While it is well known that many antidepressants are associated with weight gain, the mechanism was unclear until recently. In the past three years, large-scale studies identified the link between the genes involved in antidepressant metabolism and disturbances in cholesterol and triglyceride levels, risk of diabetes, and eventually manifesting as weight gain. Here we explain how SSRIs and other mental health drugs can disrupt your body’s metabolism of fats and carbohydrates. This information, along with genetic and blood test results, may help you and your doctor to decide how to adjust your treatment to reduce the long-term risks of SSRIs and minimize weight gain.

Previous studies linked genetic variations in two key liver enzymes, CYP2C19 and CYP2D6, to antidepressants’ effectiveness and tolerability. Now, there is additional information about the genetics of these enzymes and their impact on cholesterol, triglycerides and insulin resistance.

Antidepressants, drug metabolism and risk of weight gain

Body weight is affected by a multitude of factors, including diet, physical activity and exercise, gender and genetics. Because so many factors affect body weight, it is hard to find a definitive link between specific medication and weight gain. Yet, most antidepressants are known to cause weight gain. A notable exception, bupropion, is the only antidepressant that may lead to weight loss in some people. With SSRIs and other antidepressants, the risk of excessive weight gain is dose-dependent. As you can imagine, genes that affect the metabolism of antidepressants can also affect body weight. Indeed, there is a significant association between citalopram and total body weight with CYP2C19 metabolic status. The increase in body weight while taking citalopram was much more pronounced in people with lower drug metabolism due to the reduced function of this liver enzyme.

Psychiatry consensus and the Clinical Pharmacogenetics Implementation Consortium guidelines strongly recommended genetic testing for CYP2C19 and CYP2D6 to guide antidepressant selection and dosage. Knowing your genetic profile through DNA testing can help you and your doctor to find the optimal SSRI or other antidepressant and dose to reduce the risk of side effects and weight gain.

Recent studies of the UK Biobank data further refined the link between inherently reduced clearance of antidepressants and increased cholesterol and triglycerides, which often lead to diabetes and weight gain.

Triglycerides and psychiatric drugs

Triglycerides store unused calories and provide your body with energy. Foods rich in fat and carbohydrates (sugar, starch) lead to elevated triglycerides, which is an early marker of heart disease and diabetes. At high doses, SSRIs can disrupt sugar and fat metabolism. The strongest impact on triglyceride levels was observed with venlafaxine and sertraline, especially in people with inherently reduced clearance of these medications. Even citalopram and escitalopram, which are often the first line of treatment for depression and have a minimal impact on cholesterol levels, cause elevated triglyceride levels. The use of SSRIs paroxetine and fluoxetine, or antipsychotics, also increases triglycerides. While the genetic analysis did not find a direct link to CYP2D6 variants, it did identify that taking antipsychotics with other drugs that block the activity of the CYP2D6 enzyme resulted in higher triglyceride levels. If you have high triglycerides, reducing the SSRI dose or switching to another antidepressant may help to reduce the risk of weight gain and heart disease.

Cholesterol

Venlafaxine was associated with the highest levels of total cholesterol, followed by paroxetine and sertraline. A similar pattern was observed for LDL-C (“bad cholesterol”) and somewhat reduced levels of HDL-C (“good cholesterol”). As in the case of weight gain and triglycerides, genetic variations that reduced sertraline metabolism affected cholesterol levels. On the other hand, people taking cholesterol-lowering medications along with sertraline had almost normal cholesterol levels. This finding means that if you are taking an antidepressant and have elevated cholesterol or/and triglycerides, statin medication could help to reduce the risk of diabetes and heart disease.

HbA1c – insulin resistance and diabetes marker

There is a significant interaction between diabetic status and altered CYP2D6 enzyme function in people taking antidepressants, including SSRIs (fluoxetine, citalopram, sertraline), SNRIs (venlafaxine), and TCAs (amitriptyline). The link between reduced drug clearance and high levels of HbA1c was most prominent in diabetic patients with reduced CYP2D6 function who were taking venlafaxine. Both paroxetine and venlafaxine have been previously associated with an increased risk of diabetes, especially in people with reduced CYP2D6 function. For these patients, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend using lower doses of paroxetine and avoiding venlafaxine. Metformin is the first line of treatment for people with elevated HbA1c levels.

Lifestyle considerations for preventing weight gain while taking antidepressants

Prevent Overeating: Approaching the dinner table ravenously hungry can promote overeating. To prevent this, avoid skipping meals and always have healthy snacks readily available between meals.

Mindful Eating: Mindful eating involves paying close attention to the physical and emotional aspects of food. It can be helpful for preventing overeating and encourages nourishing food choices. Some mindful eating practices include taking a minute before eating to silently express gratitude, chewing food thoroughly, and eating slowly without distraction. Learn more about mindful eating here.

Exercise: Physical exercise is essential for weight loss, reducing the risk of heart disease, and improving mental health status. Regular physical exercise, including both aerobic and resistance training, is important for regulating weight and reducing spikes in blood sugar. For example, try taking a 30-minute walk or doing some squats after meals.

Overall dietary patterns:

• Aim for all meals and snacks to be composed of foods rich in at least two dietary fiber, healthy fat, or high-quality protein. This will increase satiety and prevent spikes in blood sugar that can promote inflammation and weight gain.

• Reducing simple carbohydrate intake, particularly added sugars and foods containing high fructose corn syrup, can help lower triglyceride levels.

• The Mediterranean diet has a good balance of complex carbs, protein, and healthy unsaturated fats. It has been shown to reduce the risk of heart disease and mental health conditions.

• A ketogenic diet (high fat, low carb, moderate protein) might not be the best choice because it can further exacerbate high cholesterol in some people.

What can you do to get effective treatment for depression and mitigate long-term risks?

1. Consider getting a pharmacogenetic test to optimize your antidepressant therapy. Matching drugs and doses to your DNA can reduce the risk of side effects, including excessive weight gain. Switching to a different SSRI or other antidepressant may help.
2. Once you have your DNA test results talk to expert pharmacists who have expertise in pharmacogenetics and nutrition.
3. Even if you have a normal weight, it might be prudent to test cholesterol, triglycerides and HbA1c levels in your blood and adjust your therapy if one of these biomarkers is above the normal threshold.
4. If dietary adjustment is insufficient, your doctor may recommend supplementing your treatment with cholesterol-lowering medications or metformin.

Looking for comprehensive support to manage your weight? Book a free call: www.thrivenutritionist.com

References

Richards-Belle A et al., Associations of antidepressants and antipsychotics with lipid parameters: Do CYP2C19/ CYP2D6 genes play a role? A UK population-based study. J Psychopharmacol. 2023 Feb 11;2698811231152748.

Austin-Zimmerman I et al.,  The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics Genes (Basel). 2021 Nov 3;12(11):1758. doi: 10.3390/genes12111758.

Bousman CA et al., Review and Consensus on Pharmacogenomic Testing in Psychiatry. Pharmacopsychiatry. 2021 Jan;54(1):5-17.

Oh RC at al., Management of Hypertriglyceridemia: Common Questions and Answers Am Fam Physician. 2020;102(6):347-354