David Baxter PhD
Late Founder
Special Report: Electromagnetic Treatments for Depression Seek to Improve on ECT
By John Gever, Staff Writer, MedPage Today
July 04, 2008
NEW YORK, July 4 -- There's a new wave of research into targeted electromagnetic treatments for resistant depression, all aiming to relegate traditional electroconvulsive therapy (ECT) to obsolescence.
An estimated 15% to 20% of depressed patients don't respond to drug or talk therapies, sending many into the realm of ECT. Although 60% to 70% of patients respond to ECT, its baggage includes frequent adverse side effects and a bad PR problem.
Now, a variety of alternative approaches that apply electrical currents to the brain are in the research pipeline, and one is FDA approved. They include:
Vagus nerve stimulation is the only electromagnetic stimulation therapy besides ECT that has been approved by the FDA, although it too has been dogged by controversy.
The approval is specifically for unipolar or bipolar depression lasting at least two years, during which patients have failed at least four other adequate treatments, and who have had multiple previous depressive episodes.
Vagus nerve stimulation involves implantation of a pacemaker-like device in the patient's chest, with wire leads wrapped around the vagus nerve in the neck.
The idea came from its earlier, successful use in treating epilepsy. Clinicians noticed mood improvements following the device's activation, leading its commercial developer, Cyberonics Inc., to sponsor formal clinical studies.
According to A. John Rush, M.D., of the University of Texas Southwestern Medical Center in Dallas, who led the device's pivotal trial in depression, pulses delivered to the vagus nerve "go to specific areas in the central nervous system that control mood, motivation, sleep, appetite, and other symptoms that are relevant to depression."
But the procedure's safety-benefit balance has been questioned. The FDA approved the device in 2005 despite staff objections that the efficacy data were weak. In the pivotal study, only 30% of patients (versus 10% of sham-treated patients) showed measurable responses after one year on the clinician-administered Hamilton Depression Rating Scale, and even fewer -- 22%, compared with 12% of sham-treated patients -- reported significant improvement on a self-assessment index.
Those objections were reinforced by the Centers for Medicare and Medicaid Services in a May 2007 decision to deny Medicare coverage for the device, saying it was "not reasonable and necessary" for treating resistant depression.
The CMS decision has effectively curtailed use of the device. Cyberonics recently reported that depression-related sales have fallen by more than 80% since the CMS ruling, even as sales for use in epilepsy rose by 10%.
Low response rates are not the only downside to vagus nerve stimulation. Once the electrodes are attached to the vagus nerve, they cannot be removed without risk to the nerve. The FDA therefore mandated that the device's labeling include a black-box notice that implantation is irreversible.
It is also invasive, unlike ECT and most other neurostimulation approaches.
On the other hand, Dr. Kennedy noted, it has an established safety record thanks to its 10 years of use in epilepsy. The main adverse effect is vocal hoarseness.
Transcranial magnetic stimulation
Transcranial magnetic stimulation is next in the pipeline, with the FDA now considering a marketing application from Neuronetics. The firm expects a decision within a few months.
Its system looks like a dentist's chair, except that the moveable arm carries a fist-sized magnetic coil instead of a drill.
Like ECT, it is essentially an electrical therapy, except that it induces currents within the brain magnetically, rather than by delivering current directly through wires.
It has been used extensively as a research tool, because placing the coil over certain regions of the brain can cause involuntary movements or affect sensory processes. It can thus be used to map brain function, for example.
Since the first clinical studies in depression appeared in the early 1990s, transcranial magnetic stimulation has evolved to deliver energy in pulses, and with a series of treatments given over weeks or months. For this reason, it is often called repetitive transcranial magnetic stimulation.
For example, a recent study with the Neuronetics system involved five sessions per week for four to six weeks.
The main target brain region has been the dorsolateral prefrontal cortex. That's because this region is known to be involved with mood, and also because it sits near the top surface of the brain. Because the strength of magnetic fields falls off exponentially with distance from the coil, deeper structures such as the cingulate and limbic cortexes are beyond reach.
Head-to-head clinical studies with transcranial magnetic stimulation and ECT have found similar response rates in patients with non-psychotic depression.
Cognitive side effects have generally been less common with the magnetic therapy, according to Dr. Kennedy. The most common adverse effects have been transient scalp discomfort and pain and tinnitus. A few cases have been reported in which the treatment appeared to induce seizures or manic episodes.
