BASES BASES NEUROBIOLÓGICAS DE LA NEUROBIOLÓGICAS DE LA

DEPRESIÓN DEPRESIÓN

Dr. Eugenio Olea B.Dr. Eugenio Olea B.Unidad DocenteUnidad Docente

Facultad de Medicina Universidad de ChileFacultad de Medicina Universidad de Chile

Instituto Psiquiátrico Instituto Psiquiátrico

HISTORIAHISTORIA ETIOPATOGENIAETIOPATOGENIA EPIGENÉTICAEPIGENÉTICA STRESSSTRESS FENÓMENOS INFLAMATORIOSFENÓMENOS INFLAMATORIOS

Historia Los conceptos de “Patología Clásica” de los griegos se Los conceptos de “Patología Clásica” de los griegos se

centraba en la teoría humoral contenida en el centraba en la teoría humoral contenida en el Corpus Corpus Hipocraticum, Hipocraticum, implicando la interacción de los cuatro implicando la interacción de los cuatro humores corporales.humores corporales.

Todas las enfermedades resultan de una perturbación Todas las enfermedades resultan de una perturbación en el equilibrio humoral, por exceso o corrupción de en el equilibrio humoral, por exceso o corrupción de uno de los humores.uno de los humores.

Teoría humoral de Empédocles (490-430 AC)

ElementoElemento CualidadCualidad Humor Humor   

FuegoFuego CalorCalor Sangre (en el corazón)Sangre (en el corazón)   

TierraTierra SequedadSequedad Phlegm (en el cerbro) Phlegm (en el cerbro)   

Agua Agua HumedadHumedad Bilis amarilla (en el higado) Bilis amarilla (en el higado)   

AireAire FríoFrío Bilis negra (en el bazo)Bilis negra (en el bazo)

PINEL

1.)Herencia 1.)Factores dañinos en el ambiente social .v.gr, falta de educación. 3.)Forma de vida irregular4.) Pasiones espasmódicas (rabia ) 5.) Pasiones opuestas o intensas (perdida,odio, temor, remordimiento) 6.) Pasiones 7.) Constitución melancólica 8.) Factores físicos ( incluye alcoholismo, amenorrea, hemorroides no sangrantes, fiebre , puerperio y trauma cerebral)

¿Qué provoca la ¿Qué provoca la depresión?depresión?

A primary deficit in monoamine function.A primary deficit in monoamine function. A primary deficit in excitatory amino acid A primary deficit in excitatory amino acid

function.function. Decrease in neurotrophin synthesis; impaired Decrease in neurotrophin synthesis; impaired

neuronal plasticity.neuronal plasticity. A change in the neuroglia/oligodendroglia A change in the neuroglia/oligodendroglia

support for the neuronal networks that cause support for the neuronal networks that cause neuronal dysfunction.neuronal dysfunction.

Impaired capacity of the brain to recycle Impaired capacity of the brain to recycle neurotoxins caused by chronic inflammation.neurotoxins caused by chronic inflammation.

Any combination or none of these !! Any combination or none of these !!

Sistema Serotoninérgico en Depresión

Niveles 5-HIAA en LCR Receptores postinápticos 5-HT2a en cerebro y plaquetas Ligando del transportador de serotonina en cerebro y plaquetas Serotonina en plaquetas Respuesta de PRL a fenfluramina Clomipramina y triptófano

Sistema Noradrenérgico en Depresión MHPG en orina y

LCR NA en plasma y

Adrenalina Unión a recept. Alfa

2 en plaquetas Respuesta de GH a

clonidina y repuesta Alfa 2 en plaquetas

Sistema Dopaminérgico en Depresión Niveles de HVA en LCR Niveles de DA y HVA en

plasma Niveles plasmáticos de

HVA en respuesta a glucoorticoides

Actividad de MAO plaquetaria

Act , de DA beta hidroxilasa

Retardo psicomotorEn depresión psicótica

Asociado a depresión psicótica

En unipolar en bipolar

Eje Hipotálamo Hipófisis AdrenalA Aumento de eventos vitales y estrés crónicoB Incremento de sensibilidad hipocampalC Atrofia hipocampalD Aumento de CRH en LCR; alteración de la

supresión con dexametasonaE Alteración de la respuesta de ACTH a CRH.

