Anxiety Disorders

lecture 5

what is the definition of anxiety

• feeling of unease, such as worry or fear, that can be mild or severe

• more constant than normal stress or anxiety and impacts daily life

different types of anxiety disorder

• Generalised anxiety disorder (GAD)

• Panic disorder

• Obsessive compulsive disorder (OCD)

• Post-traumatic stress disorder (PTSD)

• Phobias, such as claustrophobia and social phobis

symptoms of GAD

• varies in different cases:

• restless or worried

• trouble concentrating and sleeping

• dizziness

• heart palpatations

• diagnose using DSM-5

• needs to persist for over 6 months and be uncontrolable

• include at least 3 of 6 symptoms

• rule out other medical conditions

Panic disorder

• anxiety disorder with regular panic attacks

• intense symptoms that come on fast without reason

• some symptoms can overlaop with other conditions (egl low blood pressure)

• range from 1-2 a month to multiple a week

• last 5-20 mins

Obsessive compulsive disorder

• combination of obsessive thoughts and compulsive activity

• Obsession = unwanted or unpleasant thought causing anxietyb

• Compulsion = repetitive behaviour to supress negative thoughts

• must be time consuming and impact daily life

Post-traumatic stress disorder (PTSD)

• caused by traumatic effects → affects 1 in 3 who experience trauma

• re-lived through nightmares or flashbacks

• avoidance of linked memories

• cognative distortions of the event

• lasts over 1 month and impairs function

• without other cause

Phobias

• overwheling and debilitating fear of somthing with little or no danger

• specific phobias → anomals, environments, situations, bodily

• complex → agoraphobia, social phobias

3 brain regions involved in GAD

role of prefrontal cortex in GAD

• controls rational logical thought to reduce anxiety

role of anterior cingulate cortex (ACC) in GAD

• amplifies negative information, increasing anxiety

role of amygdala in GAD

• inhibits PFC and initiates fight or flight

interraction between brain regions in anxiety

• normally there is functional connectivity between PFC, ACC and amygdala to manage anxiety

• in anxiety disorders the connections are disrupted → increased amygdala activity and decreased PFC

• fMRIS show weaker functional connectivity between PFC and amygdala compared to healthy controls

• increased functional connectivity between supramarginal gyrus (SMG) and PFC and between posterior cingulate cortex (PCC) and medial temporal gyrus (MTG)

• reduced funtional connectivity between SMG and inferior temporal gyrus (ITG)

  

Genetic changes in GAD

• around 30% heritability

• Risk genes linked to monoamine neurotransmission and neurotrophic signalling:

  • 5-HT reuptake transporter short alleles (S/S homozygous)

  • 5-HT1A receptor C1019G polymorphism → increases negative feedback and decreases serotonergic signalling

  • MAO-A T941G polymorphism and long allele → increase metabolism of monoamines and reduce signalling

  • BDNF Val66Met polymorphism → reduces BDNF activity

gene-environment interraction in GAD

• 30% inherited, 70% environmental

• environmental risk factors

  • childhood trauma

  • stressfull family circumstances

  • natural disasters

• genetics enhance environmental effects → having genetic and environmental risk factor drastically increases chances of GAD

  • Childhood trauma x 5-HT transporter, COMT & MAOA variants

  • Hurricane victim x Neuropeptide Y variants

  • Daily life stress x 5-HT transporter variants

  • Family relationship scale x Neuropeptide S receptor 1 variants

GABA in GAD

• dysregulated inhibitory neurotransmission

• GABA-A receptor downregulated

  • treat with GABA-A agonist

5-HT in GAD

• treatment with SSRIs show it plays some role

Neuropeptides in GAD

• patients are hypersensitive to cholecytokinin (CCK) agonists

• but trials using CCK-antagonists were unsucessfull

HPA Axis

• Hypothalamic-pituitary-adrenal axis

  • hypothalamus → in forebrain

  • pituitary gland → below hypothalamus

  • adrenal glands → above kidneys

• together regulate stress response, mood, immune function and metabolism

• hypothalamus → (corticotrophin releasing hormone) → pituitary gland → (adrenocorticotroin releasing hormone) → adrenal glands → (cortisol, adrenaline, noradrenaline)

GAD and neurodendocrine pathway

• cortisol activates fight or flight and inhibits CRH and ACTH release

• negative feedback to reduce cortisol and NA

• in chronic stress and GAD the HPA axis is dysregulated

considerations during medical anxiety assessment

• mental health history

• environmental issues

• medical and drug history

• degree of distress and impairment

• risk of suicide

non-pharmacological treatment of GAD

• self help

• meditation and mindfullness

• CBT/therapy

• exercise

• lifestyle changes

treatment for autonomic GAD symptoms

• β-adrenoceptor antagonists

• eg. propranolol

treatments for anxiety symptoms of GAD

• SSRIs → eg. sertraline

• SNRIs (serotonin and noradrenaline reuptake inhibitors) → eg. venlafaxine

• Atypical antidepressants → eg. vilazodone or mirtazapine

• benzodiazepines → eg. diazepam

Benzodiazepines as GAD treatments

• short-term use in crisis

• used in insomnia, epilepsy and pre-surgey

• enhances effect of GABA (inhibitory)

• binds to GABA-A receptor between a and y subunits

• causes conformational change to enhance GABA binding → GABA-A receptor positive allosteric modulator (PAM)

• channel opens → Cl- influx → hyperpolarisation → reduced neural activity

next generation GAD treatments

• current medications have issues

  • non-response

  • severe side effects → sexual dysfunction, drowsiness, weight gain

  • relapse

• novel treatment targets:

  • glutamatergics eg. ketamine, riluzole, xenon

  • neurosteroids eg. aloradine

  • cannabinoids

  • MDMA

  • L-DOPA