Endless Medicines Don't Work for Depression

A new study comparing rTMS and medications again affirms its superiority

The Frontier Psychiatrists is a daily-enough health-themed newsletter. It covers effective treatments as one of our favorite beats. Recurrent Transcranial Magnetic Stimulation (rTMS) is one such approach.

Today, we have a new paper from Dalhuisen, et. al., published in AJP in Advance, that evaluates patients with depression who have not been helped by multiple trials of medication. ¹

Avid readers will recall my coverage of the ASCERTAIN-TRD trial, in which rTMS was compared to both switching antidepressant medicines or augmentation with aripiprazole after one oral antidepressant didn’t work as a first-line treatment. Short version—it’s better. By a lot:

In today’s addition to the massive pile of evidence that rTMS is a better treatment than medicines that have proven not to work, the authors evaluated N=89 individuals who had an inadequate response to prior medication trials. They proceeded to randomize those subjects to either 25 TMS sessions or switch to another antidepressant medicine based on a Dutch algorithm (given where the study was performed). This paper reports on 8-week outcomes.

Two notes on this approach—25 sessions of TMS is less than the FDA-approved course of 36, and half of the sessions in SAINT. So, if anything, they were handicapping rTMS as an intervention in this study— biasing it towards not demonstrating a difference. It’s also worth noting there was nothing fancy about this rTMS treatment. It used figure-8 coils without fancy neuronavigation at what are now ancient parameters.²

Table one? It checks out (in that the groups are not different; thus, the randomization was successful, although I wish they would note that in the table itself).

What they found is crucial to understand, and an indictment of the cruel standards of Big Health in the US:

rTMS resulted in a significantly larger reduction in depressive symptoms than medication, which was also reflected in higher response (37.5% vs. 14.6%) and remission (27.1% vs. 4.9%) rates.

Let me lean in for a moment—under 5% of patients randomized to oral medicine experienced remission of their depression.

The least fancy rTMS, which has been around with an FDA label since 2008? That got 27% of people into remission. These were not the most unwell patients:

Inclusion criteria were moderate to severe (a score >16 on the 17-item Hamilton Depression Rating Scale [HAM-D]) unipolar MDD without psychotic symptoms, with an inadequate response to at least two treatment trials (of which at least one was an antidepressant trial of an adequate dose and duration) and a current depressive episode duration of less than two years.

As someone running two clinical trials on accelerated rTMS protocols for depression RIGHT NOW at Fermata in New York, I can tell you that plenty of people have depression that has gone on longer than two years in the current episode. One gripe about this paper—the CONSORT diagram doesn’t include the number screened out; it starts with those who signed informed consent:

In the author’s favor, when it comes to anticipating nit-picking science writers like yours, truly, every subject also got a minimum of weekly group or individual psychotherapy.

After two failed trials, rTMS was vastly superior to oral antidepressant switch medication. This finding nicely echoes the Ascertain-TRD trial, where it was found to be superior after one prior antidepressant trial. Now, dear readers, my predictable indictment of healthcare policy in America: I did a review just this week of coverage policies:

Many are still using four medication trials as a standard. Some have lowered the barrier to two failed trials. The Big Health companies based that “4 medication failure” standard not on science— but, instead, on the average number of trials in the 2008 FDA-approval trial for rTMS. They made it up. Patients have suffered from its arbitrary limitations ever since.

We now know that:

1. The STAR*D trial misrepresented antidepressant effectiveness, and TMS is vastly better.

2. TMS is better after the first oral medicine has not worked.

3. After the second medicine, there is less than a 5% chance of remission in samples like those in the above paper.

The arbitrary, capricious, and—to be frank—sadistic “more failed meds” barrier to rTMS treatment, which is safer and more effective than oral medicines, needs to go away.

Oh, and it’s more cost-effective, also.

1. Dalhuisen, I., van Oostrom, I., Spijker, J., Wijnen, B., van Exel, E., van Mierlo, H., ... & van Eijndhoven, P. rTMS as a next step in antidepressant non-responders: a randomized comparison with current antidepressant treatment approaches. rTMS AS A TREATMENT FOR DEPRESSION, 169.

2. RTMS. The resting motor threshold was determined at the Beginning of every week and was defined as the minimal stimulation intensity that evoked a visible contraction in the muscle of the right thumb in ≥5 out of 10 trials. The Beam-F3 method was used to localize the left dorsolateral prefrontal cortex (7). rTMS was conducted using a high-frequency protocol (10 Hz), applying 60 trains of 50 pulses with a duration of 5 seconds and an intertrain interval of 25 seconds (3,000 pulses per session), at an intensity of 120% of the resting motor threshold. Over the course of 8 weeks, 25 sessions were scheduled (see Table S1 in the online supplement).