Lecture 1: Panic Disorder and OCD Flashcards
Anxiety Disorder and Obsessive-Compulsive Disorder
How much do we know?
*The answer for MDD is shit, BPD is shitter
and anxiety, and OCD are even worse. We
do not know what happens in the brain or
what causes it! The biochemistry, cognitive,
and neuroscience is abysmal, but we have
an okay psychological understanding of its
behavioural manifestation.
Anxiety Disorder definition
• Anxiety disorders share symptoms of
feelings of excessive fear, anxiety, and
changes in behavior
• fear = the emotional response to real or
perceived imminent threat” (both illicit the
same level of fear; physiological symptoms
of fear such as increased heart rate,
adrenaline, sweating, hard to breath etc.
during presentation and when see a lion
are the same)
• anxiety = anticipation of future threat
8 Anxiety Disorder Types
• Separation anxiety disorder (anxiety when
separated from loved one)
• Selective mutism
• Specific phobia (spider, clowns, snakes,
heights, hole s – irrational fear to things that
rationally could cause harm)
• Social anxiety disorder (i.e., fear of being
judged, not worthy, crowds etc.)
• Panic disorder & OCD (today’s lecture)
• Agoraphobia (don’t leave home)
• GAD (generalized anxiety disorder, anxious
about everything)
• Substance/medication-induced anxiety
disorder
• Anxiety disorders are distinguished by
developmental factors as well as the
situations that induce fear, anxiety, and
avoidant behaviors
Does Worrying Affect Mortality Risk?
• Gale et al. (date) examined the association
between neuroticism & mortality, and the
moderating influence of self-rated health.
• Neuroticism – the tendency to experience
negative emotions.
• Results revealed:
o higher neuroticism was associated with 6%
increase in mortality risk
o neuroticism scores tended to be lower with
increasing age
o neuroticism scores were positively
correlated with smoking and drinking
alcohol daily or nearly daily
o among people who rated their health as
poor or fair, higher neuroticism was
associated with a reduced mortality from
all causes, but such effect was not
observed in participants with excellent self-
rated health.
• Therefore, certain personality facets of
neuroticism may actually serve as a
protective factor against death
• Does Excessive Worrying Affect Mortality
Risk?
o Yes and no. it depends on your neuroticism
(high/low, what it’s linked to)
o If you are neurotic about your appearance
or body weight it can have beneficial
impacts and healthy lifestyles. Other forms
can negatively impact, psychological fear
creates physiological stress on heart/lungs
etc. which led to increased mortality risk.
Panic Disorder is characterized by… peaks within.. for these symptoms
• Characterized by the presence of recurrent
and unexpected panic attacks
(distinguishing feature)
• Panic attack is “an abrupt surge of intense
fear or intense discomfort that reaches a
peak within minutes and during which time
four or more additional symptoms occur”
• Additional symptoms include:
o Increased heart rate or palpitations
o Sweating
o Trembling (legs, hands, body)
o Chest discomfort (tightness, trouble
breathing, hyperventilating)
o Dizziness
o Fear of losing control
o Fear of dying
• Individuals with panic disorder worry about
additional panic attacks occurring and
substantially alter their behaviour to try to
avoid experiencing another panic attack.
• The frequency and severity of panic attacks
vary widely among individuals.
• Panic attacks hit you like a freight train, the
uncontrollable fear is debilitating, people
feel like they’re dying and pass out.
• No trigger required
• In most cases, the adaptive response to a
fearful stimulus (i.e., snake) would be to
away from it (flight response). A panic attack
is somewhere in between a fight or flight
response, if you have a panic attack in class
(in his example I don’t fully agree with) you
wouldn’t leave or attack the snake, you will
freeze and collapse in fear
Panic Disorder Stats
• In the United States the rate is between 2-
3%
• The disorder occurs more often in females
than males with a ratio of approximately 2:1
• Higher rates are found among
postmenopausal women
• Median age of onset between 20 and 24
years (i.e., between adolescence and
adulthood)
*hints to the role of hormones in panic
disorder
Multicultural Findings
• African Americans, Latinos, and Asian
Americans have reported lower rates of
panic disorder compared to non-Latino
whites
• Higher rates of panic disorder among gay,
lesbian, and bisexual adults in the United
States (i.e., similar to MDD where
environmental factors of bullying)
• European countries report similar prevalence
rates as the USA, while lower rates have
been reported in Latin America, Asia, Africa,
and India
*Again, we see that the prevalence is lower in
ethnic minorities than whites. Is this
biological, low ses or cultural differences in
presentation/understanding of disease, or
access to health care?
*Cultural, genetic, environmental factors!
Comorbidity
Panic disorder
• Commonly cooccurs with other
clinical/psychiatric:
o GAD
o Simple phobias
o Social phobia
o Substance abuse (drink to cope with
anxiety)
o Major depressive disorder
o Bipolar disorder
• Commonly cooccurs with chronic medical
conditions:
o Cardiovascular disease
o Hypertension
o Pulmonary disease
o Lipid disorders
o Asthma
*Panic attacks rarely occur in isolation. They
are usually tied to another condition.
*Psychological disorders associated with
panic attacks and their negative
physiological issues.
(3) Genetic Study Types
• Genetic linkage studies search for
chromosomal locations (“marker loci”)
where disease genes may be found. Aim to
determine whether specific chromosomal
regions in individuals with disease have
specific DNA markers relative to those
without the disorder.
• Candidate gene studies then explore how
specific genes and mutation(s) may be
involved in the etiology of clinical disorder
• Genome-wide association studies (GWAS)
use a specific statistical approach to scan
complete sets of DNA (genomes) of
thousands of people across all
chromosomes simultaneously to find
genetic variations associated with clinical
disorder
Heritability: Family and Twin Findings
Panic disorder
• Heritability estimates in female twins
between 20-30%
• 20 monozygotic and 29 dizygotic twins
o Panic disorder in monozygotic twins
relative to dizygotic twins is 2:1
• Population-based lifetime rates of panic
disorder range from 1.2 - 2.4 (out of 100),
while lifetime rates for first-degree relatives
of those with panic disorder were
substantially higher 7.7 – 20.5 (out of 100)
• Genetic factors likely contribute to the
development of panic disorder (highly
genetic; 0.48)
Linkage Studies and Candidate Genes
• Genetic linkage studies search for
chromosomal locations (“marker loci”)
where disease genes may be found. Aim to
determine whether specific chromosomal
regions in individuals with disease have
specific DNA markers relative to those
without the disorder.
• Susceptibility genes involve chromosomes
2, 4, 7, 10, 13, 15, 17, and 18
• Mixed findings, those that found no link
between single nucleotide polymorphisms
(SNPs) suggest that linkage studies are not
sensitive enough to capture the small
genetic effects which underlie complex
disorders like panic disorder.
• To date, linkage studies have not supported
main effects of and particular gene or
combination of genes on the development
of panic disorder. However, given that
heritability data do suggest that genetic
factors are involved it is likely that genetic
contributions to the disorder are complex.
*We know genes are involved but we have
not identified one anxiety gene, multiple are
involved and likely interact
Candidate Genes (try to identify specific genes) and Genome-Wide Association Studies
• Candidate gene studies then explore how
specific genes, polymorphisms and
mutation(s) may be involved in the etiology
of panic disorder. Identify genes piori that
may be linked to PD and compare patients
to healthy controls to see if they are
present.
• Candidate gene studies have focused on
genes involved in neurotransmission.
Specifically, genes that play a role in the:
o Production of enzymes that breakdown
neurotransmitters, particularly
catecholamines
o Functioning of pre- and postsynaptic
neurotransmitter receptors (e.g., serotonin,
norepinephrine, dopamine; release or
binding to receptors)
o Production and functioning of
neuromodulators, all have been the target
of candidate gene studies
*Abnormal release or binding of
neurotransmitters between pre to post-synaptic neuron create neurotransmitter
imbalances and result in mental disorders.
*We can look at the genes linked to the
production of, receptors they bind to or
enzymes that break them down of serotonin,
norepinephrine, dopamine
neurotransmitters. We know to look at these
specific molecules because treatments of
antipsychotics or SSRIs which target
them have successfully treated panic
disorders.
*Look at genes to find the answer, best
approach we have. The problem with this
logic is that the process of neurotransmitter
release/reuptake is not a linear system; a
small change in neurotransmitter can have a
large effect on adrenaline, we will never
fully. Understand each piece of the puzzle,
just a wider picture of what is happens. We
can treat with medication but do not
understand the biochemistry or
consequences of it in the brain.
Catechol-O-methyltransferase (COMT) Gene
• Genes involved in the regulation of the
catecholaminergic system have been
investigated because the somatic
symptoms of anxiety are closely linked to
the activation of the sympathetic nervous
system and release of catecholamines (i.e.,
COMT polymorphisms like Val158Met).
