Lecture 3 (chapter 6) Flashcards
MDD & BD
Behavioural Genetics:
• Using genetics to understand behavioural
differences
• People originally thought nurture,
socialization in the first few years of life, was
the most important cause for individual
differences.
• However, we now know that DNA (genetic)
differences between individuals accounts
for 50% of this variability. This is bigger than
the effects of psychology combined
(nurture/environment).
• Everything is heritable in biology and
behaviour!
• Twin studies loo at biology are a social
experiment
• There is an interaction between
environment and genetics.
• 99% of all our DNA is all the same in
humans. We are asking, to what extent does
this 1% influence behavioural variation? We
are looking at differences and not trying to
find universal behavioural laws like
psychologists do.
• It is no longer interesting to ask is it
heritable. We know it is. We go beyond this
now to ask how it links to developmental
disorders and pathology, interplay between
gene-environment as they effect
development, which specific genes are
involved (molecular biology).
• DNA is the best predictive tool to identify
problems, intervene early and prevent
problems. More cost effective for individuals
and society. Make individual predictions
about genetic risk/vulnerability and
resilience/protective.
Diagnostic Criteria
• DSM-5: Requires a 2-week period where five of the following symptoms are present most of the day, nearly every day o Depressed mood (may be an irritable mood in children) o Loss of interest or pleasure o Increased or decreased appetite (not hungry at all then binge eat) o Insomnia or hypersomnia (can’t fall asleep or stay asleep) o Psychomotor agitation or retardation o Loss of energy o Excessive guilt (burden) o Decreased concentration o Suicidal thoughts (escape)
*Must reach clinical significance! significant
prolonged changes in their behaviour which
causes significant distress and disrupts their
daily functioning.
Prevalence
• 16.1 million adults aged 18 or older (6.7%) in
the United States have had at least one
episode of major depressive disorder in
the past year (2015)
• Prevalence rates among individuals
between 18 and 29 years of age are three
times higher than those 60 years and older
• Females experience a 1.5–3 times higher
rate of major depressive disorder
compared to males
o Onset increases markedly during puberty
• Common comorbid conditions: Anxiety and
substance use disorders
Multicultural Findings
• Depression rates have increased among
whites relative to other ethnic groups
(2017)
• Depressive disorder is elevated in sexual
minority youth in comparison to
heterosexual young people
• Racial and ethnic minorities in the United
States experiencing depression are also
less likely to receive appropriate
intervention and care
• Differences exist among ethnic populations
with respect to genes that encode
enzymes involved in the metabolism of
psychotropic medications
• culture specific differences in symptoms
can lead to under or misdiagnosis od
depression and are less likely to receive
appropriate care
*More likely to have it or is it more likely to
be diagnosed because they have access to
health care? Minorites are at higher risk of
suicide: being bullied, told you’re going to
hell, or worthless it increases risk of
developing MDD. There is a combination of
genetic and social factors which interact to
contribute to risk of MDD.
Economy (Burden of MDD)
• Depression is the leading cause of
disability among adults under the age of 45
(can get government welfare benefits
because you cannot keep a stable job; why
would this be more common at this age in
general? What factors are contributing to
this?)
• Studies have reported that individuals
suffering from major depression are more
likely to report a poorer quality of life
during early, middle, and later adulthood.
Suicide (MDD)
• individuals with major depression are at
greater risk for attempting suicide
• Rate of suicide twice as high in families of
suicide victims
• Suicidal behavior is mediated by familial
transmission (2x increased risk if family
member commits suicide), but impulsive,
aggressive tendencies are the most
powerful predictors of suicide attempts
(genetically influenced traits)
*Important concern in NZ, higher in ethnic minorities & males. NZ has the highest rate of 18- year-old suicide in the developing world. Why?
