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
