Update on Neurobiology of Depression

Prof. Hani Hamed Dessoki, M.D.Psychiatry

Prof. Psychiatry

Chairman of Psychiatry Department

Beni Suef University

Supervisor of Psychiatry Department

El-Fayoum University

APA member

Disclosure of Interest & DisclaimerDisclosure of Interest & Disclaimer

Some of the information included in this presentation were supplied by Eli Lilly and Company or its affiliates.

AgendaAgenda

Introduction History Changing Understanding of the Neurobiology

of Depression What’s different about the depressed brain? Solution Recent Data

IntroductionIntroduction

Depression is one of the most common psychiatric disorders worldwide, affecting at least 12% of American women and 8% of American men in their lifetime. 

Prevalence rates are higher in some countries, for example, a 19% rate of depression has been reported for Lebanon. 

The World Health Organization (WHO) recently ranked depression as the leading cause of morbidity in developing nations in the next century, which will result in high utilization of health services and decreased work productivity.

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%.

The Concept of Depression The Concept of Depression Throughout HistoryThroughout History- Ancient theories.  Ancient philosophers attributed mood disorders to supernatural forces.

Hippocrates, for example, hypothesized that the alignment of the planets caused the spleen to secrete black bile, which then darkened the mood and caused melancholia. 

However, very few ancient scholars speculated about the importance of genetic factors and affective temperaments as factors in the etiology of depression.

In Anatomy of Melancholy (1621), the English scholar Robert Burton stated that melancholic people "are born to melancholic parents."

Psychodynamic TheoriesPsychodynamic Theories

The emergence of psychoanalytic theory brought with it an emphasis on early life trauma in the development of adult psychopathology.

Although Freud did not dismiss the possibility of genetic predisposition, his primary focus was the effect of early life trauma, particularly object loss, in the development of adulthood depression.  

The object-loss model is a 2-step hypothesis, starting with an early traumatic separation from a significant object of attachment. This loss predisposes the individual to depression, which is triggered by adult losses thought to revive the early traumatic loss.

Biological TheoriesBiological Theories

Adolf Meyer (1866-1950), a psychoanalyst at Johns Hopkins University, in Baltimore, Maryland, coined the term "psychobiology" to emphasize the importance of the interaction between genetic factors and life events in the causation of mental illness.  

In the 1960s, researchers from the United States and Europe, virtually simultaneously, posited the biogenic amine hypothesis of depression. This hypothesis held that depression was caused by a deficiency in the catecholeamine, norepinephrine (NE), and/or the indoleamine, serotonin (5HT).

Biological TheoriesBiological Theories

However, subsequent research reveals that mere deficiency of the biogenic amines is insufficient for the development of depression.  

Also, traditional antidepressant medications, which primarily target norepinephrine and/or serotonin neurons, are ineffective in approximately 40% of patients with MD or dysthymia.  

Therefore, the limitations of the biogenic amine theory in explaining the pathophysiology of depression and the limitation of our antidepressant have led researchers to continue the search for new etiologic models of depression.

Changing Understanding of the Neurobiology of DepressionThe Monoamine Hypothesis of Depression was just the tip of the iceberg.

1. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. 2013.2. Duman RS, Aghajanian GK. Science. 2012;338:68-72.3. Sanacora G et al. Neuropharmacology. 2012;62:63-77.

MDD is much more complex than previously suspected.

Dysregulation of specific brain circuits1,2

It isn’t just about these monoamines…1

DA 5-HT NE

Morphological changes2:• Neuronal atrophy• Synaptic loss

Susceptibility genesEpigenetic changesStressful life events2

Downstream effects2:• Regulation of gene expression• Release of growth factors

Involvement of other neurotransmitters: glutamate and GABA1,3

What’s different about the depressed brain?

Why do we care about the neurobiology of depression?

What does the science of depression tell us that may help guide our clinical practice?

A Depressed Brain Is Different From a Non- depressed Brain Evidence of both gray and white matter changes

The depressed brain Structural pathology• Decreased volume of specific regions• Reduced neuronal size• Reduced synapse number

• Dysregulated connectivity

Functional pathology

Duman RS, Aghajanian GK. Science. 2012;338:68-72.

