Transcript Anxiety Disorders - Dr Akulax

Dr.Priya Akula
Speciality Doctor in Psychiatry
Background
 Synaptic neurotransmission is the foundation of
psychopharmacology.Neurotransmission has an anatomical
structure(made of neurons-cell bodies,axons and dendrites) but
fundamentally is a very elegant chemical operation.There are several
hundreds and thousands of brain chemicals which could possibly act as
neurotransmitters but of particular relevance in psychopharmocology
are half a dozen of those sometimes referred to as the ‘’classic’’ because
they were discovered first and also because they have developed into
major target systems for psychotopic drugs namelySerotonin,norepinephrine,dopamine,acetylcholine, glutamate and
GABA.The anatomical focus in anxiety and related conditions will be
amygdala centred circuit with reciprocal connections to and from
hippocampus,anterior cingulate cortex,orbitofrontal
cortex,hypothalamus,thalamus,CSTC(cortico-striatal-thalamiccortical)loop,brainstem sites like parabrachial nucleus,periaquaductal
gray(PAG) and locus coeruleus.
Definition of Anxiety
 An emotion if when experienced in excess can can
cause an unpleasant feeling that is typically associated
with uneasiness,apprehension,fear or worry.
Components of anxiety
 Cognitive-Ex thought of something terrible
happening.
 Somatic-Ex Sweating,increases heart rate.
 Emotional-Ex gripped by fear.
 Behavioural-avoidance.
GAD
 Core features
generalised anxiety/fear
generalised worry
Associated-muscle
tension,arousal,irritability,fatigue,interrupted sleep
and concentration
Panic Disorder
 Core features
anticipatory anxiety/fear
Worry about panic attacks
Associated features-unexpected panic attacks,phobic
avoidance behavioural change
Social anxiety
 Core features
 Social/ performance anxiety/fear and worry about
exposure
 Associated with expected panic attacks and phobic
avoidance/behavioural change
PTSD
 Core features
Anxiety about reexperiencing and worry
Associated with arousal,avoidance and poor sleep.
OCD
 Anxiety or fear about obsessions or complusions
Associated worry
Circuits involved
 Amygdala-central role,the connections from and to the
amygdala integrate both sensory and cognitive
information and then use that information to
trigger(or not) a fear response.Affect of fear-feelings of
fear are regulated by reciprocal connections between
the amygdala and anterior cingulate cortex and
amygdala and the orbitofrontal cortex-overactivation
of these circuits produces feelings of fear.The corticostriatal-thalamic circuit(CSTC) is involved in
processing the information received from amygdala
and generate appropriate functional and behavioural
responses.
 Avoidance-feelings of fear may be expressed through
behaviours as avoidance which is mediated by
connections between amygdala and periaqueductal
gray matter
 other motor responses are flight or run
away,fight,freeze.
Endocrine output of fear
 Fear response may be associated with increases in
cortisol which occur because of amygdala activation of
HPA axis.Prolonged HPA activation and cortsol release
can have significant health risks-coronary artery
diseasse,type 2 diabetes and stroke.
Breathing output
 Changes in respiration may occur during a fear
response and are regulated by actvation of
parabrachial nucleus via the amygdala.Inappropriate
or excessive activation of PBN can lead not only to
increases in the rate of respiration but also to
symptoms such as shortness of breath,exacerbation of
asthma or a sense of being smothered.
Autonomic output of fear
 Autonomic responses are typically associated with
feelings of fear.These include increases in heart rate
and BP which are regulated by reciprocal connections
between the amygdala and locus coerulus
Reexperiencing
 Traumatic experiences stored in hippocampus can
activate the amygdala and generate a fear response and
is a particular feature of PTSD.
