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TRANSCRIPT
NEUROBIOLOGY OF
AFFECTIVE DISORDERS
2015-2016
Prof. Dr. Pourtois – Prof. Dr. Müller
Axelle Denolf
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LECTURE 1: INTRODUCTION
Overview of the current situation
Belgium: Health Interview Survey (2013)
Sample: 10.000 participants
Three main conclusions:
1) Compared to 2008, substantial increase (+6%) of people confronted with problems to deal with stress,
depression, misfortune/hardship…=> 32% of population! 18% psychopathology, 30% sleep disorder, 15%
depression, 10% anxiety disorder.
2) Increase of chronic diseases (diabetes, hypertension, Thyroid Problems, arthritis)
3) Increase of life expectancy (82.8 years old for women, 77.6 for men), but functional limitations increase as well
(16% above 65 declare they have to stay home or in bed/chair)
Antidepressant drugs in Belgium
1,14 million patients in 2010 (= 10% of the population when you don’t consider children etc.)
Daily doses per patient: 270,8 million
Long-term use (cutoff: 180 doses per patient per year): 83,5%
Social security bill (RIZIV): 134,2 million Euro
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Some more figures from Flanders
Depression in Flanders
Currently experiencing symptoms of depressive disorder:
Experienced a depression in the past year:
3
Used anti-depressors in the past 2 weeks:
Anxiety disorders in Flanders
Currently experiencing symptoms of an anxiety disorder:
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Psychological distress in Flanders
Experiencing psychological distress:
The cost of mental disorders in Europe
The cost of mental disorders in Europe in 2010 = €523.3 billion!
(The Gross Domestic Product (GDP) in Belgium was worth 508.12 billion US dollars in 2013.)
The great depression
Special issue on Depression, Nature, Nov. 2014
What is the best predictor of depression?
Previous depressive episodes
Genetic risk
Stress-life events; early trauma
Gender
the “kindled state”
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Gene x Environment complex interaction: The prototypical example of MDD
Genetic disposition and early-life stress interact in shaping a vulnerable phenotype with changes in cortical-limbic-
brainstem circuits. Upon stress or trauma, maladaptation in these circuits leads to increased endocrine-autonomic
and behavioral-emotional responses. Social support and successful treatments modify the stress responses system in
different components.
Levels of analysis
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About the molecular level…
An example:
a. It’s reported that D2-type medium spiny neurons are not activated in 'depressed' mice. As a consequence, β-
catenin protein remains in the cytoplasm in these cells, unable to enter the nucleus, and the Dicer1 gene is thus
inactive. 'Anti-resilience' proteins may therefore be produced from messenger RNA that would otherwise have
been inhibited by microRNAs (miRNAs) generated by the Dicer1 protein.
b. In resilient mice, β-catenin enters the nucleus of activated neurons, thereby turning on Dicer1 transcription.
Elevated levels of Dicer1 protein increase production of miRNAs and possibly other effectors of resilience. This
might, in turn, inhibit the production of anti-resilience proteins, because of binding and inhibition of mRNA by
miRNAs.
The molecular level (drugs) vs. the systems’ level (CBT)
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Two approaches
1) Cerebral localizationism
(Phrenology)
2) System-based approach: networks,
neuroplasticity
modularity*
dynamic/reciprocal inter-
actions (diaschrisis* hypothesis)
* Modularity = the ability of a system to organize
discrete, individual units that can overall increase the
efficiency of network activity and, in a biological sense,
facilitates selective forces upon the network.
* Diachrisis = the breaking up of a pattern of brain
activity by a localized injury that temporarily throws the
whole activity out of function though destroying only
part of a structure.
Former approach
Human brain mapping
Today’s main approach
Human connectome project
Depression/anxiety = hyperactive amygdala.
Depression/anxiety = functional network dysfunction.
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Taxonomies
Endophenotype
See page 20-21.
Emotional Disorder
Definition
= any mental/psychological disorder (hence emphasis on abnormal/clinical level regarding severity), not caused by
detectable organic abnormalities of the brain, and in which a major disturbance of emotions is predominant.
Focus on emotion to understand disorders of emotion
Are emotions, feelings and moods the same thing? The answer is NO!
Emotions (short-lasting events) have objects or causes; Moods (= long-term dispositional states of mind) usually
don’t.
Neuroscientific definition of emotions: “They are conceptualized as feelings, cognitions and/or behaviors that
result from activation in specific brain circuits”
explore emotions at multiple levels/components!
Example 1: altered gene expression during fear conditioning and long-term potentiation (LTP) in amygdala
Example 2: abnormal empathy and mirror neuron systems in psychopathy
Emotion and cognition are not two dissociable or separate aspects of the mind. Emotional disorders influence
information processing (“negatively”). Attention, reasoning, decision making, memory
Categories
We’re talking about…
Emotional/behavioral disorders General
Mood disorders Specific
Personality disorders Specific
Psychiatric disorders General
Internalizing disorders Specific
…
Mood disorders: Unipolar depression, Bipolar disorder
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Anxiety disorders: Panic Specific phobias, Social Phobia, OCD, GAD, PTSD
Dimensions
Dimensions on a spectrum
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Models
Anxiety, neuroticism and depression: overlapping constructs? Three alternate models:
A) Self-report measures of anxiety, depression, and
neuroticism could potentially all be tapping the same
single underlying trait.
