Trial: Deep Brain Stimulation Eases Depression Symptoms

Deep brain stimulation of the subcallosal cingulate area appears to significantly decrease the symptoms of treatment-resistant depression.

An open-label trial of 21 patients who had failed multiple medical and electroconvulsive treatments found that the electrical implants improved depression scores in up to 62% of patients, Dr. Andres M. Lozano reported in the November issue of the Journal of Neurosurgery (Epub doi: 10.3171/2011.10.JNS102122).

Photo courtesy St. Jude Medical Inc.

A prior study (J. Neurosurg. 2009;111:1209-15), showed similar positive results but was conducted only at a single center. The new study, with data on patients from three different facilities, confirms the procedure’s success, and speaks to its reproducibility in varied hands, said Dr. Lozano of the University of Toronto and his coauthors.

"The results of this multicenter study suggest that the [subcallosal cingulate gyrus] can be reliably targeted for [deep brain stimulation] electrode implantation and that the clinical effects of [the procedure] for [treatment-resistant depression] are robust and reproducible across centers."

Dr. Lozano and his colleagues reported on 21 patients who underwent deep brain stimulation for treatment-resistant depression at the universities of Toronto and British Columbia, and at McGill University in Montreal. All patients had failed repeated medical therapies; 90% had undergone electroconvulsive therapy that proved ineffective. All of the patients had also received psychotherapy. Despite treatment, their depressive symptoms remained serious: (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 47; mean Hamilton Rating Scale for Depression [HRSD-17] score, 28).

The patients were a mean of 47 years old and reported a mean of seven episodes of major depression during their lifetime. The current major depressive episode had lasted a mean of 5 years.

Researchers initially chose the subcallosal cingulate gyrus because it is involved in processing the emotion of acute sadness. It also seems to be overactive in subjects with treatment-resistant depression; this theory is supported by observation that some effective treatments reduce blood flow or metabolic activity in the subcallosal cingulate gyrus (SCG), the authors said.

During surgery, bilateral SCG targets were identified by three-dimensional magnetic resonance imaging. The electrodes were inserted into the targets and fixed to the skull. The surgeon then connected the electrodes to a pulse generator located in the infraclavicular region.

The mean stimulation amplitude after surgery was 4.2 mA, increasing to 4.9 at 6 months, and 5.2 at 12 months.

Patients were considered responders if they experienced at least a 50% reduction in the HRSD-17 score. At 1 month, 57% were classified as responders; at 6 months, 48%, and by 12 months, 29%.

The reductions in depressive symptoms were associated with global improvements in the patients, the authors said. "Patients shifted from being severely ill to being less ill after surgery, and the majority of patients improved with surgery. At 12 months, none of the 20 patients who remained in treatment were worse than at baseline." According to a graph in the paper, the actual number of patients who improved was 15 at 3 months, 13 at 6 months, and 13 at 12 months.

When evaluated with the Clinical Global Impression of Severity (CGI-S) rating scale, 70% were categorized as severely or extremely ill at baseline, while, at 1 year after surgery, 80% experienced clinical improvement and none rated as severely or extremely ill.

One patient committed suicide by drug overdose in the 8th postsurgical week. Another patient attempted suicide between the week 4 and week 5 follow-up visits. "The underlying trigger was thought to be a family matter," the authors noted.

Nine patients reported nausea, vomiting, and diarrhea, although it was unclear whether those adverse events were related to stimulating that region of the brain. One patient experienced a lead extension malfunction immediately after surgery, which required replacing the extension. Another patient experienced superficial skin erosion over a bur site, about 7 weeks after the implant was activated; the incision was revised and this resolved.

Other side effects included headache more than 1 month after surgery (six patients), agitation in reaction to amplitude increase (three), dizziness (three), polyuria (two), and weight gain, buzzing in the ears, and insomnia (one each).

The authors also addressed the apparent decrease in effectiveness by 1 year, saying it could be "somewhat of an artifact of the data analysis." Most patients continued to do well: Depression scores improved by 50% or more in a third of the patients, and 62% experiencing an improvement of at least 40%. But, the investigators said, four of the patients who improved the most dropped to the 40% improvement range by 1 year, "a small change that is likely noise, but which has a large impact when using the 50% cutoff for response in a series with a relatively small number of participants."

