What is the appropriate use and dosage of Valdoxan (agomelatine) for adults with major depressive disorder, particularly those with a history of liver disease?

Valdoxan (Agomelatine) Use in Major Depressive Disorder

Valdoxan (agomelatine) is NOT recommended as a first-line antidepressant for major depressive disorder, particularly in patients with liver disease, due to significant hepatotoxicity concerns and lack of availability in the United States. 1, 2

Critical Contraindication: Liver Disease

• Agomelatine is absolutely contraindicated in patients with any history of liver disease due to documented hepatotoxic reactions, with liver injury rates reaching 4.6% compared to 0-2.1% for other antidepressants 2
• Liver function tests (LFTs) are mandatory before starting treatment and must be monitored throughout therapy according to European regulatory requirements 1
• A dose-dependent relationship exists between agomelatine and liver injury risk, making higher doses particularly dangerous 2

First-Line Treatment Alternatives

For adults with major depressive disorder, second-generation antidepressants (SSRIs/SNRIs) or cognitive behavioral therapy should be selected instead 3, 4

Preferred Medications:

• Citalopram, escitalopram, sertraline, mirtazapine, or venlafaxine are recommended first-line options with superior safety profiles 3
• These agents have demonstrated modest superiority over placebo with number needed to treat of 7-8 for SSRIs 3
• Treatment selection should be based on cost, patient preference, and adverse effect profile 3

Agomelatine-Specific Dosing (If Used in Europe)

For the rare situation where agomelatine is prescribed in European markets:

Standard Dosing:

• 25-50 mg daily is the effective dose range for major depressive episodes in adults 5, 6
• Start at 25 mg and titrate based on response and liver function monitoring 6

Switching Considerations:

• When switching TO agomelatine: taper the previous antidepressant to minimize discontinuation symptoms 1
• Never combine with fluvoxamine due to pharmacological interactions 1
• When switching FROM agomelatine: can be stopped abruptly as it causes no significant discontinuation symptoms 1

Clinical Pitfalls to Avoid

• Do not prescribe agomelatine without establishing baseline liver function and committing to ongoing monitoring 1, 2
• Agomelatine is not approved by the FDA and is unavailable in the United States; it is only licensed by the European Medicines Agency 1, 5
• The lower liver injury rates seen in non-interventional studies likely reflect selective prescribing due to European risk minimization measures, not true safety 7
• Risk of acute liver injury appears lower than initially feared when compared to citalopram in real-world settings (OR 0.48), but this may reflect careful patient selection rather than inherent safety 7

Treatment Duration

• 4-12 months for initial episode of major depression 3
• Patients with recurrent depression may require prolonged treatment 3