Anxiety

Question 1

What is anxiety?

Answer 1

feeling of unease (worry or fear) which can range from mild to severe

Question 2

When does anxiety become a problems?

Answer 2

When the intensity changes from intermittent –> chronic

+ when source becomes irrational

Question 3

What does anxiety lead to?

Answer 3

Social disturbances
Avoidance behaviours
Incessant worry
Concentration/memory problems

Question 4

What can cause the symptoms of anxiety?

Answer 4

Difficult past/ childhood experiences

everyday life and habits - current issues or problems in every day can lead to anxiety

Diet - sugar and caffeine can trigger symptoms of anxiety

Physical and mental health can trigger or exacerbate anxiety

Drugs and medication - alcohol, recreational drugs and some prescribed medication can trigger anxiety

Genetics?

Question 5

Expand on how alcohol can cause anxiety

Answer 5

Alcohol is a depressant and has a sedative effect; however, these benefits are short-lived.

Subsequent neurotransmitter imbalance (e.g. GABA, glutamate) can lead to anxiety symptoms.

Question 6

What does research show about genetics and anxiety?

Answer 6

Research has linked genetic factors to a number of anxiety disorders (e.g. panic disorder).

However, genetic risk is currently believed to be moderate.

Only clear result that can be derived from these studies is that anxiety disorders are not based on a single gene but likely have a complex genetic basis, which can be affected by environmental factors.

Question 7

How are anxiety disorders classified?

Answer 7

Anxiety disorders:
GAD 
Specific phobias (agoraphobia)
Social phobias (selective mutism)
Panic disorder

Obsessive- compulsive (and related disorders):
OCD
PTSD

Question 8

What is GAD?

Answer 8

characterised by an ongoing state of excessive anxiety lacking clear reason or focus.

Excessive anxiety and worry occurring for at least six months, which is difficult to control and impairs activities of daily living.

Associated with three or more (of six) symptoms.

GAD sufferers symptoms likely to be different from another persons experience with GAD.

Question 9

What are specific phobias?

Answer 9

Specific phobias are extreme fears or anxieties provoked by exposure to a particular situation or object – often leads to avoidance behaviours.

Agoraphobia
Acrophobia
Orthinophobia
Podophobia

Question 10

What are social phobias?

Answer 10

Social phobias are characterised by significant anxiety provoked by exposure to certain types of social (e.g. social gatherings) or performance (e.g. public speaking) situations.

Question 11

What is selective mutism?

Answer 11

Selective mutism is a severe anxiety disorder where a person is unable to speak in certain social situations, such as with classmates at school or to relatives they do not see very often.

Question 12

What is panic disorder?

Answer 12

Panic disorder is characterised by recurring panic attacks, without a seemingly clear cause or trigger.

Question 13

What are panic attacks?

Answer 13

Panic attacks are sudden feelings of overwhelming fear with marked somatic symptoms (e.g. sweating, chest pains).

Panic attacks can occur spontaneously or be a feature of a number of anxiety disorders .

Question 14

What is OCD?

Answer 14

Obsessive compulsive disorder (OCD) is characterised by compulsive, ritualistic behaviour driven by irrational anxiety.

Obsessions: Recurrent, intrusive thoughts, images, ideas or impulses.

Compulsions:
Repetitive behaviours or mental acts that are performed to reduce anxiety associated with the obsessions.

Question 15

What is PTSD?

Answer 15

Post-traumatic stress disorder (PTSD) is characterised by distress triggered by the recall of past traumatic experiences – can lead to flashbacks and nightmares.

Question 16

Expand on the pathophysiology of anxiety disorders.

Answer 16

Hallmark of anxiety disorders is an inappropriate stress response either when a stressor is not present or not immediately threatening.

The stress response is regulated by the hypothalamus-pituitary-adrenal (HPA) axis.

HPA axis leads to the release of cortisol (a glucocorticoid).

Cortisol contributes to the body’s physiological response to stress.

Question 17

What is the role of the amygdala in the HPA axis?

