Treatment resistant depression

Sean Jackson
Author: Sean Jackson Medical Reviewer: Morgan Blair Last updated:

For most people, psychological treatments, including counseling and antidepressant medications, are effective in treating depressive disorders. However, some people’s symptoms don’t improve much (or at all) or might improve for a short period before a reoccurrence. This is often referred to as treatment resistant depression.

What is treatment resistant depression?

Treatment resistant depression, also known as medication resistant depression or drug resistant depression, occurs when depression symptoms don’t respond to initial treatments.[1][2] For example, you might be in therapy, and experience some relief, but the general darkness of depression still hangs over you. Moreover, you might be on an antidepressant treatment plan, but the medication might not have the effect you and your mental health provider hoped for.

Quantifying treatment resistant depression has proven difficult. This type of depression isn’t outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), nor are there set diagnostic rules for identifying it.[1]

Instead, clinicians tend to rely on client reports regarding their mood. Also, most psychological research on this issue seems to point to at least two unsuccessful lines of treatment as the threshold for this type of depression.[1]

Signs that you’re not responding to depression treatment

If you have tried at least two treatment options to treat your depressive symptoms and suspect you have treatment resistant depression, the essential question to ask is, “Do I feel better than I did before?” If the answer is no, it’s time to have a frank discussion with your mental health provider.

But not feeling better isn’t the only sign that you might have medication resistant depression. In some cases, you might feel worse before you feel better as your current treatment progresses. It is important to be patient with the recovery process and discuss symptoms with your mental health providers.[2] 

However, it’s important to note that all medications carry the risk of adverse effects, and while these may make you feel like you’re symptoms are getting worse initially, they are not indicative of treatment resistant depression, which occurs when several attempts of treatment haven’t resulted in any improvement of depressive symptoms.

More frequent or severe depressive episodes during treatment could be signs of treatment resistant depression.[2] Obviously, the point of seeking depression treatment is to minimize your symptoms and reduce the duration and severity of your depressive episodes. If your current treatment worsens things or demonstrates no improvement, speak with your mental health provider about changing treatment courses.

A final sign that you might have treatment resistant depression is ongoing occurrences of self-injurious behavior, suicidal ideation, or suicide attempts even during treatment.[2]

Causes of treatment resistant depression

All mental health conditions are the result of a myriad of factors. Treatment resistant depression is no different. And predicting how one’s depression plays out – whether there is a good or poor response to treatment – is extremely difficult. Nevertheless, there are a few potential causes that might indicate a higher risk of medication resistant depression.

For example, research shows that treatment resistant depression is more common in older adults. It’s also more common in women.[3] The reasons for this aren’t clear, though it is speculated that psychological and physiological factors are involved.

Another potential cause of drug resistant depression is having frequent or severe occurrences of major depression.[4] The theory seems to be that as the frequency and severity of one’s depression increase, the likelihood that treatment will succeed diminishes.[3] 

Physiological health is another potential cause. Research shows that people with chronic pain, thyroid disease, and inflammatory issues have an increased risk of treatment resistant depression. People with sleep disorders, eating disorders, and substance use disorders make medication resistant depression more likely as well.[3][4]  

Other factors might be involved, too. For example, people who have experienced trauma or frequent stressful events are at a higher risk for this type of depression. As are socially inhibited, introverted, or highly neurotic individuals. Likewise, the following might indicate a greater risk of developing drug resistant depression:[4] 

  • Dysfunction of neurotransmitters in the brain
  • Abnormal neural activity in the brain
  • Chronic illness
  • History of bipolar disorder
  • History of other psychiatric disorders
  • Personality dysfunction

How to treat treatment resistant depression

If you have treatment resistant depression, hope is not lost. While past treatments might not have garnered the results you want, other treatments might. The key is to continue working with your doctor or mental health provider to find an effective treatment. Several options are described below.

Change the way you take medication (or change the medication altogether)

If you’re taking antidepressant medication, you might need a different dosage to affect your mood. Moreover, antidepressants drugs often take several weeks to take effect, so it might be worth continuing your current treatment if enough time hasn’t passed. However, if you’ve taken your medication for six to eight weeks without improved results, it’s worth discussing a change with your doctor.

Your doctor might prescribe you a second type of antidepressant to go with the first type, or they might give you a completely different type of antidepressant (of which there are many). Adding or changing the type of antidepressant has been shown in various studies to increase response rates and reduce depressive symptoms.[1]

Try alternative medications

Another option your mental health provider might consider is adding a non-antidepressant medication in a process called “augmentation.” [1] The most common candidates for augmentation are as follows:

  • Lithium, a mood stabilizer most usedto treat mania, might be combined with tricyclic antidepressants like citalopram.
  • Triiodothyronine or T3, the active form of thyroxine (a thyroid hormone), might also be used with tricyclic antidepressants to treat drug resistant depression. T3 is typically better tolerated by patients, has fewer side effects, and requires less monitoring by a physician.
  • Second-Generation Antipsychotics or SGAs, are used to treat everything from schizophrenia to acute mania to Tourette disorder [5] and might be prescribed with first-line antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). SGAs like olanzapine, risperidone, and quetiapine are especially popular augmentative treatments.
  • Esketamine, which is made from the anesthetic ketamine, is a nasal spray that is FDA-approved for the treatment of depression. Unlike many other depression treatments, esketamine can positively affect mood in a matter of hours.[6]

Change therapies

Psychotherapy is the most common therapeutic treatment for depression. Psychotherapy effectively treats depression and comorbid disorders. This is important because having multiple psychological disorders diminishes the efficacy of first-line pharmacological treatments.[1]

Psychotherapy can be done individually or with groups, giving you and your therapist a range of options for addressing your treatment resistant depression.

