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:

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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: