BASES NEUROBIOLGICAS DE LA DEPRESIN

Dr. Eugenio Olea B.

Unidad Docente Facultad de Medicina Universidad de Chile Instituto Psiquitrico

HISTORIA ETIOPATOGENIA EPIGENTICA STRESS FENMENOS INFLAMATORIOS

Historia

Los conceptos de Patologa Clsica de los griegos se centraba en la teora humoral contenida en el Corpus Hipocraticum, implicando la interaccin de los cuatro humores corporales. Todas las enfermedades resultan de una perturbacin en el equilibrio humoral, por exceso o corrupcin de uno de los humores.

Teora humoral de Empdocles (490-430 AC)

Elemento
Fuego Cualidad Calor Humor Sangre (en el corazn)

Tierra
Agua Aire

Sequedad
Humedad

Phlegm (en el cerbro)

Bilis amarilla (en el higado) Bilis negra (en el bazo)

Fro

PINEL
1.)Herencia 1.)Factores dainos en el ambiente social .v.gr, falta de educacin. 3.)Forma de vida irregular 4.) Pasiones espasmdicas (rabia ) 5.) Pasiones opuestas o intensas (perdida,odio, temor, remordimiento) 6.) Pasiones 7.) Constitucin melanclica 8.) Factores fsicos ( incluye alcoholismo, amenorrea, hemorroides no sangrantes, fiebre , puerperio y trauma cerebral)

Qu provoca la depresin?

A primary deficit in monoamine function. A primary deficit in excitatory amino acid function. Decrease in neurotrophin synthesis; impaired neuronal plasticity. A change in the neuroglia/oligodendroglia support for the neuronal networks that cause neuronal dysfunction. Impaired capacity of the brain to recycle neurotoxins caused by chronic inflammation. Any combination or none of these !!

Sistema Serotoninrgico en Depresin

Niveles 5-HIAA en LCR Receptores postinpticos 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 triptfano

Sistema Noradrenrgico en Depresin

MHPG en orina y LCR NA en plasma y Adrenalina Unin a recept. Alfa 2 en plaquetas Respuesta de GH a clonidina y repuesta Alfa 2 en plaquetas

Sistema Dopaminrgico en Depresin

Niveles de HVA en LCR Niveles de DA y HVA en plasma Niveles plasmticos de HVA en respuesta a glucoorticoides Actividad de MAO plaquetaria Act , de DA beta hidroxilasa

Retardo psicomotor En depresin psictica Asociado a depresin psictica En unipolar en bipolar

Eje Hipotlamo Hipfisis Adrenal

A Aumento de eventos vitales y estrs crnico B Incremento de sensibilidad hipocampal C Atrofia hipocampal D Aumento de CRH en LCR; alteracin de la supresin con dexametasona E Alteracin de la respuesta de ACTH a CRH. Hipertrofia hipofisiaria F Hipertrofia corteza adrenal G Hipercortisolismo

Eje Tiroideo
A B C D E Aumento de TRH en LCR Respuesta reducida de TSH a TRH (30%) Anticuerpos antitiroideos (9-20%) Hipotiroidismo subclnico Respuesta a la potenciacin con T3 o T4

HIPTESIS CAUSALES EN DEPRESIN

Receptor down-regulation hypothesis
Post-synaptic signalling & gene expression Neuroplasticity & Circadian rhythms

Monoamine hypothesis Imipramine discovered

1950s

1960s

1970s

1980s

1990s

2000s

Despite all the wonderful neuroscience, and even more wonderful papers in Nature, Science, Cell and Neuron, we still havent improve on the efficacy of antidepressant treatments since the discovery of imipramine in 1957

TEORIA MONOAMINRGICA (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 AMINOBIOGNICA.