Development of MDD
Development
• Incidence is similar among boys and girls
prior to puberty, after which depression
rates are higher in females
o Suggesting that endocrine processes, such
as higher cortisol levels may be associated
with depression in adolescents (something
more common in females after puberty
starts; hormonal changes; gives us a place
to start and try to understand pathology)
• Personal disappointment is associated with
persistent depression in adolescents
o Adverse life events may result in a
hypersecretion of cortisol, which may lead
to memory distortions and cognitive
rumination
• Childhood depression is associated with
poor psychosocial and academic outcome
(not intelligence; it’s motivation, utility value
and self-efficacy beliefs that prohibit people
from success)
• adolescence experience periods of
remission but 53% relapse & 79% have a
comorbid diagnosis
• Children suffering from depression are
more likely to be bullied, and bullying can
induce depression in children without a
prior history of depression
• Juvenile offenders in the USA, particularly
female juvenile offenders, are at elevated
risk for depression
• Developmental Findings
• In 2017, 26% (1 in 4) of adults 65 and older
admitted to nursing home facilities in the
United States had an active diagnosis of
major depressive disorder
• The majority were white women
*Individuals’ external life experiences
(environment) induces stress responses in
the brain, which changes neuron firing
(communication), hormone secretion
(increase or decrease) and changes it
physiology which can result in MDD.
*Collectively, these findings suggest that the
nature of depression differs in children and
adults
*Physiological and neuropsychological studies have found an increased risk of subcortical vascular disease in those over 65 who suffer from depression
*What is the difference in living styles
between women from other ethnic minority
groups? Why would this be higher in older
white women? Is it genes or gene-
environment interaction?
Late onset depression (65+) is associated with:
• reductions in grey and white matter,
• reductions in CSF
• comorbidity of AD, PD, diabetes,
multiple sclerosis, and stroke
• increased mortality risk in both genders
and all age groups.
Genetics MDD
• Sample of 3,416 female adolescent twins
revealed a genetic risk of 40.4% for major
depression (2003)
• first degree relatives with MDD have double
the risk
• Major depression in parents significantly
increases the risk for depression as well as
other psychiatric disorders (we do not know
which gene[s] it is!)
• Having parents with MDD had higher
persistence of MDD, more depressive
episodes, higher social impairment,
increased rates of seeking treatment (equal
risk between one or both parents having
MDD)
• Identification of specific genes implicated in
the development of depression remains
controversial
• Despite the controversy we know that
genetics plays a role in depression
• chromosomes 3p, 12q, 15q, 18q, 1p, 17p and
8p linked to MDD (but highly unreplicable
due to variations in sample size,
comorbidity, severity of symptoms,
heterogeneity of symptoms, low statistical
power etc.)
*Collectively, family and twin studies indicate
that genetic factors mediate part of the
vulnerability to depression
*gene’s increase risk of MDD but it doesn’t
explain all of it! We do not understand which
genes it is. There is a complex interaction
between gene-environment so it’s hard to
give them a treatment which will actually
help them (need medication which will
change brain physiology and not just
cognitive-behavioural therapy).
*Historically treatment of depression has
been trial and error (electroshock,
medication, lobotomy) which we use to
develop hypothesis on what could be
causing depression (i.e., genetic, serotonin is
a major factor; give drug to increase
serotonin levels in the brain can reduce
symptoms, gene in charge of serotonin
receptors/reuptake into cell etc. this is the
process researchers do to try and identify a
treatment and then do clinical trials on
animals)
Genes that play a role in the…
• Production and regulation of transporter
proteins involved in reuptake of
neurotransmitters
• Production of enzymes that breakdown
neurotransmitters
• Synthesis of monoamine neurotransmitters
previously implicated in depression
• Production and functioning of
neurotransmitters receptors
• 200 genes have been linked to MDD (not
helpful)
*Have been investigated. Synapse – is the
key, if they work abnormally disease
develops. Dysfunctional neurotransmitter receptors which produce too much or too little molecules leads to abnormal behaviour like MDD.
Serotonin Transporter Gene (SERT)
MDD
• Serotonin has been implicated in
depression
• Serotonin transporter protein
(SERT/SLC6A4) plays a key role in reuptake
of serotonin from the synaptic cleft
(reabsorption of the neurotransmitter from
synaptic cleft into the pre synapse stops its
effect in the post synapse; stops the
beneficial effects of serotonin on the brain)
• Variations in SERT availability affect levels
of serotonin in the extracellular fluid (too
much or too little; abnormal serotonin levels
mean that MDD is at risk of developing)
• SERT availability is reduced in those with
depression (controversial finding)
• SERT is linked to other disorders such as
anxiety, OCD, Autism, PTSD, and
schizophrenia.