A pivotal study sponsored by Neuronetics, reported late last year, assigned 164 patients to four weeks of treatment with the magnetic therapy or a sham version. The active therapy led to significantly greater mean reductions in depression symptom scores.
But fewer than a quarter of patients had more than 50% reduction in symptoms scores.
On the other hand, the magnetic therapy performed somewhat better in another sham-controlled trial conducted at the University of Iowa and reported at the American Psychiatric Association meeting in May. In 94 patients with vascular depression, nearly 40% showed major symptom relief and 28% had complete remission.
Dr. Kennedy noted that little is known about the durability of response to transcranial magnetic stimulation. In an open-label extension to the Neuronetics pivotal study, in which patients were maintained on anti-depressant drugs, more than 35% required additional magnetic therapy sessions within six months to deal with recurrent symptoms.
Magnetic seizure therapy
Magnetic seizure therapy is a more intense version of transcranial magnetic stimulation. It harkens back to the original goal of ECT, using a magnetically induced current to provoke a clonic seizure.
It is intended to be more focused in the cortex than ECT, with the aim of reducing the cognitive side effects.
A series of preclinical studies and case reports published from 2000 to 2006 supported the idea, but the only one involving more than one patient found that it was also less effective than ECT.
Led by Sarah Lisanby, M.D., of Columbia University here, a colleague of ECT researcher Harold Sackeim, M.D., the case-matched study of 20 patients found that both treatments produced significant reductions in depression scores, but residual symptoms were more pronounced in those receiving the magnetic therapy (mean Hamilton score 6 for ECT versus 14 for magnetic seizure therapy, P<0.05). The results were published in 2006 in Anesthesia and Analgesia.
There have been no published reports on the treatment since then, but ClinicalTrials.gov lists a 75-patient randomized, ECT-controlled trial led by Dr. Lisanby as currently recruiting patients, with a 2010 completion date. Dr. Lisanby could not be reached for comment.
Transcranial direct current stimulation
First studied for depression in the 1960s -- and in other psychiatric disorders as far back as the early 19th century -- transcranial direct current stimulation is an ECT-Lite.
It delivers current to the brain via electrodes placed on the scalp, as does ECT. But it involves much lower currents -- no more than 2 mA, compared with 400 to 900 mA in ECT -- so that it does not induce seizures or require anesthesia.
As currently studied, it is delivered in short daily sessions over a period of weeks, similar to transcranial magnetic stimulation.
As with other electromagnetic therapies, the mechanism of action in depression remains unclear. It appears to modulate neuronal excitability, but beyond that little is known.
It's so simple that an Internet site describes how individuals can create their own treatment system with a nine-volt battery, two wires, and damp sponges.
However, much of the recent research on the treatment has been conducted with commercial stimulators produced by Magstim Co. in Wales.
One of the leading investigators has been Felipe Fregni, M.D., of Beth Israel Deaconess Medical Center in Boston.
Last year, his group published a randomized, sham-controlled study -- the first ever for this approach -- involving 40 patients with recently untreated major depression. There was no requirement to have failed earlier therapies.
The trial compared treatment applied to the left dorsolateral prefrontal cortex with stimulation of the occipital cortex -- which Dr. Fregni and colleagues anticipated would have no effect, serving as an "active control" -- and with sham treatment.
The left dorsolateral treatment was modestly effective, according to the researchers' report in the International Journal of Neuropsychopharmacology.
They found a mean reduction of 40.4% in depression scores, versus a 21.3% reduction with the occipital cortex treatment and 10.4% with sham therapy.
About 38% of patients receiving the left dorsolateral treatment had at least 50% reductions in symptom scores, compared with 20% of sham-treated patients and 0% of those receiving the occipital cortex stimulation.
However, whether patients with more treatment-resistant depression could expect such response rates is unknown.
"It's difficult to predict right now," Dr. Fregni said.
Adverse effects have included headaches and itching and redness where the electrodes are placed.
Implantable cortical stimulation
Another early-stage investigational technology takes vagus nerve stimulation a step farther. Instead of delivering electrical pulses to a nerve, it sends them to the surface of the brain.
Seattle-based Northstar Neurosciences is testing a system that, like vagus nerve stimulation, inserts a pulse generator in the patient's chest. An electrical lead is passed into the skull through a surgically drilled hole, terminating on the dural membrane over the cortex.
