Anxiety Flashcards
LO
- 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)
Compare the biological pathway of depression and anxiety
Compare the definition of depression and anxiety
Compare the example animal model experiments done for depression and anxiety
Compare the brain pathways for depression and anxiety
Compare the transmitter pathways for depression and anxiety
Compare the molecular target of depression and anxiety
Compare the drug class of depression and anxiety
Compare the clinical confounds of depression and anxiety
Depression vs. Anxiety table
What is fear…?
What are some physiological signs it causes?
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
What is anxiety…?
Anxiety is a pathophysiological state that detracts from normal function and likely impeded an organism’s success. Thus, a medical condition
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?
- 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)
What activates anxiety?
Anxiety would be the activation of these responses to neutral or emotionally ambiguous cues
This interpretational aspect suggests important cognitive component
What is fundamental to fearfulness?
What does this imply?
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
Name some conditions that anxiety is related to?
- 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)
Tell me some symptoms of panic attacks
- 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
What does Agoraphobia have similar symptoms to and when do they come about?
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
Tell me about when panic attacks would come about and what they may be associated to/ due to?
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
What is specific phobia?
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
What is social phobia?
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
What is obsessive compulsive disorder (OCD)?
What sort of things could an individual who suffers from it do and what is it defined by?
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.
What is PTSD due to?
Experienced traumatic or near-death experiences in which intense fear response ensued.
What does PTSD cause?
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
What are the two types of PTSD and the time frames for each?
1-3 months (ACUTE); >6 months (chronic)
Appears 6 months post traumas (delayed onset)
What is acute stress disorder similar to?
What sort of symptoms does it show and is there a known cause?
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
What is generalised anxiety disorder (GAD)?
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.
Tell me about two types of animal models which are used to unpick the fear circuit
There are two types of context conditioning
- Unsignalled
- 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
- Accessing the core fear circuit
- Implicating additional modulation
- Making a clear case for neuronal plasticity
What strucrture is at the core of the fear pathway?
The amygdala of the limbic system is at the core of the fear pathway
Tell me about association pathways and how they can contribute to an emotional response
Mention any other necessary componenets and what they are
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
Tell me some of the inputs that feed into the amygdala when processing an emotional response
- hippocampus
- Thalamus
- Sensory cortex
- septum
- PFC
- hypothalamus
- Brain stem
What 4 areas can the emotional response feed into and what are each of these regions involved with?
What are some current preferred treatment routes priorities for anxiety?
What are the roles of each of them?
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)
What receptors do benzodiazepines modulate?
GABAA receptors
When were the Benzodiazepines developed?
In the 1960s, the classical anxiety treatment grew out of efficacy of Chloridazepine: accidental synthesis that had calmed agitated animals
Tell me about how Benzodiazepine modulates GABA receptors, what type of modulator is it?
- 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
What is the general structure of the GABA receptor?
2 alpha subunits
2 beta subunits
Gamma subunit
Cl- ion channel central
How can the general structure of the GABA channel vary and how can this effects its selectivity?
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 areas away from synapses (away from GABA releasing sites)
- None drug sensitive GABA away from synapses i.e., those containing alpha 4 and 6
What are the different types of GABAA recpetors that can come about due to the different combination of subunits?
What are the following GABA receptor subunits that work in the following aspects…
- sedation
- anxiolysis
- muscle relaxation
- Anti-convulsive
- Amnesia
- Addiction
What type of subunits are present in the amygdala that help with benzodiazepine selectivity?
High alpha2 containing receptors (synaptic and likely containing GABA benzo. Subunit) in the amygdala- anxiolytic pharmacology related to these receptors
What are some of benzodiazepines successes?
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)
What are some of benzodiazepines limitations?
Big problem associated with protracted use of the drug
Use has become restricted due to tolerance and withdrawal problems
Acute treatment
What is a strategy used to overcome benzodiazepines limitations?
One strategy is to taper the BZ in combination with SSRI treatment
What are the effects of benzodiazepine in the VTA?
BZ cause disinhibition in VTA which is associated with reward, BZ are potent drugs in the reward pathway
Look into…
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
