Biology of anxiety disorders Flashcards
What is generalised anxiety disorder?
Excessive uncontrollable global anxiety and worries
- At least 3 of the following symptoms:
- – Restlessness
- – Fatigue
- – Irritability
- – Muscle tension
- – Sleep disturbance
- Persistent (at least 6 months)
- Significant distress or impairment
- Anxiety is general, not tied to specific objects
What are phobias?
- Phobias are when the anxiety and fear becomes excessive and unreasonable, and interferes with normal functioning
Types: - Specific object
— Marked and persistent fear of a specific object or situation
— Immediate anxiety produced by exposure to the object
— Recognition that the fear is excessive and unreasonable, but sufferer cannot control it
— Most people do not seek treatment, but instead avoid the object they fear
— Both avoidance of the object or situation, and the anxious anticipation of the object or situation, interfere with the person’s normal life - Social
— Broader, less specific type of phobia
— Marked and persistent fear of social situations where there is exposure to unfamiliar people
— May also be made worse by an unfamiliar space - Agoraphobia
— Fear of being in places or situations where escape may be difficult or embarrassing
— Leads to sufferers avoiding all such situations, by not going out - We learn phobias through classical conditioning, often at a very young age
— Hence often run in families
What is panic disorder?
- Recurrent panic attacks
- – Sudden onset of intense fear
- – Relatively transient
- – Trembling, sweating heart palpitations, chest pain, shortness of breath, feeling of choking, dizziness
- Can be an over-reaction to a normally fearful situation, or they can occur without apparent reason
- Often self perpetuation
What is obsessive compulsive disorder?
- Obsession = persistent intrusive thought, idea, impulse or image that causes anxiety
- Compulsion = repetitive and rigid behaviour that a person feels compelled to perform in order to reduce the anxiety
- Many people experience minor obsessions (e.g. worrying about upcoming exams) or compulsions (keeping desk organised in a certain way), but they do not have the disorder
- Recurrent obsessions or compulsions which are recognised by the sufferer as abnormal, but they still feel compelled to do them, thus consuming considerable time, and causing disruption to daily life
What is post traumatic stress disorder?
- Anxiety after witnessing a traumatic event
- Long lasting
- May be delayed after the event
- Re-experience event: intrusive recall (flashbacks), nightmares
- Feelings of detachment
- Hyper-arousal: sleep disturbance, irritability, anger, aggression
- May include secondary symptoms:
- – Depression
- – Sexual dysfunction
- – Self-harm
What are some models of anxiety?
- Elevated plus maze
— Plus shaped maze, where 2 arms have no walls (open arms) and 2 have opaque walls (closed walls)
— Rodents spend less time in the open arms than the closed ones
— Anxiogenic effect seen by spending less time in open arms
— Anxiolytic effect seen by spending more time in open arms - Open field
— A large (1m square) brightly lit arena
— Rodents prefer not to spend time in the middle of the arena
— Anxiogenic effect: spend even less time in the middle of the arena
— Anxiolytic effect: spend more time in the middle of the arena - Evidence for neurotransmitter imbalance in anxiety disorders
— Reduced GABA activity produces anxiety in animal models
• Drugs which increase GABA function are anxiolytic (variable)
• Suggests a role in anxiety but not necessarily in anxiety disorders
— Electrical stimulation of locus coeruleus produces anxiety in animals – a noradrenergic area
• Noradrenergic antagonist (clonidine) reduces some aspects of anxiety (tachycardia, dilated pupils, tremor, sweating)
— Clinical data:
• Benzodiazepanes are effective in reducing anxiety
• Noradrenaline may be important in panic disorder
• Antidepressants which affect NA are helpful
• OCD may involve a neurotransmitter imbalance of serotonin
• SSRIs may help many patients
Discuss the role of benzodiazepines in anxiety
- Introduced in mid 1950s
- E.g. diazepam (valium), chlordiazepoxide
- Anxiolytic dose is not sedative
- Therapeutic index was extremely high (very difficult to overdose)
- Much reduced abuse potential, but still a potential problem
- Use as anxiolytic declined in last 20 years, due to:
— Concerns over dependence
— Side effects including depression of REM sleep, confusion, dementia-like effect can result from long term treatment (especially in elderly)
— Withdrawal can lead to: rebound anxiety and insomnia, rebound vivid dreams, in extreme cases: paranoia, seizures
• Can be avoided by slow withdrawal - Action: allosteric modulators of the GABA-A receptor
— Bind to a second binding site on the extracellular part of the receptor
— Binding of the co-agonist (benzodiazepine) alters the action of the main agonist (GABA)
— Potentiate the action of active GABA - Localisation of benzodiazepine receptors:
— High density in the cortex, hippocampus olfactory bulb and amygdala (limbic).
— Lesions to the hippocampus and septo-hippocampal system produce, in animal studies, a spectrum of effects very similar to those of benzodiazepines - More selective anti-anxiety drugs interact with serotonin and noradrenaline systems.
What is Gray’s comparator theory of anxiety? (1976)
- The septo-hippocampal system acts as a comparator
— Receives information about incoming stimuli
— Compares this with predicted events
— If mismatch, or predicted aversive event, the system is activated
• This is anxiety - Results in increased arousal and inhibition of ongoing behaviour
- Septo-hippocampal system has major noradrenergic and serotonergic inputs, and high density benzodiazepine binding
— Activity in monoaminergic neurones is increased in stress
— Increasing GABA function inhibits the throughput of this activity (i.e. reduces the stress response)
— Benzodiazepines potentiate GABA effects
— Hence anxiolytic action may be through GABAergic modulation of monoamine transmission
• May account for effects of noradrenergic and serotonergic drugs on specific types of anxiety disorder
What is the noradrenergic theory of anxiety?
