It’s a nasty conundrum. As Paul Holtzheimer, a lead author on the Broaden study, put it at a conference last year, “To imagine that 50 per cent of patients that are this severely ill, this treatment-resistant, would get better and stay better for this period of time… [We] have [a large failed study], we have these really amazing open-label pilot data – it is hard to reconcile those two.”

Holtzheimer’s lament touches on two separate but connected problems. One is why the trial failed even though the patients got better. The other is why it fell short of Mayberg’s open-label studies.

The simpler question first: Why did the trial fail even though the patients markedly improved?

Perhaps the trial’s sharpest constraint was the weight placed on its six-month results. Although six months is actually long for a depression trial (trials of pharmaceutical antidepressants, for instance, typically last only six to 12 weeks), it makes a pretty short leash for Mayberg’s DBS approach, which earlier work had shown led to marked improvements between six and 24 months. A study of her first cohort of patients, operated on in Toronto, found the percentage who markedly improved – that is, cut their depression scores by at least 40 per cent – was 62.5 per cent after one year, 46.2 per cent after two years, and 75 per cent at three years; remission was achieved by 18.8 per cent at one year, 15.4 per cent at two years, and 50 per cent after three years. A study of another 17 open-label patients Mayberg treated at Emory found improvement in 41 per cent of patients at six months, which rose to 92 per cent at two years; remission rose from 18 per cent at six months to 58 per cent at two years. Betting the entire Broaden trial on favourable six-month results proved far riskier than anticipated.

So why just six months? According to several Broaden study authors, the six-month mark was set because of concerns that, given the treatment’s high effectiveness in previous studies, it would be unethical to keep a third of these very sick patients on placebo for any longer. A shorter stretch would also save St Jude a lot of money if the trial did need to be stopped. In any case, Broaden’s six-month outcome target forced an early, one-time-snapshot evaluation of a therapy that did its best work over longer periods. It also meant losing the control group from any analysis beyond six months, making it difficult to assess later progress objectively.

The second question is more involved: Why do patients in Mayberg’s open-label work – especially those she has treated since Broaden started – have such better response rates than those in the trial?

One possible contributor is bias. Researcher bias, which can take many forms, is a potential force in any study. It’s possible – arguably somewhere between likely and certain – that Mayberg’s strong role in her open-label work affected the outcomes. As is standard practice, the depression scoring was done by researchers with no ties to her or her lab. Yet Mayberg is a warm, confident, highly engaged clinician, and the bonds she builds with her patients doubtless give many of them more confidence and faith in the procedure.

As some observers have noted, Mayberg had two conflicts of interest that could bias her work: licensing and consulting fees from St Jude, and part ownership of a patent on the procedure that could generate income should it get approved. During the trial, she and Andres Lozano, the Toronto neurosurgeon who shares the patent with her, received fees from Abbott for a licence to use the procedure in the trial. Mayberg says her own licensing and consulting fees during the trial amounted each year to “about enough to buy a decent used car”. Decent-used-car money is not meaningless. But it is modest next to the shiny-new-Lexus-level fees common in clinical trial consulting agreements, and it falls far short of what Mayberg could likely demand and receive.

A more obvious difference was that the open-label work had no control groups and the Broaden trial did. As every Broaden patient was told beforehand, one in three of them would start the trial with a device that would be inactive for the first six months. Possibly this knowledge created a sort of bias within them – a reduced confidence and thus response – in both the placebo and the active groups.

The factors above may well have contributed to the different responses in the trial and the open-label work. But it seems a stretch to think they could make Mayberg’s open-label work twice as effective over six months as the trial was. The answer is more likely found in the many differences between Mayberg’s open-label treatment protocol — which changed as she went along — and the protocol in the Broaden trial.

Even as the Broaden trial was running, Mayberg continued her research, implanting new patients and, in an effort to get ever-better results, refining the way she was using DBS. This meant that her work increasingly diverged from the Broaden study in significant ways. She selected patients differently. She sited and managed the electrodes differently. She supported the patients differently. Any of these had the potential to create or widen a gap in outcome between Mayberg’s open-label work and the Broaden trial. In a sense, that was the point: She wanted to improve on the early protocol on which Broaden was largely based.

The trial and the open-label work differed in how they chose patients. To start with, the Broaden patients had suffered from treatment-resistant depression far longer than Mayberg’s patients had – on average, 12 years instead of five. This longer run may have contributed to their reduced response.

And while Broaden filtered out people with anxiety or personality disorders (as did Mayberg), it did not exclude or prioritise any depressive subtypes. Meanwhile, Mayberg had begun to identify in her open-label patients at least three psychological characteristics that predicted better response: comparatively low “mood reactivity”, or short-term responses to changing environmental conditions; a clear “psychomotor” slowing of thought and movement; and “high negative affect”, or the experience of depression not just as an absence of pleasure but as the distinct mental or even physical pain that the psychologist and philosopher William James, who often suffered depression, called “an active anguish” – the pain that Lisa Wick felt lift both times her device was implanted. These traits characterise what Mayberg calls a “classically melancholic” depression, in which calming area 25 may have more effect. Mayberg now selects for such patients; the Broaden study neither sought nor avoided them.

Another difference was that the Broaden study sited the electrodes by a method that Mayberg happened to abandon as the Broaden study began. Until 2008, Mayberg’s team sited the implants based on so-called gross anatomy. That is, they used conventional MRI scans to place the electrodes in a particular spot within the well-defined brain area, visible in any scan, called area 25. Broaden targeted its placements likewise.

Yet even as Broaden launched, Mayberg began using a newer, more detailed imaging tool, diffusion tensor imaging (DTI), that could reveal not just distinct brain areas but the white-matter bundles, called tracts, that carry neural traffic from one area to another. This DTI work showed that patients responded best if the electrodes sat at particular junctions of white-matter tracts within or next to area 25. Together with adjustments in patient selection, this has helped to improve outcomes in Mayberg’s open-label patients since 2008 – but came too late for use in the Broaden study.

Finally, Mayberg has long offered her patients comprehensive, personally tailored programmes of psychiatric and social-service support to help them rebuild their lives. After years of deep depression, most patients’ lives, relationships and ways of thinking have been entrenched in illness and disability long and deeply enough that surgery alone was unlikely to make them whole. Like a patient with a knee repair, says Mayberg, “they need rehab to get well again”. So her team helps them get psychotherapy, occupational or physical therapy to rebuild skills or physical health, and other assistance to connect them to needed social services.

The Broaden trial offered only post-surgical support, and to prevent statistical confounds it expressly ruled out the addition of any psycho- or drug therapy not underway before the trial. This successfully isolated the surgical intervention statistically – but likely reduced the chance of recovery.