*Although preliminary findings suggest a role
for the SERT gene in major depressive
disorder, findings across studies have been
inconsistent, and future studies are
warranted
*There is NO simple reason to identify a
cause of MDD and treatment of MDD. We
do not know what location it occurs in the
brain. All we have is serotonin (Parkinson’s
& Alzheimer’s was easy to explain genes
liked to pathology but hard to treat). It’s
so hard because there is so much variability
in MDD symptom presentation & research
findings. It’s not a single cause! There is a
complex combination between gene-
environment which is making it hard to find
a specific pathological cause and multiple
regions in the brain are involved, more than
one gene. No single gene is sufficient to
produce MDD.
COMT (catechol-O-methyltransferasae) Gene
MDD
• Extracellular enzyme that breaks down dopamine, epinephrine, and norepinephrine into inactive metabolites, and is encoded by the COMT gene • Individuals with the COMT Val-allele mutation have higher COMT activity and lower levels of dopamine compared to individuals without this polymorphism (controversial)
*Therefore, “Despite the significant amount
of work and the sophisticated technology, it
is not fully elucidated which genes or
regions of nuclear or mitochondrial DNA, or
else, which types of genetic changes, alone
or in combination, can represent reliable
genetic markers of anxiety and/or
depression” No conclusive findings, mixed.
Multiple genes and not one simple cause.
It’s complicated!
TPH Gene and 5-HT Receptor Gene
MDD
• Function: biosynthesis of neurotransmitters
such as serotonin (production)
• Serotonin is synthesized from tryptophan by
5HTP (5-hydroxytryptophan; always linked
with serotonin) and TPH (tryptophan
hydroxylase) on chromosome 11
• Researchers have suggested that stress
may affect TPH gene functioning
*Rats exposed to high levels of stress have lower levels of serotonin and TPH expression
Neurotransmitter Receptor Genes - reduced density of \_\_\_ receptors Nicotinic Receptor Genes - smoking, --- receptors and --- release Glutamate Receptors - are --creased
MDD
• Studies of presynaptic and postsynaptic
serotonin receptors have been
inconclusive (not enough molecules or
receptors?)
• Postmortem brains of depressed suicide
victims have a lower density and structural
abnormalities in the GABA receptor (may
explain treatment resistance or women’s
higher risk of MDD)
Nicotinic Receptor Genes
• Individuals with depression are more likely
to smoke cigarettes (behaviour) than the
general population
• A specific gene variant for the nicotinic
acetylcholine receptors (alpha7 nAChR) is
associated with major depression (are they
missing nicotine receptors? low levels of
nicotine so smoke to increase dopamine)
*Researchers who have spent their whole life
studying MDD and cannot find a solution
*Specifically, for psychology/educational
identifying people’s behaviour in MDD is a
good clue
*Mixed findings on nicotine’s involvement in
MDD
Glutamate Receptors
• Greater frequency of the GRIK4 glutamate
receptor gene in individuals with depression
compared to controls (i.e., postmortem
studies show higher frequency of these
receptors with MDD)
• These findings suggest that variants in
glutamate and GABA genes may increase
the risk of developing depression
Genome-wide association studies (GWAS)
Two genes are ___ and ___ linked to….
MDD
Genome-wide association studies (GWAS)
• Complete sets of DNA of thousands of
people simultaneously compared to find
genetic variations associated with a
particular disease or disorder (sequence
DNA)
• 10,000 Chinese women with and without
severe recurrent major depressive disorder
implicated the SIRT1 gene and the LHPP
gene
o SIRT1 is involved in the biogenesis of
mitochondria
o LHPP involved in cell metabolism (effects
resting brain acitivity)
*Look at lots of people’s gene to identify
differences in DNA which are liked with
MDD
*MDD influences everything! The serotonin,
nicotine, glutamate, gamma, mitochondria,
metabolism etc. this doesn’t help anybody.
There is no clear answer, theory, diagnosis,
or treatment to help children in education
who may have MDD.
