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What is treatment-resistant depression?

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DefinitionMedicationsOther optionsCoping strategiesSummary
If you try one or two forms of antidepressant medication and don’t feel any relief from your symptoms, medical professionals may consider this “treatment-resistant depression.”
Medically reviewed by Ericka Goodwin, MD, DFAPA
Updated on

Depression is a highly treatable condition. But for many people, the path of treatment and recovery can be challenging. 

What’s the definition of treatment-resistant depression?

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The definition of treatment-resistant depression can vary. This is because the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR) doesn’t include the condition for official clinical diagnosis.

Treatment-resistant depression typically describes people with major depressive disorder (MDD) who have tried at least two types of antidepressant medication but are yet to find relief from their symptoms. This is common, with up to two-thirds of people not responding to the first prescribed antidepressant medication.

Some experts may also define treatment-resistant depression as depression that continues to be present even after receiving first-line treatments, including medication and psychotherapy.

Co-occurring conditions, such as post-traumatic stress disorder (PTSD) or substance use disorder, may also make it more difficult to find an effective treatment for MDD.

This doesn’t mean that your depression symptoms will be resistant to all treatment types. It simply means that your depression symptoms have not responded to the treatments you have tried so far.

Reassuringly, around 40% to 60% of people with MDD find relief from their symptoms with medication.


If a medical professional says that you’re experiencing treatment-resistant depression, it likely means that you’ve already tried some form of antidepressant medication.


The most commonly prescribed antidepressants are called selective serotonin reuptake inhibitors, or SSRIs. Some common types of SSRIs include:

Some common serotonin-norepinephrine reuptake inhibitor (SNRIs) include:

Often, it takes a journey of trial and error to find the exact medication and dosage that works for you, so you and your doctor may need to discuss trying more than one or two SSRIs or SNRIs. 

It’s important not to suddenly stop taking SSRIs, as this can cause unwanted discontinuation or withdrawal symptoms, including dizziness, nausea, and “electric shock” sensations. For this reason, it is important to always follow your doctor’s advice when stopping any medication.

Other antidepressants

If SSRIs and SNRIs haven’t been effective for you, other types of medications may include:

  • norepinephrine and dopamine reuptake inhibitors (NDRIs), like bupropion (Wellbutrin)
  • tricyclic antidepressants (TCAs), like imipramine (Tofranil)
  • serotonin antagonists and reuptake inhibitors (SARIs), like trazodone (Molipaxin)
  • monoamine oxidase inhibitors (MAOIs), like phenelzine (Nardil)
  • noradrenaline and specific serotonergic antidepressants (NASSAs), like mirtazapine (Remeron)

Doctors and healthcare professionals may not always consider these medications for initial depression treatment due to their side effects, which can include:

  • drowsiness
  • insomnia
  • weight gain
  • constipation
  • increased heart rate
  • sweating

It is important to always follow the advice of your professional healthcare team.

Adjunctive medication

Doctors may sometimes treat treatment-resistant depression with a combination of antidepressant medications and another class of psychiatric medication, like an antipsychotic or mood stabilizer.

These can include lithium (Lithobid), which may especially apply if you live with bipolar depression, or a second-generation antipsychotic like aripiprazole (Abilify) or quetiapine (Seroquel).

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What other treatment options are there?

Although it can be very effective, medication isn’t the only treatment choice for treatment-resistant depression. If several different combinations and dosages of medications haven’t worked for you, or you would rather pursue nonmedicated options, there are other treatments to explore.

Talking therapies

Several types of psychotherapy or talk therapy can be effective for depression, including when you have treatment-resistant depression. Cognitive behavioral therapy (CBT) has a wealth of evidence supporting its efficacy for major depression. 

A doctor or healthcare professional will typically recommend CBT first, with a combination of CBT and medication if needed.

If you haven’t tried talking therapy, this might be your doctor’s first recommendation if medication hasn’t been successful.

In addition to CBT, other effective psychotherapeutic methods that are effective for treatment-resistant depression include:

Procedural treatments

If a combination of psychotherapy and medication is still not effective, there are newer treatments that have promising research.

Transcranial magnetic stimulation (TMS) therapy is a Food and Drug Administration (FDA)-approved brain stimulation therapy sometimes used for treatment-resistant depression. It uses electromagnetic technology to stimulate the areas of the brain affected by depression. Another effective type of brain stimulation therapy is electroconvulsive therapy (ECT)

In 2019, the FDA also approved the use of a nasal spray — esketamine (Spravato) — for treatment-resistant depression.

Additionally, a 2021 randomized clinical trial found that psilocybin may also effectively treat MDD. Psilocybin is the active and psychedelic ingredient in “magic” mushrooms, also known as shrooms. However, this does not yet have FDA approval.

Coping strategies for treatment-resistant depression

Participating in treatment courses led by qualified healthcare professionals can be an important part of depression recovery. But there are also some self-care tips and lifestyle strategies that may help you manage the condition, including:

  • getting at least a small amount of physical activity each day
  • establishing and staying connected to your support network
  • aiming for 7 to 9 hours of restful sleep each night
  • making short- and long-term goals
  • spending more time with nature
  • eating a nutritious and balanced diet
  • practicing mindfulness or other relaxation techniques

Remember, if you find it difficult to achieve these different strategies, it is crucial not to be too hard on yourself. The important thing is that you develop the best self-care plan you can, whatever that may look like.


Treatment-resistant depression generally describes people with MDD who have tried at least two different forms of active treatment.

There are many different prescription drug options for MDD, along with talk therapies, other therapies, and self-care routines. Finding the right combination of treatments, therapies, or both can be challenging. A medical professional can work with you to find an effective solution.

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