Anxiety

Question 1

LO

Answer 1

• Introduce the concept of anxiety as pathophysiological state and list the current classification and complexity of anxiety disorders
• Highlight the fear pathway as a template to understand anxiety as a brain disease
• Introduce the major drug therapies (Benzodiazepines) and discuss actions at receptors that are widely expressed in the brain can achieve some selectivity (anxiolytics)

Question 2

Compare the biological pathway of depression and anxiety

Answer 2

Question 3

Compare the definition of depression and anxiety

Answer 3

Question 4

Compare the example animal model experiments done for depression and anxiety

Answer 4

Question 5

Compare the brain pathways for depression and anxiety

Answer 5

Question 6

Compare the transmitter pathways for depression and anxiety

Answer 6

Question 7

Compare the molecular target of depression and anxiety

Answer 7

Question 8

Compare the drug class of depression and anxiety

Answer 8

Question 9

Compare the clinical confounds of depression and anxiety

Answer 9

Question 10

Depression vs. Anxiety table

Answer 10

Question 11

What is fear…?

What are some physiological signs it causes?

Answer 11

Fear is a normal physiological response helps survival

Heightened sensory state, vigilance hyper aroused, heart rate, metabolic readiness, fight and flight response

Better still predict danger indeed fearful response is a learnt response

Question 12

What is anxiety…?

Answer 12

Anxiety is a pathophysiological state that detracts from normal function and likely impeded an organism’s success. Thus, a medical condition

Question 13

Say you were anxious about your exams but do not want an anxious (fear) related state when taking your exams. What are some physical symptoms of anxiety?

Answer 13

• increased heart rate
• decreased salivation
• upset stomach
• increased respiration
• scanning and vigilance (indecisive if out of context)
• jumpiness (ease of startle)
• frequent urination and defecation (diarrhoea)
• fidgeting
• freezing (apprehensive expectation)

Question 14

What activates anxiety?

Answer 14

Anxiety would be the activation of these responses to neutral or emotionally ambiguous cues

This interpretational aspect suggests important cognitive component

Question 15

What is fundamental to fearfulness?

What does this imply?

Answer 15

The ability to use experience to modulate or modify the behaviour

Indeed, much of what is fearful must be learnt by direct experience or observation.

Monkeys not innately scared of snakes.

Butter to learn or observe others response to snakes.

This implies neuromodulatory mechanism and pathways underlying the fear response and anxiety pathophysiology

Question 16

Name some conditions that anxiety is related to?

Answer 16

• Panic attacks
• Agoraphobia
• Panic disorders
• Specific phobia
• Social phobia
• Obsessive compulsive disorder (OCD)
• Post-traumatic stress disroder (PTSD)
• Acute stress disorder
• Generalised anxiety disroder (GAD)

Question 17

Tell me some symptoms of panic attacks

Answer 17

• Palpitations
• Pounding heart
• Sweating
• Trembling
• Breathless
• Feeling of choking
• Chest discomfort
• Abdominal distress
• Dizzy or faint
• Feelings of unreality or detached from oneself
• Fear of losing control or going crazy
• Paraesthesia’s (numbness of tingling sensations)
• Chills or hot flushes
• These bouts should peak at 10 minutes

Question 18

What does Agoraphobia have similar symptoms to and when do they come about?

Answer 18

Symptoms similar to those of panic attacks when placed in an environment where escape is difficult, embarrassing or cannot be made without support.

Classified if not better explained by other conditions

Question 19

Tell me about when panic attacks would come about and what they may be associated to/ due to?

Answer 19

Recurrent panic attacks 10-minute peak.

Or remain anxious about them recurring for up to a month after an attack.

May be associated with agoraphobia. Not due to drug abuse. Are no better explained by co-morbid conditions

Question 20

What is specific phobia?

Answer 20

Excessive fear to a specific cue often recognised by sufferer not the cause for children

. Anticipation of cue or avoidance of it interferes with normal life routine.

Not explained by other conditions

Question 21

What is social phobia?

Answer 21

Anxious state induced by social situation many criteria as for specific phobia

In children they must exhibit otherwise normal ability for social interaction in familiar settings.

