More Nuanced Directions for Deep Brain Stimulation

PARIS – Deep brain stimulation could help a majority of patients with treatment-resistant major depression, preliminary studies suggest, but it’s only a start to dealing with patients’ problems.

The conceptual framework of deep brain stimulation is shifting from the idea of a global treatment for depression to targeted treatment of individual aspects of depression. There’s also a growing recognition that deep brain stimulation should be part of a holistic treatment plan, after two patients who achieved remission in early trials later committed suicide.

"These were people who had reached remission, who had actually done quite well, but were having trouble over time with other issues in their life," Dr. Helen S. Mayberg said at the annual congress of the European College of Neuropsychopharmacology. "This is not a cure, this is not a panacea, and we still have to deal with these elements of these patients."

Part of the evolving concepts of deep brain stimulation involves reframing expectations. When patients are severely depressed, what they most want is to make the psychic pain go away. Deep brain stimulation may lift that pain, but then the patient has other needs – a job, a friend, a direction in life.

"Recovery takes more than a stimulator," said Dr. Mayberg, professor of psychiatry and neurology at Emory University, Atlanta. As one patient described it, "we reset the system. We took the parking brake off the car that’s not moving," but then rehabilitation strategies are needed to help the patient drive to full recovery.

Another evolving concept involves the goal of deep brain stimulation. Dr. Mayberg likened it to the treatment of Parkinson’s disease. Physicians don’t try to treat the whole Parkinson’s syndrome; they fairly successfully treat tremor or rigidity and less successfully target gait and other aspects of the disease. "And they make no apologies about it," she said.

For major depression, it’s unclear which of the following characteristics deep brain stimulation should target: anhedonia, psychic pain, sleep disturbance, or suicidality. It’s probably unrealistic to think that deep brain stimulation can "get all of it," she said. "Having an idea in mind about which things are primary and which things are secondary might be important for this."

Preliminary studies targeting the subcallosal cingulate for stimulation hoped to affect negative mood, with a 60% response rate. Stimulation of the nucleus accumbens in other early studies focused on anhedonia, with a 50% response rate. Case reports of deep brain stimulation of the lateral habenula hoped to affect negative reward signals. Other brain sites have been targeted using different logical rationales.

Dr. Mayberg said she became preoccupied with the subcallosal cingulate in her first experiments with deep brain stimulation for depression, as evidence converged to support the hypothesis that resistance to conventional treatments was attributable to an inability to regulate this region. If the subcallosal cingulate couldn’t be talked into cooperation, drugged into cooperation, or shocked into cooperation, perhaps it could be targeted strategically with brain stimulation to modulate it.

In her pilot study in six patients who’d had treatment-resistant depression for nearly 6 years, deep brain stimulation produced a response in four patients and remission in three after 6 months (Neuron 2005;45:651-60).

She and her associates then implanted devices in 14 more patients and followed the total cohort of 20 for 1 year, at which time 55% were responding to the treatment (Biol. Psych. 2008;64:461-6). Long-term follow-up for 3-6 years showed that response and remission rates seemed to improve and stabilize over time, with an average response rate of 75% at 3 years and an overall 64% response rate at an average follow-up of 42 months. Remission rates averaged 50% at 3 years and 42% in the average 42 months of total follow-up (Am. J. Psych. 2011;168:502-10).

No late-developing side effects were seen, "so there doesn’t seem to be a price to pay for brain stimulation in this region," she said. Most meaningful was that many of the responders returned to work and meaningful activities after 5-6 years of severe illness.

Three devices were explanted because patients did not improve and because two patients in the original cohort developed infections. In addition, two patients committed suicide 3 years and 6.5 years after implantation, and not because their depression did not get better.

"Recovery takes more than a stimulator."

More recent, unpublished work by Dr. Mayberg and her associates replicated results in a 1-month, sham-controlled trial in 17 patients that also showed a difference in efficacy in patients with unipolar or bipolar depression. Average remission rates were 18% at 6 months, 36% at 1 year, and 58% at 2 years. The treatment did not induce mania or hypomania in any patients.