Hipertrofia hipofisiariaF Hipertrofia corteza adrenalG Hipercortisolismo

Eje Tiroideo

A Aumento de TRH en LCRB Respuesta reducida de TSH a TRH

(30%)C Anticuerpos antitiroideos (9-20%)D Hipotiroidismo subclínicoE Respuesta a la potenciación con T3 o

T4

HIPÓTESIS CAUSALES EN DEPRESIÓNHIPÓTESIS CAUSALES EN DEPRESIÓN

1950s 1960s 1970s 1980s 1990s 2000s

Monoamine hypothesis

Receptor down-regulation

hypothesis

Post-synaptic signalling &

gene expression

Neuroplasticity &Circadian rhythms

Imipraminediscovered

Despite all the wonderful neuroscience, and even more wonderfulpapers in Nature, Science, Cell and Neuron, we still haven’t improve

on the efficacy of antidepressant treatments since thediscovery of imipramine in 1957

TEORIA TEORIA MONOAMINÉRGICA (1) MONOAMINÉRGICA (1)

1.-SCHILDKRAUT, BUNNEY y DAVIES:RELACIONAN DEPLECION O DESBALANCE DE NOREPINEFRINA CON DEPRESION.

2.-COPPEN, LAPIN y OXENKRUG:ENFATIZAN EL ROL DE SEROTONINA.

3.-PRANGE: TEORIA DE LA PERMISIVIDAD AMINOBIOGÉNICA.

TEORIA MONOAMINÉRGICA TEORIA MONOAMINÉRGICA (2) (2)

4.-JANOWSKY:TEORÍA DEL DESBALANCE COLINÉRGICO-NORADRENÉRGICO

5.-SIEVER Y DAVIES: HIPÓTESIS DE LA DESREGULACIÓN NORADRENÉRGICA

6.-VAN PRAAG:TEORÍA DEL TRASTORNO NEUROQUÍMICO DIMENSIONAL

NoradrenalinaNoradrenalina SerotoninaSerotonina

DopaminaDopamina

Energía Interés

Impulso

Activación

Motivación

SexoApetito

Agresión

AnsiedadIrritabilidad

Ánimo, Emoción,Función Cognitiva

Roles fisiologicos / conductuales de NA, 5-HT y DA

NEUROTRASMISORES Y SINTOMAS.NEUROTRASMISORES Y SINTOMAS.

Energy

Alertness

Noradrenaline

Serotonin

Obsessions and compulsions

Anxiety

Irritability

Mood

EmotionAppetite

Sex

Loss of interest

Dopamine

Attention

Motivation

Pleasure

Stahl S. Essential Psychopharmacology. 2000.Foote SL, Aston-Jones GS. Psychopharmacology. 1995: 335345.

Nutt DJ, et al. J Psychopharmacol 2007; 21: 461471.Nutt DJ. J Clin Psychiatry 2008; 69 Suppl E1: 47.

Shelton AJ & Tomarken RC. Psychiatr Serv 2000; 52: 1469–1478.Stahl S. J Clin Psychiatry 2003; 64: 11451146.

GABA

Inhibit release/activity of each other

Influence release/activity of each other

Influence release/activity of each other

Glutamate

Increases NA release within locus coeruleus

Influence release/activity of each other

Serotonin decreases glutamatergic activity within PFC

Mecanismos moleculares de acción de los antidepresivos

Señalización sináptica e intracelular en depresión mayor

Belmaker RH, Agam G. N Engl J Med. 2008;358(1):55-68.Reprinted with permission from the Massachusetts Medical Society. 31

Neurobiología del Trastorno Neurobiología del Trastorno Depresivo MayorDepresivo Mayor

Genetic Vulnerabili

ty

Injury

Stress

Epigenetic Modulation

Based on Maletic et al. Front Biosci 2009;14:5291-338.

Cellular and Subcellular Level Impact on:

♦ Intracellular Signaling♦ Gene Transcription♦ Neurotrophic Support

NEUROTRASMISORES Y NEUROMODULADORES

Clase química SubstanciaPhenylethylamines Dopamine, noradrenaline, adrenaline,

phenylethylamine*

Indoleamines Serotonin, melatonin**, tryptamine*

Cholinomimetics Acetylcholamine, choline

Amino Acids Glutamate, aspartate, glycine, taurine, gamma- aminobutyric acid

Purines Adenosine, adenosine triphosphate

Diamines Histamine

Neuropeptides Enkephalins***, beta-endorphins, dynorphin, vasopressin, oxytocin, substance P,

cholecystokinin, neuropeptide Y, corticotropin

releasing factor, adrenocorticotropic hormone, angiotensin, etc.

