• Lifetime prevalence ~4.3–5.9% in European populations ^[1].
• In Hong Kong, community studies suggest anxiety disorders collectively affect ~4–8% of the adult population, with GAD being one of the most common presentations in primary care and psychiatric outpatient clinics.
• GAD is one of the most common psychiatric disorders encountered in general practice — patients often present with somatic complaints rather than declaring "I'm anxious."

• M:F ≈ 1:2 — females are roughly twice as likely to be affected ^[1].
• Median age of onset ~30 years — notably later than other anxiety disorders (specific phobias typically onset in childhood, social phobia in adolescence, panic disorder in early adulthood) ^[1].
• More common in socially disadvantaged groups: including those with ↓income, unemployment, divorce, separation ^[1].
• In Hong Kong specifically, contributing social stressors include high housing costs, academic pressure, long working hours, and the cultural stigma surrounding mental health help-seeking.

This is extremely high yield. GAD rarely travels alone:

• Depression: The most important comorbidity. May present as mixed anxiety-depressive disorder (MADD) or comorbid major depressive disorder (MDD). Comorbid depression is associated with ↑severity, ↑functional impairment, and ↑duration of illness ^[1].
• Other anxiety disorders ^[1]:
  • Social phobia: 23.2–34.4% comorbidity
  • Specific phobia: 24.5–35.1% comorbidity
  • Panic disorder: 22.6–23.5% comorbidity
• Other associations: substance abuse (SA), OCD, PTSD, chronic physical illness, medically unexplained symptoms ^[1].

• The amygdala is a bilateral almond-shaped nucleus (amygdala = Greek for "almond") in the medial temporal lobe.
• It is the central hub that activates the anxiety/fear response via several downstream pathways ^[3]:
  • → Hypothalamus (autonomic activation: tachycardia, sweating, GI disturbance)
  • → Periaqueductal grey (freezing behaviour, pain modulation)
  • → Locus coeruleus (noradrenaline release → arousal, hypervigilance)
  • → Cortical areas (conscious perception of fear)

• Dorsomedial hypothalamus/perifornical region coordinates rapid mobilisation of behavioural, autonomic, respiratory, and endocrinological responses to stress ^[3].
• Activates the HPA axis (hypothalamic–pituitary–adrenal):
  • Hypothalamus releases CRH → anterior pituitary releases ACTH → adrenal cortex releases cortisol
  • Cortisol sustains the stress response, increases blood glucose, suppresses immune function.
• Also activates the sympatho-adrenal-medullary (SAM) axis:
  • Sympathetic nervous system → adrenal medulla releases adrenaline and noradrenaline
  • This produces the classic "fight-or-flight" response.

• Insula: Interoceptive awareness — processes internal body signals (heartbeat, gut feelings). Hyperactivity here may explain why anxious patients are excessively aware of bodily sensations ^[3].
• Dorsal anterior cingulate cortex (dACC): Conflict monitoring and error detection — drives the "something is wrong" feeling ^[3].
• Ventromedial prefrontal cortex (VMPFC): Acts as a regulatory inhibitory role — essentially the "brake" on the amygdala. When VMPFC function is impaired, the amygdala runs unchecked → persistent anxiety ^[3].

Classification of anxiety disorders (ICD-10) ^[1]:

A. Phobic Anxiety Disorders — anxiety is intermittent and arising in particular circumstances:

• Agoraphobia: triggered by situations where escape is difficult, e.g., away from home, crowded, confined
  • ICD-10: specified with or without panic disorder
  • DSM-5: panic disorder, if present, is coded as comorbidity
• Social phobia: triggered by social situations
• Specific phobia: triggered by specific objects/situations

B. Other Anxiety Disorders — anxiety is not related to particular circumstances:

• Panic disorder: anxiety is intermittent but not related to particular circumstances
• GAD: anxiety is continuous
• Mixed anxiety-depressive disorder (MADD): both anxiety and depressive features are present and similarly prominent
  • Only present in ICD-10, diagnosed when not meeting criteria for both conditions

The ICD-11 (implemented from 2022) has restructured anxiety disorders:

• Separation Anxiety Disorder and Selective Mutism now included under anxiety disorders (previously under childhood disorders).
• OCD and PTSD have been removed from anxiety disorders and placed in their own categories.
• Agoraphobia is no longer subordinate to panic disorder in DSM-5/ICD-11.

