Transcript Neurobiology of depression - Translational Neuromodeling Unit

NEUROBIOLOGY OF DEPRESSION
01.11.13 Laura Bohleber
CONTENT
I.
Introduction
1.
2.
3.
II.
The molecular neurobiology of depression
1.
2.
3.
4.
5.
6.
7.
III.
IV.
V.
Brief repetition: symptomatology / diagnostic criteria / treatment
guidelines
We know little
Validity criteria: animal models of depression
Neural circuitry of depression
The role of monoamines
Neurotrophins and neurogenesis
Neuroendocrine and neuroimmune interactions
Epigenetic mechanisms
Resilence-related research
New insights
The subgenual anterior cingulate cortex in mood
disorders
Summary
Journal club
I.
Introduction
I.
II.
III.
II.
The molecular neurobiology of depression
1.
2.
3.
4.
5.
6.
7.
III.
IV.
V.
Brief repetition: symptomatology / diagnostic criteria /
treatment guidelines
We know little
Validity criteria: animal models of depression
Neural circuitry of depression
The role of monoamines
Neurotrophins and neurogenesis
Neuroendocrine and neuroimmune interactions
Epigenetic mechanisms
Resilence-related research
New insights
The Subgenual Anterior Cingulate Cortex in
Mood Disorders
Conclusions
Journal club
1. Brief repetition: symptomatology / diagnostic criteria / treatment
guidelines
Diagnostic criteria and Symptoms (ICD-10, F3 mood disorders)

Major Depression (MDD)

Diagnosis



Symptoms




F32 Depressive Episode: mild, moderate, severe, severe with psychotic symptoms (F32.0-F32.3)
F33 Recurrent Depressive Disorder: mild, moderate, severe, severe with psychotic symptoms
(F33.0-F33.3)
depressed mood
loss of interest and enjoyment
reduced energy, increased fatiguability
(a) reduced concentration and attention;
(b) reduced self-esteem and self-confidence;
(c) ideas of guilt and unworthiness (even in a
mild type of episode);
(d) bleak and pessimistic views of the future;
(e) ideas or acts of self-harm or suicide;
(f) disturbed sleep;
(g) diminished appetite
Bipolar disorders (BD)

Diagnosis


F31 Bipolar affective disorder, current episode hypomanic; manic without / with psychotic
features; current episode depressed: mild, moderate, severe, severe with psychotic symptoms;
current episode mixte; other bipolar disorders (F31.0-31.8)
Symptoms

Repeated episodes (at least 2) of disturbed mood & activity level: elevation of
mood and increased energy and activity (mania or hypomania), and lowering of mood
and decreased energy and activity (depression)

Treatment guidelines (Working Group on the Management of Major
Depression in Adults, 2008, (leaving psychotherapy aside))

Antidepressant drugs represent a first line of treatment for moderate or
severe depression. For mild depression, other therapeutic strategies can be
considered before antidepressant drugs.
Comparative Efficacy of Drugs
 Selective serotonin reuptake inhibitors (SSRIs) -> first choice
 TCAs are an alternative to SSRIs if a patient has not tolerated at least two
drugs from this group or is allergic to them
Duration of treatment
 Pharmacological treatment maintained in all patients for at least 6 months
after remission
 In patients with any previous episode or the presence of residual symptoms,
treatment maintained for at least 12 months after remission
 In patients with more than two previous episodes, treatment maintained for
at least 24 months after remission
Treatment resistance
 Switching from an antidepressant to any family, including another
serotonergic. Combining antidepressants.
 Augmenting the initiated treatment with lithium
 ECT should be considered as a therapeutic alternative in adults with severe
major depression
S3-Guideline/National Disease Management Guideline,
http://www.versorgungsleitlinien.de/themen/depression/pdf/s3-nvl-depression-kurz-engl.pdf
2.

We know little
Knowledge about pathophysiology of depression is
rudimentary – why?
1.
Heterogeneous syndromes with heterogeneous etiology ->
weakness of trying to construct a “unifying” theory of
depression
2.
Observing pathological changes in the brain = difficult, limited
techniques available (post mortem, neuroimaging, difficulties
in transferring knowledge acquired from animal studies✗)
3.
Idiopathy of occurance of depression (various risk factors, no
consistent genetic risk modifiers). Interaction of genetic
predispositions and environmental risk factors.

