I've taken fluoxetine (Prozac) for several years. But recently, the medicine doesn't seem to have the same effect. Can antidepressants stop working?
Answer From Simon Kung, M.D.
When depression symptoms improve after starting an antidepressant, many people need to continue taking the medicine a long time to keep symptoms from coming back.
For some people, an antidepressant may simply stop working over time. This is called antidepressant tolerance. Healthcare professionals don't fully understand what causes antidepressant tolerance, also called tachyphylaxis, to happen. They also aren't sure why it happens for some people and not others.
There also can be specific reasons an antidepressant no longer works, such as:
- Worsening depression. It's common for depression symptoms to come back or worsen at some point, even with treatment. This is called breakthrough depression. Symptoms may be triggered by stress or appear with no clear cause. The current dose of medicine may not be enough to ease symptoms when depression gets worse.
- Another medical condition. Underlying health conditions, such as hypothyroidism, can cause or worsen depression.
- A new medicine. Some medicines for conditions not related to depression can get in the way of how your body breaks down and uses an antidepressant. This can make the antidepressant less effective.
- Alcohol and other substance use. These also can make antidepressants less effective.
- Bipolar disorder not yet diagnosed. Bipolar disorder, formerly called manic depression, is a mental health condition that causes extreme mood swings that include depression. While an antidepressant is sometimes used to treat bipolar disorder, a mood-stabilizing or antipsychotic medicine generally is needed along with an antidepressant. This can keep emotional highs and lows in balance.
- Age. For some people, depression gets worse with age. As you get older, you may have changes in your brain and thinking that affect your mood. Hormone changes that occur with aging also can affect mood. And your body may not process medicines as well as it used to. You're likely to be taking more medicines too. Life changes, such as caring for aging parents, also can have an impact on mood. All these factors can play a role in depression.
For most people, depression symptoms get better again with changes to medicine. Your healthcare professional may recommend that you change the dose of your current antidepressant, change to another antidepressant, or add another antidepressant or other type of medicine to your current treatment. Don't make any changes without the advice of your doctor or other healthcare professional. Adding talk therapy, also called psychotherapy, to your treatment plan may help too.
There are many reasons depression treatment can stop working. It may help to see a doctor who specializes in diagnosing and treating mental health conditions, called a psychiatrist. Together you can decide on the best course of action.
Show References
- Jarrett RB, et al. Major depressive disorder in adults: Continuation and maintenance treatment. https://www.uptodate.com/contents/search. Accessed Jan. 15, 2025.
- Kamp CB, et al. Beneficial and harmful effects of tricyclic antidepressants for adults with major depressive disorder: A systematic review with meta-analysis and trial sequential analysis. BMJ Mental Health. 2024; doi:10.1136/bmjment-2023-300730.
- Fornaro M, et al. The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications. Pharmacological Research. 2019; doi:10.1016/j.phrs.2018.10.025.
- Kinrys G, et al. Tachyphylaxis in major depressive disorder: A review of the current state of research. Journal of Affective Disorders. 2019; doi:10.1016/j.jad.2018.10.357.
- Kung S (expert opinion). Mayo Clinic. Jan. 31, 2025.
Original article: https://www.mayoclinic.org/diseases-conditions/depression/expert-answers/antidepressants/FAQ-20057938