Lecture 8 - Anxiety and Anxiolytics

Question 1

Describe chronic stress.

Answer 1

If a pressure stimulus does not subside then a pathological stress response is initiated.
Anxiety is one part of the stress response and it is the anticipation of a perceived threat (normal part of the stress response).
Sometimes anxiety does not subside and if it begins to affect day to day life then it becomes an anxiety disorder.

Question 2

What are symptoms of an anxiety disorder?

Answer 2

Tachycardia, hypertension, shortness of breath, sweating, muscle ache, irritability, depression, memory impairment.

Question 3

Describe obsessive compulsive disorder.

Answer 3

Obsessive repetitive thoughts that are often negative, counteracted by compulsive behaviours providing temporary relief.

Question 4

Describe panic disorder with or without agoraphobia.

Answer 4

Sudden, unexpected panic attacks, intense and recurrent fear of death, palpitations, tremor, dizzy, chest pain.
Lasts minutes.
Fear of certain places can lead to phobic avoidance.

Question 5

Describe phobic disorders.

Answer 5

Excessive fear that is disproportionate to the situation, generally predictable so phobic avoidance.

Question 6

Describe post traumatic stress disorder.

Answer 6

Onset delayed weeks to months following a traumatic experience, re-experience of trauma, fear of death.
Can be triggered by sensory cues so develop avoidance symptoms.

Question 7

What brain area is most heavily implicated in fear?

Answer 7

Amygdala

Question 8

Describe the circuit involved in stress response.

Answer 8

Amygdala receives info on stressful stimulus and appraises as stored emotional memories.
Emotional memories stored in the prefrontal medial cortices and the hippocampus.
Amygdala releases corticotrophin releasing factor (CRF) to act on CRF receptors in the striatum and locus coeruleus to activate a physical response via the parasympathetic NS.
Hippocampus also acted on by CRF to activate the sympathetic NS (fight or flight).
Hypothalamus is the top part of HPA axis, activates pituitary gland via CRF to release ACTH activating adrenal glands to release adrenaline and cortisol.
Normally when the fearful stimulus is removed the stress response subsides via negative feedback.

Question 9

What happens if the threat/pressure is unrelenting?

Answer 9

Repeated activation of the pathways in the brain causes the systems to become more dysfunctional.

Question 10

What did imaging and CSF studies of PTSD patients show?

Answer 10

Imaging studies - increased activity of the amygdala so activation threshold is lower.
CSF studies - elevated levels of CRF.

Question 11

Describe noradrenaline dysfunction in anxiety disorders.

Answer 11

At rest, NA levels are not any different to someone without anxiety.
Only when fearful stimulus is present NA levels are more elevated.

Question 12

Describe the evidence for GABAergic dysfunction in anxiety disorders.

Answer 12

Decrease in expression of GABAa receptors in those with anxiety (less inhibitory action).
PTSD patients had lower levels of benzodiazepine binding in their PFC indicating lower levels go GABAa receptors.
Cortisol appears to recede expression of GABAa receptors.
Adrenalectomy (removal of adrenal glands) - increased inhibitory GABAa receptor expression.

Question 13

Describe the evidence for serotonergic dysfunction in anxiety.

Answer 13

Lower expression of 5HT1A receptor binding in anxiety seen through PET imaging in those with social anxiety disorder.
Animal models that were subjected to prolonged stress showed a decrease in expression of 5HT1A receptor.
Adrenalectomy increases 5HT1A receptor expression.

Question 14

Describe traditional anxiolytics.

Answer 14

Historically grouped with sedatives and hypnotics.
Common side effects with acute and chronic use (tolerance, dependence).
Cause CNS depression so can cause poor memory and motor coordination.

Question 15

What are 3 traditional anxiolytics?

Answer 15

Alcohol
Barbiturates
Benzodiazepines

Question 16

Describe alcohol as an anxiolytic.

Answer 16

Not prescribed.
Non-specific CNS depressant.
Rapid side effects due to high solubility.
Self medication.