*“The next challenge is to establish the
molecular mechanisms by which GWAS loci
mediate their effects and translate these
into much-needed new biomarkers and
therapeutic targets”
*identifying genes doesn’t tell us their causal
mechanism in increasing risk of MDD
Summary Genetics and Depression
Summary Genetics and Depression
• Although a number of genes and gene
variants have been associated with major
depression, linkage, association, and
candidate gene studies have not found
evidence of a “depression gene”
• No single gene is necessary and sufficient
for major depressive disorder
• Each susceptibility gene contributes a
small fraction of the total genetic risk
*Depression is likely the result of combined
risk factors that may interact with multiple
genes
Monoamine Theory and Depletion Studies
Monoamine Theory and Depletion Studies
• Patients with hypertension develop
depression after being treated with the
drug Reserpine
o Reserpine blocks the monoamine
transporter and prevents storage of
neurotransmitters (dopamine,
norepinephrine, serotonin)
o Consequently, less neurotransmitter is
available for release
• Increase in monoamine metabolites
following antidepressant treatment
• Decreased levels of serotonin metabolites
in the cerebral spinal fluid of individuals
with depression
*Collectively, these findings lead to the
monoamine theory of depression, which
predicts that depression is due to reduced
levels of monoamines involving serotonin,
dopamine, and norepinephrine
Catecholamine Depletion Studies
Catecholamine Depletion Studies
• Current perspectives reject the simplicity of
the monoamine theory
o If monoamine levels are directly related to
depression, then altering levels should
reliably affect mood
o Lowering levels would be expected to
induce depression
*Contrary to these expectations,
pharmacological agents that deplete
serotonin and norepinephrine levels do not
induce depression in healthy individuals
(more likely to lower mood in women than
men)
• Given that depression is not induced in
healthy individuals following depletion,
monoamines may play a modulatory role in
depression rather than a primary role
o Depressed individuals respond to different
types of antidepressants that target
different neurotransmitter systems
(serotonin versus norepinephrine)
o Depression may have multiple origins or at
least multiple mechanisms for attenuating
symptoms
Structural Findings
Structural Findings • Decreased hippocampal volumes • Decreased amygdala volumes (controversial) o A reduced core volume of the amygdala may have widespread implications for emotional aspects of memory, attention, and perception and emotion.
*Some people say it may not be at the
molecular/cellular level but at the structural
level. Brain imaging studies looking at the
structural differences between HC and
MDD.
*Controversial means mixed findings
Structural Differences have also been reported in the:
• Hypothalamus
• Cerebellum
• Frontal regions (anterior cingulate and
orbitofrontal cortex)
• Putamen
• Caudate nucleus
• ventricle and sulci enlargement
*This is ¾ of the brain, no specific location!
*Found in other disorders such as bipolar,
schizophrenia, anorexia nervosa, alcoholism,
AD and ASD
“Significant alterations in brain regions within a brain network presiding over emotion recognition and evaluation, including amygdala, hippocampus, insula and prefrontal cortex”
Structural Findings Across Clinical Groups
Structural Findings Across Clinical Groups • Reduced volume of the hypothalamus although found in individuals with depression have also been found in individuals with bipolar disorder, schizophrenia, autism, and Alzheimer’s disease o Difficult to interpret!
*It’s hard to make sense of the mixed,
overlapping findings, too much to interpret
and find unifying theory and effective
treatment.
structural
Transporter Proteins and Receptors
Serotonin is involved because most effective depression treatment are ___ which are serotonin ___
Do children or adults have more SERT?
SERT declines with ___
Serotonin autoreceptor abnormalities lead to dsyregulation in ___ of serotonin
Transporter Proteins and Receptors
• Serotonin reuptake inhibitors (SSRIs)
o Increase serotonin levels in the synaptic
cleft
o Most prescribed and effective
antidepressant drugs
o children have higher serotonin transporter
in the midbrain than children without MDD
o reduced SERT in limbic system
(correlational but not casual finding)
• Binding potential of serotonin transporter
declines 4.2% per decade in healthy
subjects (18–88 years)
• Age-related declines in serotonin
transporter binding might explain the poor
response to SSRIs observed in some adult
and elderly patients with depression
• Abnormal functioning (and reduction) of
serotonin autoreceptors
o Autoreceptors play a critical role in
detecting the presence of serotonin in the
extracellular fluid and triggering the
presynaptic neuron to alter release of the
neurotransmitter
o 42% reduced 5-HT1A binding in midbrain
raphe and 25-33% reduction in limbic and
cortical region
*Measures of serotonin transporter binding
sites in individuals with depression have
been mixed! reduced serotonin density is
not unique to MDD, it’s also present in
schizophrenia. correlation does not equal
causation.