That study included preplanned periods in which the stimulation was turned off in a blinded fashion in patients who had responded to treatment. That led to a slow, steady relapse over approximately a 2-week period. Improvements returned after stimulation was resumed, but recovery was not immediate.

Dr. Mayberg said she imagines a day when further research will identify the critical brain circuits to target with deep brain stimulation, imaging will guide electrode placement to effective sites for stimulation, and new devices will tune the current flow to get into the tracts that mediate the acute effects of depression.

Dr. David J. Nutt, chair of neuropsychopharmacology at Imperial College London, said at the meeting that Dr. Mayberg’s research "does tell us something very fundamental about the way we should think about this. You can, with a small number of people, well studied, well characterized with brain imaging, make huge insights. You may actually be showing us a new way of doing other kinds of interventions, not just deep brain stimulation."

Dr. Mayberg discussed the off-label, experimental use of two devices for deep brain stimulation. She has an interest in related patents and has been a consultant for St. Jude Medical, which donated devices for some of the research. Her research has been funded by grants from the National Institute of Mental Health, the Brain and Behavior Research Foundation (formerly known as the National Alliance for Research on Schizophrenia and Depression, or NARSAD), the Dana Foundation, the Woodruff Foundation, and the Stanley Medical Research Institute.

PARIS – Deep brain stimulation could help a majority of patients with treatment-resistant major depression, preliminary studies suggest, but it’s only a start to dealing with patients’ problems.

The conceptual framework of deep brain stimulation is shifting from the idea of a global treatment for depression to targeted treatment of individual aspects of depression. There’s also a growing recognition that deep brain stimulation should be part of a holistic treatment plan, after two patients who achieved remission in early trials later committed suicide.

"These were people who had reached remission, who had actually done quite well, but were having trouble over time with other issues in their life," Dr. Helen S. Mayberg said at the annual congress of the European College of Neuropsychopharmacology. "This is not a cure, this is not a panacea, and we still have to deal with these elements of these patients."

Part of the evolving concepts of deep brain stimulation involves reframing expectations. When patients are severely depressed, what they most want is to make the psychic pain go away. Deep brain stimulation may lift that pain, but then the patient has other needs – a job, a friend, a direction in life.

"Recovery takes more than a stimulator," said Dr. Mayberg, professor of psychiatry and neurology at Emory University, Atlanta. As one patient described it, "we reset the system. We took the parking brake off the car that’s not moving," but then rehabilitation strategies are needed to help the patient drive to full recovery.

Another evolving concept involves the goal of deep brain stimulation. Dr. Mayberg likened it to the treatment of Parkinson’s disease. Physicians don’t try to treat the whole Parkinson’s syndrome; they fairly successfully treat tremor or rigidity and less successfully target gait and other aspects of the disease. "And they make no apologies about it," she said.

For major depression, it’s unclear which of the following characteristics deep brain stimulation should target: anhedonia, psychic pain, sleep disturbance, or suicidality. It’s probably unrealistic to think that deep brain stimulation can "get all of it," she said. "Having an idea in mind about which things are primary and which things are secondary might be important for this."

Preliminary studies targeting the subcallosal cingulate for stimulation hoped to affect negative mood, with a 60% response rate. Stimulation of the nucleus accumbens in other early studies focused on anhedonia, with a 50% response rate. Case reports of deep brain stimulation of the lateral habenula hoped to affect negative reward signals. Other brain sites have been targeted using different logical rationales.

Dr. Mayberg said she became preoccupied with the subcallosal cingulate in her first experiments with deep brain stimulation for depression, as evidence converged to support the hypothesis that resistance to conventional treatments was attributable to an inability to regulate this region. If the subcallosal cingulate couldn’t be talked into cooperation, drugged into cooperation, or shocked into cooperation, perhaps it could be targeted strategically with brain stimulation to modulate it.