TEORIA MONOAMINRGICA (2)

4.-JANOWSKY:
TEORA DEL DESBALANCE COLINRGICONORADRENRGICO

5.-SIEVER Y DAVIES: HIPTESIS DE LA

DESREGULACIN NORADRENRGICA

6.-VAN PRAAG:
TEORA DEL TRASTORNO NEUROQUMICO DIMENSIONAL

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

Noradrenalina
Ansiedad Irritabilidad Impulso nimo, Emocin, Funcin Cognitiva Sexo Apetito Agresin

Serotonina

Energa Inters

Motivacin

Activacin

Dopamina

NEUROTRASMISORES Y SINTOMAS.
Influence release/ activity of each other

Glutamate
Attention Motivation Pleasure Loss of interest Mood Emotion

Energy Alertness
Noradrenaline Anxiety Irritability

Increases NA release within locus coeruleus

Dopamine
Influence release/ activity of each other

Appetite Sex

Influence release/ activity of each other

GABA
Inhibit release/ activity of each other

Obsessions and compulsions Serotonin

Serotonin decreases glutamatergic activity within PFC

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: 14691478. Stahl S. J Clin Psychiatry 2003; 64: 11451146.

Mecanismos moleculares de accin de los antidepresiv os

Sealizacin sinptica e intracelular en depresin mayor

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

31

Neurobiologa del Trastorno Depresivo Mayor

Network Level: Dysregulation of Neural Circuitry

Stress

Functional Changes Structural Changes

Neuropsychiatric Symptoms

Genetic Vulnerability

Neuroendocrine, Autonomic, and Immune Dysregulation

Emotional Cognitive Behavioral Physical

Systemic Manifestations

Injury

Cellular and Subcellular Level Impact on: Intracellular Signaling Gene Transcription Neurotrophic Support

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

NEUROTRASMISORES Y NEUROMODULADORES

Clase qumica Substancia Phenylethylamines Dopamine, noradrenaline, adrenaline, phenylethylamine*

Indoleamines Cholinomimetics Amino Acids Purines Diamines Neuropeptides

Serotonin, melatonin**, tryptamine* Acetylcholamine, choline Glutamate, aspartate, glycine, taurine, gammaaminobutyric acid Adenosine, adenosine triphosphate Histamine 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-g. *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 Modulation

External environment

Maternal care

Social experiences

Genetic background

Behavioral phenotype
EARLY EXPERIENCES Epigenetic modifications 1 REVERSIBILITY Epigenetic modifications 2
Post-weaning Adult

Fertilization

Pre-natal Postpartum

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

Epigenetic Modulation? Parental Stress May Influence HPA Reactivity in Children LongTerm
31 healthy young adults whose mothers experienced severe stress during pregnancy and 30 age-matched comparison group individuals who underwent TSST
60 50 ACTH (pg\mL) 40 30 20 PS CG Total Cortisol (ng/mL) 225 200 175 150 125 100

TSST

10 0 -2

p=0.06 vs CG 15 25 35 45 105 -2

TSST

p=0.03 vs CG 15 25 35 45 105

Time (mins)

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.

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

La Interaccin entre Estrs y el Polimorfismo del 5HTT Puede Precipitar la Depresin

The Risk of Developing an MDE Within 2 Months After Exposure to an SLE
9 8

N=549

Hazard Ratio for Depression Onset

7 6 5 4 3 2 1 0

Male LS/LL Male SS Female LS/LL Female SS

No SLE

Any SLE

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.

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

GENES Y DEPRESIN

Epigentica Comportamental-2

Differences in behaviour of offspring related to degree of methylation of DNA of glucocorticoid (GC) receptor gene. Methylation decrease gene expression and reduces receptor function; acetylation increases function! As HPA axis is controlled by a feed-back inhibitory mechanism, the corticosterone levels are increased as the GC receptors are under responsive.This also occurs in patients with major depression!

Epigentica comportamental-3.

Similar changes occur in the oxytocin (the bonding) gene!. Such changes are inherited. Other studies showed that communally raised rodents ( as in the wild state) are better adjusted to environmental stressors that isolated rodents; the mothers and offspring have a higher density of oxytocin receptors.

Epigentica comportamental-4.

Stressed, pregnant rats have increased methylation of the BDNF gene concerned in neuronal repair. Thus brain repair mechanisms may be reduced as a consequence. Chronic antidepressant treatments increase DNA acetylation and thereby enhance BDNF activity. Cocaine increases acetylation of histones of DNA in nucleous accumbens thereby enhancing the sensitivity to the drug. BUT beware of over extrapolation of epigenetics from rodent studies to human behaviour!

