Dr.Priya AkulaSpeciality Doctor in Psychiatry

BackgroundSynaptic 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 namely-Serotonin,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-thalamic-cortical)loop,brainstem sites like parabrachial nucleus,periaquaductal gray(PAG) and locus coeruleus.

Definition of AnxietyAn emotion if when experienced in excess

can can cause an unpleasant feeling that is typically associated with uneasiness,apprehension,fear or worry.

Components of anxietyCognitive-Ex thought of something terrible

happening.Somatic-Ex Sweating,increases heart rate.Emotional-Ex gripped by fear.Behavioural-avoidance.

GADCore features generalised anxiety/fear generalised worryAssociated-muscle

tension,arousal,irritability,fatigue,interrupted sleep and concentration

Panic DisorderCore features anticipatory anxiety/fearWorry about panic attacksAssociated features-unexpected panic

attacks,phobic avoidance behavioural change

Social anxietyCore featuresSocial/ performance anxiety/fear and worry

about exposureAssociated with expected panic attacks and

phobic avoidance/behavioural change

PTSDCore featuresAnxiety about reexperiencing and worryAssociated with arousal,avoidance and poor

sleep.

OCDAnxiety or fear about obsessions or

complusionsAssociated worry

Circuits involvedAmygdala-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 cortico-striatal-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 fearFear 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 outputChanges 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 fearAutonomic 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

ReexperiencingTraumatic 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 GABAGABA 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 GABAThe 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 receptorsPre 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 G-protein-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 inhibitionBenzodiazepine 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 disorderA 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 AnxiolyticsExcessive 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 mechanismsPartial 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 agentsPathological 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 axisThe 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 anxiolyticsIt 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 AnxietyNorepinephrine 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 extinctionWhen 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(N-methyl-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 blockersThere 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 circuitOveractivation 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 PharmacyFirst line:SSRI’S,Benzodiazepines,SNRI’S

and Buspirone.Second line:Gabapentin,Pregabalin,TCA’S

and trazodone.Adjunctive Rx:Atypical antipsychotic.CBT

Panic disorder PharmacyFirst line:SSRI’S,Benzodiazepines,SNRI’S.Second

line:Gabapentin,PREGABALIN,MAOI’s,TCA’S,trazodone.

Adjunctive Rx:Atypical antipsychotics,lamotrigine and topiramate.

Social anxiety PharmacyFirst line:SSRI’S,Benzodiazepines,SNRI’S.Second line:MAOI’S,Gabapentin,Pregabalin

and beta blockers.

PTSD PharmacyFirst 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 PharmacyFirst line:SSRI’S.Second line:Clomipramine,MAOI’S and

SNRI’S.Deep brain stimulation is an experimental

option for Rx resistant patients.