How Treatment-Resistant Depression is Treated

woman meditating at the beach


Treatment-resistant depression (TRD) is defined as depression that does not adequately respond after trying at least two medications. TRD is not an official DSM diagnosis, but it is used to identify those who may be candidates for different types of treatments.

The major areas of treatment for TRD are medications (including everything from SSRIs to antipsychotics), psychotherapy, ketamine and more invasive procedures, such as electroconvulsive therapy. People with treatment-resistant depression are more likely to be hospitalized and/or attempt suicide, so it is key to find adequate ways of treatment that work—and quickly.

Read on to learn more about some treatments that may work for depression that has previously been treatment-resistant. 


In studies of psychotherapy in addition to usual care, the following psychotherapies were successful in achieving a reduction in depression symptoms/scores, both self reported and via depression scales such as PHQ or HAMS-(D).

Additionally, as many people with treatment-resistant depression may tend to isolate, having steady contact with a therapist can be helpful. Moreover, many studies have confirmed that psychotherapy and medication typically work synergistically, magnifying the effects of each other.

Below are some of the psychotherapies that have been proven helpful for TRD:

Cognitive Therapies

Most of the therapies that have been studied to be helpful in TRD are cognitive-based, meaning that they operate on the assumption that thoughts, feelings, and behaviors are all connected, and that people can overcome difficulties by changing unhelpful thinking and distressing emotional responses.

  • Cognitive Behavioral Therapy: CBT was found to have the longest effectiveness, with one study showing positive results at both 12- and 46-month intervals.
  • Dialectical Behavioral Therapy: DBT is a type of CBT that teaches people to live in the moment, live mindfully, and find healthy ways to deal with stress and their emotions by learning relevant skills.
  • Cognitive Behavioral Analysis: This is a type of therapy created specifically to deal with depressive disorders and is a combination of interpersonal, cognitive, and behavioral therapies. Its main goal is to help people understand their interpersonal worlds and how they affect their behaviors so that they can meet interpersonal goals.
  • Interpersonal Therapy: TRD particularly responds to interpersonal therapy because medication cannot, on its own, fix interpersonal difficulties that someone may be having that are reading to their depression.
  • Intensive Short-Term Dynamic Psychotherapy: This is a modality, brief in duration, that helps people identify and address the emotional factors behind their depression by building emotional capacities.


Most people who are diagnosed with major depressive disorder (which is what you are generally diagnosed with and treated for before it progresses to TRD) are started on SSRIs or SNRIs. However, anywhere up to a third of people do not respond to SSRIs/SNRIs. Because this is so common, psychiatrists often use the following treatment algorithm to determine next steps:

  • Optimizing: Starting on an antidepressant (SSRI/SNRI/TCA/MAOI) and ensuring that it has been given an adequate trial, by both dosage and duration
  • Switching: Changing from one class of antidepressant to another (ie from an SSRI to an MAOI)
  • Combination: Adding antidepressants from different classes, (ie SSRI + atypical antidepressant, such as bupropion.)
  • Augmentation: Adding a second medication that is not an antidepressant but may enhance the antidepressant effect of the initial drug, such as lithium, psychostimulants, atypical antipsychotics (such as quetiapine, aripirparzole, olanzapine and risperidone), thyroid hormones

The biggest drawback to any of these more traditional medications is how long it takes them to work. Many of them may take up to six weeks to work fully—which can feel like an eternity when you’re struggling. Additionally, they may come with sexual side effects or side effects like weight gain.

Much research is being done right now in depression treatment and several of the below treatments have either been approved or appear to be on the precipice of it:

  • Ketamine/Esketamine: Studies first confirmed in the early 2000s that ketamine has antidepressant properties, but its popularity has exploded in the past few years, including esketamine, a nasal spray delivery system, being approved by the FDA in 2019. Also, regulations that were relaxed on account of the pandemic allowed at-home ketamine services to flourish (though they are often very expensive).
  • Auvelity: In August 2022, the FDA approved a new antidepressant called Auvelity (dextromethorphan - bupropion), which is based on research on how ketamine works in the brain. Auvelity also works faster than traditional antidepressants—often working within a week.
  • Psilocybin: If you follow any kind of mental health/depression news, you probably know that psilocybin and psychedelics in general are having a moment right now. In fact, recent research shows that even one session of psilocybin can bring relief to people dealing with depression. It is expected that psilocybin will receive FDA approval for treating depression in early 2023.
  • Anti-Inflammatories: Some theories of depression—particularly TRD—associate it with higher levels of inflammation, and research is also currently being done on treating those with high levels of inflammation with anti-inflammatories—which don’t seem to work as well on people with depression who don’t have high levels of inflammation.

