How does Pristiq differ from Zoloft? (5+ differences)

In this article, we will discuss how Pristiq is different from Zoloft. We will share several differences between them and other relevant information. 

How does Pristiq differ from Zoloft?

Pristiq differs from Zoloft in terms of its active ingredient, classification, mechanism of action, therapeutic indications, side effects, metabolism, recommended doses, and available dosage forms. Both drugs are manufactured by Pfizer. 

The active ingredient in Pristiq is desvenlafaxine which is a serotonin-norepinephrine reuptake inhibitor (SNRI). The active ingredient in Zoloft is sertraline. Both desvenlafaxine and sertraline are antidepressants. 

Although Pristiq and Zoloft are antidepressants, they are different in several ways. Whether to use Pristiq or Zoloft will be guided by your healthcare provider. This choice is based on symptoms and individual characteristics. 

What are some differences between Pristiq and Zoloft? 

Pristiq differs from Zoloft in the following ways: 

Classification and mechanism of action: 

Pristiq is classified as a serotonin-norepinephrine reuptake inhibitor (SNRI). It inhibits the reuptake of serotonin and norepinephrine (NE) and increases their concentration in the body (1). 

Zoloft is a selective serotonin reuptake inhibitor (SSRI) and it primarily acts on serotonin to block its reuptake and increase its concentration in the body. It also has effects on dopamine and NE but they are minimal (2). 

Pristiq and Zoloft have a slight difference in their mechanism of action but they both increase serotonin levels in the body. Serotonin regulates mood and alertness and its deficiency is related to the development of depression (2). 

Therapeutic indications: 

Pristiq is an FDA-approved drug for the treatment of major depressive disorder (MDD). Off-label it is prescribed to women experiencing menopausal hot flashes who cannot be prescribed estrogen (1).  

FDA has not approved Pristiq for adolescents. However, It has shown efficacy in treating treatment-resistant depression in adolescents (1). 

Zoloft is FDA-approved for the following conditions (2): 

  • post-traumatic stress disorder (PTSD)
  • social anxiety disorder (SAD)
  • obsessive-compulsive disorder (OCD)
  • premenstrual dysphoric disorder
  • panic disorder

Zoloft is used off-label for the following conditions (2): 

  • binge eating disorder
  • bulimia nervosa
  • body dysmorphic disorder 

Side effects:

Pristiq is associated with the following side effects (1,3):

  • headache
  • nausea
  • abdominal pain
  • dizziness
  • constipation
  • sweating 
  • angle-closure glaucoma 
  • low sodium levels
  • sexual dysfunction 
  • drowsiness
  • anxiety 
  • decreased appetite
  • increased risk of bruising
  • difficulty sleeping
  • suicidal ideation  

Zoloft is associated with the following side effects (2): 

  • sweating
  • dizziness
  • confusion
  • diarrhea
  • nausea
  • impotence
  • fatigue
  • lightheadedness
  • syncope
  • tremor 
  • suicidal ideation
  • somnolence
  • female sexual disorder

Pristiq and Zoloft both can cause serotonin syndrome in rare conditions (1,2). It is caused by excessive serotonin in the body and results in symptoms like pupil dilation, hyperthermia, excessive salivation, tachycardia, and diaphoresis (1). 

Dosage and administration: 

The starting therapeutic dose of Pristiq for MDD is 50 mg/day. Its maximum dose is 400mg/day. Higher doses are not more effective than 50mg/day dose. It can be taken at any time of the day with or without food (1). 

The initial dose of Zoloft for MDD is 50mg/day and the maximum dose is 200mg/day. It can be taken in the morning or evening and taking it with food enhances its absorption (2). 


Pristiq is metabolized through the liver and there is no major involvement of CYP enzymes in its metabolism. Due to this reason, there are lower risks of drug-drug interactions. Pristiq is excreted through the kidneys (1). 

Zoloft is metabolized in the liver with a significant involvement of cytochrome P456 enzymes. Zoloft is an inhibitor of CYP2D6 and has significant interactions (4). 

Dosage forms: 

Pristiq is only available in the form of an extended-release (ER) tablet. The tablet is formulated in the strengths of 25mg, 50mg, and 100 mg. You cannot cut this tablet in half because it is an ER tablet. 

Zoloft is formulated in the form of tablets and oral solutions. The tablet is formulated in the strengths of 25mg, 50mg, and 100mg. The oral solution contains 20mg of sertraline.  

Pristiq and Zoloft: which one is better?

The safety, efficacy, and tolerability of Pristiq and Zoloft are well-established in the literature. Both drugs work well for MDD. Zoloft is usually the primary choice for MDD. Pristiq is preferred for MDD when the patient also has pain disorders (5).

In a comparative study, the efficacy and safety of desvenlafaxine (the active ingredient in Pristiq) 100mg and sertraline 50mg (the active ingredient in Zoloft) were compared (6). 

In this study, the results revealed that sertraline produced better clinical results. This difference however was marginal (6). Thus, there is only a slight difference between the efficacy of Pristiq and Zoloft and it varies from person to person. 

The decision of whether to choose Pristiq or Zoloft is made by your healthcare provider based on symptoms, age, comorbidities, risk of drug-drug interactions, and contraindications. 

Can you take Pristiq and Zoloft together?

Yes, Pristiq and Zoloft can be taken together only if prescribed by your healthcare provider. Your healthcare provider will make this decision based on your condition.

Do not use Pristiq and Zoloft together unless guided by the healthcare provider as the combination can increase the risk of serotonin syndrome. Studies have shown that a combination of Pristiq and Zoloft can be effective in treating MDD (7). 

In one study patients received Pristiq and Zoloft both in a dose of 50mg/day. Patients were treated with this combination for 8 weeks and showed significant improvement in their symptoms (7). 

In my perspective, Pristiq and Zoloft are very different drugs. Pristiq has the active ingredient desvenlafaxine which is an SNRI and Zoloft has the active ingredient sertraline which is an SSRI. Pristiq and Zoloft are different in terms of their mechanism of action, indications, side effects, doses, metabolism, and dosage forms. There is a slight difference in their efficacy which varies from person to person. In some cases, they can be taken together. 

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