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Prozac vs. Zoloft: Comparison (Similarities & Differences)

Prozac and Zoloft are two common SSRI medications prescribed for the treatment of neuropsychiatric conditions, most notably, major depressive disorder (MDD).  Prozac was developed by the pharmaceutical company Eli Lilly and went on to receive initial FDA approval in December 1987 as an antidepressant.

Comparatively, Zoloft was developed by the pharmaceutical company Pfizer and went on to receive initial FDA approval in December 1991 as an antidepressant.  Despite the fact that both Prozac and Zoloft are broadly classified as SSRIs (selective-serotonin reuptake inhibitors), they contain different chemicals (fluoxetine vs. sertraline) and do not exert identical effects within the body.

Prozac vs. Zoloft (Comparison Chart)

As you can read based on the chart below, Prozac and Zoloft are similar in some ways and different in others.  Prozac contains fluoxetine, whereas Zoloft contains sertraline.

Prozac vs. Zoloft

 ProzacZoloft
IngredientFluoxetineSertraline
Drug classificationSSRI (Selective-Serotonin Reuptake Inhibitor)SSRI (Selective-Serotonin Reuptake Inhibitor)
Approved medical usesMajor depression. Obsessive-Compulsive Disorder (OCD). Panic disorder. Bulimia nervosa.Major depression. Obsessive-Compulsive Disorder (OCD). Panic disorder. Post-Traumatic Stress Disorder (PTSD). Premenstrual Dysphoric Disorder (PMDD). Social anxiety disorder.
Bioavailability~72%~44%
FormatsCapsule. Tablet. Oral solution.Tablet. Oral solution.
Dosages10 mg. 20 mg. 40 mg.25 mg. 50 mg. 100 mg.
ManufacturerEli LillyPfizer Inc.
Legal statusPrescription (Rx)-onlyPrescription (Rx)-only
Mechanism of actionInhibits reuptake of serotonin.Inhibits reuptake of serotonin.
Generic version (?)Yes.Yes.
Half-Life4 to 6 days.23 to 26 hours.
Common side effectsAbnormal dreams. Abnormal ejaculation. Anorexia. Anxiety. Asthenia. Diarrhea. Dry mouth. Dyspepsia. Flu syndrome. Impotence. Insomnia. Libido decreased. Nausea. Nervousness. Pharyngitis. Rash. Sinusitis. Somnolence. Sweating. Tremor. Vasodilatation. Yawning.Nausea. Diarrhea (loose stool). Tremor. Dyspepsia. Decreased appetite. Sweating. Ejaculation failure. Decreased libido.
Date approved1987 (December)1991 (December)
Duration of effect24 hours (standard) & 7 days (delayed-release)24 hours
MetabolismHepatic: CYP2D6 (primary). CYP2C19. CYP2B6. CYP2C9.Hepatic: CYP2B6 (primary). CYP2D6. CYP2C19. CYP2C9. CYP3A4.

Prozac vs. Zoloft: What are the major differences?

Major differences between Prozac and Zoloft include: FDA-approved uses; how the medications are metabolized; available formats; release date; bioavailability; manufacturer; half-life; the incidence rates of certain side effects.  Prozac is approved to treat bulimia nervosa (whereas Zoloft is not), but Zoloft is approved to treat social anxiety disorder and premenstrual dysphoric disorder (whereas Prozac is not).

Prozac is metabolized primarily by the enzymes CYP2D6 and CYP2C19, whereas Zoloft is metabolized primarily by the enzymes CYP2B6 and CYP2D6.  Differences in metabolism can be a big deal to persons with genetic polymorphisms that affect cytochrome P450 enzyme expression.  For example, someone who’s a CYP2C19 poor metabolizer might have a difficult time tolerating or responding to Prozac versus Zoloft.

In addition to differences in how each drug is metabolized, Prozac is available in a capsule format – plus tablet and oral solution formats, whereas Zoloft is solely available in tablet and oral solution formats.  Prozac was manufactured by Eli Lilly and released in 1987 – and Zoloft was manufactured by Pfizer, Inc. and released in 1991, making Prozac the older drug.

Though side effects associated with each of the medications are similar, it is believed that Prozac is more likely to cause dry mouth and sleep disturbances – whereas Zoloft is more likely to cause diarrhea.  In terms of bioavailability, or the percentage of the medication that exerts a relevant effect when ingested, the bioavailability of Prozac is 60-80% – whereas that of Zoloft is 44%.