In a recent sham-controlled study of 11 treatment-resistant patients sponsored by Northstar, the therapy produced mean improvements of about 22% in depression symptom scores after eight weeks.
After one year, the mean degree of improvement increased to 32%, according to the company's chief medical officer, Brian Kopell, M.D.
However, prospects that the device would reach the market dimmed earlier this year when it failed to show a significant benefit in another clinical trial involving stroke survivors. That had been the product's lead indication. The failure cast doubt on Northstar's ability to complete pivotal trials in depression and tinnitus, another application the firm has pursued.
Deep brain stimulation
Currently among the least advanced of the various electromagnetic stimulation approaches to depression, deep brain stimulation is nevertheless considered one of the most promising.
That is mainly because it already has a long track record, thanks to its use in thousands of people with Parkinson's disease. Its safety and the technical aspects of placement are therefore considered to be relatively well understood.
The technology is similar to vagus nerve and implantable cortical stimulation, except that the electrical leads are extended into a particular brain region called BA25, located within the cingulate cortex. Thus, it requires drilling a hole in the skull, as well as an incision in the chest for placing the pacemaker-like electrical pulse generator.
Only a few uncontrolled case series have been reported thus far for deep brain stimulation in depression, but these have been extremely positive.
In a 16-patient trial at the Cleveland Clinic, reported in April at the American Association of Neurological Surgeons meeting, half showed at least 50% reduction in depression symptoms for one year. (See AANS: Brain Pacemaker Effective in Resistant Depression)
At another recent meeting, Dr. Kennedy presented findings from a multicenter study (also uncontrolled) in which nine of 16 patients had at least 40% reductions in symptom scores.
However, he conceded that moving to large randomized studies would be difficult because of the invasiveness issue. Deep brain stimulation requires a neurosurgeon to implant the leads.
Both studies involved patients with long-established, severe depression that had resisted multiple anti-depressant drugs and ECT.
Electroconvulsive therapy
ECT was first developed in the 1930s, out of an even older medical tradition holding that seizures could alleviate a number of psychiatric conditions. ECT was initially tried in schizophrenia, but except for some acute psychotic states, it was not effective. But psychiatrists soon found that it was effective against severe depression.
As practiced through the 1940s, it was a frightening and dangerous procedure. Later, researchers found that side effects could be reduced without sacrificing efficacy when it was modified to deliver short electrical pulses, rather than the long blasts of current first used, along with general anesthesia and neuromuscular blockers.
Nevertheless, patients still generally emerge from an ECT session feeling confused and disoriented, lasting about an hour. Short-term memory is also frequently disrupted. Occasional reports of longer-term memory loss still come forth, contributing to persistent controversy about the procedure and psychiatry in general.
It probably doesn't help that ECT's mechanism of action remains unclear. Effects on neurotransmitter, cytokine, and neurotrophic factor pathways have been suggested, but no single mechanism has been definitively identified, according to Sidney Kennedy, M.D., a prominent neurostimulation researcher at the University of Western Ontario in London, Ontario.
But progress against side effects continues. A study published last month by Harold Sackeim, M.D., of Columbia University here, and colleagues in Brain Stimulation found that shortening the pulses to 0.3 milliseconds, versus the standard 1.5 milliseconds, reduced memory deficits significantly in a randomized trial.
In ongoing studies, Dr. Sackeim and colleagues are also exploring alternative electrode placements so that seizures are induced only in the frontal lobes, an approach known as focal electrically-applied seizure therapy.
Looking to the future
"We remain early in the development of alternative brain stimulation techniques," wrote Paul Fitzgerald, M.B.B.S., Ph.D., of Monash University in Victoria, Australia, and Zafiris Daskalakis, M.D., of the Centre for Addiction and Mental Health in Toronto, recently in Current Opinion in Psychiatry.
They noted that clinical data even for vagus nerve stimulation, which is FDA-approved, are "shallow" and dominated by company-sponsored research.
"The development of large multi-site trials of techniques such as repetitive transcranial magnetic stimulation and vagus nerve stimulation, including those independently funded, is warranted," they said.
Dr. Kennedy said that no matter how effective the approaches involving surgery prove to be, they would never become widely used.
Rather, they will probably always be reserved for those patients who fail everything else, including ECT.
"I don't see psychiatry as going to an invasive procedure early," he said.