Table 1.1 Main (classical) transmitters are underlined and act in the concentrations range ng-μg. *Trace amines characterized by acting in a low concentration (pg-ng/g) but with a very high turnover in the brain. **Probably acts as a neurotransmitter in the pineal gland; thought to regulate the circadian rhythm (at least in some species). ***Neuropeptides can act as neurotransmitters or neuromodulators; neuromodulators modify the action of classical transmitters in the brain.

The Role of Epigenetic The Role of Epigenetic ModulationModulation

Champagne et al. Cur Opin Neurobiol 2005;15(6):704-09. Copyright Elsevier (2005).

Externalenvironment

Maternal careMaternal care Social experiencesSocial experiences

Geneticbackground

Geneticbackground

EARLY EXPERIENCESEpigenetic modifications 1

AdultFertilization Pre-natal Postpartum Post-weaning

REVERSIBILITYEpigenetic modifications 2

Behavioralphenotype

TS

ST

Epigenetic Modulation? Parental Stress Epigenetic Modulation? Parental Stress May Influence HPA Reactivity in Children May Influence HPA Reactivity in Children Long-TermLong-Term

Entringer et al. Horm Behav 2009;55:292-98. Copyright Elsevier (2009).

31 healthy young adults whose mothers experienced severe stress during pregnancy and 30 age-matched comparison group individuals who underwent TSST

p=0.06 vs CG p=0.03 vs CGTS

ST

50

40

30

20

10

0

AC

TH

(p

g\m

L)

-2 15 25 35 45 105

Time (mins)

15 25 35 45

PS

CG

To

tal

Co

rtis

ol

(ng

/mL

)

*

Time (mins)*Pre-TSST cortisol levels were significantly lower (p=0.007).ACTH=Adrenocorticotropic hormone; CG=Comparator group; HPA=Hypothalamic-pituitary-adrenal axis; PS=Prenatal stress; TSST=Trier Social Stress Test.

-2 105

150

175

125

200

100

22560

5-HTT=Serotonin transporter gene; LL=Long-long allele; LS=Long-short allele; MDE=Major depressive episode; SLE=Stressful life event; SS=Short-short allele.

The Risk of Developing an MDE Within 2 Months After Exposure to an SLE

Kendler et al. Arch Gen Psychiatry 2005;62(5):529-35.

Male LS/LLMale SSFemale LS/LL

Haz

ard

Rat

iofo

r D

epre

ssio

n O

nse

tN=549

0

1

2

3

4

5

6

7

8

9

No SLE Any SLE

Female SS

La Interacción entre Estrés y el Polimorfismo La Interacción entre Estrés y el Polimorfismo del 5-HTT Puede Precipitar la Depresióndel 5-HTT Puede Precipitar la Depresión

GENES Y DEPRESIÓN

Epigenética Epigenética Comportamental-2Comportamental-2

Differences in behaviour of offspring related to Differences in behaviour of offspring related to degree of methylation of DNA of glucocorticoid (GC) degree of methylation of DNA of glucocorticoid (GC) receptor gene.receptor gene.

Methylation decrease gene expression and reduces Methylation decrease gene expression and reduces receptor function; acetylation increases function!receptor function; acetylation increases function!

As HPA axis is controlled by a “feed-back” inhibitory As HPA axis is controlled by a “feed-back” inhibitory mechanism, the corticosterone levels are increased mechanism, the corticosterone levels are increased as the GC receptors are under responsive.This also as the GC receptors are under responsive.This also occurs in patients with major depression!occurs in patients with major depression!

Epigenética Epigenética comportamental-3.comportamental-3.

Similar changes occur in the oxytocin (the bonding) Similar changes occur in the oxytocin (the bonding) gene!.gene!.

Such changes are inherited.Such changes are inherited. Other studies showed that communally raised Other studies showed that communally raised

rodents ( as in the wild state) are better adjusted to rodents ( as in the wild state) are better adjusted to environmental stressors that “isolated” rodents; the environmental stressors that “isolated” rodents; the mothers and offspring have a higher density of mothers and offspring have a higher density of oxytocin receptors.oxytocin receptors.

