Paxil vs. Zoloft: what are the similarities and differences?

Paxil and Zoloft are both antidepressant drugs. The term "antidepressant" is a bit misleading because these medications aren’t only used to treat depression. They're also used to treat anxiety disorders. In separate clinical trials, people who took Paxil reported more side effects than people who took Zoloft. 

Read on to learn more about the similarities and differences between Paxil and Zoloft. 

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Paxil (paroxetine) and Zoloft (sertraline) are antidepressant medications. Specifically, they both belong to a class of drugs called selective serotonin reuptake inhibitors (SSRIs). SSRIs work by increasing the availability of a “feel-good hormone” called serotonin in the brain. Serotonin is a chemical messenger that communicates signals from one brain cell to another. These signals regulate many brain functions, including mood, fear, sleep, hunger, and sexual behavior (Sahli, 2016).

Low levels of serotonin are thought to be a possible cause of depression. SSRIs seem to help by raising the availability of serotonin, making it easier for brain cells to communicate signals related to mood. 

Decades of research and clinical experience show that SSRIs can be an effective part of an overall treatment plan for depression and anxiety disorders, including talk therapy and lifestyle changes. However, it’s important to keep in mind that all SSRIs take several weeks to become effective. If you still don’t notice improvement after six weeks, talk to your healthcare provider. They may increase your dosage (Chu, 2021).

The Food and Drug Administration (FDA) requires antidepressant medications, including SSRIs, to carry a black box warning on their labeling. A black box warning is the strongest type of warning that the FDA can issue. 

In this case, the FDA warns healthcare providers and patients about the increased risk of suicidal thoughts and actions that have been seen with SSRIs, especially in children, teens, and young adults under 25 years old. This risk may be higher in the first few weeks after treatment is started or after your dosage gets increased. If you have thoughts of harming yourself, help is available 24/7. Seek immediate medical attention or call the National Suicide Prevention Lifeline at 800-273-8255.

Paxil is the brand name of the generic drug paroxetine, which was originally FDA-approved in 1992. Paxil comes in two forms: an oral tablet (10 mg, 20 mg, 30 mg, and 40 mg) and an oral liquid suspension (10 mg per 5 mL). Paxil is usually taken once per day  (GSK, 2021). It’s also available as Paxil CR, a controlled-release tablet that’s designed to release its active ingredient slowly throughout the day. It comes in 12.5 mg, 25 mg, and 37.5 mg. Paxil CR is also usually taken once daily (GSK, 2019).

Zoloft is the brand name of the generic drug sertraline. The FDA first approved it in 1991. It comes in two forms: an oral tablet (25 mg, 50 mg, and 100 mg) and an oral liquid solution (20 mg/mL). Zoloft is usually taken once a day (Pfizer, 2016).

Paxil and Zoloft treat most of the same conditions.

Paxil uses

The FDA-approved uses of Paxil in adults include (GSK, 2021):

• Major depressive disorder (MDD)

• Obsessive-compulsive disorder (OCD) 

• Panic disorder

• Social anxiety disorder

• Generalized anxiety disorder (GAD)

• Post-traumatic stress disorder (PTSD)

• Premenstrual dysphoric disorder (PMDD) for Paxil CR (GSK, 2019)

Off-label uses (not FDA-approved, but commonly used by providers when deemed appropriate for their patients) for Paxil include (Shrestha, 2020):

• Separation anxiety

• Persistent depressive disorder, also called dysthymia

• Body dysmorphic disorder

• Postpartum depression

• Premature ejaculation

• Cancer-related itching

Note that paroxetine is not FDA-approved for use in children or adolescents under age 18, but it’s sometimes prescribed off-label in this group for OCD and social anxiety disorder.

Zoloft uses

Zoloft’s FDA-approved uses in adults (and children when age is specified) include (GSK, 2016):

• Major depressive disorder (MDD)

• Obsessive-compulsive disorder (OCD) (age six years and older)

• Panic disorder

• Post-traumatic stress disorder (PTSD)

• Social anxiety disorder

• Premenstrual dysphoric disorder (PMDD)

Off-label (not FDA-approved) uses for Zoloft include (Singh, 2020):

• Generalized anxiety disorder (GAD)

• Binge eating disorder

• Body dysmorphic disorder

• Bulimia nervosa

As with many medications, treatment with Paxil or Zoloft can cause side effects. Because of this, your healthcare provider may recommend starting with a lower dose of Paxil or Zoloft for the first seven to ten days of treatment. This approach can help your body adjust to taking the medication and minimize side effects.

Several common side effects of Paxil and Zoloft, such as nervousness, drowsiness, or loss of appetite, tend to go away on their own after the first few weeks of treatment. If your healthcare provider increases your dose, some side effects may temporarily get worse again. 

The lists below include the most common side effects of Paxil and Zoloft, respectively. These are the side effects reported most frequently in clinical studies of each drug (in at least 5% of participants who took the drug and twice the frequency reported in participants who took a placebo). These lists do not include all possible side effects and not everyone who takes Paxil or Zoloft experiences side effects. 

