Anxiety disorder Flashcards
State whether fear is normal or pathological, time-course
Normal
short
State whether stress is normal or pathological, time-course
Normal if shorter, but if chronic pathological
Shorter or longer lasting
State whether anxiety is normal or pathological, time-course
pathological
Long
What major pathways are activated in fear, stress and anxiety?
HPA (Hypothalamis Pituitary Adrenal) axis
ANS
Outline the link between stress and inflammation
Won and Kim 2016: brief lab stressors (mental maths) increased natural killer cell activity.
This increase potentiated in individuals whose cardiovascular systems activate more in stress.
Therefore, people with biggest sympathetic and endocrine responses have the largest immune responses.
How does the HPA axis increase sympathetic tone in response to stress?
Stress causes paraventricular nucleus (PVN) of hypothalamus to release CRH (corticotropin releasing hormone) that projects to brainstem and spinal cord.
Locus Coeruleus (brainstem) stimulated to release noradrenaline.
Noradrenaline acts on alpha1 receptors in sym preganglionic neurones that are Gq coupled and therefore increase intracellular calcium concentration.
What does activation of the sympathetic nervous system cause?
Fight or flight response, increased heart rate, production of stress hormones, blood directed to muscles, skin opens up pores so sweat more.
Outline role of amygdala in limbic system
Acts as central node by communicating to lots of other brain regions… activates hypothalamus
Asks:
what can I see, how do I feel, do I need to remember, what action am I going to take.
What role does the PAG play with amygdala and where is it found?
Periacqueductal grey: found at base of brainstem and talks to amgdala.
Responsible for freezing and active defensive behaviours.
Outline role of BNST in fear and anxiety
Bed Nucleus Striatum terminalis: recieves amygdala.
Distinct subregions exert opposing effects on anxiety (Kim et al., 2013).
Lesions of BNST diminish anxiety but leave fear responses intact (Duval et al., 2015)
What are the two main types of fear?
1) learned or conditioned
and
2) innate or unconditioned
Outline circuitry involved in mediating context dependent expression of fear in response to extinguished cue. How may this relate to anxiety disorders?
Hippo to BLA: renewal of fear expression in response to extinguished conditioned stim.
Hippo-Infralimbic- amy: context dependent expression of fear to extinguished stim.
Deficits in circuits thought to accompany PTSD
What are the 3 types of validity for animal models and do all animal models need to demonstrate all three types?
1) face: phenotypically similar
2) construct: theory behind model (gene KO)
3) predictive: sensitive to clinically effective pharmacological agents
Only one type of validity needed.
State the two major types of anxiety animal experiments and how they differ.
Spontaneous (innate stim) causes stress, no direct pain.
Conditioned: stim paired with uncomfortable sensation.
Define exteroceptive and give examples of stimuli models
Outside body
Open field test, Elevated plus maze, Social interaction test.
Define interoceptive and give examples of stimuli models
Inside body
Caffeine induced anxiety, foot-shock induced aggression, electrical stimulation of the brain.
Give examples of conditioned response animal models of anxiety
Geller-Seifter (press lever to get food, this lever pressing delivers shock, more anxious = less food press).
Give examples of unconditioned response animal models of anxiety
Open field, elevated plus maze, social interaction, predator smell.
Animal: Outline the open field test
Anxious mouse spends more time in periphery close to walls.
Animal: Outline novelty supressed feeding
Anxious take longer to both approach and eat food.
Animal: Outline elevated plus maze
More anxious spend more time in arms of +
Animal: Outline social approach
More anxious spend more time with object than other mouse.
Animal: Outline light-dark test
More anxious mice spend longer in dark area
Animal: Outline fear conditioning
More anxious exhibit increased freeze behaviours and take longer to perform task
State the different ways we can test for anxiety in humans
Galvanic skin response: when anxious sympathetic is activated and therefore sweat more. Sweat increases skin conductance
ECG: T wave inversion sign of anxiety
Tests: such as GAD-7 that are questionaires.
