Breakthrough depression refers to a state where depressive symptoms persist or worsen despite an individual taking antidepressant medications that were previously effective.

Doctors may find breakthrough depression, also known as antidepressant tolerance, challenging to manage. It can also be distressing and frustrating for the individual with depression.

This article explores the concept of breakthrough depression, including its causes, symptoms, and treatment options.

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Breakthrough depression refers to the recurrence of depressive episodes in people with major depressive disorder, despite them being on a stable maintenance dose of antidepressant medication. In other words, breakthrough depression can happen when someone who was previously doing well with their treatment experiences a setback and the symptoms resurface.

Other names for breakthrough depression include antidepressant tolerance and antidepressant treatment tachyphylaxis.

Rates of breakthrough depression are highly variable. Some research shows it may affect up to 57% of those undergoing treatment, depending on the population and duration of follow-up.

Vs. nonresponse to treatment

Breakthrough depression is different from nonresponse to treatment, which is also known as treatment resistance or inadequate response to antidepressant medications.

Nonresponse refers to a situation where a person does not experience any significant improvement in their depressive symptoms despite receiving adequate treatment. In contrast, inadequate response indicates some improvement in symptoms but not to desirable levels.

Learn more about depression.

Breakthrough depression may involve several factors:

  • Nonadherence to treatment: If an individual misses doses of their medication or stops taking it altogether, it can undermine its therapeutic effects, increasing the risk of depressive relapses.
  • Worsening of depression: If depression worsens, medications may become less effective at managing symptoms.
  • Placebo effect: The beneficial effects of antidepressants may not be entirely due to the pharmacological properties of the medication. Instead, individuals may experience the placebo effect, meaning a perceived improvement in their symptoms after taking a medication they believe will be beneficial.
  • Individual factors: The complex nature of depression involves various contributing factors and neurochemical imbalances in the brain. Some individuals may have underlying health conditions or unique neurobiology, meaning they become less responsive to certain antidepressant medications.

Some research suggests breakthrough depression is more common with selective serotonin reuptake inhibitors (SSRIs) than with selective serotonin and noradrenalin reuptake inhibitors (SNRIs) and tricyclic antidepressants.

The signs and symptoms of breakthrough depression generally involve a recurrence or worsening of depressive symptoms despite ongoing treatment.

These may include:

  • persistent feelings of sadness, hopelessness, or emptiness
  • loss of interest or pleasure
  • fatigue and low energy
  • changes in appetite or weight
  • sleep disturbances
  • problems with focus, memory, and decision-making abilities.
  • feelings of worthlessness or guilt
  • thoughts of death or suicide or a preoccupation with dying

Suicide prevention

If you know someone at immediate risk of self-harm, suicide, or hurting another person:

  • Ask the tough question: “Are you considering suicide?”
  • Listen to the person without judgment.
  • Call 911 or the local emergency number, or text TALK to 741741 to communicate with a trained crisis counselor.
  • Stay with the person until professional help arrives.
  • Try to remove any weapons, medications, or other potentially harmful objects.

If you or someone you know is having thoughts of suicide, a prevention hotline can help. The 988 Suicide and Crisis Lifeline is available 24 hours a day at 988. During a crisis, people who are hard of hearing can use their preferred relay service or dial 711 then 988.

Find more links and local resources.

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It may not always be possible to prevent breakthrough depression. However, some measures may reduce the risk:

  • Adherence to treatment: It is essential for people to take prescribed medications as a doctor has directed. Following the recommended dosage and schedule and attending regular follow-up appointments to optimize treatment effectiveness.
  • Open communication: A person needs to be honest with their healthcare team and discuss any concerns, side effects, or changes in symptoms with them. This ensures appropriate adjustments in the treatment plan.
  • Appropriate lifestyle choices: Adopting a healthy lifestyle can have a positive effect on mood and overall well-being. This includes regular exercise, balanced nutrition, adequate sleep, stress reduction techniques, such as mindfulness and relaxation exercises, and avoiding excessive alcohol or substance use.
  • Support system: Building a strong community of family, friends, or support groups can provide understanding and encouragement during challenging times. Social connections and a sense of belonging can contribute to overall mental health.
  • Regular self-care: Engaging in self-care activities that promote relaxation, self-reflection, and self-nurturing can help manage stress and maintain emotional well-being. This may involve hobbies, engaging in enjoyable activities, practicing mindfulness or meditation, or seeking out activities that bring joy and fulfillment.

Learn more about avoiding relapse in depression.

There is no singular standard treatment for depression. Instead, doctors create a treatment plan for each individual that may include various medications and psychotherapy.


Medications help balance brain chemicals or change how they function. These options include:

  • SSRIs
  • norepinephrine and dopamine reuptake inhibitors
  • SNRIs

Doctors may also prescribe antipsychotics or anticonvulsant medications to make antidepressants more effective.

In cases of breakthrough depression, doctors may suggest changing the doses of antidepressants or switching the type of antidepressant medication.

Learn more about antidepressants.


Approaches, including cognitive behavioral therapy and interpersonal therapy, can help people with depression by teaching them new ways to think and behave.

If an individual has breakthrough depression, their doctor may recommend psychotherapy treatment in conjunction with medications.

Learn more about psychotherapy.

Breakthrough depression is a recurrence of depressive episodes despite adequate antidepressant medication.

It may occur due to nonadherence to treatment, biological factors, worsening depression, and the placebo effect.

It is not always possible to prevent breakthrough depression. However, a person has the best chance of successful treatment by taking their medications as a doctor recommends. They can also build a support system and maintain open communication with their healthcare team.