Functional Findings
3x studies
Findings are __ and ___ in nature
Is a single brain region involved in MDD?
Functional Findings
• Increased and decreased metabolism in
various brain regions of individuals with
depression have been reported
o Prefrontal and limbic regions
• Reduced connectivity between frontal and
parietal regions (hypoconnectivity)
• Increased connectivity between regions of
the brain implicated in affective decision-
making and self-referential thinking
(hyperconnectivity)
• Regional cerebral blood flow is significantly
lower in patients with major depression
relative to controls in the right anterior
frontal cortex, temporal cortex, thalamus,
and putamen (controversial)
• Reduction of blood flow in the primary
motor cortex
*Do dysfunctional networks result in
depression symptoms or do depression
symptoms result in observed differences in
connectivity? (Chicken or the egg)
*Cerebral blood flow of the right primary
motor cortex is a potential biomarker of
psychomotor retardation in major depressive
disorder
Study (1)
• 30 adults with major depression,
• 30 patients with Alzheimer’s disease
• 30 normal controls
o The two clinical groups showed reduced
global blood flow in different regions
§ Depression (prefrontal)
§ Alzheimer’s (parieto-temporal)
Study (2) PET
• Participants: Depression, OCD, or both
• Treated with a serotonin reuptake
inhibitor (paroxetine) and pre- and post-
antidepressant scans were compared
o Individuals with OCD who showed
increased activity in the right caudate
responded better to antidepressants
o Those with major depression who
showed reduced activity in the right
amygdala and increased activity in the
prefrontal region responded better to
antidepressants
Study (3)
• Brain changes recorded during
provocation of sadness, or presentation
of affective and neutral visual stimuli in
individuals with and without depression
• Those with major depression show
greater activation in the visual cortex
and less activation in the left prefrontal
cortex in response to negative versus
neutral stimuli
o Participants with depression who are
treated with antidepressants showed
significant increases in various brain
regions after two weeks
“No single brain region is solely implicated in major depressive disorder; rather, the
disorder appears to involve multiple large scan networks distributed throughout the brain. Specifics regarding these networks and how differences in these networks manifest as depression symptoms, however, are lacking”
Additional Etiologic Areas of Research
• Cerebrovascular diseases
• Endocrine system
• Immune system (abnormal autoimmune
receptors linked to neurotransmitter
receptor functioning in the HPA)
• Neurotrophins
• Omega 3 fatty acids
• Diet
• Lifestyle behaviors (exercises increase
BDNF & neuroplasticity; stress triggers
inflammatory response and reduces
levels of tryptophan which synthesizes
serotonin)
Antidepressants:
Brain Imaging of Placebo vs. Antidepressants
Antidepressants:
• According to the American Psychiatric
Association, most patients respond to
antidepressant treatment and many show
improvement with combinations of
antidepressants (controversial)
o Recently, the effectiveness of
antidepressants relative to placebo in
cases of mild depression have revealed
minimal benefits in adults not children
Brain Imaging of Placebo vs. Antidepressants
• Similar pattern of brain activation occurred
in both those taking the drug and those
taking a placebo
o Additional areas are activated in those
taking the antidepressant which has been
linked to their therapeutic effect
Demographics and stats
• 64% increase in the percentage of people
using antidepressants between 1999 and
2014
• 1 in 8 individuals age 12 and older reported
taking antidepressants in the past month
• 1 in 4 indicated they have taken
antidepressants for 10 or more years
• Females are twice as likely as males to
take antidepressants in all age groups
• Highest percentage (16.6%) are used by
people age 40-59
• White Americans take antidepressants
three times as much as any other race or
ethnic group
• Antidepressant use has increased among
children
*Concerns over the use of antidepressants
with this population given the unknown
long-term structural and cellular side effects
of antidepressants! do not know if it effects
children’s brain development
Exercise
Exercise
• Increases serotonin levels in the brain
• Effective at improving depression
symptoms
• Augment antidepressant treatment
*However, exercise is not more effective than
psychotherapy or pharmacological
interventions at improving symptoms of
major depressive disorder