Areas of the brain implicated Areas of the brain implicated in MDDin MDD

Modified from Charney DS, et al. Neurobiology of Mental Illness. 2004

Prefrontal Cortex (PFC)

• Involved in the “executive functions,” such as working memory, decision-making, planning, and judgment

Amygdala

• Performs a primary role in processing and memory of emotional reactions

Hippocampus

• Important for the forming, and perhaps storage, of associative and episodic memories

Nucleus Accumbens• Involved in integrating reward stimuli

Anterior Cingulate Cortex (ACC)

• Plays a role in rational cognitive functions such as reward anticipation, decision-making, empathy, and emotion

• Integrates emotional stimuli and attentional functions

Insular Cortex

• Processes convergent information to produce an emotionally relevant context for sensory experience

Striatum

• Important for movement andreward

MDD Affects Gray MatterHippocampal and frontal regions may be smaller in patients with MDD than in healthy controls.

Kempton MJ et al. Arch Gen Psychiatry. 2011;68:675-690.

Effect size ( � CI), MDD patients vs. controlMeta-analysis of 143 studies

Hippocampus, total

Frontal gray and white matter, total

Orbitofrontal gray matter, total

Caudate, total

Putamen, total

Globus pallidus, total

Thalamus, total

Gyrus rectus gray matter, total

Lateral ventricles, total

-1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1.0

Volume smaller in MDD patients Volume larger in MDD patients

Reduced Neuronal Size May ContributeTo Smaller Gray-matter Volumes in MDD

Stockmeier CA et al. Biol Psychiatry. 2004;56(9):640-650.

Hippocampal soma (pyramidal neurons) may be reduced in patients with MDD.

CONTROL

MDD

CA1 CA2 CA3 CA3i dentate gyrus, granule-cell

layer

AREA (µm2)

300

200

100

0

Pyramidal neuron soma size is decreased by 17% to 21%

There is a significant effect of diagnosis on pyramidal neuron soma size (p=.0006) in all CA fields.Least squares adjusted means � standard error.

Hippocampal Volume Loss Is Associated With MDD

Sheline YI et al. J Neurosci. 1999;19:5034-5043.

Reduction in hippocampal volume is related to total time depressed.

2800

3300

3800

4300

4800

5300

5800

24 women with a history of MDD, and 24 matched controls

0 500 1000 1500 2000 2500 3000 3500 4000

Time depressed, days

Total Hippocampal

Volume, mm3

p = .002

In Prefrontal Cortex, Synapse Density And Function Are Reduced in MDD

Kang HJ et al. Nature Med. 2012;18:1413-1417.

Spine synapse numbers decreased in MDD.

Reduced expression of 5

genes that code for the

following proteins related to

synapse function:

• calmodulin 2

• synapsin I

• Rab3A

• Rab4B

• β-tubulin-4

Spine synapses

per µm3

Control MDD

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P < 0.05

In layer II/III dlPFC. Data show the mean of 5 post-mortem samples, � SD.

White Matter Changes in MDD:Glial Cell Changes Are Also Apparent

1. Miguel-Hidalgo JJ et al. J Affect Disord. 2010;127:230-240.2. Torres-Platas SG et al. Neuropsychopharmacol. 2011;36:2650-2658.

EAAT1 / GAPDH

Astrocyte hypertrophy2↓ Glutamate transporters1

0.20

0.00

0.10

0.15

0.05

P = 0.043

Control MDDExcitatory amino acid transporter 1 (EAAT1) levels

reduced in postmortem samples3D reconstruction of fibrous white-matter astrocytes

EAAT1, excitatory amino acid transporter 1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase

Compromised White Matter Integrity Damages Connectivity

Zhu X et al. Brain Research. 2011;1369:223-229.

White matter microstructural integrity measured via diffusion tensor imaging (DTI) in first-episode, treatment-naive MDD patients (young adults).

L anterior limb internal capsule

R parahippocampal gyrus

L posterior cingulate gyrus

In young adult MDD patients, white matter integrity was significantly decreased within limbic and frontal subcortical circuits thought to be involved in emotional and cognitive regulation.

