What is ‘Well’?

Major depression is one of the most common psychiatric disorders, and the leading cause of disability in American adults, according to the National Institute of Health. It can be treated effectively, but up to one-fifth of patients fail to respond to psychotherapy and antidepressant medications, the standard interventions. In the past 15 years, a promising neurosurgical intervention for treatment-resistant depression has emerged, but a flagship clinical trial designed to test its efficacy was abruptly halted last year.

Neurologist Helen Mayberg, who pioneered the technique for treating depression, discussed possible reasons for the trial’s failure, and described her ongoing research, in the EDAB Special Lecture on Neuroethics at the 11^th FENS Forum of Neuroscience in Berlin in July. (The European Dana Alliance for the Brain (EDAB) is part of the Dana Foundation.)

Deep brain stimulation (DBS) is a highly invasive neurosurgical procedure involving the implantation of ultra-thin wire electrodes into the brain. The implanted device, often called a “brain pacemaker,” delivers pulses of electricity that alter activity in the target region. The U.S. Food and Drug Administration approved its use for treatment of Parkinson’s disease and related movement disorders in 2002; since then, it has been used to treat an estimated 100,000 patients with these conditions.

Mayberg, a professor of neurology and psychiatry, and now director of the newly-established Center for Advanced Cicruit Therapeutics at the Icahn School of Medicine at Mount Sinai in New York, began using DBS in patients with treatment-resistant depression in the early 2000s. Mayberg and her colleagues quickly identified a region of the brain that appeared to be metabolically overactive in these patients, and showed that modulating its activity with DBS could improve their mood.

Despite these early successes, the large multi-centre BROADEN trial was halted last year by its sponsors, St. Jude Medical, the company that manufactures and supplies the electrodes. The lack of significant improvement in the patients, coupled with the prohibitive cost of the procedure – up to $100,000 per patient – were likely major factors. But the way in which the trial was designed, and also the way in which the patients’ outcomes were measured, likely played an important role, too.

Feeling like one’s self

Major depression is a debilitating condition with a complex set of symptoms that include intense negativity and feelings of worthlessness, a lack of interest in other people and events, and an inability to find pleasure in normally enjoyable activities. People with depression also experience insomnia and fatigue, and many often report being unable to get out of bed, let alone get on with their daily life.

Clinicians typically use depression scales to diagnose the condition, measure its severity, and gauge the benefits of treatment. Mayberg suggests that these methods do not fully reflect the complexity of depressive symptoms, however, and may be inadequate for assessing improvements in patients.

In their early studies, Mayberg and her colleagues noticed that most of their patients experience an immediate change in mood, spontaneously reporting that they felt “sudden calmness and lightness,” or “disappearance of the void” after the electrodes are placed and switched on. Furthermore, they often described their symptoms, and any improvements, in terms of changes in their sense of self. With time, the benefits appear less pronounced, with patients reporting that they “feel lighter,” that they are “re-emerging from the well,” or that they are “no longer drowning.”

“We can’t talk about wellness in depression without first asking ourselves, ‘What are we trying to treat?’” said Mayberg. “What would recovery from this bizarre set of symptoms look like? What is ‘well,’ and what does it mean when patients say, ‘I want to feel like my old self?’ Are the standard definitions of recovery even valid?”

Treatment as Step One

Despite the immediate observed improvements in mood, Mayberg emphasizes that her patients’ recovery is a gradual process. Most of her patients showed marked improvements between 6 and 24 months after electrode implantation. In the recent BROADEN trial, however, patient outcomes were measured after just 6 months.

Furthermore, electrode implantation is just one facet of recovery. “The pacemaker enables the repair process,” said Mayberg, but it is then up to the patient to build on its effects, and learn how to cope with daily life. “If our goal is wellness, then ‘well’ may actually be a better endpoint than ‘getting well.’”

Researchers involved in the trial may also have placed their electrodes wrongly. Even as they began recruiting study participants, Mayberg continued trying to understand depression more deeply, and to refine the surgical method. Her team has recently adopted another approach, using a neuroimaging technique called diffusion tensor imaging to study the subcallosal cingulate white matter in greater detail.

Such an approach will eventually reveal the extent of differences between individuals’ brains, allowing clinicians to identify the best location for placing the electrodes on a case-by-case basis. This so-called connectome approach has already yielded a small data set that seems to confirm Mayberg’s suspicions as to why the BROADEN trial failed: in a small recent study, Mayberg and her colleagues reported seeing some benefits in the first 6 months, but more marked improvement in the 6-12 month period, in 9 out of the 11 participants, with 6 of them going into remission.

“DBS is not a quick fix,” says Mayberg. “As with any disease, people have to take care of themselves. They have to recognize the triggers for their depression and learn how to cope with a bad day without breaking down. Having supportive family and friends is important, too – then the DBS is most likely to work well.”

Disclaimer: Moheb Costandi serves on the Board of Directors of the International Neuroethics Society with Helen Mayberg.