Generalized Anxiety Disorder (GAD)

1. Clinical Overview

Summary

Generalized Anxiety Disorder (GAD) is a pervasive, chronic mental health condition defined by excessive, uncontrollable worry regarding multiple domains of daily life (e.g., health, finances, family, work) for a duration of at least 6 months. Unlike the discrete, terror-filled attacks of Panic Disorder, GAD is a "slow burn"—a state of constant, low-grade hyperarousal and apprehension, often described by patients as "feeling keyed up" or "unable to relax."

It is the single most common anxiety disorder seen in primary care, yet it remains underdiagnosed. This is largely because patients typically present with somatic manifestations of their anxiety—insomnia, tension headaches, gastrointestinal distress, or fatigue—rather than the psychological symptom of worry itself. This "somatic mask" can lead to extensive, unnecessary medical investigations if the underlying anxiety is not recognized.

The pathophysiology is complex, involving a failure of the prefrontal cortex (PFC) to inhibit the amygdala's fear response ("top-down failure"), combined with dysregulation in monoamine (Serotonin, Noradrenaline) and amino acid (GABA, Glutamate) neurotransmitter systems.

Management follows a strict Stepped Care Model (NICE CG113):

1. Step 1: Identification and Active Monitoring.
2. Step 2: Low-intensity psychological interventions (Guided Self-Help).
3. Step 3: High-intensity CBT or Pharmacotherapy (SSRIs like Sertraline).
4. Step 4: Specialist referral for complex/refractory cases.

Key Facts Table

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2. Epidemiology

Global & Regional Prevalence

GAD is a significant global health burden, though its prevalence varies by culture and region.

• High-Income Countries (HIC): Lifetime prevalence is approximately 5.0% [1].
• Middle/Low-Income Countries: Lower reported rates (~1.6-2.8%) [1]. This may reflect cultural differences in reporting "worry" vs somatic symptoms, or genuine differences in environmental stressors.
• 12-Month Prevalence: In the UK/US, ~3.1% of adults suffer from GAD in any given year.
• Primary Care: In General Practice settings, the prevalence shoots up to 7-8%, making it one of the most common reasons for a GP visit, often disguised as physical complaints [4].

Demographic Risk Factors

• Gender: consistently 2x more common in women ($OR \approx 1.9-2.2$). This gender gap persists from adolescence into old age.
• Age:
  • Bimodal Onset:
    • Early Onset: Adolescence/Early Adulthood (tend to be more chronic).
    • Late Onset: > 50 years (often precipitated by health scares or widowhood).
  • Elderly: GAD is the most common anxiety disorder in older adults (~5% prevalence), often comorbid with depression and physical frailty.
• Socioeconomic: Strong association with lower socioeconomic status, unemployment, and marital disruption (divorce/separation). Risk increases 1.6x for those living alone [1].

Genetic & Environmental Factors

• Heritability: Twin studies (e.g., Virginia Twin Registry) estimate heritability at 30-40% [2].
  • The genetic risk is not specific to GAD; it is shared with Major Depression and "Neuroticism" (a personality trait of tendency towards negative emotional states).
  • It is the environment that determines whether this vulnerability manifests as GAD or Depression.
• Gene Candidates:
  • 5-HTTLPR: Short allele of the serotonin transporter gene (SLC6A4) is linked to increased amygdala reactivity.
  • BDNF: Val66Met polymorphism affects fear extinction plasticity [11].
• Environmental Triggers:
  • Childhood Adversity: Physical/sexual abuse, parental neglect, or loss of a parent before age 10.
  • Stressful Life Events: Threat events (e.g., financial crisis, job loss) are specific triggers for GAD start.

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3. Pathophysiology: The "Deep Dive"

A. Neurocircuitry: The "Amygdala Hijack"

Current neurobiological models posit a disruption in the "Threat Detection" and "Emotion Regulation" circuits [3][11].

1. Bottom-Up Hyperactivity (The Alarm)

   • The Amygdala (specifically the basolateral complex) is hyper-reactive to both aversive stimuli (e.g., failure words) and neutral stimuli in GAD patients.
   • It generates a "false alarm" signal, interpreting uncertain situations as threats.
   • The Insula (involved in interoception) is also hyperactive, heightening awareness of physical anxiety symptoms (heartbeat, tension).

