David Baxter PhD
Late Founder
Device-Based Therapies for Refractory Depression: A Review of Neuromodulation
by Phillip G. Janicak, MD
Psychiatry Weekly, Volume 3, Issue 10, March 10, 2008
A variety of methods and mechanisms comprise the genre of neuromodulation—device-based therapies most often used to treat refractory depressive disorders. Most of these treatments are still experimental, although several of them, such as electroconvulsive therapy (ECT) have been in use for many years. Other neuromodulation therapies include vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (TMS), and deep brain stimulation.
According to Dr. Phillip G. Janicak, the standard for therapeutic modulation is ECT, which has been available for over 60 years. Only ECT and VNS have FDA-approved indications for specific types of depression. “VNS was approved as an adjunctive treatment for depression since studies were done in combination with other pharmacologic agents,” he says. “In addition, those studies involved a more resistant group of patients who, according to the FDA-approved indication, should have failed =4 adequate antidepressant trials during the index episode. This could include medication, cognitive behavioral therapy, or ECT.”
Vagus Nerve Stimulation
VNS served as an adjunctive treatment to medication in a 3-month sham control vs. active design trial. According to Dr. Janicak, “The trial demonstrated a significant difference between the active and sham procedure only on the second outcome measure, the Inventory of Depressive Symptomatology. Based on these results, the safety and tolerability profile, and patients who did not benefit from previous treatments, the advisory panel advised the FDA to approve VNS. The FDA division who had final say, however, chose not to take the panel’s advice. In the meantime, more data were collected after the 3-month sham controlled trial. Response and remission rates continued to increase over extended periods of time, such as 6 months, or 1–2 years, with more prolonged exposure to VNS. This improvement occurred in patients who generally did not experience lasting benefit from previous treatment strategies. The FDA decided that it would be better to provide VNS for these patients, and it became clinically available in July 2005.”
Numerous factors contribute to the controversy over VNS—particularly the efficacy of VNS. “One reason is that pharmacologic agents must meet FDA requirements to be approved, which usually requires 2 large, placebo-controlled, positive trials demonstrating a drug’s safety and efficacy,” says Dr. Janicak. “Second, there is a lack of experience with devices for the treatment of depression. Prior to VNS, ECT was the last form of neuromodulation to be approved. This means that the FDA division that assesses devices is more accustomed to looking at devices for medical conditions, rather than for psychiatric conditions.”
Third party payers, such as Medicare and Medicaid, have decided not to reimburse the cost of VNS implantation, which costs an average of $25,000, not including additional follow up costs and any needed adjustments. “As a result,” says Dr. Janicak, “the device may not have adequate use in a sufficient sample of patients over an extended period of time to assess its true benefit.”
Transcranial Magnetic Stimulation
“We compared ECT to TMS in a 2002 study,” says Dr. Janicak. “Patients in this study had to be clinically appropriate for ECT. Often, they were reluctant to go forward with ECT for a variety of reasons, including potential adverse effects, cost, and the social stigma attached to it. Some of these patients had dramatic improvement with TMS. While TMS will not replace ECT, I think a proportion of patients who are referred for ECT may benefit from TMS as an alternative.”
The ECT-TMS literature consists largely of several small, primarily single-site trials. 6 out of 8 studies reported that TMS was comparable to ECT and 2 studies found ECT superior. According to Dr. Janicak, “If these data are distilled into a clinically meaningful picture there may be a proportion of patients referred for ECT not because they are highly suicidal, psychotically depressed, in need of hospitalization, or having substantial compromise of their physical status, but because they have not benefited from psychotherapy, medication, or a combination of the two. In addition, some may not tolerate adequate trials of medication for their depression. Presently, ECT may be the only option for them. Based on the data from the 8 ECT-TMS comparison studies, as many as 30%–40% of patients referred for ECT might benefit from TMS.”
As the data on TMS are scrutinized, the FDA approval process for TMS has become increasingly lengthy. An FDA advisory panel aired concerns about the primary outcome measure, eg, Montgomery-?sberg Depression Rating Scale change score, comparing active TMS to a sham control in a 6-week trial. At the 4-week mark, the difference between active and sham TMS achieved a P-value of .057, just missing the conventional level of statistical significance. “However,” notes Dr. Janicak, “several secondary measures demonstrated that active TMS achieved statistical separation from the sham procedure at the 4-week juncture, including the 24-item and the 17-item HAM-D and the Inventory of Depressive Symptomatology. At the 6-week juncture, both change scores and categorical response rates demonstrated statistical separation for the active vs. sham procedure.”
