Zoloft vs. Prozac: differences and similarities

Individual results can vary with different SSRIs. So, if you’ve tried Zoloft for your anxiety disorder or depression but developed side effects, or it didn’t help, Prozac might be a better option for you. (And vice-versa if you’ve already tried Prozac.) It often takes a few tries for you and your healthcare provider to find the right drug and dosage that’s right for you. Keep reading for an overview of the differences and similarities between Zoloft and Prozac.  

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Zoloft (sertraline) and Prozac (fluoxetine) are prescription-only antidepressant medications. They both belong to a class of drugs called selective serotonin reuptake inhibitors (SSRIs).

Our bodies naturally make serotonin, often called the “feel-good hormone.” Serotonin acts as a chemical messenger in the brain, communicating signals from one brain cell to another. These signals play a major role in numerous brain functions, such as mood, fear, hunger, sleep, and sexual behavior (Sahli, 2016).

SSRIs work by blocking serotonin’s reuptake (absorption) into cells, increasing the availability of serotonin in the brain. Depression is thought to be associated with low levels of serotonin. SSRIs seem to help by making it easier for brain cells to communicate signals related to mood. Decades of clinical studies show that SSRIs can be an effective part of an overall treatment plan for depression and anxiety disorders, including talk therapy and lifestyle changes.

After starting Zoloft or Prozac, you probably won’t notice an immediate improvement in your condition. This is because it takes several weeks for SSRIs to become effective. If there’s still no improvement after several weeks, your healthcare provider will likely increase your dosage. All SSRIs can take up to 4 to 6 weeks to reach their full effectiveness (Chu, 2021).

The Food and Drug Administration (FDA) requires antidepressant medications, including SSRIs, to carry a Black Box warning about the increased risk of suicidal thoughts and behaviors. This increased risk is mainly found in children, adolescents, and young adults up to age 25, especially during the early stages of treatment or after dose increases (Chu, 2021). 

What is Zoloft?

Zoloft is the brand-name version of the generic drug sertraline. The FDA 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).

What is Prozac?

Prozac was approved by the FDA in 1987 and is the brand name of the generic drug fluoxetine. The brand-name Prozac only comes in capsules (10 mg, 20 mg, and 40 mg), but its generic form, fluoxetine, also comes in tablets (10 mg, 20 mg, and 60 mg) and an oral liquid solution (20 mg/5 mL). Prozac is usually taken once a day (Eli Lilly, 2020).

Fluoxetine is also available as a 90-mg delayed-release capsule that’s taken once per week. This option is unique because fluoxetine’s effects last longer in the body compared to other SSRIs, and the delayed-release capsule is designed for once-a-week dosing. The brand version, Prozac Weekly, is no longer available. But, the generic version may be a good option for you if you see some improvement with daily Prozac but have trouble remembering to take it every day.

While Zoloft and Prozac are similar medications, they treat a slightly different list of conditions.

 Zoloft uses

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

• Major depressive disorder (MDD)

• Obsessive-compulsive disorder (OCD) (age 6 years and older)

• Panic disorder (PD)

• Post-traumatic stress disorder (PTSD)

• Social anxiety disorder (SAD)

• 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

Prozac uses

Prozac’s FDA-approved uses in adults (and children when age is specified) include (Eli Lilly, 2020):

• Major depressive disorder (MDD) (age 8 years and older)

• Obsessive-compulsive disorder (OCD) (age 7 years and older)

• Bulimia nervosa

• Panic disorder (PD), with or without agoraphobia (fear of leaving home or entering open or crowded places)

When Prozac is combined with olanzapine (brand name of the combined product: Symbyax), it’s also FDA-approved for:

• Depressive episodes of bipolar disorder (age 10 years and older)

• Treatment-resistant depression

Off label (not FDA-approved) uses include (Sohel, 2020; Haque, 2020; Stone, 2003):

• Social anxiety disorder

• Post-traumatic stress disorder

• Borderline personality disorder

• Migraine headache prevention

• Premature ejaculation

• Selective mutism, an inability to talk in certain places or situations

• Raynaud’s phenomenon, a condition in which the blood vessels in your fingers and toes become narrow in response to cold or stress, causing attacks of numbness and pain 

As with all medications, Zoloft and Prozac can cause side effects. To help your body adjust to taking the medication and minimize side effects, your healthcare provider may recommend starting with a lower dose for the first week or so of treatment. 