Surgery and Invasive Procedures

And while many typically think of depression/mental health treatment as just psychotherapy and medication, there are also a number of physical or “somatic” treatments available for depression. However, as some of these are slightly more invasive/involved, typically they are reserved (and only covered by insurance) for after other treatments have failed:

  • Transcranial Magnetic Stimulation: Transcranial magnetic stimulation (TMS) is a treatment that uses coils and magnets on your head to administer small pulses of electric current to help symptoms of depression. Typical protocols were five times a week for six weeks, but a newly approved protocol, called the Stanford Accelerated Intelligent Neuromodulation Therapy was recently approved, which cuts the course of treatment down to just a week, with resounding success.
  • Deep Brain Stimulation (DBS): This is another treatment that physically targets parts of the brain, but it is more involved than TMS. This is a surgical procedure that implants a small pacemaker-like device in one’s chest to target electrodes placed in the brain to manage irregular brain activity.
  • Vagus nerve simulation is very similar to DBS, except that the electrodes are placed on the vagus nerve (which controls fight or flight) rather than the brain, to stimulate certain neurotransmitters.
  • Electroconvulsive therapy (ECT): Electroconvulsive therapy has gotten a bad reputation over the years, but in depression that’s really not responding to anything else, it can still be incredibly helpful. One study shows ECT helping more than 40% of participants experiencing a remission in their depression symptoms after ECT treatment.

Complementary Alternative Medicine (CAM) & Over-the-Counter (OTC) 

While no real “over the counter” remedies exist for depression the way they do for, say, allergies, there are some supplements and other over-the-counter products that may help with depression as well as other types of complementary alternative medicine (CAM) that have shown efficacy. 

  • St. John’s Wort: This is an herb that has some evidence of reducing severity of depression and improving response rates. However—it may limit the effectiveness of certain antidepressants or even lead to the life-threatening serotonin syndrome, so do not take it without consulting with a doctor.
  • Omega 3: Popular opinion would say that Omega 3 fatty acids reduce symptoms of depression, and some studies do support this, but a recent meta-analysis of 31 trials found no strong evidence of this.
  • 5-HTP: This is an amino acid that, dietarily, can be found in l-tryptophan-rich foods like turkey or red meat. In the body, it can be converted to serotonin, which helps regulate mood. Research shows that supplementing with 5-HTP can be helpful both on its own or in conjunction with an antidepressant, though too much 5-HTP may lead to serotonin syndrome.
  • SAM-e: S-adenosyl-L-methionine, more commonly known as SAM-e, is a compound that is typically found in the body that helps regulate hormones and mood. Some people who are deficient in B12 and folate may also have reduced levels of SAM-e in their bodies. Supplementing with it, either alone or in conjunction with an antidepressant, can help neurotransmitters better do their jobs.
  • Rhodiola Rosea: This is an adaptogen, meaning it helps your body better adapt to dealing with stress by working neurotransmitters implicated in depression, such as serotonin, norepinephrine, and dopamine.
  • Acupuncture: Research is somewhat inconclusive, but some data does suggest that acupuncture may help with depression by blocking stress hormones and the stress response that often show up in depression. While data may be inconclusive, there is little harm in attempting acupuncture—and even the relaxing ritual of taking time to lay there may feel helpful.

Diet and Exercise

If you are dealing with treatment-resistant depression, your mind likely isn’t on eating healthfully or exercising, but what we put into our bodies and how we move them can have a real effect on our mental health.