If aligned with another disorder this cannot underlie social phobia

Question 22

What is obsessive compulsive disorder (OCD)?

What sort of things could an individual who suffers from it do and what is it defined by?

Answer 22

Recurrent obsessive thoughts or images intrusive and inappropriate to time or place.

Try to neutralise intrusion by distracting routines.

Patient recognises the obsessive nature.

Compulsions respective behaviours (e.g., hand washing) or inappropriate/ excessive behaviours designed to reduce distress.

Recognition of the excess.

Time consuming routines 1 hour a day interfering with social or working relations.

Not due confounding condition.

Define if patient has poor or good insight into their condition.

Question 23

What is PTSD due to?

Answer 23

Experienced traumatic or near-death experiences in which intense fear response ensued.

Question 24

What does PTSD cause?

Answer 24

Intrusive recurrent memory, dreams, or sense of event.

Intense response to internal or external cues associated with event.

Physiological response by event cues.

Persistent avoidance of cue

Diminished expectations quality of life (e.g., career, family etc.)

Irritability, insomnia, hyper vigilant difficulty concentrating

Impact on social function and symptoms persist for great 1 month

Question 25

What are the two types of **PTSD** and the time frames for each?

Answer 25

1-3 months (ACUTE); \>6 months (chronic) Appears 6 months post traumas (delayed onset)

Question 26

What is **acute stress disorder** similar to? What sort of symptoms does it show and is there a known cause?

Answer 26

Cause and ensuing outcomes **similar to PTSD**. Shorter term classified lasting between 2 days and 4 weeks and occurs within 4 weeks of trauma. Individual shows dissociative behaviour during or following trauma, amnesia, depersonalisation. No substance abuse or other underlying cause

Question 27

What is **generalised anxiety disorder (GAD)**?

Answer 27

Anxiety or worry for more days than not for 6 months. Uncontrolled worry associated with restlessness, fatigue, lack of concentration blank mind, irritability muscle tension, sleep disturbances. Anxiety can not be specified by brings about disruption of normal life. Is not part of an associated syndrome.

Question 28

Tell me about two types of animal models which are used to unpick the fear circuit

Answer 28

There are two types of context conditioning 1. Unsignalled 2. Signalled * Types of **Fear conditioning** * Environment used to drive fear response **Unsignalled:** * Hair standing up is consistent with the rats expressing a fear response as the environment makes them nervous **Signalled:** * Another form of fear conditioning is signalling this has an additional queue imposed when they are shocked so that the sound brings fear as is associated with the shock * Expression of fear response is an active neuronal process 1. Accessing the core fear circuit 2. Implicating additional modulation 3. Making a clear case for neuronal plasticity

Question 29

What strucrture is at the core of the fear pathway?

Answer 29

The amygdala of the limbic system is at the core of the fear pathway

Question 30

Tell me about association pathways and how they can contribute to an emotional response Mention any other necessary componenets and what they are

Answer 30

Association pathways interact with core fear centres Integration of information goes out to active the emotional response There can be **-ve and +ve modulation** of the fear centre when producing an emotional response Can look like fear or anxiety if the response is inappropriate in the environment, it’s in Limbic system overrides and contributes to fearfulness Amygdala acts as the core fear centre

Question 31

Tell me some of the inputs that feed into the amygdala when processing an emotional response

Answer 31

* hippocampus * Thalamus * Sensory cortex * septum * PFC * hypothalamus * Brain stem

Question 32

What 4 areas can the emotional response feed into and what are each of these regions involved with?

Answer 32

Question 33

What are some current preferred treatment routes priorities for anxiety? What are the roles of each of them?

Answer 33

**1. SSRI** (selective serotonin reuptake inhibitors, increase 5HT levels) **2. Tricyclic antidepressant drugs** (increase 5HT and noradrenaline levels) **3. Benzodiazepine** (potentiate GABA mediated inhibition in the CNS and periphery) **4. Anticonvulsant drugs** (stabilise nerve activity e.g., valproate, dampen excitability in the brain, used after the first three are unsuccessful) **5. Monoamine oxidase inhibitors** (elevate 5-HT levels, **_not favoured)_**

Question 34

What receptors do benzodiazepines modulate?