By the same token, the non-invasive technologies may find niches earlier in the treatment cycle.
Dr. Fregni pointed out that ECT is already known to be effective in the treatment-resistant population.
Although not every patient responds to ECT, another unmet clinical need is for simple and benign alternatives to anti-depressant drugs that can be tried before resorting to ECT, he suggested.
The transcranial stimulation technologies, both electrical and magnetic, "are offering something less invasive," he said.
The non-invasive approaches also offer other opportunities, Dr. Fregni said.
One possibility he plans to study is to combine transcranial direct current stimulation with cognitive therapy -- that is, in the same room at the same time.
He said the electrical stimulation may "prime the brain" to be more receptive to the thought remodelling that cognitive therapy is intended to accomplish.
"You might be able to enhance the efficacy of cognitive therapy," he said.
At the moment, only the direct current therapy is feasible for this approach, according to Dr. Fregni. Present-day magnetic stimulation devices are too noisy and distracting, he said.
Drs. Fitzgerald and Daskalakis said a "neglected" niche that non-invasive neurostimulation therapies might fill is in maintenance treatments. ECT, for example, is notorious for the speed with which depression symptoms return after stopping treatment.
"It is timely to consider the development of decent studies" in this area, they suggested.
For all the electromagnetic stimulation therapies, Dr. Fregni said, considerable research still needs to be done to optimize the stimulation parameters.
In each case, the strength of the electric current or magnetic field, the duration of pulses, and the spatial location can be varied. Finding the best combinations is a time-consuming job.
Indeed, as Dr. Sackeim's continued tinkering with ECT suggests, 70 years may not be enough to complete it.
Primary source: Fitzgerald P, et al. The use of repetitive transcranial magnetic stimulation and vagal nerve stimulation in the treatment of depression. Current Opinion in Psychiatry 2008; 21: 25-29.
Additional sources Kennedy S, et al. Treatment resistant depression -- advances in somatic therapies. Annals of Clinical Psychiatry 2007; 19: 279-87.
Boggio P, et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. International Journal of Neuropsychopharmacology 2007; DOI: 10.1017/S1461145707007833.
By John Gever, Staff Writer, MedPage Today
July 04, 2008
NEW YORK, July 4 -- There's a new wave of research into targeted electromagnetic treatments for resistant depression, all aiming to relegate traditional electroconvulsive therapy (ECT) to obsolescence.
An estimated 15% to 20% of depressed patients don't respond to drug or talk therapies, sending many into the realm of ECT. Although 60% to 70% of patients respond to ECT, its baggage includes frequent adverse side effects and a bad PR problem.
Now, a variety of alternative approaches that apply electrical currents to the brain are in the research pipeline, and one is FDA approved. They include:
- Vagus nerve stimulation
- Magnetic seizure therapy
- Repetitive transcranial magnetic stimulation
- Deep brain stimulation
- Transcranial direct current stimulation
- Implantable cortical stimulation
Vagus nerve stimulation is the only electromagnetic stimulation therapy besides ECT that has been approved by the FDA, although it too has been dogged by controversy.
The approval is specifically for unipolar or bipolar depression lasting at least two years, during which patients have failed at least four other adequate treatments, and who have had multiple previous depressive episodes.
Vagus nerve stimulation involves implantation of a pacemaker-like device in the patient's chest, with wire leads wrapped around the vagus nerve in the neck.
The idea came from its earlier, successful use in treating epilepsy. Clinicians noticed mood improvements following the device's activation, leading its commercial developer, Cyberonics Inc., to sponsor formal clinical studies.
According to A. John Rush, M.D., of the University of Texas Southwestern Medical Center in Dallas, who led the device's pivotal trial in depression, pulses delivered to the vagus nerve "go to specific areas in the central nervous system that control mood, motivation, sleep, appetite, and other symptoms that are relevant to depression."
But the procedure's safety-benefit balance has been questioned. The FDA approved the device in 2005 despite staff objections that the efficacy data were weak. In the pivotal study, only 30% of patients (versus 10% of sham-treated patients) showed measurable responses after one year on the clinician-administered Hamilton Depression Rating Scale, and even fewer -- 22%, compared with 12% of sham-treated patients -- reported significant improvement on a self-assessment index.
Those objections were reinforced by the Centers for Medicare and Medicaid Services in a May 2007 decision to deny Medicare coverage for the device, saying it was "not reasonable and necessary" for treating resistant depression.