The half-life of Prozac is 4 to 6 days for chronic users which is much longer than the half-life of Zoloft (23 to 26 hours).  Despite a few differences between Prozac and Zoloft – the medications are similar in many ways, including: duration of effect; clinical effectiveness; common side effects; withdrawal symptoms; legal status; and cost.

Approved medical uses & off-label uses

Both Prozac and Zoloft are approved by the United States FDA for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and panic disorder.  Prozac is also approved by the U.S. FDA for the treatment of bulimia nervosa (Zoloft is not) – whereas Zoloft is also approved by the U.S. FDA for the treatment of premenstrual dysphoric disorder (PMDD), post-traumatic stress disorder (PTSD), and social anxiety disorder (Prozac is not).

Each of these medications are frequently prescribed as “off-label” interventions for the management of neuropsychiatric conditions.  Prozac is sometimes prescribed off-label for the treatment of cataplexy, obesity, alcohol dependence, binge eating disorder, and autism spectrum disorder – whereas Zoloft is sometimes prescribed off-label for the treatment of premature ejaculation and vascular headaches.

Cost: Which is more expensive?

Both Prozac and Zoloft are similarly-priced when sold as generic medications – neither usually costs more than $30 for a 30-day supply.  A 30-day supply of oral Prozac capsules costs between $4 and $27 at most pharmacies – regardless of whether a person is receiving the 10 mg, 20 mg, or 40 mg dosage.

A 30-day supply of oral Zoloft tablets costs between $7 and $22 at most pharmacies – regardless of whether a person is receiving the 25 mg, 50 mg, or 100 mg dosage.  A bottle of Prozac oral solution (120 mL of 20 mg per 5 mL) costs between $11 and $45, whereas a bottle of Zoloft oral solution (60 mL of 20 mg/mL) costs between $26 and $63.

It seems as though generic Prozac (fluoxetine) can be attained for a slightly lower cost at certain pharmacies than generic Zoloft (sertraline), yet at other pharmacies generic Zoloft (sertraline) is cheaper than generic Prozac (fluoxetine).  If the cost of oral solutions are compared, generic Prozac seems to be a better deal.

If the “brand name” version of each medication must be attained, then Prozac will be more expensive than Zoloft.  A 30-day supply of “brand name” Prozac costs between $912 and $980, whereas a 30-day supply of “brand name” Zoloft costs between $299 and $325.

In the event that a patient ends up using generic Prozac tablets (instead of generic Prozac capsules), the cost will far exceed the generic Prozac capsules – and the generic Zoloft tablets.  A 30-day supply of generic Prozac tablets costs: $4 to $56 (10 mg dose); $30 to $80 (20 mg dose); and $110 to $365 (60 mg dose).

Dosage & Formats

Prozac and Zoloft are similar in that they are manufactured in 3 distinct dosages:  Prozac is sold in 10 mg, 20 mg, and 40 mg capsules – and Zoloft is sold in 25 mg, 50 mg, and 100 mg tablets.  The bioavailability of Prozac is estimated as falling within the range of 60% to 80% – whereas the bioavailability of Zoloft is estimated as being around 44%.

Both generic Prozac and generic Zoloft are manufactured in the form of tablets and oral solution.  Tablets are convenient in that they can usually be split or divided by patients while titrating on and off of the medication.  However, unlike Zoloft, Prozac is also manufactured in the form of capsules.

Although Prozac is manufactured in one more format than Zoloft, the cost of generic Prozac tablets far exceeds the cost of generic Prozac capsules – and generic Zoloft tablets.  While having another format of the medication to choose from can perceived as advantageous by patients, most people will want to utilize the cheapest generic formats (capsule for Prozac and tablet for Zoloft).

It is also worth mentioning that, unlike Zoloft, Prozac is manufactured in a “delayed-release” (DR) format that allows users to take one pill per week (some refer to this format as “Prozac weekly”).  From a convenience and/or compliance perspective, some individuals and/or medical doctors may prefer delayed-release Prozac over other formats.

Effectiveness: Which drug is more effective?

There are no strong data to suggest that Prozac is significantly more effective than Zoloft (or vice-versa) for the treatment of major depressive disorder, obsessive-compulsive disorder (OCD), and panic disorder.  Both medications have proven to be more effective than placebos in large-scale, randomized controlled trials – and are approved by the FDA.

