Weight gain affects the efficacy of antidepressants, new study finds

Weight gain is a side effect of antidepressants, adding another layer of problems.

two women walking away

A woman helps an overweight person on April 12, 2016 in Berck-sur-Mer, northern France.

Photo: Philippe Huguen/AFP via Getty Images
  • A comprehensive scoping review of 12 studies found that being overweight negatively affects the efficacy of antidepressants.
  • McGill University researchers investigated SSRIs, SNRIs, tricyclic antidepressants, and tetracyclic antidepressants.
  • A double-edged sword: Obesity impacts antidepressants, yet a side effect of these drugs is weight gain.

The initial European trials for gaboxadol produced positive results. Merck and Lundbeck were convinced they had a blockbuster drug on their hands. Researchers considered it a major improvement over Ambien, which sometimes left users feeling groggy the next day. Gaboxadol also didn't produce negative effects when mixed with alcohol, making it a rare sleeping pill. Then the U.S. trials began.

The drug bombed. In 2007, the pharmaceutical giants canceled development of the drug; Lundbeck sold the rights to it in 2015. While no specific reason for its failure has been stated, pharmacology professor Richard J Miller writes that the protein molecule that carries gaboxadol also transports amino acids, such as tryptophan, across the blood-brain barrier. Since Americans consume 20 percent more daily calories from meat than Europeans, gaboxadol likely failed because it was competing with extra tryptophan.

Drugs are complex. A one-size-fits-all approach to drug development often doesn't work. If gaboxadol works for vegetarians, should it be reconsidered? Perhaps in a research field focused on individualized medicine, but that's not the system we live in. Gaboxadol is now being studied for use in treatments of Fragile X syndrome and Angelman syndrome.

There are many reasons a drug might work for you and not me. This is true of antibiotics and vaccines, though these classes of drugs have a solid track record. When considering more controversial treatments, such as antidepressants, the story changes.

Antidepressants Make it Harder to Empathize, Harder to Climax, and Harder to Cry. | Julie Holland

Add to this tale a new study, published in Journal of Affective Disorders, investigating the efficacy of antidepressants in overweight users. A team at McGill University reviewed 12 studies that focused on SSRIs, SNRIs, tricyclic antidepressants, and tetracyclic antidepressants conducted between 2004-2019. Eleven of them found that weight class or body mass index (BMI) negatively affects the efficacy of these antidepressants.

This comprehensive scoping review from the McGill team is troubling for two reasons. First, obesity is already a predictor for depression. Second, weight gain is also a side effect of antidepressants, implying that their efficacy could dwindle with long-term usage. Recent evidence confirms that extended usage of antidepressants results in withdrawal symptoms that persist for over a year, obesity included in that list.

According to the study, over 300 million people suffer from depression around the world. The WHO reports that depression is the leading cause of disability worldwide. Pharmaceutical intervention is problematic with roughly half of prescription users. While the reasons for this are not well understood, obese and overweight patients suffer from treatment-resistant depression at higher rates than those with normal weight.

man sitting in a chair holding his head

Photo by Nik Shuliahin on Unsplash

The researchers offer a few possibilities for why being overweight could negatively affect antidepressants.

  • Antidepressants might not dissolve as effectively in increased body fat.
  • Variations in plasma concentrations are caused by extra adipose tissue.
  • Obese patients are more likely to be on other drugs, any of which could effect the efficacy of antidepressants.
  • Obesity is a state of systemic low grade inflammation that impacts how drugs act in the body.
  • Excess adipose tissue secretes more adipokines, suppressing neurotransmitter systems.
  • Levels of leptin, the hormone that signals hunger, are compromised as weight gain increases.
  • Genetic factors, such as neurotransmitter receptors and drug metabolizing enzymes, could play a role.
  • Comorbid medical conditions—sleep apnea, asthma, metabolic syndrome—can contribute to depression as well as dampen the response to medications.

This wide range of potential factors shows the complexity of drug interactions within the human body. One thing is clear from the McGill team's review: being overweight reduces the efficacy of the world's most popular antidepressants. This trend reiterates the need for better mental treatments, such as psychotherapy and psychedelic therapy. The time for an overhaul of the psychiatry industry and its reliance on this class of drugs has come.


Stay in touch with Derek on Twitter, Facebook and Substack. His next book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."

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