When you’re dealing with treatment-resistant depression, it’s likely your eating habits are affected. You’re either eating too much, not enough, or eating lots of comfort food, which may raise inflammation levels, which are thought to contribute to treatment-resistant depression.

But you don’t have to overhaul your whole diet all at once. Small changes, such as reducing processed food in your diet and remembering to eat breakfast may go a long way.


Yoga: If you had a dollar for every time someone has asked you if you’ve tried yoga, you’d probably be able to pay for your treatment on just that. But it’s for good reason—while it won’t cure depression, it can reduce the symptoms and severity of it.

Walking: If, when you’re not depressed, you’re typically a person who goes hard on their exercise, you may scoff at the idea of walking for depression. However, walking and other moderate-intensity exercise, when done regularly, may even lead to remission of depression symptoms.

Things You Can Try on Your Own

While treatment-resistant depression is incredibly serious and does require working with a professional, there are some other types of treatments you can do at home/on your own.

  • Light therapy: Especially in the winter months, or if you live in a dark/cold climate, your circadian rhythms may be affected by the lack of sunlight, but the good news is that light boxes may actually help depression. Many people begin seeing benefits within the first week of using them daily for 15 minutes.
  • Bibliotherapy: One very low-cost way you can manage your treatment-resistant depression is through bibliotherapy—a fancy word for reading. Reading, particularly fiction, can help people with depression, as it helps them by getting lost in others’ worlds and forgetting about their problems as well as understanding themselves better. There are also actually several books that have been specifically studied to help in depression—Feeling Good by David Burns or Controlling Your Depression by Peter Lewinsohn. Essentially, both of these books are CBT manuals, and you are teaching yourself CBT principles.
  • Expressive writing: Psychotherapy is immensely helpful at helping people process their emotions, but it’s typically only once per week. What do you with all of those feelings in between? Expressive writing is a form of journaling, but rather than just write about the events that happened, it involves processing the emotions you feel about this event. It can help you feel like you have a sense of control over the events that are happening your life and may even be cathartic, therefore reducing symptoms of depression.

How to Make Your Treatment Most Effective

Medication Adherence

If you are not taking your medication daily or regularly as prescribed, it can be hard for it to be effective. Depression, however, can also make remembering to take it in the first place difficult. Some strategies that may help include setting a timer on your phone, using a pill case, or keeping your medications out in a place where you can’t miss them.

Avoid Alcohol and Other Drugs

Alcohol is a depressant, so it may make your depression worse and negate any help that your antidepressants are giving you, for a double whammy. Other drugs, particularly addictive ones, may cause further mental health issues, such as dependence.

Minimize Stress

We know, we know, easier said than done! However, stress only aggravates feelings and symptoms of depression. While there are plenty of stressful situations that are beyond our control, what we can control is how we deal with those situations as well as not inflicting any unnecessary stress on ourselves. Self-compassion can go a long way in helping deal with stress.

Consider Cost

Unfortunately, in the United States, mental health treatment can be incredibly costly and out of the reach of many. However, going into debt for your depression treatment will only create more stress, so look into things like free or low-cost therapy.

A Word from Verywell

Having treatment-resistant depression can feel incredibly frustrating and hopeless, but as you can see, there are many, many treatment options available these days. You haven't done anything wrong, you just haven't found the right treatment for you yet.

20 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Souery D, Oswald P, Massat I, et al. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry. 2007;68(7):1062-1070. DOI: 10.4088/jcp.v68n0713

  2. Wiles N, Williams CJ, Kessler D, Lewis G. Psychological therapies for treatment-resistant depression in adults. Cochrane Common Mental Disorders Group, ed. Cochrane Database of Systematic Reviews. DOI: 10.1002/14651858.CD010558.pub2

  3. Markowitz JC, Wright JH, Peeters F, Thase ME, Kocsis JH, Sudak DM. The neglected role of psychotherapy for treatment-resistant depression. AJP. 2022;179(2):90-93. DOI: 10.1176/appi.ajp.2021.21050535

  4. Voineskos D, Daskalakis ZJ, Blumberger DM. Management of treatment-resistant depression: challenges and strategies. Neuropsychiatr Dis Treat. 2020;16:221-234. DOI: 10.2147/NDT.S198774

