Anxiety and excessive worry

Anxiety and excessive worry is persistent, hard to control apprehension about everyday matters, with tension, restlessness, fatigue, poor concentration, irritability and sleep disturbance. Definition of generalised anxiety disorder.

Excessive anxiety and worry on most days for at least 6 months about a number of events or activities, with difficulty controlling the worry and 3 or more of: restlessness, easy fatigue, poor concentration, irritability, muscle tension and sleep disturbance (one symptom in children). Symptoms cause distress or impairment and are not caused by a substance or medical condition.

Classification of anxiety disorders. Generalised anxiety disorder, panic disorder, agoraphobia, social anxiety disorder, specific phobia, separation anxiety, selective mutism, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, illness anxiety disorder, adjustment disorder with anxiety, and anxiety due to a medical condition or substance.

Severity. The Generalised Anxiety Disorder 7 item scale (GAD-7) scores 0 to 21: 5 to 9 mild, 10 to 14 moderate, 15 to 21 severe. A score of 10 or more identifies probable generalised anxiety disorder (sensitivity about 89% and specificity 82%), and the scale also detects panic, social anxiety and posttraumatic stress disorder with less accuracy.

Mechanisms. Heightened amygdala reactivity with reduced prefrontal regulation, sympathetic arousal, altered gamma aminobutyric acid and serotonin signalling, and genetic vulnerability with early adversity. Time course. Onset commonly in adolescence or early adulthood, with a chronic fluctuating course. Anxiety frequently coexists with depression (about half), substance use and somatic illness.

Key distinctions. Worry about many realistic domains with physical tension suggests generalised anxiety disorder. Sudden surges of fear with palpitations suggest panic attacks. Fear limited to social settings suggests social anxiety. New anxiety in later life, weight loss, tremor and palpitations suggest hyperthyroidism or a medical cause.

History

• Content, duration and course of worry, ability to control it, avoidance, safety behaviours, and functional impact on work, relationships and sleep.
• Physical symptoms: palpitations, chest tightness, dyspnoea, tremor, sweating, dizziness, paraesthesia, abdominal discomfort, nausea, diarrhoea, headache, muscle tension and urinary frequency.
• Panic attacks, phobias, obsessions and compulsions, trauma exposure, flashbacks, and social avoidance.
• Depression, suicidal ideation, bipolar symptoms, psychosis, attention problems and eating disorder features.
• Alcohol, caffeine (intake in cups daily), nicotine, cannabis, stimulants and medication use, and any recent withdrawal (alcohol, benzodiazepines, antidepressants, opioids).
• Medical history: thyroid disease, cardiac arrhythmia, asthma, COPD, diabetes (hypoglycaemia), menopause, pregnancy, epilepsy, vestibular disease, anaemia and phaeochromocytoma symptoms (episodic headache, sweating, palpitations with hypertension).
• Drugs: salbutamol, theophylline, levothyroxine overdosage, corticosteroids, stimulants, decongestants (pseudoephedrine), antidepressants at initiation, bupropion, antipsychotics (akathisia), levetiracetam, and mefloquine.
• Family history, childhood adversity, violence, and current stressors.
• Safety: self harm, suicide risk, and substance risk.

Examination

• Vital signs including heart rhythm, blood pressure, temperature, respiratory rate and oxygen saturation, weight and body mass index.
• Appearance, restlessness, tremor, sweating, eye contact, speech, thought content, mood and affect, insight, and cognition.
• Physical: thyroid size and nodules, eye signs, tachycardia or arrhythmia, murmurs, wheeze, tremor, reflexes (brisk in hyperthyroidism), skin (sweating, moisture), pallor, and neurological examination.
• Bedside tests: GAD-7 and PHQ-9, glucose, ECG when palpitations or chest symptoms, pregnancy test, and peak flow when wheeze.

