The Fisher Wallace website declares: “New pilot study finds the Stimulator ® effective in treating bipolar depression: FDA-cleared wearable device available to treat six million bipolar depression patients.”1

Is this true? Well, it’s true that such a study has been published-a small randomized trial in patients with bipolar II.2 Now it’s up to you to evaluate the results, because patients who have $700 may be asking you to sign the authorization form to buy one of these devices ($600 for veterans-an interesting twist). Or they can just buy an Alpha-Stim, another device used for cranial electrotherapy stimulation (CES), without any authorization. Perhaps you should buy one of these devices and make it available for patients to try, so they won’t spend their cash until they know it works for them.

Wait a minute! Why are we even considering a treatment with no evidence for efficacy except this new 16-patient pilot study? Because, as the authors of the trial point out, the top options for treatment of bipolar depression are the olanzapine-fluoxetine combination and quetiapine, with their attendant very large risks. These are not your top medication options? Not mine either, yet they are the principal recommendations from Britain’s National Health Service and others.3,4 The pilot study’s authors demote my 2 top medication choices for bipolar II, lamotrigine and lithium, because of marginal evidence for efficacy, citing a meta-analysis by Calabrese and colleagues5 (though Calabrese co-authored a subsequent meta-analysis with a different conclusion6).

Regardless of such debates, another option for the treatment of bipolar depression is needed. So let’s look at this new study. First, an attitude check: are you hoping to find evidence in this small trial that CES is a potential treatment for bipolar depression? Or are you doubting the possibility that putting a pair of electrodes on a patient’s temples and passing a small current through the brain tissue will produce a targeted effect on mood? Skeptics should try the believers’ rose-colored glasses, because without them you’ll likely find in this study that evidence for efficacy is almost non-existent. Likewise, believers should wear the skeptics’ dark pair, because although the results here are “positive” in at least one respect, they require careful evaluation and interpretation, not unconsidered adoption as evidence of efficacy.

Perhaps it would be best to try on both pairs and look at this study through each: one view framed by hope for a new treatment option we strongly need; the other by a do-no-harm philosophy that requires new treatments to prove their worth, especially if they carry potential or unknown risk, or significant expense.

Reading the study

Don’t just start at the beginning and plod through from the introduction. You already know we need a new treatment for bipolar depression and that CES is being studied as an option. Jump straight to the results (if these are not impressive, there’s little reason to delve further, unless you’re particularly interested in this technique). In the new study, using the Beck Depression Inventory (BDI), the authors found active CES markedly superior to a sham version, producing a 13-point drop in 2 weeks, versus a 4-point drop in the control group. If you know the BDI at all, you’ll recognize this as clinically as well as statistically significant (P = .016). If you started reading my review hoping for positive evidence for CES, there you go. We’ll put the skeptics’ lenses on and return to this finding shortly.

Having found a striking positive, now it makes sense to examine the methods: who participated in the study (are they at all representative of my patients?), what did the investigators do (can I do this?), and what array of outcome measures did they plan (have they cherry-picked the results?). Here we find that the researchers studied 16 patients with bipolar II depression-a very small sample, but that’s the nature of a pilot study. Seven patients were randomized to CES using a Fisher-Wallace device; temporal electrodes were applied in the clinic. The other 9 subjects received sham treatment: the electrodes were placed and the current turned on until they could feel a tingling, but then instead of being left on at a slightly lower dose as the active CES patients received, the current was turned off. These blinded treatments were given for 20 minutes per day, 5 times per week for 2 weeks.

The primary outcome measure was the BDI. The Hamilton Rating Scale for Depression (HAM-D) was also used, but the authors cite an analysis that suggests the BDI is better at predicting outcomes than the HAM-D.7 This turns out to be a crucial assumption: more on that shortly, wearing the skeptics’ lenses.

Finally, did anything bad happen? (Evidence for benefit in a tiny sample of patients would not be sufficient to justify this treatment if there were significant problems.) Fortunately, there were no adverse events, including induction of manic symptoms. Using the Young Mania Rating Scale (YMRS),8 the authors found no significant differences between the groups after 2 weeks of treatment: YMRS scores were 1.14 and 0.22 for active and sham, respectively, and on this scale even a mild hypomania could easily generate a score of 3 to 5. Only with the darkest skeptics’ lenses can one maintain a concern about emergent hypomania with these values. There are bigger problems, however.

Donning the skeptics’ lenses

The study ran for another 6 weeks with an open, unblinded continuation (dropouts were not reported). At the 8-week mark, the BDI difference between active and sham treatments was no longer statistically significant, although a positive trend remained (P = .09). So while through rosy lenses this study could be interpreted as positive based on the BDI at 2 weeks or the trend data at 8 weeks, overall the study technically has a negative outcome. Moreover, the HAM-D was negative even at the 2-week mark: patients’ scores fell from baseline by 5.6 and 7.3 points for sham versus active treatments, respectively (P = .496).

Recall that the authors dismissed the HAM-D as less useful than the BDI longitudinally. But the reference the authors cite for this dismissal does not actually say the HAM-D is less effective for predicting outcomes. It says “self-report and clinician rating each provide unique data that is relevant to clinical prognosis.”7

The patients were taking multiple medications, including 5 in each group who were receiving antidepressants, so this is a study of an “adjunct” treatment, though not billed as such. Finally, initial severity of symptoms was sufficiently low (mild in one patient; moderate within the rest of the CES group) that there may have been a “floor” effect, preventing separation from placebo, as has been reported for the majority of antidepressant studies in MDD.9

Perhaps you think that I am being unduly hard on a small pilot study. After all, I published a similarly weak pilot study but did not hesitate to promote the treatment studied, even with only a 20-patient open-trial report.10,11 However, that treatment costs $7 and presents no evident risk to users (dark therapy for bipolar disorder using amber lenses for “virtual darkness,” now undergoing a randomized trial for treatment of inpatient mania12).

