I. Mechanism of Action and Characteristics of Agomelatine
Agomelatine is a novel antidepressant that functions as a long-acting melatonin receptor agonist and 5-HT2C receptor antagonist. It possesses multiple therapeutic effects including antidepressant, anxiolytic, sleep rhythm regulation, and circadian clock modulation. Clinically, it is commonly used to treat depression, anxiety disorders, depression with sleep disturbances, sleep disorders, and other neurological conditions, demonstrating significant efficacy, good safety profile, and low risks of addiction and drug resistance.

The mechanism of agomelatine differs from traditional antidepressants, primarily acting through two pathways:

1. Melatonin Receptor Agonism
   Melatonin, secreted by the pineal gland, plays a vital role in regulating circadian rhythms and maintaining healthy sleep as a neurotransmitter. As a long-acting melatonin receptor agonist, agomelatine activates melatonin receptors to regulate circadian rhythms, promote normal sleep-wake cycles, and restore biological clock function, thereby improving sleep cycle disorders and depression-related sleep disturbances.

2. 5-HT2C Receptor Antagonism
   The 5-HT2C receptor, a subtype of serotonin receptors widely distributed in the cerebral cortex, limbic system, and other CNS regions, inhibits the release of norepinephrine and dopamine when activated, potentially leading to depressive symptoms like low mood and lack of motivation. As a 5-HT2C receptor antagonist, agomelatine blocks receptor activation, promoting the release of norepinephrine and dopamine in the cerebral cortex and other brain regions, thereby alleviating abnormal emotions such as depression and anxiety and improving mental state.

Pharmacological characteristics of agomelatine include:

• It helps regulate circadian rhythms and improve sleep disorders without causing daytime drowsiness, unlike traditional antidepressants, and has fewer adverse effects.

• Due to low bioavailability and hepatic first-pass effects, higher doses per administration are required.

• With a half-life of 4–6 hours, it is recommended to take once daily before bedtime.

• Metabolized primarily in the liver and excreted via urine, long-term use may still cause liver and kidney damage.

II. Clinical Applications of Agomelatine
Given its unique dual mechanisms (antidepressant/anxiolytic and sleep-regulating effects), agomelatine has broad clinical applications beyond depression, including sleep disorders and circadian rhythm disruptions. Dosage and treatment duration vary by condition and should be administered under medical supervision.

1. Depression
   Depression, a common mood disorder, manifests as low mood, loss of interest, and appetite changes. Agomelatine alleviates symptoms by inhibiting 5-HT2C receptor activity, improving mood and sleep quality. Clinical studies show it significantly reduces depressive symptoms and scores on depression scales, with fewer side effects (e.g., lower rates of sexual dysfunction and weight gain) compared to traditional antidepressants.

2. Mild-to-Moderate Sleep Disorders
   Sleep disturbances (e.g., insomnia, early awakening) often accompany depression. Agomelatine’s melatonin receptor agonism regulates sleep-wake cycles, effectively improving sleep quality, reducing sleep latency, increasing total sleep time, and decreasing nighttime awakenings, with minimal daytime sedation and no significant dependence.

3. Anxiety Disorders
   Frequently comorbid with depression, anxiety disorders involve excessive worry, tension, or fear. Agomelatine modulates neurotransmitters (especially norepinephrine and dopamine), effectively reducing anxiety symptoms without pronounced sedation, making it suitable for long-term use.

4. Seasonal Affective Disorder (SAD)
   SAD, typically occurring in winter, presents with low mood, fatigue, and sleep disturbances. Agomelatine’s melatonin receptor agonism makes it a potential treatment, with studies confirming its efficacy in improving mood, sleep quality, and circadian rhythm synchronization.

5. Circadian Rhythm Sleep Disorders
   These disorders involve misalignment between sleep-wake cycles and environmental light-dark cycles (e.g., shift work, jet lag), leading to poor sleep, daytime drowsiness, and cognitive impairment. Agomelatine effectively resynchronizes circadian rhythms, enhancing sleep quality.

III. Is Long-Term Use of Agomelatine Advisable? Potential Adverse Effects
While effective for depression, anxiety, and sleep disorders, long-term agomelatine use is not recommended due to potential risks:

• Hepatotoxicity: Liver-dependent metabolism may cause elevated liver enzymes, jaundice, or severe liver dysfunction; regular monitoring is essential.

• Worsened mood symptoms: Rare cases of increased anxiety, depression, or irritability, especially with improper dosing.

• Sexual dysfunction: Possible reduced libido in isolated cases.

• Weight gain: May stimulate appetite in some patients.

IV. Guidelines for Safe Use (5 Key Points)

1. Dosage: Initial dose adjustment based on response; max 50 mg/day (exceeding increases hepatotoxicity risk). Swallow tablets whole; monitor liver function regularly.

2. Adverse reactions: Common CNS effects (dizziness, nausea, fatigue); GI symptoms; rare hepatotoxicity or sexual dysfunction. Discontinue if liver abnormalities occur.

3. Contraindications: Severe liver impairment, age <18 (safety unestablished), pregnancy/lactation, hypersensitivity. Elderly: start low, monitor renal/hepatic function.

4. Drug interactions: Avoid CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin), ketoconazole (↑ plasma levels), alcohol (↑ hepatotoxicity/CNS effects), and sedatives (↑ drowsiness).

5. Combination therapy: May augment other antidepressants for severe depression or short-term anxiolytics (e.g., alprazolam) for acute anxiety.

V. Summary
Agomelatine, a multitarget antidepressant, addresses modern challenges like sleep disorders, mild anxiety, and depression—particularly prevalent among youth. By modulating melatonin and 5-HT2C receptors, it restores sleep cycles and alleviates mood symptoms. However, long-term use requires vigilance for hepatotoxicity, dizziness, or nausea, necessitating physician-supervised liver tests and dose adjustments. Patients must seek specialist evaluation to balance safety and efficacy, reporting any adverse effects promptly for optimal outcomes.