Symptom based diagnostic approach poses obvious obstacles


To the interpretation of genome-wide association studies
To neuroimaging or post mortem investigation (with typical
heterogeneity in data acquiered from mood disorder samples, often
consistent data only in subsets)
3. Validity criteria : animal models of depression

✗Preclinical models – interpretation of animal models of
depression

Etiological validity (=depression-like behaviour need to be
caused by the same etiologies that trigger human depression.
BUT: absence of definitive aetiologies for human depression!)

Pharmacological validity (= assays are sensitive to
acutely administered known antidepressant compounds.
BUT more than half of all depressed individuals do not
respond fully to available antidepressants)

Face validity (= behavioral changes brought about by stress
or genetic manipulation superficially resemble depressive
symptoms. E.g. animal’s decreased sucrose intake after
chronic stress ≈ anhedonia)
I.
Introduction
1.
2.
3.
II.
The molecular neurobiology of depression
I.
II.
III.
IV.
V.
VI.
VII.
III.
IV.
V.
Brief repetition: symptomatology / diagnosis / treatment
guidelines
We know little
Validity criteria: animal models of depression
Neural circuitry of depression
The role of monoamines
Neurotrophins and neurogenesis
Neuroendocrine and neuroimmune interactions
Epigenetic mechanisms
Resilence-related research
New insights
The Subgenual Anterior Cingulate Cortex in
Mood Disorders
Conclusions
Journal club
1.



Neural circuitry of depression
Mayberg’s model limbic-cortical dysregulation (1997)
Some mechanisms involving limbic structures (Krishnan and
Nestler, 2008)
Specific role of the subgenual Anterior Cingulate Cortex (later,
Drevets et al., 2008))

o
o
Mayberg’s model of depression: limbic-cortical dysregulation
(Mayberg, 1997)
Sadness + depressive illness:
o  dorsal limbic & neocortical regions (red)
o  ventral paralimbic areas (blue)
Remission
o Reversal of these findings
o Inhibtion / activation (black arrows), effect facilitated by fluoxetine action
in dorsal raphe and projection side (dotted lines)
o Integrity of the rostral cingulate (yellow) -> required for adaptive changes > pretreatment metabolism predicts antidepressant treatment respons
Dorsal (red)
Ventral (blue)
Rostral (yellow)

Depression and dysfunctional changes in “limbic” regions
Implication of several brain regions and circuits regulating emotion,
reward and executive functions:
 Structural findings in post mortem studies & neuroimaging:  grey
matter &  glial density in PFC & hippocampus
-> cognitive impairments in depression
 BUT: findings are not consistent, common problem: co-morbid
diagnosis, medication history -> limited evidence for cause-effect
relation
 Functional: activity in amygdala and subgenual cingulate cortex
correlated with dysphoric emotions


!! Caution with simplistic “localization of function” approach to examine
limbic structures
Neural circuitry of depression: some mechanisms
involving limbic structures
(1)
(5)
(2)
(3)
(4)
(1) Deep brain stimulation of


white matter tracks surrounding subgenual cingulate cortex
Nucleus accumbens (NAc) (implicated in reward processing & hedonic deficits in depression)
 depressive symptoms
More recent findings?
(medial forebrain bundle?)
(2) Increased activity-dependent release of brain-derived neurotrophic
factor (BDNF) within the mesolimbic dopamine circuit mediates
susceptibility to social stress
-> probably partly through activation of the transcription factor
CREB (cyclic-AMP-response-element-binding protein)
BDNF = protein (« neurotrophine » family) acts on neurons in
the CNS and PNS helping to support the survival of existing
neurons, and encourage the growth and differentiation of new
neurons and synapses
CREB = cellular transcription factor, binding to certain DNA
sequences called cAMP response (CRE), thereby increasing or
decreasing the transcription of the downstream genes, Genes
whose transcription is regulated by CREB include: c-fos,
tyrosine hydroxylase, and many neuropeptides
(3) Neuroimaging findings : strong implication of the amygdala as an
important limbic node for processing emotionally salient
stimuli, e.g. fearful faces
(4) Stress reduces concentrations of neurotrophins (such as BDNF),
extent of neurogenesis and the complexity of neural processes
in the hippocampus -> mediated by increased cortisol
concentrations and decreased CREB activity
(5) Peripherally released metabolic hormones, such as gherlin
and leptin, produce mood related changes - in addition to
cortisol - through their effects on the hippocampus (HYP)
and several limbic regions
2. The
role of monoamines
« monoamine hypothesis »