Epigenética Epigenética comportamental-4.comportamental-4. Stressed, pregnant rats have increased Stressed, pregnant rats have increased

methylation of the BDNF gene concerned in methylation of the BDNF gene concerned in neuronal repair. Thus brain repair mechanisms neuronal repair. Thus brain repair mechanisms may be reduced as a consequence. Chronic may be reduced as a consequence. Chronic antidepressant treatments increase DNA antidepressant treatments increase DNA acetylation and thereby enhance BDNF activity.acetylation and thereby enhance BDNF activity.

Cocaine increases acetylation of histones of DNA Cocaine increases acetylation of histones of DNA in nucleous accumbens thereby enhancing the in nucleous accumbens thereby enhancing the sensitivity to the drug.sensitivity to the drug.

BUT –beware of over extrapolation of epigenetics BUT –beware of over extrapolation of epigenetics from rodent studies to human behaviour! from rodent studies to human behaviour!

Desregulación Neuroendocrina, Desregulación Neuroendocrina, Autonómica e Inmune en DMAutonómica e Inmune en DM

Miller et al. Biol Psychiatry 2009;65(9):732-41. Copyright Elsevier 2009.

ACTH=Adrenocorticotropic hormone; CRH=Corticotropin-releasing hormone; MDD=Major depressive disorder; NF-κB=Nuclear factor kappa B.

Stress, Depression and Stress, Depression and Cortisol Cortisol Cognitive changes and

Hippocampalvolume

Hypothalamus

CRF AVP

Steroid toxicity

Cortisol

ACTHPituitary

stressstressXX

Defective in Defective in depression depression

ACCIONES NEUROTRÓFICAS DEL STRESS Y LOS ANTIDEPRESIVOS EN EL HIPOCAMPO [DUMAN et al]

STRESS

HYPOTHALAMUS (P.V.NUCLEUS)

[-]

CRF receptor antagonists (-) CRF

ANTERIOR PITUITARY [-]

ACTH

ADRENAL GLAND

Mifepristone; GC antagonists[-] GLUCOCORTICOIDS

MODULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS.

Interación Glia-Neurona Puede Interación Glia-Neurona Puede Influir en los Factores Influir en los Factores NeurotróficosNeurotróficos

Miller et al. Biol Psychiatry 2008;65(9):732-41. Copyright Elsevier (2008).

5-HT=Serotonin; BDNF=Brain-derived neurotrophic factor; GLU=Glutamate; IDO=Indolamine 2,3 dioxygenase; NMDA=N-methyl-D-aspartate; QUIN=Quinolinic acid; RNS=Reactive nitrogen species; ROS=Reactive oxygen species; TNF=Tumor necrosis factor; TRP=Tryptophan.

Sumario: Cambios Sumario: Cambios Estructurales y Funcionales en Estructurales y Funcionales en Depresión MayorDepresión Mayor

Rot et al. CMAJ 2009;180(3):305-13. © Canadian Medical Association Journal, This work is protected by copyright and the making of this copy was with the permission of Access Copyright. Any alteration of its content or further copying in any form whatsoever is strictly prohibited.

MDD=Major depressive disorder.

Dendritic atrophy in Dendritic atrophy in depressiondepression

Atrophic“depressed”

“Treated”

La SinápsisTripartita : El Rol de La SinápsisTripartita : El Rol de la Astroglia la Astroglia

Halassa et al. Trends Mol Med 2007;13(2):54-63. Copyright Elsevier (2007).

Study compared resting-state serum cytokine levels in 12 unmedicated MDD patients and 11 matched healthy control subjects

2.0

1.5

0.5

1.0

0.0

0.0 1.50.5 1.0

2.0

1.5

0.5

1.0

0.0

0.0 3.01.0 2.0 4.0

Control Patients Depressed Patients

Serum IL-6 (pg/mL) Serum IL-6 (pg/mL)

Ser

um

IL-1

0 (p

g/m

L)

Ser

um

IL-1

0 (p

g/m

L)

r(10)=0.01, p=0.98r(9)=0.81, p=0.003

Pérdida de la Asociaión entre IL-6 e Pérdida de la Asociaión entre IL-6 e IL-10 en Depresión MayorIL-10 en Depresión Mayor

Dhabhar et al. J Psychiatric Res 2009;43(11):962-69. Copyright Elsevier (2009).

IL=Interleukin; MDD=Major depressive disorder.

