Is sertraline (Zoloft) use associated with the development of multiple acyl-CoA dehydrogenase deficiency (MADD)?

From the Guidelines

There is no established association between sertraline (Zoloft) use and the development of multiple acyl-CoA dehydrogenase deficiency (MADD). MADD is primarily a genetic disorder caused by mutations in genes that encode electron transfer flavoproteins or electron transfer flavoprotein dehydrogenase, which are essential for fatty acid oxidation. It is not typically acquired through medication use. Sertraline, a selective serotonin reuptake inhibitor (SSRI), works by increasing serotonin levels in the brain and does not directly affect the mitochondrial fatty acid oxidation pathways involved in MADD. The common side effects of sertraline include nausea, diarrhea, insomnia, sexual dysfunction, and potential serotonin syndrome when combined with other serotonergic medications, but mitochondrial dysfunction resembling MADD is not among them. If a patient on sertraline develops symptoms that might suggest metabolic dysfunction (such as muscle weakness, hypoglycemia, or metabolic acidosis), these should be evaluated independently, as they would likely stem from causes unrelated to sertraline use.

Key Points

• MADD is a genetic disorder and not typically associated with medication use 1.
• Sertraline's mechanism of action does not directly affect the mitochondrial fatty acid oxidation pathways involved in MADD.
• Common side effects of sertraline do not include mitochondrial dysfunction resembling MADD 1.
• Symptoms suggesting metabolic dysfunction in a patient on sertraline should be evaluated independently 1.

Recommendation

Sertraline can be used as prescribed without concern for developing MADD, as the current evidence does not support a link between sertraline use and the development of MADD 1. However, it is essential to monitor patients for any adverse effects and evaluate symptoms suggesting metabolic dysfunction independently.

From the Research

Association between Sertraline Use and MADD

• The use of sertraline has been associated with the development of a MADD-like pattern of acylcarnitines in some patients, as reported in a study published in Molecular genetics and metabolism reports 2.
• This study presented two cases of patients with biochemical profiles mimicking late-onset MADD, but with negative genetic testing, and whose symptoms improved after discontinuation of sertraline.
• Another study published in Annals of neurology found that all 7 patients with late-onset MADD without disease-causing mutations were treated with sertraline, suggesting a possible acquired form of MADD induced by the drug 3.
• The study also found that discontinuation of sertraline resulted in an improved acylcarnitine profile in some cases, and that riboflavin treatment was effective in normalizing creatine kinase and muscle biopsy findings.

Clinical Implications

• These findings suggest that sertraline may be associated with a potentially reversible form of mitochondrial dysfunction mimicking MADD, and that metabolic physicians should consider sertraline use in the differential diagnosis of MADD, particularly when genetic testing is negative 2, 3.
• The use of sertraline has been extensively studied in the treatment of mood and anxiety disorders, and has been found to be safe and well tolerated in numerous patient populations 4.
• However, the potential association between sertraline use and MADD highlights the need for further studies to confirm and estimate the risk of MADD-like presentations with the use of sertraline, as well as to identify additional contributing factors, including genetic factors 2, 3.

Diagnosis and Treatment of MADD

• MADD is a rare genetic disease involving fatty acid oxidation, and its diagnosis is typically established by characteristic abnormalities of acylcarnitine profile by tandem mass spectrometry 5.
• Treatment with riboflavin and L-carnitine has been found to be effective in improving clinical symptoms and normalizing acylcarnitine profiles in patients with MADD 5, 6.
• In cases of late-onset MADD, treatment with riboflavin and carnitine has been found to be beneficial in improving muscle weakness and preventing cardiac syncope 6.