Red flags

• Suicidal thoughts, self harm or severe depression.
• Chest pain, syncope, breathlessness with exertion, irregular pulse, or sustained tachycardia (cardiac or pulmonary cause).
• Weight loss, heat intolerance, tremor, goitre (hyperthyroidism).
• Episodic headache with sweating and hypertension (phaeochromocytoma).
• Hypoglycaemia symptoms in diabetes or with insulin secreting drugs.
• First onset after age 40 years, abrupt onset, or neurological signs.
• Confusion, hallucinations or fluctuating alertness (delirium, alcohol withdrawal).
• Severe alcohol or benzodiazepine withdrawal (tremor, sweating, seizures).
• Psychotic symptoms, mania or substance intoxication.
• Pregnancy and postpartum onset.

Special groups

• Children and adolescents: somatic complaints, irritability, school refusal and separation anxiety, requiring age specific assessment and doses.
• Pregnancy and breastfeeding: avoid paroxetine, benzodiazepines in late pregnancy, and valproate. Prefer psychological therapy and sertraline when drugs are needed.
• Older adults: new anxiety often reflects depression, cognitive decline, medical illness or drugs, and benzodiazepines increase falls and confusion.
• Medical illness: anxiety follows chronic cardiac, respiratory and endocrine disease, cancer and chronic pain.
• Region specific: culturally shaped presentations with somatic complaints, high prevalence after violence and displacement, and use of khat and alcohol.

Primary anxiety and related disorders

• Generalised anxiety disorder.
• Panic disorder with or without agoraphobia.
• Social anxiety disorder.
• Specific phobia.
• Separation anxiety disorder.
• Obsessive compulsive disorder.
• Posttraumatic stress disorder and acute stress disorder.
• Adjustment disorder with anxiety.
• Illness anxiety disorder and somatic symptom disorder.
• Body dysmorphic disorder.

Other psychiatric conditions

• Major depression with anxious distress.
• Bipolar disorder (mixed features, hypomania).
• Psychotic disorders (prodrome).
• Attention deficit hyperactivity disorder.
• Autism spectrum disorder.
• Eating disorders.
• Personality disorders.
• Insomnia disorder.
• Delirium and dementia with agitation.

Substance related

• Caffeine intoxication.
• Alcohol intoxication, withdrawal and hangover.
• Benzodiazepine and barbiturate withdrawal.
• Cannabis, stimulant (cocaine, amphetamine, khat) and hallucinogen effects.
• Nicotine withdrawal.
• Opioid withdrawal.
• Antidepressant discontinuation syndrome.
• Drug induced anxiety (bronchodilators, theophylline, levothyroxine, corticosteroids, decongestants, SSRI initiation, antipsychotic akathisia, levetiracetam, mefloquine).

Medical conditions

• Hyperthyroidism and thyroid storm.
• Cardiac arrhythmia (supraventricular tachycardia, atrial fibrillation), angina, heart failure and mitral valve prolapse.
• Pulmonary embolism, asthma, COPD and hypoxia.
• Hypoglycaemia and diabetes.
• Phaeochromocytoma and carcinoid syndrome.
• Hyperparathyroidism and hypocalcaemia.
• Cushing syndrome and Addison disease.
• Menopause and premenstrual disorders.
• Anaemia and vitamin B12 deficiency.
• Epilepsy (temporal lobe) and vestibular disorders.
• Dementia and brain tumour.
• Sleep apnoea.
• Systemic infection and sepsis.
• Anaphylaxis (early).
• Porphyria.

Step 1. Exclude danger. Check vital signs and heart rhythm. Assess suicidality, intoxication or withdrawal, delirium, chest pain and breathlessness.

Step 2. Make the psychiatric diagnosis. Use diagnostic criteria for generalised anxiety disorder and screen for other anxiety disorders, depression (PHQ-9), bipolar disorder, trauma, alcohol (AUDIT-C), drugs and caffeine. Score the GAD-7 at baseline and review. Use the Beck or Hamilton anxiety scales for research and complex care only.

Step 3. First line tests

• Thyroid stimulating hormone (with free thyroxine when abnormal), full blood count, glucose or HbA1c, urea, creatinine, electrolytes, calcium, liver tests, and vitamin B12.
• ECG for palpitations, chest symptoms, syncope, or before drugs with QT effects (citalopram, escitalopram, hydroxyzine).
• Pregnancy test and urine or serum drug screen when indicated.
• Blood alcohol or breath test when intoxication is suspected.