• Enzyme that breaks down catecholamines
and, if over or underactive, can lead to
dysfunction of neurotransmitter systems
such as dopamine, norepinephrine, and
serotonin
• Implicated in panic disorder
• Mixed findings in Val158Met (i.e., some
show it is increased in women with PD and
not men, found in 19.6% of those with PD
and 2.2% of HCs, found no association
between Val158Met and PD, Val158Met
only linked to PD in Caucasian females
only)
• COMT Val158Met polymorphism may be a
vulnerability factor in select populations
only.
• It has been postulated that COMT
Val158Met polymorphism is linked to PD is
that it affects dopaminergic functioning in
the limbic and prefrontal regions resulting
in increased activation in response to
unpleasant stimuli
• COMT Val158Met polymorphism has been
implicated in other clinical disorders such
as ADHD, OCD, Schizophrenia, Bipolar
Disorder, and Substance Use Disorder.
COMT Val158Met polymorphism has shown
to vary by gender and ethnicity.
Reduce dopamine in pfc and amygdala
*the role of COMT Val158Met polymorphism
in Panic Disorder remains uncertain.
Serotonin Transporter Gene and Serotonin Receptor Gene
• Serotonin transporter (5-HTT) is encoded
by the SLC6A4 gene which effects the
availability of the serotonin transporter
protein.
• SLC6A4 mutations effect the level of
serotonin available in the extracellular fluid
• No significant difference in frequencies of
the SLC6A4 gene PD patients
• However, preliminary findings show
decreased 5-HT1A binding in untreated PD
patients and 5-HT1A polymorphisms and
PD. 5-HT1A polymorphisms have also been
linked to other clinical disorders.
Adenosine 2A receptor gene (ADORA2A - variant of Adenosine 2A receptor gene)
Panic Disorder
• Adenosine are released by neurons and
glial cells and serves as a neuromodulation
that increases neuronal inhibition, and
activate neurons in pathways involved in
anxiety
• Overrepresentation of a particular
polymorphism of the ADORA2A gene in
patients with panic disorder (rs5751876)
• ADORA2A polymorphisms also linked to
personality traits such as harm avoidance in
PD relative to controls.
• Adenosine gene variants and are not
unique to panic disorder, also linked to ASD
• Adenosine – i.e., increases inhibition
meaning it has a calming effect, better able
to control emotions and stop panic attack.
Doing studies with mice to see if modifying
receptor genes, mutating ADORA2A gene
to induce anxiety symptoms in mice and
show its role in PD.
Additional Candidate Genes
• Other candidate genes researched include:
BDNF, dopamine transporters, dopamine
receptors, cholecystokinin receptors, and
norepinephrine transporters and receptors.
• Only a few of the polymorphisms were
associated with panic disorder in a
subgroup of the population.
• Meta-analysis showed only three gene
variants were associated with panic
disorder indicating it “likely involves genetic
variation in a multitude of biological
pathways that is diverse among
populations”
• Despite evidence that panic disorder has a
strong family heredity component the
genetic factors remained obscure.
• Genome-wide studies looking at nucleotide
polymorphisms found no significant
relationship with panic disorder.
• likely due to methodological variables,
sample size, comorbidity, severity of
symptoms, heterogeneity of symptoms, low
statistical power, and not including
environmental-gene interactions all linked
to inconsistent findings.
*Not a single gene, mixed findings on which
genes are involved, multiple and interactive
effects = it’s complicated and we don’t know
*Gene-environment interaction as well *We know this drug works, not sure why, but
still use it
Can Panic Attacks Be Provoked?
• Due to panic attacks spontaneous nature it
is hard to study them as they naturally
occur.
• Research indicates that substances can
induce panic-like symptoms, including
recreational drugs such as cocaine and
ecstasy and medications such as asthma
medications and prescription stimulants
• The synthetic neuropeptide (CCK-4) and
CCK receptor agonists (Pentagastrin) can
provoke anxiety symptoms in humans that
closely resemble spontaneously occurring
panic attacks
• CCK is a neuropeptide that plays a critical
role in anxiety-related behaviours in PD
• CCk-4 induced panic in majority of PD
patients and not HCs
• Panic attacks have been observed during
fMRI, revealing increased activation in the
amygdala, and left temporal gyrus
• rsFC changes in HCs as a result of
chemically induced panic attacks linked to
increased rsFC in the limbic system, anterior
cingulate gyrus, the claustrum-insular-
amygdala region, and the cerebella vermis
with concomitant reductions in blood flow in
the frontal regions.
• Collectively, these findings support that
distinct physiologic changes occur during
panic episodes and support involvement of
limbic and prefrontal regions
*Still genes but more into biochemistry. Can
panic attacks be induced/triggered by
drugs? This would allow us to do
neuroimaging during one to see what
happens, before, during and after in the
brain. Very useful information but it has an
impact on physiology outside the
brain (breathing and heart rate). This can
bias the findings if the neuroimaging method
uses a voltage signal (i.e., fMRI).
*Increasing heart rate confounds and makes
neuroimaging study findings useless if it
measure voltage
*So far, genes are a complicated approach,
giving drugs and measuring brain activity is
not going to work, the last approach is
environmental by putting someone in an
fMRI and show scary images then measure
brain activity (best controlled measure of PD)
Brain structures involved in PD
- Hippocampus
- Amygdala
- Temporal gyrus
- Anterior cingulate
- Cerebellum
- Frontal and temporal lobes
Structure
• Reduced volume (~9%) of the temporal
lobes (most common but the specific
structure in the temporal lobe linked to PD
remain unknown)
• Smaller amygdala volume (emotion
regulation and threat detection)
• Volume reductions in the insula (automatic
sympathetic nervous system function) and
basal ganglia (motor control, executive
functioning, emotion)
• Additional research is needed!
reading: some studies show enlarged ventricles in patients with PD relative to controls, but this is not specific to PD it is also seen in other clinical disorders.
Gray and White Matter Findings
• Differences in gray matter volume in limbic
structures including the
o Amygdala
o Hippocampus
o Basal ganglia
o Pituitary
o Frontal, cingulate and temporal cortical
areas
o Midbrain and pons
• Gray matter reductions in the right inferior
frontal gyrus and right insula in participants
with panic disorder (studied could
differentiate between PD and MDD to by
different gray matter reduction patterns)
Reading: Na et al. (2013) found gray matter reduction in the orbital frontal region in PD patients with and without agoraphobia to healthy controls and found reduced volume of orbital frontal gyrus in only in in PD patients with agoraphobia. Shang et al. (2014) compared PD with other anxiety disorders and found reduced volume in the right anterior cingulate and left frontal gyrus which is consistent with neuroanatomical models of physiological fear responses. These findings support the role of the anterior cingulate and prefrontal cortex in mediating anxiety symptoms, but the specific pathways remain unclear. similar gray matter reductions have been found in conduct disorder and autism.
*This describes most of the brain. How is this
helpful? Is the whole brain broken? How can
I fix it with this shit, too complex needs to be
simplified.
*Grey–cell bodies
White Matter Findings
Panic Disorder
• Significant volumetric reductions in
widespread white matter regions including
fronto-limbic, thalamo-cortical, and
cerebellar pathways
• The degree of white matter alterations is
associated with self-reported anxiety
sensitivity and avoidance behaviours in PD
relative to HCs
• more research is needed with larger sample
sizes, HCs and clinical comparisons.
• white matter volume reduction in temporal
lobe and hippocampus is linked to other
clinical disorders (BD & PTSD) and aging.
*White – myeline, interneuron connectivity,
transduction of signal
*Structural changes in PD: gray matter
reduction In most brain regions and
reduced brain region interconnectivity
(white matter)
Functional Findings
• Unprovoked panic attacks often occur at
random and are therefore difficult to
capture
• Provocation of panic attacks often leads to
hyperventilation and vasoconstriction,
which may obfuscate blood flow changes in
the brain
• patients with PD may be more sensitive to
panic inducing substances
• the experience of being in a scanner may
influence glucose metabolism, blood flow,
and medication effects the brain
• reduced cerebral blood flow in temporal
regions in patients with PD was negatively
correlated with severity and duration of
illness.
• compared to patients with OCD, patients
with PD did not have reduced cerebral
blood flow in caudate.
• Thus, functional neuroimaging studies of
panic disorder are difficult and findings
should be interpreted with these
methodological issues in mind.
Resting States
PD
• At rest, those with panic disorder tend to
display increased activation in the
hippocampal and frontal regions relative to
control participants and decreased
activation in the anterior cingulate gyrus,
amygdala, parietal, and temporal lobe
regions
• These findings suggest differential patterns
of brain activation may exist in patients with
panic disorder compared to healthy
controls
Activity States During Cognitive Tasks
• Looking at functional differences while
exposed to visual images (i.e., neutral vs
emotional/threatening) or during cognitive,
motor or sensory tasks.