What is the neural circuitry that underlies anxiety?
Duval et al., 2015: There is no common circuit for all diff types of anxiety.
E.g. hyperactivation of hippocampus implicated in PTSD (hypo also in PTSD) and social anxiety disorder. But hippo plays more than one role so most likely involved in different processes in both.
State differential neurocircuitry associated with GAD
Duval et al., 2015: hypoactivation of ACC, PFC when percieved threat.
Hyperarousal to emotion due to ineffective PFC processing.
State differential neurocircuitry associated with OCD
Duval et al., 2015: CSTC
Cortex underactive so stay locked in loop.
Greater activation of direct pathway than neurotypical and hypo of indirect
State differential neurocircuitry associated with SAD
Duval et al., 2015: hyperacativation of limbic system esp, amygdala in response to social stim.
Disfunction between corticolimbic.
Hyperactivation of insula and PFC in response to social emotion.
State differential neurocircuitry associated with PD
Duval et al., 2015: hyperactivation of fear network, brainstem and hypothalamus (though panic symptoms).
Hyper insula - bodily sensations.
State differential neurocircuitry associated with PTSD
Duval et al., 2015: hyperactivation of lateral and BLA for fear consolidation and expression.
Hyper insula
Hypo ACC and PFC which leads to insufficient regulation of limbic.
What is the ACC and role in anxiety?
Anterior Cingulate cortex (part of limbic cortex).
Emotional processing: conflict monitoring, error detection.
What is PFC and role in anxiety?
Prefrontal cortex
When PFC hypo or not efficient amygdala takes on bigger role (bad as less regulation)
Outline function of the Cortico-striatal-thalamo-cortical pathway and state anxiety disorder it has been implicated in
brain circuit that controls movement execution, habit formation and reward. Hyperactivity = OCD
Radulescu et al., 2017
State lifetime prevalence, symptoms and prognosis of GAD
LP: 5.1%
Symptoms: 3 or more of (restlessness, fatigue, concentration difficulties, irritability, muscle tension, sleep disturbances.
Prognosis: ~70% recover
What does GAD stand for and give medical definition
Generalised anxiety disorder: excessive worry occuring more days than not for at least 6 months.
Generalised Anxiety Disorder Questionnaire (GAD-7) is how diagnosed
State treatments used for GAD
Drug: SSRI and BDZ (BDZ are effective and provide rapid relief but are not prescribed for use over 4 weeks due to concern about withdrawal). BDZ slowly withdrawn and only SSRI remains after.
TCAs and MAOis
Other: CBT
What does PD in anxiety stand for and state medical definition
Panic disorder: discrete period of intense fear or discomfort in which symptoms develop abruptly and peak within 10 minutes. 4 or more panic attacks in period of four weeks.
State lifetime prevalence, symptoms and prognosis of PD
LP: 3.5%
Symptoms: palpatations, sweating, trembling, shortness of breath, naseua or abdominal pain, depersonalisation, numbness or tingling.
Prognosis: 25-45% improve
State treatments used for PD
Drug: SSRI and Alprazolam only (BDZ with short half life) Other BDZ are effective only at high doses and therapeutic effect slower.
Also treated with antidepressants: TCAs, MAOi (phenelzine)
Other: Exposure
NB: evidence shows treatments with longest duration of effect in decending order…
CBT, Self help, pharmacological
When does PD most frequently first occur?
Early 20’s
How many times more likely is it for women to suffer from PD and why?
2.5X
Progesterone: converted in brain to allopregnanolone which enhances function of GABA A thus acting as anxiolytic via allosteric modulation and increases CL-
In PMS, decreased progesterone which mimicked in rats by BDZ abrupt withdrawal.
More alpha 4 subunit encoding therefore subunit expression changes. less inhibition of amygdala. (Smith et al., 1998)
Furthermore, as oestrogen drops in some women so does serotonin…
Outline co-morbidity of GAD, major depression, and panic disorder
GAD: 2.6X more likely major D, 5.2X more likely panic disorder.
