agomelatine

Action and Spectrum

Actions and spectrum: 

Action: 

• Melatonergic Agonist: agomelatine primarily acts as an agonist at melatonin receptors (MT1 and MT2) and as an antagonist at serotonin (5-HT2C) receptors. By stimulating melatonin receptors, agomelatine helps regulate the circadian rhythm and sleep-wake cycle. This action is thought to contribute to its antidepressant effects, as disruptions in circadian rhythms are often associated with mood disorders. 
• Serotonin Antagonism: agomelatine also inhibits the activity of serotonin (5-HT2C) receptors. This dual action on melatonin and serotonin receptors is distinctive and sets agomelatine apart from other antidepressants. By antagonizing serotonin receptors, agomelatine indirectly influences the release of dopamine and norepinephrine, which play a role in mood regulation. 

Spectrum: 

• Major Depressive Disorder (MDD): agomelatine is primarily used to alleviate symptoms of major depressive disorder, including loss of interest, changes in appetite, fatigue, and feelings of worthlessness. 
• Prevention of Relapse: In some cases, agomelatine may be used to prevent the recurrence of depressive episodes in individuals with recurrent MDD. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Nausea 

Headache 

Insomnia 

Paresthesia 

Diarrhea 

Upper abdominal pain 

Eczema 

Back pain 

increased ALT/AST 

Anxiety 

Hypomania 

Pruritus 

Drowsiness 

Irritability 

Hallucinations 

Hepatic failure 

Weight gain 

Dizziness 

Somnolence 

Migraine 

Blurred vision 

Constipation 

Hyperhidrosis 

Erythema 

Fatigue 

Hepatitis 

Suicidal tendencies 

Agitation 

Mania 

Aggression 

Restlessness 

Vomiting 

Jaundice 

Weight los 

Black Box Warning

Black Box Warning: 

There were no specific black box warnings associated with agomelatine.  

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: Individuals with a known hypersensitivity or allergy to agomelatine or any of its components should not use the medication. 
• Severe Liver Disease: agomelatine is metabolized in the liver, and individuals with severe liver impairment or liver disease should avoid its use. It is contraindicated in patients with hepatic impairment, particularly severe impairment, due to the risk of increased exposure to the drug. 
• History of Abnormal Liver Function Tests: If an individual has had recent abnormal liver function tests or currently has liver issues, the use of agomelatine may not be recommended. 
• Pregnancy and Lactation: Its use during pregnancy and breastfeeding should be carefully considered, and potential risks and benefits should be discussed.

Caution: 

• Co-administration with CYP1A2 Substrates: agomelatine is a moderate inhibitor of the enzyme CYP1A2. It affects the metabolism of other drugs metabolized by this enzyme. Caution should be exercised when agomelatine is used in combination with medications metabolized by CYP1A2, as it may alter their blood levels. 
• Suicidal Ideation: As with many antidepressant medications, individuals taking agomelatine, especially those with major depressive disorder, should be monitored for suicidal ideation or worsening of depressive symptoms. Close supervision and regular follow-up are essential during treatment. 
• Renal Function: While agomelatine is primarily metabolized in the liver, its use should be approached with caution in individuals with renal impairment due to the potential for interactions or variations in its pharmacokinetics. 
• Psychiatric Disorders: Individuals with a history of other psychiatric disorders, such as bipolar disorder or anxiety disorders, should use agomelatine cautiously. The medication’s effects on mood and symptoms should be monitored closely.

Comorbidities: 

• Anxiety Disorders: The Generalized anxiety disorder or social anxiety disorder, frequently coexist with MDD. agomelatine may be considered in individuals with comorbid anxiety and depression. 
• Bipolar Disorder:  bipolar disorder may experience depressive episodes, which can be similar in presentation to MDD. agomelatine may be used with caution in individuals with bipolar disorder to manage depressive symptoms, but mood-stabilizing medications are typically the first-line treatment for bipolar depression. 
• Sleep Disorders: Sleep disturbances, including insomnia and circadian rhythm disruptions, are common in individuals with depression. agomelatine’s action on circadian rhythms and sleep-wake cycles may make it a suitable option for individuals with comorbid sleep disorders. 
• Substance Use Disorders: Substance abuse or dependence may co-occur with depression. The treatment of substance use disorders may involve addressing both the addiction and any underlying depressive symptoms. 