In her pilot study in six patients who’d had treatment-resistant depression for nearly 6 years, deep brain stimulation produced a response in four patients and remission in three after 6 months (Neuron 2005;45:651-60).

She and her associates then implanted devices in 14 more patients and followed the total cohort of 20 for 1 year, at which time 55% were responding to the treatment (Biol. Psych. 2008;64:461-6). Long-term follow-up for 3-6 years showed that response and remission rates seemed to improve and stabilize over time, with an average response rate of 75% at 3 years and an overall 64% response rate at an average follow-up of 42 months. Remission rates averaged 50% at 3 years and 42% in the average 42 months of total follow-up (Am. J. Psych. 2011;168:502-10).

No late-developing side effects were seen, "so there doesn’t seem to be a price to pay for brain stimulation in this region," she said. Most meaningful was that many of the responders returned to work and meaningful activities after 5-6 years of severe illness.

Three devices were explanted because patients did not improve and because two patients in the original cohort developed infections. In addition, two patients committed suicide 3 years and 6.5 years after implantation, and not because their depression did not get better.

"Recovery takes more than a stimulator."

More recent, unpublished work by Dr. Mayberg and her associates replicated results in a 1-month, sham-controlled trial in 17 patients that also showed a difference in efficacy in patients with unipolar or bipolar depression. Average remission rates were 18% at 6 months, 36% at 1 year, and 58% at 2 years. The treatment did not induce mania or hypomania in any patients.

That study included preplanned periods in which the stimulation was turned off in a blinded fashion in patients who had responded to treatment. That led to a slow, steady relapse over approximately a 2-week period. Improvements returned after stimulation was resumed, but recovery was not immediate.

Dr. Mayberg said she imagines a day when further research will identify the critical brain circuits to target with deep brain stimulation, imaging will guide electrode placement to effective sites for stimulation, and new devices will tune the current flow to get into the tracts that mediate the acute effects of depression.

Dr. David J. Nutt, chair of neuropsychopharmacology at Imperial College London, said at the meeting that Dr. Mayberg’s research "does tell us something very fundamental about the way we should think about this. You can, with a small number of people, well studied, well characterized with brain imaging, make huge insights. You may actually be showing us a new way of doing other kinds of interventions, not just deep brain stimulation."

Dr. Mayberg discussed the off-label, experimental use of two devices for deep brain stimulation. She has an interest in related patents and has been a consultant for St. Jude Medical, which donated devices for some of the research. Her research has been funded by grants from the National Institute of Mental Health, the Brain and Behavior Research Foundation (formerly known as the National Alliance for Research on Schizophrenia and Depression, or NARSAD), the Dana Foundation, the Woodruff Foundation, and the Stanley Medical Research Institute.

PARIS – Deep brain stimulation could help a majority of patients with treatment-resistant major depression, preliminary studies suggest, but it’s only a start to dealing with patients’ problems.

The conceptual framework of deep brain stimulation is shifting from the idea of a global treatment for depression to targeted treatment of individual aspects of depression. There’s also a growing recognition that deep brain stimulation should be part of a holistic treatment plan, after two patients who achieved remission in early trials later committed suicide.

"These were people who had reached remission, who had actually done quite well, but were having trouble over time with other issues in their life," Dr. Helen S. Mayberg said at the annual congress of the European College of Neuropsychopharmacology. "This is not a cure, this is not a panacea, and we still have to deal with these elements of these patients."

Part of the evolving concepts of deep brain stimulation involves reframing expectations. When patients are severely depressed, what they most want is to make the psychic pain go away. Deep brain stimulation may lift that pain, but then the patient has other needs – a job, a friend, a direction in life.

"Recovery takes more than a stimulator," said Dr. Mayberg, professor of psychiatry and neurology at Emory University, Atlanta. As one patient described it, "we reset the system. We took the parking brake off the car that’s not moving," but then rehabilitation strategies are needed to help the patient drive to full recovery.