• Activations patterns of patients with and
without panic disorder in response to neutral
and disorder-related (threatening) visual
images
o Participants with panic disorder display
greater activation to disorder-related
images compared to neutral scenes in
several brain regions, including the brain
stem, insula, thalamus amygdala, and
cingulate cortex; most studies reports
differences in patterns of activation in some
but not all of these structures.
o Together these studies suggest that
patients with panic disorder have a
heightened sensitivity to anxiety-provoking
stimuli that is characterized by increased
neuronal activity in subcortical, limbic, and
frontal regions
• PD’s have heightened awareness of
emotion-specific stimuli and interoceptive
stimuli (i.e., internal bodily sensations)
• Participants with panic disorder, specific
phobia or PTSD have the same activation
patterns in response to fearful stimuli with
greater activation in the left amygdala and
reduced activation in the ventromedial
prefrontal cortex but these are characteristic
of all anxiety disorders and not just panic
disorder.
Motor control (basal ganglia) Panic Disorder
• Basal ganglia studied due to increase in
bilateral and reduced cortical activation in
healthy controls in response to fearful
stimuli.
• During motor tasks PD patients show
reduced activation of the putamen (part of
the basal ganglia) during motor tasks
• Basal ganglia transform incoming sensory
information into motor movement.
• Deep brain stimulation of the basal ganglia
triggers panic attacks in patients without
panic disorder
Sensory Processing
Panic Disorder
• Auditory task:
o Participants with panic disorder showed
reduced glucose metabolism (activity
decreases) in the left parietal lobe and
Increases in the orbital frontal cortex
• Word fluency production (cognitive task):
o Participants with panic disorder show
reduced activation of the prefrontal cortex
• Olfaction task:
o Participants with PD show different
activation patterns in the amygdala,
thalamus, prefrontal regions, and anterior
cingulate.
• Collectively, findings from motor and
sensory tasks support differences in
activation responses in participants with
panic disorder relative to controls
Summary
• Differential activation patterns at rest and
during cognitive, sensory, and motor tasks
• Reduced gray matter
• Altered white matter connectivity
• Decreased and increased neuronal
activation in pathways extending from the
amygdala and hippocampal regions to the
frontal cortex
• These findings support theoretical models
of panic disorder and anxiety models
*All correlational findings, and mixed, we still
do not know the cause of PD!
*Findings do not reveal the cause of the
functional differences between those with
and without panic
Anxiety Models
A single, universally accepted structural and functional theory explaining panic disorder DOES NOT exist. However, some models have been proposed
Model #1
• Emphasises the role of the “fear network”:
prefrontal cortex, brain stem, amygdala,
hippocampus, thalamus, hypothalamus,
periaqueductal gray, and locus cerulues in
anxiety disorders.
• Panic occurs due to deficit exists in “relay
and coordination of upstream (cortical) and
downstream (brain stem) sensory
information, which results in heightened
amygdala activity with resultant behavioral,
autonomic, and neuroendocrine activation (nervous system controling heart rate etc. and stress hormones)
o Participants with PD have a lower threshold
for activating the “fear network”, this
hyperactive activation leads to stimulation
of the autonomic and neuroendocrine
systems (projection from the amygdala to
the brain stem and hypothalamus).
Stimulation of the automatic sympathetic
nervous system and neuroendocrine
systems result in physiological symptoms.
§ Heart rate
§ Stress hormones
§ Release of norepinephrine
§ Increased blood pressure
o Meanwhile, the prefrontal cortex receives
this sensory input from the limbic system
and processes it. Faulty processing results
in the interoceptive (bodily sensations)
being misinterpreted and excitatory
projections being sent to the amygdala and
other limbic structures heightening the fear
response = panic.
Reading: patients with panic disorder have heightened elevated plasma levels of norepinephrine. Panic disorder is highly familial and environmental factors, such as early childhood trauma and disruptions in parent-infant attachment, increase the risk of developing the disorder. Specifically, PD patients inherit a CNS which is overly sensitive to fear, the degree of sensitivity will vary among people. This model doesn’t address the HPA axis.
Model #2
• Hypo-thalamic-pituitary-adrenal axis (HPA)
o The HPA axis is involved in the stress
response and the release of stress-related
hormones such as corticotropin-releasing
factor (CRF)
§ CRF increases the release of
norepinephrine as well as other peptides
and steroids
• Antidepressants are hypothesized to
normalize functioning of a hyperactive
hypothalamic-pituitary-adrenal system in
panic disorder
• The symptoms of panic disorder are similar
to those with hyperthyroidism, there is a
high rate of comorbidity between
hyperthyroidism and anxiety.
Summary
• Theoretical models of anxiety emphasise
the role of the brain stem, cortex, and
subcortical structures in the
pathophysiology of anxiety disorder.
• At the level of the brain stem and
subcortical structures:
o Physiologic alterations result in a
hyperactive “fear network” that triggers
stimulation of sympathetic nervous system
and neuroendocrine systems
• At the level of the cortex:
o Misinterpretation of interoceptive signals
leads to misperceptions of danger that
further stimulates the “fear network”
leading to physiologic symptoms of panic
*Communication between neurons and
pathways between the subcortical and
cortical regions of the brain occur via
neurotransmission.
Neurotransmitters
• Most major neurotransmitter systems have been implicated in panic disorder o Serotonin o GABA o Dopamine o Norepinephrine o Glutamate
Serotonin
Panic Disorder
Serotonin
• Implicated in panic disorder due to the
efficacy of antidepressants in reducing
anxiety symptoms
o Tricyclics
o Monoamine oxidase inhibitors
o SSRIs (most efficient – reduce anxiety
symptoms without dependency, and
have limited side effects)
o SNRIs
Serotonin
• Brain serotonin turnover is increased
approximately fourfold in subcortical brain
regions and in the cerebral cortex in
participants with panic disorder
• Serotonin turnover is highest in participants
with the most severe symptoms and
significantly reduced with treatment of
SSRIs.
• Lower rCBF have been found in women
with PD In the temporal cortex, and
increased significant following treatment
with a serotonin agonist.
• These findings show that serotonin
increases may modulate an underlying
functional pathology of the serotonergic
system in patients with panic disorder
• SSRIs (serotonin agonists) showed a
dramatic reduction in panic attack
frequency but no difference was fund with
serotonin antagonists.
Serotonin
• The specific role that serotonin plays in
panic disorder is unclear, possibly the
serotonin pre and postsynaptic receptors
(5-HT1A) are implicated
o Lower density of serotonin receptors in
several brain regions
§ Anterior and posterior cingulate cortex
§ Orbitofrontal cortex
§ Temporal cortex
§ Amygdala
§ Raphe nuclei
Serotonin
• Decreased binding of the serotonin
transporter in the thalamus and
hippocampus, and increased serotonin
transporter (SERT) binding in the rephe
nuclei and several other cortical areas in
patients with PD.
• Gender differences in SERT are present
with women having higher levels of
serotonin transporter (SERT) binding than
males in several brain regions, including the
hippocampus
• Differences in serotonin receptor
expression and functioning exists between
healthy males and females, and may also
be implicated in the higher rate of panic
disorder among females than males
Dopamine and Norepinephrine
Dopamine and Norepinephrine
• Dopamine has been studied in PD
because:
o Norepinephrine is biosynthesized from
dopamine
o Dopamine agonists have been found to
produce panic symptoms
o Dopamine antagonists have been found to
extinguish conditioned fear responses in
mice
o Plasma dopamine levels tend to be higher
in patients prior to antidepressant
treatment and may normalize following
treatment
• However, norepinephrine typically is the
primary focus
Dopamine and Norepinephrine
• Norepinephrine is focused on in PD due to
its known effects on the nervous system
“fight or flight” response that results in
increased arousal, vigilance, heart rate, and
blood pressure
• Serotonin and norepinephrine systems
function interactively (abnormality in their
interaction may result in anxiety pathology
i.e., serotonergic neurons project from the
raphe nuclei to the locus coeruleus and
have an inhibitory effect on neurons. The
locus coeruleus is rich in norepinephrine-
releasing neurons which project into the
midbrain and forebrain to modulate fear
and anxiety responses. They can have an
excitatory effect resulting in increased
heart rate and blood pressure)
• Consequently, factors that disrupt the
homeostasis of the serotonin system can
affect norepinephrine neurotransmitter
system and result in symptomatic
behaviour such as panic.
SSRIs
Panic Disoder
• SSRIs alter both serotonin and
norepinephrine cerebral spinal fluid
metabolite levels and lead to symptom
improvement
o When serotonin activity and availability is
increased by SSRIs, norepinephrine
receptors activity decreases
§ Symptoms of panic disorder are decreased
• SSRIs decrease the release of stress-
related hormones (cortisol) from the
hypothalamus and adrenal gland, thereby
decreasing heart rate, blood pressure, …
• SSRIs modulate the effects of glutamate, by
decreasing their excitatory effects in the
amygdala, hypothalamus and brain stem to
mitigate anxiety symptoms.