Adverse Effects of Neuromodulation
Some VNS studies have included bipolar and unipolar patients, and, according to Dr. Janicak, several patients have become manic during VNS. “It is hard to know, however, if they spontaneously moved into a manic state or if VNS induced it,” he says. “However, I think the bipolar group was too small to make any meaningful conclusions.”
“The most common complications of VNS include voice alteration, such as hoarseness and other related symptoms, which occurred in ~50% of patients,” says Dr. Janicak. “These symptoms were not serious enough, though, to require large numbers of patients to withdraw from the studies. In the sham controlled trial, shortness of breath, neck pain, dysphasia, and parathesias occurred in >10% of patients, and 25%–35% experienced a cough. Most of these symptoms gradually subsided.”
In the trials for TMS, the most commonly reported side effects were headaches and discomfort at the site of the application of the magnetic pulses. According to Dr. Janicak, “the discontinuation rate due to these adverse events was quite low. In terms of serious adverse events, no seizures or deaths occurred in >10,000 sessions involving >300 patients. From a safety and tolerability point of view, TMS appears to be a benign treatment. Over extended periods of time, however, the loud clicking sound that occurs near the acoustic nerve could potentially cause damage, and all patients were required to wear ear plugs during the procedure. Changes in the auditory threshold between the sham and active procedure did not differ.”
Conclusion
“VNS is primarily a maintenance treatment strategy,” says Dr. Janicak. It appears that the longer a patient is exposed, the greater the benefit. ECT, however, is usually an acute treatment. Treatment resistant patients could possibly use both approaches, treating the acute episode with a course of ECT, then using VNS as a maintenance strategy. VNS also does not result in any systemic effects associated with the pharmacologic treatments, such as sexual dysfunction and sedation.”
“As for TMS,” he continues, “its safety and tolerability profile looks much better than that of ECT or VNS. Prior studies that used TMS as an augmentation strategy in partially but insufficiently responsive patients also reported that it was safe to combine TMS with various medications for depression.”
by Phillip G. Janicak, MD
Psychiatry Weekly, Volume 3, Issue 10, March 10, 2008
A variety of methods and mechanisms comprise the genre of neuromodulation—device-based therapies most often used to treat refractory depressive disorders. Most of these treatments are still experimental, although several of them, such as electroconvulsive therapy (ECT) have been in use for many years. Other neuromodulation therapies include vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (TMS), and deep brain stimulation.
According to Dr. Phillip G. Janicak, the standard for therapeutic modulation is ECT, which has been available for over 60 years. Only ECT and VNS have FDA-approved indications for specific types of depression. “VNS was approved as an adjunctive treatment for depression since studies were done in combination with other pharmacologic agents,” he says. “In addition, those studies involved a more resistant group of patients who, according to the FDA-approved indication, should have failed =4 adequate antidepressant trials during the index episode. This could include medication, cognitive behavioral therapy, or ECT.”
Vagus Nerve Stimulation
VNS served as an adjunctive treatment to medication in a 3-month sham control vs. active design trial. According to Dr. Janicak, “The trial demonstrated a significant difference between the active and sham procedure only on the second outcome measure, the Inventory of Depressive Symptomatology. Based on these results, the safety and tolerability profile, and patients who did not benefit from previous treatments, the advisory panel advised the FDA to approve VNS. The FDA division who had final say, however, chose not to take the panel’s advice. In the meantime, more data were collected after the 3-month sham controlled trial. Response and remission rates continued to increase over extended periods of time, such as 6 months, or 1–2 years, with more prolonged exposure to VNS. This improvement occurred in patients who generally did not experience lasting benefit from previous treatment strategies. The FDA decided that it would be better to provide VNS for these patients, and it became clinically available in July 2005.”
Numerous factors contribute to the controversy over VNS—particularly the efficacy of VNS. “One reason is that pharmacologic agents must meet FDA requirements to be approved, which usually requires 2 large, placebo-controlled, positive trials demonstrating a drug’s safety and efficacy,” says Dr. Janicak. “Second, there is a lack of experience with devices for the treatment of depression. Prior to VNS, ECT was the last form of neuromodulation to be approved. This means that the FDA division that assesses devices is more accustomed to looking at devices for medical conditions, rather than for psychiatric conditions.”
