What Is Treatment-Resistant Depression (TRD)?

What Is Treatment-Resistant Depression (TRD)?

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Jamie Hope - Methyl-Life® Founder

Edited By:

Jamie Hope - Methyl-Life® Founder
Last updated:

Symptoms of treatment-resistant depression

Symptoms of TRD are the same as those for clinical depression (also known as major depressive disorder or MDD). The difference between TRD and clinical depression is that in TRD, symptoms persist despite taking medication, and the individual doesn’t respond to other conventional forms of treatment such as behavioural therapy or counselling.


These symptoms may include:

  • Persistently feeling sad, low, and hopeless for weeks at a time
  • A loss of interest in the activities you used to enjoy
  • Feelings of guilt or worthlessness
  • Lack of energy/fatigue
  • Poor concentration
  • Reduced or increased appetite 
  • Restlessness and agitation 
  • Slowed physical movements and thoughts
  • Trouble sleeping 
  • Thoughts of suicide


These symptoms persist most of the day every day for at least two weeks at a time.


A large proportion of people with TRD are also thought to be pseudo‐resistant, in which a patient doesn't respond to treatment because they were undertreated or misdiagnosed. Pseudo-resistance can also occur when a patient doesn't take their medication as they should. 

How common is TRD?

TRD is relatively common. It’s estimated that at least 30% of people with depression will develop TRD.7 International population studies have shown that more than 100 million people globally may be affected by TRD.8

However, differences in the definition of TRD have resulted in highly variable estimates of its prevalence rate.

Other research notes that up to 50-60% of patients in clinical care do not achieve an adequate response following antidepressant treatment.9


Around 10‐15% of patients in primary care have symptoms of clinical depression, but only about half of these cases are diagnosed. Of these, around 25% are prescribed antidepressant medication.10

People with chronic depression have a lower chance of recovery and are often affected by TRD.11

How is TRD diagnosed?

To be diagnosed with TRD, a patient must first be diagnosed with MDD (major depressive disorder) and then fail to respond to at least one (or two) antidepressant treatments.12

However, diagnosis can be problematic for several reasons. First of all, there is currently no clinical definition for “failure to respond” to antidepressant medication. There are also a number of other factors to consider, including the type of medication, the dose, the duration of treatment, and whether the patient has been taking it correctly. Current and past medications must also be considered, as some can interfere with antidepressants.
 

It should also be noted that around half of individuals with MDD are not correctly diagnosed. It can also be the case that someone with depression who has not responded to multiple antidepressants actually has bipolar disorder, which requires a different medication.13 In fact, it is reported that individuals prescribed multiple failed antidepressant trials (i.e. TRD) have a much greater likelihood of an underlying diagnosis of bipolar disorder as compared to persons prescribed a single antidepressant trial.14

What can you do if you suffer from TRD?

Managing TRD is different for every person, and you must discuss your treatment regime with your healthcare practitioner.
 

Currently, treatment options for TRD may include:


  • Methylfolate has been shown in numerous studies to improve response to antidepressants, including selective serotonin reuptake inhibitors (SSRIs). Methylfolate increases neurotransmitter production which then allows the antidepressant medication to take effect. Several clinical trials have found that taking 15mg L-methylfolate per day with an SSRI is more effective than taking SSRIs alone in people with depression.15

  • Esketamine (Spravato) is an FDA-approved, prescription-only nasal spray form of ketamine. It is only available through a restricted distribution system for adults who have tried multiple antidepressants without response.

  • Lithium is often prescribed for those with treatment-resistant depression to enhance the effect of antidepressants. However, its clinical efficacy is uncertain.16

  • Psilocybin (the chemical component of ‘magic mushrooms’) has been shown to produce positive and sustained antidepressant effects in patients with MDD and TRD when used alongside supportive psychotherapy. One trial found that 63% of 19 participants with TRD responded within one week of treatment, and 32% did not require any antidepressant or therapy for a further year.17 However, further research is pending.