Neurotransmitters that regulate
the fear circuits

Fear

I

Amygdala centred circuit

I

5HT,GABA , Glutamate,
CRF/HPAcorticotrophin releasing factor,
NE(norepinephrine)and voltage gated ion channels
Role of GABA
GABA is the principal inhibitory neurotransmitter in
the brain and normally serves an important regulatory
role in reducing the activity of many
neurons,including those in amygdala and in the CSTC
loops.Benzodiazepines,perhaps the best known and
most widely used anxiolytics act by enhancing the
actions of GABA at the level of amygdala and the
prefrontal cortex within the CSTC loops to relieve
anxiety.
Production and termination of
GABA
 The aminoacid glutamate,a precursor to GABA,is
converted by the enzyme glutamic acid decarboxylase
to GABA which is transported into synaptic vesicles via
vesicular inhibitory amino acid transporters(VIAATS)
and stored until its release into the synapse during
neurotransmission.Termination:GABA can be
transported back into presynaptic neuron via the
GABA transporter(GAT) where it can be repackaged
for future use.Alternatively,once GABA has been
transported back into the cell,it may be converted into
an inactive substance via the enzyme GABA
transaminase.
GABA receptors
 Pre synaptic-GAT,GABA-A,B and C-post synaptic.
 GABA-A and GABA-c are ligand gated ion channels,they
are part of a macromolecular complex that forms ann
inhibitory chloride channel.GABA-B receptors are Gprotein-linked receptors that may be coupled with calcium
or potassium channels.Different types of subunits combine
to form GABA-receptor(alpha,beta,gamma,delta,epsioln,pi
and theta).Benzodiazepine-sensitive GABA-A receptor
contains gamma and alpha sub units.Those containing
alpha 1 subunits are involved in sleep,while those
containing alpha 2 and/or alpha 2 subunits are involved in
anxiety.
Tonic and Phasic inhibition
 Benzodiazepine sensitive GABA-A receptors(those
containing gamma and alpha 1 through alpha 3
subunits)are post synaptic receptors that mediate
phasic inhibition,which occurs in bursts triggered by
peak concentrations of synaptically released
GABA.Benzodiazeoine-insensitive GABA-A
receptors(those containing alpha 4,alpha 6,gamma 1,or
delta subunits)are extra synaptic and capture GABA
that diffuses away from the synapse and these
receptors mediate inhibition that is tonic i.e,mediated
by ambient levels of extracellular GABA that has
escaped from the synapse.
Positive allosteric
modulation(PAM)
 When GABA binds to its sites on GABA-A receptors it
increases the frequency of opening of chloride channel
and thus allows more chloride to pass through.When a
positive allosteric modulator such as benzodiazepine
binds to GABA-A receptor in the presence of GABA,it
causes the channel to open even more frequently than
when GABA is present alone.When Benzodiazepine
binds to GABA-A receptor in the absence of GABA it
has no effect on chloride channel.
Benzodiazepine agonist spectrun in
Panic disorder
 A theory about the biological basis of panic disorder is that
there is an abnormality in the set point for benzodiazepine
receptors.The normal sensitivity of these receptors is
switched rendering the receptors less sensitive to full
agonists and experiencing antagonists as inverse
agonists.This notion is supported by the fact that the
antagonist flumazenil is ‘silent’ and has no effect in
unmedicated normal controls but can induce mild anxiety
in unmedicated patients with panic disorder.Flumazenil
acts as a negative allosreic modulator and is mostly a silent
antagonist but will reverse the positive allosteric
modulation of Benzo’s and is used clinically to reverse
sedation when Benzo’s are taken in a overdose.
Benzodiazepines as Anxiolytics
 Excessive amygdala activity is theoretically reduced by
enhancing the phasic inhibitory actions of
benzodiazepines at the postsynaptis GABA-A
receptors within the amygdala to blunt fear-associated
outputs.
