Anxiety disorders: Neurobiology, neurochemistry and treatment

Question 1

Which part of the brain plays a role in fear?

Answer 1

Amygdala

Question 2

What does activation of the amygdala cause?

Answer 2

Tachycardia, paleness, pupil dilation, blood pressure elevation
Behavioural and EEG arousal increased vigilance
Corticosteroid response

Question 3

What does the amygdala excite?

Answer 3

Locus coeruleus

Hypothalamus

Question 4

Describe the acute stress response

Answer 4

• Avoidance behaviour
• Increased vigilance and arousal
• Activation of the sympathetic division of the ANS
• Release of cortisol from the adrenal glands

Question 5

Describe the HPA axis

Answer 5

Hypothalamus releases CRH
Pituitary releases ACTH 
Adrenal cortex releases cortisol
	(stress hormone)
(CRH: corticotropin releasing hormone
ACTH: adrenocorticotropic hormone)

Question 6

What does the Locus Coeruleus release?

Answer 6

Norepinephrine

Question 7

What is the regulation of HPA axis?

Answer 7

Push and pull regulation

Question 8

What happens during Chronic activation of glucocorticoid receptors in hippocampus?

Answer 8

• increased Ca2+ entry into neurons
  - too much Ca2+ - excitotoxic - cells dieHippocampus can’t feedback to limit cortisol production

Question 9

What do anxiety disorders result from?

Answer 9

• diminished activity of hippocampus
• loss of feedback to the amygdala
• inappropriate fear responding

(evidence - hippocampal volume in PTSD patients reduced)

Question 10

What is the noradrenergic system involved in?

Answer 10

Arousal and attention

Question 11

What is the serotonergic system involved in?

Answer 11

Mood and emotion

Question 12

Where do the noradrenergic and serotonergic systems project to?

Answer 12

Throughout the forebrain to both cortical and limbic areas as well as connections to each other
They are also thought to balance each other

Question 13

What can dysregulation of limbic systems or connections cause?

Answer 13

Inappropriate fear and anxiety responses

Question 14

List some anxiety disorders

Answer 14

Post traumatic stress disorder
Panic disorder
Generalized anxiety disorder
Phobia
Obsessive compulsive disorder

Question 15

What is PTSD?

Answer 15

persistent psychological stress following exposure to extreme stress, e.g. war, physical assault

Question 16

What is panic disorder?

Answer 16

rapid-onset attack of extreme fear and severe stress
Characterized by unrealistic, unfounded fear and anxiety; acute and unremitting terror for variable lengths of time (sec to hours).

Question 17

What is Generalized Anxiety Disorder (GAD):

Answer 17

stress and anxiety in the absence of obvious precipitating stimulus

Question 18

What are phobias?

Answer 18

similar to GAD, but triggered by particular objects (e.g. spiders, birds) or situations (e.g. crowds, darkness)

Question 19

What is Obsessive Compulsive Disorder (OCD):

Answer 19

frequently recurring, uncontrollable, anxiety-producing thoughts (obsessions) and impulses (compulsions). Responding to them, e.g. repeated, compulsive hand washing, dissipates associated anxiety.

Question 20

Describe the features of panic disorder

Answer 20

Anxiety is normally useful/adaptive
Universal basic symptoms, e.g. shortness of breath, “impending death”, irregular heartbeat, clammy sweat, dizziness, faintness
Onset in young adulthood
More likely to appear in women
Treatable
Anticipatory anxiety (fear that another panic attack will strike) often leads to development of agoraphobia
Often accompanied by other serious problems: depression, alcoholism or drug abuse

Question 21

Describe the treatment of panic disorder

Answer 21

Benzodiazepines, partial agonists of the GABA(A) receptor, anxiolytic [sedation & sleep induction, reduced muscle tone & coordination, anticonvulsant effects, anterograde amnesia]

Serotonin, SSRIs (serotonin selective reuptake inhibitors)
Cognitive Behavioural Therapy (CBT)

Question 22

In what anxiety disorders do benzodiazepines work well?

Answer 22

Generalized Anxiety Disorder (GAD)
Panic Disorder (PD)

Question 23

In what anxiety disorders do benzodiazepines not work as well?

Answer 23

Obsessive Compulsive Disorder (OCD)

Post Traumatic Stress Disorder (PTSD)

Question 24

In what anxiety disorders do SSRIs work well in?

