How does hydroxyzine work for anxiety?

How Hydroxyzine Works for Anxiety

Hydroxyzine is a first-generation antihistamine that provides anxiolytic effects primarily through antagonism of histamine H1 receptors, with additional anticholinergic and sedative properties, though it is notably absent from major anxiety disorder treatment guidelines and should not be considered a first-line agent for generalized anxiety disorder. 1

Mechanism of Action

Hydroxyzine functions as a sedative antihistamine with anxiolytic properties through several pathways 1:

• Primary mechanism: Antagonism of histamine H1 receptors in the central nervous system, which produces both sedative and anxiolytic effects 1, 2
• Secondary effects: Anticholinergic activity that contributes to its sedating profile but also raises concerns about cognitive effects, particularly with long-term use 3, 4
• The medication lacks the dependency potential associated with benzodiazepines and does not demonstrate organ toxicity 2

Clinical Efficacy Evidence

The evidence for hydroxyzine's effectiveness in anxiety is limited but shows some benefit:

• Versus placebo: Hydroxyzine at 50 mg/day demonstrates statistically significant anxiolytic effects beginning in the first week of treatment, with particular improvement in the cognitive component of anxiety 5, 6
• Comparative effectiveness: When compared to benzodiazepines (bromazepam, chloridiazepoxide) and buspirone, hydroxyzine showed equivalent efficacy but with a higher rate of drowsiness 7, 5
• Important limitation: A 2010 Cochrane review concluded that due to high risk of bias in available studies, small sample sizes, and limited number of trials, hydroxyzine cannot be recommended as a reliable first-line treatment for GAD 7

Clinical Positioning and Guidelines

Hydroxyzine is conspicuously absent from all major anxiety disorder treatment guidelines (NICE, S3, Canadian CPG, AACAP 2020) as a recommended agent 1:

• First-line treatments remain: SSRIs and SNRIs are the evidence-based first-line pharmacological treatments for generalized anxiety disorder in both adults and children/adolescents based on robust evidence 8, 1
• Appropriate use scenarios: Hydroxyzine is approved and practical for procedural anxiolysis in pediatric populations during medical procedures 1
• Psychiatric settings: Can be used as chemical restraint in children and adolescents, though JCAHO standards prohibit its use as PRN chemical restraint 1

Safety Profile and Adverse Effects

Common Side Effects

• Most frequent: Transient sleepiness/drowsiness (28% vs 14% with placebo), which typically appears during the first week and progressively diminishes 6
• Other effects: Dry mouth (14% vs 5% placebo), weight gain (12% vs 10%), loss of concentration (9% vs 8%), and insomnia (9% vs 6%) 6

Serious Concerns and Contraindications

• Cognitive effects: The American Academy of Allergy, Asthma, and Immunology notes that anticholinergic burden from first-generation antihistamines is associated with cognitive decline, primarily in elderly populations 3
• Older adults: The Mayo Clinic rates hydroxyzine as causing CNS impairment, delirium, and sedation in older adults with moderate strength of evidence 4
• Pregnancy: Contraindicated in early pregnancy per UK manufacturer guidelines 1
• Liver disease: Should be avoided in severe liver disease due to inappropriate sedating effects 1

Critical Clinical Pitfalls

Hydroxyzine should not be used as a substitute for adequate treatment of underlying psychiatric conditions 4:

• The American Academy of Child and Adolescent Psychiatry explicitly states that hydroxyzine lacks evidence for treating anger, irritability, or mood instability in adolescents 4
• It should never replace adequate antidepressant dosing when depression is present 4
• When used, prescribe the lowest effective dose for the shortest duration necessary to minimize anticholinergic burden and cognitive effects 3

Monitoring Recommendations

• Long-term use concerns: The Journal of Allergy and Clinical Immunology advises monitoring for cognitive effects, particularly with prolonged use 3
• Drug interactions: Avoid combining with other medications that have anticholinergic properties to prevent cumulative effects 3
• Procedural considerations: Must be stopped 7-10 days before oral food challenge testing due to antihistamine properties 4

Comparative Safety in Pediatrics

When anxiolysis is needed in younger populations, hydroxyzine has fewer safety concerns than benzodiazepines (which are often not recommended in children under 16 years), with the most common side effects being transient sleepiness rather than cognitive impairment 3. However, non-pharmacological approaches should be considered first when appropriate, and if long-term medication is necessary, second-generation antihistamines with less anticholinergic activity may be preferable 3.