What is the mechanism of action of hydroxyzine (Hydroxyzine) for generalized anxiety disorder (GAD)?

From the Guidelines

Hydroxyzine treats generalized anxiety disorder primarily by blocking histamine H1 receptors in the central nervous system, which produces sedative and anxiolytic effects. The mechanism of action of hydroxyzine for generalized anxiety disorder (GAD) is complex and involves multiple pathways.

Key Mechanisms

• Blocking histamine H1 receptors in the central nervous system, leading to sedative and anxiolytic effects 1
• Anticholinergic properties, which may contribute to its anxiety-reducing effects, but also increase the risk of side effects such as dry mouth, constipation, and urinary retention 1
• Blocking serotonin receptors, which may also contribute to its anxiety-reducing effects 1

Important Considerations

• Unlike benzodiazepines, hydroxyzine does not act directly on GABA receptors, making it non-habit forming and lacking abuse potential
• Hydroxyzine is typically prescribed at 25-100 mg doses taken 3-4 times daily, with a maximum daily dose of 400 mg for adults
• The medication begins working within 15-30 minutes after oral administration, with effects lasting 4-6 hours
• Common side effects include drowsiness, dry mouth, and constipation
• Hydroxyzine is particularly useful for patients with comorbid anxiety and insomnia, those with substance abuse concerns, or as a short-term alternative to benzodiazepines
• The medication should be used cautiously in elderly patients and those with certain medical conditions like narrow-angle glaucoma or prostatic hypertrophy due to its anticholinergic effects 1

From the FDA Drug Label

Hydroxyzine hydrochloride is unrelated chemically to the phenothiazines, reserpine, meprobamate or the benzodiazepines. Hydroxyzine is not a cortical depressant, but its action may be due to a suppression of activity in certain key regions of the subcortical area of the central nervous system. The mechanism of action of hydroxyzine for generalized anxiety disorder (GAD) may be due to a suppression of activity in certain key regions of the subcortical area of the central nervous system.

• The exact mechanism is not explicitly stated in the label. 2

From the Research

Mechanism of Action of Hydroxyzine for Generalized Anxiety Disorder (GAD)

The mechanism of action of hydroxyzine for GAD is not explicitly stated in the provided studies. However, the studies suggest that hydroxyzine is effective in reducing anxiety symptoms in patients with GAD.

Efficacy of Hydroxyzine in GAD

• Hydroxyzine has been shown to be more effective than placebo in reducing anxiety symptoms in patients with GAD 3, 4, 5, 6.
• Hydroxyzine has been found to be equivalent in terms of efficacy to other anxiolytic agents such as benzodiazepines and buspirone 3, 6.
• The efficacy of hydroxyzine in GAD has been demonstrated in both short-term and long-term studies 4, 5.

Side Effects of Hydroxyzine

• Hydroxyzine has been associated with a higher rate of sleepiness/drowsiness compared to placebo and other anxiolytic agents 3, 4, 5.
• Other common side effects of hydroxyzine include weight gain, dry mouth, loss of concentration, and insomnia 4, 5.
• The side effects of hydroxyzine have been found to be generally well-tolerated and transient 4, 5.

Comparison with Other Anxiolytic Agents

• Hydroxyzine has been compared to benzodiazepines, buspirone, and placebo in several studies 3, 4, 5, 6.
• Hydroxyzine has been found to be equivalent in terms of efficacy to benzodiazepines and buspirone, but with a different side effect profile 3, 6.
• Hydroxyzine may be a useful alternative treatment to benzodiazepines for patients with GAD 5.