How Bad Is Zoloft-Induced Weight Gain?

Zoloft has a tendency to promote weight gain, an undesirable side effect for many patients. The effect of Zoloft on weight is relatively modest compared to atypical antipsychotics like Seroquel (quetiapine), which have pronounced metabolic effects independent of their appetite-stimulating effects.

Antidepressants tend to affect pathways that regulate body weight and increase the possibility of weight gain. Zoloft is no exception. Research shows that although it is well-tolerated, Zoloft contributes to weight gain through a variety of mechanisms:

  • Blockade of both alpha-1 adrenergic and 5-HT2C receptors, which increases appetite
  • Increased insulin resistance, which is a feature of diabetes

When stimulated by an agonist, both the alpha-1 adrenergic and the 5-HT2C receptors activate appetite suppression. Zoloft antagonizes those receptor sites and dampens the appetite-suppressing effect, leading to weight gain. It also increases insulin resistance, a quality that research links to weight gain and obesity.

Metabolic effects of antidepressants – like increased insulin resistance – are much more concerning than their effects on appetite. Increased appetite can be managed with portion control, but metabolic effects can lead to weight gain that is different to control.


Zoloft is the trade name for the generic drug called sertraline. It belongs to the class of drugs called selective serotonin reuptake inhibitors (SSRIs). Zoloft works by blocking the reuptake of serotonin, which prolongs the activity of serotonin in the synaptic cleft.

Since research has found low levels to induce aggression and erratic behavior, increased levels of serotonin are theorized to regulate the mood pathways of the brain. Zoloft is used to treat a variety of conditions including social anxiety disorder, post-traumatic stress disorder, depressive disorder, and some psychiatric disorders.

Antidepressants and Weight Gain

A 2015 cross-sectional study found that weight gain occurred in 55.2% of 362 psychiatric patients; out of those patients, 40.6% had gained weight 7% above their baseline. The patients were taking antidepressants for 6 to 36 months. The research found that weight gain occurred in the patients using the following drugs:

  • Sertraline (Zoloft)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Paroxetine (Paxil)
  • Venlafaxine (Effexor)
  • Duloxetine (Cymbalta)
  • Mirtazapine (Remeron)

Out of the drugs mentioned, four are SSRIs (sertraline, citalopram, escitalopram, paroxetine), two are serotonin-norepinephrine reuptake inhibitors (SNRIs) (paroxetine, venlafaxine), and one is a tetracyclic antidepressant (TeCA) (mirtazapine).

Do different classes of SSRIs contribute to variable weight gain?

A different study sought to answer this question with a large pool of electronic health record data.

The study identified 22,610 adults with antidepressant-associated weight. Researchers tracked the patients’ recorded weights over 12 months since the initial date of prescription. They found that specific tricyclic antidepressants (TCAs) and one aminoketone antidepressant produced the least weight gain compared to citalopram, an SSRI.

Mechanisms of Zoloft-Induced Weight Gain

Role of Insulin Resistance

Weight regulation involves a complex interplay of neuroendocrine pathways. The role antidepressants play in weight gain is difficult to determine.

One of way that Zoloft tends to increase body weight is by increasing insulin resistance. Insulin is a hormone that regulates glucose homeostasis and metabolism in the body. After a meal, the pancreatic cells secrete insulin in response to heightened blood sugar. Insulin promotes sugar uptake into cells which lowers blood sugar. Insulin resistance occurs when insulin receptors become less sensitive to the effects of insulin and this response is blunted.

One study determined that antidepressants diabetes risk by increasing insulin resistance. Compared to other classes, SSRIs were the least likely to promote insulin resistance. The risk of developing SSRI-related insulin resistance was dose-dependent.

Alpha-1 Adrenergic Signaling

Another quality of Zoloft is that it is an alpha-1 adrenergic antagonist. Activation of the alpha-1 adrenergic receptor by a ligand tends to suppress appetite.

Since Zoloft is blocks alpha-1 adrenergic signaling, it opposes the effect an agonist would produce. Thus, Zoloft reduces the chance for the body to evoke a decreased appetite response through the alpha-1 adrenergic receptor.

Zoloft is also an antagonist for the 5-HT2C receptor. Agonists that bind the 5-HT2C receptor activate pathways that decrease appetite. SSRI drugs have the unique property of downregulating 5-HT2C receptors, resulting in desensitization. Through this mechanism, Zoloft causes increased appetite and weight gain.