1. What’s Different About the Depressed Brain?

Answer 1:Answer 1:

Decreased gray matter Decreased gray matter in cortical and limbic brain in cortical and limbic brain regions (especially prefrontal cortex and regions (especially prefrontal cortex and hippocampus) that control emotion, mood, and hippocampus) that control emotion, mood, and cognitioncognition

Abnormal changes in white matterAbnormal changes in white matter, including , including hypertrophy and compromised integrityhypertrophy and compromised integrity

Some evidence suggests Some evidence suggests a a progressive nature progressive nature to to these structural pathologiesthese structural pathologies

Decreased Connectivity in Key Regionsof the Depressed BrainFunctional imaging studies highlight the role of hippocampus and PFC1

Insula

MDD

A

Control

mPFC

In 14 adolescents with MDD2:

•Amygdala activation was greater than in controls•Amygdala connectivity was reduced

medial PFC insula

•Less connectivity correlated with poorer psychosocial function

A poorly modulated, overreactive amygdala may contribute to poor emotional regulation.

1. Duman RS, Aghajanian GK. Science. 2012;338:68-72; 2. Perlman G et al. J Affect Disord. 2012;139:75-84.

Changes in Brain Connectivity Patterns in MDD Appear to be Both Sensitive and Specific

Zeng LL et al. Brain. 2012;135:1498-1507.

Complex functional connectivity changes occur across many circuits.Preliminary data show that the overall change may create a pattern that is highly sensitive and specific to MDD.

89.7%of the 29 controls

were correctly

identified

100%of the 24 MDD patients

were correctly

identified

In an fMRI study of 53 subjects:

The altered pathways with highest discriminative power were in circuits implicated in MDD (e.g. amygdala, anterior cingulate cortex, hippocampus)

1. What’s Different About the Depressed Brain?

Answer 2:Altered brain connectivityAltered brain connectivity - evidence suggests - evidence suggests a complex disruption of brain circuits in MDD:a complex disruption of brain circuits in MDD:

•Reduced connectivity of some regions Reduced connectivity of some regions (hippocampus, PFC)(hippocampus, PFC)

•Preliminary data reveals an overall pattern of Preliminary data reveals an overall pattern of altered connectivity involving the amygdala, altered connectivity involving the amygdala, anterior cingulate cortex, and hippocampal anterior cingulate cortex, and hippocampal circuitscircuits

Stress + Vulnerability Depression

Willner et al. Neurosci Biobehav Rev. 2013;37:2331-71; http://dx.doi.orf/10.1016/j.neubiorev.2012-12-007.

Stressors, interacting with an individual’s vulnerability to depression, can precipitate a depressive episode.

Level of vulnerability

(diathesis)

Early lifeexperiences

Genetics

Personality STRESSOR

Major life event (bereavement)

Hormonalchallenge

Multiple minor stressors

depressiveepisode

The larger the vulnerability...

With repeated depressive episodes, the brain is “kindled” to respond to weaker and weaker precipitants.

...the smaller the stressor required

How Does Stress Drive Structural and Functional Changes in MDD?

1. Willner et al. Neurosci Biobehav Rev. 2013;37:2331-71; 2. Sen S et al. Biol Psychiatry. 2008;64(6):527-532.

Excessive activation of the HPA axis can affect morphology and function1.

Failure to cope with stress

Activation of the amygdala and the HPA axis

Hippocampal changes• GC receptor loss• Reduced neurogenesis• Reduced volume• Dendritic atrophy• Reduced BDNF production2

Symptoms of depression

• Disinhibition of HPA axis• Prolonged corticosteroid

stimulation

Reduced monoamine levels

Disrupted function• Disrupted information

processing in forebrain circuits (PFC)

• ...and in the systems they regulate (amygdala, nucleus accumbens)

Stress Induces Dendritic Atrophy in Rat Models

Liu RJ, Aghajanian GK. Proc Natl Acad Sci. 2008;105:359-364.

Reduced apical dendritic branch length has been demonstrated in rat mPFC pyramidal neurons after restraint stress.

