What Is the Best Antidepressant?

Choosing the right antidepressant is important. There are a vast array of antidepressants and knowing where to start can be confusing.

Here are five ways that I, as a psychiatrist, think about choosing an antidepressant:

1. Selective Serotonin Reuptake Inhibitors (SSRIs): These were revolutionary when they were introduced in the 1980s. Examples are fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro). SSRIs are well-tolerated, weight-neutral, mostly non-sedating, and are safe in children, the elderly, and after medical illnesses such as heart attacks. Sertraline (Zoloft) is an example of an SSRI that is commonly used in pregnancy and breastfeeding. Certain people may have a genetic variant that makes them less likely to respond to these SSRIs and genetic testing via a cheek swab can be helpful.
2. Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): These were the next generation of antidepressants after SSRIs. They work via serotonin and norepinephrine, so they have a dual mechanism of action. Examples are venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta), and milnacipran (Savella). I like the dual mechanism of action because the depression pathway involves numerous neurotransmitters, not just serotonin. I also like that SNRIs can help pain symptoms, especially nerve pain and the aches and pains of depression and fibromyalgia, which the SSRIs typically don’t. Side effects are similar to the SSRIs above.
3. Sedating Antidepressants: These include mirtazapine, trazodone, and doxepin. For many patients with depression, improving sleep is a priority and these medications can really help insomnia from the get-go because they are sedating.
4. Ketamine and Esketamine: Intravenous infusions of ketamine or esketamine (Spravato) nasal spray are newer treatments. These work faster than regular antidepressants, so that’s a game-changer. They are also useful for treatment-resistant depression where a person has not responded adequately to previous antidepressants and suicidal thoughts. Blood pressure needs to be monitored for about two hours so that can be challenging for patients who work. Spravato is only prescribed by certified Spravato treatment centers such as mine.
5. Antidepressants without sexual side effects: In some people, SNRIs and SSRIs can impact libido, erection, and orgasm and, while there are workarounds, it can be troublesome. Uniquely, bupropion (Wellbutrin) works via dopamine and has no sexual side effects. It can help with ADHD and smoking cessation. Bupropion can rarely increase the risk of seizures and people who drink alcohol should be careful because alcohol also increases the risk of seizures.

Antidepressants are an amazing tool and, in my opinion, one of the greatest inventions of the 20th century. It’s not, however, all about medications.

Targeting the triggers for depression, addressing loss, improving work and relationships, reducing alcohol and cannabis, and pursuing a healthy lifestyle are also helpful.

Depression may actually be an opportunity to rethink and grow. Seeing depression from this perspective is easier said than done but meaningful change can be liberating. The right antidepressant can be the first step along a new pathway of hope.

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