GABA
• The locus coeruleus contains cells which
also release neuropeptides and other
neurotransmitters such as GABA.
• Benzodiazepines, which act on GABA
receptors, improve anxiety symptoms and
are used in the treatment of panic disorder
o In a study, individuals who experienced
panic attacks and were being treated for
alcohol or drug abuse, used alcohol—a
GABA agonist—to self-medicate their
attacks, described this method as effective
at reducing or preventing panic attacks
• Benzodiazepines are also effective at
reducing panic symptoms by enhancing
GABA transmission
Pharmacological Intervention
• The primary treatment approach for anxiety
disorders is pharmacological
o SSRIs (Prozac, Paxil, Zoloft) —– Preferred
treatment
o SNRIs (Venlafaxine, Effexor)
o Tricyclic antidepressants (Anafranil, Tofranil)
o MAOIs (Marplan, Nardil)
o Benzodiazepines (Valium, Xanax, klonopin;
are used short-term due to high risk of
dependence/withdrawl and can be used in
conjunction with SSRIs for severe cases)
• Reading:
o BuSpar is a non-sedating anxiolytic
serotonin agonist that is also used to treat
PD, as are beta-blockers. Beta-Blockers are
prescribed to enhance heart rhythm and
are used off label to treat PD.
o Note the drugs prescribed by clinicians do
not always follow clinical guidelines. That
Is, beta-blockers and benzodiazepines are
prescribed more than tricyclic
antidepressants.
o The mode of action between the most
prescribed medications are very different.
SSRIs are serotonin agonists and
benzodiazepines are GABA agonists (bind
to GABA receptor to modulate the effects
of GABA by allowing lower concentrations
to open -Cl channel and facilitates neural
inhibition). Patients with PD have lower
GABA receptors in hippocampus, left
temporal lobe, prefrontal cortex and global
reduction in benzodiazepine binding
throughout the brain. This is also seen in
alcoholics and patients with PTSD.
o Due to mixed findings the role of GABA
transmission in PD remain unclear.
Pharmacological Intervention
Pharmacological Intervention
• Temporary use of benzodiazepines in
conjunction with SSRIs is recommended in
severe cases
o The mode of action of benzodiazepines
and SSRIs is substantially different
§ SSRIs are serotonin agonists
§ Benzodiazepines are GABA agonists
Pharmacological Intervention
• Long-term treatment of panic disorder
typically involves medication in conjunction
with cognitive-behavioral therapy to
improve treatment response (due to
methodological issues it is hard to
determine if there is additive effects)
• Some researchers have argued that
cognitive-behavioral therapy is preferable
to pharmacological interventions
o Others advocate for the management of
panic disorder with short-term use of
benzodiazepines and long-term use of
SSRIs
Alternative Interventions
Panic Disorder
Alternative Interventions
• Transcranial magnetic stimulation (TMS) has
been studied but has not yet been
approved by the FDA for treating anxiety
disorders
• Systematic review of the use of TMS in the
treatment of anxiety disorders concluded
that TMS has a significant effect, but in
some studies, the effect is small and short
lived
Neurosurgery
• Used in rare cases of treatment-resistant
anxiety disorders
o Study (bilateral lesioning of the internal
capsule - capsulotomy):
§ 5 with social phobia
§ 13 with GAD
§ 8 with panic disorder
• 67% responded favorably to the procedure
but seven of the 26 demonstrated
neuropsychological impairment on
executive function tasks and emotional
apathy (i.e., adverse side effects)
Exercise
• Several studies have reported that regular,
high intensity exercise is associated with
significant improvement in symptoms of
panic disorder but appears to be less
effective than treatment with an
antidepressant
• Acupuncture, autogenic training, and
biofeedback are often recommended,
however, only a few methodologically
sound studies are currently available
Summary of Panic Disorder:
- higher rates in females than men at all ages
- high genetic component but no single gene
has been identified - serotonin, norepinephrine and GABA are
neurotransmitters linked to PD - Acute treatment of panic disorder involved
benzodiazepines, and a combination of
SSRIs or SNRIs, and CBT is recommended
for long-term management.
Obsessive-Compulsive Disorder (OCD)
Is it an Anxiety Disorder?
What is OCD?
Does OCD always present with obsessions and compulsions?
• No longer classified as an anxiety disorder;
now it is classified under “OCD and related
disorders”
Obsessive-Compulsive Disorder (OCD)
• Recurrent obsessions and/or compulsions
that are time consuming or cause
significant distress and impairment in daily
living
o Obsessions are persistent ideas, impulses,
thoughts, or images that are intrusive and
unwanted
o Compulsions are repetitive overt or mental
acts that an individual feels compelled to
perform
*whilst developmental differences have been
found, they do not belong to a specific age
group
*Two components of OCD
obsession/compulsion. Most OCD patients
have both.
Common obsessions and compulsions
Common obsessions
• Contamination (dirty/sick/unclean; found in 45-
60% of OCD cases)
• Doubts (worried didn’t lock door, turn stove off
etc.)
• Symmetry or exactness (colour coding)
• Somatic fears (hyperfocus on
• Sexual thoughts
• Thoughts of harm
• Contamination is the most common obsession,
45–60% of OCD patients suffer from this.
obsession
Common compulsions • Cleaning • Checking • Counting • Ordering
Common compulsions
• Most patients with OCD have obsessions and
compulsions
o OCD symptoms fall into distinct subtypes
(classification)
§ Symmetry/repeating/ordering/counting
§ Forbidden thoughts/checking
§ Contamination/washing
§ Hoarding
• Obsessions tend to be highly idiosyncratic and
are often connected with “magical” or
implausible beliefs
• OCD/MDD is not linked to intellect!
Uncontrollable thoughts due to anatomical and
neurological changes in the brain.
Prevalence, Cross-Cultural, Diversity
OCD
• In the United States the prevalence of OCD is approximately 1.2% • Similar rates have been reported in other countries • Italy ~3% of adolescents reported significant OCD symptoms • 0.25% of British children aged 5–15 reported significant OCD symptoms • Native Hawaiians have a twofold higher risk for OCD than other ethnicities • OCD is less common among black than non-Hispanic white respondents • More common in black than whites (genetic/cultural component)
Religiosity and OCD
• OCD symptoms and the course of the
disorder can be shaped by cultural, ethnic,
and religious experiences
o Study: Most common obsessions in patients
from Bali, Indonesia, included the need-to-
know information about passersby, somatic
obsessions (i.e., body image, touching body
part over and over again), and obsessions
concerning witchcraft and spirits
o Study: Most common obsessions in 90
patients with OCD attending an outpatient
clinic in Cairo, Egypt, were religious and
contamination obsessions
(disease/cleanliness), and the most
common compulsion was repeating rituals
*Expression of OCD is highly correlated with
religious beliefs. Meaning that cultural
ideologies shape what obsessions and
compulsion you form. Religious beliefs do
not cause OCD.
• Study: 42% of a sample of 45 patients with
OCD had religious obsessions
• Study: A group of college students that self-
reported highly devout participants
(Catholics, Protestants) scored higher on
religious obsessive compulsive symptoms
than less religious participants (more
religious you are the more likely your OCD
obsessions will be expressed religiously)
• Study: Reported that religious symptoms
were found in 13 of 19 ultraorthodox Jewish
patients with OCD but only 1 of 15 non-
ultraorthodox Jewish patients with OCD
• These studies suggest that OCD may be
expressed in religious practices but is not a
determinant of the disorder
*Do not have to be religious to have OCD but
if you are religious and have OCD than it’s
highly likely your obsessions will be
expressed religiously.
*Culture, ethnic and religious experiences
shape progression and symptoms of OCD
Diversity (prevalence)
• Equally common in adults of both sexes but
more common in boys during childhood
(gender distribution equal)
• Begins in adolescence or adulthood (late
teens or early 20s)
o Males have an earlier onset than females
• More likely to occur in males with tic or
other anxiety disorders such as phobias
(more prevalent in males with
comorbidities)
• Females are more likely to have an acute
onset of OCD symptoms
• In majority of OCD cases, it is a chronic
condition with periods of diminishing
symptoms (waxing and waning).
• Childhood onset of OCD is associated with
continuation of symptoms into adulthood in
majority of cases.