Other therapies include marriage, couples, family, or group therapy. All of which can focus on your relationships and reducing relational stress.[1]

Specialized treatment options include dialectical behavior therapy, which assists you in developing problem-solving skills and devising acceptance strategies [7]. Also, acceptance and commitment therapy, which focuses on training you to take part in positive behaviors, even when experiencing negative thoughts or emotions.[8]

Try brain stimulation

In instances in which your depression has been resistant to multiple therapies and drug treatments, your mental health provider might suggest one of many different brain stimulation techniques, as outlined below:

  • Electroconvulsive therapy, or ECT, has long been used to treat psychotic and affective disorders. ECT uses high-frequency electrical impulses to the brain to produce a short-term seizure that usually lasts less than a minute. ECT is typically delivered two to three times per week and lasts anywhere from half a dozen sessions to a dozen-and-a-half sessions.[1]ECT is effective in up to 80 percent of patients.[3]
  • Repetitive Transcranial Magnetic Stimulation, or rTMS, involves using focused discharges of an electromagnetic coil over the scalp. Doing so stimulates neurons in the brain’s cortical area and alters neurons’ excitability without inducing a seizure. The Federal Drug Administration approves it as a treatment for depression.[2]
  • Vagus Nerve Stimulation, or VNS, uses electrical impulses from an implant in your chest to stimulate the vagus nerve in the brain. Again, these brief electrical signals have shown promise for reducing symptoms of depression. However, VNS is usually the last course of action and is typically undertaken only if rTMS and ECT have not been effective.[1]

Several other brain stimulation techniques exist for treating drug resistant depression. These include magnetic seizure therapy, theta-burst stimulation, and deep brain stimulation.

Use self-help techniques

Of course, there are some things you can do on your own to improve your mood and lessen the symptoms of your medication resistant depression. These include:

  • Taking your medication as prescribed by your doctor and participating fully in psychotherapy or other treatments
  • Getting plenty of rest
  • Learning methods to effectively deal with stress and anxiety
  • Avoiding the use of alcohol or recreational drugs
  • Exercising regularly
  • Eating a healthy diet

Strive to maintain connections with loved ones, too. Having moral support, a kind ear, or a shoulder to cry on can be highly beneficial as you navigate life with treatment resistant depression.

  1. Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M. (2020). Management of treatment-resistant depression: Challenges and strategies. Neuropsychiatric Disease and Treatment, 16, 221–234. Retrieved June 6, 2023, from
  2. Al-Harbi K. S. (2012). Treatment-resistant depression: Therapeutic trends, challenges, and future directions. Patient Preference and Adherence, 6, 369–388. Retrieved June 6, 2023, from
  3. Brown, J. (2018, April 30). 4 things we now know about treatment-resistant depression.Johnson & Johnson Health & Wellness. Retrieved June 6, 2023, from 
  4. Murphy, J. A., Sarris, J., & Byrne, G. J. (2017). A Review of the conceptualisation and risk factors associated with treatment-resistant depression. Depression Research and Treatment, 2017, 4176825. Retrieved June 6, 2023, from
  5. Chokhawala, K., & Stevens, L. (2023, February 26). Antipsychotic medications. National Library of Medicine. Retrieved June 6, 2023, from
  6. Johns Hopkins Medicine. (n.d.). Esketamine for treatment-resistant depression. Retrieved June 6, 2023, from
  7. Lynch, T. R., & Bronner, L. L. (2006). Mindfulness and dialectical behavior therapy (DBT): Application with depressed older adults with personality disorders. In R. A. Baer (Ed.), Mindfulness-based treatment approaches: Clinician’s guide to evidence base and applications (pp. 217–236). Elsevier Academic Press. Retrieved June 6, 2023, from
  8. Society of Clinical Psychology. (n.d.). Diagnosis: Depression. Treatment: Acceptance and commitment therapy for depression. Retrieved June 6, 2023, from
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Sean Jackson
Author Sean Jackson Writer

Sean Jackson is a medical writer with 25+ years of experience, holding a B.A. degree from the University of Nottingham.

Published: Jul 12th 2023, Last edited: Oct 26th 2023

Morgan Blair
Medical Reviewer Morgan Blair MA, LPCC

Morgan Blair is a licensed therapist, writer and medical reviewer, holding a master’s degree in clinical mental health counseling from Northwestern University.

Content reviewed by a medical professional. Last reviewed: Jul 12th 2023