home Message Future direction

Depression … the 21Depression … the 21stst Century illnessCentury illness

االهرام، االهرام، جريدة القعدة 2222الخميس الخميس جريدة ذى القعدة من ذى 4560845608 العدد العدد 136136السنة السنة 20112011اكتوبر اكتوبر 2020هـ   هـ   14321432من

يصيب أصبح الذي والعصبي النفسي إنسان 450المرض مليون . األرض سطح فوق

الي وصل وحده االكتئاب , 140وان انسان مليون الي العالم في وصلت فقد والخوف القلق حاالت مليون 200أما

.. وقلق خائف انسان الي أيضا العالم في اإلدمان .. 130ووصل مدمن إنسان مليون و مليون وجود تؤكد فإنها مصر في األرقام إنسان 200أما ألف

. االكتئاب عذاب يعاني مصري

DepressionDepression

Samedi 9 novembre 2013

7

World Bank Reports World Bank Reports

Year 2000

Year 2020

Anxiety Depression is

4th greatest health problem

Will be 2nd greatest health

problem causing disability

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

ChallengesChallenges

By the year 2020, depression is projected to

reach 2nd place of the ranking of DALYs

10 Leading causes of burden of disease (DALYs), world 2004 and 2030(WHO)

ChallengesChallenges

Depressed patients

a 2 times greater overall mortality risk

than the general population

Direct causes

(e.g. suicide)

Indirect causes

(e.g. medical illness)

Lost productivity—55%

Outpatient care—6%

Suicide—17%

Inpatient care—19%

Pharmaceuticals—3%

Greenberg PE, et al. J Clin Psychiatry. 1993;54:405-418.

Economics of Depression —Economics of Depression —U.S.A. Data - Total Annual Cost ~$44 BillionU.S.A. Data - Total Annual Cost ~$44 Billion

U.S. data.

Freeling and Tylee (1992); Regier et al (1988); Vazquez-Barquero et al (1987)

Recognition of general practice Recognition of general practice patientspatients

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.

Prevalence of depressionPrevalence of depression

WHO - Fact Sheet N° 265, December  2001

Copeland et al (1987); Gräsbeck (1996); Hagnell et al (1982)

9.5% of women

5.8% of men

10-15% of elderly 65 years

Depressed Patients Usually Depressed Patients Usually Present with Physical SymptomsPresent with Physical Symptoms

69%PresentedONLY With Physical Symptoms

Other

N = 1146 patients with major depression

1. Simon GE, et al. N. Engl J Med. 1999;341(18):1329-1335.

51%

42%

25%

23%

17%

12%

11%

27%

Parkinson's disease

Cancer

Diabetes

MI

Stroke

CAD

HIV

Alzheimer's disease

Prevalence of Depression in Prevalence of Depression in Chronic DiseaseChronic Disease

NHDS, NAMCS, NHAMCSSutor B, et al. Mayo Clin Proc. 1998;73(4):329-337; Jiang et al, CNS Drugs, 2002

Mechanisms of depression andMechanisms of depression and medical comorbidity medical comorbidity

Ellison et al. Mood Disorders in Later Life. Informa 2009

Primary medical illness/condition

Premorbid coping skills, cognitive set, and

personality traits

Pathologic mood state

e.g., depression

Social supports

Neuroendocrine, immune dysfunction, inflammatory change

Blacker and Clare (1987); Bridges et al (1991); Freeling et al (1985)

General practice patients and General practice patients and recognised major depressionrecognised 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.

Gurland et al (1988)

Depression is associated with disability caused by a variety of diseases.

Cardiac

Myocardial infarction

Rheumatic

Arthritis

Pulmonary

Chronic obstructive pulmonary disease

StrokeAlzheimer’s diseaseParkinson’s disease

CNS

The association between The association between depression and medical illnessdepression and medical illness

DepressioDepressionnDepressioDepressionn

Medical Medical illnessillnessMedical Medical illnessillness

Neglect healthNeglect healthNeglect healthNeglect health

Biochemical changesBiochemical changesBiochemical changesBiochemical changes

MorbidityMorbidityMorbidityMorbidityNegative attitudeNegative attitudeNegative attitudeNegative attitude

Functional ability Functional ability Functional ability Functional ability

Cause or Effect?Cause or Effect?

PainPain DepressionDepression

RECIPROCAL RELATIONSHIPRECIPROCAL RELATIONSHIP

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.

Chronic pain & depressionChronic pain & depression

Major Depressive Disorder (MDD)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. Kendler et al. Am J Psychiatry 2000;157(8):1243-51.2. Maletic et al. Int J Clin Pract 2007;61(12):2030-40.

3. Keller et al. Arch Gen Psychiatry 1992;49(10):809-16.4. APA. Am J Psychiatry 2000;157(4 suppl):1-45.

DepressionDepression

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

Rates of Recovery Diminish with Rates of Recovery Diminish with Duration of Major Depressive EpisodeDuration of Major Depressive Episode

Keller et al. Arch Gen Psychiatry 1992;49(10):809-16.

