Sheila M. Dowd, PhD

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/therapeutic-neuromodulation.html#comments

The brain is an electrochemical organ, and its activity can be modulated for therapeutic purposes by electrical, pharmacologic, or combined approaches. In general, neuromodulation induces electrical current in peripheral or central nervous tissue, which is accomplished by various techniques, including:

• electroconvulsive therapy (ECT)
• vagus nerve stimulation (VNS)
• transcranial magnetic stimulation (TMS)
• deep brain stimulation (DBS).

It is thought that therapeutic benefit occurs by regulating functional disturbances in relevant distributed neural circuits.¹ Depending on the stimulation method, the frequencies chosen may excite or inhibit different or the same areas of the brain in varying patterns. Unlike medication, neuromodulation impacts the brain episodically, which may mitigate adaptation to the therapy’s beneficial effects and avoid systemic adverse effects.

Neuromodulation techniques are categorized based on their risk level as invasive or noninvasive and seizurogenic or nonseizurogenic (Table 1). Although these and other approaches are being considered for various neuropsychiatric disorders (Table 2), the most common application is for severe, treatment-resistant depression. Therefore, this article focuses on FDA-approved neuromodulation treatments for depression, with limited discussion of other indications.

Table 1

Therapeutic neuromodulation: Categorization based on risk

Table 2

Approved and investigational indications of neuromodulation

ECT: Oldest and most effective

ECT has remained the most effective therapeutic neuromodulation technique for more than 7 decades. It is indicated primarily for severe depressive episodes (eg, psychotic, melancholic), particularly in older patients.

ECT delivers electrical current to the CNS that is sufficient to produce a seizure. Under modified conditions, a typical course of 6 to 12 sessions can resolve severe depressive episodes and may also benefit other disorders, such as bipolar mania and acute psychosis. Although ECT is potentially life-saving, its use was markedly curtailed with the advent of effective antidepressants in the 1950s. Multiple factors impede its use, including:

• access and expertise are limited in many areas
• cognition is at least temporarily adversely affected
• relapse rates after acute benefit are high
• cost
• public perception often is negative.

Studies are addressing several of these concerns. For example, the National Institute of Mental Health-sponsored Consortium on Research with ECT (CORE) group is considering how to more effectively maintain acute benefits of ECT. They compared the potential merits of maintenance ECT with maintenance pharmacotherapy (nortriptyline plus lithium) over 6 months. Although the 2 strategies had comparable results, retention rates were <50% and about one-third relapsed in both groups.^2,3 Potential alternative strategies include a more frequent ECT maintenance schedule and/or combining maintenance ECT with medication(s).

Magnetic seizure therapy (MST) and focal electrically administered seizure therapy (FEAST) are attempts to produce similar efficacy and less cognitive disruption compared with ECT.^4,5 Work also continues on electrode placement (eg, bifrontal) and alteration of waveform characteristics (eg, ultra-brief) to maintain or enhance efficacy while minimizing adverse effects.^6,7

Stimulating the vagus nerve

VNS was introduced for treating refractory epilepsy in 1997. In 2005, it became the first FDA-approved implantable device for managing chronic or recurrent treatment-resistant depression.

The vagus nerve is the principal parasympathetic, efferent tract regulating heart rate, intestinal motility, and gastric acid secretion. Information about pain, hunger, and satiety is conveyed by these fibers to the median raphe nucleus and locus coeruleus, brain regions with significant serotonergic and noradrenergic innervation. These neurotransmitters also are believed to play a pivotal role in major depression.

With VNS, a pacemaker-like pulse generator is surgically implanted subcutaneously in the patient’s upper left chest. Wires extend from this device to the left vagus nerve (80% of whose fibers are afferent) located in the neck, to which the pulse generator sends electrical signals every few seconds (Table 3). The right vagus nerve is not used because it provides parasympathetic innervation to the heart. A clinician adjusts stimulation parameters using a computer and a noninvasive handheld device. Common adverse effects include voice alteration or hoarseness, cough, and shortness of breath, which occur during active stimulation because of the proximity of the electrodes to the laryngeal and pharyngeal branches of the vagus nerve. These effects may improve by adjusting stimulation intensity. The device permits a wide range of duty cycles, but preclinical animal studies indicate that >50% activation periods may damage the vagus nerve. If patients become too uncomfortable, they may deactivate the device with a magnet held over the implantation area.