2. Top-Down Failure (The Broken Brake)

   • In a healthy brain, the Prefrontal Cortex (PFC) (specifically the Ventromedial PFC and Anterior Cingulate Cortex) exerts inhibitory control over the amygdala via GABAergic interneurons. It says: "Relax, that email is not a threat."
   • In GAD, there is dorsolateral PFC hypofunction and reduced functional connectivity between the PFC and Amygdala (via the uncinate fasciculus). The brain cannot "shut off" the worry once it starts.

3. Default Mode Network (DMN) Dysfunction

   • The DMN (structures active when resting/daydreaming) is overactive in GAD. This correlates with chronic self-referential worry and the inability to focus on the external task (concentration impairment).

B. Neurochemistry

• GABA (Gamma-Aminobutyric Acid): Lower benzodiazepine binding potential in the temporal lobes suggests a downregulation of GABA-A receptors. This leads to a failure of tonic inhibition (the brain's primary "calming" system).
• Noradrenaline (NE): Dysregulated firing in the Locus Coeruleus leads to autonomic sympathetic overactivity (tachycardia, sweating). This is the target of SNRIs (Venlafaxine).
• Serotonin (5-HT): Serotonergic projections from the Raphe Nuclei to the PFC and Amygdala are disrupted. 5-HT plays a complex modulatory role in anxiety; acute increases can increase anxiety, while chronic increases (via SSRIs) downregulate anxiogenic receptors.
• Glutamate: Excitatory excess. Pregabalin works by inhibiting voltage-gated Calcium channels, thereby reducing the release of glutamate (and NE/Substance P).

C. Cognitive Models

Understanding the psychology of GAD is crucial for therapy.

1. Intolerance of Uncertainty (Dugas Model):
   • GAD patients have a "meta-cognitive" belief that uncertainty is dangerous. They worry to try to "solve" uncertainty, believing that if they worry enough, they can predict/prevent the bad outcome [9].
2. Cognitive Avoidance Theory:
   • Worry (verbal linguistic thought) is actually an avoidance mechanism. By worrying in words ("What if X happens?"), the patient avoids generating a mental image of the catastrophe, which would be more emotionally distressing. Thus, worry prevents emotional processing and habituation.
3. Metacognition (Wells Model):
   • Type 1 Worry: Worry about external events (Health, money).
   • Type 2 Worry: Worry about worrying ("My worrying is out of control," "Worrying will make me go mad"). This Type 2 worry drives the disorder.

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4. Clinical Presentation

Core Symptom: Pathological Worry

The worry in GAD typically shifts from topic to topic. As soon as one issue is resolved, the anxiety latches onto another.

• Content: Everyday concerns (Health of self/family, Punctuality, Chores, Finances, World events).
• Quality: Intrusive, difficult to dismiss, and disproportionate.

DSM-5 Diagnostic Criteria

A. Excessive anxiety/worry occurring more days than not for at least 6 months, about a number of events. B. The individual finds it difficult to control the worry. C. The anxiety and worry are associated with 3 (or more) of the following 6 symptoms (Note: Only 1 item is required in children):

1. Restlessness or feeling keyed up or on edge.
2. Being easily fatigued. (Paradoxical fatigue—"tired but wired").
3. Difficulty concentrating or mind going blank.
4. Irritability.
5. Muscle tension. (Somatic hallmark of GAD).
6. Sleep disturbance (Difficulty falling or staying asleep, or restless, unsatisfying sleep). D. Significant Distress or Impairment. E. Not due to substance or medical condition. F. Not better explained by another mental disorder (e.g., Panic Disorder).

ICD-11 vs DSM-5

The "Somatic Mask"

Patients often present with:

• Gastrointestinal: IBS, Nausea ("butterflies"), Epigastric discomfort.
• Neurological: Tension headaches (band-like), Dizziness (psychogenic).
• Cardiovascular: Palpitations (Sinus tachycardia).
• Respiratory: Hyperventilation, subjective dyspnoea/air hunger.

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5. Investigations & Differential Diagnosis

Basic Workup (Exclusion of Organic Anxiety)

In a new presentation, basic organic screens are mandatory.

• Thyroid Function Tests (TFTs): Rule out Hyperthyroidism (tremor, anxiety, weight loss).
• Full Blood Count (FBC): Rule out Anaemia (tachycardia, fatigue).
• Urine Toxicology: Screen for cocaine/amphetamine use if indicated.
• ECG: If palpitations are prominent (Rule out SVT/AF).
• Glucose: Rule out hypoglycaemia (sweating, tremor) - rare without diabetes history.

Differential Diagnosis Table

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6. Management: Psychological ("The Therapy Room")

Following the NICE Stepped Care Model, psychological therapy is the cornerstone.

