Co-authored by Eugene Rubin, M.D., Ph.D., and Charles Zorumski, M.D.
About one-third of patients with major depressive disorder do not respond adequately to medications and/or psychotherapy. If an individual hasn’t responded to two adequate trials of antidepressants, the chances of a good response to a third medication trial is less than 15 percent.
Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression. Would rTMS help people with major depressive disorder who have failed to respond to two medication trials? Does rTMS work better than a third medication trial? These questions are addressed in a study recently published in the American Journal of Psychiatry by Iris Dalhuisen and colleagues.
Study Design
These investigators compared the benefits of rTMS in combination with psychotherapy to a switch to a new medication in combination with psychotherapy. Adult patients with moderate to severe nonpsychotic unipolar depression were recruited from six specialized mental health centers in the Netherlands. All had experienced inadequate response to at least two treatment trials at least one of which was with medications.
Eighty-nine participants were randomly assigned to receive either rTMS in conjunction with their current antidepressant (if applicable) plus psychotherapy or a trial of a new medication plus psychotherapy. The medication chosen for each participant in the medication arm of the study was determined by a specific treatment algorithm.
This was an 8-week “pragmatic randomized controlled” trial. Over the 8-week study, participants treated with rTMS received 25 treatments using standard high-frequency (10 Hz) stimulation of the left dorsolateral prefrontal cortex with 3,000 pulses per session. Subjects in both treatment groups received psychotherapy of different types at least once per week.
The current publication reports the results at the end of the 8-week trial. Results from longer-term follow-up will be reported in the future.
Response to treatment was assessed with the Hamilton Depression Rating Scale (Ham-D), a standard instrument used to quantify depression severity. Response to treatment was defined as a 50 percent reduction in HAM-D scores, and remission of symptoms was defined as a HAM-D score of less than 8.
In addition, various scales were utilized to assess specific symptoms, for example, anxiety, anhedonia (lack of interest or pleasure), and rumination. Patient expectations of both treatments were measured at baseline by the Credibility/Expectancy Questionnaire.
It is important to note that this was not a blinded study. Both participants and evaluators were aware of which treatment an individual was receiving.
Results
There were substantial and clinically relevant differences between the two treatment arms of this study. After 8 weeks, there was a higher response rate with rTMS than with a medication switch (37.5 percent vs. 14.6 percent). Even more impressive, 27.1 percent of those treated with rTMS were in remission compared to 4.9 percent of those who switched to a new medication. A greater decrease in symptoms of anhedonia and anxiety was observed in the rTMS group.
Participants’ expectations of improvement with each treatment modality at baseline were correlated with improvement measured at eight weeks. Thus, placebo effects may have had some influence on the observed outcomes. It also appears that individuals in the rTMS group may have spent increased time with research personnel in the process of receiving 25 rTMS treatments. It is possible that this increased attention may have had an impact on response and remission rates.
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Reflections
Treatment-resistant depression and its associated disabilities are major health problems. A treatment that helps over 25 percent of people with refractory depression achieve remission is potentially a major step in the right direction.
The authors note that the follow-up period for this study is ongoing. These results will be crucial in determining the longer-term benefits of rTMS, as well as its cost-effectiveness. It will also be important to replicate the results of this study in trials with more complex designs to control for subject expectations and contact with study personnel.
There are now several approaches to treating moderate to severe depression, including psychotherapies, medications, rTMS, electroconvulsive therapy (ECT), and ketamine/esketamine. Developing new and better treatments for this disabling illness will go a long way in lessening disabilities and improving overall health.