Theme 3 Lecture 10 – Anxiety disorders : Neurobiology, neurochemistry and treatment

question

What does conditioned fear stimulus and unconditioned fear stimulus on the amygdala do to the a) Lateral hypothalamus b) VTA, LC, DLTN c) Paraventricular nucleus in the hypothalamus
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a) Sympathetic activation, tachycardia, paleness, blood pressure elevation, pupil dilation b) Activation of DA, NA and Ach, EEG arousal and increased vigilance c) Release of CRH from hypothalamus and release from ACTH from the pituitary, cortisol release from the adrenal cortex, ‘fight or flight’ response
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What does the amygdala excite?
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The loccus coeruleus and the hypothalamus
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What is the HPA axis and what’s involved in it?
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The HPA axis is the hypothalamic pituitary adrenal axis Stress causes the paraventricular nucleus in the hypothalamus to release CRH (corticotrophic releasing hormone), the pituitary gland releases ACTH (adrenocorticotropic hormone), the adrenal cortex releases cortisol which is detected by the glucocorticoid receptors on the hypothalamus and hippocampus, inhibited by negative feedback. The hippocampus directly inhibits the hypothalamus. The loccus coerulus is also activated, releases noradrenaline which triggers a ‘fight or flight’ response. The cortisol released from the adrenal cortex has an effect on the serotonergic and 5HT system which directly inhibits the loccus coerulus.
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What affect does chronic stress have on the glucocorticoid receptors of the hippocampus?
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Chronic activation of the glucocorticoid receptors causes increased calcium entry into neurons and excessive release is excitotoxic, causing neurons to die. The hippocampus cannot feedback to cortisol production
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What do anxiety disorders result from? (4)
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Under-activity of the hippocampus Loss of feedback to the amygdala Inappropriate fear responding Lowered hippocampal volume
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What kind of response does the hippocampus give off when it is under stress?
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Feedforward response to the stress reponse
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What is the reduced hippocampal volume a sign of?
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Premature aging
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Explain the push-pull regulation of the HPA axis. What happens when the receptors of the hippocampus die?
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When there is a stimulus, the amygdala sends signals to the HPA axis The HPA makes cortisol which reaches the hippocampus and the hippocampus regulates the HPA by negative feedback If receptors on the hippocampus die because of the excess calcium, the hippocampus cannot control the HPA by negative feedback, leaving the positive signal from the HPA to the hippocampus, meaning that cortisol production still goes to the hippocampus – causing excessive stress
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What is the noradrenergic system for? What is the serotonergic system for?
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Noradrenergic – arousal and attention (fight or flight) Serotonergic – mood and emotion
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Where do the noradrenergic and serotonergic systems project to?
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They project to the forebrain and to the cortical and limbic areas
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What do the noradrenergic and serotonergic systems do to each other?
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They balance each other out and serotonin inhibits the loccus coeruleus from firing
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What is the result of dysregulation of the limbic system?
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Inappropriate fear and anxiety responses
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What are the 5 kinds of anxiety disorders?
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Post-traumatic stress disorder Panic disorder Generalized anxiety disorder Phobias Obsessive compulsive disorder
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What is post-traumatic stress disorder?
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Persistent psychological stress following the exposure to extreme stress
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What is panic disorder?
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Rapid-onset attacks of extreme fear and severe stress
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What is generalized anxiety disorder?
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Stress and anxiety in the absence of obvious precipitating stimulus
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What is a phobia?
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Stress and anxiety triggered by particular objects or situations
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What is obsessive compulsive disorder?
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Frequently recurring, uncontrollable, anxiety producing thoughts and impulses and responding to them dissipates associated anxiety
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What are the 3 treatments of panic disorder?
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Benzodiazepines which are GABA(A) receptor agonists SSRIs – selective serotonin reuptake inhibitor Cognitive behavioural therapy
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What are the effects of benzodiazepines?
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Anxiolytic effects – sedation and sleep induction, reduced muscle tone and coordination, anti-convulsants, anterograde amnesia
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What is panic disorder characterized by?
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It is characterized by unrealistic, unfounded fear and anxiety, acute and remitting terror for a variable length of time
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What are some of the features of panic disorder?
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Anxiety is normally helpful It causes the universal basic symptoms – breathlessness, irregular heartbeat, impending doom, sweating, dizziness, faintness Treatable Young adulthood onset Anticipatory anxiety – fear that another panic attack will follow leading to agoraphobia Associated with serious issues – alcoholism, depression, drug abuse
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What is an example of a benzodiazepine?
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Diazepam
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For which conditions do benzodiazepines work well and not so effectively in?
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Works well in GAD and PD but not so effectively in OSD and PTSD
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For which conditions do SSRIs work well in?
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GAD, PD, OSD, PTSD
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What are some of the undesirable effects of SSRIs?
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They can be anxiogenic in the short term, first few days of treatment The anxiolytic effects may not become apparent for a few weeks
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What is an example of a 5-HT receptor agonist?
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Buspirone