Paxil side effects

The most common side effects of Paxil include (GSK, 2021):

• Sexual side effects (see next section for details) 

• Weakness

• Constipation or diarrhea

• Decreased appetite

• Dizziness

• Dry mouth

• Infections

• Insomnia

• Nausea

• Nervousness

• Sleepiness

• Increased sweating

• Tremor

• Yawning

Zoloft side effects

The most common side effects of Zoloft include (GSK, 2016):

• Nausea

• Diarrhea or loose stool

• Indigestion

• Reduced appetite

• Tremor

• Increased sweating

• Sexual problems (see next section for details)

Sexual side effects

Sexual problems are possible side effects of all SSRI antidepressants, especially if you take a high dose. Not everyone who takes SSRIs notices sexual side effects, but people experience these sexual side effects more commonly with Paxil than Zoloft (Jing, 2016).

The most common sexual side effects with Paxil include (GSK, 2021):

• Delayed ejaculation

• Difficulty or inability to reach climax or orgasm in males and females (referring to sex assigned at birth)

• Inability to get or maintain an erection in males

• Inadequate lubrication in females

• Decreased sex drive

The most common sexual problems reported with Zoloft are (GSK, 2016):

• Failure to ejaculate

• Decreased sex drive

If you’re experiencing sexual side effects, it’s essential to talk about it with your healthcare provider. They might be able to adjust your dosage or suggest other treatment options. If you’re having trouble with erectile dysfunction (ED), you could consider ED medications such as Viagra (sildenafil) to help (Jing, 2016).

Withdrawal symptoms

It’s best not to stop taking Paxil or Zoloft suddenly. If you and your healthcare provider decide that you should stop Paxil or Zoloft, they’ll guide you on gradually lowering your dose before you stop treatment. This is important because suddenly stopping an SSRI can cause side effects called withdrawal symptoms. 

Withdrawal symptoms tend to be more severe with Paxil than with other SSRIs and may include dizziness, tiredness, nausea, vomiting, headache, fever, chills, vivid dreams, electric shock-like sensations, uncontrolled muscle movements, crying, or feeling anxious (Shrestha, 2020).

Several medications can interact with SSRIs. Drug interactions can lead to harmful effects. Because of this, it's important to always check with your pharmacist or healthcare provider before starting any new medications, including over-the-counter drugs or dietary supplements.

Serotonin syndrome

Serotonin syndrome is a rare but serious risk that comes with SSRIs. Combining certain drugs can further increase this risk. SSRIs work by increasing the availability of serotonin in your brain. However, if serotonin levels become too high, you could develop serotonin syndrome, ranging from mild to life-threatening. Symptoms of serotonin syndrome include nausea, vomiting, excess sweating, dizziness, heart rate or blood pressure changes, increased body temperature, tremor, muscle stiffness, or seizures (Chu, 2021). 

Several types of medications increase the risk of serotonin syndrome and should generally be avoided with SSRIs, such as (Chu, 2021; GSK, 2021):

• Other types of antidepressants, including tricyclics such as amitriptyline (Elavil)

• Buspirone (Buspar)

• Amphetamines, such as Adderall

• Triptans, such as sumatriptan (Imitrex) 

• Certain pain medications such as fentanyl (Duragesic) and tramadol (Ultram)

• Lithium

• St. John’s Wort, an herbal remedy reported to have antidepressant effects

• Monoamine oxidase inhibitors (MAOIs), such as linezolid (Zyvox). You must wait at least 14 days after stopping an MAOI to start any SSRI (and vice-versa).

Bleeding risk

Taking SSRIs with certain medications can increase the risk of bleeding, including bruising easily, frequent or severe nosebleeds, stomach ulcers, or stomach bleeding. Because of this risk, it’s best to avoid certain medications that have blood-thinning effects if you also take an SSRI, such as Paxil or Zoloft. Some examples include:

• Aspirin

• Anticoagulant drugs, commonly called blood-thinners, such as warfarin (Coumadin)

• Antiplatelet drugs, such as clopidogrel (Plavix)

• Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn)

Other drug interactions

Some SSRIs, including Paxil, may interact with certain medications that are broken down by a specific enzyme in your body known as CYP2D6. Because of this, Paxil can reduce the effectiveness of a breast cancer medication, tamoxifen (Nolvadex); thus, the combination is not recommended (GSK, 2021). 

Other medications may require dosage adjustments or careful monitoring for side effects if they’re taken with SSRIs. For specific drug interaction questions, it’s best to check with your pharmacist or healthcare professional.

If you become pregnant or have plans to become pregnant, it’s important to talk with your healthcare provider. They’ll help you consider the risks and benefits of whether you should continue taking an SSRI during pregnancy or while breastfeeding. 

If you’re taking Paxil, tell your doctor right away if you become pregnant. Most SSRIs are considered safe to take in certain situations, such as severe depression, during pregnancy. However, Paxil is not recommended during pregnancy or while breastfeeding. In this case, your healthcare provider will guide you on switching to a different SSRI or offer other medical advice (GSK, 2021; Shrestha, 2020). 

We’ve given you a lot of information regarding the differences and similarities between these two SSRIs medications. Here is a summary:

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Current version

July 23, 2021

Written by

Patricia Weiser, PharmD

Fact checked by

Felix Gussone, MD

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About the medical reviewer

Felix Gussone, MD, Ro

Felix Gussone is a physician, health journalist and a Manager, Medical Content & Education at Ro.