How Do Antidepressants Work? What Is Known and What Is Not

The short answer

The National Institute of Mental Health (NIMH) says antidepressants work by changing how the brain produces or uses certain chemicals involved in mood or stress. MedlinePlus uses careful wording too: researchers think antidepressants may help improve the way your brain uses certain chemicals that control mood or stress.

Notice the words "think" and "may." Science has a useful working picture of these medicines, and it is still incomplete. Knowing that can be a relief. If you were told that depression is simply a chemical shortage that a pill refills, the research picture is less tidy than that.

What FDA labels say about specific medicines

Each FDA label has a section called Mechanism of Action, and reading a few side by side is revealing. Some describe an action in the brain. Others say outright that the reason the medicine helps depression is not known.

• Sertraline, an SSRI. The label says it increases serotonin activity in the central nervous system by blocking the reuptake of serotonin into nerve cells.
• Venlafaxine, an SNRI. The label says its mechanism is unclear, but is thought to be related to boosting serotonin and norepinephrine by blocking their reuptake.
• Bupropion. The label says its mechanism is unknown, "as is the case with other antidepressants," and is presumed to involve norepinephrine, dopamine or both. It does not block the reuptake of serotonin.
• Esketamine. The label says it blocks a receptor for a brain chemical called glutamate, and that the way it produces an antidepressant effect is unknown. It is given only in a certified healthcare setting, so it is not something an online visit can provide.

What reuptake means

Nerve cells pass messages using chemicals, and reuptake is the step where a nerve cell takes a chemical back in. Medicines called reuptake inhibitors act on that step, which is where the names SSRI and SNRI come from. The labels above describe this for sertraline and venlafaxine.

It would be easy to read this as a simple story: block reuptake, feel better. The venlafaxine and bupropion labels are more cautious than that, using words like "unclear," "thought to be" and "presumed." So treat this as a description of what the medicine does in the brain, and not as a full explanation of why a person's mood lifts.

What this does and does not tell you

How a medicine acts does not predict how you will respond. MedlinePlus says our bodies and brains work differently, so one antidepressant will not work for everyone, and you may need to try two or more before finding one that works for you. It also says each type works differently.

Mechanism is also not a reason to prefer one medicine over another. Choosing is a decision for you and your prescriber, based on things like your symptoms, your other medicines and your health. Our medicine library has separate pages on sertraline and bupropion, including what each is approved for.

Depression itself is more than brain chemistry. NIMH says research suggests genetic, biological, environmental and psychological factors play a role. It also says psychotherapy can help by teaching new ways of thinking and behaving, which is one reason many treatment plans include depression therapy alongside medicine or instead of it.

Why the safety information still matters

An incomplete explanation of how a medicine helps does not mean its risks are unknown. Antidepressant labels carry a boxed warning that these medicines increased the risk of suicidal thoughts and behaviors in children, teens and young adults, and that everyone taking one should be closely monitored for worsening or new suicidal thoughts. The labels for sertraline and venlafaxine also warn of serotonin syndrome, and say they must not be taken with an MAOI. Tell your prescriber about everything you take.

If you are in crisis, call or text 988, or call 911. Locascio Wellness does not provide emergency services.

Talking this through with us

If you have questions about how a medicine might act, a psychiatrist is a good person to ask. A licensed psychiatrist on our team, a Doctor of Osteopathic Medicine with more than three decades of practice, offers online depression treatment by secure video. You must be physically located in Pennsylvania or New York during each visit.

Whether a medicine is an option for you is a decision for you and your prescriber. Ask us whether our psychiatrist can help, using our medication care contact form. Our therapists do not prescribe, and they see clients in Pennsylvania, West Virginia, Arizona, Colorado and Florida, not New York.