Step 2: Low-Intensity Interventions

• Guided Self-Help: The patient works through a CBT-based workbook ("Overcoming Worry") with brief support (e.g., 5-7 sessions of 20 mins) from a Psychological Wellbeing Practitioner (PWP).
• Psychoeducation Groups: 6 weekly sessions learning about the physiology of anxiety.

Step 3: High-Intensity CBT

Cognitive Behavioural Therapy is the Gold Standard (NNT reported between 3-5). A typical course is 12-15 weekly sessions.

Anatomy of a GAD CBT Protocol

1. Psychoeducation: Teaching the "Worry Awareness Training." Learning to distinguish between Hypothetical Worry ("What if the plane crashes?") and Real-Event Worry ("I have a bill to pay").
2. Relaxation Training: Progressive Muscle Relaxation (PMR) to target the physical tension.
3. Cognitive Restructuring:
   • Challenging "Probability Overestimation" (e.g., "Is it really 90% likely you will be fired?").
   • Challenging "Catastrophising" (e.g., "If you are fired, is it truly the end of the world, or would you find another job?").
4. Behavioral Experiments: Testing beliefs. Example: "Don't call your husband to check he is safe for one day. See if he still comes home."
5. Worry Exposure: Scheduled "Worry Time" (e.g., 5:00 PM - 5:30 PM). If a worry comes up at 10 AM, write it down and save it for 5 PM. This builds control.

Applied Relaxation

An alternative to CBT focused solely on the physical tension. The patient learns to relax muscles on cue ("Release-only relaxation"). High efficacy, equal to CBT in some trials [5][8].

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7. Management: Pharmacological ("Drug Monograph")

Drugs are indicated at Step 3 (High Intensity) if the patient prefers them or if psychological and self-help interventions have failed.

A. First-Line: SSRIs (Selective Serotonin Reuptake Inhibitors)

1. Sertraline

• Status: NICE First-line choice (Cost-effective) [5].
• Dose: Start 50 mg OD (Take with food to reduce nausea). May increase by 50 mg increments every 2-4 weeks up to 200 mg.
• Pharmacokinetics:
  • $T_0.5$ (Parent): 26 hours.
  • $T_0.5$ (Metabolite): N-desmethylsertraline ~62-104 hours (Very long).
  • Metabolism: CYP450 broad spectrum (2B6, 2C19, 2C9, 3A4, 2D6). Low potential for drug-drug interactions compared to Fluoxetine/Paroxetine.
• "Jitteriness Syndrome": anxiety may worsen in the first 7-10 days due to initial 5-HT autoreceptor activation.
  • Advice: "Stick with it, it will pass." Consider starting at 25 mg in sensitive patients.

2. Escitalopram

• Status: Highly effective, often considered superior efficacy in meta-analyses [7].
• Dose: Start 10 mg OD. Max 20 mg.
• QT Prolongation: Warning. Dose limited to 10 mg in elderly (> 65) or those with cardiac risk factors.

3. Paroxetine

• Status: Licensed, but avoid as first-line due to short half-life and severe discontinuation syndrome. Also high anticholinergic burden (weight gain, sedation).

B. Second-Line: SNRIs

Venlafaxine XL (Extended Release)

• Indication: Step 3 alternative if SSRIs fail.
• Mechanism: Dual reuptake inhibition (5-HT at low dose, 5-HT + NE at > 150 mg doses).
• Dose: 75 mg - 225 mg daily.
• Pharmacokinetics:
  • $T_0.5$: Short (~5 hours for parent). Requires XL formulation for GAD compliance.
  • Metabolism: CYP2D6 to active metabolite Desvenlafaxine. Genetic "Poor Metabolizers" may have higher side effects.
• Adverse Effects:
  • Hypertension: Dose-dependent increase in diastolic BP (due to Noradrenaline). Monitor BP.
  • Withdrawal: "Brain Zaps" (electric shock sensations) are common if missed. Taper VERY slowly.

Duloxetine

• Dose: 60 mg - 120 mg.
• Utility: Good if comorbid neuropathic pain or fibromyalgia.

C. Other Agents

Pregabalin

• Status: Step 3 alternative (NICE) but increasingly restricted due to abuse liability.
• Mechanism: Alpha-2-delta ligand (Calcium channel blocker). NOT a GABA agonist.
• Dose: Start 75 mg BD. Max 300 mg BD (600 mg daily).
• Pros: Rapid onset (1 week vs 4-6 weeks for SSRIs). No sexual dysfunction. Good for somatic anxiety.
• Cons: Sedation, Weight Gain, Edema. Class C Controlled Drug (UK). Respiratory depression risk if combined with opioids/alcohol.