Step 4. Targeted tests

• Cardiac monitoring (24 hour or event monitor) and echocardiography for suspected arrhythmia or structural heart disease.
• Plasma free metanephrines or 24 hour urinary fractionated metanephrines for episodic hypertension, sweating and palpitations (suspected phaeochromocytoma).
• Chest imaging, spirometry and D-dimer or CT pulmonary angiography directed by symptoms and risk.
• Morning cortisol, parathyroid hormone, ferritin, vitamin D, and sex hormones directed by clinical features.
• Electroencephalogram and brain imaging for seizure features, neurological signs, or onset after age 40 years.
• Sleep study for suspected sleep apnoea.

Interpretation. Correct medical contributors, but treat anxiety disorders concurrently because many persist after the cause is treated. A normal screen is expected in most anxiety disorders, and extensive repeated testing can increase health anxiety.

Limits. Screening instruments do not diagnose. Symptoms overlap with depression, medical disease and drugs. Cultural expression of distress differs.

Immediate. Reassure, assess safety and provide a calm environment. For suicidal risk or psychosis, arrange same day mental health assessment. For acute severe anxiety that is distressing, slow breathing exercises and a calm explanation are first. A short course of benzodiazepine is reserved for crisis. Psychological treatment (first line for mild to moderate, and combined for severe).

Psychoeducation, cognitive behavioural therapy (typically 12 to 20 sessions), applied relaxation, supported self help and internet delivered programmes, regular physical activity, sleep regularity and reduction of caffeine, alcohol and nicotine.

Pharmacological treatment (moderate to severe disease, or failure or unavailability of psychological treatment)

• Sertraline 25 mg orally once daily for 1 week, then 50 mg daily, increased every 2 weeks as needed to usual 50 to 150 mg and maximum 200 mg daily.
• Escitalopram 5 mg orally once daily for 1 week, then 10 mg daily, maximum 20 mg daily (10 mg over 65 years and in hepatic impairment; monitor QT interval).
• Paroxetine 10 mg orally once daily, increased to 20 mg after 1 to 2 weeks, up to 50 mg daily (30 mg in the elderly). It has more discontinuation symptoms and anticholinergic effects, and is avoided in pregnancy.
• Venlafaxine modified release 37.5 mg once daily for 1 week, then 75 mg, maximum 225 mg daily. Monitor blood pressure and adjust for kidney and liver impairment.
• Duloxetine 30 mg once daily for 1 to 2 weeks, then 60 mg, maximum 120 mg daily.
• Pregabalin 75 mg orally twice daily (or 150 mg daily in divided doses), increased after 1 week to 150 mg twice daily, maximum 300 mg twice daily.
• Adjust pregabalin for kidney function (creatinine clearance 30 to 60 mL/min: total daily dose 75 to 300 mg; 15 to 30 mL/min: 25 to 150 mg; under 15 mL/min: 25 to 75 mg).
• Pregabalin causes sedation, dizziness, weight gain and oedema, carries misuse potential and risk with opioids and alcohol (respiratory depression), and must be tapered over at least 1 week.
• Buspirone 5 mg orally twice or three times daily, increased every 2 to 3 days to a usual 15 to 30 mg daily in divided doses, maximum 60 mg daily (reduce in hepatic and kidney impairment, avoid with monoamine oxidase inhibitors). Onset takes 2 to 4 weeks.
• Hydroxyzine 50 mg orally daily in divided doses up to 100 mg daily (maximum 50 mg daily in older adults) as short term treatment, with QT prolongation, sedation and anticholinergic effects.
• Propranolol 10 to 40 mg orally 30 to 60 minutes before performance situations for somatic symptoms (avoid in asthma, heart block and diabetes with hypoglycaemia risk).
• Benzodiazepines only for short term crisis (maximum 2 to 4 weeks): diazepam 2 mg orally three times daily, or lorazepam 0.5 to 1 mg orally 2 to 3 times daily. Avoid in older adults, respiratory disease, sleep apnoea, substance misuse, pregnancy and driving.
• Taper by 5 to 10% every 1 to 2 weeks after prolonged use (transfer to diazepam for long acting cover).
• Antipsychotics (quetiapine 50 mg at night) are not first line, with weak evidence and metabolic risk.

