What is the evidence for the effectiveness of hydroxyzine (an antihistamine) in treating anxiety?

Evidence for Hydroxyzine in Anxiety

Hydroxyzine demonstrates efficacy superior to placebo for generalized anxiety disorder (GAD) but cannot be recommended as a reliable first-line treatment due to high risk of bias in available studies, small sample sizes, and lack of long-term safety data beyond 4 months. 1, 2

FDA-Approved Indication and Limitations

• Hydroxyzine is FDA-approved for "symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested" 1
• The FDA label explicitly states that "the effectiveness of hydroxyzine as an antianxiety agent for long term use, that is more than 4 months, has not been assessed by systematic clinical studies" 1
• Physicians must periodically reassess the usefulness of the drug for individual patients 1

Evidence Quality and Efficacy

Superiority Over Placebo

• A 2010 Cochrane systematic review of 5 studies (884 participants) found hydroxyzine more effective than placebo for GAD (OR 0.30,95% CI 0.15 to 0.58) 2
• However, the Cochrane review concluded that due to high risk of bias, small number of studies, and overall small sample size, hydroxyzine cannot be recommended as a reliable first-line treatment in GAD 2
• The anxiolytic effect begins within the first week of treatment at 50 mg/day and is maintained throughout 4 weeks 3

Comparison to Other Anxiolytics

• Hydroxyzine demonstrated equivalent efficacy to benzodiazepines (chlordiazepoxide) and buspirone in terms of treatment response (OR 0.75,95% CI 0.35 to 1.62 for chlordiazepoxide; OR 0.76,95% CI 0.40 to 1.42 for buspirone) 2
• One study suggested hydroxyzine may provide greater and more rapid cognitive improvement compared to lorazepam 4

Current Guideline Recommendations for Anxiety Disorders

First-Line Treatments (Not Hydroxyzine)

• SSRIs and SNRIs are the recommended first-line pharmacologic treatments for anxiety disorders in both adults and adolescents 5
• For social anxiety disorder specifically, the Japanese Society of Anxiety recommends SSRIs (fluvoxamine, paroxetine, escitalopram) as first choice with GRADE 2C evidence 5
• Cognitive behavioral therapy (CBT) is recommended as initial treatment for most anxiety patients, with pharmacotherapy reserved for those without access to CBT, those preferring medication, or those not improving with psychological interventions 5

Hydroxyzine's Absence from Modern Guidelines

• Major anxiety disorder guidelines from 2020-2023 do not include hydroxyzine in their treatment algorithms 5
• The Japanese guideline explicitly states that "other classes of drugs (e.g., antiepileptics and analogs, antipsychotics, benzodiazepines, beta blockers, MAOIs, NARIs, NaSSAs, RIMAs, and SARIs) have not been adequately studied and are thus not included in the guideline with or without recommendations" 5

Tolerability Profile

Common Side Effects

• Sleepiness/drowsiness is the most common side effect, occurring in 28% of patients versus 14% with placebo 3
• Hydroxyzine was associated with higher rates of sleepiness/drowsiness than active comparators (OR 1.74,95% CI 0.86 to 3.53) 2
• Other side effects include dry mouth (14% vs 5% placebo), weight gain (12% vs 10%), loss of concentration (9% vs 8%), and insomnia (9% vs 6%) 3
• Sedation typically appears during the first week and progressively diminishes during continued treatment 3

Acceptability and Discontinuation

• Overall acceptability was comparable to placebo (OR 1.00,95% CI 0.63 to 1.58) and tolerability was similar (OR 1.49,95% CI 0.92 to 2.40) 2
• No rebound anxiety or withdrawal symptoms were observed after abrupt discontinuation following 4 weeks of treatment 3

Special Populations and Contraindications

Pregnancy

• Hydroxyzine is specifically contraindicated during early pregnancy 6
• If antihistamine therapy is absolutely necessary during pregnancy, chlorphenamine is preferred due to its longer safety record 6

Renal Impairment

• Patients with moderate renal impairment (creatinine clearance 10-20 mL/min) require dose reduction to half the standard dose 6
• Hydroxyzine should be avoided entirely in severe renal impairment (creatinine clearance <10 mL/min) 6

Hepatic Impairment

• Hydroxyzine should be avoided in severe liver disease due to inappropriate sedating effects 6, 7

Elderly Patients

• Start elderly patients on low doses and monitor closely for confusion, over-sedation, and fall risk 6
• Elderly patients have increased sensitivity to psychomotor impairment 6

Clinical Context and Practical Considerations

Potential Role in Clinical Practice

• Hydroxyzine may have utility as adjunctive nighttime therapy when sedation is desired, similar to its use in pruritus management 7, 8
• It demonstrated usefulness as transitional support during benzodiazepine withdrawal, with hydroxyzine 50 mg showing improvement in anxiety and reduction of withdrawal symptoms 9
• The lack of dependency and organ toxicity noted in older literature may be advantageous in specific clinical scenarios 4

Why Hydroxyzine Is Not First-Line

• The evidence base consists primarily of small studies from the 1990s with methodological limitations 2, 4, 3
• SSRIs and SNRIs have substantially more robust evidence, including data on long-term efficacy and safety 5
• The sedating properties of hydroxyzine limit its utility for daytime anxiety management 6, 7
• Modern guidelines prioritize treatments with better-established efficacy profiles and lower risk of cognitive impairment 5