The CMS decision has effectively curtailed use of the device. Cyberonics recently reported that depression-related sales have fallen by more than 80% since the CMS ruling, even as sales for use in epilepsy rose by 10%.
Low response rates are not the only downside to vagus nerve stimulation. Once the electrodes are attached to the vagus nerve, they cannot be removed without risk to the nerve. The FDA therefore mandated that the device's labeling include a black-box notice that implantation is irreversible.
It is also invasive, unlike ECT and most other neurostimulation approaches.
On the other hand, Dr. Kennedy noted, it has an established safety record thanks to its 10 years of use in epilepsy. The main adverse effect is vocal hoarseness.
Transcranial magnetic stimulation
Transcranial magnetic stimulation is next in the pipeline, with the FDA now considering a marketing application from Neuronetics. The firm expects a decision within a few months.
Its system looks like a dentist's chair, except that the moveable arm carries a fist-sized magnetic coil instead of a drill.
Like ECT, it is essentially an electrical therapy, except that it induces currents within the brain magnetically, rather than by delivering current directly through wires.
It has been used extensively as a research tool, because placing the coil over certain regions of the brain can cause involuntary movements or affect sensory processes. It can thus be used to map brain function, for example.
Since the first clinical studies in depression appeared in the early 1990s, transcranial magnetic stimulation has evolved to deliver energy in pulses, and with a series of treatments given over weeks or months. For this reason, it is often called repetitive transcranial magnetic stimulation.
For example, a recent study with the Neuronetics system involved five sessions per week for four to six weeks.
The main target brain region has been the dorsolateral prefrontal cortex. That's because this region is known to be involved with mood, and also because it sits near the top surface of the brain. Because the strength of magnetic fields falls off exponentially with distance from the coil, deeper structures such as the cingulate and limbic cortexes are beyond reach.
Head-to-head clinical studies with transcranial magnetic stimulation and ECT have found similar response rates in patients with non-psychotic depression.
Cognitive side effects have generally been less common with the magnetic therapy, according to Dr. Kennedy. The most common adverse effects have been transient scalp discomfort and pain and tinnitus. A few cases have been reported in which the treatment appeared to induce seizures or manic episodes.
A pivotal study sponsored by Neuronetics, reported late last year, assigned 164 patients to four weeks of treatment with the magnetic therapy or a sham version. The active therapy led to significantly greater mean reductions in depression symptom scores.
But fewer than a quarter of patients had more than 50% reduction in symptoms scores.
On the other hand, the magnetic therapy performed somewhat better in another sham-controlled trial conducted at the University of Iowa and reported at the American Psychiatric Association meeting in May. In 94 patients with vascular depression, nearly 40% showed major symptom relief and 28% had complete remission.
Dr. Kennedy noted that little is known about the durability of response to transcranial magnetic stimulation. In an open-label extension to the Neuronetics pivotal study, in which patients were maintained on anti-depressant drugs, more than 35% required additional magnetic therapy sessions within six months to deal with recurrent symptoms.
Magnetic seizure therapy
Magnetic seizure therapy is a more intense version of transcranial magnetic stimulation. It harkens back to the original goal of ECT, using a magnetically induced current to provoke a clonic seizure.
It is intended to be more focused in the cortex than ECT, with the aim of reducing the cognitive side effects.
A series of preclinical studies and case reports published from 2000 to 2006 supported the idea, but the only one involving more than one patient found that it was also less effective than ECT.
Led by Sarah Lisanby, M.D., of Columbia University here, a colleague of ECT researcher Harold Sackeim, M.D., the case-matched study of 20 patients found that both treatments produced significant reductions in depression scores, but residual symptoms were more pronounced in those receiving the magnetic therapy (mean Hamilton score 6 for ECT versus 14 for magnetic seizure therapy, P<0.05). The results were published in 2006 in Anesthesia and Analgesia.
There have been no published reports on the treatment since then, but ClinicalTrials.gov lists a 75-patient randomized, ECT-controlled trial led by Dr. Lisanby as currently recruiting patients, with a 2010 completion date. Dr. Lisanby could not be reached for comment.
Transcranial direct current stimulation
First studied for depression in the 1960s -- and in other psychiatric disorders as far back as the early 19th century -- transcranial direct current stimulation is an ECT-Lite.
