Anxiety Disorders

• Female sex (2:1 across most anxiety disorders) — likely related to hormonal factors (oestrogen modulates serotonergic and HPA axis function), greater amygdala reactivity, and psychosocial factors
• Family history / genetics (see Aetiology section for detail)
• Chronic medical illness (especially those causing autonomic symptoms — thyrotoxicosis, cardiac arrhythmias, COPD, asthma)
• Temperament of behavioural inhibition — a childhood temperamental trait of being timid and shy in novel situations, strongly predictive of later anxiety disorders

• Neuroticism — the personality trait of experiencing negative emotions easily; shared risk factor with depression ^[2][3]
• Early environment: parental separation, physical and sexual abuse, non-caring or overprotective parenting styles ^[3]
• Anxious attachment style — bidirectional escalation of anxiety in parent-child dyad ^[2]
• Cognitive biases — attentional bias towards threat, catastrophising, intolerance of uncertainty

• Lack of supportive networks, poorly functioning relationships, and poor social integration ^[3]
• Stress and trauma: long-term difficulties, recent life events (in particular events that lead to feelings of entrapment and humiliation) ^[3]
• Lower socioeconomic status
• Substance use (both as risk factor and consequence)

The amygdala is the central hub for processing fear. It is an almond-shaped ("amygdala" = Greek for "almond") structure in the medial temporal lobe ^[2].

Inputs to the amygdala:

• Thalamus → direct "quick and dirty" sensory relay (allows rapid fear response before conscious processing)
• Hippocampus → contextual memory cues ("I was attacked in this alley before") ^[2]
• Medial prefrontal cortex (mPFC) → top-down cognitive control and regulation of fear response ^[2]

Outputs from the amygdala (these explain the clinical features of anxiety):

^[2]

Worry is mediated by the cortico-striato-thalamo-cortical (CSTC) loop ^[2]:

• Arises from the dorsolateral prefrontal cortex (DLPFC) → passes through striatum → thalamus → back to DLPFC
• This circuit is thought to account for recurrent, ruminative thoughts in anxiety disorders (e.g., ruminations, obsessions)
• Modulated by 5HT, GABA, DA, NA, glutamate ^[2]
• COMT polymorphisms may affect monoamine metabolism within this circuit → vulnerability to excessive worrying ^[2]

• Inhibitory neurotransmitter ^[1]
• Suppresses other neurotransmitters e.g. serotonin, norepinephrine, dopamine etc. ^[1]
• GABA is the principal inhibitory neurotransmitter in the brain
• Mechanism: GABA-A receptors are chloride-channel-linked → when GABA binds → Cl⁻ influx → neuronal hyperpolarisation → ↓neuronal excitability
• In anxiety disorders: ↓GABA activity → failure to suppress amygdala and CSTC circuits → unchecked fear and worry responses
• Pharmacological implication: Benzodiazepines (BZDs) are positive allosteric modulators of GABA-A receptors → enhance GABA effect → rapid anxiolysis ^[2]

• Autonomic arousal and somatic symptoms in anxiety ^[1]
• Released from the locus coeruleus (LC) in the brainstem
• Mechanism: LC activation → widespread noradrenaline release → sympathetic activation → tachycardia, sweating, tremor, GI upset, pupil dilation
• In anxiety disorders: ↑central NA levels → autonomic hyperarousal
• Pharmacological implication: Long-term SNRIs → downregulation of adrenergic receptors → anxiolysis; β-blockers (e.g., propranolol) can block peripheral autonomic symptoms ^[2]

• Appetite, energy, sleep, mood, libido and cognitive function in anxiety ^[1]
• Serotonin innervates the amygdala and all elements of the CSTC circuit ^[2]
• Postulated role: signals presence of anxiety-producing stimuli but restrains associated behavioural responses — so serotonin is like a brake on anxiety behaviour
• In anxiety disorders: ↓cortical 5HT1A binding (demonstrated in panic disorder) → failure of this "braking" mechanism
• Pharmacological implication: SSRIs/SNRIs are first-line treatment — they increase serotonergic tone and restore the inhibitory modulation of anxiety ^[2]