Decreased monoamine function in the brain



Monoamine neurotransmitters and neuromodulators include
serotonine, dopamine, norepinephrine and epinephrine
Antidepressant effects of iproniazid (irreversible and nonselective
monoamine oxidase inhibitor (MAOI), discovered in the 1950,
originally used as medication against tubercolosis) & imipramine (first
tricyclic antidepressant, originally meant to be used as a neuroleptic
to treat schizophrenia)
Modern antidepressants = designed to increase monoamine
transmission acutely by:

Inhibiting neuronal reuptake (SSRIs (selective serotonine
reuptake inhibitors))

Inhibiting degradation (monoamine oxidase inhibitors (MAOI) ->
tranylcypromine (Jatrosom))

Acute increases in the amount of synaptic monoamines induced by
antidepressants may produce secondary neuroplastic changes
that are on a longer timescale and involve transciptional and
translational changes mediating molecular and cellular plasticity

Monoamine-based antidepressants remain the first line of therapy
for depression

But: long therapeutic delay and low remission rates
-> search for more effective agents!

E.g. research on the role of P-glycoprotein

Several antidepressants serve as substrates (e.g. citalopram) for
P-glycoprotein

Human polymorphisms in the gene encoding P-glycoprotein
significantly alter antidepressant efficacy
-> value of a pharmacogenetic approach when selecting an
antidepressant
3. Neurotrophins and neurogenesis

Neurotrophic factors: neurodevelopmentally expressed growth factors
that also regulate plasticity within adult brain
« BDNF hypothesis »

Brain-derived Neurotrophic Factor = abundantly expressed in adult
limbic structures

Preclinical studies show


Several forms of stress reduce BDNF-mediated signalling in the
hippocampus
Chronic treatment with antidepressants increase BDNF-mediated
signalling
Post mortem data from depressed humans
Decrease in the amount of BDNF in the
hippocampus
Increase in the NAc

BUT: recent findings suggest that BDNF hypothesis: too simplistic

Knock-in mice that express Met-66 BDNF (Val66Met is a gene variation, a single
nucleotide polymorphism (SNP) in the BDNF gene that codes for BDNF)
Equivalent response in forced swim test
 Increased anxiety like behaviour
 Increased resilience (behavioral and molecular changes) to social
defeat

 BDNF-mediated signalling is involved in neuroplastic responses to
stress and antidepressants
BUT: effects = region specific and antidepressant-specific and function
in the background of potent genetic and environmental modifiers
4. Neuroendocrine and neuroimmune interactions
(a)
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction
(b)
“Cytokine hypothesis”
(a)
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction
CRH = Corticotropin-releasing hormone
ACTH = adrenocorticotropic hormone
Dysfunctional Hypothalamic-pituitary-adrenal (HPA) axis

Chronic administration of glucocorticoides can lead to depression-like
symptoms in rodents

Excess in glucocorticoides can reduce subgranular zone profileration
(one of two major zones of adult neurogenesis) and produce atrophic
changes in hippocampal subregions
this could lead to hippocampal volume reduction seen in
depression
Hypercortisolaemia is manifest at many levels in depressed patients

Early adverse experiences play a preeminent role in the development
of mood and anxiety disorders
 Association mediated by corticotropin-releasing factor (CRF)
system?
 Evidence from preclinical studies (rats, non human primates):
increased CRF may be the persisting neurobiological consequence of
stress early in development

Findings in women after sexual and physical abuse in childhood (Heim et al.,
2000)
 4 groups (healthy, Early Life Stress (ELS) +no Major Depressive Disorder
(MDD), ELS + MDD, no ELS + MDD); psychosocial stress protocol;
hormone + heart rate measures
! Note that subjects without early stress experiences showed
normal stress reactivity, suggesting differential pathophysiology
in subtypes of depression.