Interestingly enough, a study found that all SSRI drugs including Zoloft are 5-HT2C receptor antagonists.

The more weight-gain pathways a drug upregulates, the more likely that drug will contribute to weight gain. Zoloft develops insulin resistance and is an alpha-1 adrenergic and a 5-HT2C receptor antagonist. Escitalopram, another SSRI, is only a 5-HT2C receptor antagonist. Researchers have not yet investigated the weight gain differences between Zoloft and escitalopram. One study suggests that weight gain may be reduced in patients taking escitalopram because perturbs fewer weight regulation pathways.


Another study compared the effects of escitalopram and duloxetine on body weight. Escitalopram is a conventional SSRI (tradename Lexapro), whereas Duloxetine is an SNRI or serotonin-norepinephrine reuptake inhibitor. Escitalopram was much more likely to product weight gain.

A body of research showed that duloxetine did not upregulate any pathway directly related to weight gain, such as dampening the effects of appetite suppression. Other research showed that duloxetine even resulted in minor weight loss or weight gain in patients treated for certain chronic painful conditions. Duloxetine has the advantage that it increases norepinpehrine which tends to decrease weight.

Atypical Antidepressants

Mirtazapine, a TeCA, causes larger amounts of weight gain. It is an antagonist for the alpha-1 adrenergic receptor, the histamine H1 (H1) receptor, 5-HT2C receptor, and 5-HT2A receptor. Recent studies have linked antagonism to the H1 receptor with significant treatment-induced weight gain. In addition, mirtazapine promotes insulin resistance like Zoloft does. Given the variety of orexigenic (appetite-stimulating) effects mirtazapine downregulates, its tendency to produce significant weight gain is predictable.

Doctors should warn patients about potential weight gain resulting from Zoloft and other antidepressants; patients can be more aware of eating triggers if know they’ll have them. Patients should pay attention to their diet and ensure they are regularly exercising. Though such strategies can be difficult to maintain by patients, especially those who are mentally ill, caretakers and primary physicians should make efforts to prevent weight gain. Performing routine bloodwork, monitoring blood glucose levels, and taking vital signs are a few ways to prevent uncontrolled weight gain.

Combating Zoloft-Induced Weight Gain

There are several drugs available that some clinicians use to counteract weight gain associated with Zoloft.

Clinicians may first try lowering the dosage of Zoloft before switching to another antidepressant. That’s because antidepressant-induced weight gain is dose-dependent.

Other options include prescribing anti-obesity medications. For example, chromium picolinate is a supplement used to improve insulin sensitivity in diabetics and promote weight loss. Chromium picolinate may also decrease carbohydrate cravings in depressed patients.


  • Medications like Zoloft are used to treat conditions that cause changes in mood and behavior.
  • Antidepressants of all classes have varying effects on pathways that regulate body weight.
  • Some antidepressants like Zoloft produce less weight gain compared to other drugs.
  • Weight gain is linked to co-morbidities like diabetes, heart disease, and obesity.

Additionally, patients may be less compliant with their antidepressants if they result in unwanted weight gain. Clinicians and researchers should consider the benefits of Zoloft against the undesirable effects it may have on the body.


Uguz F, Sahingoz M, Gungor B, Aksoy F, Askin R. Weight gain and associated factors in patients using newer antidepressant drugs. Gen Hosp Psychiatry. 2015;37(1):46-8.

Blumenthal SR, Castro VM, Clements CC, et al. An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry. 2014;71(8):889-96.

Gaynor P, Mccarberg B, Zheng W, Shoemaker S, Duenas H. Weight change with long-term duloxetine use in chronic painful conditions: an analysis of 16 clinical studies. Int J Clin Pract. 2011;65(3):341-9.

Boudreau DM, Arterburn D, Bogart A, et al. Influence of body mass index on the choice of therapy for depression and follow-up care. Obesity (Silver Spring). 2013;21(3):E303-13.

Nihalani N, Schwartz TL, Siddiqui UA, Megna JL. Weight gain, obesity, and psychotropic prescribing. J Obes. 2011;2011:893629.

Leave a Comment

Your email address will not be published. Required fields are marked *