Answer 17

Amygdala – role in emotion and fear response

Stimulates HPA axis (green) to promote cortisol release

Amygdala hyperactivity linked to anxiety disorders

Question 18

What is the role of the hippocampus in the HPA axis?

Answer 18

Hippocampus – role in learning and memory

Supresses HPA axis (red) to prevent excessive cortisol release

Hippocampus underactivity linked to anxiety disorders

Question 19

How does hippocampal degeneration link with anxiety?

Answer 19

e.g. PTSD

Continuous exposure to cortisol (e.g. during periods of chronic stress) can cause neuronal degeneration in the hippocampus.

Sets off a vicious cycle in which the stress response becomes more pronounced, leading to greater cortisol release and more hippocampal damage.

For example, there is a decrease in hippocampal volume in some people who suffer from PTSD.

Question 20

Give examples of anxiolytic drugs

Answer 20

GABA(A) receptor modulators:
Barbituates
benzodiazepines

5-HT(1A) receptor agonists

𝛽-Adrenoceptor antagonists

Question 21

Expand on the GABA(A) receptor as a key target for anxiolytics and hypnotics

Answer 21

LGIC 
pentameric structure - 
Six α subtypes (α1 – α6)
Three β subtypes (β1-3)
Three γ subtypes (γ1-3)
Also δ ε π θ subunits
2α 2β γ most common configuration

Multiple binding sites:

• Agonists/antagonists e.g. GABA
• Benzodiazepine binding site
• Channel blockers e.g. picrotoxin
• Channel modulators e.g. GA
• Allosteric modulators e.g. barbiturates

Question 22

How is GABA activity terminated?

Answer 22

Upon reuptake by GAT

Question 23

What are barbituates?

Answer 23

Barbiturates are a class of GABAA allosteric modulators – no longer recommended as anxiolytics (or hypnotics).

Barbiturates are positive allosteric modulators (PAMs).

Barbiturates increase the activity of GABAA receptors – binding increases channel opening beyond that seen with GABA alone.

Barbiturates are responsible for severe depressant effect on the CNS…

Question 24

What other actions do barbiturates have at high doses?

Answer 24

Increase[ ] direct GABAA agonist
Glycine receptor – also stabilises open channel
nAChR & 5-HT3 receptor blockade
AMPA/kainate receptor blockade
Blockade of Ca2+-dependent neurotransmitter release

increase inhibition, decrease excitation

Question 25

What may barbiturates still be used for?

Answer 25

Epilepsy General Anaesthesia Capital punishment

Question 26

Expand on benzodiazepines.

Answer 26

Benzodiazepines are a class of GABAA modulators – most widely used class of anxiolytics (and hypnotics). Benzodiazepines bind to a distinct regulatory site on GABAA receptors. Benzodiazepines stabilise the GABAA receptor binding site for GABA in the open configuration - increases GABA affinity for its binding site and produces a general enhancement of its neuroinhibitory actions. 'cleaner' compounds compared to barbiturates

Question 27

How do you choose which benzodiazepine to use?

Answer 27

Benzodiazepine choice made based on duration of action (e.g. short-acting preferred as hypnotics to avoid sedation throughout day).

Question 28

What are barbiturates and benzodiazepines associated with?

Answer 28

Barbiturates and benzodiazepines are associated with tolerance and withdrawal symptoms.

Question 29

How do barbiturates and benzodiazepines induce withdrawal symptoms?

Answer 29

Symptomatic: it's been proposed that there's an imbalance between GABA (inhibitory) and glutamate (excitatory) in anxiety disorders - GABA usuall low In order to address this imbalance, a patient can be prescribed benzodiazepines (BZDs). BZDs act as PAM (at the BZD binding site on the GABAA receptor) --> stabilise the GABAA receptor binding site for GABA in the open configuration--> increases GABA affinity for its binding site --> produces enhancement of GABA’s neuroinhibitory actions --> supress symptoms of anxiety in some patients. Tolerance: Over time, a patient can develop tolerance to BZDs. It has been proposed that this is due to trafficking of additional glutamate receptors to the cell membrane. This serves to restore the initial imbalance seen in the ”symptomatic” stage. Patients therefore need to take a higher dose of BZDs to address this new imbalance between inhibitory and excitatory neurotransmission. Withdrawal: If a patient suddenly withdraws from taking these high doses of BZDs, there is a sudden decrease in inhibitory GABA neurotransmission. Coupled with increased excitatory glutamate neurotransmission, this can lead to the development of seizures.