• α₂δ ligands (e.g., pregabalin, gabapentin): bind α₂δ subunit of presynaptic voltage-sensitive calcium channels (VSCCs) → ↓release of excitatory neurotransmitters (especially glutamate) → anxiolytic effects ^[2]
• Glutamate: principal excitatory neurotransmitter; excessive glutamatergic activity in amygdala and CSTC circuit contributes to anxiety
• Dopamine: plays a role in CSTC circuit modulation; less directly implicated than 5HT/NA/GABA but relevant in certain anxiety-related conditions (e.g., social anxiety)
• HPA axis: chronic anxiety → sustained cortisol elevation → hippocampal damage (↓volume), immune dysregulation, metabolic effects

ICD-11 (which has now replaced ICD-10) similarly separates anxiety disorders from OCD-related and stress-related disorders:

• 6B00 Generalised Anxiety Disorder
• 6B01 Panic Disorder
• 6B02 Agoraphobia
• 6B03 Specific Phobia
• 6B04 Social Anxiety Disorder
• 6B05 Separation Anxiety Disorder
• 6B06 Selective Mutism

• Commonest mental disorders of childhood ^[2]
• Content of anxiety is influenced by developmental stage ^[2]:
  • Infants: fear of strangers → social anxiety
  • Preschool: fear of separation, specific objects → separation anxiety, specific phobias
  • Early adolescence: fear of social situations / personal adequacy → social phobia
  • Late adolescence: resembles adult patterns → GAD, panic disorders
• Diagnosis: only when developmentally inappropriate (more severe and prolonged than usual) and causes significant distress + functional impairment ^[2]

Definition: Excessive, uncontrollable worry about multiple everyday concerns (work, health, family, finances, minor matters) occurring more days than not for ≥6 months (DSM-5) ^[2].

Core features:

• Pervasive, excessive worry about multiple topics — the worry is "free-floating" (not focused on one specific situation or object)
• Difficulty controlling the worry — the person recognises it's excessive but cannot stop
• Associated with ≥3 of: restlessness, easy fatigability, difficulty concentrating, irritability, muscle tension, sleep disturbance (DSM-5 criteria)
• The anxiety and worry cause clinically significant distress or functional impairment
• Not attributable to substance or medical condition

Pathophysiology-clinical correlation: GAD is thought to primarily involve the CSTC worry circuit with altered activity in cortical regulatory regions (e.g., VLPFC) and altered connectivity with amygdala → inability to regulate excessive anxiety ^[2]

Special features:

• Blood-injury phobia shows a unique vasovagal response: initial tachycardia → then bradycardia, pallor, dizziness, N/V, fainting (diphasic response) — contrast to the pure sympathetic activation seen in other anxiety disorders ^[2]

Definition: Recurrent, unexpected panic attacks — abrupt surges of intense fear/discomfort peaking within minutes, followed by persistent worry about future attacks or maladaptive behavioural changes ^[2].

Panic attack symptoms (≥4 of the following, peaking within minutes):

1. Palpitations / tachycardia
2. Sweating
3. Trembling / shaking
4. Shortness of breath / smothering
5. Feelings of choking
6. Chest pain / discomfort
7. Nausea / abdominal distress
8. Dizziness / lightheadedness / faintness
9. Chills / hot flushes
10. Paraesthesias (numbness / tingling)
11. Derealisation / depersonalisation
12. Fear of losing control / "going crazy"
13. Fear of dying

Key distinguishing features:

• Unexpected: no obvious cue or trigger → can occur during sleep (nocturnal panic) or relaxation ^[2]
• Recurrent: at least one within one month
• Worry/behaviour change: persistent concern about additional attacks, worry about implications (heart attack, losing control), or significant maladaptive behaviour change (avoiding exercise, reorganising daily life) ^[2]
• These somatic symptoms may prompt help-seeking — patients often present to ED thinking they are having a heart attack or dying ^[2]

D/dx of panic attacks within anxiety disorders: Panic attacks can occur in ANY anxiety disorder, but are expected/predictable in those contexts (e.g., encountering feared object in phobia). Only in panic disorder are they truly unexpected ^[2].