  5. Abbass AA. Intensive Short-Term Dynamic Psychotherapy of treatment-resistant depression: a pilot study. Depress Anxiety. 2006;23(7):449-452. DOI: 10.1002/da.20203

  6. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-388. DOI: 10.2147/PPA.S29716

  7. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637-1648. DOI: 10.1056/NEJMoa2206443

  8. Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. AJP. 2020;177(8):716-726. DOI: 10.1176/appi.ajp.2021.20101429

  9. Pycroft L, Stein J, Aziz T. Deep brain stimulation: An overview of history, methods, and future developments. Brain and Neuroscience Advances. 2018;2:239821281881601. DOI: 10.1177/2398212818816017

  10. Brus O, Cao Y, Gustafsson E, et al. Self-assessed remission rates after electroconvulsive therapy of depressive disorders. Eur psychiatr. 2017;45:154-160. DOI: 10.1016/j.eurpsy.2017.06.015

  11. Deane KHO, Jimoh OF, Biswas P, et al. Omega-3 and polyunsaturated fat for prevention of depression and anxiety symptoms: systematic review and meta-analysis of randomised trials. The British Journal of Psychiatry. 2021;218(3):135-142. DOI: 10.1192/bjp.2019.234

  12. Iovieno N, Dalton ED, Fava M, Mischoulon D. Second-tier natural antidepressants: Review and critique. Journal of Affective Disorders. 2011;130(3):343-357. DOI: 10.1016/j.jad.2010.06.010

  13. Dome P, Tombor L, Lazary J, Gonda X, Rihmer Z. Natural health products, dietary minerals and over-the-counter medications as add-on therapies to antidepressants in the treatment of major depressive disorder: a review. Brain Research Bulletin. 2019;146:51-78. DOI: 10.1016/j.brainresbull.2018.12.015

  14. Smith CA, Armour M, Lee MS, Wang LQ, Hay PJ. Acupuncture for depression. Cochrane Database of Systematic Reviews. 2018;(3). DOI: 10.1002/14651858.CD004046.pub4.

  15. Brinsley J, Schuch F, Lederman O, et al. Effects of yoga on depressive symptoms in people with mental disorders: a systematic review and meta-analysis. Br J Sports Med. 2021;55(17):992-1000. DOI: 10.1136/bjsports-2019-101242

  16. Mota-Pereira J, Silverio J, Carvalho S, Ribeiro JC, Fonte D, Ramos J. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. J Psychiatr Res. 2011;45(8):1005-1011. DOI: 10.1016/j.jpsychires.2011.02.005

  17. Bookworms versus nerds: Exposure to fiction versus non-fiction, divergent associations with social ability, and the simulation of fictional social worlds. Journal of Research in Personality. 2006;40(5):694-712. DOI: 10.1016/j.jrp.2005.08.002

  18. Gualano MR, Bert F, Martorana M, et al. The long-term effects of bibliotherapy in depression treatment: Systematic review of randomized clinical trials. Clinical Psychology Review. 2017;58:49-58. DOI: 10.1016/j.cpr.2017.09.006

  19. Krpan KM, Kross E, Berman MG, Deldin PJ, Askren MK, Jonides J. An everyday activity as a treatment for depression: The benefits of expressive writing for people diagnosed with major depressive disorder. J Affect Disord. 2013;150(3):1148-1151.  DOI: 10.1016/j.jad.2013.05.065

  20. Yang L, Zhao Y, Wang Y, et al. The effects of psychological stress on depression. Curr Neuropharmacol. 2015;13(4):494-504. DOI: 10.2174/1570159X1304150831150507

By Theodora Blanchfield, AMFT
Theodora Blanchfield is an Associate Marriage and Family Therapist and mental health writer using her experiences to help others. She holds a master's degree in clinical psychology from Antioch University and is a board member of Still I Run, a non-profit for runners raising mental health awareness. Theodora has been published on sites including Women's Health, Bustle, Healthline, and more and quoted in sites including the New York Times, Shape, and Marie Claire.