Why Are My Antidepressants Not Working?

Common Reasons Your Meds May Not Be Helping Your Mood

Why antidepressant stops working

Verywell / Bailey Mariner

An antidepressant can work wonders for people dealing with symptoms like low mood, loss of interest in things they once enjoyed, ennui, and lack of energy. This is especially true of those who have moderate, severe, or chronic depression; mild depression isn't as responsive to medication.

However, an antidepressant is not a miracle cure, nor is it a permanent fix. Some studies suggest that the rate of relapse while using an antidepressant is about 23% during a two-year period.

Possible reasons why your antidepressant is no longer working include: using another medication that interferes with its effects, using alcohol or other drugs, having another medical condition, undergoing added stress, and more.

Understanding the reasons why antidepressants stop working can help you and your healthcare provider figure out what to do about it.

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Why Antidepressants Lose Effectiveness

There are several potential reasons for an antidepressant to stop working. Once you and your healthcare team have honed in on the reason (or reasons) you're no longer getting relief from your antidepressant, you'll be better able to make changes.

Starting a New Medication

It's common for drug interactions to interfere with how well medication works. In the case of antidepressants, possible culprits are antibiotics and steroids.

Both can make an antidepressant less effective. What's more, steroids can have a direct impact on your mood.

Next Steps

Discuss the medications you are taking, including prescription, over-the-counter, vitamins, and supplements, with all of your healthcare providers. This will help prevent drug interactions and enable your doctors to prescribe the best course of treatment for your physical and mental health.

Smoking and/or Drinking

Many people experiencing depression use nicotine and alcohol. In addition to exacerbating symptoms of depression, both tobacco smoke and alcohol can interfere with the way antidepressants are metabolized in the body.

Interactions between alcohol and some antidepressants can be very serious, and even life-threatening. For example, drinking while taking a monoamine oxidase inhibitor (MAOI) can cause blood pressure to rise and potentially result in a stroke. Also, when alcohol and antidepressants are combined, the liver might not be able to successfully process toxins, resulting in fatal toxicity.

Next Steps

If you are using alcohol, nicotine, or any other illicit substance, be honest with your healthcare provider. Together, you can figure out a plan to treat both your depression and your addiction simultaneously.

Another Medical Condition

A secondary health problem, like diabetes or hypothyroidism, can independently cause depression and make it harder to respond to treatment. Other conditions that are known to trigger symptoms of depression include Alzheimer's disease, Parkinson's disease, pancreatic cancer, hepatitis C, and multiple sclerosis (MS).

Next Steps

If you've developed a separate health problem, visit your doctor to get a proper diagnosis and plan of treatment. Once you begin treatment for the other health condition, your antidepressant may become helpful again.


If your antidepressants are not working during pregnancy, it's possible you need your dosage adjusted. If your weight increases during pregnancy, your original dosage may no longer be effective. Talk to a doctor if you are taking antidepressants while pregnant or while you're planning to become pregnant, as some are safer than others during pregnancy.

Added Stress

Work pressure? Family issues? Big changes in your daily life, such as a move or a new job? Any type of added stress can alter your brain chemistry enough to counteract the effects of your antidepressant and cause breakthrough symptoms of depression.

Next Steps

If stress is an issue, psychotherapy or counseling can be a useful addition to your depression treatment.

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Changes in metabolism and body composition in older adults can have an impact on how well medications are absorbed, metabolized, distributed, and removed from the body—which can impact the effectiveness of the medication.

For example, the digestive system becomes slower with age, causing a possible delay in the action of the medication. A decrease in liver function can make it harder for the body to break down medications. It's also common for people who are older to take medications for multiple health conditions, which can also impact how an antidepressant works.

Next Steps

Discuss the pros and cons of taking antidepressants as you age with your doctor, as well as any adjunct therapies like cognitive behavioral therapy that can help balance any delays or sensitivities to medications.

Undiagnosed Bipolar Disorder

Sometimes, the loss of effectiveness of an antidepressant may actually be due to the cyclic change in mood that's characteristic of bipolar disorder. For people with bipolar disorder, an antidepressant can induce mania and make symptoms worse.

Next Steps

If you have any symptoms of mania or hypomania, it's important to talk to your doctor and perhaps undergo testing to see if you may have bipolar disorder rather than major depressive disorder. If you have bipolar disorder, you may be prescribed a mood stabilizer or antipsychotic medication in addition to your antidepressant.


When medication no longer works as well for someone as it did when they first started taking it, that person is said to have developed a tolerance for the drug. The medical term for decreased effectiveness of the medication is tachyphylaxis, although some people refer to it as "Prozac poop-out."

This phenomenon can occur with any selective serotonin reuptake inhibitor (SSRI) used to treat depression. Studies suggest that 25% of people taking an SSRI will notice a decrease in effectiveness over time.

While no one knows for sure why these medications lose their effectiveness over time, one theory is that the receptors in the brain become less sensitive to the medication. Besides Prozac (fluoxetine), other common SSRIs prescribed for depression include:

Next Steps

If you've built a tolerance to an SSRI, your doctor may discuss making changes to your prescription (such as increasing the dose), adding another medication (like buspirone), switching you to a different class of antidepressant, adding psychotherapy or counseling to your treatment plan, or making lifestyle changes that may help with depression.

Delayed Effects

It's not uncommon for an antidepressant to make you feel worse before you feel better.

If you just started taking an antidepressant, it's possible its effects will take a few weeks to kick in. You might be feeling worse because of the side effects of an antidepressant—such as anxiety, fatigue, nausea, or weight gain. Some will go away on their own, but it's important to speak with a doctor about any side effects you experience.

Depending on the severity of the side effects, a doctor may change your dosage and/or medication type, or they may monitor you over the course of a few weeks to see if your symptoms improve.

Signs Your Antidepressant Isn't Working

How do you know your antidepressant isn't working? If you're experiencing a depression relapse, it's likely that your medication is no longer effective.

Depression relapse means a person who previously was responding well to an antidepressant begins to have symptoms of depression again—everything from feeling sad, irritable, or anxious to having thoughts of self-harm or physical pain.

If your antidepressants are not working for anxiety, you'll likely experience the symptoms of anxiety you had prior to taking medication or, in some cases, worsened symptoms.

If you are having suicidal thoughts, contact the National Suicide Prevention Lifeline at 988 for support and assistance from a trained counselor. If you or a loved one are in immediate danger, call 911. 

For more mental health resources, see our National Helpline Database.

SSRIs are generally considered the strongest or most effective antidepressants, but a doctor might prescribe a different type of antidepressant or adjust your dosage if your current medication isn't working.

A Word From Verywell

Regularly tracking your symptoms and keeping scheduled appointments with the healthcare provider who prescribed your medication can help you quickly find a remedy if your antidepressant stops working for you.

Realizing tht your medication is no longer working can be frustrating, especially since figuring out the right antidepressant likely took some trial and error in the first place. Do your best to stay patient and hopeful. It is possible to find a solution so you can feel your best again.

11 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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By Nancy Schimelpfening
Nancy Schimelpfening, MS is the administrator for the non-profit depression support group Depression Sanctuary. Nancy has a lifetime of experience with depression, experiencing firsthand how devastating this illness can be.