Another evolving concept involves the goal of deep brain stimulation. Dr. Mayberg likened it to the treatment of Parkinson’s disease. Physicians don’t try to treat the whole Parkinson’s syndrome; they fairly successfully treat tremor or rigidity and less successfully target gait and other aspects of the disease. "And they make no apologies about it," she said.

For major depression, it’s unclear which of the following characteristics deep brain stimulation should target: anhedonia, psychic pain, sleep disturbance, or suicidality. It’s probably unrealistic to think that deep brain stimulation can "get all of it," she said. "Having an idea in mind about which things are primary and which things are secondary might be important for this."

Preliminary studies targeting the subcallosal cingulate for stimulation hoped to affect negative mood, with a 60% response rate. Stimulation of the nucleus accumbens in other early studies focused on anhedonia, with a 50% response rate. Case reports of deep brain stimulation of the lateral habenula hoped to affect negative reward signals. Other brain sites have been targeted using different logical rationales.

Dr. Mayberg said she became preoccupied with the subcallosal cingulate in her first experiments with deep brain stimulation for depression, as evidence converged to support the hypothesis that resistance to conventional treatments was attributable to an inability to regulate this region. If the subcallosal cingulate couldn’t be talked into cooperation, drugged into cooperation, or shocked into cooperation, perhaps it could be targeted strategically with brain stimulation to modulate it.

In her pilot study in six patients who’d had treatment-resistant depression for nearly 6 years, deep brain stimulation produced a response in four patients and remission in three after 6 months (Neuron 2005;45:651-60).

She and her associates then implanted devices in 14 more patients and followed the total cohort of 20 for 1 year, at which time 55% were responding to the treatment (Biol. Psych. 2008;64:461-6). Long-term follow-up for 3-6 years showed that response and remission rates seemed to improve and stabilize over time, with an average response rate of 75% at 3 years and an overall 64% response rate at an average follow-up of 42 months. Remission rates averaged 50% at 3 years and 42% in the average 42 months of total follow-up (Am. J. Psych. 2011;168:502-10).

No late-developing side effects were seen, "so there doesn’t seem to be a price to pay for brain stimulation in this region," she said. Most meaningful was that many of the responders returned to work and meaningful activities after 5-6 years of severe illness.

Three devices were explanted because patients did not improve and because two patients in the original cohort developed infections. In addition, two patients committed suicide 3 years and 6.5 years after implantation, and not because their depression did not get better.

"Recovery takes more than a stimulator."

More recent, unpublished work by Dr. Mayberg and her associates replicated results in a 1-month, sham-controlled trial in 17 patients that also showed a difference in efficacy in patients with unipolar or bipolar depression. Average remission rates were 18% at 6 months, 36% at 1 year, and 58% at 2 years. The treatment did not induce mania or hypomania in any patients.

That study included preplanned periods in which the stimulation was turned off in a blinded fashion in patients who had responded to treatment. That led to a slow, steady relapse over approximately a 2-week period. Improvements returned after stimulation was resumed, but recovery was not immediate.

Dr. Mayberg said she imagines a day when further research will identify the critical brain circuits to target with deep brain stimulation, imaging will guide electrode placement to effective sites for stimulation, and new devices will tune the current flow to get into the tracts that mediate the acute effects of depression.

Dr. David J. Nutt, chair of neuropsychopharmacology at Imperial College London, said at the meeting that Dr. Mayberg’s research "does tell us something very fundamental about the way we should think about this. You can, with a small number of people, well studied, well characterized with brain imaging, make huge insights. You may actually be showing us a new way of doing other kinds of interventions, not just deep brain stimulation."

Dr. Mayberg discussed the off-label, experimental use of two devices for deep brain stimulation. She has an interest in related patents and has been a consultant for St. Jude Medical, which donated devices for some of the research. Her research has been funded by grants from the National Institute of Mental Health, the Brain and Behavior Research Foundation (formerly known as the National Alliance for Research on Schizophrenia and Depression, or NARSAD), the Dana Foundation, the Woodruff Foundation, and the Stanley Medical Research Institute.