Anxiolytic Drugs

Anxiolytic drugs reduce anxiety in generalised anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder and acute stress. Antidepressants are the main long-term treatment. Benzodiazepines, buspirone, pregabalin, hydroxyzine and propranolol have narrower roles.

Mechanism. Selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors enhance serotonin and noradrenaline signalling. Buspirone is a 5-HT1A partial agonist. Pregabalin binds the alpha-2-delta subunit of calcium channels and reduces excitatory release. Hydroxyzine blocks histamine H1 and 5-HT2A receptors. Propranolol blocks beta receptors and reduces physical symptoms. Benzodiazepines enhance GABA-A activity.

Pharmacokinetics. Buspirone half-life 2 to 3 hours, extensive first-pass metabolism by CYP3A4. Pregabalin is cleared unchanged by the kidney, half-life 6 hours. Hydroxyzine half-life 20 hours in adults.

Differences. Antidepressants cover comorbid depression and panic but need weeks, and can worsen anxiety in the first 1 to 2 weeks. Buspirone is non-sedating, has no dependence, and is weak for panic. Pregabalin acts fast but carries misuse and dependence risk. Hydroxyzine is sedating and prolongs the QT interval.

• Generalised anxiety disorder, panic disorder, social anxiety disorder: sertraline or escitalopram first-line; venlafaxine or duloxetine if no response; pregabalin as an alternative. Start at half the usual dose in panic disorder.
• Post-traumatic stress disorder: sertraline, paroxetine or venlafaxine, with trauma-focused therapy.
• Obsessive compulsive disorder: higher doses of sertraline (up to 200 mg), fluoxetine (up to 80 mg) or clomipramine, for 8 to 12 weeks before judging response.
• Short-term relief: a benzodiazepine for no more than 2 to 4 weeks, only when anxiety is severe or disabling, or hydroxyzine as an alternative.
• Performance anxiety: propranolol before the event.
• Duration: continue for 6 to 12 months after remission, then taper over weeks.
• Avoid benzodiazepines in panic disorder as a long-term treatment and in post-traumatic stress disorder.

Special groups. Pregnancy: psychological therapy first; sertraline has the most data; avoid paroxetine in early pregnancy and benzodiazepines late in pregnancy. Breastfeeding: sertraline, with low infant exposure. Children: sertraline or fluoxetine under specialist care, with monitoring for suicidal thoughts. Older adults: halve starting doses, avoid benzodiazepines and hydroxyzine, and check sodium on starting SSRIs.

Kidney impairment: reduce pregabalin by creatinine clearance (150 mg daily at 30 to 60 mL/min, 75 mg daily at 15 to 30 mL/min). Liver impairment: reduce SSRI doses and avoid duloxetine. Regional: anxiety is often presented as physical complaints; psychological therapy by trained community workers is an option where medicines are scarce; khat and alcohol worsen anxiety; HIV and efavirenz add anxiety and sleep problems.

Adverse effects. Antidepressants: nausea, sexual dysfunction, early jitteriness, sleep change, and discontinuation symptoms on stopping. Buspirone: dizziness, nausea, headache. Pregabalin: dizziness, sedation, weight gain, oedema, misuse, and respiratory depression with opioids. Hydroxyzine: sedation, dry mouth, QT prolongation. Propranolol: bradycardia, fatigue.

Contraindications. Propranolol in asthma and heart block. Buspirone with monoamine oxidase inhibitors. Hydroxyzine with QT prolongation, and in early pregnancy.

Interactions. Buspirone levels rise with CYP3A4 inhibitors (erythromycin, itraconazole, ritonavir; use a low dose) and fall with rifampicin and carbamazepine. Pregabalin adds to opioids and alcohol. Hydroxyzine adds to other QT-prolonging drugs.

Monitoring. Anxiety scale at baseline and every 4 to 6 weeks, suicidal thoughts in under 25s, sodium in older adults, blood pressure with venlafaxine, ECG with hydroxyzine in cardiac disease.

Referral and escalation. Suicidal thoughts, no response to two adequate courses of medicine, severe functional impairment, or comorbid substance misuse.