It delivers current to the brain via electrodes placed on the scalp, as does ECT. But it involves much lower currents -- no more than 2 mA, compared with 400 to 900 mA in ECT -- so that it does not induce seizures or require anesthesia.
As currently studied, it is delivered in short daily sessions over a period of weeks, similar to transcranial magnetic stimulation.
As with other electromagnetic therapies, the mechanism of action in depression remains unclear. It appears to modulate neuronal excitability, but beyond that little is known.
It's so simple that an Internet site describes how individuals can create their own treatment system with a nine-volt battery, two wires, and damp sponges.
However, much of the recent research on the treatment has been conducted with commercial stimulators produced by Magstim Co. in Wales.
One of the leading investigators has been Felipe Fregni, M.D., of Beth Israel Deaconess Medical Center in Boston.
Last year, his group published a randomized, sham-controlled study -- the first ever for this approach -- involving 40 patients with recently untreated major depression. There was no requirement to have failed earlier therapies.
The trial compared treatment applied to the left dorsolateral prefrontal cortex with stimulation of the occipital cortex -- which Dr. Fregni and colleagues anticipated would have no effect, serving as an "active control" -- and with sham treatment.
The left dorsolateral treatment was modestly effective, according to the researchers' report in the International Journal of Neuropsychopharmacology.
They found a mean reduction of 40.4% in depression scores, versus a 21.3% reduction with the occipital cortex treatment and 10.4% with sham therapy.
About 38% of patients receiving the left dorsolateral treatment had at least 50% reductions in symptom scores, compared with 20% of sham-treated patients and 0% of those receiving the occipital cortex stimulation.
However, whether patients with more treatment-resistant depression could expect such response rates is unknown.
"It's difficult to predict right now," Dr. Fregni said.
Adverse effects have included headaches and itching and redness where the electrodes are placed.
Implantable cortical stimulation
Another early-stage investigational technology takes vagus nerve stimulation a step farther. Instead of delivering electrical pulses to a nerve, it sends them to the surface of the brain.
Seattle-based Northstar Neurosciences is testing a system that, like vagus nerve stimulation, inserts a pulse generator in the patient's chest. An electrical lead is passed into the skull through a surgically drilled hole, terminating on the dural membrane over the cortex.
In a recent sham-controlled study of 11 treatment-resistant patients sponsored by Northstar, the therapy produced mean improvements of about 22% in depression symptom scores after eight weeks.
After one year, the mean degree of improvement increased to 32%, according to the company's chief medical officer, Brian Kopell, M.D.
However, prospects that the device would reach the market dimmed earlier this year when it failed to show a significant benefit in another clinical trial involving stroke survivors. That had been the product's lead indication. The failure cast doubt on Northstar's ability to complete pivotal trials in depression and tinnitus, another application the firm has pursued.
Deep brain stimulation
Currently among the least advanced of the various electromagnetic stimulation approaches to depression, deep brain stimulation is nevertheless considered one of the most promising.
That is mainly because it already has a long track record, thanks to its use in thousands of people with Parkinson's disease. Its safety and the technical aspects of placement are therefore considered to be relatively well understood.
The technology is similar to vagus nerve and implantable cortical stimulation, except that the electrical leads are extended into a particular brain region called BA25, located within the cingulate cortex. Thus, it requires drilling a hole in the skull, as well as an incision in the chest for placing the pacemaker-like electrical pulse generator.
Only a few uncontrolled case series have been reported thus far for deep brain stimulation in depression, but these have been extremely positive.
In a 16-patient trial at the Cleveland Clinic, reported in April at the American Association of Neurological Surgeons meeting, half showed at least 50% reduction in depression symptoms for one year. (See AANS: Brain Pacemaker Effective in Resistant Depression)
At another recent meeting, Dr. Kennedy presented findings from a multicenter study (also uncontrolled) in which nine of 16 patients had at least 40% reductions in symptom scores.
However, he conceded that moving to large randomized studies would be difficult because of the invasiveness issue. Deep brain stimulation requires a neurosurgeon to implant the leads.
Both studies involved patients with long-established, severe depression that had resisted multiple anti-depressant drugs and ECT.
Electroconvulsive therapy
ECT was first developed in the 1930s, out of an even older medical tradition holding that seizures could alleviate a number of psychiatric conditions. ECT was initially tried in schizophrenia, but except for some acute psychotic states, it was not effective. But psychiatrists soon found that it was effective against severe depression.