Also known historically as: irritable heart, Da Costa's syndrome, neurocirculatory asthenia, disorderly action of the heart, effort syndrome ^[2]

Definition: Marked fear/anxiety about ≥2 of the following situations, due to concern that escape might be difficult or help might be unavailable if panic-like symptoms develop:

1. Using public transportation
2. Being in open spaces
3. Being in enclosed places
4. Standing in line / being in a crowd
5. Being outside the home alone

Key features:

• The situations are actively avoided, require a companion, or endured with intense fear/anxiety
• Fear is out of proportion to actual danger
• Persists ≥6 months
• 95% comorbid with panic disorder ^[2]
• Lifetime prevalence: 1.1% (with PD), 0.8% (without PD) ^[2]
• Can exist independently of panic disorder in DSM-5 (a change from DSM-IV)

Definition: Marked fear/anxiety about social situations in which the individual is exposed to possible scrutiny by others ^[2].

Core features:

• Fear that they will behave in a way or show anxiety symptoms that will be negatively evaluated (humiliated, embarrassed, rejected, or offending others) ^[2]
• Fear is out of proportion to actual threat
• Can be generalised (widespread social situations) or performance-only (discrete triggers like public speaking) ^[2]
• Associated with: blushing, tremor, nausea, urinary urgency ^[2]
• Anticipatory anxiety and avoidance behaviour → significant distress and functional impairment ^[2]
• Onset: typically mid-teens as intensification of pre-existing shyness, or following stressful social experience ^[2]
• Course: only 50% seek treatment, usually after many years of symptoms ^[2]

D/dx from normal shyness: normal shyness tends to be less severe and pervasive, and associated with little distress and functional impairment ^[2]

Definition: Marked fear/anxiety about a specific object or situation ^[2].

Types: animal, natural environment, blood-injection-injury, situational, other

Core features:

• Fear recognised as completely irrational or excessive but unable to be controlled ^[2]
• Fear is intense/severe and out of proportion to actual danger ^[2]
• Evoked nearly every time individual contacts phobic stimulus ^[2]
• Associated with anticipatory anxiety and avoidance behaviour ^[2]
• Blood-injection-injury phobia: unique diphasic response — initial tachycardia → vasovagal response (↓HR, pallor, dizziness, N/V, fainting) ^[2]

Onset: generally mid-childhood/early adolescence; animals/blood-injury in childhood; situational/natural environment in late adolescence to early adulthood ^[2]

• Excessive or prolonged fear of separation from home or major attachment figures ^[2]
• Historically considered exclusively a childhood disorder, but DSM-5 recognises it can occur in adults
• May present with psychosomatic complaints, school refusal, clinging behaviour, nightmares about separation ^[2]

The theme/focus of the anxiety helps identify the underlying diagnosis:

The theme/focus of anxiety is the key differentiating feature ^[2]:

Comorbidity for GAD ^[1]:

• 2/3 of GAD patients have other psychiatric diagnosis
• Depression
• Other anxiety disorders (e.g. panic, social anxiety)
• Personality disorder (e.g. anankastic, paranoid, avoidant)
• Alcohol and drug abuse

Adjustment disorder is essentially what you diagnose when someone has a disproportionate reaction to a stressor but doesn't tick the boxes for anything more specific. If they meet GAD criteria, diagnose GAD. If they meet PTSD criteria, diagnose PTSD. Adjustment disorder is the "none of the above" category.

Before diving into individual criteria, understand that all anxiety disorder diagnostic criteria share the same logical skeleton:

1. Core symptom cluster — the specific pattern of fear/anxiety/worry
2. Trigger/context specificity — what triggers it (or whether it is "free-floating")
3. Duration threshold — minimum time symptoms must be present (prevents diagnosing transient normal reactions)
4. Severity threshold — must cause clinically significant distress or functional impairment
5. Exclusion criteria — not attributable to substance/medical condition; not better explained by another mental disorder

The exclusion criteria exist because of the diagnostic hierarchy: organic → substance → psychotic → mood → anxiety. You only diagnose a primary anxiety disorder after ruling out conditions higher in the hierarchy ^[2].

