Updates in Treatment-Resistant Depression

woman suffering from depression sat in the corridor and cried.
Although brain stimulation techniques are not considered first-line treatments, these are often used in treatment-resistant depression, with electroconvulsive therapy representing the established best therapeutic option for treatment-resistant depression.

According to the National Institute of Mental Health, major depressive disorder (MDD) affects an estimated 7.1% of adults and 13.3% of adolescents in the United States. A substantial portion of these individuals – approximately 35% of adults and 60% of adolescents – did not receive any type of treatment for depression.1

Other reports indicate that among those who do receive treatment for MDD, at least 30% of patients demonstrate resistance to antidepressant medications.2,3 While there is ongoing debate regarding the conceptualization of treatment-resistant depression (TRD) – including how it should be staged and whether the term is even appropriate – there is a general consensus that patients who do not respond adequately to 2 trials of antidepressant pharmacotherapy meet the definition of TRD.2

For patients with an inadequate or no response to a first-line antidepressant medication, the standard approach is augmentation with a second agent; those with the strongest supporting evidence of efficacy vs placebo are lithium, T3, and second-generation antipsychotics. Subsequent strategies typically include switching medications (with best results shown for switching to a different class), shifting to psychotherapeutic approaches after several failed medication trials, or combining medication with psychotherapy or other modalities.2

Although brain stimulation techniques are not considered first-line treatments, these are often used in TRD, with electroconvulsive therapy representing the “established best therapeutic option for TRD,” according to a paper published online in January 2020 in Neuropsychiatric Disease and Treatment.2 Findings suggest response rates of more than 50% and superiority to placebo, sham electroconvulsive therapy (ECT), and antidepressant agents. Repetitive transcranial magnetic stimulation (rTMS) is another FDA-approved approach that has demonstrated efficacy for depression treatment across multiple RCTs.2

To learn more about these and other updates in TRD treatment, we interviewed Irving Reti, MBBS, MD, research psychiatrist and associate professor in the Departments of Psychiatry and Neuroscience at the Johns Hopkins University School of Medicine, and director of the Electroconvulsive Therapy Service at the Johns Hopkins Hospital in Baltimore, Maryland (and co-author of guidelines on treating depression with rTMS4); and Amit Anand, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine, vice-chair for Research for the Center for Behavioral Health, and director of the Mood and Emotional Disorders Across the Life Span (MEDALS) program at the Cleveland Clinic in Cleveland, Ohio.

What have been the most notable recent developments in the area of TRD?

Dr Anand: The main development in this area has been the introduction of ketamine and ketamine-like drugs. Prior to the 2019 approval of intranasal esketamine, there had not been an approval of a new antidepressant for many years. [Editor’s note: In a randomized controlled trial (RCT) investigating intranasal ketamine, 44% of patients met response criteria 24 hours after ketamine administration vs 6% of placebo (P =.033).]5 However, intravenous ketamine is still commonly used because the new drug is very expensive. 

The N-methyl-D-aspartate (NDMA) antagonists including ketamine, nitrous oxide, and dextromethorphan, and psychedelic drugs such as psilocybin are currently the 2 main areas of interest.

ECT is still one of the best therapies for TRD.

Dr Reti: In the TMS field, the hottest thing at the moment is theta burst stimulation, which uses pulses that are consistent with patterns of firing in the brain and might be longer-lasting. The first study of this technique demonstrated long-term connectivity changes in the motor system, and it has more recently been investigated as a treatment for depression.6

A recent open-label study showed a high rate of remission, and this is being followed by a RCT.7 [Of the 21 participants, 90.5% met remission criteria (score of <11 on the Montgomery-Åsberg Depression Rating Scale).]

Another area of TMS with that has garnered a lot of interest is deep TMS that utilizes a different coil (H1-coil) design than the traditional figure-8 coil – in which the field is strongest at the central segment, so it’s very focal and relatively superficial.

[In a double-blind RCT published in World Psychiatry in 2015, patients undergoing deep TMS demonstrated higher response and remission rates compared to those in the sham group (response: 38.4 vs 21.4%; remission: 32.6 vs 14.6%), and these differences remained stable at 12 weeks.]8

Israeli post-docs9 developed a coil that stimulates more deeply and also diffusely, so it may be more likely that you wind up hitting the circuits you need to, compared to sort of hoping you’re hitting the right area with the figure-8 coil. [In a 2019 study, the H1-coil was associated with a significantly better response compared to the figure-8 coil (OR, 2.33; 95% CI, 1.04–5.21 (P =.040).]10 Just one trial so far shows superiority, but there is a lot of interest in whether this design is more effective than the figure-8 design.

