The most commonly prescribed medications for depression are SSRIs, a class of antidepressants that includes well-known names like Prozac, Zoloft, and Lexapro. But SSRIs are just one of several options. Doctors choose from multiple classes of antidepressants based on your symptoms, how you respond to treatment, and what side effects you want to avoid.
SSRIs: The Most Common Starting Point
Selective serotonin reuptake inhibitors, or SSRIs, are typically the first medication prescribed for depression. They work by blocking brain cells from reabsorbing serotonin after it delivers a signal, leaving more of it available to pass messages between cells. This boost in serotonin activity helps regulate mood over time.
The FDA has approved five SSRIs for depression:
- Fluoxetine (Prozac)
- Sertraline (Zoloft)
- Escitalopram (Lexapro)
- Citalopram (Celexa)
- Paroxetine (Paxil)
SSRIs are popular because they tend to cause fewer serious side effects than older antidepressants. That said, they’re not side-effect-free. Common issues include nausea, headaches, sedation, agitation, and sexual dysfunction. Sexual side effects in particular are one of the most frequent reasons people switch to a different medication.
SNRIs: A Dual-Action Alternative
Serotonin and norepinephrine reuptake inhibitors work similarly to SSRIs but target two brain chemicals instead of one. By blocking the reabsorption of both serotonin and norepinephrine, they keep both active in the brain longer. Norepinephrine plays a role in energy, alertness, and concentration, so SNRIs can be a good fit when depression comes with significant fatigue or difficulty focusing.
Common SNRIs include:
- Venlafaxine (Effexor)
- Duloxetine (Cymbalta)
- Desvenlafaxine (Pristiq)
- Levomilnacipran (Fetzima)
Duloxetine is also frequently prescribed for chronic pain conditions, making it a practical choice when depression and pain overlap.
Atypical Antidepressants
Several antidepressants don’t fit neatly into the SSRI or SNRI categories. These are sometimes called “atypical” antidepressants, and each works through a different mechanism.
Bupropion (Wellbutrin) targets dopamine and norepinephrine rather than serotonin. This distinction matters because bupropion has significantly lower rates of sexual dysfunction compared to SSRIs like fluoxetine, paroxetine, and sertraline. It’s often chosen for people who experienced sexual side effects on other antidepressants or who want to avoid them. Bupropion also tends not to cause weight gain, which sets it apart from many other options.
Mirtazapine (Remeron) works through a different pathway that affects serotonin, histamine, and other receptors. Research involving seven clinical trials found it has a faster onset of action compared to several common SSRIs, including fluoxetine and sertraline. The tradeoff is that it commonly causes increased appetite and drowsiness, so it’s sometimes prescribed specifically for people whose depression involves insomnia and weight loss.
Trazodone affects serotonin receptors and is notably sedating. In fact, clinical trials showed higher rates of sleepiness with trazodone than with most other antidepressants. While it’s approved for depression, it’s very commonly prescribed at lower doses as a sleep aid.
Older Antidepressants: TCAs and MAOIs
Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) were among the first medications developed for depression. They’re effective, but they’ve largely been replaced by newer drugs that are safer and cause fewer side effects.
MAOIs carry a unique restriction: they interact dangerously with foods high in an amino acid called tyramine. Aged cheeses, cured meats, draft beer, and other fermented or aged foods can cause dangerously high blood pressure spikes when combined with an MAOI. They also interact seriously with many common medications, including certain pain relievers and cold medicines. FDA-approved MAOIs include phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan), along with a skin patch form called selegiline (Emsam).
Because of these dietary and drug interactions, MAOIs are generally reserved for people who haven’t responded to other antidepressants.
How Long Antidepressants Take to Work
One of the most frustrating aspects of antidepressant treatment is the wait. Most standard antidepressants need at least six to eight weeks at an adequate dose before you can judge whether they’re working. Clinical trials evaluating antidepressant effectiveness typically run 8 to 12 weeks, and the FDA considers 6 to 8 weeks adequate for assessing a drug’s benefit.
That initial phase is just the beginning. Guidelines recommend continuing antidepressant therapy for an additional 4 to 9 months after symptoms improve during acute treatment. Stopping too soon increases the risk of relapse. Many people stay on antidepressants for a year or longer, and some take them indefinitely if depression is recurrent.
When Standard Medications Don’t Work
Treatment-resistant depression is diagnosed when at least two different first-line antidepressants, each taken at an adequate dose for at least six to eight weeks, fail to improve symptoms. This affects a significant portion of people with depression, and it opens the door to newer treatment approaches.
Esketamine (Spravato) is a nasal spray approved for treatment-resistant depression. It works on a completely different brain system than traditional antidepressants, blocking a receptor involved in glutamate signaling rather than targeting serotonin or norepinephrine. The experience of taking it is unlike a typical antidepressant pill. You receive it in a certified healthcare setting, not at home. After using the nasal spray, you’re monitored for at least two hours because it can cause sedation and dissociation (a feeling of being detached from yourself or your surroundings). You’ll need someone to drive you home afterward, and you’re advised not to drive or operate machinery until the next day after a full night’s sleep.
Auvelity is a newer oral medication that combines dextromethorphan (a compound that also acts on the glutamate system) with bupropion. In clinical trials, it showed a statistically significant difference from placebo as early as one week, which is notably faster than the typical six-to-eight-week timeline for most antidepressants. This faster onset makes it a compelling option for people who need quicker relief.
Side Effects Across Classes
Every antidepressant class carries a different side effect profile, and understanding the differences can help you have a more productive conversation about what to try. SSRIs and SNRIs commonly cause nausea, headaches, and sexual dysfunction. Bupropion avoids the sexual side effects but can increase anxiety or cause insomnia in some people. Mirtazapine and trazodone tend to cause drowsiness and weight gain. MAOIs require strict dietary monitoring. The side effect you’re least willing to tolerate often guides which medication makes sense to try first.
One safety note applies across the board. All antidepressants carry an FDA boxed warning about an increased risk of suicidal thoughts and behavior in children and adolescents. A combined analysis of clinical trials found that the rate of suicidal thinking or behavior in young people taking antidepressants was 4%, compared to 2% on placebo. This risk is highest during the first few months of treatment and during dose changes. Close monitoring during this period is standard practice, especially for anyone under 25.
Finding the Right Medication
Choosing an antidepressant is rarely a one-and-done process. The first medication prescribed works well for some people, but many need to try two or more before finding the right fit. Factors that influence the choice include your specific symptoms (fatigue vs. insomnia, appetite changes, anxiety), your tolerance for certain side effects, other medications you take, and whether you’ve tried antidepressants before.
If one class doesn’t work, switching to a different class or combining medications is common. Some people do well adding a second medication to boost the effect of the first. The process requires patience, since each new trial needs those six to eight weeks to show results. But the range of available options means that most people with depression can eventually find a medication, or combination, that meaningfully improves their symptoms.