Woman experiencing depressive thoughts on her bed
Woman experiencing depressive thoughts on her bed
Woman experiencing depressive thoughts on her bed

Why Aren't My Antidepressants Working?

Reviewed By:

If you feel like your antidepressant has stopped working, you're not alone. It's common for a medication that once worked wonders to become ineffective, especially if you've been taking it for a long time. Symptoms return for up to 33% of people using antidepressants — it's called breakthrough depression.

"Usually an antidepressant that's worked for a patient will keep working," says Paul Nestadt, M.D., psychiatrist and co-director of the Jack and Mary McGlasson Anxiety Disorders Clinic at Johns Hopkins. "But sometimes, a new episode of depression might come up that's not as responsive to that medication, or the medication might just stop working altogether."

What causes depression medications to stop working?

Multiple factors can change the way your body responds to an antidepressant, including:

  • Drug or alcohol use. Illicit drug use and alcohol can cause strong mood changes, which can make antidepressants ineffective.
  • Pregnancy. Your body's weight and blood volume increase when you're pregnant. Talk to your doctor about taking antidepressants while pregnant, and about potentially adjusting your dosage to continue relieving symptoms.
  • New stressors. A new stressful situation at home or work can result in a mood response for which the antidepressant can't compensate.
  • Other medications. Interactions between antidepressants and medications for other health conditions can affect how well an antidepressant works.

Most often, though, antidepressants stop working for what seems to be no reason. "There's no good research that shows why a medication may stop working for someone," says Nestadt. "I think it's less an issue of building up tolerance and more likely constantly changing stressors and factors in the brain."

When to See a Doctor

If your depression symptoms return for more than a few days, it's time to see your doctor. But even if you feel like your antidepressant isn't working, it's important to keep taking it until your doctor advises otherwise. You may need a dosage increase or a slow tapering off process. With many antidepressant medications, stopping their use too quickly can cause withdrawal effects such as:

  • Headaches
  • Nausea
  • Diarrhea or constipation
  • Greater anxiety
  • Suicidal thoughts

Early warning signs of breakthrough depression are the symptoms you typically experience when an episode of depression is coming on, says Nestadt. Depression symptoms vary from person to person, but signs include:

  • Low mood
  • Changes in sleep or appetite
  • Decreased socializing
  • Loss of interest in previously enjoyable activities

If your symptoms return, don't worry — adjusting the dose or switching to another antidepressant often solves the problem. (Note: If you have self-harm or suicidal thoughts, see your doctor immediately, call 911 or go to an emergency room.)

Changing Your Depression Medications

If you and your doctor have ruled out factors that could interfere with your current medication, your doctor may increase the dosage, switch you to another antidepressant or recommend you take an additional medication. Drug therapies that treat depression include:

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRI drugs are the most commonly prescribed antidepressants and are often considered the first line of defense against depression. They increase your brain's level of a neurotransmitter (a chemical that transfers messages from brain cell to brain cell) called serotonin. This neurotransmitter is associated with feeling happy and content. SSRI side effects tend to be mild, and depression symptoms improve significantly for about 60% of people with moderate to severe depression.

Selective Serotonin Noradrenaline Reuptake Inhibitors (SSNRIs)

Both SSNRI and SSRI medications affect serotonin levels, but SSNRI drugs also impact the level of norepinephrine, another neurotransmitter that may affect mood. This type of medication is helpful for those who have extreme fatigue associated with depression, or who have had side effects or poor response to SSRI drugs.

Tricyclic Antidepressants (TCAs)

TCA drugs increase serotonin and norepinephrine in the brain, but unlike other antidepressant types, they also block acetylcholine, a neurotransmitter associated with increased stress, anxiety and depression. You may experience more side effects with TCA medications than with SSRI or SSNRI drugs.

Monoamine Oxidase Inhibitors (MAOIs)

MAOI drugs inhibit the breakdown of dopamine, norepinephrine and serotonin, which increases their concentration in the brain. Low levels of these neurotransmitters are associated with depression and anxiety. MAOI drugs have a greater number of serious side effects. People taking them have to be mindful of the medication's interactions with certain foods and other drugs.


Bupropion acts on dopamine and norepinephrine. Its main advantage is that it doesn't cause troublesome side effects such as decreased libido and weight gain like other types of antidepressants do. However, it may be less helpful for depression with anxiety features.


This newer drug provides relief from depression symptoms within hours by increasing levels of glutamate, the most abundant neurotransmitter in the brain. Esketamine comes in a nasal spray that must be administered in a clinic because it can cause hallucinations and other sensory side effects for up to two hours after treatment. It's an effective drug for those who haven't responded to other antidepressants.

If you're experiencing breakthrough depression, it's important to consult with your doctor so you can feel better again. "It's not unusual for medications to stop working," says Nestadt. "It happens with other sorts of medical treatments as well. Sometimes your blood pressure medicine is no longer effective and it has to be switched. It's just the nature of treating illness."

Request an Appointment

Find a Doctor
Find a Doctor