Two open-label studies evaluated VNS to treat major depression. The first involved 10 weeks of stimulation in 59 subjects with chronic or recurrent, nonpsychotic, unipolar or bipolar depression who failed at least 2 adequate antidepressant trials in the current episode.⁸ Stable doses of concomitant antidepressants or mood stabilizers were allowed. After 3 months, 18 (31%) patients responded within an average of 45.5 days, and nearly 15% achieved remission. Response was defined as 50% reduction in baseline Hamilton Depression Rating Scale-28 (HDRS-28) score; remission was defined as HDRS-28 score ≤10. Further, clinical response did not differ between unipolar and bipolar depression patients.

In the second trial, 74 patients with treatment-resistant depression received fixed dose antidepressants and VNS for 3 months, followed by 9 months of flexibly dosed VNS and antidepressants.⁹ At 3 months, response (≥50% reduction in HDRS-28 score) and remission (HDRS-28 score <10) rates were 37% and 17%, respectively, and increased to 53% and 33% at 1 year.

A sham-controlled trial of VNS in 235 depressed patients used similar inclusion and exclusion criteria as in the open-label study by Sackeim et al.^8,10 Two weeks after device implantation, patients were randomized to active treatment (stimulator turned on) or sham control (stimulator left off). At 3 months, the primary outcome measure—response rate based on HDRS-24 score—did not differ significantly between the active and control groups (15% vs 10%, respectively). There was, however, a significantly greater improvement in Inventory of Depressive Symptomatology-Self Report Scale scores with active VNS vs sham VNS.

Patients on sham treatment then were switched to active treatment and both groups were followed for 12 additional months, at which time response and remission rates nearly doubled for both groups.¹¹ In a post-hoc analysis, the same investigators found significant improvement with VNS compared with a naturalistic, matched control group with similar treatment-resistant depression.¹² The FDA considered this adequate to support efficacy and approved the device for chronic or recurrent treatment-resistant depression in an episode not responsive to at least 4 adequate treatment trials with pharmacotherapy or ECT. Perhaps because post-hoc analyses typically are not sufficient to gain FDA approval, most insurance companies do not reimburse for VNS treatment of depression, and VNS is not frequently used for refractory depression.

Table 3

Vagus nerve stimulation treatment parameters

A newer option: TMS

TMS is the most recently FDA-approved therapeutic neuromodulation technique for treating depression. In October 2008, a TMS device became available for patients failing to respond to 1 adequate antidepressant trial during the current episode.

TMS delivers intense, intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The pulse intensity is similar to that produced by MRI. The coil usually is placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC) and pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the adjacent cerebral cortex, as well as distal effects in other relevant neural circuits (Table 4). TMS typically is administered on an outpatient basis. A standard treatment course for depression consists of 5 treatment sessions per week for 4 to 8 weeks, depending on symptom severity and how quickly patients respond.

TMS initially was examined in several small, open-label studies that looked at various treatment parameters and stimulation sites. Several sham-controlled studies generally found TMS efficacious and further refined treatment administration. Its role in treating depression—and possibly other psychiatric disorders—has been supported by 2 recent meta-analyses.^13,14

O’Reardon et al¹⁵ conducted the largest double-blind trial of active vs sham TMS (N=301) for moderately treatment-resistant major depression. This study began with a 4- to 6-week, blinded, randomized phase followed by 6 weeks of open-label TMS for initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressants. This trial utilized the most aggressive treatment parameters to date (ie, 10 Hz; 75 4-second trains; 26-second inter-train interval; 120% motor threshold) delivering 3,000 pulses per treatment over an average of 24 sessions. Compared with the sham procedure, patients who received active TMS showed significantly higher response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, remission rate—defined as a MADRS score <10—was significantly higher in the active treatment group (14%) compared with the sham procedure (6%). A post-hoc analysis found that the most robust benefit occurred in patients with only 1 failed adequate antidepressant trial (effect size=0.83).¹⁶ This administration protocol was well tolerated, with no deaths or seizures and a low rate of discontinuation because of adverse events (5%).¹⁷ The most common adverse effects were application site pain or discomfort and headaches.

