Anxiety (A*)

Question 1

What is the difference between anxiety in normal health and anxiety in anxiety disorders?

Answer 1

• Anxiety in health is a normal, adaptive response to a perceived stressor.
• Anxiety in anxiety disorders is maladaptive, and often occurs in the absence of a stressor.

Question 2

Is the origin of anxiety central or peripheral?

Answer 2

• The origin of anxiety likely has both central and peripheral mechanisms.
• E.g. the changes in autonomic function such as increased heart rate and sweating is due to central mechanisms. Also, the anxiety response induced by some factors can reduce with time, suggesting the anxiety response is amenable to learned changes (another central function involving plastic changes).
• Peripheral inflammation has been shown to be associated with stress vulnerability and resilience. Mice released more IL-6 and TNF-alpha when under stress (Avitsur et al., 2004).
• Also, coffee is thought to induce symptoms of anxiety through both central and peripheral mechanisms (potential A* content here).

Question 3

List 3 anxiety disorders.

Answer 3

Examples of anxiety disorders include:

1 - Generalised anxiety disorder.

2 - Panic disorder.

3 - Phobias.

*There are many others.

Question 4

List the two neurotransmitters targeted by anxiolytic drugs.

Give an example of a drug targeting each neurotransmitter.

Answer 4

• Anxiolytics generally target either GABA or 5HT.
• Benzodiazepines (potentiate GABA transmission).
• Buspirone (a 5HT1A partial agonist).

Question 5

Which regions of the brain are involved in anxiety disorders?

Answer 5

Many regions of the brain are involved in anxiety disorders (cortex, subcortical structures and brainstem), however the key structure is the amygdala.

Question 6

Describe the neural pathways involved in anxiety responses.

Answer 6

• Anxiety-inducing stimuli are processed by the amygdalae. This sends neurones to 5 sites:

1 - Hypothalamus.

• This mediates sympathetic responses.

2 - Locus coeruleus.

• This mediates sympathetic responses and increases arousal via noradrenaline.

3 - Ventral tegmental area.

• This increases arousal via its dopaminergic connections to the limbic system and cortex.

4 - Brainstem structures such as the periaqueductal grey area.

• This is involved in behavioural inhibition (this is what causes some people to freeze in some fear responses).

5 - Cortex.

• This allows cognitive processing of the stimulus and mediates the emotional response.

Question 7

List 3 drugs that bind to GABA receptors other than GABA.

How do these drugs affect GABA transmission?

Answer 7

Drugs that bind to GABA receptors include:

1 - Benzodiazepines.

2 - Alcohol.

3 - Barbiturates.

All of these drugs potentiate GABA receptor transmission (and are anxiolytic!).

Question 8

Give an example of a drug class that is anxiogenic.

Answer 8

Sympathomimetics are anxiogenic (e.g. amphetamines and cocaine, which remember are reuptake inhibitors for noradrenaline and dopamine respectively).

Question 9

What is known about 5HT receptor signalling in anxiety disorders?

Answer 9

Defects of 5HT signalling in anxiety disorders:

1 - 5HT transmission defect is likely to be a local defect rather than a global defect.

2 - There are thought to be 5HT transporter polymorphisms involved.

3 - 5HT1A receptors are thought to be involved (e.g. Buspirone, which was accidentally discovered, targets 5HT1A).

Question 10

Which neurotransmitter is thought to play a role in panic attacks?

Answer 10

CCK is thought to play a role in panic attacks.

Question 11

What is the galvanic skin test?

Why is it useful?

Answer 11

• The galvanic skin test is a way of measuring anxiety by measuring the release of salts on the skin due to sweating.
• It is useful because measuring anxiety using questionnaires is relatively inconsistent.

Question 12

List 2 examples of experimental techniques used to measure anxiety in animal models.

Answer 12

Experimental techniques used in animal models to test anxiety include:

1 - The elevated plus maze (see behavioural models lecture).

2 - Observing social interactions.

Question 13

List 4 reasons for the relatively poor success of anxiolytic drugs.

Answer 13

The reason for the relatively poor success of anxiolytic drugs is due to limitations of animal models and the complex nature of the disease:

1 - Animal models can only investigate healthy anxiety responses, not pathological ones (however there are wistar-kyoto rats are genetically modified to induce pathological anxiety).

2 - Animal models such as the elevated plus maze only investigate one aspect of anxiety.

3 - Animal models involve more acute stress whereas anxiety disorders in humans are chronic conditions.

4 - Many pathways and neurotransmitters are implicated, making a targeted therapy difficult.

Question 14

List 6 emerging targets for anxiety disorders.

Answer 14

Emerging targets for anxiety disorders include:

1 - CCK.

2 - Neuropeptide Y (NPY).

3 - Cannabinoids.