Comorbidity
OCD
• Depression (most common comorbid condition) • Eating psychotic (not a spelling mistake; term used in textbook) • Tic disorders • Tourette’s disorder
*OCD rarely occurs on its own
Differences in OCD symptoms based comorbid condition
• Participants with comorbid OCD and
Tourette’s disorder have more sexual,
violent, and symmetrical obsessions as well
as counting, blinking, and touching
compulsions
• Those with only OCD have more
contamination obsessions and cleaning
compulsions
• Patients with OCD and comorbid tic
disorder have significantly more rubbing,
touching, tapping, blinking, and staring
compulsions (but didn’t differ in obsessions)
• Patients with comorbid bipolar disorder
have a higher rate of sexual obsessions and
fewer ordering compulsions than those with
OCD alone
• Touching, tapping, rubbing, hoarding,
ordering, and self-mutilating behaviors are
more common in patients with autistic
disorder. More contamination, sexual,
aggressive, and religious obsessions with
comorbid autism.
• Patients with anorexia and OCD have a
higher need for symmetry and ordering than
those with OCD alone
• Patients with schizophrenia and comorbid
OCD have a poorer prognosis and
treatment outcome
*behavioral differences reflect differential
neurophysiological underpinnings of OCD
relative to OCD with a comorbid condition
Genetics
Heritability
OCD
• It is important to recognise that increased
familial transmission of OCD can be due to
either shared genetic or environmental
factors
• No environmental risk factors have
convincingly been associated with OCD (if
not environment than it must be genetic;
may still be involved but no specific factors
found yet)
• 20% of patients with OCD have a family
history of OCD (strong genetic component)
• Fourfold increase in the likelihood of
developing OCD in first-degree relatives of
adult patients with the disorder
• Relatives of patients with early onset OCD
have a tenfold increase of developing the
disorder
• Familial studies support a heritability
component to OCD
Twin Studies
OCD
• Study: 1,054 female twins exhibited a
heritability estimate of 33% for obsessions
and 26% for compulsions
• Meta-analysis of twin studies suggests the
heritability estimate of OCD is 40%
• concordance of OCD between twins ranges
between .63 -.87 but for every 10
monozygotic pairs in concordance with
OCD, 4 or so are discordant. Thus, showing
non-genetic factors also plat an important
role in the development of OCD.
Linkage studies identifying chromosome locations
• No firm conclusions
• Studies continue to explore variants of a
number of susceptibility genes particularly
those involved in the serotonergic and
dopaminergic neurotransmitter systems
Reading:
• Linkage studies found susceptibility genes
in chromosome locations 1q, 1p21, 1p36,
2p14, 3q27-28, 5q13, 6p25, 6q, 9p24, 10p13,
15q11-13, 15q14, 16q24, 17p12, and 22q11.
However, these studies have been
inconsistent, and no firm conclusions can
be drawn.
Serotonin Genes
OCD
Serotonin Genes
• Reasons for investigation of serotonin
genes in OCD:
o Serotonin agonists including
antidepressants such as SSRIs (Prozac) and
tricyclics (clomipramine) are effective at
reducing OCD symptoms
o Serotonin antagonists can trigger or
worsen OCD symptoms
o Some recreational drugs that are serotonin
agonists (LSD, ecstasy, psilocybin) have
been found to improve OCD symptoms
Serotonin Candidate Genes
• The serotonin transporter gene (SLC6A4)
has been extensively investigated in OCD
given that serotonin reuptake inhibitors
block the serotonin transporter and reduce
OCD symptoms
• Specific polymorphisms in the SLC6A4
gene are associated with OCD (5-HTTLPR,
controversial)
Serotonin Receptor Genes
• Polymorphisms of the serotonin receptor
gene HTR2A is associated with OCD
• The HTR2A gene is located on
chromosome 13 and encodes the serotonin
receptor 5-HT2A
• Interestingly, this receptor has been found
to down-regulate with the chronic
administration of SSRIs
• 5HT3A receptor gene polymorphisms also
have been linked to OCD. Their activation in
the insula of mice is associated with disgust
response and may be linked to
contamination concerns and hand washing.
*meta-analysis indicates that 5HTTLPR and
receptor HTR2A polymorphisms
(rs6311/rs6313) are most consistently linked
to OCD
Dopamine Genes
Dopamine Genes • Reasons for investigations: o Dopamine agonists such as amphetamine induce or worsen OCD symptoms o Dopamine antagonists such as antipsychotic medications improve OCD symptoms o Neuroimaging and brain stimulation studies support involvement of the dopaminergic systems
Dopamine Transporter Genes
• The dopamine transporter gene (SLC6A3,
DAT1) is located on chromosome 5 and is a
candidate gene in OCD
• A specific polymorphism (VNTR) of the
dopamine transporter gene has been found
to increase susceptibility to Tourette’s
disorder that is often comorbid with OCD
(controversial)
Dopamine Receptor Genes
• Polymorphisms of the dopamine
postsynaptic receptor gene (DRD4) is lower
in patients with OCD.
• The DRD4 gene encodes the dopamine
receptor (D4) and antipsychotic medications
such as clozapine (serotonin antagonist)
have a high affinity for the D4 receptor
Glutamate Genes
OCD
Glutamate Genes
• Study: Mice genetically engineered to lack
the SAPAP3 gene
o SAPAP3 encodes proteins expressed in
the striatum and important in glutamate
signaling
o Mice groomed themselves compulsively
and exhibited additional anxiety behaviors
• When the mice were treated with an SSRI
the OCD-like behaviors improved, and
when the gene was reinserted, the
behaviors were prevented
Glutamate Transporter Genes
• The glutamate transporter gene, SLC1A1,
located on chromosome 9, encodes
glutamate transporters.
• Polymorphisms of this gene have been
implicated in OCD.
• These gene variants are believed to alter
the retrieval of glutamate from the synaptic
cleft and transporting it across the plasma
membrane
Glutamate Receptor Genes (NMDA)
• Polymorphisms (rs1019385) and variants of
NMDA receptor genes (GRIN2A GRIN2B)
have been consistently linked to OCD
• Located in the fronto-parietal-temporal
cortex, amygdala, and basal ganglia
Additional Candidate Genes
Genes which encode monoamine oxidase, catechol-o-methyltransferase, BDNF, and others have been mixed but are more common in women suggesting that gender differences of the susceptibility of OCD.
Genetic Summary
• Collectively, family and twin studies support
a heritability component to OCD
• Over 100 genetic association studies
involving over 200 polymorphisms and
gene variants
• OCD is likely to be associated with multiple
genes with most having small to modest
effects, and their main effects remain
largely unknown.
• The heterogeneity of OCD, as well as
methodological challenges, increases the
difficulty of elucidating the complex
relationships among genetic and other
factors
Structural Findings
OCD
• Meta-analysis revealed reductions in
cortical and subcortical brain regions in
patients with OCD:
o Smaller hippocampal volumes (adults;
larger in medicated adults)
o Larger pallidum volumes (adults; larger in
medicated adults)
o Larger thalamic volumes (medication naïve
children)
o Reduced hippocampal volumes (adults)
o Severity of OCD symptoms tends to be
negatively correlated with hippocampal
size
Decreased cortical thickness
- Superior and inferior frontal regions
- Posterior cingulate
- Temporal lobe
- Inferior parietal lobe
- Precuneus gyri
*Cortical thinning linked with increased age
and medication response
*Small change makes a big difference
*Widespread structural abnormalities
contribute to the vulnerability of OCD and
not just cortical thinning
Gray Matter
• Changes in gray matter in participants with OCD: o Frontal o Striatal o Thalamus (hand washing severity negatively correlated with gray matter volume) o Parietal o Cerebellar o Frontal eye fields o Medial frontal gyrus o Anterior cingulate cortex o Basal ganglia (increased/reduced/no difference; some speculate that increases basal ganglia size is a neuroplastic change that results from chronic compulsive behaviour)
*Highly variable
*OCD involves many pathways, more than the
traditional orbitofrontal region! *Too many
structures and pathways are identified for the
information to be useful
White Matter
• Both reduced and increased density of
white matter has been reported
• Studies in the corpus callosum
(inconclusive results)
• Changes in lateral frontal and parietal
regions and pathways linking areas of the
prefrontal cortex to posterior parietal and
occipital association cortices
• Inconsistent findings in reductions of white
matter volume in the corpus callosum.
• Additional research is needed to further
explore white matter density in participants
with OCD
*Mixed findings, debate
*Reduced and increased white matter
density in different regions of the brain
Amygdala
• Amygdala volume is smaller in participants
with OCD (controversial)
• Other studies which found that the left
amygdala was significantly larger in
patients with OCD (controversial)
Summary of Structural Differences
• Findings are not consistent among studies
o Findings likely reflects differences among
participants with OCD, such as age of
onset, comorbid disorders, ethnicity, family
history of OCD, medication history, as well
as methodological characteristics of the
studies
*Correlational findings, no causal findings!