On mental state examination (MSE):

• Appearance/Behaviour: Restless, fidgeting, poor eye contact, tense posture, wringing hands
• Speech: May be rapid, pressured, or hesitant
• Mood: "Anxious," "worried," "on edge" (subjective); objectively anxious
• Thought: Content — worries about multiple domains (health, finances, family, work); Form — may show circumstantiality (going round and round the same worries)
• Perception: Usually normal (distinguish from psychotic anxiety); may report depersonalisation/derealisation during panic
• Cognition: Subjectively impaired concentration; formal testing usually normal (distinguishing from dementia)
• Insight: Usually preserved — patients recognise their worry is excessive but cannot control it

Why this matters pathophysiologically: GAD and depression share serotonergic and noradrenergic dysfunction, which is why they co-occur so frequently and both respond to SSRIs/SNRIs. The shared genetic vulnerability (5-HT transporter polymorphism) explains the massive overlap.

The underlying mechanism: In panic disorder, there is a sudden, massive surge of sympathetic activation (likely originating from brainstem locus coeruleus and parabrachial nucleus) that triggers the full "fight-or-flight" cascade. In GAD, the amygdala-VMPFC circuit is chronically dysregulated, producing a tonic rather than phasic anxiety state.

In social anxiety disorder, the worry is mainly concerning social situations in which they must perform or be evaluated by others. The individual often has anticipatory anxiety focused upon upcoming social situations. ^[4]

In GAD, the individual worries whether or not they are being evaluated. ^[4]

In ICD-10, GAD is not diagnosed if criteria for phobic anxiety were met, but this is possible in DSM-5. ^[4]

So the critical question is: Does the anxiety persist outside of social situations? If yes → more likely GAD. If the anxiety is exclusively about social performance and evaluation → social anxiety disorder.

Why this distinction matters: OCD involves a specific dysfunction in the cortico-striato-thalamo-cortical (CSTC) loop — particularly the orbitofrontal cortex and caudate nucleus — producing stereotyped, repetitive thought-behaviour patterns. GAD involves more diffuse prefrontal-amygdala dysregulation. Different circuits, different phenomenology, different treatment nuances.

Prominent anxiety symptoms may be present in PTSD/adjustment disorder. However, a diagnosis of PTSD takes precedence if they can explain the anxiety symptoms, and the diagnosis of adjustment disorder is only made when other diagnoses (including GAD) cannot be made. ^[4]

For adjustment disorder specifically:

• There must be a clear temporal relationship to a stressor (onset ≤3 months) ^[8]
• Severity is out of proportion to original stressor ^[8]
• It is a residual category — should NOT be diagnosed if another specific disorder (including GAD) can be diagnosed ^[8]

For PTSD:

• The stressor must be traumatic in nature
• Characterized by re-experiencing (flashbacks, nightmares, intrusive images), avoidance, and hyperarousal ^[1]
• Anxiety is part of the hyperarousal cluster but is accompanied by the characteristic re-experiencing and avoidance features

GAD is commonly associated with concerns about medically unexplained symptoms, but GAD is usually characterized by worries about multiple different things, whereas hypochondriacal pt worry principally about illness. ^[4]

The key distinction: In GAD, health worry is one of many worries (alongside work, finances, relationships). In hypochondriasis/illness anxiety disorder, the dominant preoccupation is with having or acquiring a serious illness.

Both are marked by high levels of anxiety and somatic symptoms, but anxiety is pervasive over multiple aspects of life in GAD ^[9]. In somatic symptom disorder, the excessive thoughts, feelings, and behaviours are specifically directed toward the somatic symptoms themselves.

Anxiety may be secondary to distressing symptoms of medical conditions. Mis-attributing these symptoms to anxiety may lead to failure to recognize medical conditions. ^[2]

Anxiety that occurs only in the context of substance/medication use and that are present most severely in the morning (when withdrawal is typically most severe) may be due to effects of a substance. ^[4]

Anxiety often occurs secondary to other psychopathologies ^[2]. The diagnostic principle: identify the theme of the anxiety to find the underlying disorder.