DSM-5 Criteria [1][2]

A. Marked fear or anxiety about two (or more) of the following five situations ^[1]:

1. Using public transportation (buses, trains, ships, planes)
2. Being in open spaces (parking lots, marketplaces, bridges)
3. Being in enclosed places (shops, theatres, cinemas)
4. Standing in line or being in a crowd
5. Being outside of the home alone

B. The individual fears or avoids these situations because of thoughts that escape might be difficult or help might not be available in the event of developing panic-like symptoms or other incapacitating or embarrassing symptoms. ^[1]

This is the core cognitive distortion in agoraphobia — it's NOT a fear of the place itself, but a fear of what might happen (panic, incapacitation) and the inability to escape or get help. This is why "agoraphobia" (Greek: "agora" = marketplace + "phobos" = fear → "fear of the marketplace") is slightly misleading — it's not really fear of open spaces, but fear of being unable to escape/get help in those spaces.

C. The agoraphobic situations almost always provoke fear or anxiety. ^[1]

D. The agoraphobic situations are actively avoided, require the presence of a companion, or are endured with intense fear or anxiety. ^[1]

E. The fear or anxiety is out of proportion to the actual danger posed by the agoraphobic situations and to the sociocultural context. ^[1]

F. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more. ^[1]

G. The fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. ^[1]

H. If another medical condition (e.g., IBD, PD) is present, the fear, anxiety, or avoidance is clearly excessive. ^[1]

I. Not better explained by other mental disorder. ^[1]

DSM-5 Criteria (Abbreviated) [2]

• A. Exposure to actual or threatened death, serious injury, or sexual violence (directly, witnessing, learning about, or repeated exposure)
• B. ≥1 intrusion symptoms: recurrent intrusive memories, distressing dreams, dissociative reactions (flashbacks), psychological/physiological distress at trauma cues
• C. Persistent avoidance of stimuli associated with the traumatic event (≥1 of: avoidance of distressing memories/thoughts/feelings; avoidance of external reminders)
• D. Negative alterations in cognitions and mood associated with the event (≥2 of: inability to remember, negative beliefs, distorted cognitions, negative emotional state, diminished interest, detachment, inability to experience positive emotions)
• E. Marked alterations in arousal and reactivity (≥2 of: irritable behaviour, reckless behaviour, hypervigilance, exaggerated startle, concentration problems, sleep disturbance)
• F. Lasting > 1 month in duration (< 1 month = Acute Stress Disorder)
• G. Clinically significant distress or functional impairment
• H. Not attributable to substance or medical condition

^[2]

• Stressor: identifiable stressor of any severity (not necessarily traumatic), onset ≤3 months of stressor ^[2]
• Symptoms: emotional/behavioural symptoms out of proportion to stressor
• Residual category: should NOT be diagnosed if criteria for another specific disorder (GAD, MDD, PTSD) are met ^[2]
• Subtypes: with depressed mood, with anxiety, with mixed anxiety and depressed mood, with disturbance of conduct, with mixed disturbance of emotions and conduct, unspecified

These are the essential investigations when anxiety is the presenting complaint, particularly when clinical features suggest a possible organic aetiology (e.g., new onset in middle age, atypical features, lack of psychological triggers, prominent autonomic symptoms at rest):

These are not diagnostic but help quantify severity, track treatment response, and screen for comorbidities:

Before starting medications (especially SSRIs, SNRIs, TCAs, or pregabalin), the following baseline investigations are recommended:

The diagnostic process in practice involves:

1. Comprehensive psychiatric assessment:

• History of presenting complaint: onset, duration, triggers, content of worry/fear, avoidance patterns, functional impact
• Key questions to ask:
  • "What do you worry about?" (GAD = multiple topics; social anxiety = scrutiny; OCD = intrusive thoughts)
  • "Does the anxiety come on suddenly or is it always there?" (Panic = sudden, episodic; GAD = continuous)
  • "Are there specific situations that trigger it?" (Phobic disorders = yes; GAD = no)
  • "Do you avoid any situations because of the anxiety?" (Avoidance = phobic disorders, PTSD)
  • "Have you had any traumatic experiences?" (PTSD screening)
  • "Do you have any repetitive thoughts you can't get rid of, or rituals you feel compelled to do?" (OCD screening)
• Past psychiatric history: previous episodes, treatments tried, response
• Family history: anxiety, depression, bipolar, substance use
• Substance use history: alcohol, caffeine, illicit drugs, over-the-counter medications
• Medical history: thyroid disease, cardiac conditions, respiratory conditions
• Medication history: recent changes, new medications

2. Mental state examination (MSE):

• Appearance/Behaviour: restless, fidgeting, tremor, sweating, tense posture
• Speech: may be rapid, pressured (if anxious)
• Mood: "anxious", "nervous", "worried"
• Affect: anxious, apprehensive, fearful
• Thought content: worries (content helps differentiate disorder), catastrophic cognitions, obsessions
• Thought form: usually normal; may be circumstantial if overly detailed about worries
• Perception: usually normal (no hallucinations in primary anxiety disorders — if present, consider psychosis)
• Cognition: may have difficulty concentrating (but no true cognitive impairment — if present, consider dementia presenting with anxiety)
• Insight: usually preserved (patients typically recognise their anxiety is excessive)
• Risk: suicidal ideation (especially with comorbid depression), self-harm, substance use

3. Targeted investigations (as above — to exclude organic causes)

4. Apply diagnostic criteria (DSM-5 or ICD-11)

5. Screen for comorbidities (depression, substance use, personality disorders)

When evaluating anxiety, certain history features should raise your index of suspicion for organic or secondary causes:

• Vague, inconsistent history mixed with normal physical sensation and abnormal checking behaviour → consider somatoform/somatic symptom disorder ^[2]
• Symptoms that don't fit known disease patterns or anatomical confines → consider functional neurological disorder
• Persistent anxiety and concern despite repeated help-seeking, reassurance, negative investigations, and treatment → consider illness anxiety disorder (hypochondriasis) ^[2]
• Late onset (middle age or elderly) without clear psychological trigger → think organic cause or dementia (BPSD)
• Prominent autonomic symptoms at rest without psychological component → think thyrotoxicosis, phaeochromocytoma
• Morning-predominant anxiety → think substance withdrawal (especially alcohol, benzodiazepines) ^[2]

Most antidepressants result in ↑anxiety symptoms (apprehension, sleeplessness, palpitations) initially → dose should be increased very slowly ^[2]

Practical approach:

• GAD/Social anxiety: Start at half the usual antidepressant starting dose (e.g., sertraline 25 mg instead of 50 mg)
• Panic disorder: Start at quarter dose (e.g., sertraline 12.5 mg) — panic patients are exquisitely sensitive to somatic sensations and paradoxical anxiety is particularly distressing
• Increase dose every 1–2 weeks as tolerated
• Can use short-term BZD to cover the initial anxiogenic period

• Continue effective treatment for at least 6 months after symptom control
• For GAD: many guidelines recommend 12–18 months given the chronic relapsing nature
• For PTSD/social anxiety: at least 12 months
• When discontinuing: taper gradually over weeks to months to avoid discontinuation syndrome (especially paroxetine, venlafaxine)
• Relapse rates are significant after discontinuation — discuss with patient

CBT + pharmacotherapy combination may give better response in early stages but long-term results are uncertain ^[2]

• In practice, combination therapy is commonly used for moderate-severe cases
• The CBT teaches skills that persist after medication is discontinued
• Medication provides symptom relief that allows the patient to engage in CBT more effectively

Depression is the most frequent and clinically significant comorbidity across all anxiety disorders ^[1][2].