  • Second-generation antipsychotics (SGAs) have also been investigated as adjunctive therapies in combination with antidepressants. These drugs are still being tested, but are known to have some effect on serotonin receptors, which enhance SSRI/SNRIs. SGAs that have been effective include quetiapine, aripiprazole, olanzapine and risperidone.18

  • Electroconvulsive therapy (ECT) is a recognized mode of treatment for a variety of mental disorders, including treatment-resistant depression. ECT is still the most consistently effective in patients with treatment-resistant depression, with a response rate of 50%–70%.19

  • Repetitive transcranial magnetic stimulation (rTMS) is emerging as a treatment for various psychiatric and neurological disorders. It is a safe, non-invasive treatment that involves using high and low-intensity magnetic fields to change cortical excitability in specific regions of the brain. The FDA has approved a range of rTMS devices for treating people with TRD.20

  • Neurofeedback is a type of therapy that helps people consciously control their brain waves using real-time feedback from electroencephalography (EEG) recordings. This treatment focuses on different brain wave types (alpha, beta, theta) and allows individuals to learn how to self-regulate their brain activity. Studies show that neurofeedback treatment may be effective alongside antidepressants.21

Living with treatment-resistant depression

If you have been diagnosed with depression and have not responded to antidepressants, there are still many ways to support your mental well-being.


Research shows that a nutritious diet can lower the risk of developing depression as well as support conventional treatment. Nutrients that can help enhance antidepressant therapy include folate (especially high-dose methylfolate), Omega-3 fatty acids, Vitamin D, zinc, magnesium, and Vitamin B12.22

A genetic test can reveal whether you are affected by a MTHFR mutation, which may mean methylfolate supplementation is a viable option. Speak to your healthcare professional. 

Other forms of therapy include ECT, rTMS, counselling, and adjunctive prescription medications. 

What is treatment-resistant depression (TRD)?

Treatment-resistant depression (TRD) occurs when depression doesn’t improve after taking at least two antidepressant medications. 1

Though there is no official definition of TRD, it is most commonly diagnosed after the individual has not responded to two or more antidepressant treatments given at an adequate dose for at least six weeks.2


A wide range of factors that might contribute to treatment resistance include a number of psychiatric/medical comorbidities, environmental stressors such as familial conflicts, marital discordance, postpartum depression, history of physical/sexual abuse, and genetic vulnerabilities.3 The diagnosis of TRD must consider a range of factors including the type of medication, duration of the depression, the patient’s adherence to medication, other medications or conditions that could impact treatment, and more.


The MTHFR genetic mutation is another possible cause of treatment-resistant depression. MTHFR is an enzyme responsible for catalyzing the conversion of folic acid and folate into L-methylfolate. L-methylfolate is required for neurotransmitter synthesis. A mutation on the MTHFR gene results in low levels of L-methylfolate and, subsequently, low levels of neurotransmitters, like serotonin, in the brain. 

Several studies show that people with the MTHFR C677T mutation have higher rates of depression.4 Antidepressants like SSRIs work by blocking the reuptake of serotonin, allowing more of it to remain available in the brain. This helps improve mood, but only if there’s enough serotonin to begin with. If serotonin levels are too low, the medication has little to work with.


This is where methylfolate can help. Methylfolate plays a key role in neurotransmitter production, including serotonin. If methylfolate levels are low, the brain may struggle to produce enough serotonin, which may then limit the effectiveness of antidepressants.
The good news is that methylfolate levels can be increased with supplementation. Studies show that taking methylfolate can improve the efficacy of antidepressants because methylfolate increases the availability of serotonin.5

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  • Vitamin B12 with Methyl for Neurotransmitter Synthesis10
  • 3rd-Party Tested for Purity, Potency & Safety
  • Pour Cap Contents Under Tongue for Max B12 Absorption

Product Recommendations

L Methylfolate 15 mg - A Mood-Boosting Supplement

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  • High-Dose L Methylfolate 15 Mg for Natural Mood Support²
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  • 90 Vegan, Non-GMO, Chewable Mint Tablets

Frequently Asked Questions about treatment-resistant depression

What are the symptoms of treatment-resistant depression?

Symptoms of TRD are the same as those of clinical depression, but in TRD, symptoms persist despite taking medication or other forms of treatment such as behavioral therapy or counseling. Symptoms of depression include persistent feelings of sadness and worthlessness, lack of joy in former interests, fatigue, changes in appetite, poor concentration, trouble sleeping, and thoughts of suicide. These symptoms must persist for most of the day over a period of at least two weeks.