By contrast, a Fisher-Wallace device costs at least $600. The Alpha-Stim unit, also used for CES, costs $800 to $1200 and has no efficacy study in bipolar depression and only one published study in patients with a mixture of depression and anxiety.13,14 The long-term consequences of using these devices are unknown. Putting electricity through your brain for days or weeks? One would think a long pause might be warranted, even after solid evidence for efficacy.

On the other hand, we certainly need treatment options for bipolar depression that don’t require adjunctive thyroid hormone 10% of the time (lithium) or cause diabetes 10% of the time (quetiapine, at least when used with divalproex15). Indeed we need as many tools as we can get. Through rosy lenses, this study suggests that CES warrants continued study as a possible alternative treatment.

Conclusions

1. Don’t give patients one of these devices for just one week to see if it “works.”

There was a very significant placebo effect at week 1: patients undergoing sham treatment experienced a 9-point drop on the BDI at that point, before falling back to a loss of only 4 points after week 2. Thus, practitioners must not judge the efficacy of these devices after 1 week of treatment: per the results of this study, at that point nearly everyone will have improved a great deal! At minimum patients should try it for 2 weeks-and preferably for 2 months, given the longer-term outcome in the study reviewed here. As you know from clinical experience, a lot can happen in 2 months that will make interpretation of benefit difficult for a single patient, but by that time you’ll at least have winnowed out most placebo responders. Perhaps practitioners who advocate these devices should purchase one and allow patients to “demo’” it for at least 2 weeks, preferably longer, before they buy one from the manufacturers.

2. Keep those skeptics’ lenses and share them-gently-with patients.

The Fisher Wallace website cites “18 published depression studies.” By contrast, the pilot report’s introduction, where one would expect to find a review of at least the most rigorous of those prior works, cites only one study, in patients whose primary diagnosis was anxiety; depression was a secondary measure.14 Apparently no other randomized trials in mood disorders have preceded the one reviewed here (clinicaltrials.gov indicates no unpublished negative trials).

Granted, in any given patient with a mood disorder, a substantial placebo response to nearly any treatment offered can be expected at least 20% of the time, likely more if the practitioner truly believes in the efficacy of the treatment offered (authoritative confidence can spawn belief, and belief can spawn good outcomes-a principle that of course we utilize routinely to promote good responses). If the Fisher Wallace Stimulation technique was known somehow to be harmless, perhaps a 20% to 25% chance of a good response is worth a $600 to $1200 investment? Patients with major depression could spend that much in co-pays, travel, work time lost, and other expenses for a year’s treatment with antidepressants, with no better response than with placebo unless they have moderate to severe depression.9

But we have less expensive options to offer patients with mood disorders who are attracted by non-pharmaceutical approaches, with far more data supporting efficacy and more experience to confirm safety, such as fish oil.16 Of course, fish oil just doesn’t have the same cachet.

Disclosures:

Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, OR. He is the Bipolar Disorder Section Editor for Psychiatric Times.

References:

1. Fisher Wallace. http://www.fisherwallace.com/. Accessed November 4, 2015.

2. McClure D, Greenman SC, Koppolu SS, et al. A pilot study of safety and efficacy of cranial electrotherapy stimulation in treatment of bipolar II depression. J Nerv Ment Dis. September 25, 2015; [Epub ahead of print].

3. NICE Recommendation 1.6.3. National Institute for Health and Care Excellence, 2014b. http://www.nice.org.uk/guidance/cg185/chapter/1-recommendations#managing-bipolar-depression-in-adults-in-secondary-care-2. Accessed November 4, 2015.

4. McIntyre R, Frye M, Neirenberg A. Diagnosing and managing depressive episodes in the DSM-5 era. Presented at: Industry-sponsored symposium, International Society for Bipolar Disorders Meeting; June 3-6, 2015; Toronto, Canada.

5. Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008;10:323-333.

6. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194:4-9.

7. Uher R, Perlis RH, Placentino A, et al. Self-report and clinician-rated measures of depression severity: can one replace the other? Depress Anxiety. 2012;29:1043-1049.

8. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435.

9. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303:47-53.

10. Burkhart K, Phelps JR. Amber lenses to block blue light and improve sleep: a randomized trial. Chronobiol Int. 2009;26:1602-1612.

11. Phelps J. Dark therapy for bipolar disorder using amber lenses for blue light blockade. Med Hypotheses. 2008;70:224-229.

12. Henriksen TE, Skrede S, Fasmer OB, et al. Blocking blue light during mania markedly increased regularity of sleep and rapid improvement of symptoms: a case report. Bipolar Disord. 2014;16:894-898.

13. Alpha-Stim. http://www.alpha-stim.com/shop/. Accessed November 4, 2015.

14. Barclay TH, Barclay RD. A clinical trial of cranial electrotherapy stimulation for anxiety and comorbid depression. J Affect Disord. 2014;164:171-177.

15. Weisler RH, Nolen WA, Neijber A, et al for the Trial 144 Study Investigators. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study). J Clin Psychiatry. 2011;72:1452-1464.

16. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72:1577-1584.