• 2/3 of GAD patients have other psychiatric diagnosis, with depression being the most common ^[1]
• Comorbidity of panic disorder: depression ^[1]
• Co-morbidities of PTSD: depression ^[4]
• Co-morbidities of OCD: > 60% have lifetime diagnosis of a mood disorder, MDD being the most common ^[4]

Why does anxiety lead to depression? The mechanism is both neurobiological and psychological:

• Neurobiological: Chronic anxiety → sustained HPA axis activation → ↑cortisol → hippocampal damage (↓volume) + monoamine depletion (5-HT, NA, DA) — the same neurotransmitter systems implicated in depression. The shared serotonin transporter gene polymorphism and shared heritability with neuroticism mean these conditions arise from overlapping biological substrates ^[2].
• Psychological: Persistent anxiety → avoidance → social withdrawal → loss of positive reinforcement → helplessness and hopelessness → depressive cognitions. The person who avoids social situations due to social anxiety eventually becomes isolated, loses friendships, and feels worthless — a direct pathway to depression.
• Temporal relationship: Anxiety disorders typically precede depression (anxiety has earlier onset — teens/early twenties; depression often develops later). Social anxiety disorder: depression is considered a risk factor for subsequent development ^[2]. This makes screening for depression in every anxiety patient essential.

Other anxiety disorders (e.g., panic, social anxiety) ^[1]

• Anxiety disorders cluster together. A patient with one anxiety disorder has a markedly elevated risk of having another:
  • GAD comorbid with: social phobia 23.2–34.4%, specific phobia 24.5–35.1%, panic disorder 22.6–23.5% ^[2]
  • Agoraphobia: other anxiety disorder 49–64% ^[2]
  • OCD: > 70% have lifetime diagnosis of an anxiety disorder such as PD, SAD, GAD, phobia ^[4]
• Why? Shared genetic vulnerability (neuroticism, 5-HT transporter polymorphism), shared neurobiological substrates (amygdala overactivation, CSTC loop dysregulation), and shared psychological risk factors (behavioural inhibition, cognitive biases) mean that vulnerability to one anxiety disorder confers vulnerability to others.

Alcohol and drug abuse ^[1]

• Comorbidity of panic disorder: alcohol and drug abuse ^[1]
• Comorbidity for GAD: alcohol and drug abuse ^[1]
• Co-morbidities of PTSD: substance use disorders ^[4]
• Agoraphobia: substance use disorder ~1/3 ^[2]
• Anxiety disorders occur in 32% of alcoholics, often as a form of self-medication ^[2]

Why does anxiety lead to substance use? The mechanism is straightforward self-medication:

• Alcohol is a GABA-A positive allosteric modulator (similar mechanism to benzodiazepines) → drinking provides rapid anxiolysis by enhancing GABA-mediated inhibition of the amygdala
• Cannabis has anxiolytic properties at low doses via CB₁ receptor activation in the amygdala
• Benzodiazepine misuse/dependence can develop from prescribed or illicitly obtained BZDs

Why is this a complication rather than just a comorbidity? Because substance use creates a vicious cycle:

1. Anxiety → alcohol/drug use for relief
2. Chronic use → tolerance (need more for the same effect)
3. Withdrawal → rebound anxiety that is worse than the original anxiety (because GABA-A receptors have downregulated)
4. Worse anxiety → more substance use
5. Additional consequences: hepatic damage, social deterioration, accidents, dependence syndrome

Social anxiety disorder: substance abuse is a risk factor for subsequent substance abuse (as coping) ^[2]. This progression is so predictable that it's essentially a natural history of untreated social anxiety.

Personality disorder (e.g., anankastic, paranoid, avoidant) ^[1]

• Avoidant personality disorder overlaps extensively with social anxiety disorder (shared heritability ~55%) ^[2]
• Dependent personality disorder can develop from chronic agoraphobia (patient becomes reliant on companions)
• Anankastic (obsessive-compulsive) personality shares traits with OCD and GAD
• Chronic childhood anxiety, if untreated, can shape personality development in maladaptive directions

• Poor concentration → ↓work performance
• Avoidance → inability to attend meetings, presentations, or work-related social functions
• Panic attacks at work → embarrassment → further avoidance → absenteeism
• GAD: chronic worry → indecisiveness → difficulty completing tasks → job loss
• Social anxiety: inability to function in team settings, networking, interviews → career limitation