Novel anxiolytics involving GABA
mechanisms
 Partial agonists that are selective for alpha 2 or 3 subunits
of GABA-A receptor may,like current benzodiazepines that
bind there,be anxiolytic yet may also cause less sedation
and have less abuse potential.Inhibition of the GABA
transporter-GAT for example by the anticonvulsant
tiagabine has been shown to provide anxiolytic
effects.Some anticonvulsants may increase GABA’s release
or reduce its destruction via GABA transaminase either of
which could have anxiolytic effects.Finally,it is possible that
GABA-B receptors may play a role in anxiety thus positive
modulators of those receptors are potential therapeutic
agents.
Potential therapeutic effects of
Serotonergic agents
 Pathological fear/anxiety mediated by overactivation
of amygdala circuits which receives inout from
serotonergic neurons and thus serotonergic agents
may be useful in alleviating anxiety by enhancing
serotonin output into amygdala.This is substantiated
by the anxiolytic actions of Buspirone at both pre and
post synaptic 5HT1-A receptors and also therapeutic
benefits from various SSRI’S as well as
SNRI’S.Note:Buspirone,serotonin partial 1 A agonist is
recognized as a generalised anxiolytic but not for
anxiety disorder subtypes.
Born fearful?
 The type of serotonin transporter (SERT)gene you are
born with determines whether your amygdala
overreacts to fearful faces.
 Individuals who are carriers of the s-variant of the gene
for SERT appear to be more vulnerable to the effects of
stress or anxiety where as those who carry the I variant
appear to be more resilient.
Does brain atrophy under stress?
 Some reports have suggested that hippocampal atrophy may
actually occur with chronic stress,major depression,or various
anxiety disorders particularly PTSD.One factor that could
contribute to potential brain atrophy is the impact of chronic
stress on Brain derived neutrophic factor(BDNF) which plays a
role in growth and maintenance of neurons and neuronal
connections.During chronic stress the genes for BDNF may be
turned off,potentially reducing its production which could
compromise the brain’s ability to create and maintain neurons
and their connections and this could lead to loss of synapses or
even whole neurons by apoptosis.Serotonin can increase the
availability of BDNF by initiating signal transduction cascades
and thus brain does have copensatory mechanisms that can
reverse or prevent neuronal loss resultinf from suppression of
BDNF genes.These actions can be further boosted by agents like
SSRI’S.
Stress and HPA axis
 The normal stress response involves activation of the
hypothalamus and a resultant increase in corticotrophin
releasing factor(CRF),which in turn stimulates the release of
adrenocorticotrophic hormone(ACTH) which causes
glucocorticoid release from adrenal gland which in turn feeds
back to hypothalamus and inhibits CRF release terminating the
stress response.In situations of chronic stress,excessive
glucocorticoid release may eventually cause hippocampal atrphy
and because the hippocampus inhibits the HPA axis,the atrophy
in this region may lead to chronic activation of HPA axis which
may increase risk of psychiatric illness.Because the HPA axis is
central to stress processing,it may be that novel targets for
treating the stress induced disorder lie within this
axis.Mechanisms being examined include antagonism of
glucocorticoid receptors,CRF-1 receptors and vasopressin-B
receptors.
Alpha 2 delta ligands as anxiolytics
 It has been found that agents that bind to the alpha 2
delta subunit of the presynaptic N/Q voltage-sensitive
calcium channels can block excessive activation of
neurons in amygdala and thereby reduce symptoms of
anxiety.An interesting aspect of alpha 2 delta ligands is
that they appear to have much greater affinity for their
binding site when their channel is in use and thus may
be most effective in situations where neurons have
excessive activity,as hypothesized for anxiety disorders
in the amygdala while the patient is still experiencing
anxiety and fear.Examples include Pregabalin and
Gabapentin.
Noradrenergic hyperactivity in
Anxiety
 Norepinephrine is another neurotransmitter with important
regulatory input to the amygdala as well as many projection areas
of amygdala.Excessive noradrenergic output from the locus
coeruleus can result not only in numerous peripheral
manifestations of autonomic overdrive but can also trigger
numerous central symptoms of anxiety and fear such as
nightmares,hyperarousal states,flashbacks,panic attacks.In some
patients such symptoms can be relieved by traetment either with
beta adrenergic blockers(propranolol)or alpha 1 adrenergic
blockers(Prazosin).Although antidepressants with prominent
NA actions(like SNRI’S which inhibit norepinephrine
transporter) are not favoured over SSRI’S some patients do
respond to them presumably due in part to desensitize
postsynaptic beta and alpha 1 noradrenergic receptors over time.
