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