Pregnancy / Lactation

Pregnancy consideration: pregnancy category: not assigned 

Lactation: excreted into human milk: unknown  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.   
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

agomelatine is a unique antidepressant with a distinct pharmacological profile. Its primary mechanism of action involves acting as an agonist at melatonin receptors (MT1 and MT2) and as an antagonist at serotonin receptors. By stimulating melatonin receptors, agomelatine helps regulate the circadian rhythm and sleep-wake cycle, which is believed to be crucial in managing mood disorders like depression.

Simultaneously, its antagonism of serotonin receptors indirectly influences the release of dopamine and norepinephrine, which play a role in mood regulation. This dual mechanism sets agomelatine apart from traditional antidepressants. It is known for its potential to address depression symptoms while also improving sleep patterns, making it an option for individuals with mood disturbances related to disruptions in their sleep-wake cycle.  

Pharmacodynamics: 

• Melatonergic Agonism: agomelatine is a potent agonist at melatonin receptors, specifically MT1 and MT2 receptors. This action is like the natural hormone melatonin, which helps in regulating circadian rhythm and the sleep-wake cycle. agomelatine’s melatonergic effects contribute to its role in improving sleep patterns and restoring circadian rhythms in individuals with mood disorders, particularly depression. 
• Serotonin Receptor Antagonism: agomelatine acts as an antagonist at serotonin 5-HT2C receptors. This serotonin antagonism indirectly influences the release of other neurotransmitters, including dopamine and norepinephrine, in specific brain regions. By modulating the balance of these neurotransmitters, agomelatine exerts its antidepressant effects. 
• Circadian Rhythm Stabilization: The regulation of circadian rhythms and sleep-wake cycles is a unique feature of agomelatine. By synchronizing the body’s internal clock and improving sleep quality, it helps address mood disturbances associated with circadian rhythm disruptions. 
• Antidepressant Efficacy: agomelatine’s combined actions on melatonin and serotonin receptors are thought to contribute to its antidepressant efficacy. It can alleviate symptoms of major depressive disorder (MDD), such as persistent sadness, loss of interest or pleasure, changes in appetite and sleep patterns, fatigue, and feelings of worthlessness.

Pharmacokinetics: 

Absorption 

agomelatine is administered orally in the form of tablets. It is well-absorbed from the gastrointestinal tract after oral ingestion. 

Distribution 

agomelatine has moderate plasma protein binding, meaning that a significant portion of the drug binds to proteins in the bloodstream and is not readily available to exert its effects. agomelatine is distributed throughout the body, including the brain, where it exerts its effects on melatonin and serotonin receptors. 

Metabolism 

agomelatine undergoes extensive hepatic (liver) metabolism. It is primarily metabolized by the liver’s cytochrome P450 enzymes, including CYP1A2 and CYP2C9, resulting in the formation of several metabolites. 

Elimination and excretion 

agomelatine and its metabolites are excreted from the body primarily through the urine and feces. A small portion of the drug may be eliminated in the urine unchanged, while the majority is excreted as metabolites. The elimination half-life of agomelatine is short, 1-2 hours. This short half-life allows for flexibility in dosing and the potential for once-daily administration. 

Adminstartion

Administration: 

• Dosage: The dosage of agomelatine is determined by the healthcare provider based on the individual’s specific condition, the severity of depression, and their response to treatment. It is essential to follow the prescribed dosage instructions carefully. 
• Oral Administration: agomelatine is taken by mouth, and the tablets should be swallowed whole with a glass of water. They should not be crushed, broken, or chewed unless specifically instructed by the healthcare provider. 
• Timing: agomelatine is typically taken once daily, usually in the evening, shortly before bedtime. This timing is intended to align with its role in regulating circadian rhythms and improving sleep patterns. However, specific dosing instructions should be followed as directed by the healthcare provider. 
• Duration: The duration of agomelatine treatment depends on the individual’s condition, response to treatment, and the healthcare provider’s assessment. It is often prescribed for several weeks or months to address depressive symptoms effectively. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: agomelatine 

Pronounced: (uh-go-MEL-uh-teen)  

Why do we use agomelatine? 

agomelatine is indicated for the treatment of major depressive disorder, a common and severe form of depression. It is used to alleviate the symptoms of MDD, which may include loss of interest, persistent sadness, changes in appetite and sleep patterns, fatigue, feelings of worthlessness, and difficulty concentrating.