As practiced through the 1940s, it was a frightening and dangerous procedure. Later, researchers found that side effects could be reduced without sacrificing efficacy when it was modified to deliver short electrical pulses, rather than the long blasts of current first used, along with general anesthesia and neuromuscular blockers.
Nevertheless, patients still generally emerge from an ECT session feeling confused and disoriented, lasting about an hour. Short-term memory is also frequently disrupted. Occasional reports of longer-term memory loss still come forth, contributing to persistent controversy about the procedure and psychiatry in general.
It probably doesn't help that ECT's mechanism of action remains unclear. Effects on neurotransmitter, cytokine, and neurotrophic factor pathways have been suggested, but no single mechanism has been definitively identified, according to Sidney Kennedy, M.D., a prominent neurostimulation researcher at the University of Western Ontario in London, Ontario.
But progress against side effects continues. A study published last month by Harold Sackeim, M.D., of Columbia University here, and colleagues in Brain Stimulation found that shortening the pulses to 0.3 milliseconds, versus the standard 1.5 milliseconds, reduced memory deficits significantly in a randomized trial.
In ongoing studies, Dr. Sackeim and colleagues are also exploring alternative electrode placements so that seizures are induced only in the frontal lobes, an approach known as focal electrically-applied seizure therapy.
Looking to the future
"We remain early in the development of alternative brain stimulation techniques," wrote Paul Fitzgerald, M.B.B.S., Ph.D., of Monash University in Victoria, Australia, and Zafiris Daskalakis, M.D., of the Centre for Addiction and Mental Health in Toronto, recently in Current Opinion in Psychiatry.
They noted that clinical data even for vagus nerve stimulation, which is FDA-approved, are "shallow" and dominated by company-sponsored research.
"The development of large multi-site trials of techniques such as repetitive transcranial magnetic stimulation and vagus nerve stimulation, including those independently funded, is warranted," they said.
Dr. Kennedy said that no matter how effective the approaches involving surgery prove to be, they would never become widely used.
Rather, they will probably always be reserved for those patients who fail everything else, including ECT.
"I don't see psychiatry as going to an invasive procedure early," he said.
By the same token, the non-invasive technologies may find niches earlier in the treatment cycle.
Dr. Fregni pointed out that ECT is already known to be effective in the treatment-resistant population.
Although not every patient responds to ECT, another unmet clinical need is for simple and benign alternatives to anti-depressant drugs that can be tried before resorting to ECT, he suggested.
The transcranial stimulation technologies, both electrical and magnetic, "are offering something less invasive," he said.
The non-invasive approaches also offer other opportunities, Dr. Fregni said.
One possibility he plans to study is to combine transcranial direct current stimulation with cognitive therapy -- that is, in the same room at the same time.
He said the electrical stimulation may "prime the brain" to be more receptive to the thought remodelling that cognitive therapy is intended to accomplish.
"You might be able to enhance the efficacy of cognitive therapy," he said.
At the moment, only the direct current therapy is feasible for this approach, according to Dr. Fregni. Present-day magnetic stimulation devices are too noisy and distracting, he said.
Drs. Fitzgerald and Daskalakis said a "neglected" niche that non-invasive neurostimulation therapies might fill is in maintenance treatments. ECT, for example, is notorious for the speed with which depression symptoms return after stopping treatment.
"It is timely to consider the development of decent studies" in this area, they suggested.
For all the electromagnetic stimulation therapies, Dr. Fregni said, considerable research still needs to be done to optimize the stimulation parameters.
In each case, the strength of the electric current or magnetic field, the duration of pulses, and the spatial location can be varied. Finding the best combinations is a time-consuming job.
Indeed, as Dr. Sackeim's continued tinkering with ECT suggests, 70 years may not be enough to complete it.
Primary source: Fitzgerald P, et al. The use of repetitive transcranial magnetic stimulation and vagal nerve stimulation in the treatment of depression. Current Opinion in Psychiatry 2008; 21: 25-29.
Additional sources Kennedy S, et al. Treatment resistant depression -- advances in somatic therapies. Annals of Clinical Psychiatry 2007; 19: 279-87.
Boggio P, et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. International Journal of Neuropsychopharmacology 2007; DOI: 10.1017/S1461145707007833.