A recent report on 20 of the patients concluded that the benefit of DBS was long-lasting (Am. J. Psych. 2011;168:502-10).

"The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (3-6 years), the average response rate was 64.3%," wrote lead author Dr. Sidney Kennedy of the University of Toronto.

The present study raises some additional questions, said Dr. Lozano and his coauthors. Since the procedure was open label, the analysis cannot account for a placebo effect. Additionally, they said, disease heterogeneity, anatomic variation, and stimulation variants might play a part in which patients respond and which do not.

Nor is the SCG the only possible treatment target, they said. "It is clear that other brain targets may also be useful ... including the nucleus accumbens and the anterior limb of the internal capsule. The specific attributes and potential uses of each of these possible therapeutic targets will require much more investigation."

According to a press statement, St. Jude Medical, the company that created the DBS system in the study, is now conducting a similar study at 20 facilities in the United States and internationally, under a U.S. Food and Drug Administration Investigational Device Exemption.

Dr. Lozano disclosed that he holds intellectual property rights in the field of using DBS for depression and is a consultant for St. Jude Medical Inc. in Minneapolis, which developed the device used in this study.* Other authors indicated relationships with multiple drug companies. Dr. Burchiel reported having no disclosures.

*CLARIFICATION, 11/29/11: Information was added to clarify this sentence.

Deep brain stimulation of the subcallosal cingulate area appears to significantly decrease the symptoms of treatment-resistant depression.

An open-label trial of 21 patients who had failed multiple medical and electroconvulsive treatments found that the electrical implants improved depression scores in up to 62% of patients, Dr. Andres M. Lozano reported in the November issue of the Journal of Neurosurgery (Epub doi: 10.3171/2011.10.JNS102122).

Photo courtesy St. Jude Medical Inc.

A prior study (J. Neurosurg. 2009;111:1209-15), showed similar positive results but was conducted only at a single center. The new study, with data on patients from three different facilities, confirms the procedure’s success, and speaks to its reproducibility in varied hands, said Dr. Lozano of the University of Toronto and his coauthors.

"The results of this multicenter study suggest that the [subcallosal cingulate gyrus] can be reliably targeted for [deep brain stimulation] electrode implantation and that the clinical effects of [the procedure] for [treatment-resistant depression] are robust and reproducible across centers."

Dr. Lozano and his colleagues reported on 21 patients who underwent deep brain stimulation for treatment-resistant depression at the universities of Toronto and British Columbia, and at McGill University in Montreal. All patients had failed repeated medical therapies; 90% had undergone electroconvulsive therapy that proved ineffective. All of the patients had also received psychotherapy. Despite treatment, their depressive symptoms remained serious: (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 47; mean Hamilton Rating Scale for Depression [HRSD-17] score, 28).

The patients were a mean of 47 years old and reported a mean of seven episodes of major depression during their lifetime. The current major depressive episode had lasted a mean of 5 years.

Researchers initially chose the subcallosal cingulate gyrus because it is involved in processing the emotion of acute sadness. It also seems to be overactive in subjects with treatment-resistant depression; this theory is supported by observation that some effective treatments reduce blood flow or metabolic activity in the subcallosal cingulate gyrus (SCG), the authors said.

During surgery, bilateral SCG targets were identified by three-dimensional magnetic resonance imaging. The electrodes were inserted into the targets and fixed to the skull. The surgeon then connected the electrodes to a pulse generator located in the infraclavicular region.

The mean stimulation amplitude after surgery was 4.2 mA, increasing to 4.9 at 6 months, and 5.2 at 12 months.

Patients were considered responders if they experienced at least a 50% reduction in the HRSD-17 score. At 1 month, 57% were classified as responders; at 6 months, 48%, and by 12 months, 29%.

The reductions in depressive symptoms were associated with global improvements in the patients, the authors said. "Patients shifted from being severely ill to being less ill after surgery, and the majority of patients improved with surgery. At 12 months, none of the 20 patients who remained in treatment were worse than at baseline." According to a graph in the paper, the actual number of patients who improved was 15 at 3 months, 13 at 6 months, and 13 at 12 months.

