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Can we predict TMS response

Is it possible to predict nonresponse to Transcranial Magnetic Stimulation (TMS) in major depressive disorder?

Treatment resistant depression

Depressive disorders are arguably one of the most researched topics in psychology, research which has spawned a plethora of treatment options for those who struggle with profound symptoms of depression. Unfortunately, treatment resistant conditions are ubiquitous among psychiatric disorders and depression is no exception. Many patients who suffer from major depressive disorder (MDD), or any psychological disorder where the primary complaint is depressive symptoms, find their condition to be resistant to both standard and alternative treatment methods.

How responsive is MDD to antidepressant medication?

Medication is often the first treatment option explored when confronted with a diagnosis of depression. However, it is a well documented fact that medication falls far short of 100% efficacy rates in terms of treating depression. In an article presented on the Institute for Quality and Efficiency in Health Care page they place the response rate of depressed patients to antidepressant medication somewhere between 40 and 60% which is only 20% higher than response rates achieved with placebo treatment (2020).

Different treatments for the same condition

Rush et al. (2006), conducted an ambitious study in which they offered participants several treatment options in a four step program which was primarily based around psychiatric medications, but did integrate some elements of cognitive therapy. Utilising this comprehensive treatment progression plan they attained an overall cumulative remission rate of 67%. Interestingly only 36.8% of patients achieved remission with the first treatment they tried, 30.6% on the second, 13.7% of patients by the time they opted for phase 3, and 13.0% only managed to achieve remission on the fourth and final acute treatment step. This landmark study demonstrates just how difficult it is to determine the most effective treatment for depression with different cases varying widely in terms of their responsivity.

To complicate matters further, Casacalenda et al. (2002), found that psychiatric and psychotherapeutic interventions were equally effective in the treatment of depression. This means that there is no obvious treatment option for MDD patients to favour.

Determining responsiveness to treatment

Despite this difficulty in determining the correct course of treatment, it is crucial to identify when a patient is not responding to a particular treatment as quickly as possible. The suffering associated with MDD is common knowledge and one of the main global goals of mental health treatment is to alleviate suffering as quickly, safely and sustainably as possible. Furthermore, many patients with MDD can pose a risk to their own safety if suicidal ideation is present. In a comparison between patients with MDD and control groups, the lifetime prevalence of suicidal ideation, suicide planning and suicide attempts were observed to be 13.97, 9.51 and 3.45 times higher respectively (Cai et al., 2021). Therefore, it is doubly important to ensure that an effective treatment is identified in a timely manner when managing depression.

Treatments often need time to work

However, this urgency needs to be tempered with patience as many treatments for depression require a number of weeks to take effect before the signs of improvement become apparent. Antidepressants can take anywhere from one to eight weeks before a patient can expect to feel any effects (Perez & Sutherb, 2021). It is hypothesised that antidepressants do not act as direct mood enhancers but rather shifts the balance in emotional processing from the negative to the positive which then has a knock-on effect on mood thus accounting for the delay (Harmer et al., 2018). Talk therapy can have an immediate relieving effect on those who avail of it, but in some cases, it can take months for an individual to build up sufficient trust with their therapist and subsequently yield the maximum therapeutic benefit (Gould, 2023).

TMS and MDD

TMS has emerged as a very promising treatment for a range of psychological disorders including MDD. Reardon et al. (2007) measured TMS treatment to be significantly more effective than sham treatment in a multisite, randomised, controlled trial. This finding was then supported by naturalistic data analysed by Carpenter et al. (2012). Based on its non-invasive nature, high success rate and efficiency at treating resistant conditions it has been suggested that TMS should be the first line of treatment considered when treating depression (Sackheim et al., 2023).

How quickly does MDD respond to TMS?

In terms rate of response, TMS is no different than other treatments for depression in that some patients will feel positive effects very soon after commencing treatment, while it can take others considerably longer to respond.

Feffer et al. (2018), found that patients achieving <20% improvement at session 10 were correctly predicted as non-responders with negative predictive values (NPV) of over 80% accuracy. This result suggests that a patient’s suitability to TMS can be determined early in the treatment process. However, Beck et al. (2020), found similar levels of accuracy when assessing patients at week 2 of treatment but found that the accuracy of their NPV was greatly diminished when the course of treatment was extended beyond week 4.