Recently, the second largest (N=190) sham-controlled trial of TMS for treatment-resistant major depression was published.¹⁸ This National Institute of Mental Health-sponsored, multiphase study included an initial 2-week, treatment-free period; 3 weeks of daily treatments over the left DLPFC using the same device and parameters as in the O’Reardon study; and an additional 3 weeks of treatment in patients who were improving. Those not responding to initial treatment were crossed over to open-label active TMS. This study advanced TMS development by:

• using a novel somatosensory system that produced similar sensations with sham and active TMS
• assessing the success of maintaining the blind
• establishing a rigorous clinical rating system
• utilizing MRI-guided adjustment of coil placement in a subset of patients.

The authors concluded that active TMS was significantly better than sham treatment in achieving remission (14% vs 5%). In addition, the raters, treaters, and patients were effectively blinded to the treatment condition. MRI-assisted coil placement found that in 33% of the sample, site placement determined by standardized assessment was over the premotor cortex rather than the prefrontal cortex, so the coil was moved 1 additional cm anteriorly in these patients. Similar to those observed by O’Reardon et al, adverse effects of active TMS were generally mild to moderate, did not differ by treatment condition, and led to a low discontinuation rate (5.5%).

Table 4

Treatment parameters of transcranial magnetic stimulation

Deep brain stimulation

DBS is a “functional neurosurgical” procedure that delivers electrical current directly to specific areas within the brain.¹⁹ Its mechanism of action remains uncertain; depolarization blockade, synaptic inhibition, and “neural jamming” are leading hypotheses. In contrast to conventional ablative surgeries, DBS is reversible and adjustable. Implantation involves positioning pacemaker-like battery devices subcutaneously in the left and right upper chest. Electrodes attached to wires are run subcutaneously behind the ears and, with stereotactic guidance, placed through burr holes in the skull into specific CNS areas implicated in the pathophysiology of conditions such as Parkinson’s disease, refractory depression, and severe obsessive-compulsive disorder (OCD).

Antidepressant effects. The FDA recently approved DBS under its humanitarian device exemption program for intractable, severe, disabling OCD based on promising results from open and blind trials that stimulated areas such as the internal capsule and adjacent ventral striatum.^20-22 These studies reported that DBS of the caudate nucleus for OCD and subthalamic nucleus for Parkinson’s disease also produced antidepressant effects. Subsequently, trials targeting the subgenual region (Brodmann’s area 25), the ventral capsule/ventral striatum, and nucleus accumbens demonstrated antidepressant effects.^23-27 Pending the results of ongoing pilot trials, large, multi-center studies using different devices and target areas are being planned to clarify the role of DBS for patients with severe, disabling, refractory depression.

Adverse effects of DBS can be:

• surgical-related (eg, seizure, bleeding, infection)
• device-related (eg, lead breakage, malfunction)
• stimulation-related (eg, paresthesia, dysarthria, memory disruption, cognitive changes, psychiatric symptoms).

The most serious risk is intracranial bleeding, which occurs in 2% to 3% of patients. Clearly, the risk-benefit ratio must be carefully considered.

Cost and reimbursement

Cost of treatment and potential for third-party reimbursement are important considerations for any risk-benefit analysis. Many patients who seek neuromodulation treatments will not have insurance or other coverage entitlements.^28-30 Further, newer treatments are not routinely covered by insurance; however, individual case coverage may be allowed and some device manufacturers have programs to assist providers and patients obtain coverage.^28-30 Even ECT, which has long been a covered treatment for major depression, is still considered investigational for other disorders. Thus, it is important to pre-certify with the patient’s health insurance provider before initiating treatment.