For this reason, most psychiatrists and medical doctors believe that Prozac and Zoloft are equally useful first-line interventions for the treatment of major depressive disorder, obsessive-compulsive disorder (OCD), and panic disorder.  That said, a meta-analysis by Cipriani et al. (2009) reported that Zoloft (sertraline) might be a better treatment for moderate to severe depression in adults – compared to Prozac (fluoxetine).

In fact, the findings by Cipriani et al. indicated that Zoloft exhibited the best balance between benefits, tolerability, and cost – relative to 12 other antidepressants.  Another study by Cipriani et al. (2010) reported that Zoloft might be superior in terms of effectiveness and tolerability – relative to other antidepressants, including Prozac.

Nonetheless, it’s important to underscore that there’s significant interindividual variance in terms of antidepressant efficacy.  Certain individuals may respond better to Prozac for depression, others may respond better to Zoloft for depression – and some might find that neither medication is more effective (comparatively) than the other; responses are often determined by gene expression and neurophysiology.

Because Prozac is FDA approved for the treatment of bulimia nervosa (and Zoloft is not), it’s reasonable to surmise that Prozac would likely be the more effective option for bulimia.  On the other hand, because Zoloft is FDA approved for the treatment of social anxiety disorder, PTSD, and premenstrual dysphoric disorder – it’s reasonable to surmise that Zoloft would be the more effective intervention for these conditions.

Mechanism of action

In terms of pharmacodynamics (mechanism of action), Prozac and Zoloft are similar.  Each medication functions primarily as a selective-serotonin reuptake inhibitor (SSRI) whereby they inhibit the reuptake of the neurotransmitter serotonin (5-HT) or prevent serotonin from reentering the presynaptic cell.

This action is understood to increase serotonin concentrations in the synaptic cleft for binding to the postsynaptic receptor.  Increased binding of serotonin to postsynaptic receptors is thought to counteract depressed mood, obsessive-compulsive tendencies, and forms of anxiety.

As selective-serotonin reuptake inhibitors, both Prozac and Zoloft are capable of dramatically altering neurochemical activity and neural connectivity within hours of ingestion.  Moreover, with ongoing treatment (4 to 8 weeks), Prozac and Zoloft downregulate 5-HT1A receptor activation (which further enhances serotonin signaling) and increase BDNF to promote hippocampal neurogenesis.

Despite exhibiting many similarities in pharmacodynamics, there are differences in the secondary neurochemical targets with which each medication interacts.  Prozac is understood to interact with 5-HT2C and 5-HT2A receptors (at high doses), whereas Zoloft interacts with the dopamine transporter (at high doses) such that it increases dopamine concentrations.

Metabolism & Half-Life

The metabolism and elimination half-life differs significantly between Prozac and Zoloft.  Prozac is metabolized in the liver by cytochrome P450 isoenzymes, most notably, CYP2D6 and CYP2C19.  (To a lesser extent, CYP2B6 and CYP2C9 are suggested as being involved in Prozac metabolism).

CYP2D6 is needed to convert fluoxetine into its only biologically-active metabolite “norfluoxetine.”  The bioavailability of Prozac is considered fairly high (~72%) and peak plasma concentrations are attained within 6 to 8 hours of administration.

The elimination half-life of Prozac and its primary active metabolite (norfluoxetine) is considered long.  Prozac has an elimination half-life of 1 to 3 days after a single dose – and 4 to 6 days after multiple doses, and norfluoxetine (the biologically active metabolite) has a half-life of 16 days after multiple doses.

Like Prozac, Zoloft is also metabolized in the liver by cytochrome P450 isoenzymes, including CYP2D6, CYP2C19, CYP2B6, and CYP2C9.  However, Zoloft is also metabolized by CYP3A4 and is primarily metabolized by CYP2B6 (rather than CYP2D6).

The bioavailability of Zoloft is relatively moderate (~44%) and peak plasma concentrations are attained within 4 to 6 hours of administration.  The elimination half-life of Zoloft is 23 to 26 hours, and the elimination half-life of its primary biologically-active metabolite (norsertraline) is ~66 hours.

Popularity

Prozac was popular before Zoloft hit the market for retail, but in recent years, Zoloft may have surpassed the popularity of Prozac.  In 2010, over 24.4 million prescriptions for generic Prozac were filled in the United States, which made it the third-most prescribed antidepressant following Zoloft and Celexa.