Question 17

Describe barbiturates as anxiolytics.

Answer 17

Effective but small therapeutic window - clinical dose is 10-100x lower than what would cause death so easy to overdose.
Potentiated by alcohol.
Should not be used for anxiety.

Question 18

What are 3 examples of benzodiazepines.

Answer 18

Midazolam
Oxazepam
Xanax

Question 19

Describe benzodiazepines as anxiolytics.

Answer 19

Number of therapeutic uses - short term sedation, relief of muscle tension, short term anxiolysis, hypnosis, anticonvulsant,
Commonly misused.
Side effects - unwanted sedation, amnesia (can be mistaken for dementia in elderly patients), reduced condition, reduction of motor coordination, decreased REM sleep, potentiated by alcohol.
Can be victim to tolerance, dependence and withdrawal syndrome after chronic use.

Question 20

What benzodiazepines have short half lives and what does this mean?

Answer 20

Midazolam and oxazepam.
Well absorbed and generally have a plasma peak in 1 hour so there is decreased daytime drowsiness and hangover.

Question 21

What benzo has an intermediate half life?

Answer 21

Xanax

Question 22

What benzos have a long half life and what does this mean?

Answer 22

Librium and valium.
Metabolised into active metabolites.

Question 23

Describe the mechanism of action of barbiturates on GABAa receptors.

Answer 23

Mechanism not well understood.
Can open the Cl- channel in absence of GABA enhancing inhibitory action (not safe in overdose).

Question 24

Describe the mechanism of action of benzo and alcohol on GABAa receptors.

Answer 24

Need GABA to open the receptor.
Enhance the action of GABA.
More Cl- enters to suppress the neuronal activity and suppresses the over activation of the fear pathway.

Question 25

Why do traditional anxiolytics have so many unwanted side effects?

Answer 25

There are many GABAa receptor combinations in the brain.
Benzo not selective and will activate any GABA receptor that has 2 alpha, beta and gamma molecules.
Alcohol even less selective as it targets any GABA receptor with 2 alpha and beta and 1 gamma molecules.
Activation of different subtypes of GABA receptors means different consequences - a1 subunit contain receptors associated with sedation, a3 subunit contains receptors associated with anxiolysis, a5 subunit contains receptors associated with learning and memory.

Question 26

Describe benzo chronic use side effects.

Answer 26

When using for a long time tolerance and withdrawal become a problem.
GABAa receptor decreases over time and the benzo effect is reduced as the receptors become more tolerant to it.
This means a higher dosage is needed and patients then have worse anxiety than to begin with.

Question 27

What are the 5 current anxiolytics used to treat anxiety?

Answer 27

Selective serotonin reuptake inhibitors (SSRIs).
Serotonin noradrenaline reuptake inhibitors (SNRIs).
Tricyclic antidepressants.
Monoamine oxidase inhibitors (MAOIs).
Buspirone.

Question 28

How do SSRIs, SNRIs, TCAs and MAOIs work?

Answer 28

Inhibit the transporter to prevent uptake of serotonin into the presynaptic terminal so more neurotransmitter is in the terminal to activate neurons in the postsynaptic cleft.
Acute use increases 5HT neurotransmission.

Question 29

How does buspirone work?

Answer 29

5HT1A receptor expression is decreased in anxiety disorders.
Buspirone is a partial 5HT1A receptor agonist, inhibiting 5HT release.

Question 30

What are some pieces of evidence for SSRIs decreasing the anxiety response?

Answer 30

Acute SSRI increases anxiety initially so how is there therapeutic effect reduction in anxiety?
5HT2C receptors involved in initial increase in anxiety when 5HT levels increase. SSRIs are 5HT2C agonists, decreasing 5HT2C receptors and therefore decreasing anxiety.
SSRIs can decrease the activation in the brain so CRF release is decreased which suppresses anxiety.
Anxious rats had heightened HPA axis response to air puff startle but chronic SSRIs decreased the HPA response (cortisol and ACTH levels) decreasing anxiety response.