Coverage, however, is not the only consideration when weighing cost effectiveness. Economic studies can assist with clinical and ethical decisions relating to treatment choice.³¹ These studies, however, need to be critically evaluated (eg, what costs were included in the analysis). Although direct costs are easier to evaluate, indirect costs—such as the patient’s ability to continue to work while receiving the treatment, caretaker availability during treatment, and whether treatment is an inpatient or outpatient procedure—are more difficult to evaluate and should be discussed with the patient. Because these specialized options have the potential to further benefit patients with depression and other neuropsychiatric disorders, it is essential to balance the pressures of cost containment with the need for more effective and better tolerated treatments.^32-34

Related Resource

• Brunoni AR, Teng CT, Correa C, et al. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Arq Neuropsiquiatr. 2010;68(3):433-451.

Drug Brand Names

• Lithium • Eskalith, Lithobid
• Nortriptyline • Aventyl, Pamelor

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/therapeutic-neuromodulation.html#comments

The brain is an electrochemical organ, and its activity can be modulated for therapeutic purposes by electrical, pharmacologic, or combined approaches. In general, neuromodulation induces electrical current in peripheral or central nervous tissue, which is accomplished by various techniques, including:

• electroconvulsive therapy (ECT)
• vagus nerve stimulation (VNS)
• transcranial magnetic stimulation (TMS)
• deep brain stimulation (DBS).

It is thought that therapeutic benefit occurs by regulating functional disturbances in relevant distributed neural circuits.¹ Depending on the stimulation method, the frequencies chosen may excite or inhibit different or the same areas of the brain in varying patterns. Unlike medication, neuromodulation impacts the brain episodically, which may mitigate adaptation to the therapy’s beneficial effects and avoid systemic adverse effects.

Neuromodulation techniques are categorized based on their risk level as invasive or noninvasive and seizurogenic or nonseizurogenic (Table 1). Although these and other approaches are being considered for various neuropsychiatric disorders (Table 2), the most common application is for severe, treatment-resistant depression. Therefore, this article focuses on FDA-approved neuromodulation treatments for depression, with limited discussion of other indications.

Table 1

Therapeutic neuromodulation: Categorization based on risk

Table 2

Approved and investigational indications of neuromodulation

ECT: Oldest and most effective

ECT has remained the most effective therapeutic neuromodulation technique for more than 7 decades. It is indicated primarily for severe depressive episodes (eg, psychotic, melancholic), particularly in older patients.

ECT delivers electrical current to the CNS that is sufficient to produce a seizure. Under modified conditions, a typical course of 6 to 12 sessions can resolve severe depressive episodes and may also benefit other disorders, such as bipolar mania and acute psychosis. Although ECT is potentially life-saving, its use was markedly curtailed with the advent of effective antidepressants in the 1950s. Multiple factors impede its use, including:

• access and expertise are limited in many areas
• cognition is at least temporarily adversely affected
• relapse rates after acute benefit are high
• cost
• public perception often is negative.

Studies are addressing several of these concerns. For example, the National Institute of Mental Health-sponsored Consortium on Research with ECT (CORE) group is considering how to more effectively maintain acute benefits of ECT. They compared the potential merits of maintenance ECT with maintenance pharmacotherapy (nortriptyline plus lithium) over 6 months. Although the 2 strategies had comparable results, retention rates were <50% and about one-third relapsed in both groups.^2,3 Potential alternative strategies include a more frequent ECT maintenance schedule and/or combining maintenance ECT with medication(s).

Magnetic seizure therapy (MST) and focal electrically administered seizure therapy (FEAST) are attempts to produce similar efficacy and less cognitive disruption compared with ECT.^4,5 Work also continues on electrode placement (eg, bifrontal) and alteration of waveform characteristics (eg, ultra-brief) to maintain or enhance efficacy while minimizing adverse effects.^6,7

Stimulating the vagus nerve

VNS was introduced for treating refractory epilepsy in 1997. In 2005, it became the first FDA-approved implantable device for managing chronic or recurrent treatment-resistant depression.

The vagus nerve is the principal parasympathetic, efferent tract regulating heart rate, intestinal motility, and gastric acid secretion. Information about pain, hunger, and satiety is conveyed by these fibers to the median raphe nucleus and locus coeruleus, brain regions with significant serotonergic and noradrenergic innervation. These neurotransmitters also are believed to play a pivotal role in major depression.