In 2011, over 6 million prescriptions were filled for Prozac in the United Kingdom.  As of 2013, over 41 million prescriptions were written for Zoloft – which made it the most prescribed antidepressant and the second most prescribed psychiatric medication in the United States.

Within the past year (2017 to 2018), it appears as though ~38.8 million prescriptions were filled for generic Zoloft (making it the #1 most-prescribed SSRI), whereas ~28.3 million prescriptions were filled for generic Prozac (making it the #2 most-prescribed SSRI) in the United States.  Based on this data, it’s reasonable to state that Zoloft is presently the more popular medication.

Side effects

The most common side effects associated with Prozac (according to FDA packaging data) include: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn.

The most common side effects associated with Zoloft (according to FDA packaging data) include: nausea, diarrhea or loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido.

From this data, it would appear as though Prozac is more likely to cause a greater number of side effects than Zoloft.  Side effects like: abnormal dreams, anorexia, anxiety, asthenia, dry mouth, flu syndrome, insomnia, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, vasodilation, and yawn – occur more frequently among Prozac users.

Comparatively, decreased appetite is more likely to occur among Zoloft users.  Both medications appear to provoke side effects like: decreased libido, excessive sweating, tremor, dyspepsia (indigestion), and ejaculation failure.

Withdrawal

Both Prozac and Zoloft can cause withdrawal symptoms or a discontinuation syndrome – following cessation.  Withdrawal symptoms are understood to occur as a form of neurophysiologic recalibration or readjustment to compensate for the activity of the SSRI.

With chronic or long-term Prozac or Zoloft treatment, a person’s neurophysiology (brain, CNS, etc.) adapts to the presence and serotonergic of these medications such that receptor sites in the brain upregulate and/or downregulate – and the medications become necessary to maintain neurochemical balance.

When the medications are discontinued, a user’s neurophysiology is still expecting the serotonergic effects of these medications – and reacts harshly when no medication is delivered.  A former user’s neurophysiology requires time to adjust back to homeostasis (pre-Prozac or pre-Zoloft functioning) – and until the full adjustment takes place, withdrawal symptoms occur.

Though there are similarities between Prozac withdrawal symptoms and Zoloft withdrawal symptoms – some experts believe that Prozac discontinuation symptoms are easier to manage due to the fact that Prozac has a much longer half-life.  The longer half-life of Prozac (and its active metabolite, norfluoxetine) may be advantageous because the drug remains in a user’s system for a long time after discontinuation.

Because Prozac can remain in systemic circulation for up to 33 days and its metabolite norfluoxetine can remain in systemic circulation for up to 88 days after discontinuation, this helps the body gradually readjust to functioning with lower levels of an SSRI over a prolonged duration – enabling for smoother neurophysiologic recalibration.  Zoloft remains in the body for around 6 days and its metabolite norsertraline remains in the body for up to 16 days – which likely makes for a harsher withdrawal (compared to Prozac).

Similarities (Recap): Prozac vs. Zoloft

Included below is a summary of the commonalities between Prozac and Zoloft.

  • Abuse potential: Neither Prozac nor Zoloft is known to have the potential for abuse. In other words, people aren’t seeking out these medications to get “high” – or for an intoxicating or euphoriant effect.
  • Cost: The cost of Prozac and Zoloft are relatively similar for a 30-day supply. Generic Prozac costs between $4 and $27 – and generic Zoloft costs between $7 and $22 (depending on the pharmacy).
  • Drug class: Both Prozac and Zoloft are officially classified as SSRIs (selective-serotonin reuptake inhibitors) and function by increasing extracellular concentrations of the neurotransmitter “serotonin” (5-HT) within the brain.
  • Duration of effect: The duration of effect for Prozac and Zoloft is identical – each exerts an effect that lasts 24 hours.
  • Effectiveness: Prozac and Zoloft are considered to be of similar effectiveness for the treatment of major depressive disorder (MDD). Each medication is more effective than a placebo in randomized controlled trials.  There’s no evidence suggesting that one medication is more effective than the other.
  • Generic availability: Prozac and Zoloft are manufactured and sold in generic formats under the names “fluoxetine” and “sertraline” – respectively.
  • Legal status: Prozac and Zoloft are prescription-only (Rx-only) medications that can be attained with the prescription of a medical doctor. Neither medication is classified as a controlled substance.
  • Mechanism of action: Each of these medications functions primarily by inhibiting the reuptake of serotonin. Inhibiting the reuptake of serotonin increases extracellular concentrations of serotonin – which is believed to enhance mood.
  • Medical uses: Both Prozac and Zoloft can be utilized for the treatment of major depressive disorder.
  • Side effects: The side effect profiles of Prozac and Zoloft are very similar. Common side effects associated with each medication include: agitation, anxiety, sweating, diarrhea, dry mouth, weakness, insomnia, tremor, and abnormal ejaculation.
  • Withdrawal: Discontinuing both Prozac and Zoloft can be difficult due to the fact that the neurophysiology of users adapts to the presence of each medication over time. When the medications are discontinued – withdrawal symptoms can occur.