120

100

80

60

40

20

0

% C

ontr

ol

Total branch length (µm)mean � SEM

ControlStress

*

*P<0.05

BDNF Loss Is a Key Contributor to Changes in the Depressed Brain

1. Barde YA et al. EMBO J. 1982;1:549–553; 2. Autry AE, Monteggia LM. Pharmacol Rev. 2012;64:238-258; 3. Smith MA et al. J Neurosci. 1995;15:1768–1777; 4. Sen S et al. Biol Psychiatry. 2008;64:527-532; 5. Liu RJ et al. Biol Psychiatry. 2012;71:996-1005.

BDNFpurified1

1980s 1990s 2000s 2010s

Role for BDNF in axonal growth and synaptic plasticity2

Stress reduced BDNF expression in animal models3

BDNF levels were consistently lower in MDD vs. controls4

BDNF loss causes dendritic atrophy, mirroring that caused by stress5

BDNF Loss Causes Dendritic Atrophy, Mirroring That Caused by Stress

Liu RJ et al. Biol Psychiatry. 2012;71(11):996-1005.

Reduction in BDNF impairs formation or maturation of synapses in mouse PFC.

*P<0.05, **P<0.01 vs. wild-type

4500

4000

3500

3000

2500

2000

1500

1000

500

0Apical dendrites

Den

driti

c le

ngth

(µm

)

Val/Val

Met/Met

Val/Met

Wild-type, normal BDNF

Heterozygous, 1 impaired BDNF gene

Homozygous, 2 impaired BDNF genes

Gene-dose effect, showing reduced branch length of apical dendrites.

Mice with knock-in BDNF polymorphism (Val66Met) *

**

Recap: What’s Different About the Depressed Brain?

Altered structure• Dendritic atrophy, reduced neuronal density

• Many changes driven by activation of the HPA axis and reduction in BDNF levels

Altered connectivity• Including monoaminergic circuits, and glutamate

• Disruption of the complex connections, interactions,and function of circuits and neurotransmitters

Altered susceptibility to stress• Stressors, interacting with an individual’s vulnerability to depression,

can precipitate a depressive episode

Are Structural and Anatomical Changesin the Depressed Brain Reversible?

Evidence for recoveryKey brain structures are smaller in•e.g. hippocampus1,2, total brain gray matter2

Key brain structure sizes are not different in v. •e.g. hippocampus1, total brain gray matter2

Current MDD Remitted MDD

Remitted MDD Control

Evidence against recoveryKey brain structures are smaller in •e.g. hippocampus2,3

Remitted MDD Control

1. Kempton MJ et al. Arch Gen Psychiatry. 2011;68:675-690 2. Geerlings MI et al. Psychological Medicine. 2013;43:317-328 3. Sheline YI et al. J Neurosci. 1999;19:5034-5043 4. McEwen BS Ann NY Acad Sci. 2004;1032:1-7

vs.

vs.

vs.

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┴

DA

/NE agents

NE/5HT agents

Loss of positive

affect

Negative affect

Depression with anxiety

Loss of pleasure/enjoyment

Loss of motivationAnd energy

Loss of interest Low mood

Sadness

Fear

Guilt

Anxiety

Irritability

Hypothetical model showing differential actions of antidepressant agents on symptoms of positive and negative affect

Nutt D. et al., 2006; J. Clinic. Psychiatry, 67:46-49

Type of Affect

The Importance of Choosing an The Importance of Choosing an Effective Treatment FirstEffective Treatment First “The rapid remission of the depressive symptoms is the

most important predictor for the favorable long-term outcome…” (N = 196, 2-year study)1

Longer duration (12 weeks) of the previous episode reduced the likelihood of recovery by 37% (N = 250, 2-year study)2

The presence of pain is associated with worse outcome3

Lack of adequate response to the first antidepressant is a predictor of future treatment resistance (N = 996)4

1. Szadoczky et al. J Affect Disord 2004;83(1):49-57.2. Spijker et al. J Affect Disord 2004;81(3):231-40.

3. Bair et al. Arch Intern Med 2003;163(20):2433-45. 4. Oswald et al. Eur Neuropsychopharmacol 2005;15(suppl 3):S326-7.

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 Pat

ient

s

15.2%

67.6%

(n = 71) (n = 112)