Functional Findings
• Pathways from subcortical structures to the
prefrontal cortex and back again (cortico-
striatal-thalamic loop)
o Glucose metabolic rates are higher in the
cortico-striatal-thalamic loop in OCD
(specifically. in the left orbital gyrus and
bilateral caudate nuclei)
• Different patterns of activation during rest
conditions as well as during cognitive,
memory, executive function, and emotional
tasks that illicit emotions of fear, disgust,
guilt, and shame
*Take home message for OCD and Anxiety is
that there are emotional reactions caused
by a stimulus. If the stimulus and the
prefrontal cortex do not align well then
individuals can have intense uncontrollable
reactions to real/perceived stimulus
because the executive control function is
not effectively regulating their emotions or
behaviour
Beyond the Cortico-Striatal-Thalamic Loop
• Studies now implicate limbic structures,
temporal cortex, parietal cortex, pallidum,
anterior cingulate cortex, angular gyrus, and
cerebellum in OCD
o Increased activation in cortico-cerebellar
regions of participants with OCD with hand-
washing rituals
o Patients with checking rituals show
decreased activation in the left caudate
and left anterior cingulate cortex compared
to healthy controls
• Advocates for a more neurobiological
model of OCD.
o evidence of increased activation in the
anterior cingulate cortex, insula, caudate
head, and putamen during affective tasks
with OCD. These structural changes linked
to salience, arousal and habitual
responding which are problematic in OCD.
They showed decreased activity in medial,
prefrontal cortex and posterior caudate
which are implicated in cognitive and
behavioural control.
o during non-affective tasks OCD patients
there is a pattern of increased activation in
structures linked to self-referential
processing (precuneus, posterior cingulate)
and decreased activation in the subcortical
regions involved in goal-directed behaviour
and motor control (pallidum, ventral
anterior thalamus, posterior caudate).
o overall, this indicates increased affective
and self-referential processing, habitual
responding, and blunted cognitive control
in participants with OCD
What Happens in the Brain When OCD Symptoms Are Provoked?
• While in an fRMI scanner, participants with
OCD are shown visual images of scenes
that trigger OCD symptoms (dirty door
knobs, food crusted dishes, messy clothing,
crooked paintings, pet hair)
• While viewing the images patients have
consistently shown increased activation of
the cortico-striatal-thalamic loop as well as
temporal and parietal cortices and
subcortical structures (anterior cingulate
cortex, globus pallidus, hippocampus,
uncus)
• Increased activity in the orbitofrontal
regions contributes to evaluation of the
occurrence of negative consequences
following an action, which in turn leads to
the generation of obsessive thoughts
• In order to prevent the imagined negative
consequences, and or anxiety, repetitive or
ritualistic behaviors are performed
• These obsessive thoughts and compulsive
behaviors are mediated by complex
pathways within the cortico-striatal-thalamic
loop, temporal and parietal cortices,
cerebellum, and subcortical structures,
including the anterior cingulate cortex,
amygdala, basal ganglia and limbic
structures
• This theory is circular in nature because
neuroimaging data is only correlational
Functional Findings and Medication
• Higher rCBF in caudate cingulate, and
dorsolateral prefrontal region of medication
naïve patients with OCD relative to controls.
Following treatment with SSRIs these
regions have showed significant reductions
in rCBF.
• Increased activation in the cortico-striatal-
thalamic loop has been associated with
increased severity of OCD symptoms
• SSRI treatment generates changes in
glucose metabolism changes in the
putamen, cerebellum, and hippocampus
that are associated with improved
performance on neuropsychological tasks
• Pathophysiology of OCD may differ with
age at which OCD symptoms began. for
example, prior to age 10 and after age 12
both groups showed decreased rCBF in the
right orbitofrontal regions. However,
participants with early onset show reduced
rCBF in the left anterior cingulate and
increased rCBF in right cerebellum
compared to controls. In addition, early
onset showed reduced rCBF in the right
thalamus.
• Children with OCD had larger thalamus
volumes, but they returned to healthy
leaves following 12-week treatment of
SSRIs. Contrary to expectations, CBT was
not linked to thalamus volumes (i.e.,
pharmacology linked to neuroplasticity
changes and not CBT).
Summary
• Functional studies implicate cortico-striatal-
thalamic pathways
• Treatment with SSRIs has been found to
decrease activity within these regions
• Inconsistencies likely reflect participant
characteristics
• Cortico-striatal-thalamic pathways are
implicated in other disorders (ADHD,
Tourette’s disorder)
• Neuroimaging data is correlational in
nature, no causal pathways have been
identified.
• A disorder-specific structural
pathophysiology of OCD is far from
identified!
Does Strep Throat Cause OCD?
• Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal
infections (PANDAS) has been used to
describe children and in some cases adults
who have abrupt onset of OCD or tics
following streptococcal infections.
o Increased basal ganglia volumes that
corresponded with severity of abrupt OCD
or tic symptoms due to the increased
antibodies within the basal ganglia in
reaction to the streptococcal infection
• Mixed findings on whether antibodies are
helpful in preventing or decreasing
PANDAS-related OCD symptoms. It may be
that people who develop OCD from
streptococcal infections are genetically
susceptible to OCD.
• The clinical implications of PANDAS
remains hotly debated!
Neurotransmitters
Neurotransmitters: Serotonin
• Serotonin agonists, including antidepressants such as SSRIs and tricyclics reduce OCD symptoms • Serotonin antagonists trigger OCD symptoms • Recreational drugs that are serotonin agonists (LSD, ecstacy, psilocybin) improve OCD • Unmedicated individuals with OCD have 25% higher serotonin transporter binding in the midbrain and pons regions relative to controls and binding is highest in individuals with early onset OCD.
• Reading:
o No significant difference in serotonin
transporter binding in the striatum.
(Controversial because other studies
found reduced or no difference in
serotonin transporter availability this is
due to two confounding factors:
Medication history and age of onset).
o A study to address these concerns found
significantly higher serotonin transporter
availability in the putamen of early onset
participants, not in other structures, and
was not associated with symptom severity.
Indicating there are structural binding
differences between early and late onset
OCD in the putamen and persist with
SSRIs treatment (do not know if this is due
to increased capacity for serotonin
reuptake or higher density of serotonin
transporters to compensate for low
serotonin levels remains unclear)
o Serotonin receptors: some studies found
no differences between OCD and HCs
serotonin receptor binding. Others found
reduced serotonin receptor 5-HT2A in
frontal, dorsolateral, and medial frontal
cortex, parietal and temporal cortex in
OCD patients relative to HCs. Another
found receptor availability in the
orbitofrontal and dorsolateral frontal
cortex was linked to OCD symptom
severity. No difference in 5-HT1B
receptors between OCD and HCs.
o The role of serotonin receptors in OCD is
inconclusive and remains unknown.
Neurotransmitters: Dopamine
Neurotransmitters: Dopamine • Animal studies have demonstrated that dopamine agonists can induce behavior that resembles OCD behavior in humans • Dopamine antagonists can improve OCD symptoms • Dopamine agonists can trigger or worsen OCD symptoms • Studies: Compulsive behavior in mice, rats, and dogs • Rats and mice treated with dopamine receptor agonists develop checking behavior and excessive lever pressing • Dogs, cats, and rabbits often spontaneously display compulsive behaviors (licking, tail chasing, circling behavior) can be treated with antidepressants, such as clomipramine and dopamine antagonists • Dopamine antagonists have also been used in the treatment of OCD in humans who do not respond to SSRIs or to augment SSRIs
Dopamine transporter protein (DAT) • DAT density in dogs with compulsive behaviors is either abnormally high or abnormally low in the striatum • Reduced availability of dopamine receptors in participants with OCD (controversial) o 18% decrease in striatal dopamine receptors (D2) availability in participants with OCD o an association between effectiveness of antipsychotic mediation (dopamine antagonist) and D2 and D3 receptor affinity.
Parkinson’s, Tourette’s and ADHD
• Genetic, structural, and functional studies
have implicated dopamine in all three of
these disorders, and OCD is often
comorbid with these disorders
• Interestingly, amphetamines that primarily
affect the dopaminergic system and are
used to treat ADHD, have been found to
sometimes induce OCD symptoms in
children and adults
• A side effect of dopamine agonists used to
treat Parkinson’s disease is compulsive,
repetitive behaviors
Dopaminergic agonist (Cocaine)
• There is a relationship between cocaine
use, dopamine agonist, and increased risk
of OCD in adults. The intricacies of this
relationship are poorly understood.
• The serotonergic and dopaminergic
neurotransmitter systems function
interactively, and it is possible that
decreased inhibitory influences of
serotonin on dopaminergic neurons results
in hyperactivity of dopaminergic neurons
within the basal ganglia
• OCD may be the consequence of
dysfunctional interactive neurotransmitter
systems within the basal ganglia
Neurotransmitters: Glutamate
• 40 - 60% of patients with OCD who do not
respond to antidepressants often respond
to other types of medications suggests
other neurotransmitter are involved in the
disorder
• Glutamate system directly affects
dopamine-releasing neurons in the
striatum, and glutamate antagonists have
been found to improve OCD symptoms in
treatment resistant cases
• Glutamate concentrations are higher in
patients with OCD but were reduced to
HCs levels following antidepressant
treatment (i.e., dysfunction in glutamate
system in the caudate nucleus is
reversible with antidepressant treatment).