Noting the theme/focus of anxiety may be helpful in reaching diagnosis ^[2]:

This is an extraordinarily useful clinical framework. When a patient presents with anxiety, always ask: "What are you anxious about?" The content of the worry often points to the correct diagnosis.

The psychiatric history for anxiety should cover:

Validated rating scales serve two purposes: (1) structured screening in primary care, (2) monitoring treatment response.

Every patient presenting with significant anxiety symptoms for the first time should have a basic organic screen:

These are NOT routine but should be ordered when specific clinical features raise suspicion for particular organic causes.

Before initiating pharmacotherapy, certain baseline investigations are recommended:

How SSRIs work — from first principles ^[18]:

"SSRI" → "Selective Serotonin Reuptake Inhibitor" — the name tells you the mechanism:

• Selective = primarily targets serotonin (not noradrenaline or dopamine)
• Reuptake = the process by which serotonin is pumped back into the presynaptic neuron by the serotonin transporter (SERT)
• Inhibitor = blocks SERT → serotonin stays in the synaptic cleft longer → enhanced serotonergic neurotransmission

Serotonin: blocking SERT to ↑synaptic availability, modulating actions of 5HT1-3, 7 receptors ^[18]

The therapeutic effect in anxiety is mediated primarily through:

• 5HT1A receptor: Regulates mood (primary target of antidepressants). Regulates adaptive response to stress ^[18]. Presynaptic 5HT1A autoreceptors at the raphe nucleus initially downregulate downstream 5HT release → slowly desensitized → accounts for delayed action of antidepressants ^[18]
• 5HT2C receptor: Regulates anxiety and feeding ^[18]

Practical prescribing points for anxiety:

• Initiation: most result in ↑anxiety symptoms (apprehension, sleeplessness, palpitations) initially → dose should be increased very slowly ^[15]. This paradoxical initial worsening is because:
  • Early SERT blockade → ↑5HT in synapse → stimulates 5HT2A and 5HT2C receptors → mediates 5HT-related S/Es (sexual dysfunction, insomnia, activation, anxiety) ^[18]
  • The therapeutic effect requires desensitisation of presynaptic 5HT1A autoreceptors, which takes 2–4 weeks
  • Start low, go slow: In panic disorder particularly, start at half the usual dose (e.g., sertraline 25 mg, escitalopram 5 mg) and titrate up over 1–2 weeks
• Duration: usually maintained for ≥6 months to prevent relapse ^[15]. In practice, 12–18 months is recommended, and patients with recurrent anxiety may need long-term maintenance.
• Onset of action: 2–4 weeks for initial effect, 8–12 weeks for full effect. Warn patients.
• Discontinuation: Taper slowly over weeks to months to avoid discontinuation syndrome (dizziness, nausea, electric shock sensations "brain zaps," irritability, insomnia).

SSRI Side Effects (mechanism-based):

Contraindications/Cautions:

• Absolute: concurrent MAOI use (serotonin syndrome risk — potentially fatal)
• Relative: active GI bleeding, severe hepatic impairment, QTc > 500ms (for citalopram/escitalopram), pregnancy (paroxetine — teratogenic; others generally safer but risk-benefit analysis needed), breastfeeding

BZDs: effective in controlling panic attacks when given at ↑↑doses ^[15]

NOT as primary treatment (usually an antidepressant), only as short-term Tx not more than 1 month ^[19]

Mechanism ^[19]:

• Work at GABAA-BDZ receptor complex on neuronal membrane
• GABA-binding site at interface between α and β subunits
• BDZ-binding site at interface between α and γ subunits
• BZDs are positive allosteric modulators — they don't activate the GABA-A receptor themselves but increase the frequency of chloride channel opening when GABA binds → ↑Cl⁻ influx → neuronal hyperpolarisation → ↓neuronal excitability → anxiolysis, sedation, muscle relaxation, anticonvulsion.