Answer 24

OCD
PTSD
Panic Disorder
GAD

Question 25

Which drug works in GAD?

Answer 25

GAD

Question 26

Name some drugs which increase GABA activity to reduce anxiety

Answer 26

Partial agonist Alcohol Indirect agonists Barbiturates Benzodiazepines

Question 27

Which drugs which decrease GABA activity to increase anxiety?

Answer 27

Benzodiazepine antagonist Flumazenil These drugs all act at the GABA(A) ionotropic receptor

Question 28

What happens to the benzodiazepine binding sites in the brain of someone with panic disorder?

Answer 28

Fewer binding sites

Question 29

Which area of the brain shows increased activity during periods of anxiety?

Answer 29

the frontal cortex normally shows increased activity during periods of anxiety

Question 30

Describe anxiety and depression

Answer 30

often comorbid (e.g.~85% depressed show symptoms of GAD) both treatable with SSRIs both weeks before therapeutic actions are visible Therapeutic effect is not simply boosting the synaptic levels of serotonin - otherwise changes would be seen on initiation of treatment Instead as a result of adaptive changes by the nervous system to the chronically elevated levels of serotonin

Question 31

Describe neuroplasticity downstream of antidepressants

Answer 31

Intracellular cascades downstream of 5-HT receptor activation can lead to changes in neuronal plasticity and morphology Remember: neurogenesis in adult hippocampus Reversal of stress induced changes may restore normal function to a brain Hypothesis may hold for depression and anxiety

Question 32

Where do the opposing functions of various brain areas in panic disorder act?

Answer 32

Opposing functions in various brain areas hippocampus amygdala hypothalamus

Question 33

Describe Obsessive compulsive disorders

Answer 33

Frequently recurring, uncontrollable, anxiety-producing thoughts (obsessions) and impulses (compulsions). Responding to them, e.g. repeated, compulsive hand washing, dissipates associated anxiety. OCD patients recognize their thoughts and behaviours are senseless. 1-2% incidence Categories of compulsions: counting, checking, cleaning, avoidance (exaggeration of natural human tendencies) e.g. trichotillomania, onychophagia Greater concordance with monozygotic than dizygotic twins Common underlying genotype for Tourette’s and OCD Can be environmental as well - Streptococcal infection Experience also plays a role, e.g. stressful life events A disorder of the basal ganglia? Repeated behaviours - follow rituals Associated with Tourette’s syndrome – hereditary chronic motor tic disorder (muscular and vocal tics) that has its locus in the basal ganglia Imbalance between indirect and direct pathways through basal ganglia

Question 34

What gives rise to the direct and indirect pathways?

Answer 34

Two types of dopamine receptors (D1 and D2) are located on different sets of output neurons in the striatum that give rise to the direct and indirect pathways.

Question 35

Describe how the direct and indirect pathway link to OCD

Answer 35

Direct pathway controlling previously learned behavioural sequences so they become automatic and can be rapidly executed Indirect pathway involved in suppressing these automatic behaviours allowing the person to switch to other more adaptive behaviours (behavioural flexibility). Overactivity of direct pathway may lead to these compulsive behaviours without being able to switch them off

Question 36

What is the best drug treatment of OCD?

Answer 36

SSRIs | e.g. fluoxetine but also clomipramine (TCA)

Question 37

Describe how caudate hyperactivity leads to OCD

Answer 37

``` The caudate sends GABAergic inhibitory projections to the GP, which sends inhibitory projections to the thalamus, which then projects to the OFC. ``` It’s possible that OCD involves a disinhibition which leads to activity reverberating in this circuit. CBT and SSRIs lead to a similar biological change .

Question 38

Describe the pros and cons of using benzodiazepines in the treatment of anxiety disorders

Answer 38

good immediate effects, but patients can develop tolerance and there is potential for abuse, and anxiety during withdrawal

Question 39

Describe the pros and cons of using SSRIs in the treatment of anxiety disorders

Answer 39

are effective, but have a delayed onset. Initially can be anxiogenic.

Question 40

What is the best strategy in treatment of anxiety disorders?

Answer 40

Combining benzodiazepines and SSRIs initially and then tapering off the BDZs as the SSRIs take effect