Neurotransmitters: Opioids
OCD
• The rate of OCD is four times higher in
individuals addicted to opioids
• Oral weekly doses of morphine reduces
OCD symptoms in OCD treatment-
resistant patients
• Findings have been mixed regarding the
effectiveness of opioid antagonists in
reducing OCD symptoms.
Interventions: Pharmacological
• Antidepressants are the most commonly
used medications for treating OCD,
particularly SSRIs and the tricyclic
antidepressant clomipramine.
o SSRIs and cognitive behavior therapy are
the most effective form of treatment in
both children and adults
§ Greatest benefits are found after 6 weeks
of initiating SSRIs (symptoms are reduced
not abolished – treatment responders
often still show symptoms of OCD)
§ different forms of SSRIs show the same
benefits, higher doses lead to greater
symptom improvement but increases risk
of side effects.
Clomipramine (Serotonin Reuptake Inhibitor)
• Highly effective at reducing OCD symptomatology but is associated with more side effects and have lower compliance rates. • Side effects include: o Dry mouth o Blurred vision o Constipation o Fatigue o Tremor o Cardiac arrhythmia
Augmentation
• treatment non-response to medication or
CBT is not uncommon (i.e., 40-60%). It is
recommended to try other SSRIs,
serotonin-norepinephrine reuptake
inhibitor, or CBT.
• in treatment resistant cases it is also
recommended to augment treatment with
neuroleptics.
• the combination of SSRIs and
Clomipramine is more effective at reducing
OCD symptoms than either drug alone.
Neurosurgery
• Used in patients with chronically severe
and treatment-resistant mental illness,
including mood, anxiety disorders, and
OCD
• 5 types of surgeries:
1. Subcaudate tractotomy: Lesion of area
under the head of the caudate nucleus to
interrupt connections between subcortical
and orbitofrontal regions
2. Anterior capsulotomy: Lesion of pathways
connecting the thalamus and the frontal
lobes
3. Anterior cingulotomy: Lesion of the
anterior cingulate cortex
4. Limbic leucotomy: (a combination of
anterior cingulotomy and capsulotomy)
5. Gamma ventral capsulotomy: Delivery of
gamma rays through the skull. Gamma
rays destroy cells on the pathways
connecting the dorsomedial thalamus and
ventral prefrontal cortex and destroy cells
therein (does not require opening the
skull)
Neurosurgery Stats
• Neurosurgical procedures are effective at
reducing intractable OCD symptoms in 35–
75% of cases, with benefits extending 6–24
months after surgery
• Commonly reported negative side effects
associated with these procedures include:
o Memory deficits
o Apathy
o Urinary incontinence
o Seizures
• Neurosurgical treatment of OCD does not
have deleterious effects on personality
• Patients who show OCD symptom
reduction also reported a reduction in
neuroticism and an increase in extraversion,
novelty seeking, and self-directedness
Reading:
• following a bilateral orbitomedial leucotomy
revealed significant reductions of activity in
the caudate, anterior cingulate, thalamus,
and several frontal regions 18 days later,
and sustained reduced glucose metabolism
in these regions for three years. These
reductions in activity were associated with
improvement of symptoms and support
involvement of subcortical-cortical
pathways in OCD. Others found decreases
in the medial frontal cortex, cingulate, and
striatum.
What do we do? How do we treat OCD with all these mixed findings? Their life is still impaired, and we do not know how to help. We cannot use talk therapy, surgery/stimulation, medication to “fix” them without knowing the neurochemistry behind the disorder. They know there is something wrong/irrational with them, they do not need to be told that, they seek help on how to change it.
Beyond the Cortico-Striatal-Thalamic Loop
• Studies now implicate limbic structures,
temporal cortex, parietal cortex, pallidum,
anterior cingulate cortex, angular gyrus, and
cerebellum in OCD
o Increased activation in cortico-cerebellar
regions of participants with OCD with hand-
washing rituals
o Patients with checking rituals show
decreased activation in the left caudate
and left anterior cingulate cortex compared
to healthy controls
• Advocates for a more neurobiological
model of OCD.
o evidence of increased activation in the
anterior cingulate cortex, insula, caudate
head, and putamen during affective tasks
with OCD. These structural changes linked
to salience, arousal and habitual
responding which are problematic in OCD.
They showed decreased activity in medial,
prefrontal cortex and posterior caudate
which are implicated in cognitive and
behavioural control.
o during non-affective tasks OCD patients
there is a pattern of increased activation in
structures linked to self-referential
processing (precuneus, posterior cingulate)
and decreased activation in the subcortical
regions involved in goal-directed behaviour
and motor control (pallidum, ventral
anterior thalamus, posterior caudate).
o overall, this indicates increased affective
and self-referential processing, habitual
responding, and blunted cognitive control
in participants with OCD
What Happens in the Brain When OCD Symptoms Are Provoked?
• While in an fRMI scanner, participants with
OCD are shown visual images of scenes
that trigger OCD symptoms (dirty door
knobs, food crusted dishes, messy clothing,
crooked paintings, pet hair)
• While viewing the images patients have
consistently shown increased activation of
the cortico-striatal-thalamic loop as well as
temporal and parietal cortices and
subcortical structures (anterior cingulate
cortex, globus pallidus, hippocampus,
uncus)
• Increased activity in the orbitofrontal
regions contributes to evaluation of the
occurrence of negative consequences
following an action, which in turn leads to
the generation of obsessive thoughts
• In order to prevent the imagined negative
consequences, and or anxiety, repetitive or
ritualistic behaviors are performed
• These obsessive thoughts and compulsive
behaviors are mediated by complex
pathways within the cortico-striatal-thalamic
loop, temporal and parietal cortices,
cerebellum, and subcortical structures,
including the anterior cingulate cortex,
amygdala, basal ganglia and limbic
structures
• This theory is circular in nature because
neuroimaging data is only correlational
Functional Findings and Medication
• Higher rCBF in caudate cingulate, and
dorsolateral prefrontal region of medication
naïve patients with OCD relative to controls.
Following treatment with SSRIs these
regions have showed significant reductions
in rCBF.
• Increased activation in the cortico-striatal-
thalamic loop has been associated with
increased severity of OCD symptoms
• SSRI treatment generates changes in
glucose metabolism changes in the
putamen, cerebellum, and hippocampus
that are associated with improved
performance on neuropsychological tasks
• Pathophysiology of OCD may differ with
age at which OCD symptoms began. for
example, prior to age 10 and after age 12
both groups showed decreased rCBF in the
right orbitofrontal regions. However,
participants with early onset show reduced
rCBF in the left anterior cingulate and
increased rCBF in right cerebellum
compared to controls. In addition, early
onset showed reduced rCBF in the right
thalamus.
• Children with OCD had larger thalamus
volumes, but they returned to healthy
leaves following 12-week treatment of
SSRIs. Contrary to expectations, CBT was
not linked to thalamus volumes (i.e.,
pharmacology linked to neuroplasticity
changes and not CBT).
Summary
• Functional studies implicate cortico-striatal-
thalamic pathways
• Treatment with SSRIs has been found to
decrease activity within these regions
• Inconsistencies likely reflect participant
characteristics
• Cortico-striatal-thalamic pathways are
implicated in other disorders (ADHD,
Tourette’s disorder)
• Neuroimaging data is correlational in
nature, no causal pathways have been
identified.
• A disorder-specific structural
pathophysiology of OCD is far from
identified!
Does Strep Throat Cause OCD?
• Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal
infections (PANDAS) has been used to
describe children and in some cases adults
who have abrupt onset of OCD or tics
following streptococcal infections.
o Increased basal ganglia volumes that
corresponded with severity of abrupt OCD
or tic symptoms due to the increased
antibodies within the basal ganglia in
reaction to the streptococcal infection
• Mixed findings on whether antibodies are
helpful in preventing or decreasing
PANDAS-related OCD symptoms. It may be
that people who develop OCD from
streptococcal infections are genetically
susceptible to OCD.
• The clinical implications of PANDAS
remains hotly debated!
Neurotransmitters
Neurotransmitters: Serotonin
OCD
• Serotonin agonists, including antidepressants such as SSRIs and tricyclics reduce OCD symptoms • Serotonin antagonists trigger OCD symptoms • Recreational drugs that are serotonin agonists (LSD, ecstacy, psilocybin) improve OCD • Unmedicated individuals with OCD have 25% higher serotonin transporter binding in the midbrain and pons regions relative to controls and binding is highest in individuals with early onset OCD.