With VNS, a pacemaker-like pulse generator is surgically implanted subcutaneously in the patient’s upper left chest. Wires extend from this device to the left vagus nerve (80% of whose fibers are afferent) located in the neck, to which the pulse generator sends electrical signals every few seconds (Table 3). The right vagus nerve is not used because it provides parasympathetic innervation to the heart. A clinician adjusts stimulation parameters using a computer and a noninvasive handheld device. Common adverse effects include voice alteration or hoarseness, cough, and shortness of breath, which occur during active stimulation because of the proximity of the electrodes to the laryngeal and pharyngeal branches of the vagus nerve. These effects may improve by adjusting stimulation intensity. The device permits a wide range of duty cycles, but preclinical animal studies indicate that >50% activation periods may damage the vagus nerve. If patients become too uncomfortable, they may deactivate the device with a magnet held over the implantation area.

Two open-label studies evaluated VNS to treat major depression. The first involved 10 weeks of stimulation in 59 subjects with chronic or recurrent, nonpsychotic, unipolar or bipolar depression who failed at least 2 adequate antidepressant trials in the current episode.⁸ Stable doses of concomitant antidepressants or mood stabilizers were allowed. After 3 months, 18 (31%) patients responded within an average of 45.5 days, and nearly 15% achieved remission. Response was defined as 50% reduction in baseline Hamilton Depression Rating Scale-28 (HDRS-28) score; remission was defined as HDRS-28 score ≤10. Further, clinical response did not differ between unipolar and bipolar depression patients.

In the second trial, 74 patients with treatment-resistant depression received fixed dose antidepressants and VNS for 3 months, followed by 9 months of flexibly dosed VNS and antidepressants.⁹ At 3 months, response (≥50% reduction in HDRS-28 score) and remission (HDRS-28 score <10) rates were 37% and 17%, respectively, and increased to 53% and 33% at 1 year.

A sham-controlled trial of VNS in 235 depressed patients used similar inclusion and exclusion criteria as in the open-label study by Sackeim et al.^8,10 Two weeks after device implantation, patients were randomized to active treatment (stimulator turned on) or sham control (stimulator left off). At 3 months, the primary outcome measure—response rate based on HDRS-24 score—did not differ significantly between the active and control groups (15% vs 10%, respectively). There was, however, a significantly greater improvement in Inventory of Depressive Symptomatology-Self Report Scale scores with active VNS vs sham VNS.

Patients on sham treatment then were switched to active treatment and both groups were followed for 12 additional months, at which time response and remission rates nearly doubled for both groups.¹¹ In a post-hoc analysis, the same investigators found significant improvement with VNS compared with a naturalistic, matched control group with similar treatment-resistant depression.¹² The FDA considered this adequate to support efficacy and approved the device for chronic or recurrent treatment-resistant depression in an episode not responsive to at least 4 adequate treatment trials with pharmacotherapy or ECT. Perhaps because post-hoc analyses typically are not sufficient to gain FDA approval, most insurance companies do not reimburse for VNS treatment of depression, and VNS is not frequently used for refractory depression.

Table 3

Vagus nerve stimulation treatment parameters

A newer option: TMS

TMS is the most recently FDA-approved therapeutic neuromodulation technique for treating depression. In October 2008, a TMS device became available for patients failing to respond to 1 adequate antidepressant trial during the current episode.

TMS delivers intense, intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The pulse intensity is similar to that produced by MRI. The coil usually is placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC) and pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the adjacent cerebral cortex, as well as distal effects in other relevant neural circuits (Table 4). TMS typically is administered on an outpatient basis. A standard treatment course for depression consists of 5 treatment sessions per week for 4 to 8 weeks, depending on symptom severity and how quickly patients respond.

