Treatment

Tickling the Brain - VNS, rTMS, DBS

Can these alternatives to ECT live up to their promise?

ECT developed from the observation that electricity used to stun slaughterhouse pigs often resulted in convulsion, a sledge hammer approach that was applied with varying degrees of success and controversy to humans. These days, science is working on developing more subtle instruments, ones that tickle the brain with hopefully little or no side effects. But are they effective? To begin ...

Vagus Nerve Stimulation

In July 2005, the FDA approved the use of a surgical implant for adjunctive long-term treatment of treatment resistant depression. After initially turning down its own panel's recommendation in August 2004, in late December the FDA granted "approvable" status, pending the resolution of a number of conditions. The therapy is called vagus nerve stimulation (VNS).

In July 1998, surgeons implanted a pacemaker-like device into the chest of a bipolar patient with severe depression. Within eight weeks, the patient moved out of his parents’ house and found a job (though he did cycle into irritable mania).

The implement sends an electrical pulse up a wire into the vagus nerve in the neck at the base of the brain. The pulses usually last thirty seconds and occur every three to five minutes. The battery lasts five years. PET scans reveal that VNS therapy modulates activity in regions of the brain believed to be involved in mood regulation, including limbic structures and specific cortical areas such as the orbitofrontal cortex.

VNS has been in use for epilepsy patients in Europe since 1994 and the US since 1997. Cyberonics, the Houston company that developed and manufactures the device, first approached Mark George MD, a psychiatrist and neurologist at the Medical University of South Carolina to see if there might be a wider application . Because epilepsy meds also work for bipolar patients, Dr George thought there might be a parallel. Dr George recruited three other researchers - Lauren Marangell MD at Baylor College of Medicine, A John Rush MD of the University of Texas Southwestern Medical Center, and Harold Sackeim PhD at Columbia University - and together they enrolled 30 depressed unipolar and bipolar patients for an open trial, and 30 more patients a year later.

The patients had been in major depression for more than six years and had failed numerous treatments - including antidepressants, mood stabilizers, and ECT. Patients were allowed to stay on their current medications According to Dr George, the 60 patients represented "maybe the most ill cohort ever published."

Thirty percent of the patients responded after 12 weeks. A "response" is measured as at least a 50 percent improvement in symptoms. Patients who had failed on two or three antidepressants fared best. Those who failed on more than seven antidepressants did not respond at all. Twenty-one percent of all the patients remitted - that is, they achieved a symptom-free or near symptom-free state - a finding that took the researchers by surprise: "I’ve been treating these kinds of patients for more than a decade and I’ve never seen anything like it," Dr George told this writer in 2002.

The bipolar depressed patients had similar results as the unipolar depressed patients. One bipolar patient and one unipolar patient switched into hypomania, causing one drop-out amongst the entire 60.

After one year, 41 percent of the original 30 patients had responded, and 26 had remitted. At least 90 percent of the responders were still responding after one year. After two years, response rates had climbed to 54 percent.. Dr George did not rule out the fact that the improved numbers over the course of time could have been due to the patients’ depressions independently abating, but he also pointed out that it is unlikely a placebo response could have been maintained for two years.

In 2001, Cyberonics enlisted 235 patients in a 12-week double-blind clinical trial (in which half of the devices were switched on and the other half left off), along with their current meds. Subjects had failed at least two and up to six different types of antidepressant treatments in their current episodes, had been in their current depression two or more years or had experienced recurring depression four or more times, with Hamilton depression scores of at least 20.

Said Cyberonics CEO Skip Cummins on a June 2004 conference call: "These were hopeless, desperate, suicidal patients, not expected to respond."

Unfortunately, the patients lived up to expectations. Trial results in early 2002 turned out to be a major disappointment, delaying indefinitely what had been considered imminent FDA approval (which had been granted fast track review). Undaunted, Cyberonics continued with the study with 205 patients, this time switching on all the devices. At the same time, the company enrolled 124 similarly depressed patients for treatment as usual without VNS. After 12 months, response rates for the VNS group on two different depression scales were 21 percent and 30 percent, respectively vs 12 and 13 percent in the treatment as usual group. Remission rates were 16 and 17 percent for the VNS group vs five and seven percent for those on treatment as usual.

Ordinarily, a study with this design and these results never would have made it past the FDA door man. Two randomized double-blind controlled studies with at least a 50 percent response is generally what it takes to get a panel to review a manufacturer's submission. This was but a single open trial, effectively comparing apples to oranges, with a mere 30 percent success rate (or putting it another way, a 70 percent failure rate), and the statistician and others on the panel reacted to the data in a matter akin to the membership committee at the Augusta National Country Club hearing of someone with a skirt on the premises.

What carried the day was a forceful presentation by Cyberonics that 20 percent of 19 million depressed Americans fall into the "treatment resistant" category - people who fail their meds or ECT and suffer constant rounds of recurring episodes. These people, said Cyberonics, have no FDA approved treatment alternatives.