B) Alternatively, anxiety and depression might be separate
components of the broader trait of neuroticism. In
keeping with this perspective, the NEO-PI-R includes
anxiety and depression as subfactors, or “facets,” of
neuroticism (Costa & McCrae; 1995).
C) Tripartite model of anxiety and depression:
A third theoretical stance, represented by Clark and
Watson’s (1991) tripartite model, asserts that anxiety
and depression not only have a shared component of
negative affect or general distress (potentially
corresponding to the construct of neuroticism) but also
unique components of “anxious arousal” (autonomic
hyperactivity) and “anhedonic depression” (low positive
affect).
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A study
Results from a hierarchical clustering analysis performed on data, using nine measures obtained from
standardized self-report questionnaires assessing aspects of negative affective style:
- BDI = Beck Depression
Inventory.
- CESD = Center for
Epidemiologic Studies
Depression Scale.
- Anhedonia Depression is from
the MASQ.
- STAI trait depression is part of
the Spielberger STAI trait
subscale.
- The Neuroticism Scale is from
the Eysenck Personality
Questionnaire.
- PSWQ = Penn State Worry
Questionnaire.
- STAI trait anxiety is part of the
Spielberger STAI trait subscale.
- Anxious Arousal is are from the
MASQ.
- ASI = Anxiety Sensitivity Index.
Hierarchical clustering analysis of the questionnaire data revealed a top-level distinction between measures tapping
anxiety and depression-related affect. Two sub-clusters were anxiety related: one cognitive (Neuroticism, Penn State
Worry Questionnaire, and STAI trait anxiety) and one physiological (MASQ anxious arousal and Anxiety Sensitivity
Index). In addition, two depression-related subclusters indexed negative mood (Beck Depression Inventory and
Center for Epidemiologic Studies Depression Scale) and anhedonia (MASQ anhedonic depression and STAI trait
depression).
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Differences in node-to-network resting state connectivity associated with (A) anxious affect, (B) the physiological
subdimension of anxiety, and (C) the cognitive subdimension of anxiety:
Direction and streng-
th of differences in
connectivity:
Blue indicates a
decrease in node-to-
network connectivity,
and red indicates an
increase. Dark blue
and red indicate
connectivity
differences that were
significant. Light blue
and light red indicate
connectivity
decreases that were
significant.
Different brain network: Purple = insula. Green = medial prefrontal cortex (mPFC). Light sky blue = amygdala–
hippocampal network. Red = orbitofrontal cortex (OFC)–subcortical network. Yellow = frontoparietal–Posterior
Cingulate Cortex (PCC)–precunous network. Blue = cingulate.
So, reduced connectivity between the insula and amygdala-hippocampal networks was linked to anxious affect in
general, whereas decreased connectivity between insula nodes and both medial prefrontal cortex (mPFC) and
orbitofrontal cortex (OFC)–subcortical networks was additionally associated with physiological anxiety.
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Classifications and diagnostic tools
Prior to any taxonomy/classification attempt:
valid and reliable measurement of illness severity
Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety
Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI)
Brief Psychiatric Rating Scale (BPRS)
Positive and Negative Syndrome Scale (PANSS)
Mini-Mental Status Exam (MMSE)
Testotheek (FPPW – UGENT)
Standard practice today in the field: interview (psychiatrist or certified clinical psychologist) + use of
questionnaires/scales/inventories
What we’re going to review today:
the Diagnostic and Statistical Manual of Mental Disorders (DSM)
the International Classification of Diseases (ICD)
the Research Domain Criteria (RDoC)
Caveat: DSM/ICD used by psychiatric drug regulation agencies, health insurance companies, pharmaceutical
companies, the legal system, and policy makers. Copyrighted. APA $100 millions (richer)
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Diagnostic and Statistical Manual of Mental Disorders (DSM)
American Psychiatric Association (APA); Version V
DSM (section II of manual):
Neurodevelopmental disorders Feeding and eating disorders
Schizophrenia spectrum and other psychotic disorders Sleep–wake disorders
Bipolar and related disorders Sexual dysfunctions
Depressive disorders Gender dysphoria
Anxiety disorders Disruptive, impulse-control, and conduct disorders
Obsessive-compulsive and related disorders Substance-related and addictive disorders
Trauma- and stressor-related disorders Neurocognitive disorders (dementia)
Dissociative disorders Paraphilic disorders
Somatic symptom and related disorders Personality disorders
Summary of changes in DSM-V:
Axes:
1) Axis I: All psychological diagnostic categories except mental retardation and personality disorder
2) Axis II: Personality disorders and mental retardation
3) Axis III: General medical condition; acute medical conditions and physical disorders
4) Axis IV: Psychosocial and environmental factors contributing to the disorder
5) Axis V: Global Assessment of Functioning or Children’s Global Assessment Scale for children and teens under the
age of 18
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International Classification of Diseases (ICD)
World Health Organization (WHO) – United Nations (UN); Version 10-11
ICD (section “Mental and behavioural disorders”):
Organic, including symptomatic, mental disorders
Mental and behavioural disorders due to
psychoactive substance use
Schizophrenia, schizotypal and delusional disorders
Mood (affective) disorders
Neurotic, stress-related and somatoform disorders
Mental retardation
Disorders of adult personality and behaviour
Behavioural and emotional disorders with onset
usually occurring in childhood and adolescence
Disorders of psychological development
Behavioural syndromes associated with
physiological disturbances and physical factors
Unspecified mental disorder
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Research Domain Criteria (RDoC)
National Institute of Mental Health (NIMH)
Researchers didn’t get any information/explanation about the responses to medicine. Nowadays, they try to achieve
that by combinations, i.e. a matrix.