What should be the focus of additional research in this area?

Dr Anand: We are conducting a large study (ELEKT-D) comparing the effectiveness of ECT vs ketamine in treating TRD.11 We had planned to produce results next year but have experienced delays due to COVID-19.

In other studies, rTMS should be compared to ketamine and other approaches, and researchers are still trying to identify the optimal area of the brain to stimulate to get results with deep brain stimulation. There is also ongoing interest in GABAergic neurosteroids for depression treatment.12

Dr Reti: In line with a precision medicine approach, one major area of focus is the identification of biomarkers that can predict response treatment, particularly for TMS which is very expensive and time-consuming. The hope is that with genetics, EEG, and functional neuroimaging we will be able to get to that point. For example, there is a lot of interest in neuroimaging work with pathways of connectivity to indicate whether a patient is more likely to respond to a given therapy.

In clinical practice, what is the optimal approach to identifying adequate treatment strategies for patients with TRD?

Dr Anand: First, look at the diagnosis again and confirm that it is correct. Are there personality issues, major stressors, or schizophrenia, for example? These will not respond to antidepressant therapies. Next, confirm that the patient is compliant and taking the meds properly. Then, it becomes a stepwise approach of trying different meds using available treatment algorithms. 

As genetic testing, algorithms, and neuroimaging techniques continue to become more refined, these tools could ultimately help to guide treatment in TRD.

What are other needs to consider regarding treatment for this patient group?

Dr Reti: TMS is still investigational and not yet part of routine practice. As things currently stand, if you have a patient who is very ill – suicidal, catatonic, or clearly psychotic – and need a response quickly, then you do ECT rather than TMS. ECT is the standard for these patients.


According to the rTMS guidelines, Irving Reti, MBBS, MD reported current or prior research support from the National Institutes of Health, the US Department of Defense, the Hope for Depression Research Foundation, the Simons Foundation Autism Research Initiative, The Dana Foundation, The Johns Hopkins University School of Public Health, Neuronetics, and Brainsway and is also under contract with John Wiley and Sons for editing the volume Brain Stimulation: Methodologies and Interventions.”

According to his Cleveland Clinic bio, Amit Anand, MD has reported no financial relationship with industry that is applicable to this listing as of 7/17/1019.


1.     National Institutes of Mental Health. Major depression. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Updated February 2019. Accessed on August 3, 2020.

2.     Voineskos D, Daskalakis ZJ, Blumberger DM. Management of treatment-resistant depression: challenges and strategies. Neuropsychiatr Dis Treat. 2020;16:221-234.

3.     Murphy JA, Sarris J, Byrne GJ. A Review of the conceptualisation and risk factors associated with treatment-resistant depression. Depress Res Treat. 2017;2017:4176825.

4.     McClintock SM, Reti IM, Carpenter LL, et al. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry. 2018;79(1):16cs10905.

5.     Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970-976.

6.     Li CT, Cheng CM, Chen MH, et al. Antidepressant efficacy of prolonged intermittent theta burst stimulation monotherapy for recurrent depression and comparison of methods for coil positioning: a randomized, double-blind, sham-controlled study. Biol Psychiatry. 2020;87(5):443-450.

7.     Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford Accelerated Intelligent Neuromodulation Therapy for treatment-resistant depression. Am J Psychiatry. 2020;177(8):716-726.

8.     Levkovitz Y, Isserles M, Padberg F, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry. 2015;14(1):64-73.

9.     Heller C. Israeli scientists probe deeper to lift depression. Reuters. https://www.reuters.com/article/us-israel-depression/israeli-scientists-probe-deeper-to-lift-depression-idUSL0557346920061207. Accessed on August 6, 2020.

10.  Filipčić I, Šimunović Filipčić I, Milovac Ž, et al. Efficacy of repetitive transcranial magnetic stimulation using a figure-8-coil or an H1-Coil in treatment of major depressive disorder; A randomized clinical trial. J Psychiatr Res. 2019;114:113-119.

11.  Cleveland Clinic. ELEKT-D study information. http://elektd.org/study-information/. Accessed on August 3, 2020.

12.  Zorumski CF, Paul SM, Covey DF, Mennerick S. Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiol Stress. 2019;11:100196.