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Which condition does buspirone work for and how long does it take to exert a therapeutic potential?
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Works for generalized anxiety disorder and takes 4-6 weeks to exert a therapeutic effect
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What kind of drugs are anxiolytic?
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Drugs that increase GABA activity, decrease anxiety
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What are partial agonists? What are indirect agonists?
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Partial – alcohol, barbiturates Indirect – benzodiazepines
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What kind of drugs are anxiogenic?
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Drugs that decrease GABA activity, increase anxiety
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What drug is an example of a benzodiazepine antagonist?
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Flumazenil
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Which GABA receptor do benzodiazepine drugs work on?
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GABA(A) ionotropic receptor
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What are the drug actions on GABA(A) receptors with diazepam?
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When diazepam is present, there is increased chloride conductance and increased hyperpolarizing current. GABA antagonists will still decrease chloride conductance even if there are benzodiazepines present
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What is the evidence of GABAergic dysfunction in anxiety disorders?
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Flumazenil shows the binding sites for benzodiazepines. Patients with panic disorder have fewer BZDRs and means that they do not have sufficient inhibitory control in the cortical and limbic systems to suppress inappropriate fear and panic attacks
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Which cortex has increased activity during anxiety?
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Frontal cortex
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What is an example of a SSRI and what does it do?
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Selective serotonin reuptake inhibitor Fluoxetine/Prozac – used to prolong the 5HT in the synapse
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What is an example of a 5HT partial agonist?
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Buspirone
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What is the disadvantage of using SSRIs?
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There are no therapeutic effects until weeks into treatment and they are anxiogenic during the first few days
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What is the link between anxiety and depression? (3)
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They usually co-morbid each other – 85% of the depressed patients will have symptoms of GAD They are both treatable by SSRIs Both weeks before therapeutic actions are visible
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Why are changes not involved in initial treatment?
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Because boosting the levels of serotonin does not produce a therapeutic effect The therapeutic effect is a result of adaptive changes by the nervous system to the chronically elevated levels of serotonin
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What are the actions of antidepressants?
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Intracellular cascades stimulated by the activation of the 5-HT receptors lead to changes in the neuronal plasticity and morphology
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How can brain function be restored by antidepressants?
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The reversal of stress induced changes can restore brain function
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What is the more traditional hypothesis of a panic disorder?
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Serotonergic systems and noradrenaline systems project diffusely through the brain and have opposing functions Noradrenaline release stimulates arousal and alertness Serotonin inhibits noradrenaline release
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What are the opposing functions in the brain areas?
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Hippocampus, amygdala, hypothalamus
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What kind of shift causes panic attacks? How do SSRIs fix this balance?
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A shifted balance between the pathways to noradrenaline causes fear responses to inappropriate stimuli SSRIs increase the 5-HT release and pushes the balance back
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What are the compulsions involved in OCD?
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Counting, checking, cleaning, avoidance – exaggeration of normal human tendencies
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What is trichotillomania and onychophagia?
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Pulling out hair and biting fingernails
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What is the link between OCD and Tourette’s?
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There is a common genotype between OCD and Tourette’s
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What is Tourette’s syndrome and what kind of disorder is it?
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Tourette’s is a hereditary chronic motor tic disorder (muscular tic and vocal tic) and has its locus in the basal ganglia
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What does the direct pathway do?
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Control previously learned behavioural sequences so that they become automatic and can be rapidly executed
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What does the indirect pathway do?
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It is involved in suppressing the automatic behaviours to allow the person to switch to more adaptive behaviours – behavioural flexibility
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What in terms of direct and indirect pathways occur in compulsive behaviours?
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Overactivity of the direct pathway leading to compulsive behaviours not being able to switch off
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What are the best drugs to treat OCD?
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SSRIs – fluoxetine
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What is the relationship between the caudate and OCD?
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The caudate sends GABAergic inhibitory projections to the globus pallidus, which sends inhibitory projections to the thalamus and then projects onto the orbito-frontal cortex OCD involves a disinhibition which leads to activity continuing in this circuit
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What is the link between OCD and OFC dysfunction?
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The OFC is underactive in a reversal learning task in patients with OCD and unaffected patients There is a new endophenotype for OCD which could be a vulnerable marker
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What are the 3 treatment strategies?
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Benzodiazepine – Diazapram – but patients can develop tolerance, anxiety during withdrawal, potential for abuse but has good immediate effects SSRIs – fluoxetine – effective but take a while to produce a therapeutic effect, can be initially anxiogenic Combining benzodiazepines and SSRIs – can taper off the benzodiazepine until the SSRI takes an effect

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