54

16

11

61

0

20

40

60

6 Months 1 Year 2 Years 4 Years 5 Years

% R

eco

very

Rat

e

100

Recovery = 8 weeks of Psychiatric Status Rating (PSR) 1 or 2Recovery = sustained remission

N = 431

Progression of Depression: Adverse Progression of Depression: Adverse Effects of Each Successive EpisodeEffects of Each Successive Episode

Kendler et al. Am J Psychiatry 2000;157(8):1243-51.

Number of Previous Depressive Episodes

10

Ris

k (O

dd

s R

atio

)

0 1 2 3 4 5 6 7-8

0

2

4

6

8

9-11

Female subjects only N = 2395

Likelihood of recent life stress precipitating depression

Risk (Odds Ratio) of depression onset per month

Key Brain Areas Involved in Key Brain Areas Involved in Regulation of MoodRegulation of Mood (A) Ventromedial prefrontal cortex (VMPFC)1

• Modulates pain and aggression, and sexual and eating behaviors2

• Regulates autonomic and neuroendocrine response

(B) Lateral orbital prefrontal cortex (LOPFC)3 • Activity is increased in depression, obsessive-

compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder

• Corrects and inhibits maladaptive, perseverative, and emotional responses

(C) Dorsolateral prefrontal cortex (DLPFC)4 • 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

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.

Reprinted with permissions, from the Annual Review of Psychology, Volume 53, © 2002 by Annual Reviews www.annualreviews.org

A5

B5

C5

Key Brain Areas Involved in Key Brain Areas Involved in Regulation of Mood Regulation of Mood (Cont.)(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

(B) Hippocampus: has a role in episodic,contextual learning and memory3,4

• Rich in corticosteroid receptors5

• Regulatory feedback to hypothalamic-pituitary-adrenal 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.

A6

B6

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.

Reprinted with permissions, from the Annual Review of Psychology, Volume 53, © 2002 by Annual

Reviews www.annualreviews.org

Serotonin (5-HT) and Norepinephrine Serotonin (5-HT) and Norepinephrine (NE) Pathways in the Human Brain(NE) Pathways in the Human Brain11

1.Cooper et al. In: The Biochemical Basis of Neuropharmacology 2003.

Limbic SystemLimbic System

PrefrontalPrefrontalCortexCortex LocusLocus

CoeruleusCoeruleus(NE source)(NE source)

Raphe NucleiRaphe Nuclei(5-HT source)(5-HT source)

AmygdalaAmygdala

HippocampusHippocampus

Descending 5-HT pathways

DescendingNE pathways

By permission of Oxford University Press, Inc. Page 209, figure 8.11 from “Biochemical Basis of Neuropharmacology” by Cooper Jack (2002)

Brain Atrophy in Depression?Brain Atrophy in Depression?

Bremner et al. Am J Psychiatry 2000;157(1):115-8.

Atrophy of the Hippocampus in Depression

Normal DepressionReprinted with permission from Bremner et al. Am J Psychiatry 2000

Correlation Between Hippocampal Volume and Correlation Between Hippocampal Volume and Duration of Untreated DepressionDuration 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.

Female Outpatients With Recurrent Depression in Remission

Days of Untreated Depression

To

tal H

ipp

oca

mp

al

Vo

lum

e (m

m3 )

R2 = .28 N = 38

0 1000 2000 3000 40003000

3500

4000

4500

5000

5500

6000

Hippocampal Dysfunction Contributes to Hippocampal Dysfunction Contributes to Neuroendocrine DysregulationNeuroendocrine Dysregulation

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

Major Depressive Disorder May Major Depressive Disorder May Have Systemic ConsequencesHave Systemic Consequences

Musselman et al. Arch Gen Psychiatry 1998;55(7):580-92.

Musselman DL, et al. Archives of General Psychiatry. 1998;55(7):580-592. Copyright © (1998), American Medical Association.

Brain-derived Neurotrophic Factor (BDNF), Brain-derived Neurotrophic Factor (BDNF), Stress, and Neurogenesis in the Adult BrainStress, 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 hippocampus2

• 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.

The Monoamine Hypothesis of Gene Action:The Monoamine Hypothesis of Gene Action:The Impact of Stress on BDNFThe Impact of Stress on BDNF

Stahl. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:187.Preprinted with permissions from Cambridge University Press.

Pain and Stress Lower BDNF Gene Pain and Stress Lower BDNF Gene Expression in Animal ModelsExpression in Animal Models

*p<.05 compared to controlDuric and McCarson. Neuroscience 2005;133(4):999-1006.