To help make its case, Cyberonics turned to one of the top depression experts in the field, Dr Rush, a pioneer in psychiatric treatment algorithms, head of the NIMH-underwritten STAR*D clinical trials for treating depression, as well as one of the lead researchers involved in the VNS studies. Before the FDA panel, he painted a clinical picture of despairing and suicidal patients unable to work full-time, frequently using the hospital or ER, frequently changing meds. Treatment resistant depression is a long standing, life-threatening disabling illness, he concluded, equivalent to other severe psychiatric illness, including schizophrenia.

The panel was also swayed by the testimony of some of the study patients. One such patient, who simply identified herself as Patient 012 from Site 050 and testified before the FDA on her own volition and at her own expense, i well worth quoting at length:

"My case (and testimony) may be of particular interest to this panel because: I went into the study on no medications; remained off medications throughout the study; and, am still on no medications. There is no other explanation for my response other than the device, itself. It is good science. Turn the device up, I respond. Turn the device down, I decline. ...

"I realize that most on this panel and most in attendance are experts in their field ... but there is one thing I can offer you about which you know nothing: and that is first-hand knowledge of what it is like to have severe, recalcitrant depression.

"And to do so, I ask you to imagine the unimaginable. To think the unthinkable. To experience second-degree emotional burns with third-degree prognosis. All you experience is pain, but with no cure. In fact, there is no viable treatment. You can attempt to salve it. Only death solves it.

"But the medical community does not accept death as a cure. It asks us to continue to hang on and to continue to live, yet offers us no viable treatments. Trust me, it’s not that we don’t want to live. It’s that we don’t want to live ‘like this.’ Our illness is embedded in our physical bodies, our cells, we are prisoners there and our sentence is life.

"Menacing insomnia; isolation; fear; anxiety; sadness; hopelessness; general malaise; malingering fatigue; physical exhaustion; apathy; lack of motivation, concentration, and focus; absence of pleasure; amplification of pain; agitation; sensitivity to criticism; thoughts that life isn’t worth living. You are familiar with this short-sheeted laundry list of symptoms. Now imagine having them all at once. Imagine passing from one room to another in the House of Pain where some symptoms are more prevalent than others, sometimes exacerbated by the very medications that were meant to alleviate them.

"I will not bore you with the details of the pharmacopoeia that I have tried and that have failed, not to mention the acupuncture; homeopathy; herbal remedies; extreme dietary changes and supplements; light therapy; counseling; yoga, and of course religion. What God would let a child suffer like this?

"And then comes the inevitable: electroconvulsive therapy. ECT. A therapy so beyond the vernacular, that it doesn’t even pass an automated spell check. I’d stop at the word, too. But as a person with treatment-resistant depression, I could not stop. I relented to this FDA-approved treatment as a last resort. Average session: 3-5 treatments: I had 33 nearly consecutive treatments. I lost, retrograde, 20 years of my life through memory loss: a dismal blessing. At least I could not remember the horrific pain that preceded it for years. ...

"I am not going to idealize nor sentimentalize the device. I know I am one of the third who have responded to it. I know there are others who continue to suffer the burden of treatment-resistant depression. I see it in their faces as I sit in the lobby and wait my turn at my site. I know that pain. I suffered it prior to the VNS. Still, I have windows of it now and again.

"I am passionate - yet realistic - about the device. I do not romanticize its results for me nor dismiss its lack-of-results for others. I am well aware of its side effects, shortcomings, and current experimental status. But, I do know one thing: we need viable treatment options for those with recalcitrant depression, and the VNS has worked for me."

What also influenced the panel was the device's relatively benign side effects profile. Only three percent in the VNS group dropped out over 12 months due to adverse events. By contrast, about 15 percent of patients drop out of antidepressant trials due to adverse events after just four to eight weeks. The main side effect was voice alteration (hoarseness), which occurred in 68 percent of the patients during the initial 12-week phase of the study. Twenty-nine percent of the patients experienced coughing. Physicians can adjust settings using special software, and patients can diminish side effects by turning down the device with a magnetic wand.

The FDA indication is the first ever for treatment resistant depression, a coup for Cyberonics, but the panel did stipulate that the device should only be used for patients who did not respond to at least four other types of treatment. The panel also set other conditions, including educating the surgeons who would implant the device, educating psychiatrists and patients, and establishing a patient registry.

Patients interested in VNS should expect sticker shock. The current model retails at $15,000, a future one is expected to be priced at $18,000, and the surgical procedure may go $15,000 and higher. Cyberonics, however, has an answer to this. A 2004 Cyberonics study showed that patients who had changed their meds eight times incurred health care costs of $1,200 per month, twice that of patients who had just two med changes. The company is confident health care providers will do the numbers and see the cost-benefit of including VNS in their coverage. CMS, which administers US Medicaid and Medicare, has already approved the device for epilepsy. Other providers have granted conditional approval for treatment resistant depression.

The surgery is fairly straightforward. Epilepsy.com reports that "the surgeon first makes an incision along the outer side of the chest on the left side, and the device is implanted under the skin. Then a second incision is made horizontally in the lower neck, along a crease of skin, and the wire from the stimulator is wound around the vagus nerve in the left side of the neck. The brain itself is not involved in the surgery. ...