MD: 26.5X more likely panic
Panic: 9.4X more likely MD
What is agoraphobia and how does it relate to panic disorder
extreme or irrational fear of entering open or crowded places, of leaving one’s own home, or of being in places from which escape is difficult.
95% of patients with panic disorder will develop.
State lifetime prevalence, symptoms and prognosis of PTSD
LP: 6.2-8.2% men 13-20.4% women (Byrant, 2019)
Symptoms: re-experiencing trauma (flashbacks or nightmares), avoidancen(decreased participation) hyperarousal and emotional numbness ( agression, hypervigilance, difficulty sleeping, problems concentrating)
Prognosis: Over 50% leave ‘clinical’ class
What does PTSD stand for, give definition
Post Traumatic Stress Disorder: Diagnosed when person experiences symptoms for at least one month following event.
NB: symptoms may not appear until several months or years after event.
What types of events lead to PTSD?
Exposure to actual or threatened death, serious injury or sexual violation.
State lifetime prevalence, symptoms and prognosis of OCD
LP: 2.5%
Symptoms: Obsessive thoughts (unwanted and unpleasant, repeatedly enters mind) and compulsive behaviours (repetitive behaviour or mental act that you feel you need to carry out to temporarily relive unpleasant feelings)
Prognosis: 60% improve within a year
Define OCD
Obsessive compulsive disorder: no test for OCD diagnosed after asked about symptoms.
State lifetime prevalence and prognosis of specific phobias
LP: 11.3%
Prognosis: reduction common but loss of phobia rare
State lifetime prevalence and prognosis of social phobias
LP: 13.3%
Prognosis: 75% replapse on drug withdrawal
Give evidence via animal models that anxiety disorders are disorders of synaptic plasticity
McEwen, 2000: chronic restraint stress caused apical dendrites of pyramidal ca3 cells in rats to atropy.
Wang et al., 2020: Mice experience maternal stress early in life have decreased post synaptic density in hippocampus later in life. Greater anxiety scores in open field test etc
Issue with experiment is that MS stress group also recieved chronic restraint. So combo…
Outline animal experiment on effect of progesterone on anxiety
Hantsoo and Epperson 2020: progesterone exposure and rapid withdrawal upregulated expression of alpha 4 subunit in rats.
Increased alpha 4 associated with increased anxiety
How is BDNF implicated in synaptic plasticity
BDNF (brain derived neurotropic factor)
Mahan and Ressler (2012): single nucleotide polymorphism (SNP) found in brains of humans and alters BDNF stability and release. SNP humans show greater recruitment of amygdala. KI mice showed increase anxiety, impaired NMDA plasticity. BDNF binds to TrkB and activates, ras/erk pathway. (inhib of erk shown to prevent ampar insertion).
Braham and Messaoudi (2005):TrkB is localised to glutamatergic NMDARs and enhances function.
Give evidence of structural and functional plasticity in anxiety
Stress reduces spine density and impairs LTP in the PFC and hippocampus pyramidal neurons (Rosenkranz et al., 2010
Give clinical/human evidence for plasticity in anxiety
Hippocampus stress-induced shrinkage of hippocampal neurons in rodents and reduced volume in depressed human patients.
However, inconsistency in volume in amygdala where diff studies show increase, decrease and no change in volume (Christoffel, 2011)
Give general molecular structure of BDZs
Contain aromatic rings
Outline the structure of a GABA A receptor
Pentameric transmembrane ionotropic receptor that opens to cause Cl- influx.
5 subunits (2 alpha1, 2 beta1 and gamma2) most common around ion channel pore.
Where is BDZ site on GABA AR?
on most common found gamma2 and alpha1
How do BDZ impact GABA A? name one
Increases frequency of channel opening: causes GABA dose-response curve to shift to left.
