Hydroxyzine is Neither an SSRI nor an SNRI
Hydroxyzine is a first-generation antihistamine with sedating and anticholinergic properties—it is not a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). 1
Mechanism of Action
- Hydroxyzine is an H1-receptor antagonist (antihistamine) that is chemically unrelated to phenothiazines, reserpine, meprobamate, or benzodiazepines 2
- Its action is due to suppression of activity in key regions of the subcortical area of the central nervous system, not through serotonin or norepinephrine reuptake inhibition 2
- The drug also possesses anticholinergic properties and alpha-adrenergic antagonism activity, which distinguishes it from SSRIs and SNRIs 1, 3
Clinical Classification and Uses
- Hydroxyzine is classified as a sedating antihistamine approved for anxiolytic use in both Europe and the United States 1
- It is used for symptomatic relief of anxiety and tension, nausea/vomiting, atopic dermatitis, and eczema 4, 5
- The drug is often added at night (10-50 mg) to help patients sleep better, though it has significant sedating effects 1
Key Distinguishing Features from SSRIs/SNRIs
SSRIs and SNRIs Work Differently
- SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine) inhibit presynaptic reuptake of serotonin specifically 1
- SNRIs (venlafaxine, desvenlafaxine, duloxetine, levomilnacipran) inhibit presynaptic reuptake of both norepinephrine and serotonin 1
- Hydroxyzine does not affect serotonin or norepinephrine reuptake mechanisms 2
Side Effect Profile Differs Markedly
- Hydroxyzine causes sedation, drowsiness, and performance impairment through CNS depression and anticholinergic effects (dry mouth, constipation, urinary hesitancy) 1, 6
- SSRIs/SNRIs cause different adverse effects including diaphoresis, nausea, sexual dysfunction, and potential serotonin syndrome 1
- Hydroxyzine impairs driving ability and cognitive function, particularly in elderly patients, which is a concern distinct from SSRI/SNRI profiles 1, 5
Critical Clinical Pitfall
- Do not confuse hydroxyzine's anxiolytic properties with SSRI/SNRI mechanisms—while hydroxyzine can treat anxiety, it does so through histamine receptor antagonism and CNS suppression, not through monoamine reuptake inhibition 1, 4, 7
- The American Academy of Allergy, Asthma, and Immunology recommends switching from hydroxyzine to second-generation antihistamines (fexofenadine, loratadine, cetirizine) when anticholinergic effects become problematic, as these provide equivalent efficacy without sedation 6