Response and duration. SSRIs and serotonin and noradrenaline reuptake inhibitors take 4 to 6 weeks (and up to 12 weeks) for full effect. Early side effects include increased jitteriness, nausea and insomnia, which can be reduced by starting low. Review at 2 weeks and 4 to 6 weeks.

If under 20% improvement at 4 to 6 weeks on an adequate dose, increase the dose, then switch class. Continue for 12 months after remission, then taper over at least 4 weeks. Avoid antidepressants with a short half life when adherence is poor.

Special populations

• Pregnancy and breastfeeding: psychological therapy first. If drugs are needed sertraline is preferred. Avoid paroxetine and benzodiazepines in late pregnancy, and give lowest effective doses.
• Children and adolescents: cognitive behavioural therapy first. Sertraline 25 mg once daily increasing to 50 mg and up to 200 mg, or fluoxetine 10 mg daily increasing to 20 to 40 mg, with weekly review in the first month for suicidality.
• Older adults: psychological therapy first. Start SSRIs at half doses (sertraline 25 mg), check sodium at 2 weeks, and avoid benzodiazepines and anticholinergic drugs.
• Medical illness: treat coexisting illness, review drugs causing anxiety, and prefer sertraline in cardiac disease.
• Kidney and liver impairment: reduce doses of pregabalin, duloxetine, venlafaxine and buspirone.

Specific causes

• Hyperthyroidism: treat the thyroid disease, with propranolol 10 to 40 mg three or four times daily (up to 160 mg daily) for symptoms until euthyroid.
• Supraventricular tachycardia or arrhythmia: treat by rhythm and specialist care.
• Phaeochromocytoma: alpha blockade with phenoxybenzamine 10 mg twice daily increased to 20 to 40 mg 2 to 3 times daily, or doxazosin 2 to 16 mg daily, before beta blockade and surgery.
• Hypoglycaemia: oral glucose 15 to 20 g or glucagon 1 mg intramuscularly, with review of insulin or sulphonylurea dosing.
• Alcohol or benzodiazepine withdrawal: chlordiazepoxide 15 to 30 mg orally every 6 hours reducing over 5 to 7 days (or diazepam 10 mg every 6 hours reducing).
• Thiamine 100 mg orally daily (200 to 500 mg intravenously three times daily when Wernicke encephalopathy is possible).
• Monitor for seizures and delirium tremens, with symptom triggered dosing in specialist units.
• Caffeine and stimulants: reduce intake gradually to under 200 mg of caffeine daily (about 2 cups of coffee) to avoid withdrawal headache.
• Antidepressant discontinuation: restart and taper slowly.
• Drug induced anxiety: reduce or change the drug.

Monitoring. Repeat the GAD-7 at each visit, with a 4 point fall indicating change and a score under 5 indicating remission. Review adherence, adverse effects, alcohol and substance use, suicidality, blood pressure (venlafaxine and duloxetine), sodium and QT (as needed), and function.

Referral and escalation. Mental health services urgently for suicidal ideation, psychosis, severe functional impairment and severe substance withdrawal. Routine referral for diagnostic uncertainty, comorbid depression, bipolar disorder, treatment resistance and trauma related disorders. Cardiology, endocrinology or neurology when a medical cause is found. Addiction services for substance dependence.

Admission criteria. Suicidal intent or risk to others, psychosis, severe withdrawal or delirium, severe self neglect, and failure of community support.

Discharge and follow up. Review at 2 to 4 weeks after starting treatment, then monthly until stable. Safety net advice: return for worsening anxiety, thoughts of self harm, chest pain, fainting, persistent palpitations, new confusion, or severe side effects.