Answer 34

GABA_A receptors

Question 35

When were the Benzodiazepines developed?

Answer 35

In the 1960s, the classical anxiety treatment grew out of efficacy of Chloridazepine: accidental synthesis that had calmed agitated animals

Question 36

Tell me about how Benzodiazepine modulates GABA receptors, what type of modulator is it?

Answer 36

* It **modulates the levels of inhibition** in the nervous system * Clinically used drugs (anxiolytic, sedative, muscle relaxant) potentiate the level of inhibition * Bring about **allosteric modulation** response when benzodiazepines bind to GABA (binding to site which is not the one used to activate receptor- allosteric) * GABA is TMP, **Cl- ion channel** in centre, Cl- flow out --\> in normally, increase negativity on the inside of the cell, making it less excitable and therefore **inhibit neuronal excitability** * Benzodiazepine bind to allosteric site, allosteric modulation, can have +ve and -ve allosteric modulators, -ve act against the GABA and the Cl- opening and lead to more excitable state, where as the +ve act for the GABA and encourage the Cl- opening and lead to inhibition

Question 37

What is the general structure of the GABA receptor?

Answer 37

2 alpha subunits 2 beta subunits Gamma subunit Cl- ion channel central

Question 38

How can the general structure of the GABA channel vary and how can this effects its selectivity?

Answer 38

Can have the following subunits: * alpha subunit 1-6 * Beta subunit 1-3 * Gamma subunit 1-3 * Delta subunit 1 * Epsilon subunit 1 * Theta subunit 1 * As shown above there are lots of different subunits which can contribute to the different combinations of GABA receptors that are present in the brain, these different GABA receptor combination types are shown on the right * Sometimes have delta subunits instead of gamma, this means not sensitive to benzo. * Those GABA receptors containing the **alpha 1,2,3,5** are found **synaptically** and are usually the ones which are **benzodiazepine Sensitive** * The **alpha 4,6** are usually distributed at **distal area**s away from synapses (away from GABA releasing sites) * **None drug sensitive GABA** away from synapses i.e., those containing alpha 4 and 6

Question 39

What are the different types of GABA_A recpetors that can come about due to the different combination of subunits?

Answer 39

Question 40

What are the following GABA receptor subunits that work in the following aspects... * sedation * anxiolysis * muscle relaxation * Anti-convulsive * Amnesia * Addiction

Answer 40

Question 41

What type of subunits are present in the amygdala that help with benzodiazepine selectivity?

Answer 41

High **alpha2** containing receptors (synaptic and likely containing GABA benzo. Subunit) in the amygdala- anxiolytic pharmacology related to these receptors

Question 42

What are some of benzodiazepines successes?

Answer 42

**Rapidly acting** (cf the SSRI that require long treatments \>8-12 weeks for full efficacy) **Anxiolytic** **sedative**, **hypnotic** **muscle relaxant** (now know these effects are through distinct GABAAreceptor types **Receptors expressed broadly** in the anatomical regions of the circuit including BZ sensitive GABA receptors in amygdala **Excellent efficacy by amnesic** (memory is less strong when taking the drug). **Very limited toxicity** (cf barbiturates that they superseded)

Question 43

What are some of benzodiazepines limitations?

Answer 43

Big problem associated with protracted use of the drug Use has become restricted due to **tolerance and withdrawal problems** **Acute treatment**

Question 44

What is a strategy used to overcome benzodiazepines limitations?

Answer 44

One strategy is to **taper the BZ in combination with SSRI treatment**

Question 45

What are the effects of benzodiazepine in the VTA?

Answer 45

BZ cause disinhibition in VTA which is associated with reward, BZ are potent drugs in the reward pathway

Question 46

Look into...

Answer 46

The wider context of the neuropharmacology of affective disorders is both current, debated and incompletely understood. Guardian paper on Prozac not working to read by Sarah Bozely 2008