Anxiety Pathophysiology

What is anxiety?

• Is an emotional state caused by perception of real or perceived ganger that threatens person’s security

  • normal response that is experienced by everyone to varying degrees

  • is an adaptive response that is transient in nature

  • allows people to prepare for- and react to- changes in the environment around them

What is disordered anxiety?

• potentially debilitating psychological and physical reactions from chronic and/or excessive/irrational anxiety 

  • leading to persistent daily function 

  • no longer adaptive response 

True or False: Anxiety disorders are well treated.

False.

What is the prevalence of anxiety disoders?

• lifetime prevalence ~31%

• women > men to suffer

What is the neuroanatomy of fear and anxiety?

• amygdala (temporal lobe) 

  • critical role in assessment of fear stimuli and the learned response we have to fear

• locus coeruleus (brainstem)

  • primary NE containing site with widespread projections to areas of the brain

• hippocampus 

  • integral part in consolidation of traumatic memory and contextual fear conditioning

• hypothalamus

  • principle area for integrating neuroendocrine and autonomic responses to a threat

What neuro-biochemicals are involved in the signaling of anxiety?

• NE

• GABA

• 5-HT

• corticotropin-releasing factor (CRF)

• glutamate

• dopamine

• cholecystokinin

What are the different pathophysiological hypotheses for anxiety disorders?

• Noradrenergic model 

• GABA-receptor model 

• serotonin model 

What is the noradrenergic model for anxiety disorder pathophysiology?

• locus coeruleus (LC) is alarm center that activates NE release → stimulate SNS and PSNS

  • if activated chronically (eg. chronic stress) → increase NE in LC, amygdala, hippocampus and medial prefrontal cortex (MPFC) → increases HPA axis activity by reducing HPA negative feedback 

  • also, chronically leads to downregulation of alpha-adrenoreceptors (making more sensitive to NE)

How do anxiolytics work on the noradrenergic model?

• will inhibit the LC from firing → decreasing NE → blocking anxiogenic pathway

What is the GABA model for anxiety disorder pathophysiology?

• GABA major inhibitory NT involved in 5-HT, NE and DA systems in MPFC and amygdala

  • negative feedback mediated by GABA strongly influences fear and anxiety behaviours including termination 

How do anxiolytics work on the GABA model?

• GABA-A and GABA-B receptors are targets

  • GABA-A → reduces neuronal excitability (benzos enhance inhibitory effects) 

  • GABA-B → inhibit GABA release pre-synaptically 

What is the serotonin model for anxiety disorder pathophysiology?

*lacks evidence to prove abnormal function leads to disorder 

• data shows serotonin system is dysregulated in patients with anxiety disorder 

• serotonin primarily inhibitory originating in raphe nucleus but projected diffusely throughout the brain 

• abnormalities in functioning through release and uptake of presynaptic autoreceptors, SERT or affect of serotonin at postsynaptic receptors may play a role

  • known 5-HT and NE pathways are closely linked and interaction between 2 systems may vary

What are the different etiologies of anxiety disorders?

• Is due to interactions between combinations of factors including vulnerabilities

  • genetic predisposition

  • childhood adversity and neurobiological adaptations

  • external stresses (e.g occupational, trauma)

What are the risk factors for anxiety disorders?

• family history of anxiety/mood disorders

• personal trauma

• isolation

• low education level 

• parental deficiency or over protection 

• chronic physical illnesses (CVD, diabetes) 

What are the comorbid psychiatric illnesses that have symptoms of anxiety?

• mood disorders

• schizophrenia

• dementia

• ADHD

• substance use disorders 

*most patients with psychiatric illnesses will have 2+ comorbid disorders → important to diagnose and treat comorbid conditions in patients that present with anxiety 

What are the different types of anxiety disorders?

• generalized anxiety disorder (GAD)

• social anxiety disorder (SAD)

• panic disorder 

• agoraphobia 

• specific phobia

• separation anxiety disorder 

What criteria do the symptoms have to meet to consider an anxiety disorder?

• characteristic features and anxiety and avoidant behaviour

• symptoms cause significant distress and impairment in social, occupational or other areas of daily living

• not found to be secondary to medication or unhealthy substance use 

• not part of a general medical disorder or occurring solely as part of another psychiatric disorder 

What is generalized anxiety disorder?

• unrealistic or excessive anxiety or worry about events/activities that are persistent for > 6 months 

  • where symptoms interfere with activities of daily living → high probability of seeking help due to impact on QoL  

• is a gradual onset 

• females 2x higher prevalence

What is the average age of onset for GAD? 

• typically in late adolescence to early adulthood, ~21y/o

• bimodal distribution 

  • may also present later in life when GAD is a secondary presentation exacerbated later in life by severe psychological stressors or life changes; typically then 30-45 y/o

What is the diagnosis criteria for GAD?

• excessive worry (anxiety, worry apprehensive expectation) occurring more than not for 6+ months 

• difficult to control the worry 

• 3+ associated symptoms: 

  • restlessness or feeling on edge

  • easily fatigued 

  • difficulty concentrating, mind blanking 

  • irritable

  • muscular tension 

  • sleep disturbances 

• significant distress/functional impairment 

• not due to other causes

  • substance use

  • medication-induced

  • medical conditions (hypothyroidism)

• not due to another psychiatric disorder

  • anxiety/worry about panic attacks

  • negative evaluation of SAD

  • contamination or other obsessions of OCD 

  • separation from attachment figures in separation anxiety 

What is panic disorder?