Desregulacin Neuroendocrina, Autonmica e Inmune en DM

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

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

Stress, Depression and Cortisol

Cognitive changes and Hippocampal volume Steroid toxicity

stress

Hypothalamus

Cortisol
Defective in depression

CRF

AVP

Pituitary

ACTH

ACCIONES NEUROTRFICAS 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.

Interacin Glia-Neurona Puede Influir en los Factores Neurotrficos

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.

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

Sumario: Cambios Estructurales y Funcionales en Depresin Mayor

MDD=Major depressive disorder. 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.

Dendritic atrophy in depression

Atrophic depressed

Treated

La SinpsisTripartita : El Rol de la Astroglia

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

Prdida de la Asociain entre IL-6 e IL-10 en Depresin Mayor

Control Patients
2.0 r(9)=0.81, p=0.003 2.0

Depressed Patients
r(10)=0.01, p=0.98

Serum IL-10 (pg/mL)

1.5

Serum IL-10 (pg/mL)

0.0 1.5

1.5

1.0

1.0

0.5

0.5

0.0

0.0

0.5

1.0

0.0

1.0

2.0

3.0

4.0

Serum IL-6 (pg/mL)

Serum IL-6 (pg/mL)

Study compared resting-state serum cytokine levels in 12 unmedicated MDD patients and 11 matched healthy control subjects
IL=Interleukin; MDD=Major depressive disorder.

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

Relacin de Citokinas Inflamatorias y Factores Neurotrficos en Depresin

35 30 35 30

HAMD17 Score

25 20 15 10 5 r=0.376; p=0.0062 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

HAMD17 Score

25 20 15 10 5 0 0 r=-0.353; p=0.0012 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

pIL-6 (pg/mL)

pBDNF (ng/mL)

Positive correlation between depression and IL-6

Negative correlation between depression and BDNF

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

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

Respuesta al Tratamiento en Depresin, y su Impacto en Marcadores de Inflamacin

p<0.001 p<0.001 p<0.001 p<0.05

p<0.001

3.4
pTNF- (pg/mL)

3.0
pIL-6 (pg/mL)

20 18 16 14 12 10 8 6 4 2 0

2.6 2.2 1.8

1.4
1.0
Healthy Controls (n=30) SSRI/SNRI Responsive (n=31) SSRI/SNRI Refractory (n=20)

Healthy Controls (n=30)

SSRI/SNRI Responsive (n=31)

SSRI/SNRI Refractory (n=20)

pIL-6=Plasma interleukin-6; pTNF-=Plasma tumor necrosis factor-; SNRI=Serotoninnorepinephrine reuptake inhibitor; SSRI=Selective serotonin reuptake inhibitor.

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

El Tratamiento Antidepresivo Puede Normalizar los Niveles de BDNF

45
40 sBDNF (ng/dL) 35
X

HAMD: 23.2

HAMD: 8.2

60 sBDNF Levels (ng/dL)

50
40 30 20
p<0.001*

30
25 20 15

10
5

p=0.007

10
0

N=10 Baseline Follow-up

Baseline Follow-up Controls (n=18) (n=28) (n=28) BDNF Levels After 8 Weeks Antidepressant Treatment2

BDNF Levels After 12 Weeks Antidepressant Treatment1

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

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.

Cbz
Felbamate Lamatrigine OxCbz Phenytoin

Mood Disorders: Glutamate modulation-1

Voltage dependant Na+ channel

Topiramate
Valproate Zonisamide

2 subunit of
L-type Ca++ channel Gabapentin Pregabalin

K+

K+ + O O Glutamate +

Felbamate Na+ Ca++ Na+ Ca++

Topirimate

Mood Disorders: GABA modulation-2

Glutamate
Valproate + O Glia

GAD

Glia

Gaba
gaba Gaba-T

Vigabatrin

Tiagabine

Succinic Semialdehyde

Gaba transporter
Gaba A

+ O

Cl-

gaba Bzds Barbiturates Felbemate Topiramate

Clasificacin

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 finsimo de pelo de camello, l etc, m que acaban de romper el jarrn, n que de lejos parecen moscas Jorge Luis Borges Emporio celestial de conocimientos benevolos