Is there any hope for treatment-resistant depression?

Yes, there are many ways to manage and recover from treatment-resistant depression. Options include taking methylfolate alongside antidepressants, as methylfolate helps to increase the neurotransmitters that support healthy mood.23 Other prescription medications such as lithium, antipsychotics, and therapies such as rTMS are also available. Alternative therapy options like Esketamine and Psilocybin need further research, but have been gaining in popularity. Talk to your healthcare professional about the right treatment for you.

How to get rid of treatment-resistant depression?

TRD is a complex condition that may stem from many different factors. The right treatment for you depends on your own personal needs, so it’s best to consult with your healthcare professional. This may involve combining your current medication with methylfolate or other drugs, and/or therapies such as rTMS, ECT, and counseling.

References

  1. Shane J. O’Connor, Nilay Hewitt, Joanna Kuc, Lucinda S. Orsini; "Predictors and Risk Factors of Treatment-Resistant Depression: A Systematic Review"; The Journal of Clinical Psychiatry: 2023 Nov

    https://www.psychiatrist.com/jcp/predictors-risk-factors-treatment-resistant-depression-systematic-review/

  2. Abebaw Fekadu, Jacek G Donocik, Anthony J Cleare; "Standardisation framework for the Maudsley staging method for treatment resistance in depression"; BMC Psychiatry; 2018 Apr

    https://pubmed.ncbi.nlm.nih.gov/29642877/

  3. Khalid Saad Al-Harbi; "Treatment-resistant depression: therapeutic trends, challenges, and future directions"; Patient Preference and Adherence; 2012 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC3363299/

  4. Kemal Sayar, Samet Kose; "L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy"; Psychiatry and Clinical Psychopharmacology Vol. 28, No. 4, pg. 359-362; 2018

    https://www.tandfonline.com/doi/epdf/10.1080/24750573.2018.1552401?needAccess=true

  5. Richard C Shelton, J Sloan Manning, Lori W Barrentine, Eleanor V Tipa; "Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial"; The Primary Care Companion for CNS Disorders; 2013 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC3869616

  6. Roger S McIntyre, Mohammad Alsuwaidan, Bernhard T Baune, Michael Berk, Koen Demyttenaere, Joseph F Goldberg, Philip Gorwood, Roger Ho, Siegfried Kasper, Sidney H Kennedy, Josefina Ly‐Uson, Rodrigo B Mansur, R Hamish McAllister‐Williams, James W Murrough, Charles B Nemeroff, Andrew A Nierenberg, Joshua D Rosenblat, Gerard Sanacora, Alan F Schatzberg, Richard Shelton, Stephen M Stahl, Madhukar H Trivedi, Eduard Vieta, Maj Vinberg, Nolan Williams, Allan H Young, Mario Maj; "Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions"; World Psychiatry; 2023 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10503923/

  7. Roger S McIntyre, Mohammad Alsuwaidan, Bernhard T Baune, Michael Berk, Koen Demyttenaere, Joseph F Goldberg, Philip Gorwood, Roger Ho, Siegfried Kasper, Sidney H Kennedy, Josefina Ly‐Uson, Rodrigo B Mansur, R Hamish McAllister‐Williams, James W Murrough, Charles B Nemeroff, Andrew A Nierenberg, Joshua D Rosenblat, Gerard Sanacora, Alan F Schatzberg, Richard Shelton, Stephen M Stahl, Madhukar H Trivedi, Eduard Vieta, Maj Vinberg, Nolan Williams, Allan H Young, Mario Maj; "Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions"; World Psychiatry; 2023 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10503923/