This means less GABA needed to produce same response.
diazepam
If alpha1 subunit of GABA A is eliminated what effect is eliminated?
sedation
If gamma2 subunit of GABA A is eliminated what effect is eliminated?
anxiolytic
How do barbituates impact GABA A? name one
Increase length of time cl- (chloride) pore stays open. Shifts dose-response curve to the left and increases maximal possible response.
Pentobarbital
How do steriods impact GABA A? name one
Potentiate actions of GABA via increasing opening frequency and lifetime.
allopregnanaolone
The lower the Ki…
The greater the binding affinity
How does affinity relate to therapeutic dose for BDZ
The greater the affinity (the lower the Ki value) the lower the therapeutic dose.
State other properties of BDZ use other than anxiolytic
Sedation, anti-epileptic, amnesia, can cause loss of inhibitions
State and explain reasons that BDZ are used as anxiolytics instead of barbituates.
1) Barbituates have low therapeutic index (LD50/ED50 as low as 3:1 whereas BDZ 1:300), therefore high risk overdose.
2) Barb causes respiratory depression
3) Barb shows rapid tolerance and convulsions upon withdrawal
4) Barb induce liver microsomal enzymes which modify the blood level of other drugs.
Name an antagonist for BDZs and state why this is useful
Flumazenil: can reverse effects (if for some lethal too high dose)
Note flumazenil has a short half-life and multiple use is often required in benzodiazepine overdose
Outline how OCD is managed
Drug: SSRIs
Other: CBT
often offered in combo
Outline how specific phobias are treated
Behaviour therapy but if immediate help is required (for help in air travel) BDZs can be used.
Outline how social phobia is treated
Beta-blockers as the symptoms are peripheral rather than central (propranolol drug of choice)
Define insomnia
sleep disorder characterised by difficulty falling or staying asleep
Describe obstructive sleep apnea
Partly or complete blockage of upper airway when asleep. So continuously wake up due to lack of oxygen.
Describe central sleep disorder
Lower brainstem dysfunction causes you to wake up regularly during sleep.
Describe hypersomnia
Trouble staying awake during the day
Describe parasomnia
Disruptive sleep disorders that can occur during arousals from REM sleep or partial arousals from non-REM sleep. Include nightmares, night terrors, sleepwalking, confusional arousals etc.
Describe REM sleep disorder
Paralysis that usually occurs in REM sleep is absent allowing person to act out his or her dreams
Describe narcolepsy
Suddenly fall asleep at innappropriate times, neurological disorder
Outline when circadian rhythm sleep disruptions occur
Time zone changes, pre-menopause and AD or Parkinson’s
Outline lifestyle changes to treat imsomnia
Go to bed and get up same time everyday, avoid caffeine and alcohol in evening, avoid naps, if you cannot sleep get up and occupy yourseld until you feel sleepy.
Outline drugs used to treat imsomnia
Hypnotics:
Short acting BDZs and Z (Zolpidem, selective for alpha1 containing subunits.
Zopiclone: non selective adn longer half life
Zaleplon: v short half life selectivity same as Zolpidem
BDZ can be used as both an anxiolytic and a hypnotic: explain
Higher dose = sedative as greater receptor activation (80%).
anxiolytic only 30% receptor activation recquired.
Why do we want the time course of hypnotics and anxiolytics to be different
Hypnotics: we want short time course so can wake up
Anxiolytic: long time course
Why do we want the time course of hypnotics and anxiolytics to be different
Hypnotics: we want short time course so can wake up
Anxiolytic: long time course
State molecular structure of hypnotic BDZs
Multiple phenyl rings
Outline drug interactions of BDZs
When combined with CNS depressants will exacerbate sedative effects and leads to decreases in psychomotor performance.
CNS: antidepressants, narcotic analgesics, antipsychotics, antihistamines, alcohol.
Can be life threatening in combo.
Outline PTSD treatment
Drug: antidepressants (sertraline etc used for adults).
Other: CBT, group therapy, eye movement desensitisation, reprocessing (EMDR)
Outline EMDR
Subjects make specific eye movements (thought to decrease negative emotion) while talking about memory. Faster than regular talking.