4 - Corticotropin-releasing hormone.

5 - Oestrogen.

6 - NMDA.

Question 15

Big boy A* material:

Describe 3 mechanisms by which caffeine is thought to induce anxiety.

Answer 15

• Caffeine exposure in adolescent humans and in rat models predisposes to anxiety disorders. Potential mechanisms include:

1 - Disturbance of the HPA axis, e.g. caffeine increases secretion of corticotropin-releasing hormone. This results in an increase in ACTH and therefore cortisol, mediating a stress response.

• Thought to have a parallel effect on depression.
• This is an example of a central mechanism.
• A recent study showed that chronic caffeine exposure had no effect on anxiety in adult rats, but did have an effect in adolescent rats (O’Neill at al., 2016).
• Therefore, it is thought that caffeine interferes with the neuroplastic changes in the HPA axis that occur during development.
• CRH antagonists are being explored as a novel therapeutics for anxiety.

2 - Adenosine signalling in the brain provides inhibitory feedback to inflammatory cytokines such as IL-1 which are associated with anxiety.

• Caffeine decreases adenosine-mediated inhibition in the brain by nonselectively and competitively antagonising adenosine receptors.

3 - Peripheral cardiovascular mechanisms:

• In endothelial cells, caffeine increases intracellular calcium, which increases production of nitric oxide by changing expression of eNOS.
• NO causes vasodilation.
• Caffeine also increases heart rate and contractility by nonselectively and competitively antagonising adenosine receptors in the heart.

Question 16

Big boy A* material:

List 2 anxiolytic benzodiazepines.

Describe the mechanism of action of benzodiazepines as anxiolytics.

List the pitfalls of this treatment.

Answer 16

• Alprazolam (Xanax) and midazolam are anxiolytic benzodiazepines.

Anxiolytic mechanism:

• Benzodiazepines potentiate GABA transmission by binding to the benzodiazepine binding site on GABAA receptors. This increases the affinity of GABAA receptors for GABA, and therefore increases inhibitory GABA transmission.
• Since there are many GABAergic neurones in the amygdala, increasing GABA transmission can inhibit the anxiety signals produced by the amygdala during an anxiety response (see card 6).

Potential pitfalls:

1 - Patients can become dependent on benzodiazepines, and there is potential for abuse.

• This is thought to be caused by benzodiazepine-induced neuroplastic changes in the VTA dopaminergic reward (mesolimbic) pathway that result in a decrease in GABAergic inhibition (Tan et al., 2010).

2 - Benzodiazepines cause drowsiness and many other side effects.

• Drowsiness due to increased GABAergic inhibition has a negative impact on arousal, e.g. reducing activity of neurones in the cortex, locus coeruleus and VTA, which are required to maintain arousal.

3 - Benzodiazepines are effective at alleviating acute anxiety but have limited / no long-term benefit on anxiety.

Question 17

Big boy A* material:

List 2 anxiolytic 5-HT1A agonists.

Describe the mechanism of action of 5-HT1A antagonists as anxiolytics.

Give an advantage and disadvantage of these drugs over benzodiazepines.

What are their advantages and disadvantages?

Answer 17

• Buspirone and tandospirone are anxiolytic 5-HT1A agonists.
• Buspirone has also shown to have affinity for 5-HT2 and D2 receptors.
• 5-HT1A is coupled to Gi/o, therefore is an inhibitory receptor.
• Polymorphisms in 5-HT1A receptors have been linked to anxiety disorders.
• Mechanism of action is unknown but is thought to involve increasing inhibitory serotonergic activity in the stress pathways, as 5-HT1A receptors are highly expressed in limbic regions (such as those mentioned in card 6). In this sense, the mechanism is similar to that of benzodiazepines.
• An advantage of these drugs over benzodiazepines is that they do not cause dependence / withdrawal effects.
• A disadvantage is that buspirone is less effective than benzodiazepines and takes longer to show an effect.

Question 18

Big boy A* material:

List 3 relatively recent anxiolytic drug classes.

Give an example of each.

What are their advantages and disadvantages?

Answer 18

Relatively recent anxiolytic drug classes include:

1 - Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine.

2 - Serotonin and noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine.

• SSRIs are first-line anxiolytic drugs because they have the best benefit : side effect ratio and are not addictive.
• These are antidepressant drugs. The causal relationship between depression and anxiety is not clearly understood, but the fact that antidepressant drugs work as anxiolytics is evidence for the overlap between the two conditions.
• High cortisol might underpin the relationship between anxiety and depression.
• An advantage of using antidepressants is that since anxiety and depression often coexist, by administering an antidepressant, only one drug is necessary to treat both conditions.
• The pitfalls of these drugs is that they have diverse side effects and drug interactions (due to the ubiquity of the neurotransmitters they target) and take a long time to work (due to the time taken for the neuroadaptive changes to occur).
• Also, SSRIs are not effective for relieving acute anxiety. They are only useful for relieving long-term anxiety.