• Childhood/adolescent anxiety → school refusal, poor exam performance, difficulty with peer relationships
• Anxiety in childhood may have atypical presentation, e.g., school refusal, frequent somatic complaints, difficulties with peer relationships, low self-esteem ^[2]
• Test anxiety → underperformance relative to ability
• Social anxiety → inability to participate in group discussions, presentations

• Avoidance behaviour → progressive social isolation
• Social anxiety disorder: only 50% seek treatment, usually after many years of symptoms, and can persist for many years ^[2]
• Agoraphobia: as the condition progresses, situations are increasingly avoided with shrinkage of 'safe zone', ultimately culminating in confinement to home ^[2]
• Relationship difficulties: partners may become frustrated with the patient's avoidance; conversely, some partners become "enablers" who accommodate the avoidance (e.g., always accompanying the agoraphobic patient), inadvertently maintaining the disorder
• Selective mutism: prognosis often poor, with 58% remission rate at 13y; associated with later development of phobia, social anxiety, ↑risk for depression, substance misuse in unresolved cases ^[2]

Impact: associated with functional impairment and ↑cardiovascular mortality ^[2]

Impact: QoL, functioning and all-cause mortality (especially cardiovascular disorders) ^[2]

Why does anxiety increase cardiovascular risk? The pathophysiology is multi-layered:

1. Chronic sympathetic activation → sustained ↑heart rate, ↑blood pressure → accelerated atherosclerosis, endothelial dysfunction
2. HPA axis dysregulation → chronic ↑cortisol → insulin resistance, dyslipidaemia, visceral adiposity → metabolic syndrome → ↑CVD risk
3. Platelet hyperactivation: catecholamines activate platelets → ↑thrombotic tendency → ↑risk of MI, stroke
4. Autonomic imbalance: ↓parasympathetic (vagal) tone + ↑sympathetic tone → ↓heart rate variability → ↑risk of arrhythmias and sudden cardiac death
5. Behavioural mediators: anxiety → physical inactivity (avoidance), poor diet, smoking, alcohol use → additional CVD risk factors

Think of it this way: the fight-or-flight response was designed for brief, intense threats. When it runs continuously for months or years, it's like leaving your car engine redlining — eventually something breaks. The cardiovascular system takes the brunt.

Panic disorder: medical comorbidities (asthma, CAD, HTN, ulcers) ^[2]

Anxiety and chronic pain frequently co-occur through shared neurobiological pathways:

• Central sensitisation: chronic anxiety → ↑descending facilitation of pain pathways → ↓pain threshold
• Catastrophising: cognitive bias amplifies pain perception
• Muscle tension: sustained sympathetic activation → tension-type pain
• Shared neurotransmitters: 5-HT and NA modulate both mood and descending pain inhibition — dysfunction in these systems contributes to both anxiety and chronic pain

• The most common iatrogenic complication of anxiety disorder management
• Develops rapidly (within 2–4 weeks of regular use)
• Withdrawal syndrome: rebound anxiety (often worse than original), insomnia, tremor, perceptual disturbances, seizures (potentially life-threatening)
• Cognitive impairment: ↓memory, ↓psychomotor speed, ↑fall risk (especially elderly)
• Paradoxical disinhibition (especially in elderly, brain-injured, or personality-disordered patients)

• Initial anxiety worsening (first 1–2 weeks) — can cause patients to discontinue treatment prematurely
• Sexual dysfunction — common, persistent, and a major cause of non-adherence
• Discontinuation syndrome (especially paroxetine, venlafaxine) — dizziness, nausea, electric shock sensations ("brain zaps"), anxiety, insomnia
• Hyponatraemia (SIADH) — especially in elderly patients; can present with confusion, seizures
• QTc prolongation — especially citalopram/escitalopram at higher doses → risk of torsades de pointes
• Serotonin syndrome — if combined with MAOIs or other serotonergic agents (fever, agitation, clonus, diaphoresis — medical emergency)

• Many patients with anxiety disorders (particularly social anxiety and agoraphobia) avoid seeking treatment due to the nature of their condition — the very symptoms prevent help-seeking
• Only 50% of social anxiety patients seek treatment, usually after many years ^[2]
• This delay allows complications to accumulate