  8. Global Health Data Exchange | Discover the World's Health Data

    https://ghdx.healthdata.org/

  9. Maurizio Fava; "Diagnosis and definition of treatment-resistant depression"; Biological Psychiatry; 2003 Apr

    https://pubmed.ncbi.nlm.nih.gov/12706951

  10. Brian W Pence, Julie K O'Donnell, Bradley N Gaynes; "The depression treatment cascade in primary care: a public health perspective"; Current Psychiatry Reports; 2012 Aug

    https://pubmed.ncbi.nlm.nih.gov/22580833/

  11. Brian W Pence, Julie K O'Donnell, Bradley N Gaynes; "The depression treatment cascade in primary care: a public health perspective"; Current Psychiatry Reports; 2012 Aug

    https://pubmed.ncbi.nlm.nih.gov/22580833/

  12. Maurizio Fava; "Diagnosis and definition of treatment-resistant depression"; Biological Psychiatry; 2003 Apr

    https://pubmed.ncbi.nlm.nih.gov/12706951

  13. Roger S McIntyre, Joseph R Calabrese; "Bipolar depression: the clinical characteristics and unmet needs of a complex disorder"; Current Medical Research and Opinion; 2019 Nov

    https://pubmed.ncbi.nlm.nih.gov/31311335/

  14. Cheng-Ta Li, Ya-Mei Bai, Yu-Lin Huang, Ying-Sheue Chen, Tzeng-Ji Chen, Ju-Yin Cheng, Tung-Ping Su; "Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study"; The British Journal of Psychiatry: The Journal of Mental Science; 2012 Jan

    https://pubmed.ncbi.nlm.nih.gov/22016435/

  15. Samet Kose, Kemal Sayar; "L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy"; Psychiatry and Clinical Psychopharmacology Vol. 28, Iss. 4; 2018 Dec

    https://www.tandfonline.com/doi/full/10.1080/24750573.2018.1552401

  16. Hiroko Sugawara, Kaoru Sakamoto, Tsuyoto Harada, Jun Ishigooka; "Predictors of efficacy in lithium augmentation for treatment-resistant depression"; Journal of Affective Disorders Vol. 125, Iss. 1–3, Pg. 165-168; 2010 Sep

    https://www.sciencedirect.com/science/article/abs/pii/S0165032710000042

  17. Robin L Carhart-Harris, Mark Bolstridge, James Rucker, Camilla M J Day, David Erritzoe, Mendel Kaelen, Michael Bloomfield, James A Rickard, Ben Forbes, Amanda Feilding, David Taylor, Steve Pilling, Valerie H Curran, David J Nutt; "Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study"; The Lancet Psychiatry; 2016 Jul

    https://pubmed.ncbi.nlm.nih.gov/27210031/

  18. Daphne Voineskos, Zafiris J Daskalakis, Daniel M Blumberger; "Management of Treatment-Resistant Depression: Challenges and Strategies"; Neuropsychiatric Disease and Treatment; 2020 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6982454

  19. Richard C Shelton, Olawale Osuntokun, Alexandra N Heinloth, Sara A Corya; "Therapeutic options for treatment-resistant depression"; CNS Drugs; 2010 Feb

    https://pubmed.ncbi.nlm.nih.gov/20088620/

  20. Sukhmanjeet Kaur Mann, Narpinder K. Malhi; "Repetitive Transcranial Magnetic Stimulation"; StatPearls [Internet]; 2023 Mar

    https://www.ncbi.nlm.nih.gov/books/NBK568715/

  21. Young-Ji Lee, Ga-Won Lee, Wan-Seok Seo, Bon-Hoon Koo, Hye-Geum Kim, Eun-Jin Cheon; "Neurofeedback Treatment on Depressive Symptoms and Functional Recovery in Treatment-Resistant Patients with Major Depressive Disorder: an Open-Label Pilot Study"; Journal of Korean Medical Science: 2019 Oct

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6823520/

  22. Agnieszka Mechlińska, Adam Włodarczyk, Marta Gruchała-Niedoszytko, Sylwia Małgorzewicz, Wiesław Jerzy Cubała; "Dietary Patterns of Treatment-Resistant Depression Patients"; Nutrients; 2022 Sep

    https://pubmed.ncbi.nlm.nih.gov/36145142/

  23. Samet Kose, Kemal Sayar; "L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy"; Psychiatry and Clinical Psychopharmacology Vol. 28, Iss. 4; 2018 Dec

    https://www.tandfonline.com/doi/full/10.1080/24750573.2018.1552401#d1e241

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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