When evaluated with the Clinical Global Impression of Severity (CGI-S) rating scale, 70% were categorized as severely or extremely ill at baseline, while, at 1 year after surgery, 80% experienced clinical improvement and none rated as severely or extremely ill.

One patient committed suicide by drug overdose in the 8th postsurgical week. Another patient attempted suicide between the week 4 and week 5 follow-up visits. "The underlying trigger was thought to be a family matter," the authors noted.

Nine patients reported nausea, vomiting, and diarrhea, although it was unclear whether those adverse events were related to stimulating that region of the brain. One patient experienced a lead extension malfunction immediately after surgery, which required replacing the extension. Another patient experienced superficial skin erosion over a bur site, about 7 weeks after the implant was activated; the incision was revised and this resolved.

Other side effects included headache more than 1 month after surgery (six patients), agitation in reaction to amplitude increase (three), dizziness (three), polyuria (two), and weight gain, buzzing in the ears, and insomnia (one each).

The authors also addressed the apparent decrease in effectiveness by 1 year, saying it could be "somewhat of an artifact of the data analysis." Most patients continued to do well: Depression scores improved by 50% or more in a third of the patients, and 62% experiencing an improvement of at least 40%. But, the investigators said, four of the patients who improved the most dropped to the 40% improvement range by 1 year, "a small change that is likely noise, but which has a large impact when using the 50% cutoff for response in a series with a relatively small number of participants."

A recent report on 20 of the patients concluded that the benefit of DBS was long-lasting (Am. J. Psych. 2011;168:502-10).

"The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (3-6 years), the average response rate was 64.3%," wrote lead author Dr. Sidney Kennedy of the University of Toronto.

The present study raises some additional questions, said Dr. Lozano and his coauthors. Since the procedure was open label, the analysis cannot account for a placebo effect. Additionally, they said, disease heterogeneity, anatomic variation, and stimulation variants might play a part in which patients respond and which do not.

Nor is the SCG the only possible treatment target, they said. "It is clear that other brain targets may also be useful ... including the nucleus accumbens and the anterior limb of the internal capsule. The specific attributes and potential uses of each of these possible therapeutic targets will require much more investigation."

According to a press statement, St. Jude Medical, the company that created the DBS system in the study, is now conducting a similar study at 20 facilities in the United States and internationally, under a U.S. Food and Drug Administration Investigational Device Exemption.

Dr. Lozano disclosed that he holds intellectual property rights in the field of using DBS for depression and is a consultant for St. Jude Medical Inc. in Minneapolis, which developed the device used in this study.* Other authors indicated relationships with multiple drug companies. Dr. Burchiel reported having no disclosures.

*CLARIFICATION, 11/29/11: Information was added to clarify this sentence.

Deep brain stimulation of the subcallosal cingulate area appears to significantly decrease the symptoms of treatment-resistant depression.

An open-label trial of 21 patients who had failed multiple medical and electroconvulsive treatments found that the electrical implants improved depression scores in up to 62% of patients, Dr. Andres M. Lozano reported in the November issue of the Journal of Neurosurgery (Epub doi: 10.3171/2011.10.JNS102122).

Photo courtesy St. Jude Medical Inc.

A prior study (J. Neurosurg. 2009;111:1209-15), showed similar positive results but was conducted only at a single center. The new study, with data on patients from three different facilities, confirms the procedure’s success, and speaks to its reproducibility in varied hands, said Dr. Lozano of the University of Toronto and his coauthors.

"The results of this multicenter study suggest that the [subcallosal cingulate gyrus] can be reliably targeted for [deep brain stimulation] electrode implantation and that the clinical effects of [the procedure] for [treatment-resistant depression] are robust and reproducible across centers."

Dr. Lozano and his colleagues reported on 21 patients who underwent deep brain stimulation for treatment-resistant depression at the universities of Toronto and British Columbia, and at McGill University in Montreal. All patients had failed repeated medical therapies; 90% had undergone electroconvulsive therapy that proved ineffective. All of the patients had also received psychotherapy. Despite treatment, their depressive symptoms remained serious: (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 47; mean Hamilton Rating Scale for Depression [HRSD-17] score, 28).