“Grid”, “Matrix”
New framework
“Translational” approach: A view of disorders in terms of dysregulation in basic mechanisms
Philosophy = classify mental disorders based on dimensions of observable behavior and neurobiological
measures.
Biomaker/endophenotype
http://www.nimh.nih.gov/research-priorities/rdoc/nimh-research-domain-criteria-rdoc.shtml
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“Stratified medicine”
Current focus/priority is the use of genetic and/or endophenotypic measures to allow more precise diagnostics and
better targeting of treatments. Stratified medicine for mental disorders aims to identify somatic, cognitive, affective,
motor and social behaviour domains defined by associated, potentially common, aetiological neural mechanisms.
ROAMER – A Road map for Mental Health Research in Europe:
(accessed 1.05.2013).
Available from: http://www.roamer-mh.org
Endophenotype (biomarker)
Measurable component, strict criteria (heritability; link to gene), animal model, foster new treatments
Quantitative traits hypothesized to represent genetic risk for polygenic disorders at more biologically tractable
levels than distal behavioural and clinical phenotypes.
Can be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive or neuropsychological.
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Example Schizophrenia:
Symptoms: Psychosis, executive functions (EF) (working memory (WM)) deficits
Genetic alteration: Reelin protein (RELN)
Endophenotype: Prepulse Inhibition
Example Internalizing Disorders:
Symptoms/traits: (Excessive) fear, rumination, worry, error processing
Biological/genetic ground: Altered dopamine (DA) processing in basal ganglia (BG) and the dorsal/rostral part of
the anterior cingulate cortex (ACC)
Endophenotype: Increased error-related negativity (ERN), which is a component of an event-related potential
(ERP)
Example Obsessive-Compulsive Disorder (OCD):
Symptoms: Compulsive thoughts and/or actions (e.g., cleaning behavior)
Neuroanatomy: Reduced grey matter in orbitofrontal and right inferior frontal regions + increased grey matter in
cingulate, parietal and striatal regions
Endophenotype: Abnormal (motor) inhibition
The importance of inhibitory failures in Obsessive-Compulsive Disorder (OCD):
(Cognitive control
Executive functions (= inhibition,
monitoring, planning, working
memory…);
Keep in mind that this does not only
happen in the prefrontal cortex!)
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Epidemiology
A few facts and figures from the National Comorbidity Survey Replication (NCS-R) gathered by the WHO World
Mental Health Survey Consortium (2004):
Prevalence rates: 4.3% in China; 26.4% in USA
Lifetime prevalence: 47.4% in USA
Treatment prevalence: 15.3% in USA
There are ethnic group differences.
Anxiety disorders are the most common disorders. (Second most: mood disorders.)
Are we better off in Europe? NO! Huge burden!
In Europe:
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Epidemiology of Anxiety Disorders
From the National Comorbidity Survey Replication (NCS-R), gathered by the WHO World Mental Health Survey
Consortium (2004):
Lifetime prevalence USA: 29%; 12-month prevalence: 15%
Specific phobia: 12.5%
Social phobia: 12%
OCD: 2.3%
GAD: 4% (average: 3.4 episodes; duration: 11 months); mean age of initial treatment: 34.7 years
PTSD: 10% females; 5% males (25% of individuals exposed to traumatic event will develop PTSD)
Epidemiology of Depression
From the National Comorbidity Survey Replication (NCS-R), gathered by the WHO World Mental Health Survey
Consortium (2004):
4th leading cause of all disease burden
Lifetime prevalence of MDD: 16.2% USA (3% Japan)
Treatment and hospitalization of depressed patients: 60% reported being treated and 10% being hospitalized
Mean number of episodes: 5 Recurrence!
Mean duration: 24 weeks
Comorbidity (!): 3/4 of responders carry an additional syndromal psychiatric diagnosis; 1/3 anxiety disorder
Median age of onset: 32 years
Women/men ratio: 2/1
Socioeconomic status (< 20.000 $/year)
Level of educational attainment and/or urbanicity less clear
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Special issue on Depression, Nature, Nov. 2014:
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World Health Organization, 1996:
The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost
due to ill-health, disability or early death.
The Global Burden of Disease Study, 2010:
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Special issue on Depression, Nature, Nov. 2014:
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Life satisfaction: