PSY493H1 Lecture Notes - Lecture 9: Research Domain Criteria, Psychomotor Retardation, Suicidal Ideation
What is normal?
Normal people might be quantitively different than abnormal people
-
Biomedical model
Applied to mental illness, it presumes that
Mental disorders are caused by neurobiological abnormalities
○
Mental disorders are not meaningfully distinct in kind from physical disease
Diabetes metaphor for depression
§
○
Biological treatment should be predominantly considered and applied
○
-
Depression
One of the most prevalent mental illness diagnoses
-
Symptoms
Pronounced sad, depressed mood
○
Anhedonia
○
Sleep disturbances (too much or not enough)
○
Non appetite or eat too much
○
Psychomotor retardation (slowing in movements and speech, cognitive ability)
○
Lethargy
○
Distraction
○
Feelings of worthlessness, guilt, suicidal ideation
○
-
Diagnostic Statistical Manual (DSM)
Structured clinical interview for DSM (SCID)
To be diagnosed, need to have minimum symptom duration and number
○
-
Self-report: social, functional problems, thoughts and attitudes
-
Do the symptoms map onto a specific mental illness category (e.g. depression,
schizophrenia, anxiety)
-
Minimum symptom and time duration requirements
-
Do have recommendation for treatment
Symptoms alone rarely indicate the best course of treatment
○
-
Categories or Dimensions?
The categorical approach (DSM) uses minimum symptom presence and duration for
diagnostic criteria. This approach assumes:
A mental disorder can be diagnosed from specific symptoms that are shown
during a mental health assessment
○
Thoughts, feelings and behaviour can be organized into categories representing
discrete disorders
All or nothing principle; you have it or you don't
Cons: low inter-reliability, symptom overlap, stigma, arbitrary □
Pros: easy to use across many different settings and practitioners □
§
○
-
The dimensional approach quantifies a person's symptoms on a continuum, no
categories. Less diagnosis, more about degree of impairment/presence of maladaptive
symptom
Prons:
More detailed info on each symptom
§
Takes into account a wider range of factors
§
A profile is created instead of labelling
§
○
Cones:
Time consuming
§
There is currently no standard inventory to compare scores making
diagnosis difficult
§
○
-
Do categories make sense?
It disparate mental disorder cannot be empirically supported
-
Comorbidity complicates the idea of discrete diagnoses
-
We haven't found any reliable biomarkers for any psychiatric disorder
Tons of overlap, polygenic risk
○
-
The p factor
General psychopathology (p) factor
Analogous to g for general intelligence
○
-
High in p -> have more comorbid symptoms
-
Dimensional factor that comprises many facets of psychopathology related to
symptomatology
High p individuals have more co-morbidity, symptom severity, worse brain
function, more overall life impairments
○
Differences in p explain life outcomes better than internalizing and externalizing
behaviours, which were found to be delineated by sex
Women exhibit more internalizing symptoms (depression, anxiety )
§
Men exhibit more externalizing symptoms (addiction, antisocial)
§
○
-
DSM replaces by RDoC
National Institute of Health (NIH) has abandoned the DSM in favor of the Research
Domain Criteria (RDoC)
-
New classification system to diagnose mental illness based on behavioural dimensions
and neurobiological measures
Genetic, neuroscience, and behavioural science
○
-
Matrix of functional dimensions grouped into areas like cognition and reward-based
systems, also looks at brain circuits (i.e. cognitive control)
-
Longitudinal focus on neurodevelopment and environmental factors
-
Instead of working backwards from the symptoms, look at the brain and behaviour to
improve diagnosis and see similarities across illness
-
RDoC Domains
Negative valence systems (fear, anxiety, loss)
-
Positive valence systems (reward learning, reward valuation)
-
Cognitive systems (attention, perception, working memory, cognitive control)
-
Systems for social processes (attachment formation, social communication, perception
of self, perception of others)
-
Arousal/modulatory systems 9arousal, circadian rhythm, sleep and wakefulness)
-
Using different of analysis: genes, molecules, cells neural circuits, physiological,
behaviours and self-reports
-
Meanwhile..
We need to develop models for mental illness
-
Mental illness is a major cause for debility worldwide
-
Research has often turned to animal models to help us understand the neuroscience of
psychopathology
-
Many provide ideas about possible interventions and insight into pathogenesis and
neurobiology
-
Rodent models
Cheaper, easier to train and short reproduction cycle
-
Human vs. Rodent brain
We have bigger PFC than rodent
-
Valid models
Face validity: be reasonably analogous to human disorder in its symptomatology 1.
Cause changes that can be monitored objectively 2.
Predictive validity produce behavioural changes that are reversed by the same
treatment modalities that are effective in humans
3.
Animal models of depression
Developed as screening programs for antidepressant efficacy
-
Assess behavioural outcomes related to depressive symptomatology
-
Make inferences from motor behaviour to mood changes - guessing
-
Endophenotypes
We cannot perfectly mirror depression in animals
-
Relay on reproducing endophenotypes in animals to study the neuroscience of
depression
-
An endophenotype is an intermediate component that lies b/w the pathway of a
disease and its genotype (i.e. endocrinological, neuroanatomical, cognitive,
biochemical, etc)
Ex. Sensory gating deficits in schizophrenia, anhedonia in depression
○
-
We need valid animal models to understand the molecular, genetic and epigenetic
factors involved in depression
-
-
Endophenotypes of depression
Anhedonia ( assessed by sucrose preference or intracranial self-stimulation)
-
Behavioural despair (assessed by forced-swimming test or tail suspension test)
-
Changes in appetite or weight gain
-
Neuroanatomy
-
Neuroendocrine disturbance
-
Alternations in sleep architecture
-
Anxiety-related behaviour
-
Animal models of depression
Learned helplessness
-
Chronic mild stress
-
Social stress
-
Maternal deprivation
-
Olfactory bulbectomy
-
Genetics
-
Pharmacology
-
Animal paradigms of depression
Forced swim test (behavioural despair test)
Measure time until it stops trying
○
Behavioural despair (behaviourally depressed)
Anti-depressant revered the behaviour
§
○
-
Tail suspension test
Measure immobility
○
-
Sucrose preference
-
Intracranial stimulation (thigmotactic)
-
Elevated plus maze
-
Depression
WHO, depression is leading cause to burden of disease in developed countries
-
Leading cause of years lost from disability worldwide
Estimated of 17-41% lifetime prevalence rate
○
-
Women are 1.5 times more likely to suffer from MDD than men (internalizing
tendencies)
-
Men are likely to suffer from substance abuse disorders (externalizing tendencies)
-
Neural correlates of depression
dIPFC deficits
-
mPFC pyramidal reductions
-
Reduced hippocampal volume
-
Reduced subgenual ACC volume
-
Enlarged, overactive amygdala
-
Reduce orbital/VMPFC, anterior cingulate cortex, hippocampus, DLPFC
-
Neurochemical:
Increase: cortisol, cytokines
-
Decrease: BDNF, 5-HT, NA
-
Necessary conditions for claiming causality
Temporal precedence
If A causes B, we must show that A occurs in time before B
○
-
Correlation
A must be correlated with B
○
-
Rule out 3rd variables
Height and computer skills
○
-
Spurious correlation: have to manipulate things in order to measure otherwise the variables
are non sense
Competing theories
-Monoamine deficiency hypothesis
○Mostly serotonergic focus
○Evidence is very mixed
-HPA-dysregulation hypothesis
○Chronic stress causes hippocampal volume reductions and a cascade of other
events (e.g. PFC dysregulation, VTA-NAc disruptions)
○Also has converse effects in amygdala resulting in hyperactivity and hypertrophy
and corresponds to negative affect
Genetic contributions
-ADRA2B polymorphism
○ADRA2b deletion carriers: more vivid emotional memory for negative stimuli
§Better recall for emotional stimuli
§Linked with PTSD
-Serotonin transporter gene (5-HTTLPR)
○2 short alleles -> more likely to get depression
○Long -> higher 5-HTT
○Short -> lower 5-HTT
Not just genes!
-Phenotype = genotype + environment + GxE
-Depression = 5-HTTLPR + environment + GxE
Not 1 to 1!
-Tiny effect sizes
Chanllenges
-Genes too far from phenotype
-A lot of genes (30000+) = large computations
-Small effect of single genes
-Multiple comparison
-Gene-gene interactions
-Gene-environment interaction
-Disease definition? Misdiagnosis?
Hippocampal neurogenesis
-Depression is increasingly seen as a stress disorder
-Glucocorticoid dysregulation from chronic stress causes dendritic retraction in
hippocampus
○Metabolic neurotoxicity
○Reversible with psychotherapy, drugs and exercise
-Hippocampus exerts control over HPA
VTA-Nac dysregulation
-Angedonia and decreased motivation are core features of depression
-VTA-Nac receive many glutamateric connections from frontal cortices, hippocampus,
amygdala, hypothalamys
-Acute stress increases DA activation in VTA and Nac, but over time compensatory
mechanisms activate leading to down-regulation of DA neurons
-Chronic stress exhibits effects on Nac circuitry and function by reducing tonic DA
release
-Decreased DA-VTA activation related to immobility in forced swim test
Neuroinflammation
-People with depression show more pro-inflammatory cytokines in their blood and CSF
-People with more pro-inflammatory cytokines experience
-Increased anxiety and depression and symptom severity correlated with increased
peripheral inflammatory blood markers
-Psychosocial stress has been shown to initiate various inflammatory pathways
throughout the body and the brain
Inflammation effects
-Myelination
Interpretations?
-Depression is related to chronic stress and dysregulated HPA-axis that causes many
deleterious effects
-Might these widespread change be an adaptive response to stop the damage of long-
term elevated glucocorticoid levels
Cognitive maintenance
-Rumination
○Reflective ponding: more problem solving focused
○Brooding: obsessive repetition and focus of negative thoughts and feelings
-Working through the feelings and thoughts in a reflective way can help resolves
depressive episodes
-Hyperactivity of MPFC (self narrative thinking) and Anterior cingulate cortex (detecting
errors) in depressed patients and depression severity correlated with MPFC, ACC &
amygdala functional connectivity (ruminative network, negative self-referential
thought)
Diathesis Stress Model ( a biopsychosocial model)
-Diathesis is a vulnerability
-Focuses on risk factors related to genetics, early experience, coping mechanisms and
environment to understand how mental illness arises
Risk factors
-Prenatal development
-Childhood trauma
-Genetics
-Traumatic brain injury TBI
-Chemical imbalances (e.g. substance abuse, diet, sleep)
-Life events (extreme poverty)
Psychiatric epidemiology
-World health organization
-Anxiety most prevalent followed by depression
-US has highest overall mental illness prevalence rates
-These numbers are increasing world wide (especially for depression & anxiety)
Psychiatric medication
-Billions in revenue in North America
-Some are addictive, long-lasting side effects, withdrawal symptoms (not well studied)
-Efficacy is questionable for many, long-term risk
○Antipsychotics cause diabetes, metabolic syndrome, gray matter volume
reductions, risk of Alzheimer's with anxiolytics
Psychiatric medication
-Direct-to-consumer advertising
-Drug cocktails (mix drugs for different functions)
-Treating the side effects
-Long-term effects
-Treating children
○We have no idea what these do long-term or to the developing brain
Heritability
-Depression is about 37%-50% heritable
-Schizophrenia, bipolar disorder and Parkinson's disease estimated 80% heritable
-Twin studies are flawed, inflates genetic influence
○Not random, environment too similar
-Missing heritability problem; individual genes do not account for much of the
heritability in diseases, behaviours or phenotypes
Problem with diagnostics
-The issue of emergence from complex processes
-Imagine studying and trying to understand everything possible about the members of
Nirvana in the hope of understanding how their music was create
-This whole is greater than the sum of its parts, reductionism fails
-Interaction effects and bidirectional causation (e.g. gene X environment, epigenetics)
-Depression isn't a unitary disorder or state, huge overlap b/w anxiety, panic disorders,
instances of trauma
-Different "biotypes": based on resting state functional connectivity, not related to
differences in symptoms
Treatment is suboptimal
-Antidepressants work within 4 months in 60 of people however symptoms return after
cessation
-Cognitive behavioural therapy (CBT) has similar recovery rates but the relapse is slower
than with drugs. Same holds for anxiety
-Only short-term antidepressant use is effective and only for serious depression
-Increased suicidal ideation especially in kids
-Many people cannot quit taking them due to withdrawal effects (not well studied)
Why is efficacy so low for antidepressants?
-No good evidence of chemical imbalance or reliable biotypes
-Systematic bias in clinical trials
○Inflated effect sizes in published trials 9clinical vs. statistical significance)
○Publication bias of positive trials
§Newer drugs with patents have bigger effect sizes
-Antidepressants are crude in their effects
-Symptom management vs. disease treatment
-Etiology matters
Biomedical vs. Social models
-Biological psychiatry has focused on a medical model of mental illness
○Chemical imbalance hypotheses, neuroanatomical anomalies
-Social models focus more on the environmental determinants of mental illness
○Stress, trauma, childhood
Prevention vs. treatment
-More than half of adults with mental illness present with symptoms in adolescence
and childhood
-The biggest predictor of well-being in adulthood is childhood emotional health and
stability
-Early intervention is vital to preventing mental illness in adulthood
○Train parents and educators, teach emotional management
Onset of depression
-Life adversity
○90% severe adverse life events before depressive episode
○Social adversity and depression found worldwide
-Loss of role: social disruptions and lack of social support
-Failure of achievement: work and autonomy more important
-Gene X environment interactions: biological, developmental, psychological and
sociodemographic factors
What determines well-being?
-Once basic needs are met, many things come into play
○Family & friendship
○Health
○Work
○Emotional resiliency
○Meaning
-Proposed 3 components: life satisfaction, positive affect and a lack of negative affect
○Set point: genetic baseline that regulates personality and temperament
§Circumstances: gender, martial status, income, cultural background
§Activities: what you choose to do with your time. Family, friends,
hobbies.
The malady of culture
-We evolved in small tribes and now live in massive communities based on societies
governed by collective values called culture
-We are an extraordinary adaptive species, but there are limits
-We're overworked and stressed, bleak future outlook, global warming
-The dominant culture does not support qualities that result in general well-being (I,e,
connectedness, strong sense of meaning)
-What does popular North American Culture value?
○The influence of capitalism
§Money, youth, sex, power, status
Social connectedness deteriorates
Culture of self-blame
Culture of stigma
-Mental illness is highly stigmatized
○Exceptionalism, personal responsibility
-Focus on endogenous cause
-People cannot afford help
○Psychiatrists vs. psychologists vs. social workers vs. counselling psychologists
-Much harder to make a good living
-Fewer well-paying jobs, gig economy
We ignore the environment
-Understanding the environmental influences of mental illness is vital
-Early interventions
-Less cost of burden
-Less reliance on medication
-Reduction of recurrent episodes
-Will allow for preventative measures (e.g. self-care)
Self- care
-Eating well
-Sleep
-Exercise
-Healthy social interaction
-Mindfulness
-Meaning
Altering emotions
Temporary change Long-term change
-Cognitive reappraisal - particular
situation
-Distraction / avoidance
-Mind/ mood altering substances
-Cognitive reappraisal - of emotional experience
itself
-Therapy
-Mindfulness medication
Mindfulness
-Focus on interoceptive awareness; sustained attention to bodily sensations
-Differs from cognitive reappraisal, which relies on memory and evaluation to re-
interpret negative experiences
-Meta analysis showed that mindfulness-based therapy reduced depression and anxiety
symptoms
○Coming into the present moment to really experience what's here
○Training attention (executive function)
○Awareness of bodily sensations
○Awareness of emotions (labeling)
○Awareness of thoughts
○Ability to stay with difficult emotions /sensations
Epigenetics!!!
Gene A ≠ Disease A
Lecture 9
Monday, June 11, 2018
6:13 PM
What is normal?
Normal people might be quantitively different than abnormal people
-
Biomedical model
Applied to mental illness, it presumes that
Mental disorders are caused by neurobiological abnormalities
○
Mental disorders are not meaningfully distinct in kind from physical disease
Diabetes metaphor for depression
§
○
Biological treatment should be predominantly considered and applied
○
-
Depression
One of the most prevalent mental illness diagnoses
-
Symptoms
Pronounced sad, depressed mood
○
Anhedonia
○
Sleep disturbances (too much or not enough)
○
Non appetite or eat too much
○
Psychomotor retardation (slowing in movements and speech, cognitive ability)
○
Lethargy
○
Distraction
○
Feelings of worthlessness, guilt, suicidal ideation
○
-
Diagnostic Statistical Manual (DSM)
Structured clinical interview for DSM (SCID)
To be diagnosed, need to have minimum symptom duration and number
○
-
Self-report: social, functional problems, thoughts and attitudes
-
Do the symptoms map onto a specific mental illness category (e.g. depression,
schizophrenia, anxiety)
-
Minimum symptom and time duration requirements
-
Do have recommendation for treatment
Symptoms alone rarely indicate the best course of treatment
○
-
Categories or Dimensions?
The categorical approach (DSM) uses minimum symptom presence and duration for
diagnostic criteria. This approach assumes:
A mental disorder can be diagnosed from specific symptoms that are shown
during a mental health assessment
○
Thoughts, feelings and behaviour can be organized into categories representing
discrete disorders
All or nothing principle; you have it or you don't
Cons: low inter-reliability, symptom overlap, stigma, arbitrary
□
Pros: easy to use across many different settings and practitioners
□
§
○
-
The dimensional approach quantifies a person's symptoms on a continuum, no
categories. Less diagnosis, more about degree of impairment/presence of maladaptive
symptom
Prons:
More detailed info on each symptom
§
Takes into account a wider range of factors
§
A profile is created instead of labelling
§
○
Cones:
Time consuming
§
There is currently no standard inventory to compare scores making
diagnosis difficult
§
○
-
Do categories make sense?
It disparate mental disorder cannot be empirically supported
-
Comorbidity complicates the idea of discrete diagnoses
-
We haven't found any reliable biomarkers for any psychiatric disorder
Tons of overlap, polygenic risk
○
-
The p factor
General psychopathology (p) factor
Analogous to g for general intelligence
○
-
High in p -> have more comorbid symptoms
-
Dimensional factor that comprises many facets of psychopathology related to
symptomatology
High p individuals have more co-morbidity, symptom severity, worse brain
function, more overall life impairments
○
Differences in p explain life outcomes better than internalizing and externalizing
behaviours, which were found to be delineated by sex
Women exhibit more internalizing symptoms (depression, anxiety )
§
Men exhibit more externalizing symptoms (addiction, antisocial)
§
○
-
DSM replaces by RDoC
National Institute of Health (NIH) has abandoned the DSM in favor of the Research
Domain Criteria (RDoC)
-
New classification system to diagnose mental illness based on behavioural dimensions
and neurobiological measures
Genetic, neuroscience, and behavioural science
○
-
Matrix of functional dimensions grouped into areas like cognition and reward-based
systems, also looks at brain circuits (i.e. cognitive control)
-
Longitudinal focus on neurodevelopment and environmental factors
-
Instead of working backwards from the symptoms, look at the brain and behaviour to
improve diagnosis and see similarities across illness
-
RDoC Domains
Negative valence systems (fear, anxiety, loss)
-
Positive valence systems (reward learning, reward valuation)
-
Cognitive systems (attention, perception, working memory, cognitive control)
-
Systems for social processes (attachment formation, social communication, perception
of self, perception of others)
-
Arousal/modulatory systems 9arousal, circadian rhythm, sleep and wakefulness)
-
Using different of analysis: genes, molecules, cells neural circuits, physiological,
behaviours and self-reports
-
Meanwhile..
We need to develop models for mental illness
-
Mental illness is a major cause for debility worldwide
-
Research has often turned to animal models to help us understand the neuroscience of
psychopathology
-
Many provide ideas about possible interventions and insight into pathogenesis and
neurobiology
-
Rodent models
Cheaper, easier to train and short reproduction cycle
-
Human vs. Rodent brain
We have bigger PFC than rodent
-
Valid models
Face validity: be reasonably analogous to human disorder in its symptomatology 1.
Cause changes that can be monitored objectively 2.
Predictive validity produce behavioural changes that are reversed by the same
treatment modalities that are effective in humans
3.
Animal models of depression
Developed as screening programs for antidepressant efficacy
-
Assess behavioural outcomes related to depressive symptomatology
-
Make inferences from motor behaviour to mood changes - guessing
-
Endophenotypes
We cannot perfectly mirror depression in animals
-
Relay on reproducing endophenotypes in animals to study the neuroscience of
depression
-
An endophenotype is an intermediate component that lies b/w the pathway of a
disease and its genotype (i.e. endocrinological, neuroanatomical, cognitive,
biochemical, etc)
Ex. Sensory gating deficits in schizophrenia, anhedonia in depression
○
-
We need valid animal models to understand the molecular, genetic and epigenetic
factors involved in depression
-
-
Endophenotypes of depression
Anhedonia ( assessed by sucrose preference or intracranial self-stimulation)
-
Behavioural despair (assessed by forced-swimming test or tail suspension test)
-
Changes in appetite or weight gain
-
Neuroanatomy
-
Neuroendocrine disturbance
-
Alternations in sleep architecture
-
Anxiety-related behaviour
-
Animal models of depression
Learned helplessness
-
Chronic mild stress
-
Social stress
-
Maternal deprivation
-
Olfactory bulbectomy
-
Genetics
-
Pharmacology
-
Animal paradigms of depression
Forced swim test (behavioural despair test)
Measure time until it stops trying
○
Behavioural despair (behaviourally depressed)
Anti-depressant revered the behaviour
§
○
-
Tail suspension test
Measure immobility
○
-
Sucrose preference
-
Intracranial stimulation (thigmotactic)
-
Elevated plus maze
-
Depression
WHO, depression is leading cause to burden of disease in developed countries
-
Leading cause of years lost from disability worldwide
Estimated of 17-41% lifetime prevalence rate
○
-
Women are 1.5 times more likely to suffer from MDD than men (internalizing
tendencies)
-
Men are likely to suffer from substance abuse disorders (externalizing tendencies)
-
Neural correlates of depression
dIPFC deficits
-
mPFC pyramidal reductions
-
Reduced hippocampal volume
-
Reduced subgenual ACC volume
-
Enlarged, overactive amygdala
-
Reduce orbital/VMPFC, anterior cingulate cortex, hippocampus, DLPFC
-
Neurochemical:
Increase: cortisol, cytokines
-
Decrease: BDNF, 5-HT, NA
-
Necessary conditions for claiming causality
Temporal precedence
If A causes B, we must show that A occurs in time before B
○
-
Correlation
A must be correlated with B
○
-
Rule out 3rd variables
Height and computer skills
○
-
Spurious correlation: have to manipulate things in order to measure otherwise the variables
are non sense
Competing theories
-Monoamine deficiency hypothesis
○Mostly serotonergic focus
○Evidence is very mixed
-HPA-dysregulation hypothesis
○Chronic stress causes hippocampal volume reductions and a cascade of other
events (e.g. PFC dysregulation, VTA-NAc disruptions)
○Also has converse effects in amygdala resulting in hyperactivity and hypertrophy
and corresponds to negative affect
Genetic contributions
-ADRA2B polymorphism
○ADRA2b deletion carriers: more vivid emotional memory for negative stimuli
§Better recall for emotional stimuli
§Linked with PTSD
-Serotonin transporter gene (5-HTTLPR)
○2 short alleles -> more likely to get depression
○Long -> higher 5-HTT
○Short -> lower 5-HTT
Not just genes!
-Phenotype = genotype + environment + GxE
-Depression = 5-HTTLPR + environment + GxE
Not 1 to 1!
-Tiny effect sizes
Chanllenges
-Genes too far from phenotype
-A lot of genes (30000+) = large computations
-Small effect of single genes
-Multiple comparison
-Gene-gene interactions
-Gene-environment interaction
-Disease definition? Misdiagnosis?
Hippocampal neurogenesis
-Depression is increasingly seen as a stress disorder
-Glucocorticoid dysregulation from chronic stress causes dendritic retraction in
hippocampus
○Metabolic neurotoxicity
○Reversible with psychotherapy, drugs and exercise
-Hippocampus exerts control over HPA
VTA-Nac dysregulation
-Angedonia and decreased motivation are core features of depression
-VTA-Nac receive many glutamateric connections from frontal cortices, hippocampus,
amygdala, hypothalamys
-Acute stress increases DA activation in VTA and Nac, but over time compensatory
mechanisms activate leading to down-regulation of DA neurons
-Chronic stress exhibits effects on Nac circuitry and function by reducing tonic DA
release
-Decreased DA-VTA activation related to immobility in forced swim test
Neuroinflammation
-People with depression show more pro-inflammatory cytokines in their blood and CSF
-People with more pro-inflammatory cytokines experience
-Increased anxiety and depression and symptom severity correlated with increased
peripheral inflammatory blood markers
-Psychosocial stress has been shown to initiate various inflammatory pathways
throughout the body and the brain
Inflammation effects
-Myelination
Interpretations?
-Depression is related to chronic stress and dysregulated HPA-axis that causes many
deleterious effects
-Might these widespread change be an adaptive response to stop the damage of long-
term elevated glucocorticoid levels
Cognitive maintenance
-Rumination
○Reflective ponding: more problem solving focused
○Brooding: obsessive repetition and focus of negative thoughts and feelings
-Working through the feelings and thoughts in a reflective way can help resolves
depressive episodes
-Hyperactivity of MPFC (self narrative thinking) and Anterior cingulate cortex (detecting
errors) in depressed patients and depression severity correlated with MPFC, ACC &
amygdala functional connectivity (ruminative network, negative self-referential
thought)
Diathesis Stress Model ( a biopsychosocial model)
-Diathesis is a vulnerability
-Focuses on risk factors related to genetics, early experience, coping mechanisms and
environment to understand how mental illness arises
Risk factors
-Prenatal development
-Childhood trauma
-Genetics
-Traumatic brain injury TBI
-Chemical imbalances (e.g. substance abuse, diet, sleep)
-Life events (extreme poverty)
Psychiatric epidemiology
-World health organization
-Anxiety most prevalent followed by depression
-US has highest overall mental illness prevalence rates
-These numbers are increasing world wide (especially for depression & anxiety)
Psychiatric medication
-Billions in revenue in North America
-Some are addictive, long-lasting side effects, withdrawal symptoms (not well studied)
-Efficacy is questionable for many, long-term risk
○Antipsychotics cause diabetes, metabolic syndrome, gray matter volume
reductions, risk of Alzheimer's with anxiolytics
Psychiatric medication
-Direct-to-consumer advertising
-Drug cocktails (mix drugs for different functions)
-Treating the side effects
-Long-term effects
-Treating children
○We have no idea what these do long-term or to the developing brain
Heritability
-Depression is about 37%-50% heritable
-Schizophrenia, bipolar disorder and Parkinson's disease estimated 80% heritable
-Twin studies are flawed, inflates genetic influence
○Not random, environment too similar
-Missing heritability problem; individual genes do not account for much of the
heritability in diseases, behaviours or phenotypes
Problem with diagnostics
-The issue of emergence from complex processes
-Imagine studying and trying to understand everything possible about the members of
Nirvana in the hope of understanding how their music was create
-This whole is greater than the sum of its parts, reductionism fails
-Interaction effects and bidirectional causation (e.g. gene X environment, epigenetics)
-Depression isn't a unitary disorder or state, huge overlap b/w anxiety, panic disorders,
instances of trauma
-Different "biotypes": based on resting state functional connectivity, not related to
differences in symptoms
Treatment is suboptimal
-Antidepressants work within 4 months in 60 of people however symptoms return after
cessation
-Cognitive behavioural therapy (CBT) has similar recovery rates but the relapse is slower
than with drugs. Same holds for anxiety
-Only short-term antidepressant use is effective and only for serious depression
-Increased suicidal ideation especially in kids
-Many people cannot quit taking them due to withdrawal effects (not well studied)
Why is efficacy so low for antidepressants?
-No good evidence of chemical imbalance or reliable biotypes
-Systematic bias in clinical trials
○Inflated effect sizes in published trials 9clinical vs. statistical significance)
○Publication bias of positive trials
§Newer drugs with patents have bigger effect sizes
-Antidepressants are crude in their effects
-Symptom management vs. disease treatment
-Etiology matters
Biomedical vs. Social models
-Biological psychiatry has focused on a medical model of mental illness
○Chemical imbalance hypotheses, neuroanatomical anomalies
-Social models focus more on the environmental determinants of mental illness
○Stress, trauma, childhood
Prevention vs. treatment
-More than half of adults with mental illness present with symptoms in adolescence
and childhood
-The biggest predictor of well-being in adulthood is childhood emotional health and
stability
-Early intervention is vital to preventing mental illness in adulthood
○Train parents and educators, teach emotional management
Onset of depression
-Life adversity
○90% severe adverse life events before depressive episode
○Social adversity and depression found worldwide
-Loss of role: social disruptions and lack of social support
-Failure of achievement: work and autonomy more important
-Gene X environment interactions: biological, developmental, psychological and
sociodemographic factors
What determines well-being?
-Once basic needs are met, many things come into play
○Family & friendship
○Health
○Work
○Emotional resiliency
○Meaning
-Proposed 3 components: life satisfaction, positive affect and a lack of negative affect
○Set point: genetic baseline that regulates personality and temperament
§Circumstances: gender, martial status, income, cultural background
§Activities: what you choose to do with your time. Family, friends,
hobbies.
The malady of culture
-We evolved in small tribes and now live in massive communities based on societies
governed by collective values called culture
-We are an extraordinary adaptive species, but there are limits
-We're overworked and stressed, bleak future outlook, global warming
-The dominant culture does not support qualities that result in general well-being (I,e,
connectedness, strong sense of meaning)
-What does popular North American Culture value?
○The influence of capitalism
§Money, youth, sex, power, status
Social connectedness deteriorates
Culture of self-blame
Culture of stigma
-Mental illness is highly stigmatized
○Exceptionalism, personal responsibility
-Focus on endogenous cause
-People cannot afford help
○Psychiatrists vs. psychologists vs. social workers vs. counselling psychologists
-Much harder to make a good living
-Fewer well-paying jobs, gig economy
We ignore the environment
-Understanding the environmental influences of mental illness is vital
-Early interventions
-Less cost of burden
-Less reliance on medication
-Reduction of recurrent episodes
-Will allow for preventative measures (e.g. self-care)
Self- care
-Eating well
-Sleep
-Exercise
-Healthy social interaction
-Mindfulness
-Meaning
Altering emotions
Temporary change Long-term change
-Cognitive reappraisal - particular
situation
-Distraction / avoidance
-Mind/ mood altering substances
-Cognitive reappraisal - of emotional experience
itself
-Therapy
-Mindfulness medication
Mindfulness
-Focus on interoceptive awareness; sustained attention to bodily sensations
-Differs from cognitive reappraisal, which relies on memory and evaluation to re-
interpret negative experiences
-Meta analysis showed that mindfulness-based therapy reduced depression and anxiety
symptoms
○Coming into the present moment to really experience what's here
○Training attention (executive function)
○Awareness of bodily sensations
○Awareness of emotions (labeling)
○Awareness of thoughts
○Ability to stay with difficult emotions /sensations
Epigenetics!!!
Gene A ≠ Disease A
Lecture 9
Monday, June 11, 2018 6:13 PM
What is normal?
Normal people might be quantitively different than abnormal people
-
Biomedical model
Applied to mental illness, it presumes that
Mental disorders are caused by neurobiological abnormalities
○
Mental disorders are not meaningfully distinct in kind from physical disease
Diabetes metaphor for depression
§
○
Biological treatment should be predominantly considered and applied
○
-
Depression
One of the most prevalent mental illness diagnoses
-
Symptoms
Pronounced sad, depressed mood
○
Anhedonia
○
Sleep disturbances (too much or not enough)
○
Non appetite or eat too much
○
Psychomotor retardation (slowing in movements and speech, cognitive ability)
○
Lethargy
○
Distraction
○
Feelings of worthlessness, guilt, suicidal ideation
○
-
Diagnostic Statistical Manual (DSM)
Structured clinical interview for DSM (SCID)
To be diagnosed, need to have minimum symptom duration and number
○
-
Self-report: social, functional problems, thoughts and attitudes
-
Do the symptoms map onto a specific mental illness category (e.g. depression,
schizophrenia, anxiety)
-
Minimum symptom and time duration requirements
-
Do have recommendation for treatment
Symptoms alone rarely indicate the best course of treatment
○
-
Categories or Dimensions?
The categorical approach (DSM) uses minimum symptom presence and duration for
diagnostic criteria. This approach assumes:
A mental disorder can be diagnosed from specific symptoms that are shown
during a mental health assessment
○
Thoughts, feelings and behaviour can be organized into categories representing
discrete disorders
All or nothing principle; you have it or you don't
Cons: low inter-reliability, symptom overlap, stigma, arbitrary □
Pros: easy to use across many different settings and practitioners □
§
○
-
The dimensional approach quantifies a person's symptoms on a continuum, no
categories. Less diagnosis, more about degree of impairment/presence of maladaptive
symptom
Prons:
More detailed info on each symptom
§
Takes into account a wider range of factors
§
A profile is created instead of labelling
§
○
Cones:
Time consuming
§
There is currently no standard inventory to compare scores making
diagnosis difficult
§
○
-
Do categories make sense?
It disparate mental disorder cannot be empirically supported
-
Comorbidity complicates the idea of discrete diagnoses
-
We haven't found any reliable biomarkers for any psychiatric disorder
Tons of overlap, polygenic risk
○
-
The p factor
General psychopathology (p) factor
Analogous to g for general intelligence
○
-
High in p -> have more comorbid symptoms
-
Dimensional factor that comprises many facets of psychopathology related to
symptomatology
High p individuals have more co-morbidity, symptom severity, worse brain
function, more overall life impairments
○
Differences in p explain life outcomes better than internalizing and externalizing
behaviours, which were found to be delineated by sex
Women exhibit more internalizing symptoms (depression, anxiety )
§
Men exhibit more externalizing symptoms (addiction, antisocial)
§
○
-
DSM replaces by RDoC
National Institute of Health (NIH) has abandoned the DSM in favor of the Research
Domain Criteria (RDoC)
-
New classification system to diagnose mental illness based on behavioural dimensions
and neurobiological measures
Genetic, neuroscience, and behavioural science
○
-
Matrix of functional dimensions grouped into areas like cognition and reward-based
systems, also looks at brain circuits (i.e. cognitive control)
-
Longitudinal focus on neurodevelopment and environmental factors
-
Instead of working backwards from the symptoms, look at the brain and behaviour to
improve diagnosis and see similarities across illness
-
RDoC Domains
Negative valence systems (fear, anxiety, loss)
-
Positive valence systems (reward learning, reward valuation)
-
Cognitive systems (attention, perception, working memory, cognitive control)
-
Systems for social processes (attachment formation, social communication, perception
of self, perception of others)
-
Arousal/modulatory systems 9arousal, circadian rhythm, sleep and wakefulness)
-
Using different of analysis: genes, molecules, cells neural circuits, physiological,
behaviours and self-reports
-
Meanwhile..
We need to develop models for mental illness
-
Mental illness is a major cause for debility worldwide
-
Research has often turned to animal models to help us understand the neuroscience of
psychopathology
-
Many provide ideas about possible interventions and insight into pathogenesis and
neurobiology
-
Rodent models
Cheaper, easier to train and short reproduction cycle
-
Human vs. Rodent brain
We have bigger PFC than rodent
-
Valid models
Face validity: be reasonably analogous to human disorder in its symptomatology
1.
Cause changes that can be monitored objectively
2.
Predictive validity produce behavioural changes that are reversed by the same
treatment modalities that are effective in humans
3.
Animal models of depression
Developed as screening programs for antidepressant efficacy
-
Assess behavioural outcomes related to depressive symptomatology
-
Make inferences from motor behaviour to mood changes - guessing
-
Endophenotypes
We cannot perfectly mirror depression in animals
-
Relay on reproducing endophenotypes in animals to study the neuroscience of
depression
-
An endophenotype is an intermediate component that lies b/w the pathway of a
disease and its genotype (i.e. endocrinological, neuroanatomical, cognitive,
biochemical, etc)
Ex. Sensory gating deficits in schizophrenia, anhedonia in depression
○
-
We need valid animal models to understand the molecular, genetic and epigenetic
factors involved in depression
-
-
Endophenotypes of depression
Anhedonia ( assessed by sucrose preference or intracranial self-stimulation)
-
Behavioural despair (assessed by forced-swimming test or tail suspension test)
-
Changes in appetite or weight gain
-
Neuroanatomy
-
Neuroendocrine disturbance
-
Alternations in sleep architecture
-
Anxiety-related behaviour
-
Animal models of depression
Learned helplessness
-
Chronic mild stress
-
Social stress
-
Maternal deprivation
-
Olfactory bulbectomy
-
Genetics
-
Pharmacology
-
Animal paradigms of depression
Forced swim test (behavioural despair test)
Measure time until it stops trying
○
Behavioural despair (behaviourally depressed)
Anti-depressant revered the behaviour
§
○
-
Tail suspension test
Measure immobility
○
-
Sucrose preference
-
Intracranial stimulation (thigmotactic)
-
Elevated plus maze
-
Depression
WHO, depression is leading cause to burden of disease in developed countries
-
Leading cause of years lost from disability worldwide
Estimated of 17-41% lifetime prevalence rate
○
-
Women are 1.5 times more likely to suffer from MDD than men (internalizing
tendencies)
-
Men are likely to suffer from substance abuse disorders (externalizing tendencies)
-
Neural correlates of depression
dIPFC deficits
-
mPFC pyramidal reductions
-
Reduced hippocampal volume
-
Reduced subgenual ACC volume
-
Enlarged, overactive amygdala
-
Reduce orbital/VMPFC, anterior cingulate cortex, hippocampus, DLPFC
-
Neurochemical:
Increase: cortisol, cytokines
-
Decrease: BDNF, 5-HT, NA
-
Necessary conditions for claiming causality
Temporal precedence
If A causes B, we must show that A occurs in time before B
○
-
Correlation
A must be correlated with B
○
-
Rule out 3rd variables
Height and computer skills
○
-
Spurious correlation: have to manipulate things in order to measure otherwise the variables
are non sense
Competing theories
-Monoamine deficiency hypothesis
○Mostly serotonergic focus
○Evidence is very mixed
-HPA-dysregulation hypothesis
○Chronic stress causes hippocampal volume reductions and a cascade of other
events (e.g. PFC dysregulation, VTA-NAc disruptions)
○Also has converse effects in amygdala resulting in hyperactivity and hypertrophy
and corresponds to negative affect
Genetic contributions
-ADRA2B polymorphism
○ADRA2b deletion carriers: more vivid emotional memory for negative stimuli
§Better recall for emotional stimuli
§Linked with PTSD
-Serotonin transporter gene (5-HTTLPR)
○2 short alleles -> more likely to get depression
○Long -> higher 5-HTT
○Short -> lower 5-HTT
Not just genes!
-Phenotype = genotype + environment + GxE
-Depression = 5-HTTLPR + environment + GxE
Not 1 to 1!
-Tiny effect sizes
Chanllenges
-Genes too far from phenotype
-A lot of genes (30000+) = large computations
-Small effect of single genes
-Multiple comparison
-Gene-gene interactions
-Gene-environment interaction
-Disease definition? Misdiagnosis?
Hippocampal neurogenesis
-Depression is increasingly seen as a stress disorder
-Glucocorticoid dysregulation from chronic stress causes dendritic retraction in
hippocampus
○Metabolic neurotoxicity
○Reversible with psychotherapy, drugs and exercise
-Hippocampus exerts control over HPA
VTA-Nac dysregulation
-Angedonia and decreased motivation are core features of depression
-VTA-Nac receive many glutamateric connections from frontal cortices, hippocampus,
amygdala, hypothalamys
-Acute stress increases DA activation in VTA and Nac, but over time compensatory
mechanisms activate leading to down-regulation of DA neurons
-Chronic stress exhibits effects on Nac circuitry and function by reducing tonic DA
release
-Decreased DA-VTA activation related to immobility in forced swim test
Neuroinflammation
-People with depression show more pro-inflammatory cytokines in their blood and CSF
-People with more pro-inflammatory cytokines experience
-Increased anxiety and depression and symptom severity correlated with increased
peripheral inflammatory blood markers
-Psychosocial stress has been shown to initiate various inflammatory pathways
throughout the body and the brain
Inflammation effects
-Myelination
Interpretations?