TMS initially was examined in several small, open-label studies that looked at various treatment parameters and stimulation sites. Several sham-controlled studies generally found TMS efficacious and further refined treatment administration. Its role in treating depression—and possibly other psychiatric disorders—has been supported by 2 recent meta-analyses.^13,14

O’Reardon et al¹⁵ conducted the largest double-blind trial of active vs sham TMS (N=301) for moderately treatment-resistant major depression. This study began with a 4- to 6-week, blinded, randomized phase followed by 6 weeks of open-label TMS for initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressants. This trial utilized the most aggressive treatment parameters to date (ie, 10 Hz; 75 4-second trains; 26-second inter-train interval; 120% motor threshold) delivering 3,000 pulses per treatment over an average of 24 sessions. Compared with the sham procedure, patients who received active TMS showed significantly higher response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, remission rate—defined as a MADRS score <10—was significantly higher in the active treatment group (14%) compared with the sham procedure (6%). A post-hoc analysis found that the most robust benefit occurred in patients with only 1 failed adequate antidepressant trial (effect size=0.83).¹⁶ This administration protocol was well tolerated, with no deaths or seizures and a low rate of discontinuation because of adverse events (5%).¹⁷ The most common adverse effects were application site pain or discomfort and headaches.

Recently, the second largest (N=190) sham-controlled trial of TMS for treatment-resistant major depression was published.¹⁸ This National Institute of Mental Health-sponsored, multiphase study included an initial 2-week, treatment-free period; 3 weeks of daily treatments over the left DLPFC using the same device and parameters as in the O’Reardon study; and an additional 3 weeks of treatment in patients who were improving. Those not responding to initial treatment were crossed over to open-label active TMS. This study advanced TMS development by:

• using a novel somatosensory system that produced similar sensations with sham and active TMS
• assessing the success of maintaining the blind
• establishing a rigorous clinical rating system
• utilizing MRI-guided adjustment of coil placement in a subset of patients.

The authors concluded that active TMS was significantly better than sham treatment in achieving remission (14% vs 5%). In addition, the raters, treaters, and patients were effectively blinded to the treatment condition. MRI-assisted coil placement found that in 33% of the sample, site placement determined by standardized assessment was over the premotor cortex rather than the prefrontal cortex, so the coil was moved 1 additional cm anteriorly in these patients. Similar to those observed by O’Reardon et al, adverse effects of active TMS were generally mild to moderate, did not differ by treatment condition, and led to a low discontinuation rate (5.5%).

Table 4

Treatment parameters of transcranial magnetic stimulation

Deep brain stimulation

DBS is a “functional neurosurgical” procedure that delivers electrical current directly to specific areas within the brain.¹⁹ Its mechanism of action remains uncertain; depolarization blockade, synaptic inhibition, and “neural jamming” are leading hypotheses. In contrast to conventional ablative surgeries, DBS is reversible and adjustable. Implantation involves positioning pacemaker-like battery devices subcutaneously in the left and right upper chest. Electrodes attached to wires are run subcutaneously behind the ears and, with stereotactic guidance, placed through burr holes in the skull into specific CNS areas implicated in the pathophysiology of conditions such as Parkinson’s disease, refractory depression, and severe obsessive-compulsive disorder (OCD).

Antidepressant effects. The FDA recently approved DBS under its humanitarian device exemption program for intractable, severe, disabling OCD based on promising results from open and blind trials that stimulated areas such as the internal capsule and adjacent ventral striatum.^20-22 These studies reported that DBS of the caudate nucleus for OCD and subthalamic nucleus for Parkinson’s disease also produced antidepressant effects. Subsequently, trials targeting the subgenual region (Brodmann’s area 25), the ventral capsule/ventral striatum, and nucleus accumbens demonstrated antidepressant effects.^23-27 Pending the results of ongoing pilot trials, large, multi-center studies using different devices and target areas are being planned to clarify the role of DBS for patients with severe, disabling, refractory depression.

Adverse effects of DBS can be:

• surgical-related (eg, seizure, bleeding, infection)
• device-related (eg, lead breakage, malfunction)
• stimulation-related (eg, paresthesia, dysarthria, memory disruption, cognitive changes, psychiatric symptoms).

The most serious risk is intracranial bleeding, which occurs in 2% to 3% of patients. Clearly, the risk-benefit ratio must be carefully considered.