Fear conditioning versus fear
extinction
When an individual encounters a stressful or fearful
experience,the sensory output is relayed to th
amygdala,where it is integrated with the ventromedial
prefrontal cortex(VMPFC) and hippocampus,so that a
fear response can either be generated or
suppressed.The amygdala may ‘’remember’’stimuli
associated with that experience by increasing the
efficiency of glutamate neurotransmission,so that on
future exposure to stimuli,a fear response is more
efficiently triggered.If this is not countered by input
from VMPFC to suppress the fear response fear
conditioning occurs.
Learning to forgive but not forget
Fear conditioning is not readily reversed,but it can be
inhibited through new learning.This new learning is
termed fear extinction and is the progressive reduction
of the response to a feared stimulus that is repeatedly
presented without adverse consequences.Thus the
VMPFC and hippocampus learn a new context for the
feared stimulus and send input to the amygdala to
suppress fear response.The ‘’memory’’of
theconditioned fear is still present though.
Novel therapeutics
 Strengthening of synapses involved in fear extinction
could help enhance the development of fear extinction
learning in amygdala and reduce symptomps of
anxiety disorders.Administration of the NMDA(Nmethyl-d-aspartate)co-agonist d-cycloserine while an
individual is receiving exposure therapy could increase
the efficiency of glutamate neurotransmission at
synapses involved in fear extinction.
Preemptive treatment with beta
blockers
 There is some research to suggest that admininstration
of beta adrenergicblockers immediately following
exposure to trauma could block fear conditioning
before it even occurs.Blockade of beta receptors in the
VMPFC and hippocampus may prevent input from
reaching the amygdala thus preventing fear
conditioning.Some even call it postexposure
‘’inoculation’’.
Worry/Obsessions circuit
 Overactivation of CSTC(cortico-striatal-thalamic-
cortical)loop originating and ending in dorsolateral
prefrontal cortex(DLPFC) may lead to worry and
obsessions.This circuit is regulated by
serotonin,GABA,Dopamine,Norepinephrine,glutamate
and voltage gated ion channels.Genotype for the
enzyme COMT(Catechol-O-methyl-transferase)not
only regulate the availability of dopamine in prefrontal
cortex but also how such differences may affect the risk
for worry and anxiety disorder and may well determine
whether you were born worried.
GAD Pharmacy
 First line:SSRI’S,Benzodiazepines,SNRI’S and
Buspirone.
 Second line:Gabapentin,Pregabalin,TCA’S and
trazodone.
 Adjunctive Rx:Atypical antipsychotic.
 CBT
Panic disorder Pharmacy
 First line:SSRI’S,Benzodiazepines,SNRI’S.
 Second
line:Gabapentin,PREGABALIN,MAOI’s,TCA’S,trazodo
ne.
 Adjunctive Rx:Atypical antipsychotics,lamotrigine and
topiramate.
Social anxiety Pharmacy
 First line:SSRI’S,Benzodiazepines,SNRI’S.
 Second line:MAOI’S,Gabapentin,Pregabalin and beta
blockers.
PTSD Pharmacy
 First line:SSRI’S and SNRI’S.
 In PTSD,unlike in other anxiety
disorders,benzodiazepines have not been found to be
helpful,although they may be considered with caution
as second line along with
gabapentin,pregabalin,TCA’S,MAOI’S.
OCD Pharmacy
 First line:SSRI’S.
 Second line:Clomipramine,MAOI’S and SNRI’S.
 Deep brain stimulation is an experimental option for
Rx resistant patients.