Positive correlation between depression and IL-6

Negative correlation between depression and BDNF

r=0.376; p=0.0062 r=-0.353; p=0.0012

Relación de Citokinas Inflamatorias y Relación de Citokinas Inflamatorias y Factores Neurotróficos en DepresiónFactores Neurotróficos en Depresión

Yoshimura et al. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(4):722-26. Copyright Elsevier (2009).

pBDNF=Plasma brain-derived neurotrophic factor; HAMD=Hamilton Depression Rating Scale; pIL-6=Plasma interleukin-6.

35

30

25

20

15

10

5

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8H

AM

D17

Sco

re

35

30

25

20

15

10

5

00

HA

MD

17 S

core

0.5 1.0 1.5 2.0 2.5 3.0 3.5pIL-6 (pg/mL) pBDNF (ng/mL)

00 2.0

Respuesta al Tratamiento en Depresión, Respuesta al Tratamiento en Depresión, y su Impacto en Marcadores de Inflamación y su Impacto en Marcadores de Inflamación

Yoshimura et al. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(4):722-26.

pIL-6=Plasma interleukin-6; pTNF-α=Plasma tumor necrosis factor-α; SNRI=Serotonin–norepinephrine reuptake inhibitor; SSRI=Selective serotonin reuptake inhibitor.

3.4

3.0

2.6

2.2

1.8

1.4

1.0Healthy Controls

(n=30)

SSRI/SNRIResponsive

(n=31)

SSRI/SNRIRefractory

(n=20)

pIL

-6 (

pg

/mL

)

p<0.05p<0.001

p<0.001

Healthy Controls

(n=30)

SSRI/SNRIResponsive

(n=31)

SSRI/SNRIRefractory

(n=20)

161412

10

864

2

0

pT

NF

-α (

pg

/mL

)

p<0.001

p<0.001

1820

BDNF Levels After 8 Weeks’ Antidepressant Treatment2

HAMD: 23.2 HAMD: 8.2

N=10p=0.007

p<0.001*

*Value is for difference between baseline and follow-up in treated samples.sBDNF=Serum brain-derived neurotrophic factor; HAMD=Hamilton Depression Rating Scale.

BDNF Levels After 12 Weeks’ Antidepressant Treatment1

25

30

35

40

45

5

10

15

20

Baseline Follow-up

X

X

30

40

50

10

20

Baseline Follow-up Controls(n=18)(n=28)

sBD

NF

Lev

els

(ng

/dL

)

sBD

NF

(n

g/d

L)

El Tratamiento Antidepresivo El Tratamiento Antidepresivo Puede Normalizar los Niveles de BDNF Puede Normalizar los Niveles de BDNF

1. Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(2):261-65. Copyright Elsevier (2005).

2. Gonul et al. Eur Arch Psychiatry Clin Neurosci 2005;255(6):381-86. With kind permission from Springer Science + Business Media.

0 0

60

(n=28)

Mood Disorders: Mood Disorders: Glutamate modulation-1Glutamate modulation-1

α2δ subunit of L-type Ca++ channel

Voltage dependant Na+ channel

nmda ampa

K+ K+

Na+ Ca++ Na+ Ca++

Felbamate ΘΘ Topirimate

Glutamate O+O+

Gabapentin

Pregabalin

Cbz

Felbamate

Lamatrigine

OxCbz

Phenytoin

Topiramate

Valproate

Zonisamide

Θ

Θ

Mood Disorders: GABA Mood Disorders: GABA modulation-2modulation-2

Gaba transporter Bzds

Barbiturates

Felbemate

Topiramate

O+

Tiagabine Θ

Glia

Θ

gaba

gaba

Gaba

A

Cl-

Vigabatrin

Glia

Θ

gaba

Θ

Glutamate

Gaba

Succinic Semialdehyde

GA

DG

aba-T

Valproate O+

Θ

Clasificación “los animales se clasifican en “a”

pertenecientes al emperador, “b” embalsamados, “c” amaestrados, “d” lechones, “e” sirenas, “f” fabulosos, “g” perros sueltos, “h” incluidos en esta clasificacion, “I”, que se agitan como locos, “j” innumerables, “k” dibujados con un pincel finísimo de pelo de camello, “l” etc, “m” que acaban de romper el jarrón, “n” que de lejos parecen moscas”

Jorge Luis Borges “Emporio celestial de conocimientos benevolos”