Increased NA release leads to anxiety, via excessive or dysfunctional arousal
What is the role of serotonin in anxiety?
- Evidence is confusing and at times contradictory for its role
- There are 2 major serotonergic systems in the brain: the medial raphe nuclei (MRN) and the dorsal raphe nuclei (DRN)
- – These are morphologically distinct, have different afferent and efferent projections (Graeff, 1990; Azmitia and Whitaker, 1995), and function in parallel and together (Tork and Hornung, 1990)
- – Both systems are believed to be important in anxiety
- – Grove et al (1997) proposed a model in which the DRN is important in the modulation of fear and anticipatory anxiety, and the DRN in modulating cognitive processes
- L-tryptophan and 5-HTP are precursors of 5-HT: these are known to cause sedation and anxiolysis
- – Charney et al, 1987; Nutt and Cowen, 1987; Westenberg and den Boer, 1989
- The anxiety response to 5-HT agonists could simply be a cognitive misinterpretation of the side effects produced by these drugs
- – Kahn et al., 1988
- An acute increase in 5-HT leads to increased anxiety, later with anxiolysis on chronic stimulation
- – It had been proposed (Kahn et al., 1988) that this was because initial stimulation of hypersensitive 5-HT receptors is followed by down-regulation in response to chronic bombardment
- – But animal studies with microdialysis contradict this idea
What is the role of cholecystokinin in anxiety?
- Found in relatively high concentrations in the mammalian brain, where it is believed to act as a neurotransmitter and/or neuromodulator
— Rehfeld, 1985 - Has been shown to provoke panic
- The brain contains 2 pharmacologically distinct receptors for CCK
— CCK-a receptor is the least numerous in the brain
— CCKb subtype is primarily located in the brain
• Has a high affinity for the tetrapeptide CCK-4 and pentagastrin
• Panic can be induced by CCK-4 in anybody, but panic patients are sensitive to much lower doses (Bradwejn et al., 1990; Bradwejn et al., 1991)
— A specific CCKb-receptor antagonist may be useful in the treatment of spontaneous panic
What is the role of hypercapnia in anxiety?
- It can induce panic
- If severe enough, it can induce panic in anybody
- Sensitivity to CO2 varies with personality (Waeber et al., 1982) and with cognitive interpretation (Sanderson et al., 1989)
What is the role of sodium lactate in anxiety?
- Sodium lactate = a panicogen
- Anxious individuals produce more lactate on exercise than healthy controls do
- – Jones and mellersh, 1946
- Lactate infusions can cause severe anxiety in susceptible individuals
- – Pitts and McClure, 1967
- – Those with panic disorders have increased susceptibility
What anxiolytics can be used to treat anxiety?
Taylor and Nutt (2004)
- Anti-convulsants = act via the transmission of GABA and glutamate
— Preclinical research shows anxiolytic properties for these drugs, but the evidence in humans is less impressive
— Hence second line or adjunctive therapy
- Anti-depressants:
— The efficacy of TCAs and MAOIs in the treatment of anxiety disorders has been established for decades
— TCAs efficacy = related to the reuptake inhibition of 5HT and NA
• But use is limited due to their side effects
— MAOIs = increase synaptic availability of 5HT, NA and dopamine
• Also have a significant side effect profile
— SSRIs are licensed for use in the treatment of GAD, OCD, panic disorder, social anxiety disorder and PTSD
• First line therapy for each of the major anxiety disorders
• But has discontinuation syndromes if abruptly terminated
- Anti-psychotics:
— Originally used as major tranquillizers
• But this has little support from controlled trials
— There is evidence for the use of haloperidol and the atypical drugs risperidone and quetiapine in OCD, where they are used to augment SSRI treatment
— Controlled trials have reported benefits for the atypical drug olanzapine in social anxiety disorder (Barnett et al., 2002) and in addition to SSRIs in PTSD (Stein et al., 2002).
Travis and Argyropoulos (2004)
- Antidepressants and benzodiazepanes are effective in treating panic disorder
— SSRIs are the current first-line option
- A variety of distinct classes of drugs and specific forms of psychotherapy are
- A serious problem affecting pharmacological studies in panic is a relatively high placebo response rate, which may mask true effects
— Also, the variables used to chart progress in panic studies are not always comparable so it can be difficult to interpret the results of the pharmacological studies
- The onset of action may vary from 2–3 weeks up to 12 weeks, so perseverance with treatment is required
Bakker et al., 2002
- Little difference between the various SSRIs, clomipramine and imipramine in the treatment of panic
— But direct comparisons are generally lacking
Barlow et al., (2000)
- Compared imipramine (TCA), CBT, imipramine plus CBT, and placebo alone
- The combination of drug and psychotherapy did not confer any advantage in global measures of severity early on
- But it was better at the end of the maintenance phase, 9 months into treatment
What are some predictors of poor outcomes in panic disorder?
Travis and Argyropoulos (2004)
- Longer duration of symptoms before treatment
- Severity of ‘phobic’ avoidance
- Comorbid affective disorder
- Alcohol and/or substance misuse
- Personality disorder
- Incomplete remission of symptoms with treatment
- Female sex