Lack of longterm research and some people believes promotes dissociation.
Some see reliving as making new memories as synaptic plasticity.
Why do anxiolytic drugs target GABA receptors
Low levels of GABA implicated in anxiety disorders.
Deactivation of enzyme needed for GABA synthesis = loss of anxiolytic BZD effects. (Nuss 2015)
Name neurosteroids and impact on anxiety
Serotonin: decreases via activation of serotonin
Allopregnanolone: enhances function of GABA AR, increases channel opening frequency and lifetime
Pregnenolone sulfate (note E): acts as antagonist to GABA AR.
Outline mechanism of action of SSRIs
Selective Serotonin Reuptake Inhibitors inhibit the serotonin transporter (SERT), increased 5-HT in synaptic cleft.
List side effects SSRIs and state why they have less side effects than TCAs and MAOis.
SE: weight changes, dizziness, sexual dysfunction
As no effect on dopamine, noradrenaline, histamine etc. SSRIs are specific.
Outline mechanism of action of tricyclic antidepressants
Acts on different neurotransmitter pathways:
1) block serotonin reuptake
2) block noradrenaline reuptake.
3) decrease 2-adrenoreceptor sensitivity as competitive antagonists to acetylcholine, acetylcholine decreases release into presynapse. (alpha1,2 and histaminergic receptors).
4) reduce Beta1 sensitivity, connected to K, therefore, less K influx and more hyperpol.
1 and 2 = antidepressant
Describe mechanism of action of MAOi’s and state what acronym stands for
Monoamine oxidase inhibitors: block action fo monoamine oxidase enzyme which breaks down (noradrenaline, serotonin, dopamine and tyramine). Thus, increasing level in brain, increased response from above transmitters.
Describe mechanism of action of propanolol
beta-adrenoreceptor 1 and 2 antagonist.
When above receptors activated, increased cAMP which leads to increased contractability of muscle fibres in heart
Give evidence for antihistamines as an axiolytic
h1R antagonist improved anxiety in open field test.
Outline how cannabis is regarded as both an axioltyic and an anxiogenic
THC: anxiogenic
CBD: anxiolytic
However, low dose CBD (4mg) increased intoxicating effects of THC whereas high (400mg) decreased.
Conversely…biphasic effect: low dose cannabinoids interact with cortical glutamergic CB1 receptor terminals = anxiolytic
At higher doses… interacts with CB1 receptors on GABAergic terminals = anxiogenic.
Why are TCAs only used for severe anxiety
Low therapeutic index (prone to overdose).
Side effects: block of acetylcholine. dry mouth.
slight blurring of vision, constipation, problems passing urine.
drowsiness.
dizziness.
weight gain.
This is due to block of choline receptors.
Why can MAOis be used to treat parkinson’s?
Decreased DA in PD, so….
blocking enzyme increases DA therefore good.
Why have MAOis been replaced?
increase blood pressure therefore have to be on strict diet.
Possibility of serotonin syndrome.
How does histamine receptor block anxiolytic?
Histamines = inflammatory therefore anxiogenic
Antihistamines = anti-inflam, sedative and have anxiolytic effect
Outline HPA activation in stress
Hypothalamus activated by amygdala and signals to pituitary by releasing CRH (corticotrophin releasing hormone).
Pituitary release ACTH (adrenocorticotropic releasing hormone).
ACTH causes adrenal gland to release cortisol.
There are feedback loops ie (when cortisol released less ACTH and CRH released).
Theory behind PTSD?
At time of trauma: surge in number of stress hormones = strong associative learning event.
Byrant, 2019
Volumetric brain changes in PTSD?
Kuhn et al.,
MRI on soldiers before and after deployment.
findings: no diff in hippocampus (smaller predisposes), reduction in ACC, mPFC, thalamus (extinction learning) that persist.
Issues: few women sampled, no soldiers developed PTSD, childhood etc.