Effective to ↓pathological anxiety, agitation and tension ^[19] Prefer long-acting drugs to ↓withdrawal ^[19] Panic attacks may require high-potency agents (e.g., alprazolam, clonazepam) ^[19]

Side effects:

• Sedation, drowsiness, psychomotor impairment
• Cognitive impairment, amnesia
• Dependence (tolerance and withdrawal develop within 2–4 weeks of regular use)
• Withdrawal syndrome: rebound anxiety, insomnia, irritability, tremor, seizures (in severe cases)
• Paradoxical reaction ( < 1%): esp in ↓IQ, neurological disease, extremes of age and with Hx of aggression → may have unexpected ↑aggressive or impulsive behaviour ^[19]
• Respiratory depression (especially when combined with opioids or alcohol)

Contraindications:

• Acute narrow-angle glaucoma (anticholinergic-like effect on ciliary muscle)
• Severe respiratory insufficiency (respiratory depression)
• Sleep apnoea (worsens upper airway obstruction)
• Severe hepatic impairment (except lorazepam)
• Myasthenia gravis (worsens weakness)
• History of substance use disorder (high abuse potential)
• Pregnancy (teratogenic — cleft palate risk in first trimester; floppy infant syndrome in third trimester)

CBT is the gold standard psychological treatment for all anxiety disorders ^[15][16][20].

CBT: targets fears of physical effects of anxiety ^[15] Involves: pointing out sequence of physical symptoms leading to fear → question patient's belief in feared outcome ^[15] Efficacy: as effective as antidepressants in Tx of panic disorders, combination Tx may give better response in early stages but long-term results are uncertain ^[15]

How CBT works in anxiety — First Principles:

The cognitive-behavioural model of anxiety posits that anxiety is maintained by:

1. Cognitive distortions: Overestimation of threat probability and severity; underestimation of coping ability
2. Avoidance/safety behaviours: Prevent disconfirmation of feared catastrophe → anxiety never extinguishes
3. Physiological hyperarousal: Misinterpreted as evidence of danger → feeds the cycle

CBT directly targets all three:

Format: Typically 12–16 sessions of individual CBT, delivered weekly.

CBT (desensitisation, flooding, modelling) ^[16]:

Involves: pt imagines a scene from trauma, focusing on accompanying cognition and arousal, while the therapist moves two fingers across the patient's visual field and instructs the patient to track fingers → sequence repeated until anxiety decreases, with patient instructed to generate a more adaptive thought ^[17]

Efficacy: most studies show that it is efficacious in PTSD, superior to other less specific psychotherapy ^[17]

This is the single most clinically significant complication. Depression (MADD or comorbid MDD, a/w ↑severity, functional impairment and ↑duration of illness) ^[1].

Why does anxiety lead to depression?

The two conditions share:

• Neurochemical substrates: Both involve serotonergic and noradrenergic dysfunction. Chronic anxiety depletes 5-HT reserves over time. The same 5-HT transporter polymorphisms predispose to both.
• HPA axis dysregulation: Chronic cortisol elevation from sustained anxiety → hippocampal atrophy (cortisol is neurotoxic to hippocampal CA1 neurons) → impaired stress regulation and memory consolidation → depressive cognitions.
• Cognitive overlap: Chronic worry about the future (anxiety) gradually shifts to rumination about past failures and helplessness (depression) as the patient's functional capacity declines and they feel increasingly unable to cope.
• Learned helplessness: Persistent anxiety with failed attempts to control it → sense of uncontrollability → hopelessness → depression.

Early onset a/w more protracted course and usually a/w comorbid depression ^[1].

Clinical significance: Comorbid anxiety + depression is associated with:

• Greater symptom severity than either disorder alone
• Longer duration of illness
• Poorer treatment response
• ↑Suicidal ideation and attempts (see below)

Anxiety disorders independently increase suicide risk, and this risk is dramatically amplified when comorbid with depression.

• Panic disorder is particularly associated with suicidal ideation — the sheer terror of repeated panic attacks, the feeling of "going crazy," and the sense that life is unlivable during attacks drives despair.
• Impact: ↓QoL, functioning and ↑all-cause mortality (esp cardiovascular disorders) ^[21].
• GAD patients with comorbid depression have suicide attempt rates approaching those of depression alone.

