Clarifying Hydroxyzine's Pharmacological Classification
Hydroxyzine is definitively not an antidepressant—it is an antihistamine with anxiolytic (anti-anxiety) properties that works through sedation and suppression of subcortical brain activity, not through antidepressant mechanisms. 1
What Hydroxyzine Actually Is
Hydroxyzine is chemically unrelated to antidepressants: The FDA label explicitly states that hydroxyzine hydrochloride is "unrelated chemically to the phenothiazines, reserpine, meprobamate or the benzodiazepines" and is not a cortical depressant. 1
Its mechanism is antihistaminic with anxiolytic effects: Hydroxyzine's action may be due to suppression of activity in certain key regions of the subcortical area of the central nervous system, producing sedation and anxiety relief through this pathway—not through serotonin, norepinephrine, or dopamine modulation like antidepressants. 1
It has demonstrated efficacy for anxiety, not depression: Research shows hydroxyzine is more effective than placebo for generalized anxiety disorder (GAD), but there is no evidence base for treating depression. 2
Why the Confusion May Have Occurred
Hydroxyzine is sometimes used alongside antidepressants: Guidelines note that hydroxyzine can be combined with SSRIs for anxiety symptoms, which may have led to confusion about its classification. 3
Historical context of anxiolytic use: In older literature, hydroxyzine was studied in combination with antidepressants (particularly SSRIs like fluvoxamine and fluoxetine) for patients with both depression and anxiety, but this does not make hydroxyzine itself an antidepressant. 3
The combination has important caveats: Research from animal models suggests that unlike benzodiazepines (which can antagonize antidepressant effects), hydroxyzine does not interfere with the therapeutic action of SSRIs, making it a potentially safer anxiolytic to combine with antidepressants. 3
How to Explain This to Your Patient
Frame it as a medication classification issue, not questioning what their provider told them:
"Hydroxyzine is an antihistamine that has calming effects—it's approved and effective for anxiety, which may be why your provider prescribed it. However, it's not classified as an antidepressant because it doesn't work on the brain chemicals (like serotonin) that antidepressants target." 1, 2
Acknowledge the therapeutic overlap: "Sometimes medications for anxiety are used alongside antidepressants, and that might be where the confusion came from. Hydroxyzine can help with anxiety symptoms, but if you need treatment for depression specifically, we would need to consider an actual antidepressant medication." 3
Emphasize what it does well: "Hydroxyzine works quickly—usually within 15 to 30 minutes—to reduce anxiety through its calming, sedating effects. This is different from antidepressants, which take weeks to work and target mood regulation." 1
Important Clinical Considerations
Hydroxyzine has significant sedative effects: It is associated with drowsiness, impaired concentration, and can affect driving ability—these are antihistamine side effects, not antidepressant effects. 4
It should be discontinued before certain medical procedures: Guidelines recommend stopping hydroxyzine 7-10 days before oral food challenge testing due to its antihistamine properties, which would not be necessary for antidepressants. 5
Anticholinergic burden concerns: In older adults, hydroxyzine is listed among anticholinergic medications that can cause CNS impairment, delirium, and sedation—risks that differ from antidepressant side effect profiles. 5
Limited evidence for anger or mood symptoms: Guidelines specifically note that hydroxyzine lacks evidence for treating anger, irritability, or mood instability in adolescents and should not be used as a substitute for adequate antidepressant dosing when depression is present. 6