• Reading:
o No significant difference in serotonin
transporter binding in the striatum.
(Controversial because other studies
found reduced or no difference in
serotonin transporter availability this is
due to two confounding factors:
Medication history and age of onset).
o A study to address these concerns found
significantly higher serotonin transporter
availability in the putamen of early onset
participants, not in other structures, and
was not associated with symptom severity.
Indicating there are structural binding
differences between early and late onset
OCD in the putamen and persist with
SSRIs treatment (do not know if this is due
to increased capacity for serotonin
reuptake or higher density of serotonin
transporters to compensate for low
serotonin levels remains unclear)
o Serotonin receptors: some studies found
no differences between OCD and HCs
serotonin receptor binding. Others found
reduced serotonin receptor 5-HT2A in
frontal, dorsolateral, and medial frontal
cortex, parietal and temporal cortex in
OCD patients relative to HCs. Another
found receptor availability in the
orbitofrontal and dorsolateral frontal
cortex was linked to OCD symptom
severity. No difference in 5-HT1B
receptors between OCD and HCs.
o The role of serotonin receptors in OCD is
inconclusive and remains unknown.
Neurotransmitters: Dopamine
OCD
Neurotransmitters: Dopamine • Animal studies have demonstrated that dopamine agonists can induce behavior that resembles OCD behavior in humans • Dopamine antagonists can improve OCD symptoms • Dopamine agonists can trigger or worsen OCD symptoms • Studies: Compulsive behavior in mice, rats, and dogs • Rats and mice treated with dopamine receptor agonists develop checking behavior and excessive lever pressing • Dogs, cats, and rabbits often spontaneously display compulsive behaviors (licking, tail chasing, circling behavior) can be treated with antidepressants, such as clomipramine and dopamine antagonists • Dopamine antagonists have also been used in the treatment of OCD in humans who do not respond to SSRIs or to augment SSRIs
Dopamine transporter protein (DAT) • DAT density in dogs with compulsive behaviors is either abnormally high or abnormally low in the striatum • Reduced availability of dopamine receptors in participants with OCD (controversial) o 18% decrease in striatal dopamine receptors (D2) availability in participants with OCD o an association between effectiveness of antipsychotic mediation (dopamine antagonist) and D2 and D3 receptor affinity.
Parkinson’s, Tourette’s and ADHD
• Genetic, structural, and functional studies
have implicated dopamine in all three of
these disorders, and OCD is often
comorbid with these disorders
• Interestingly, amphetamines that primarily
affect the dopaminergic system and are
used to treat ADHD, have been found to
sometimes induce OCD symptoms in
children and adults
• A side effect of dopamine agonists used to
treat Parkinson’s disease is compulsive,
repetitive behaviors
Dopaminergic agonist (Cocaine) OCD
• There is a relationship between cocaine
use, dopamine agonist, and increased risk
of OCD in adults. The intricacies of this
relationship are poorly understood.
• The serotonergic and dopaminergic
neurotransmitter systems function
interactively, and it is possible that
decreased inhibitory influences of
serotonin on dopaminergic neurons results
in hyperactivity of dopaminergic neurons
within the basal ganglia
• OCD may be the consequence of
dysfunctional interactive neurotransmitter
systems within the basal ganglia
Neurotransmitters: Glutamate
OCD
Link to dopamine
Link to treatment
- 40 - 60% of patients with OCD who do not respond to antidepressants often respond to other types of medications suggests other neurotransmitter are involved in the disorder
- Glutamate system directly affects dopamine-releasing neurons in the striatum, and glutamate antagonists have been found to improve OCD symptoms in treatment resistant cases
- Glutamate concentrations are higher in patients with OCD but were reduced to HCs levels following antidepressant treatment (i.e., dysfunction in glutamate system in the caudate nucleus is reversible with antidepressant treatment).
Neurotransmitters: Opioids
OCD
• The rate of OCD is four times higher in individuals addicted to opioids
- in treatment resistant ocd cased weekly oral doses of morphine (opioids) reduces OCD symptoms in OCD treatment-resistant patients
- Findings have been mixed regarding the effectiveness of opioid antagonists in reducing OCD symptoms.
Interventions: Pharmacological
OCD
• Antidepressants are the most commonly used medications for treating OCD, particularly SSRIs and the tricyclic antidepressant clomipramine.
o SSRIs and cognitive behavior therapy are the most effective form of treatment in both children and adults
§ Greatest benefits are found after 6 weeks of initiating SSRIs (symptoms are reduced not abolished – treatment responders often still show symptoms of OCD)
§ different forms of SSRIs show the same benefits, higher doses lead to greater symptom improvement but increases risk of side effects.
Clomipramine (trycilic antidepressants)
OCD
• Highly effective at reducing OCD symptomatology but is associated with more side effects and have lower compliance rates. • Side effects include: o Dry mouth o Blurred vision o Constipation o Fatigue o Tremor o Cardiac arrhythmia
Augmentation
- treatment non-response to medication or CBT is not uncommon (i.e., 40-60%). It is recommended to try other SSRIs, serotonin-norepinephrine reuptake inhibitor, or CBT.
- in treatment resistant cases it is also recommended to augment treatment with neuroleptics.
- the combination of SSRIs and Clomipramine is more effective at reducing OCD symptoms than either drug alone.
Neurosurgery
OCD
• Used in patients with chronically severe and treatment-resistant mental illness, including mood, anxiety disorders, and OCD
• 5 types of surgeries:
1. Subcaudate tractotomy: Lesion of area under the head of the caudate nucleus to interrupt connections between subcortical and orbitofrontal regions
2. Anterior capsulotomy: Lesion of pathways connecting the thalamus and the frontal lobes
3. Anterior cingulotomy: Lesion of the anterior cingulate cortex
4. Limbic leucotomy: (a combination of anterior cingulotomy and capsulotomy)
5. Gamma ventral capsulotomy: Delivery of gamma rays through the skull. Gamma rays destroy cells on the pathways connecting the dorsomedial thalamus and ventral prefrontal cortex and destroy cells therein (does not require opening the skull)
Neurosurgery Stats
• Neurosurgical procedures are effective at reducing intractable OCD symptoms in 35–75% of cases, with benefits extending 6–24 months after surgery
• Commonly reported negative side effects associated with these procedures include:
o Memory deficits
o Apathy
o Urinary incontinence
o Seizures
• Neurosurgical treatment of OCD does not have deleterious effects on personality
• Patients who show OCD symptom reduction also reported a reduction in neuroticism and an increase in extraversion, novelty seeking, and self-directedness
Reading:
• following a bilateral orbitomedial leucotomy revealed significant reductions of activity in the caudate, anterior cingulate, thalamus, and several frontal regions 18 days later, and sustained reduced glucose metabolism in these regions for three years. These reductions in activity were associated with improvement of symptoms and support involvement of subcortical-cortical pathways in OCD. Others found decreases in the medial frontal cortex, cingulate, and striatum.
What do we do? How do we treat OCD with all these mixed findings? Their life is still impaired, and we do not know how to help. We cannot use talk therapy, surgery/stimulation, medication to “fix” them without knowing the neurochemistry behind the disorder. They know there is something wrong/irrational with them, they do not need to be told that, they seek help on how to change it.
Brain Stimulation
Brain Stimulation Techniques: DBS
OCD
Brain Stimulation Techniques: DBS
• When used for OCD, DBS placement
typically involves the anterior limb of the
internal capsule/nucleus accumbens or
thalamus/subthalamic nucleus
o Difference in Unilateral vs. Bilateral
stimulation benefits remains unclear (some
advocate bilateral over unilateral)
• Study: Two of three patients showed
sustained improvement of symptoms over
time (33 months) with no harmful side
effects.
• Empirical evidence supports the efficacy of
DBS in treatment-resistant OCD with
assumable side effects
Brain Stimulation Techniques: ECT
OCD
• ECT has shown short- and long-term
reduction in OCD symptoms
• Study: Nearly all of 32 patients with
intractable OCD benefited from ECT and
that improvement was sustained over a 1-
year period
• A number of side effects are associated
with ECT including headaches, memory
impairment, nausea, and muscle aches
• very controversial to use on children –
most clinicians do not
Brain Stimulation Techniques: rTMS & trans cranial direct current stimulation: tDCS
• rTMS involves he rapid delivery of brief
magnetic pulses to the scalp that induce
neural depolarisation (increases excitation)
while low frequency pulses are thought to
increase neural inhibition.
• tDCS passes small electrical currents
through the skull and has a modulatory
effect on neurotransmission by either
increasing or decreasing neural firing at the
level of the cortex.
• To date, compared to pharmacological
interventions, relatively few studies have
investigated the efficacy of these
techniques at improving OCD symptoms
but preliminary findings are encouraging
