I recently read the randomized controlled trial for a new neuromodulation device called ProlivRX. It’s an external nerve stimulator that is now FDA approved for major depressive disorder in patients who are already on antidepressants and haven’t benefited from them.
This comes on the heels of the recent FDA approval of the Flow Neuroscience FLX-100 transcranial direct current stimulation (tDCS) device for depression. It’s interesting that we’re seeing multiple new neuromodulation devices entering the space at the same time, and that both are home-based treatments.
The randomized controlled trial was reasonably sized with 124 patients total. It was a blinded, sham-controlled, multi-site trial, and it was industry sponsored by the device manufacturer, NeuroLief, an Israeli company.
The device stimulates branches of the trigeminal nerve along the forehead as well as occipital nerve branches at the back of the head. There has actually been another trigeminal nerve stimulation device that was FDA cleared for ADHD in the past. A more recent randomized controlled trial of trigeminal nerve stimulation for ADHD in children and adolescents was negative, it did not show benefit over placebo.
In this trial, the authors point to studies suggesting that stimulating these nerves can affect brain circuits involved in mood regulation and attention networks. At some level, everything in the brain is connected, so stimulating one peripheral input is going to have downstream effects somewhere else. I’m not particularly impressed by that line of reasoning on its own, but it provides the rationale for why they tested this approach. Their specific hypothesis was that combining trigeminal and occipital nerve stimulation might be synergistic.
The currents used in this trial were quite high compared to tDCS. Typical tDCS uses about 1–2 milliamps, whereas this device used currents in the range of roughly 6–18 milliamps. That’s a substantial difference, and it would definitely be noticeable to the patient. That said, the electrodes are spaced much closer together and the current is passing through superficial tissue rather than through the skull, as in tDCS. The device also uses a biphasic alternating current rather than direct current, so the electrical properties are quite different overall.
The sham condition involved stimulation at a much lower current amplitude and lower frequency. Based on their blinding integrity testing, the blind mostly held. About 14% of participants in the active group correctly guessed they were receiving active treatment, and about 6% in the sham group correctly guessed they were in the sham condition. The authors modeled the effects of this partial unblinding and concluded that it did not meaningfully alter the primary outcome.
The primary result was a statistically significant effect. The active treatment group had about an 8-point reduction on the Hamilton Depression Rating Scale, compared to about a 6-point reduction in the sham group. That works out to roughly a 2.6-point difference between groups. This translated into an effect size of around 0.7 to 0.8, which is surprisingly large given the relatively small absolute difference on the Hamilton scale.
Effect sizes, of course, depend heavily on variability. My suspicion is that the trial design intentionally limited variability, shrinking the denominator in the effect size calculation and inflating the apparent magnitude. I’ll probably write more about this in the future, because this is a general issue with how effect sizes are interpreted. For context, typical SSRI trials show effect sizes around 0.3–0.4, so an effect size approaching 0.8 stands out—especially in a population that includes patients who have already failed antidepressant treatment. I can’t recall whether all participants met strict criteria for treatment-resistant depression, but at least a subset had failed two or more antidepressant trials.
If you look at remission rates, the results are more modest. Remission was on the order of 20–30%, with somewhat higher response rates. Still, if those numbers hold up, a roughly 20% remission rate for a relatively benign, home-based treatment may be meaningful for some patients.
The randomized portion of the trial lasted eight weeks, which is when the primary outcome was assessed. After that, the study continued in an open-label phase for an additional sixteen weeks. Once participants were unblinded, they continued treatment and showed incremental improvement over that longer period, which is encouraging.
The treatment protocol involved using the device for 40 minutes at a time, twice daily, five to seven days per week.
There were essentially no major device-related adverse events reported.
So what do we make of all this? I’ve already hinted at some skepticism. Most psychiatric treatments—whether medications, ECT, or neuromodulation—do fairly nonspecific things. That’s likely why many treatments have efficacy across multiple diagnoses that probably involve very different underlying mechanisms. The brain is deeply interconnected, and almost any intervention will have widespread effects.
This was an industry-sponsored trial, and while the authors offer putative mechanisms, the true mechanism is no clearer than it is for most psychiatric interventions. In terms of mechanism, the neuromodulation modality where we have the most hypothesis-driven, model-based understanding is probably TMS, where focal stimulation and functional imaging allow for more direct testing of circuit-level theories.
Another important point is timing. The primary outcome wasn’t reached until week eight, with further gradual improvement afterward. This is not an acute treatment for severe or urgent depression. For someone who is severely ill or needs rapid symptom relief, options like ketamine, ECT, or aggressively titrated medications are likely more appropriate.
That said, for patients with lower-urgency depression who are well resourced and can afford a device like this, it may be reasonable to try. If I were choosing between this device and a home-based tDCS device, I would personally lean toward tDCS, simply because there is a much larger research literature and somewhat more confidence about the circuits being targeted. Still, this appears to be a relatively harmless intervention. The worst-case scenario is mostly lost time and money.
For low-urgency depression, it’s worth considering. And, as always, it’s helpful to have more tools in the toolkit.