Severe stress early in life  persistent sensitization of the pituitaryadrenal and autonomic stress response  probably a risk factor for
adulthood psychopathology

glucocorticoid and corticotropin-releasing factor receptor antagonists as
treatment option?
BUT:
 Divergent findings dependend on depression subtypes
 MDD without ELS?
 Hypercortisolaemia -> only in severe depressive episodes
 Atypical depression, esp. subtype with hyperphagia and hypersomnia > hypocortisolaemia
(b) « Cytokine hypothesis »
Cytokines (Greek cyto-, cell; and -kinos, movement)

a diverse group of soluble proteins, peptides, or glycoproteins

act as hormonal regulators or signaling molecules at nano- topicomolar concentrations and help in cell signaling

humoral mediators of innate and adaptive immunity

important modulators of mood

Some evidence from clinical and preclinical studies for a role in
depression


30% of patients treated with recombinant interferons develop
depression as side effects

In rodents: blocking pro-inflammatory cytokine-mediated
signalling can produce antidepressant effects
BUT: mechanisms are not yet understood
 further research is needed to elucitade the largely unknown
neural circuitry involved in the behavioural effects of cytokines
and underlying intercellular interactions
5. Epigenetic mechanisms



Epigenetics -> study of heritable changes in gene expression or cellular
phenotype, caused by mechanismes other than changes in the underlying
DNA sequence
 E.g. DNA methylation and histone modification -> alteration of gene
expression without altering the underlying DNA sequence
Epigenetic changes -> mechanisms by which environmental experiences
can modify gene function in absence of DNA sequence changes
 -> might help to explain largely inconsistent genetic association studies
of depression
Epigenetic modifications in the pathophysiology of depression ?
 Covalent changes to DNA (e.g. DNA methylation)
 Post-translational modifications of histone N-terminal trials (e.g.
acetylation and methylation)
 Non transcriptional gene-silencing mechanisms (e.g. RNAs)
Depression research has focused on two main chromatin-modifying
processes:
1.
1.
DNA methylation (of cytosine)

Seems to be important in the influence of maternal behaviour
on adult emotional processing

 maternal behaviour (licking & grooming) ->  anxiety
expression of glucocorticoide receptors
Histone acetylation

Seems to be a key substrate
for antidepressant action
 The transcriptional potential of genes involved in neuroplastic
responses to stress or antidepressant treatments can be regulated
through chromatin-remodelling events catalysed by specific
enzymes
6. Resilence-related research

Humans react very different to stress and adversity

Evidence from animal models:

Distinct transcriptional profiles in the Ventral Tegmental Area
(VTA) and NAc in gene expression profiling of stress-vulnerable
and stress-resilent mice

Suggesting that resilent behaviour represents a distinct, active
neurobiological process (≠ only the absence of vulnerability)

Concerning the neurobiology of stress and the pathophysiology of
depression: More research is needed on mechanisms on allostasis
(efforts to maintain homeostasis) and antivulnerability
processes
7. New Insights

Actions of glutamate (major excitatory NT in the brain)?



Limited evidence for dysfunction in specific glutamate systems
BUT: antidepressant effect of ketamine (a non-competitive
NMDA (N-methyl-D-asparte) glutamate receptor antagonist
and psychotomimetic (mimics symptoms of psychosis)
Pathways involved in the control of feeding and metabolism
and their interaction with substrates of mood


Pro-depressant role of MCH (melanin-concentrating hormone > regulator of feeding and arousal) ?
Antidperessant role of ghrelin and leptin (peptides ->
peripheral metabolic signals) ?
I.
Introduction
1.
2.
3.
II.
The molecular neurobiology of depression
1.
2.
3.
4.
5.
6.
7.
III.
IV.
V.
Brief repetition: symptomatology / diagnosis / treatment
guidelines
We know little
Validity criteria: animal models of depression
Neural circuitry of depression
The role of monoamines
Neurotrophins and neurogenesis
Neuroendocrine and neuroimmune interactions
Epigenetic mechanisms
Resilence-related research
New insights
The subgenual anterior cingulate cortex in
mood disorders
Conclusions
Journal club
I.
The subgenual anterior cingulate cortex in
mood disorders
a)
Specificity of structural neuroimaging abnormalities in the sgACC
b)
Anatomical specificity of sgACC abnormalities
c)
Neurphysiological imaging studies of sgACC activity
d)
e)
f)
Neuropathological measures: correlations with rodent models of repeated
stress
Relationship between structural abnormalities in the sgACC and other
regions
Potential clinical correlates of subgenual prefrontal cortex dysfunction
Introduction & (a) Specificity of structural neuroimaging
abnormalities in the sgACC