Why anxiety increases suicide risk from first principles: Chronic anxiety → functional impairment → social isolation → hopelessness → loss of reasons for living. Additionally, the agitation component of anxiety may lower the threshold for impulsive suicidal acts — a patient with depression alone may have suicidal thoughts but lack the energy to act; add anxiety-driven agitation and the risk of action increases.

Other associations: SA, OCD, PTSD, chronic physical illness, medically unexplained symptoms ^[1].

The self-medication hypothesis: Anxious patients discover that alcohol, benzodiazepines, cannabis, or other substances temporarily relieve their distress. This negative reinforcement drives escalating use.

• Alcohol: Acts on GABA-A receptors → anxiolysis. But chronic use → GABA-A receptor downregulation → tolerance → need for higher doses → dependence → withdrawal anxiety worse than baseline → vicious cycle. Panic disorder: 37% with lifetime Hx of major depression... Others: alcohol (self-medication) ^[5].
• Benzodiazepines: Same GABA-A mechanism. Iatrogenic dependence when prescribed long-term is a significant problem, particularly in Hong Kong where benzodiazepine overuse in primary care is well-documented.
• Cannabis: Initially anxiolytic at low doses (CB1 receptor activation in amygdala) but at higher doses or chronic use → ↑anxiety, paranoia. Also associated with amotivational syndrome.

Potential complications of somatoform presentations: substance use disorders in attempt to ↓distress, e.g., narcotic analgesics, benzodiazepines ^[22].

Anxiety disorders breed more anxiety disorders. A patient with one anxiety disorder is at significantly elevated risk of developing another:

• Associated comorbidities: other anxiety disorders (social phobia 23.2–34.4%, specific phobia 24.5–35.1%, panic disorder 22.6–23.5%) ^[1].
• Panic disorder → Agoraphobia: This is the classic progression. Repeated unexpected panic attacks → anticipatory anxiety about having further attacks → avoidance of situations where attacks occurred or escape would be difficult → progressively restricted activities → full-blown agoraphobia. Often develops into agoraphobia as an attempt to avoid panic attacks and their consequences ^[5].
• GAD → Panic disorder: Escalating, uncontrollable worry → panic attacks. Though unexpected panic attacks are unusual in GAD, the boundary can blur.

In children: Nearly 2/3 expected to disappear in 3–5y, but ~1/3 of them will have other categories of anxiety disorders at follow-up ^[23].

While OCD is now classified separately from anxiety disorders, anxious patients can develop obsessional features — particularly checking behaviours, reassurance-seeking, and repetitive mental acts. These represent the brain's attempt to achieve certainty and control in the face of intolerable uncertainty.

Impact: a/w functional impairment and ↑CVS mortality ^[1].

↑all-cause mortality (esp cardiovascular disorders) ^[21].

Why chronic anxiety damages the cardiovascular system — First Principles:

1. Chronic sympathetic activation → sustained ↑heart rate + ↑blood pressure → ↑cardiac workload → accelerated atherosclerosis, endothelial damage
2. HPA axis dysregulation → chronic cortisol elevation → insulin resistance → metabolic syndrome (visceral obesity, dyslipidaemia, hyperglycaemia) → atherogenic milieu
3. Inflammation: Chronic stress → ↑pro-inflammatory cytokines (IL-6, TNF-α, CRP) → endothelial inflammation → plaque formation and instability
4. Platelet activation: Stress hormones → ↑platelet reactivity → ↑thrombotic risk
5. Autonomic imbalance: ↓Heart rate variability (a marker of ↓vagal tone and ↑sympathetic dominance) → arrhythmia risk
6. Behavioural mediators: Anxious patients are more likely to smoke, be sedentary, eat poorly, and have poor medication adherence

Meta-analyses show that GAD is associated with a 26% increased risk of coronary heart disease events and a 48% increased risk of cardiac death independent of traditional cardiovascular risk factors.

