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5 Signs Your Depression is Treatment-Resistant

Reviewed by: HU Medical Review Board | Last reviewed: March 2024

Living with depression is a challenging journey. For some, finding effective treatment can feel like an uphill battle. If you have been feeling persistently depressed – despite trying various treatments – you may be experiencing what is known as treatment-resistant depression (TRD).1

TRD is quite common. About 30 percent of people with depression have TRD.2,3

What is treatment-resistant depression?

Treatment-resistant depression is a type of depression in which at least 2 different first-line antidepressants have not worked to treat your symptoms. First-line antidepressants include SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors).2,4

To be diagnosed with TRD, you must have been on 2 different antidepressants for at least 6 to 8 weeks each. Typically, a psychiatrist diagnoses TRD.2,3

5 signs you might have treatment-resistant depression

There are several signs you may have TRD. If you have any of the following, contact your doctor so together you can find the right treatment that works.

Symptoms that do not go away, even with treatment

If you have been taking medicine for your depression for about a month but have not seen any improvement in symptoms, you might have TRD. Your healthcare provider may adjust your dosage, switch medicines, or try other therapies.1-3

In addition, if you have had your medicine dosage adjusted, switched medicines, or tried other therapies with still no changes to your depression symptoms, you also likely have TRD.1-3

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More severe symptoms

With TRD, symptoms may be more severe. These symptoms can include:2

  • Persistent sadness
  • Lack of energy
  • Changes in appetite or weight
  • Difficulty concentrating
  • Thoughts of self-harm or suicide

If you have thoughts of suicide, get help. Contact the Suicide and Crisis Lifeline by calling or texting 988.2

More frequent and longer-lasting depressive episodes

People with TRD may have recurrent episodes of depression, even after periods of remission. Despite periods of feeling better, the symptoms may return, often with increased severity.2,4


People with TRD are more likely to have anxiety in addition to their depression. A solution may be to prescribe you medicine that treats both your anxiety and depression.2

Inability to find enjoyment or pleasure in life

People with TRD are also more likely to have anhedonia. Anhedonia is the inability to experience pleasure in things you once enjoyed.2

Factors that might be contributing to TRD

It is not clear what exactly causes TRD. But experts believe several things may contribute to the development of TRD, including:1-3

  • Genetics – A family history of depression or other mental health disorders can increase the likelihood of TRD.
  • Co-occurring mental health conditions – The presence of other mental health conditions like anxiety or substance use disorder can complicate depression treatment.
  • Chronic stress – Prolonged stress can impact the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis plays a key role in regulating how the body handles stress. Experts think that when the HPA axis gets dysregulated, it may make a person with depression more resistant to treatment.
  • Other medical conditions – Certain medical conditions like chronic pain, autoimmune disorders, thyroid issues, or heart disease can add to the complexity of depression, resulting in TRD.

Steps to take if you suspect treatment-resistant depression

If you think you may have TRD, here are the steps you should take to get help:1,4

Talk with your doctor

Schedule an appointment with a mental health professional, such as a psychiatrist or psychologist. They will evaluate your symptoms, treatment history, and overall health to help you determine the best course of action.1-4

Consider additional testing

Those with diagnosed TRD might benefit from pharmacogenetic testing. This kind of testing analyzes a person’s genetic makeup to predict how they may respond to certain medicines. This testing can help identify which antidepressants are likely to be most effective. Remember that it is not a guaranteed fix, but it can help reduce the trial-and-error process of finding the right drug(s).1

Explore new treatment options

Aside from adjusting your existing medicine or trying a different type of medicine, other medical procedures can be tried. These can include:1-4

  • Psychotherapy – Also known as talk therapy, psychotherapy involves meeting with a trained therapist to discuss and work through emotional and mental health issues.
  • Transcranial magnetic stimulation (TMS) – A noninvasive procedure where magnetic fields stimulate the cells in the brain. TMS helps regulate mood by altering brain activity in areas associated with mood regulation.
  • Electroconvulsive therapy (ECT) – ECT involves passing small electric currents through the brain to intentionally trigger a brief seizure. ECT changes brain chemistry and has been shown to improve mood and provide relief from symptoms.
  • Vagus nerve stimulation (VNS) – VNS involves implanting a device in the chest that sends electrical impulses to the vagus nerve in the neck. It helps regulate mood and reduce symptoms of depression by influencing the mood centers in the brain.
  • Deep brain stimulation (DBS)DBS is a surgical procedure where electrodes are implanted into specific areas of the brain to deliver electrical impulses. DVS helps with a variety of mood and neurological issues, including TRD.

Don't give up

Overcoming treatment-resistant depression requires time, patience, and persistence. Be open to trying new approaches. There are still treatment options you can try. This could mean increasing or adjusting your current dosage, switching medicines, or adding another medicine. Talk with your doctor to get the help you need.1

This article represents the opinions, thoughts, and experiences of the author; none of this content has been paid for by any advertiser. The team does not recommend or endorse any products or treatments discussed herein. Learn more about how we maintain editorial integrity here.