Ventral ACC -> increasingly has been implicated in the modulation of
emotional behaviour (neuroimaging, lesion studies in animals)
MDD and familial BD: reduction of CBF and glucose metablolism in the
PFC ventral to corpus callosum: voxel by voxel analysis: peak
difference of activation in the sgACC (JC paper, Drevets et al.,
1997)
 Activation differences accounted for by corresponding reduction in
cortex


reduction of grey matter volume in the left sgACC
 associated with a reduction of glia, but no equivalent loss of
neurons (Ongür, Drevets, et al., 1998)
 already early in the illness course of MDD and BD,
 persisting during antidepressent treatment
 present in manic and depressed phases of bipolar disorder
 present in psychotic unipolar and bipolar depression and bipolar
spectrum disorders
BUT:
 high variability
 findings not always replicated
-> Attempts to enhance sensitivity for identifying neuorbiological markers
« familial pure depressive disease » (MDD subject with a first-degree
relative with MDD, but no first degree relative with mania, alcoholism,
or sociopathy)
-> volumetric + metabolic differences in sgACC
 BD with first-degree relatives with BD

-> reduced sgACC volume
o Morphometric MRI studies
divided anterior and posterior
sgACC (Ongür et al., 2003)


Posterior sgACC reduced in MDD with psychotic features vs
schizophrenic patients (Coryell et al., 2005)
GAS (Global Assessment Scale) scores correlated positively with
cortical thickness at baseline and volume increase during follow up
-> volumetric abnormalities in posterior sgACC may predict
and reflect the course of depression
-> need for further longitudinal studies
o
Chronic lithium treatment
(exerting robust neurothrophic
effects in animal models) has been
associated with increasing gray
matter volume toward normal in
treatment responders in the sgACC
and other PFC areas (Caeteno et
al., 2005)
(b) Anatomical specificity of sgACC abnormalities

pregenualACC (pgACC - ACC situated anterior to corpus callosum)


Abnormalities in MDD concerning CBF/metabolism, tissue
volume, glia cells
Part of the ventral “emotion” circuit implicated in affective illness
(Phillips, Drevets et al., 2003)

sgACC shares similarities with the pgACC -> the distinctions of the
cortex at the actual sgACC/pgACC interface seem arbitrary

Abnormal reductions of glia in MDD extend to the pgACC, as well
as to the orbitofrontal and dorsal anterolateral PFC and the
amygdala
(c) Neurophysiological imaging studies of sgACC activity

HOWEVER: distinct functions of the anterior sgACC and more dorsal
regions of the pgACC (neuroimaging studies of emotional behavior)

In mood disorders…



sgACC activity positive correlation to the severity of depressive
symptomes
pgACC activity has more consistently been linked to treatment outcome
Also…


Some evidence for reduction in resting sgACC CBF/metabolism
Some findings that metabolic reduction in sgACC presate onset of
clinical symptoms



BUT: also contradictory findings (with increased activity in sgACC)
-> due to the interrelationships between deficits in gray matter
volume and physiological imaging data?
-> need for partial volume corrections? (sgACC volume reduction
sufficiently prominent to produce partial volume effects in functional
brain images

Even…
 sgACC metabolism is elevated during depressed phase versus
remitted
 sgACC activity decreases during
 Effective antidepressant treatment (Drevets et al., 1997; Drevets et
al., 2002; Mayberg et al., 2000)
 ECT (Nobler et al., 2001)
 Deep brain stimulation of sgACC (Mayberg et al., 2005)
(d) Neuropathological measures: correlations with rodent models
of repeated stress

Repeated stress results in dendritic atrophy and reductions in glial
cells in rodents in regions homologous to areas where grey matter
reductions are evident in humans with MDD (e.g. medial PFC,
hippocampus) (Bansar et al., 2007; Czeh et al., 2005; McEwan et al.,
2001; …)

Dentric atrophy could be reversed by lithium administration in rats
(McEwan et al., 2001)

Impaired sgACC function in mood disorders may conceivably
contribute to cortisol hypersecretion in depression

Major role of glucocorticoid receptors expressed in the ventral ACC
in the negative feedback effect of glucocorticoid secretion during
stress (Diorio et al., 1993)
(e) Relationship between structural abnormalities in the
sgACC and other regions

Substantial (predominantly ipsilateral) anatomical connections
with the amygdala and subiculum



Left-lateralized volumetric reductions in these areas might
be related
Mixed evidence for volumetric changes (existence and
direction) in mood disorders
sgACC projects to the ventromedial striatum and the
accumbens area reported to be abnormally small in a post
mortum study of mood disorders
Data suggest that mood disorders are associated with a
neuropathological process affecting circuits that involve the
sgACC together with anatomically related parts of the
orbitomedial PFC, amygdala, hippocampus, striatum, and
thalamus
(e) Potential clinical correlates of subgenual prefrontal cortex
dysfunction