The patients were a mean of 47 years old and reported a mean of seven episodes of major depression during their lifetime. The current major depressive episode had lasted a mean of 5 years.

Researchers initially chose the subcallosal cingulate gyrus because it is involved in processing the emotion of acute sadness. It also seems to be overactive in subjects with treatment-resistant depression; this theory is supported by observation that some effective treatments reduce blood flow or metabolic activity in the subcallosal cingulate gyrus (SCG), the authors said.

During surgery, bilateral SCG targets were identified by three-dimensional magnetic resonance imaging. The electrodes were inserted into the targets and fixed to the skull. The surgeon then connected the electrodes to a pulse generator located in the infraclavicular region.

The mean stimulation amplitude after surgery was 4.2 mA, increasing to 4.9 at 6 months, and 5.2 at 12 months.

Patients were considered responders if they experienced at least a 50% reduction in the HRSD-17 score. At 1 month, 57% were classified as responders; at 6 months, 48%, and by 12 months, 29%.

The reductions in depressive symptoms were associated with global improvements in the patients, the authors said. "Patients shifted from being severely ill to being less ill after surgery, and the majority of patients improved with surgery. At 12 months, none of the 20 patients who remained in treatment were worse than at baseline." According to a graph in the paper, the actual number of patients who improved was 15 at 3 months, 13 at 6 months, and 13 at 12 months.

When evaluated with the Clinical Global Impression of Severity (CGI-S) rating scale, 70% were categorized as severely or extremely ill at baseline, while, at 1 year after surgery, 80% experienced clinical improvement and none rated as severely or extremely ill.

One patient committed suicide by drug overdose in the 8th postsurgical week. Another patient attempted suicide between the week 4 and week 5 follow-up visits. "The underlying trigger was thought to be a family matter," the authors noted.

Nine patients reported nausea, vomiting, and diarrhea, although it was unclear whether those adverse events were related to stimulating that region of the brain. One patient experienced a lead extension malfunction immediately after surgery, which required replacing the extension. Another patient experienced superficial skin erosion over a bur site, about 7 weeks after the implant was activated; the incision was revised and this resolved.

Other side effects included headache more than 1 month after surgery (six patients), agitation in reaction to amplitude increase (three), dizziness (three), polyuria (two), and weight gain, buzzing in the ears, and insomnia (one each).

The authors also addressed the apparent decrease in effectiveness by 1 year, saying it could be "somewhat of an artifact of the data analysis." Most patients continued to do well: Depression scores improved by 50% or more in a third of the patients, and 62% experiencing an improvement of at least 40%. But, the investigators said, four of the patients who improved the most dropped to the 40% improvement range by 1 year, "a small change that is likely noise, but which has a large impact when using the 50% cutoff for response in a series with a relatively small number of participants."

A recent report on 20 of the patients concluded that the benefit of DBS was long-lasting (Am. J. Psych. 2011;168:502-10).

"The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (3-6 years), the average response rate was 64.3%," wrote lead author Dr. Sidney Kennedy of the University of Toronto.

The present study raises some additional questions, said Dr. Lozano and his coauthors. Since the procedure was open label, the analysis cannot account for a placebo effect. Additionally, they said, disease heterogeneity, anatomic variation, and stimulation variants might play a part in which patients respond and which do not.

Nor is the SCG the only possible treatment target, they said. "It is clear that other brain targets may also be useful ... including the nucleus accumbens and the anterior limb of the internal capsule. The specific attributes and potential uses of each of these possible therapeutic targets will require much more investigation."

According to a press statement, St. Jude Medical, the company that created the DBS system in the study, is now conducting a similar study at 20 facilities in the United States and internationally, under a U.S. Food and Drug Administration Investigational Device Exemption.

Dr. Lozano disclosed that he holds intellectual property rights in the field of using DBS for depression and is a consultant for St. Jude Medical Inc. in Minneapolis, which developed the device used in this study.* Other authors indicated relationships with multiple drug companies. Dr. Burchiel reported having no disclosures.

*CLARIFICATION, 11/29/11: Information was added to clarify this sentence.