What is the most appropriate first-line medication for major depressive disorder?

• A. Amitriptyline
• B. Bupropion
• C. Fluoxetine
• D. Phenelzine

Answer: (C)

SSRIs are first-line for major depressive disorder because they offer a favorable balance of effectiveness and tolerability with a safer overdose profile compared with older antidepressants. Fluoxetine, a well-studied SSRI, is a common first-line choice due to its robust evidence base, once-daily dosing, and long half-life (which can reduce withdrawal symptoms if a dose is missed). It tends to be well tolerated, with side effects that are usually manageable, such as mild GI upset or sleep changes, and it has a lower risk of cardiotoxicity or fatal overdose than TCAs or MAOIs.

Amitriptyline is a tricyclic antidepressant with significant anticholinergic effects, sedation, weight gain, and a higher risk of dangerous cardiac arrhythmias in overdose, making it less suitable as a first-line option. Phenelzine is an MAOI with many dietary and drug interactions and dietary restrictions, reserved for treatment-resistant cases. Bupropion can be effective and is useful in patients with sexual dysfunction or weight concerns, but it is not universally first-line due to potential seizure risk and other considerations; SSRIs remain the typical initial choice.