3 - Anticonvulsants such as pregabalin.

• Pregabalin is a P/Q voltage-gated Ca2+ channel blocker, reducing glutamate release.
• Mechanism is thought to be by reducing the activity of stress pathways, such as the amygdala and associated brain regions (see card 6).
• Pregabalin generally has fewer side effects than other anxiolytic drugs.

Question 19

Big boy A* material:

What is the Research Domain Criteria project?

Answer 19

The use of ICD-11 and DSM-5 mean that all anxiety patients are categorised together.

• In reality anxiety is a multidimensional disorder.
• The Research Domain Criteria project has been set up to improve understanding of the various dimensions of mental health.
• Without this understanding, it is difficult to treat patients with anxiety / other neuropsychiatric condition because treatment cannot be tailored to the characteristics of a patient’s specific disorder.

Question 20

Big boy A* material:

Describe 2 anxiolytic mechanisms of cannabinoids.

Answer 20

Anxiolytic mechanisms of cannabinoids:

1 - Adenosine signalling in the brain provides inhibitory feedback to inflammatory cytokines such as IL-1 which are associated with anxiety.

• Cannabinoids are adenosine uptake inhibitors. This increases availability of adenosine, and therefore increases adenosine signalling.
• This facilitates the anxiolytic effect produced by adenosine receptors.

2 - CB1 receptors are Gi/o linked (inhibitory) GPCRs.

• They cause inhibition of glutamatergic neurones in the brain, hence have an anxiolytic effect.
• TRPV1 is thought to have an antagonistic effect to CB1, reducing inhibitory drive.
• The TRPV1 antagonist capsazepine was shown to have anxiolytic effects in rats.
• CB1 and TRPV1 are therefore potential targets for anxiolytic drugs.

Other points:

• Cannabinoids are novel targets for anxiety.
• Many people report anxiolytic effects of marijuana.
• Synthetic cannabinoid agonists are being developed.
• Rimonabant, a CB1 antagonist has been shown to be anxiogenic. This is evidence for the anxiolytic effect of CB1 receptors.
• Some cannabinoids are anxiogenic, some are anxiolytic, so improved understanding of mechanisms and dose response required for drug development.

Question 21

Big boy A* material:

Describe the anxiolytic mechanisms of neuropeptide Y.

Answer 21

• Neuropeptide Y acts on Y1 receptors in the locus coeruleus, hypothalamus, nucleus tractus solitarius and hippocampus to produce an anxiolytic effect.
• All neuropeptide Y receptors are coupled to Gi/o, so produce an inhibitory effect.
• Stimulating the Y1 receptors is a potential target for anxiety, but no drugs have been developed yet.

Question 22

Big boy A* material:

Describe the relationship between anxiety and depression.

What might underlie this relationship?

Answer 22

• 45% of patients with major depressive disorder have at some stage been diagnosed with an anxiety disorder (Kessler et al., 2015).
• The link between anxiety and depression is multifactorial. Potential mechanisms include:

1 - Hyperfunction of the amygdala.

• Enlarged amygdala volume has been linked to anxiety disorders (Baur et al., 2012), and increased uptake of glucose has been observed in the amygdalae of patients with panic disorder, indicating hyperfunction of neurones in the amygdala (Martin et al., 2017).
• The central nucleus of the amygdala plays a facilitatory role in the HPA axis by its indirect connections with the hippocampus and hypothalamus through the bed nucleus of the stria terminalis.
• Hyperfunction of the amygdala might therefore result in hypersecretion of cortisol, one of the primary factors thought to underlie depression.

2 - Underexpression of 5-HT1A receptors and overexpression of 5-HT2C receptors.

• 5-HT1A receptors are inhibitory Gi/o GPCRs that are normally expressed in limbic structures (such as those mentioned in card 6).
• 5-HT2C receptors are excitatory Gq GPCRs that are normally expressed in limbic structures such as the amygdala and hippocampus.
• Underexpression of 5-HT1A receptors and overexpression of 5-HT2C receptors in limbic structures has been identified in both patients with depressive disorders and patients with anxiety disorders.
• This might underlie the hyperfunction of stress pathways in both depressive and anxiety disorders.

Question 23

A* idea from neuropeptides lecture

Answer 23

Emerging neuropeptide receptor-targeting drugs include:

1 - CCK antagonists as antidepressants / anxiolytics.

2 - NK1 antagonists as antidepressants / anxiolytics and antiemetics.

3 - NK3 agonists as antidepressants / anxiolytics.

*Surprisingly, NK1 receptor antagonists failed as analgesics!