In monkeys and other experimental animals, the homologous cortex
to the sgACC shares extensive anatomical connections with i.e. the
amygdala, subiculum, hypothalamus, ventral tegemtal area (VTA)
and others



-> regions implicated in the modulation of emotional behaviour
-> abnormal synaptic interactions between these areas and the
sgACC might contribute to disturbances in emotional processing
or regulation
Evidence from rat studies


left ventromedial PFC lesions disinhibit the function of the right
ventromedial PFC, which mediates the heightened sympathetic
autonomic, affective, and hypothalamic-pituitary-adrenal axis
arousal seen in left lesioned animals
-> in mood disorders, an altered balance between left and right
sgACC function conceivably may contribute to the heightened
affective, neuroendocrine, and sympathic autonomic arousal seen
in depression (e.g. understimulation of parasympathic tone)



Lesions including sgACC (humans) -> abnormal autonomic responses to
emotional experience, inability to experience emotion related to concepts
that ordinarily evoke emotion, and inability to use information regarding
the likelihood of punishment versus reward in guiding social behavior
Role of visceral feedback for evaluating consequences of social
behavior? -> visceral feedback mediated through interactions between the
ventromedial PFC, hypothalamic autonomic centers, and brain-stem
monoaminergic neurotransmitter systems?
ACC may be involved in evaluating the salience of rewards -> role of the
ventral ACC in modulating the electrophysiological responses of VTA
(Ventral Tegmental Area) dopamine neurons (BA24 of the ACC receives
dense dopamine innervation)

Decreased sgACC activity (but!!) is associated with diminished
stimulation of mesolimbic dopamine relase, resulting in the
absence of behaviour incentive, apathy, and anhedonia
sgACC in conclusion….
There is evidence for an

extended anatomical network formed by the neural
projections of the sgACC and other areas of the
orbitomedial PFC with the amygdala, hippocampus, superior
and medial temproal gyri, ventral striatum, mid- and
posterior cingulate cortex, thalamus, hypothalamus,
periaqueductal gray, and habenula
-> implicated in the regulation of evaluative,
expressive, and experiential aspects of emotion
Impaired function within this network could conceivably give
rise to the clinical signs and symptoms of depression and
mania
I.
Introduction
1.
2.
3.
II.
The molecular neurobiology of depression
1.
2.
3.
4.
5.
6.
7.
III.
IV.
V.
Brief repetition: symptomatology / diagnosis / treatment
guidelines
We know little
Validity criteria: animal models of depression
Neural circuitry of depression
The role of monoamines
Neurotrophins and neurogenesis
Neuroendocrine and neuroimmune interactions
Epigenetic mechanisms
Resilence-related research
New insights
The subgenual anterior cingulate cortex in
mood disorders
Conclusions
Journal club
IV. Conclusions…. Discussion!

Polysyndromic nature of depression, heterogenous and complex
etiology, multilevel processes involved


Many open questions
A multidisciplinary approach is needed to explore the
neurobiological bases for depression’s many subtypes

Transfer from preclinical to clinical research and practice ?
RDoC research strategy NIMH
 http://www.nimh.nih.gov/research-priorities/rdoc/nimhresearch-domain-criteria-rdoc.shtml



What do you think what are the current central research
questions?
Which approaches are adequate?
I.
Introduction
1.
2.
3.
II.
The molecular neurobiology of depression
1.
2.
3.
4.
5.
6.
7.
III.
IV.
V.
Brief repetition: symptomatology / diagnosis / treatment
guidelines
We know little
Validity criteria: animal models of depression
Neural circuitry of depression
The role of monoamines
Neurotrophins and neurogenesis
Neuroendocrine and neuroimmune interactions
Epigenetic mechanisms
Resilence-related research
New insights
The subgenual anterior cingulate cortex in
mood disorders
Conclusions
Journal club
V. Journal club
Drevets WC, Price JL, Simpson JR Jr, et al.
Subgenual prefrontal cortex abnormalities in mood
disorders.
Nature 1997;386:824–827.
Methods
3rd independant
group
BF = Blood Flow
Mrglu= Metabolic
rate for glucose
« family pure
depressed disease »
+++ resolution
Synergistic use of MRI and PET image data
Results
Thank you for your attention!!