-Depression is related to chronic stress and dysregulated HPA-axis that causes many
deleterious effects
-Might these widespread change be an adaptive response to stop the damage of long-
term elevated glucocorticoid levels
Cognitive maintenance
-Rumination
○Reflective ponding: more problem solving focused
○Brooding: obsessive repetition and focus of negative thoughts and feelings
-Working through the feelings and thoughts in a reflective way can help resolves
depressive episodes
-Hyperactivity of MPFC (self narrative thinking) and Anterior cingulate cortex (detecting
errors) in depressed patients and depression severity correlated with MPFC, ACC &
amygdala functional connectivity (ruminative network, negative self-referential
thought)
Diathesis Stress Model ( a biopsychosocial model)
-Diathesis is a vulnerability
-Focuses on risk factors related to genetics, early experience, coping mechanisms and
environment to understand how mental illness arises
Risk factors
-Prenatal development
-Childhood trauma
-Genetics
-Traumatic brain injury TBI
-Chemical imbalances (e.g. substance abuse, diet, sleep)
-Life events (extreme poverty)
Psychiatric epidemiology
-World health organization
-Anxiety most prevalent followed by depression
-US has highest overall mental illness prevalence rates
-These numbers are increasing world wide (especially for depression & anxiety)
Psychiatric medication
-Billions in revenue in North America
-Some are addictive, long-lasting side effects, withdrawal symptoms (not well studied)
-Efficacy is questionable for many, long-term risk
○Antipsychotics cause diabetes, metabolic syndrome, gray matter volume
reductions, risk of Alzheimer's with anxiolytics
Psychiatric medication
-Direct-to-consumer advertising
-Drug cocktails (mix drugs for different functions)
-Treating the side effects
-Long-term effects
-Treating children
○We have no idea what these do long-term or to the developing brain
Heritability
-Depression is about 37%-50% heritable
-Schizophrenia, bipolar disorder and Parkinson's disease estimated 80% heritable
-Twin studies are flawed, inflates genetic influence
○Not random, environment too similar
-Missing heritability problem; individual genes do not account for much of the
heritability in diseases, behaviours or phenotypes
Problem with diagnostics
-The issue of emergence from complex processes
-Imagine studying and trying to understand everything possible about the members of
Nirvana in the hope of understanding how their music was create
-This whole is greater than the sum of its parts, reductionism fails
-Interaction effects and bidirectional causation (e.g. gene X environment, epigenetics)
-Depression isn't a unitary disorder or state, huge overlap b/w anxiety, panic disorders,
instances of trauma
-Different "biotypes": based on resting state functional connectivity, not related to
differences in symptoms
Treatment is suboptimal
-Antidepressants work within 4 months in 60 of people however symptoms return after
cessation
-Cognitive behavioural therapy (CBT) has similar recovery rates but the relapse is slower
than with drugs. Same holds for anxiety
-Only short-term antidepressant use is effective and only for serious depression
-Increased suicidal ideation especially in kids
-Many people cannot quit taking them due to withdrawal effects (not well studied)
Why is efficacy so low for antidepressants?
-No good evidence of chemical imbalance or reliable biotypes
-Systematic bias in clinical trials
○Inflated effect sizes in published trials 9clinical vs. statistical significance)
○Publication bias of positive trials
§Newer drugs with patents have bigger effect sizes
-Antidepressants are crude in their effects
-Symptom management vs. disease treatment
-Etiology matters
Biomedical vs. Social models
-Biological psychiatry has focused on a medical model of mental illness
○Chemical imbalance hypotheses, neuroanatomical anomalies
-Social models focus more on the environmental determinants of mental illness
○Stress, trauma, childhood
Prevention vs. treatment
-More than half of adults with mental illness present with symptoms in adolescence
and childhood
-The biggest predictor of well-being in adulthood is childhood emotional health and
stability
-Early intervention is vital to preventing mental illness in adulthood
○Train parents and educators, teach emotional management
Onset of depression
-Life adversity
○90% severe adverse life events before depressive episode
○Social adversity and depression found worldwide
-Loss of role: social disruptions and lack of social support
-Failure of achievement: work and autonomy more important
-Gene X environment interactions: biological, developmental, psychological and
sociodemographic factors
What determines well-being?
-Once basic needs are met, many things come into play
○Family & friendship
○Health
○Work
○Emotional resiliency
○Meaning
-Proposed 3 components: life satisfaction, positive affect and a lack of negative affect
○Set point: genetic baseline that regulates personality and temperament
§Circumstances: gender, martial status, income, cultural background
§Activities: what you choose to do with your time. Family, friends,
hobbies.
The malady of culture
-We evolved in small tribes and now live in massive communities based on societies
governed by collective values called culture
-We are an extraordinary adaptive species, but there are limits
-We're overworked and stressed, bleak future outlook, global warming
-The dominant culture does not support qualities that result in general well-being (I,e,
connectedness, strong sense of meaning)
-What does popular North American Culture value?
○The influence of capitalism
§Money, youth, sex, power, status
Social connectedness deteriorates
Culture of self-blame
Culture of stigma
-Mental illness is highly stigmatized
○Exceptionalism, personal responsibility
-Focus on endogenous cause
-People cannot afford help
○Psychiatrists vs. psychologists vs. social workers vs. counselling psychologists
-Much harder to make a good living
-Fewer well-paying jobs, gig economy
We ignore the environment
-Understanding the environmental influences of mental illness is vital
-Early interventions
-Less cost of burden
-Less reliance on medication
-Reduction of recurrent episodes
-Will allow for preventative measures (e.g. self-care)
Self- care
-Eating well
-Sleep
-Exercise
-Healthy social interaction
-Mindfulness
-Meaning
Altering emotions
Temporary change Long-term change
-Cognitive reappraisal - particular
situation
-Distraction / avoidance
-Mind/ mood altering substances
-Cognitive reappraisal - of emotional experience
itself
-Therapy
-Mindfulness medication
Mindfulness
-Focus on interoceptive awareness; sustained attention to bodily sensations
-Differs from cognitive reappraisal, which relies on memory and evaluation to re-
interpret negative experiences
-Meta analysis showed that mindfulness-based therapy reduced depression and anxiety
symptoms
○Coming into the present moment to really experience what's here
○Training attention (executive function)
○Awareness of bodily sensations
○Awareness of emotions (labeling)
○Awareness of thoughts
○Ability to stay with difficult emotions /sensations
Epigenetics!!!
Gene A ≠ Disease A
Lecture 9
Monday, June 11, 2018 6:13 PM
Document Summary
Normal people might be quantitively different than abnormal people. Mental disorders are not meaningfully distinct in kind from physical disease. Biological treatment should be predominantly considered and applied. One of the most prevalent mental illness diagnoses. Psychomotor retardation (slowing in movements and speech, cognitive ability) To be diagnosed, need to have minimum symptom duration and number. Do the symptoms map onto a specific mental illness category (e. g. depression, schizophrenia, anxiety) Symptoms alone rarely indicate the best course of treatment. The categorical approach (dsm) uses minimum symptom presence and duration for diagnostic criteria. A mental disorder can be diagnosed from specific symptoms that are shown during a mental health assessment during a mental health assessment. Thoughts, feelings and behaviour can be organized into categories representing discrete disorders. All or nothing principle; you have it or you don"t. Pros: easy to use across many different settings and practitioners. The dimensional approach quantifies a person"s symptoms on a continuum, no categories.