Third party payers, such as Medicare and Medicaid, have decided not to reimburse the cost of VNS implantation, which costs an average of $25,000, not including additional follow up costs and any needed adjustments. “As a result,” says Dr. Janicak, “the device may not have adequate use in a sufficient sample of patients over an extended period of time to assess its true benefit.”
Transcranial Magnetic Stimulation
“We compared ECT to TMS in a 2002 study,” says Dr. Janicak. “Patients in this study had to be clinically appropriate for ECT. Often, they were reluctant to go forward with ECT for a variety of reasons, including potential adverse effects, cost, and the social stigma attached to it. Some of these patients had dramatic improvement with TMS. While TMS will not replace ECT, I think a proportion of patients who are referred for ECT may benefit from TMS as an alternative.”
The ECT-TMS literature consists largely of several small, primarily single-site trials. 6 out of 8 studies reported that TMS was comparable to ECT and 2 studies found ECT superior. According to Dr. Janicak, “If these data are distilled into a clinically meaningful picture there may be a proportion of patients referred for ECT not because they are highly suicidal, psychotically depressed, in need of hospitalization, or having substantial compromise of their physical status, but because they have not benefited from psychotherapy, medication, or a combination of the two. In addition, some may not tolerate adequate trials of medication for their depression. Presently, ECT may be the only option for them. Based on the data from the 8 ECT-TMS comparison studies, as many as 30%–40% of patients referred for ECT might benefit from TMS.”
As the data on TMS are scrutinized, the FDA approval process for TMS has become increasingly lengthy. An FDA advisory panel aired concerns about the primary outcome measure, eg, Montgomery-?sberg Depression Rating Scale change score, comparing active TMS to a sham control in a 6-week trial. At the 4-week mark, the difference between active and sham TMS achieved a P-value of .057, just missing the conventional level of statistical significance. “However,” notes Dr. Janicak, “several secondary measures demonstrated that active TMS achieved statistical separation from the sham procedure at the 4-week juncture, including the 24-item and the 17-item HAM-D and the Inventory of Depressive Symptomatology. At the 6-week juncture, both change scores and categorical response rates demonstrated statistical separation for the active vs. sham procedure.”
Adverse Effects of Neuromodulation
Some VNS studies have included bipolar and unipolar patients, and, according to Dr. Janicak, several patients have become manic during VNS. “It is hard to know, however, if they spontaneously moved into a manic state or if VNS induced it,” he says. “However, I think the bipolar group was too small to make any meaningful conclusions.”
“The most common complications of VNS include voice alteration, such as hoarseness and other related symptoms, which occurred in ~50% of patients,” says Dr. Janicak. “These symptoms were not serious enough, though, to require large numbers of patients to withdraw from the studies. In the sham controlled trial, shortness of breath, neck pain, dysphasia, and parathesias occurred in >10% of patients, and 25%–35% experienced a cough. Most of these symptoms gradually subsided.”
In the trials for TMS, the most commonly reported side effects were headaches and discomfort at the site of the application of the magnetic pulses. According to Dr. Janicak, “the discontinuation rate due to these adverse events was quite low. In terms of serious adverse events, no seizures or deaths occurred in >10,000 sessions involving >300 patients. From a safety and tolerability point of view, TMS appears to be a benign treatment. Over extended periods of time, however, the loud clicking sound that occurs near the acoustic nerve could potentially cause damage, and all patients were required to wear ear plugs during the procedure. Changes in the auditory threshold between the sham and active procedure did not differ.”
Conclusion
“VNS is primarily a maintenance treatment strategy,” says Dr. Janicak. It appears that the longer a patient is exposed, the greater the benefit. ECT, however, is usually an acute treatment. Treatment resistant patients could possibly use both approaches, treating the acute episode with a course of ECT, then using VNS as a maintenance strategy. VNS also does not result in any systemic effects associated with the pharmacologic treatments, such as sexual dysfunction and sedation.”
“As for TMS,” he continues, “its safety and tolerability profile looks much better than that of ECT or VNS. Prior studies that used TMS as an augmentation strategy in partially but insufficiently responsive patients also reported that it was safe to combine TMS with various medications for depression.”