Question 30

Expand on 5-HT receptor agonists

Answer 30

Metabotropic - GPCRs Receptor 1A-F: Gi/o to inhibit AC Receptor 2A-C: Gq to stimulate IP3 and DAG formation Receptor 3: LGIC Receptor 4: Gs to stimulate AC Receptor 5A, 5B, 6, 7: Gs to stimulate AC by 6 & 7, 5 not established

Question 31

Expand on 5-HT1A receptors

Answer 31

5-HT1A receptor agonists (e.g. buspirone) are a class of drugs primarily used to treat anxiety – less tolerance and withdrawal symptoms compared to the benzodiazepines. Buspirone is the most commonly prescribed 5-HT1A agonist for generalised anxiety disorder (GAD). Activates pre-synaptic 5-HT1A autoreceptors – this inhibits 5-HT release. Also reduces activity of noradrenergic neurons and decreases arousal (but does not induce sleep). Delay of several days before clinical effects are seen…

Question 32

How does buspirone work compared to SSRIs?

Answer 32

Buspirone is a 5-HT1A receptor agonist. Receptors are autoinhibitory therefore, buspirone initially inhibits 5-HT release. However, if buspirone is taken over a period of time (e.g. weeks), buspirone can induce desensitisation of autoinhibitory 5-HT1A receptors --> downregulation of 5-HT1A receptors on the pre-synaptic plasma membrane --> heightened excitation of serotonergic neurons and enhanced 5-HT release --> suppress the symptoms of anxiety in some patients. Selective serotonin re-uptake inhibitors (SSRIs) inhibit the re-uptake of 5-HT via the serotonin transporter (SERT) - this leads to an increase in 5-HT availability. If SSRIs are taken over a period of time (e.g. weeks), SSRIs can induce desensitisation of autoinhibitory 5-HT1A receptors - this can lead to downregulation of 5-HT1A receptors on the pre-synaptic plasma membrane. However, in addition, SSRIs can also lead to the downregulation of 5-HT receptors on the post-synaptic plasma membrane. Overall, there is an increase in 5-HT neurotransmission (via fewer autoinhibitory 5-HT1A receptors and inhibiting the re-uptake of 5-HT) and a decrease in 5-HT neurotransmission (via fewer post-synaptic 5-HT receptors). On the balance of these changes, there is an overall increase in 5-HT neurotransmission, which can suppress the symptoms of anxiety in some patients.

Question 33

Expand on the structure of adrenoceptors

Answer 33

Metabotropic - GPCR Subtypes: α1 couples to Gq proteins to activate phospholipase C α2 couples to Gi/o and inhibits adenylate cyclase β1 and β2 couple to Gs and activate adenylate cyclase Signalling: NA NERT MAO

Question 34

What are the functions of beta-adrenoceptors?

Answer 34

β1 The heart: increases heart rate, impulse conduction, contraction and ejection fraction Increases renin release by Juxtaglomerular cells β2 Increases renin release by juxtaglomerular cells

Question 35

What are 𝛽-adrenoceptor antagonists?

Answer 35

𝛽-adrenoceptor antagonists (e.g. propranolol) are a class of drugs used to treat some symptoms of anxiety. 𝛽-adrenoceptor antagonists reduce some of the peripheral manifestations of anxiety (notably tremor, sweating, tachycardia and diarrhoea). However, there is no effect on the central CNS affective component. Accordingly, they find abuse in some sports (reduce tremor) and the performing arts (reduce stage fright).