Chronic anxiety drives central sensitisation — the nervous system becomes hyperexcitable and amplifies pain signals. This manifests as:

• Chronic tension-type headache (sustained muscle contraction of temporalis, frontalis, cervical muscles)
• Fibromyalgia (central sensitisation → widespread pain, fatigue, cognitive dysfunction)
• Irritable bowel syndrome (gut-brain axis dysregulation; visceral hypersensitivity)
• Chronic musculoskeletal pain (shoulder, back, jaw/TMJ)

The pathophysiology: Chronic cortisol and noradrenaline → ↓descending inhibitory pain modulation (serotonergic/noradrenergic pathways in periaqueductal grey and rostroventromedial medulla) → ↑pain perception.

The gut-brain axis is a bidirectional communication system. Chronic anxiety:

• ↑Gut permeability ("leaky gut") via cortisol-mediated effects on tight junctions
• Alters gut microbiome composition (dysbiosis)
• Exacerbates functional GI disorders: IBS, functional dyspepsia, GERD

Chronic cortisol elevation → immunosuppression (↓T-cell function, ↓NK cell activity, ↓antibody production) → ↑susceptibility to infections, impaired wound healing, and potentially ↑cancer risk (though the latter remains debated).

Paradoxically, chronic low-grade inflammation also co-occurs (cortisol resistance at the immune cell level) → autoimmune exacerbation.

• Insomnia: Both a symptom and a complication. Chronic insomnia from anxiety → sleep deprivation → impaired prefrontal function → ↓top-down amygdala inhibition → ↑anxiety. This is a self-perpetuating cycle.
• Obstructive sleep apnoea may be exacerbated by weight gain from sedentary lifestyle or medication side effects (mirtazapine, pregabalin).

• ↓Concentration and ↓decision-making capacity → poor work performance
• Avoidance behaviour → absenteeism, inability to meet deadlines
• Social anxiety → inability to attend meetings, present, or network
• Economic burden: GAD is one of the psychiatric disorders associated with the highest number of lost work productivity days. In Hong Kong, where competitive work culture is the norm, this creates a particularly vicious cycle of ↑stress → ↑anxiety → ↓performance → ↑stress.

Highly relevant in the Hong Kong context. Anxiety disorders in adolescents and young adults → poor academic performance → missed educational opportunities → long-term socioeconomic consequences.

• Avoidance of social situations → social isolation → loneliness → ↑depression
• Irritability and emotional dysregulation → interpersonal conflict
• Reassurance-seeking → strain on relationships (partners/family become exhausted)
• Sexual dysfunction (both anxiety-driven and medication-induced) → relationship strain

In severe cases (especially panic disorder with agoraphobia), patients may become progressively housebound. This represents one of the most devastating functional outcomes:

• Complete loss of independence
• Inability to work, shop, or attend medical appointments
• Total dependence on family/caregivers
• Profound social isolation

• Dependence and withdrawal: The most significant iatrogenic complication. Physical dependence develops within 2–4 weeks of regular use. Withdrawal can include rebound anxiety (worse than baseline), insomnia, tremor, and in severe cases withdrawal seizures (life-threatening).
• Cognitive impairment: Long-term BZD use is associated with impaired memory consolidation, ↓processing speed, and possibly ↑dementia risk (controversial but concerning).
• Falls and fractures: Particularly in the elderly — sedation + muscle relaxation + impaired coordination → falls → hip fractures → significant morbidity/mortality.
• Road traffic accidents: Psychomotor impairment equivalent to legal alcohol intoxication.
• Paradoxical reaction ( < 1%): esp in ↓IQ, neurological disease, extremes of age and with Hx of aggression → may have unexpected ↑aggressive or impulsive behaviour ^[19].

Unnecessary invasive procedures with iatrogenic complications ^[22].

When anxiety presents primarily with somatic symptoms (as it often does in Hong Kong), patients may undergo repeated investigations — CT scans, endoscopies, cardiac catheterisations, lumbar punctures — searching for an organic cause that doesn't exist. Each investigation carries its own risks:

• Radiation exposure (cumulative from repeated CT scans)
• Procedural complications (perforation, bleeding, infection)
• False-positive results → further unnecessary investigations (the investigation cascade)
• Reinforcement of illness beliefs (each new test confirms the patient's belief that something must be physically wrong)

Ix: judicious → false-positive results may lead to unnecessary invasive investigations and risks ^[24].