Many of the common side effects of Zoloft and Prozac, such as nausea or reduced appetite, go away after the first few weeks of treatment. If your healthcare provider increases your dose, some side effects may come back temporarily. 

The lists below include the most common side effects of Prozac and Zoloft, respectively. They’re considered “most common” because they were reported most frequently in clinical studies of the 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 of the possible side effects, and not everyone who takes Prozac or Zoloft experiences side effects.  

Prozac side effects

Here are the most common side effects of Prozac (Eli Lilly, 2020):

• Unusual dreams

• Sexual problems

• Reduced appetite, diarrhea, indigestion, nausea

• Anxiety

• Weakness 

• Dry mouth

• Flu-like symptoms

• Insomnia

• Nervousness

• Sore throat or sinus infection

• Rash

• Sleepiness

• Sweating

• Tremor

• Flushing

• Yawning

Zoloft side effects

Here are the most common side effects of Zoloft (Pfizer, 2016):

• Nausea, diarrhea or loose stool, indigestion, reduced appetite

• Tremor

• Increased sweating

• Sexual problems

Sexual side effects

The most frequently reported sexual problems with Prozac are issues with ejaculation, such as delayed ejaculation. Other sexual side effects include difficulty achieving an erection or orgasm and low sex drive (Eli Lilly, 2020; Jing, 2016). The sexual problems most often reported with Zoloft are failure to ejaculate and low sex drive (Pfizer, 2016).

The chance of developing sexual side effects with either Prozac or Zoloft seems to be lower compared to other SSRIs, such as Paxil (paroxetine). If you’re experiencing sexual side effects, it’s important to talk about it with your healthcare provider. They might adjust your dosage or suggest other treatment options to help relieve this side effect (Jing, 2016).

Withdrawal symptoms

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

Withdrawal symptoms can include nausea, headache, fatigue, tremor, trouble sleeping, dizziness, or feeling irritable and anxious. However, this is relatively less common with Prozac due to its long-lasting effects on the body (Gabriel, 2017).

Certain medications can increase the risk of bleeding with SSRIs. This can lead to bruising easily, excessive nosebleeds, or severe stomach ulcers or bleeding. 

Types of medications that increase the risk of bleeding with SSRIs include:

• Aspirin

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

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

• Antiplatelet drugs, such as clopidogrel (Plavix)

Certain drugs can increase the risk of a rare but serious condition called serotonin syndrome. SSRIs work by increasing the availability of serotonin in your brain. However, if serotonin levels become too high, you could develop this rare but possibly life-threatening reaction. Signs and symptoms of serotonin syndrome include nausea, vomiting, excess sweating, dizziness, changes in heart rate or blood pressure, increased body temperature, tremor, muscle stiffness, or seizures. 

Several types of medications increase the risk of serotonin syndrome with SSRIs, such as (Pfizer, 2016):

• Monoamine oxidase inhibitors (MAOIs), such as linezolid (Zyvox). If you’ve been treated with an MAOI, you must wait at least 14 days to start any SSRI and vice-versa.

• other types of antidepressants, including tricyclic antidepressants such as amitriptyline (Elavil)

• Triptans, such as sumatriptan (Imitrex) 

• Fentanyl (Duragesic)

• Lithium

• Tramadol (Ultram)

• Buspirone (Buspar)

• Amphetamines, such as Adderall

• St. John’s Wort, an herbal remedy that’s thought to support mental health

If you’re taking Zoloft or Prozac, it's always a good idea to consult your pharmacist or healthcare provider before taking any new medications, including over-the-counter drugs or dietary supplements.

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

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How we reviewed this article

Every article on Health Guide goes through rigorous fact-checking by our team of medical reviewers. Our reviewers are trained medical professionals who ensure each article contains the most up-to-date information, and that medical details have been correctly interpreted by the writer.

Current version

July 09, 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.