Benzodiazepines (e.g., Diazepam)

• Status: Crisis Use Only. NOT for long-term treatment.
• Mechanism: GABA-A Positive Allosteric Modulator.
• Course: Max 2-4 weeks.
• Risks: Tolerance builds in 2 weeks. Dependence. Falls. Cognitive impairment.

Quetiapine (Atypical Antipsychotic)

• Status: Off-label, 3rd/4th line augmentation.
• Use: Low dose (25-100 mg) for sedation/severe anxiety.
• Risk: Metabolic syndrome (Weight, Lipids, Glucose).

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8. Clinical Vignettes: Applying the Guidelines

Case A: The "High-Functioning" Worrier

Patient: Sarah, 28, Lawyer. Presentation: "I just can't switch off." Worries about making mistakes at work, her parents dying, and whether she locked the door. Poor sleep. Muscle tension in shoulders. GAD-7 score: 16 (Severe). Management:

1. Diagnosis: GAD (Clear extensive worry > 6 months).
2. Step 2: She is high-functioning but high distress. Offer Guided Self-Help first? She declines time constraints.
3. Step 3: She prefers therapy over pills. Referral for High-Intensity CBT.
4. Outcome: After 12 sessions, she learned "Worry Time" techniques. Function improved.

Case B: The "Somatic" Presenter

Patient: Ahmed, 54, Taxi Driver. Presentation: 3rd visit for "heart palpitations" and "stomach churning." ECG normal. bloods normal. Admits to financial stress but says "The stress is fine, it's my heart I'm worried about." Management:

1. Reframing: Explaining the physical symptoms of anxiety (Adrenaline).
2. Pharmacology: He is sceptical of "talking". Trial of Sertraline 50 mg.
3. Safety Netting: Warned about initial jitteriness.
4. Review: At 4 weeks, palpitations reduced. Worry about finances remains but is "manageable."

Case C: The Complex/Resistant Patient

Patient: Brenda, 45. History of GAD x 10 years. History: Trials of Citralopram, Sertraline, and Fluoxetine failed or "stopped working." CBT helped briefly 5 years ago. Management:

1. Review: Check adherence. Was the dose high enough? (Often SSRIs are under-dosed).
2. Switch Class: Effect switch to SNRI (Venlafaxine MR).
3. Augmentation: Add Pregabalin if Venlafaxine partial response.
4. Referral: Step 4 (CMHT) referral for psychiatric review due to treatment resistance.

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9. Patient Resources (FAQ)

Q: Will the medication change my personality? A: No. SSRIs aim to return your chemical balance to normal, "turning down the volume" on the anxiety so you can be yourself again.

Q: How long do I need to take it? A: Evidence suggests continuing for at least 1 year after you feel better. Stopping too early is the most common cause of relapse.

Q: Is anxiety hereditary? A: Partly (about 30%). But you learn ways to cope. Therapy can "rewire" how you handle that vulnerability.

Q: What if I have a panic attack? A: Remember panic cannot kill you. It is a false alarm. Use the "5-4-3-2-1" grounding technique (5 things you see, 4 you feel...) to bring your brain back to the present.

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10. References

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3. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164(10):1476-1488. [PMID: 17898138]
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5. National Institute for Health and Care Excellence (NICE). Generalised anxiety disorder and panic disorder in adults: management (CG113). London: NICE; 2011 (Updated 2019).
6. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-439. [PMID: 24713617]
7. Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019;393(10173):768-777. [PMID: 30712903]
8. Cuijpers P, Sijbrandij M, Koole S, et al. Psychological treatment of generalized anxiety disorder: a meta-analysis. Clin Psychol Rev. 2014;34(2):130-140. [PMID: 24451000]
9. Dugas MJ, Buhr K, Ladouceur R. The role of intolerance of uncertainty in etiology and maintenance. Generalized Anxiety Disorder: Advances in Research and Practice. 2004.
10. Hofmann SG, Asnaani A, Vonk IJJ, et al. The efficacy of CBT: A review of meta-analyses. Cognit Ther Res. 2012;36(5):427-440. [PMID: 23459093]
11. Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013.
12. DeMartini J, Patel G, Fancher TL. Generalized anxiety disorder. Ann Intern Med. 2019;170(7):ITC49-ITC64. [PMID: 30934083]