0

2

4

6

8

Pg

BD

NF

mR

NA

/ng

-a

ctin

m

RN

A

Control AcuteStress

ChronicStress

* *

Formalin

Acute and Chronic Stress

0

2

4

6

8

Pg

BD

NF

mR

NA

/ng

-a

ctin

m

RN

AControl 2:45h 24h

**

6h

*

10-DayCFA

*

Acute and Chronic Pain

Changes in Hippocampal BDNF Synthesis

Major Depressive Disorder: Major Depressive Disorder: The ConsequencesThe 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 innervation2

1. Sheline. Biol Psychiatry 2000;48(8):791-800.2. Manji et al. Nat Med 2001;7(5):541-7.

Antidepressants:Antidepressants:The Importance of Serotonin and The Importance of Serotonin and Norepinephrine in the Treatment Norepinephrine in the Treatment

of Depressionof Depression

Beyond Synapse: 5-HT and NE Aid BDNF Beyond Synapse: 5-HT and NE Aid BDNF Synthesis (Preclinical Evidence)Synthesis (Preclinical Evidence)

1. Manji et al. Biol Psychiatry 2003;53(8):707-42.2. Tsankova et al. Nat Neurosci 2006;9(4):519-25.

= inhibitory┴

Successful Antidepressant Treatment Successful Antidepressant Treatment can be Associated with BDNF Increasecan be Associated with BDNF Increase

*p<.01 vs. control or treatedMixed group of antidepressants used for treatmentHAMD17 = 27.810.2 and 18.811.4 for untreated and treated groups respectivelyShimizu et al. Biol Psychiatry 2003;54(1):70-5.

0

5

10

15

20

25

30

35

Pla

sma

BD

NF

(n

g/m

L)

Control Depressed-treatment-naïve

Depressed-treated

*

(n = 50) (n = 16) (n = 17)

Network Hypothesis of DepressionNetwork Hypothesis of Depression

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

Summary: Summary: BDNF, Depression, and AntidepressantsBDNF, 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. Duman et al. Arch Gen Psychiatry 1997;54(7):597-606.2. Shimizu et al. Biol Psychiatry 2003;54(1):70-5.3. Duric and McCarson. Neuroscience 2005;133(4):999-1006.

Remission, Not Response, is the Remission, Not Response, is the Goal of Treatment of DepressionGoal of Treatment of Depression

Regional Blood Flow Abnormalities Regional Blood Flow Abnormalities in Patients with Depressionin Patients with Depression

Amygdala

Medial Orbital

Ventrolateral PFC

t-value

0 2.0 4.5

t-value

0 2.0 4.0

Patients with depression had increased blood flow in amygdala and left medial and lateral orbital cortex, extending to ventrolateral PFCDrevets et al. J Neurosci 1992;12(9):3628-41.

Structural Difference in Structural Difference in tthe Hippocampus of he Hippocampus of Remitted vs. Nonremitted PatientsRemitted vs. Nonremitted Patients

Frodl et al. J Clin Psychiatry 2004;65(4):492-9.

Remitted, left hippocampusRemitted, right hippocampus

Nonremitted, right hippocampus

Nonremitted, left hippocampus

3.0

3.5

4.0

4.5

Remitted(N = 18)

Nonremitted(N = 12)

Remitted(N = 18)

Nonremitted(N = 12)

Left Hemisphere

Right Hemisphere

Hip

po

cam

pal

Vo

lum

e (m

m3 )

Summary: Summary: Restoring Homeostasis and HarmonyRestoring Homeostasis and Harmony

Continuous antidepressant use may be associated with increased 5-HT and/or NE in the prefrontal cortex andlimbic 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. Mayberg et al. Biol Psychiatry 2000;48(8):830-43.2. Brody et al. Biol Psychiatry 2001;50(3):171-8.3. Duman. Neuromolecular Med 2004;5(1):11-25.

What Happens if Remission is Not What Happens if Remission is Not Achieved?Achieved?

Pintor et al. J Affect Disord 2003;73(3):237-44.

0

10

20

30

40

50

60

70

80

90

100

% of Patients Who Relapsed (2-Year Follow-up Study)

Patients Not in Remission

Patients in Remission

% o

f P

atie

nts

15.2%

67.6%

(n = 71) (n = 112)

*

*p<.0001

Functional Benefits of RemissionFunctional Benefits of Remission

*p≤.05 vs. nonresponse**p≤.05 vs. responseOnly remitters function at levels comparable to healthy people

Miller et al. J Clin Psychiatry 1998;59(11):608-19.

1

2

3

4

Wo

rk C

om

po

site

Sca

le o

f th

e S

oci

al A

dju

stm

ent

Sca

le-S

R (

Mea

n ±

SD

)

***

*

(n = 202) (n = 122) (n = 299)(n = 482)

NonresponseResponseRemissionNormal

Take Home MessageTake 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.

Future DirectionsFuture Directions

diagnosisdiagnosistrials and errorstrials and errors effective treatmenteffective treatment

TODAY….TODAY….

TOMORROW….TOMORROW….

tailor madetailor made

Future of Behavioral Health has Future of Behavioral Health has ArrivedArrived

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).

Cells Show Signs of Faster Aging After Cells Show Signs of Faster Aging After DepressionDepression

Study found structures called telomeres were shorter in people with the condition

By Brenda GoodmanHealthDay 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.

TelomeresTelomeres

A telomereA 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.