Does hydroxyzine interact with Zoloft? (3 side effects)

In this article, we will discuss whether there is an interaction between hydroxyzine and Zoloft (sertraline). We will also talk about the potential benefits and risks of taking these two medications together.

Does hydroxyzine interact with Zoloft?

Hydroxyzine does not necessarily interact with Zoloft, a selective serotonin reuptake inhibitor. However, these medications may cause additive side effects when used together. Both hydroxyzine and Zoloft are prescription medications and should not be used without your doctor’s approval (1,2). 

Zoloft is primarily used to manage anxiety and depression, while hydroxyzine is primarily used as an antihistamine but is also frequently prescribed for the management of anxiety.

Zoloft is often prescribed with hydroxyzine for managing both depression and anxiety, and the combination does not interact chemically. This means these drugs do not cancel out their effects or affect each other’s metabolism. 

However, individuals are different and can respond differently to medications, so this combination might not be suitable for everyone.

What does research suggest?

There is limited research on the concomitant use of sertraline (Zoloft) and hydroxyzine. However, research suggests that hydroxyzine is a potential anxiolytic agent and can be taken with antidepressants to manage depression comorbid with anxiety. 

One research study indicated that combining hydroxyzine with serotonergic antidepressants such as sertraline and fluoxetine can help manage anxiety more effectively (3). 

However, some research studies have indicated that taking an SSRI with hydroxyzine can trigger serotonin syndrome in susceptible individuals (4). Therefore, this combination should be used cautiously in certain people.

What are the potential benefits of taking hydroxyzine with Zoloft?

The potential benefits of taking hydroxyzine with Zoloft include: (1,2)

Enhanced treatment of depression comorbid with anxiety

The combination of hydroxyzine and Zoloft can be effective in managing symptoms when depression is comorbid with anxiety. Hydroxyzine complements Zoloft’s action and manages both conditions effectively.

Management of sertraline-induced early anxiety

Some individuals may experience initial anxiety when starting sertraline. Hydroxyzine can help alleviate this early anxiety, providing a smoother journey until Zoloft kicks in. 

Better sleep

Hydroxyzine is known for its sedative effects, which can contribute to better sleep quality. When taken with Zoloft, especially if Zoloft is affecting sleep patterns, hydroxyzine can help manage that.

What are the potential risks of taking hydroxyzine with Zoloft?

The potential risks of taking hydroxyzine with Zoloft include: (1,2)

Sedation and drowsiness

Both hydroxyzine and Zoloft can cause sedation as a side effect. When taken together, there is an increased risk of drowsiness, affecting alertness and cognitive function.

Impaired coordination

The sedative properties of hydroxyzine can add to the potential coordination impairment caused by Zoloft. Make sure you avoid driving or operating heavy machinery while taking this combination.

Increased risk of serotonin syndrome

Combining hydroxyzine with Zoloft raises the risk of serotonin syndrome, a potentially serious condition characterised by symptoms like confusion, rapid heart rate, and elevated body temperature.

Is there any alternative to hydroxyzine for allergy symptoms?

There are suitable alternatives to hydroxyzine if you’re taking this medication to manage allergy symptoms while on Zoloft. These include: (5)

AntihistamineCommon Brand NamesTypical Dosages
CetirizineZyrtec5 to 10 mg once daily
LoratadineClaritin10 mg once daily
Fexofenadine Allegra60 mg or 180 mg once daily
DesloratadineClarinex5 mg once daily
LevocetirizineXyzal5 mg once daily 

These antihistamines are non-sedative second-generation antihistamines, which do not cause sedation. So, they are safe to take with sertraline, which may cause sedation or dizziness in some individuals. 

As a pharmacist, I always advise opting for these antihistamines to manage common cold and flu symptoms while taking antidepressants. First-generation sedative antihistamines can cause sleepiness, which may exacerbate the drowsiness induced by antidepressants. If your symptoms persist, please reach out to your healthcare provider.


  1. Singh HK, Saadabadi A. Sertraline. 2023 Feb 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 31613469. Available from:
  1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. Hydroxyzine. 2017 Jan 16. PMID: 31643458. 
  1. Martin P, Guillou N, Lacroix P, Billardon M. Effets d’une coadministration d’antidépresseur et d’anxiolytique dans le paradigme de “learned-helplessness”: intérêt de l’hydroxyzine [Effects of co-administration of an antidepressant and an anxiolytic drug in the “learned helplessness” paradigm: importance of hydroxyzine]. Encephale. 1996 Jul-Aug;22(4):270-9. French. PMID: 9035982. 
  1. Hudd TR, Blake CS, Rimola-Dejesus Y, Nguyen TT, Zaiken K. A Case Report of Serotonin Syndrome in a Patient on Selective Serotonin Reuptake Inhibitor (SSRI) Monotherapy. J Pharm Pract. 2020 Apr;33(2):206-212. doi: 10.1177/0897190019841742. Epub 2019 Apr 28. PMID: 31030620.
  1. Philpot EE. Safety of second-generation antihistamines. Allergy Asthma Proc. 2000 Jan-Feb;21(1):15-20. doi: 10.2500/108854100778249033. PMID: 10748947. 

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