"The procedure usually lasts about 50 to 90 minutes with the patient under general anesthesia. Sometimes a hospital stay of one night is required. Some surgeons have performed the procedure with local anesthesia and the patient has been discharged the same day."

rTMS

Transcranial magnetic stimulation was first developed by Dr Anthony Barker and his colleagues at the University of Sheffield (UK) in the 1980s. The technique is based on the principle that running a current through a coil of wire generates a magnetic field, which passes through the skull and into the brain. The neurons in the brain are activated by a secondary current induced by the magnetic field.

Technological improvements led to repetitive transcranial magnetic stimulation (rTMS), and new coil design made it easier to target small areas of the brain. In the early 1990s, scientists began applying rTMS to mood disorders. rTMS works by stimulating parts of the prefrontal cortex, resulting in dopamine release in the caudate region, according to a 2001 PET scan study. rTMS has a limited range in the brain, but a number of brain scan studies reveal activity deeper down in the limbic system, thanks to circuitry extending down from the cortex.

rTMS is an outpatient procedure, but not a particularly pleasant one. Depending on the intensity of the frequency, patients can experience headaches and unwelcome noise The most critical concern is the risk of seizure. For this reason, low frequency rTMS is preferred over high frequency. Frequencies are adjusted to an individual's "motor threshold."

A 2003 study of 60 depressed patients found high frequency rTMS applied to the left side or low frequency rTMS applied to the right prefrontal cortex yielded better results than sham treatment. It took at least four weeks to receive a clinical benefit. A 2002 study of 60 depressed patients (20 treatments over four weeks) found rTMS compared favorably to ECT. Studies on patients with psychotic depression, however, have found that ECT is more effective than rTMS for this population. A 2004 study found the treatment worked for bipolar depression.

A 2004 open study of nine manic patients using adjunctive rTMS suggested a potential benefit. A 2003 study, however, failed.

These and other small studies are encouraging, but hardly constitute a strong body of clinical evidence. An rTMS manufacturer, Neuronetics, is attempting to rectify that by recruiting patients for a major trial in 14 states, with the goal of seeking an FDA indication.

MST

A new twist to rTMS occurred in mid-2001 when researchers at Columbia University induced seizures similar to ECT. Known as magnetic seizure therapy (MST), ten people were given both ECT and TMS. According to the
study's author, Sarah Lisanby MD, it took patients 13 minutes to become reoriented after ECT compared to less than two minutes after TMS.

With ECT, the skull acts as a resistor, which results in the scattering of energy throughout the brain, producing unintended side effects. With TMS, energy passes through the skull as if it were transparent. According to information provided by Columbia U:

"Magnetic stimulation may offer a better way to perform convulsive therapy because magnetic fields enter the brain more easily than the electricity used with ECT. This means that the magnetic fields can be focused more precisely on specific regions of the brain important to depression, allowing us to avoid the regions of the brain that control memory."

A 2003 Columbia University study of 10 patients with severe depression alternated MST and ECT sessions during a course of treatments, with patients examined after each session. According to the authors of the study: "Patients had fewer subjective side effects and recovered orientation more quickly with MST than ECT. MST was also superior to ECT on measures of attention, retrograde amnesia, and category fluency."

Sarah Lisanby MD of Columbia University explained at the 2005 APA meeting that MST allows for more precise targeting into the brain. The aim is to induce seizures that do not spread to the motor cortex, thus sparing the memory regions of the brain. A study on primates showed better memory after MST than electroshock. Human subjects reoriented themselves much quicker after MST than ECT and experienced less retrograde amnesia.

Brain Probes and Deep Brain Stimulation

A taste of the future was offered at the 2005 APA meeting by Benjamin Greenberg MD PhD of Brown University. Needle-like leads with four electrodes are inserted into targeted regions of the brain, guided by MRI scans. An extension wire runs from each lead to one or more VNS-like devices implanted in the chest. The treatment is FDA-approved for Parkinson’s, and is being investigated for OCD and depression. OCD patients reported changes in mood within two minutes of the device being switched on. A small pilot study on depressed patients had a similar effect. When the device was turned off or the battery failed, the patients got worse.

A 2005 study by Helen Mayberg MD of Emory University identified Brodmann area 25 (not to be confused with Area 52) in the subgenual cingulate region. Four of six treatment-resistant patients remitted when the adjacent white matter was stimulated.

Deep brain stimulation may supplant cingulotomies and capsulotomies, surgeries that have been used for OCD and are being investigated for depression. Guided by brain scans, a "Gamma Knife" (beams of gamma radiation) cuts lesions in specific areas of the brain. Unlike deep brain stimulation, the surgery is irreversible.

MRI Scans

A funny thing happened when researchers at McLean Hospital outside Boston performed a routine brain scan study of depressed bipolar patients: Many of them emerged from a new type of MRI machine announcing they were feeling a lot better.

A follow up study in 2003 found 23 of 30 patients reported significant improvement after undergoing an MRI compared to those having a sham MRI.

Updated May 15, 2007, reviewed Feb 10, 2008