Differences (Recap): Prozac vs. Zoloft

Included below is a summary of the differences between Prozac and Zoloft.

  • Formats: Prozac is manufactured in many formats including: capsule, tablet, and oral solution – whereas Zoloft is solely manufactured in tablet and oral solution formats.
  • Half-life: The half-life of Prozac is 1 to 3 days (single dose) and 4 to 6 days (multi-dose), whereas the half-life of Zoloft is 23 to 26 hours.
  • Ingredients: The active ingredient in Prozac is the chemical fluoxetine, whereas the active ingredient in Zoloft is the chemical sertraline.
  • Manufacturers: Prozac was developed and manufactured by Eli Lilly, whereas Zoloft was developed and manufactured by Pfizer, Inc.
  • Medical uses: Prozac is medically approved for the treatment of major depressive disorder and bulimia nervosa – whereas Zoloft is medically approved for the treatment of major depressive disorder, social anxiety disorder, and premenstrual dysphoric disorder.
  • Mechanism of action: Though both medications function primarily as selective-serotonin reuptake inhibitors, they exhibit different affinities for secondary neurochemical targets. The secondary neurochemical targets for Prozac are the 5-HT2C and 5-HT2A receptors – and the secondary target for Zoloft is the dopamine transporter.
  • Metabolism: Prozac is metabolized in the liver by the enzymes CYP2D6 and CYP2C19, whereas Zoloft is metabolized in the liver by the enzyme CYP2B6 and CYP2D6.
  • Popularity: In 2013 Zoloft was the most prescribed antidepressant in the United States (with ~41 million prescriptions). Although Prozac is probably the most “well-known” of all SSRI medications – Zoloft is likely the more popular medication.
  • Withdrawal: It is generally thought that withdrawal from Prozac may be easier than withdrawal from Zoloft due to the long half-life of fluoxetine (and its metabolite). It is common for Prozac to be used as a “bridge” to help individuals manage withdrawal from SSRIs like Zoloft.

Which medication is better for depression? (Prozac vs. Zoloft)

Anyone who pursues a general medical doctor or psychiatrist for the treatment of major depressive disorder will likely be presented with Prozac and Zoloft as potential first-line pharmacological interventions.  Most medical doctors will regard Prozac and Zoloft as safe, effective, low-risk medications for persons with major depressive disorder to try.

Although everyone wants to know whether one medication is more effective than the other – the truth is that the efficacies of each medication will be subject to significant individual variation among users.  Certain individuals will respond much better to Prozac than Zoloft, others will respond better to Zoloft than Prozac – and others might not notice any substantial differences in terms of efficacy and/or side effects between the medications.

It’ll usually take some trial and error before you know whether one medication is more effective and/or tolerable than the other.  When choosing between Prozac and Zoloft, it is recommended to work closely with an experienced psychiatrist – and maintain a daily journal to track precisely how well the medication is working over an extended duration (e.g. 1-2 months).

Which medication do you prefer: Prozac or Zoloft?

If you’ve tried both Prozac and Zoloft, leave a comment mentioning whether you have a preference for one medication over the other.  If you have a preference for one medication over the other – report the reason(s) as to why you have this preference.

Possible reasons for preferring one drug over another include: greater efficacy; fewer unwanted side effects (e.g. weight gain, sexual dysfunction, etc.); lower cost; easier withdrawal symptoms, etc.  To help others get an accurate understanding of your situation, share some details like: how long you used each medication, your dosages of each, and the medical condition you were treating (e.g. major depression).

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