Anxiety disorders: Neurobiology, neurochemistry and treatment Flashcards
Which part of the brain plays a role in fear?
Amygdala
What does activation of the amygdala cause?
Tachycardia, paleness, pupil dilation, blood pressure elevation
Behavioural and EEG arousal increased vigilance
Corticosteroid response
What does the amygdala excite?
Locus coeruleus
Hypothalamus
Describe the acute stress response
- Avoidance behaviour
- Increased vigilance and arousal
- Activation of the sympathetic division of the ANS
- Release of cortisol from the adrenal glands
Describe the HPA axis
Hypothalamus releases CRH Pituitary releases ACTH Adrenal cortex releases cortisol (stress hormone) (CRH: corticotropin releasing hormone ACTH: adrenocorticotropic hormone)
What does the Locus Coeruleus release?
Norepinephrine
What is the regulation of HPA axis?
Push and pull regulation
What happens during Chronic activation of glucocorticoid receptors in hippocampus?
- increased Ca2+ entry into neurons
- too much Ca2+ - excitotoxic - cells dieHippocampus can’t feedback to limit cortisol production
What do anxiety disorders result from?
- diminished activity of hippocampus
- loss of feedback to the amygdala
- inappropriate fear responding
(evidence - hippocampal volume in PTSD patients reduced)
What is the noradrenergic system involved in?
Arousal and attention
What is the serotonergic system involved in?
Mood and emotion
Where do the noradrenergic and serotonergic systems project to?
Throughout the forebrain to both cortical and limbic areas as well as connections to each other
They are also thought to balance each other
What can dysregulation of limbic systems or connections cause?
Inappropriate fear and anxiety responses
List some anxiety disorders
Post traumatic stress disorder Panic disorder Generalized anxiety disorder Phobia Obsessive compulsive disorder
What is PTSD?
persistent psychological stress following exposure to extreme stress, e.g. war, physical assault
What is panic disorder?
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).
What is Generalized Anxiety Disorder (GAD):
stress and anxiety in the absence of obvious precipitating stimulus
What are phobias?
similar to GAD, but triggered by particular objects (e.g. spiders, birds) or situations (e.g. crowds, darkness)
What is Obsessive Compulsive Disorder (OCD):
frequently recurring, uncontrollable, anxiety-producing thoughts (obsessions) and impulses (compulsions). Responding to them, e.g. repeated, compulsive hand washing, dissipates associated anxiety.
Describe the features of panic disorder
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
Describe the treatment of panic disorder
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)
In what anxiety disorders do benzodiazepines work well?
Generalized Anxiety Disorder (GAD) Panic Disorder (PD)
In what anxiety disorders do benzodiazepines not work as well?
Obsessive Compulsive Disorder (OCD)
Post Traumatic Stress Disorder (PTSD)
In what anxiety disorders do SSRIs work well in?
OCD
PTSD
Panic Disorder
GAD
Which drug works in GAD?
GAD
Name some drugs which increase GABA activity to reduce anxiety
Partial agonist Alcohol
Indirect agonists Barbiturates
Benzodiazepines
Which drugs which decrease GABA activity to increase anxiety?
Benzodiazepine antagonist Flumazenil
These drugs all act at the GABA(A) ionotropic receptor
What happens to the benzodiazepine binding sites in the brain of someone with panic disorder?
Fewer binding sites
Which area of the brain shows increased activity during periods of anxiety?
the frontal cortex normally shows increased activity during periods of anxiety
Describe anxiety and depression
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
Describe neuroplasticity downstream of antidepressants
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
Where do the opposing functions of various brain areas in panic disorder act?
Opposing functions in various brain areas
hippocampus
amygdala
hypothalamus
Describe Obsessive compulsive disorders
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
What gives rise to the direct and indirect pathways?
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.
Describe how the direct and indirect pathway link to OCD
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
What is the best drug treatment of OCD?
SSRIs
e.g. fluoxetine but also clomipramine (TCA)
Describe how caudate hyperactivity leads to OCD
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 .
Describe the pros and cons of using benzodiazepines in the treatment of anxiety disorders
good immediate effects, but patients can develop tolerance and there is potential for abuse, and anxiety during withdrawal
Describe the pros and cons of using SSRIs in the treatment of anxiety disorders
are effective, but have a delayed onset. Initially can be anxiogenic.
What is the best strategy in treatment of anxiety disorders?
Combining benzodiazepines and SSRIs initially and then tapering off the BDZs as the SSRIs take effect