*

*p<.0001

Duloxetine vs. Other Antidepressants Duloxetine vs. Other Antidepressants

Remission rates with duloxetine were higher compared to those achieved with SSRIs in patients with moderate to severe MDD

Duloxetine may offer some important efficacy advantages over SSRIs in patients with moderate to severe MDD

Duloxetine-treated Patients Achieved Higher Duloxetine-treated Patients Achieved Higher Remission Rate than Those Treated with SSRIsRemission Rate than Those Treated with SSRIs

*p = .034, MMRM-CATThe secondary endpoint, HAMD17 showed a significant remission; however, the primary endpoint, remission at week 12 by QIDS-SR did not show significant differenceRemission: HAMD17 total score ≤7 at 12 weeks (MMRM-CAT)

Martinez et al. Int clin Psychopharmacol 2012;27(1):17-26.

Estimated probability of remission: Duloxetine vs. Generic SSRIs

*

N = 378 N = 372

Duloxetine Remission Rates vs. Duloxetine Remission Rates vs. Paroxetine in an Asian PopulationParoxetine in an Asian Population

*p = .855, based on Fisher’s exact testRemission: HAMD17 total score ≤7 at endpoint (8 weeks)Lee et al. Psychiatry Clin Neurosci 2007;61(6):295-307.

*

Remission at endpoint: Duloxetine vs. Paroxetine

N = 240 N = 238

Duloxetine Achieved Significantly Higher Duloxetine Achieved Significantly Higher Remission Rates vs. PlaceboRemission Rates vs. Placebo Regardless of Regardless of Episode DurationEpisode Duration

*p<.001 vs. placeboRemission: HAMD17 total score ≤7

Patie

nts

Ach

ievi

ng R

emis

sion

, %

**

*

Perahia et al. Int Clin Psychopharmacol 2006;21(5):285-95.

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.

Recent DataRecent Data

30-second Overview:The Potential Role of Glutamate in MDD

1. Sanacora et al. Neuropharmacology. 2012; 62:63-77. 2. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. 2013.

Glutamate is employed by the majority of neurons in circuits

connecting areas implicated in the pathophysiology of MDD1.

GLUTAMATEThe major excitatory neurotransmitter in the nervous system1,2

A growing body of evidence suggests a significant role of glutamate in the etiology of MDD1

• Measurable abnormal changes in glutamate release and transmission

• Malfunction in the mechanisms regulating clearance of glutamate

As a result, there has been an increased interest in glutamatergic receptors (e.g., AMPA, NMDA, mGluRs).Glutamate may affect monoaminergic

neurotransmission (e.g., via innervation of monoamine neurons in the brainstem2)

30-second Overview:The Potential Role of GABA in MDD

1. Choudary PV et al. Proc. Natl. Acad. Sciences. U.S.A. 2005;102:15653-15658.2. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. 2013.

Alterations in both glutamate and GABA may contribute to the pathology of depression1

GABAThe major inhibitory neurotransmitter in the nervous system

Evidence suggests a significant role of the balance of GABA and glutamate in the etiology of MDD1

• Biosynthesis of GABA is tightly coupled to glutamate recycling

• Altered genetic regulation of the subunits of the GABA complex may lead to glutamate over-excitability

• Elevated levels of GABA and glutamate have been observed in the cerebral cortex of MDD subjects

Further research is necessary to determine the mechanisms that influence genetic regulation of GABA in MDD patients.

GABA is released from interneurons and may affect monoaminergic neurotransmission2

Multiple studies have demonstrated that other non-Multiple studies have demonstrated that other non-monoamine neurochemical systems likely play a role monoamine neurochemical systems likely play a role in the etiology and treatment of depression.in the etiology and treatment of depression.  

Among these newly discovered systems are various Among these newly discovered systems are various immune system components, such as immune system components, such as cytokinescytokines, and , and the neuropeptide neurotransmitters, such as the neuropeptide neurotransmitters, such as corticotropin-releasing factor (CRF), thyrotropin-corticotropin-releasing factor (CRF), thyrotropin-releasing hormone (TRH), somatostatin, and growth releasing hormone (TRH), somatostatin, and growth hormone releasing factor (GHRF). hormone releasing factor (GHRF).

Future Directions