Agomelatine, Side Effects

Agomelatine is an atypical antidepressant that has gained attention for its innovative approach to treating major depression in adults. Unlike traditional antidepressants, such as selective serotonin reuptake inhibitors, agomelatine acts as an agonist at melatonin receptors (MT1 and MT2) and an antagonist at serotonergic 5-HT2C receptors, allowing it to regulate circadian rhythms and improve mood without directly altering serotonin levels. This unique mechanism not only addresses the emotional symptoms of depression but also improves sleep quality, a critical aspect of overall well-being.
However, as with any medication, understanding its side effects and necessary precautions is essential to ensure safe and effective treatment. Below, we explore agomelatine's side effects, the biochemical processes involved, and practical measures to minimize risks, integrating a holistic approach that combines pharmacology, nutrition, and lifestyle.
Agomelatine can cause a variety of side effects, some of which are related to its action on neurotransmitters and biological rhythms. One of the most common effects is gastrointestinal discomfort, such as nausea, diarrhea, or abdominal pain. These symptoms are usually mild and transient, but reflect the drug's influence on the digestive system, possibly due to the modulation of serotonergic receptors, which are also found in the gastrointestinal tract. These receptors regulate intestinal motility and secretion, and their blockage by agomelatine can temporarily alter these processes.

In some cases, patients report dizziness or headaches, which are linked to changes in the release of dopamine and norepinephrine in the frontal cortex, affecting the central nervous system. These neurotransmitters are essential for attention and mood, but their modulation can cause neurological discomfort at the beginning of treatment.

Less commonly, agomelatine may induce drowsiness or insomnia, a reflection of its action on circadian rhythms through melatonin receptors. These effects on the circadian system can disrupt the sleep-wake cycle, especially in the first few weeks, while the body adapts. Fatigue may also occur, which could be related to the decrease in body temperature induced by the activation of MT1 and MT2 receptors, a process that mimics the natural action of melatonin.

Rarely, more serious effects have been reported, such as liver damage, manifested by elevations of liver enzymes (ALT and AST). This risk is associated with agomelatine's metabolism in the liver, where the cytochrome P450 system (specifically CYP1A2) processes the drug. Hepatotoxicity can cause symptoms such as jaundice, unusual fatigue, or severe abdominal pain, underscoring the importance of monitoring liver function.

In rare cases, agomelatine may affect the emotional system, with rare reports of suicidal thoughts or aggressive behavior, particularly in patients with a history of bipolar disorder or suicidal ideation. These effects are related to the modulation of the neurotransmitters dopamine and norepinephrine, which influence mood and impulsivity.

Furthermore, skin reactions, such as eczema, have been documented, which could be linked to mild immune responses triggered by the drug or its metabolites, affecting the integumentary system. In the musculoskeletal system, back pain is an occasional side effect, possibly related to muscle tension induced by changes in the nervous system or posture during sleep. Finally, hyperhidrosis (excessive sweating) can affect the sudoriferous system, likely as a side effect of autonomic nervous system stimulation.
Drug interactions are a critical consideration with agomelatine.
The concomitant use of potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin, is contraindicated, as these drugs significantly increase agomelatine plasma concentrations, increasing the risk of liver toxicity. Moderate inhibitors, such as propranolol, require caution.

Smoking, by inducing CYP1A2, may reduce the drug's efficacy, while quitting smoking may increase its concentration, requiring adjustments in medical monitoring. No significant interactions have been reported with lithium, alcohol, alprazolam, paroxetine, or fluconazole, which offers some flexibility in therapeutic combinations.
To minimize risks, patients should follow strict precautions. Liver function tests are essential before starting treatment and periodically (at 3, 6, 12, and 24 weeks), and the drug should be discontinued if liver enzymes exceed three times the upper limit of normal. Patients with liver impairment, obesity, diabetes, or high alcohol consumption should be carefully evaluated, as these factors increase the risk of hepatotoxicity.
Agomelatine is contraindicated in patients over 75 years of age due to a lack of safety data in this group and in patients with severe renal impairment, where clinical data are limited. Pregnant or breastfeeding women should avoid its use, as metabolites are excreted in breast milk in animal studies, and safety in humans has not been established.
Agomelatine is primarily prescribed for the treatment of major depressive episodes in adults. Its ability to regulate circadian rhythms also makes it useful in the management of sleep disorders associated with depression, such as insomnia, and it may have benefits in conditions related to circadian disruptions, such as seasonal affective disorder. Although not officially approved for other uses, research suggests potential in the treatment of generalized anxiety and as a neuroprotector against oxidative stress, although these uses require further study.
The drug is administered orally, at an initial dose of 25 mg once daily before bedtime, to take advantage of its effect on the sleep-wake cycle. If there is no improvement after two weeks, the dose can be increased to 50 mg (two 25 mg tablets) under medical supervision. No tapering is required upon discontinuation of treatment, unlike with selective serotonin reuptake inhibitors, which reduces the risk of withdrawal symptoms.

No special diet is specified, but it is recommended to avoid excessive alcohol consumption, as it may increase the risk of liver damage. Patients should inform their doctor about any supplements or medications they are taking to avoid interactions. If a dose is missed, it should be taken as soon as remembered, but the dose should not be doubled to make up for it. Agomelatine should be stored at room temperature, away from moisture and heat, and disposed of according to local drug disposal regulations, avoiding disposal of it in the drain or regular trash.
In case of overdose, symptoms may include confusion, extreme drowsiness, or abdominal pain. It is crucial to seek immediate medical attention by contacting a poison control center or going to the emergency room. Additionally, patients should be alert for signs of liver damage, such as dark urine, jaundice, or unusual fatigue, and report them immediately.
The most well-known brand names of agomelatine include Valdoxan® and Thymanax®. There are no approved combination products that include agomelatine, which simplifies administration but requires vigilance in polypharmacy.

Agomelatine is a valuable option for treating major depression, with additional benefits in sleep regulation thanks to its action on melatonin and serotonin receptors. However, its side effects, which primarily affect the digestive, nervous, circadian, emotional, integumentary, musculoskeletal, sweat, and hepatic systems (in rare cases), require careful monitoring.

Gastrointestinal discomfort, dizziness, sleep disturbances, and the risk of hepatotoxicity are the most relevant, but most are manageable with monitoring and lifestyle adjustments. A balanced diet rich in antioxidants (such as fruits and vegetables) can support liver function, while regular physical activity and a consistent sleep schedule reinforce the drug's circadian benefits. Avoiding alcohol and smoking is crucial to minimize risks and optimize treatment efficacy.

For safe use, patients should work closely with their physician, undergo regular liver tests, and report any unusual symptoms. This approach not only reduces risks, but also empowers patients to take control of their mental health and overall well-being.