• starts as series of unexpected panic attacks 

  • panic attack → sudden surge of anxiety that is an abrupt surge of intense fear/discomfort, often associated with psychological and physical symptoms (at least 4) lasting 20-30 minutes

• followed by at least 1 month of worrying or maladaptive behaviour due to the panic attacks 

• often misdiagnosed b/c mimics other medical conditions

What are the symptoms of a panic attack?

*4+ to consider panic attack

• psychological symptoms

  • depersonalization (detached from self) 

  • derealization (detached from reality)

  • fear of losing control, going crazy or dying

• physical symptoms

  • abdominal distress

  • chest pain or discomfort

  • dizziness/light-headedness

  • nausea

  • palpitations

  • feeling short of breath or smothered 

  • tachycardia 

  • chills

  • feeling of choking 

  • heat sensations

  • paresthesia 

  • sweating

  • trembling or shaking 

What is social anxiety disorder?

• pronounced fear about 1 or more social situations where the person may be scrutinized 

  • where exposure to the situation causes immediate panic attack 

  • the fear/anxiety response if out of proportion to the actual threat

• fear and anxiety may last for 6+ months 

• chronic condition lasting average of 20 years 

  • onset in mid-teens

  • female slightly higher rates

• if restricted to speaking/performing in public → SAD specified as performance anxiety disorder

Why can social anxiety disorder be difficult to differentiate from other anxiety disorders?

• panic attacks occur in SAD and panic disorder

• distinction is based on the rationale of the fear

  • fear of anxiety symptoms → panic disorder

  • fear of embarrassment of social interaction → SAD

True or False: Majority of SAD patients end up having concurrent mood and substance use disorder. 

True.

What are the potential fears commonly associated with SAD?

• general fears

  • being scrutinized by other people 

  • being evaluated negatively 

• situation fears 

  • eating/writing in front of other people 

  • interacting with authority figures 

  • public speaking 

  • speaking with strangers 

  • using public facilities 

What are common clinical presentations of SAD?

• blushing

• feeling of “butterflies” in stomach 

• diarrhea

• sweating

• tachycardia 

• trembling 

What is agoraphobia?

• distinct fear or anxiety about being in:

  • 2+ situations where escaping might be difficult

  • a situation where help may not be available in the event of a panic attack

• fear leads to avoidance of specific situations

  • enclosed spaces, public transport

• ½ patients with panic disorder will develop 

What are specific phobias?

• a persistent and marked fear of a specific object or situation (eg. high places or insects)

• fear leads to immediate anxiety upon exposure, often resulting in avoidance behavior

• apart from contact with object/situation do not have symptoms 

  • people will avoid or adjust to certain restrictions to their activities to remain without symptoms 

What needs to be ruled up before diagnosing with anxiety disorder?

• medication or substance-induced

• medical condition

  • cardiovascular

  • endocrine and metabolic 

  • GI 

  • neurologic 

  • respiratory 

  • systemic 

What are the different medications/substances that induce anxiety?

• anticonvulsants → CBZ, PHT

• antidepressants → SSRIs, SNRIs, bupropion 

• antiHTN → clonidine, felodipine 

• antibiotics → quinolones, isoniazid 

• bronchodilators → salbutamol, theophylline

• steroids → prednisone 

• DA agonists → amantadine, levodopa

• herbals → ginseng, ephedra

• substances → ecstasy, cocaine, cannabis

• NSAIDs → ibuprofen, indomethacin

• stimulants → amphetamines, methylphenidate, caffeine, nicotine

• sympathomimetics → pseudoephedrine, phenylephrine

• thyroid hormones → levothyroxine

*can occur in dose-dependent manner; even minimal amount can result in anxiety/panic attacks and quickly after starting new therapy or increasing dose

What are the potential CV conditions associated with anxiety symptoms that need to be ruled out in differential diagnosis?

• angina

• arrhythmia

• cardiomyopathy

• CHF

• HTN

• ischemic heart disease

• MI

What are the potential endocrine and metabolic conditions associated with anxiety symptoms that need to be ruled out in differential diagnosis?

• Cushing disease

• diabetes

• hyperthyroidism 

• hypothyroidism 

• hypoglycemia 

• hyperkalemia 

What are the potential GI conditions associated with anxiety symptoms that need to be ruled out in differential diagnosis?

• Crohn’s disease

• IBS

• ulcerative colitis

• peptic ulcer disease

What are the potential neurologic conditions associated with anxiety symptoms that need to be ruled out in differential diagnosis?

• migraine

• seizures

• stroke

• neoplasm

• poorly controlled pain

What are the potential respiratory conditions associated with anxiety symptoms that need to be ruled out in differential diagnosis?

• asthma

• COPD 

• PE 

• pneumonia

What are the potential systemic conditions associated with anxiety symptoms that need to be ruled out in differential diagnosis?

• anemia 

• cancer

• vestibular dysfunction