Latent responders

Hutton et al. (2023), found that on average approximately half the improvements in a patient’s symptoms would be achieved by their 10th TMS session. However, they also discovered that 15.7% of patients in the extended treatment group only began responding after session 30, and that from the 30th session onwards, remission rate increased from 14.7% to 29.7% in this cohort. This demonstrates that there is a sizable contingent which show a delayed responsivity to TMS treatment. For this reason, it can be difficult to determine at what point one can conclude that a particular patient will not respond to TMS treatment.

Predicting responsiveness

Hutton et al., carried out an additional study in 2024 where they attempted to predict responsivity rates in TMS patients. They found that an early positive response was a good predictor of high responsivity which meant they could achieve a high accuracy rate when predicting responder rates as early as session 10. However, the sizable cohort of latent responders, discussed above, meant that their ability to predict non-responders was poor when using data from only the first 10 sessions. At the 10 session assessment, nearly half the patients predicted to be non-responders were later classified as endpoint responders. This rate improved in subsequent assessments but never reached adequate levels to be able to inform clinical decisions.

When to hold and when to fold

These studies suggest that while an early response to TMS treatment is a strong indication of an overall positive response, there is a substantial minority of patients who will not respond until later in their treatment. As such, it could be worth extending the window of time afforded to patients to respond to TMS treatment, potentially up to 30 sessions. However, it is also important to consider that if a patient does not respond to treatment by session 10, their likelihood of ultimate responsivity drops to about 50% based on Hutton et al.’s findings (2024).

Statistics do not always mean much to the individual and as discussed above there is a minority of patients who first respond to TMS treatment only after their 30th session. However, it is important that patients are aware that while they may show an initial response beyond the first ten sessions, their chances of this occurring are worse than if they show an early positive response. Patients can bear this in mind when considering whether it is worth investing the time and resources associated with TMS treatment for the chance of noticing an improvement beyond their 10th session.

Written by our Dublin practitioner, Joe.

References

  1. Beck Q.M., Tirrell E., Fukuda A.M., Kokdere F., Carpenter L.L., (2020) Can early treatment response serve as a predictor of antidepressant outcome of repetitive Transcranial Magnetic Stimulation? Brain Stimul;13(2):420-421
  2. Cai H, Xie XM, Zhang Q, Cui X, Lin JX, Sim K, Ungvari GS, Zhang L, Xiang YT. (2021) Prevalence of Suicidality in Major Depressive Disorder: A Systematic Review and Meta-Analysis of Comparative Studies. Front Psychiatry.
  3. Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA. (2012) Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety;29(7):587–96.
  4. Casacalenda, N., Perry, C., Looper, K., (2002) Remission in Major Depressive Disorder: A Comparison of Pharmacotherapy, Psychotherapy, and Control Conditions. American Journal of Psychiatry, Vol 159 Issue 8
  5. Feffer K, Lee HH, Mansouri F, Giacobbe P, Vila-Rodriguez F, Kennedy SH, Daskalakis ZJ, Blumberger DM, Downar J, (2018) Early symptom improvement at 10 sessions as a predictor of rTMS treatment outcome in major depression. Brain Stimulation
  6. Gould, W.R., (2023) How long does it take for therapy to work? Very Well Mind https://www.verywellmind.com/how-long-does-it-take-for-therapy-to-work-6834455
  7. Harmer, C.J., Goodwin, G.M., Cowen, P.J., (2018) Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Cambridge University Press
  8. Institute for Quality and Efficiency in Health Care (2020) Depression: How effective are antidepressants? https://www.ncbi.nlm.nih.gov/books/NBK361016/
  9. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA. (2007) Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry;62 (11):1208–16
  10. Perez, A., & Sutherb, R., (2021) How Long Do Antidepressants Take to Work? Psych Central https://psychcentral.com/depression/how-long-do-antidepressants-take-to-work
    Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905–17.
  11. Sackeim, H.A., Aaronson, S.T., Carpenter, L.L., Hutton, T.M., Pages, K., Lucasi, L., Chen, B., (2024) When to hold and when to fold: Early prediction of nonresponse to transcranial magnetic stimulation in major depressive disorder. Brain Stimulation (17) 2, pp272-282
  12. Sackeim HA, Aaronson ST, Carpenter LL, Hutton TM, Mina M, Pages K, et al. Clinical outcomes in a large registry of patients with major depressive disorder treated with Transcranial Magnetic Stimulation. J Affect Disord 2020;277:65–74.