Cost and reimbursement

Cost of treatment and potential for third-party reimbursement are important considerations for any risk-benefit analysis. Many patients who seek neuromodulation treatments will not have insurance or other coverage entitlements.^28-30 Further, newer treatments are not routinely covered by insurance; however, individual case coverage may be allowed and some device manufacturers have programs to assist providers and patients obtain coverage.^28-30 Even ECT, which has long been a covered treatment for major depression, is still considered investigational for other disorders. Thus, it is important to pre-certify with the patient’s health insurance provider before initiating treatment.

Coverage, however, is not the only consideration when weighing cost effectiveness. Economic studies can assist with clinical and ethical decisions relating to treatment choice.³¹ These studies, however, need to be critically evaluated (eg, what costs were included in the analysis). Although direct costs are easier to evaluate, indirect costs—such as the patient’s ability to continue to work while receiving the treatment, caretaker availability during treatment, and whether treatment is an inpatient or outpatient procedure—are more difficult to evaluate and should be discussed with the patient. Because these specialized options have the potential to further benefit patients with depression and other neuropsychiatric disorders, it is essential to balance the pressures of cost containment with the need for more effective and better tolerated treatments.^32-34

Related Resource

• Brunoni AR, Teng CT, Correa C, et al. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Arq Neuropsiquiatr. 2010;68(3):433-451.

Drug Brand Names

• Lithium • Eskalith, Lithobid
• Nortriptyline • Aventyl, Pamelor

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/therapeutic-neuromodulation.html#comments

The brain is an electrochemical organ, and its activity can be modulated for therapeutic purposes by electrical, pharmacologic, or combined approaches. In general, neuromodulation induces electrical current in peripheral or central nervous tissue, which is accomplished by various techniques, including:

• electroconvulsive therapy (ECT)
• vagus nerve stimulation (VNS)
• transcranial magnetic stimulation (TMS)
• deep brain stimulation (DBS).

It is thought that therapeutic benefit occurs by regulating functional disturbances in relevant distributed neural circuits.¹ Depending on the stimulation method, the frequencies chosen may excite or inhibit different or the same areas of the brain in varying patterns. Unlike medication, neuromodulation impacts the brain episodically, which may mitigate adaptation to the therapy’s beneficial effects and avoid systemic adverse effects.

Neuromodulation techniques are categorized based on their risk level as invasive or noninvasive and seizurogenic or nonseizurogenic (Table 1). Although these and other approaches are being considered for various neuropsychiatric disorders (Table 2), the most common application is for severe, treatment-resistant depression. Therefore, this article focuses on FDA-approved neuromodulation treatments for depression, with limited discussion of other indications.

Table 1

Therapeutic neuromodulation: Categorization based on risk

Table 2

Approved and investigational indications of neuromodulation

ECT: Oldest and most effective

ECT has remained the most effective therapeutic neuromodulation technique for more than 7 decades. It is indicated primarily for severe depressive episodes (eg, psychotic, melancholic), particularly in older patients.

ECT delivers electrical current to the CNS that is sufficient to produce a seizure. Under modified conditions, a typical course of 6 to 12 sessions can resolve severe depressive episodes and may also benefit other disorders, such as bipolar mania and acute psychosis. Although ECT is potentially life-saving, its use was markedly curtailed with the advent of effective antidepressants in the 1950s. Multiple factors impede its use, including:

• access and expertise are limited in many areas
• cognition is at least temporarily adversely affected
• relapse rates after acute benefit are high
• cost
• public perception often is negative.

Studies are addressing several of these concerns. For example, the National Institute of Mental Health-sponsored Consortium on Research with ECT (CORE) group is considering how to more effectively maintain acute benefits of ECT. They compared the potential merits of maintenance ECT with maintenance pharmacotherapy (nortriptyline plus lithium) over 6 months. Although the 2 strategies had comparable results, retention rates were <50% and about one-third relapsed in both groups.^2,3 Potential alternative strategies include a more frequent ECT maintenance schedule and/or combining maintenance ECT with medication(s).

Magnetic seizure therapy (MST) and focal electrically administered seizure therapy (FEAST) are attempts to produce similar efficacy and less cognitive disruption compared with ECT.^4,5 Work also continues on electrode placement (eg, bifrontal) and alteration of waveform characteristics (eg, ultra-brief) to maintain or enhance efficacy while minimizing adverse effects.^6,7

Stimulating the vagus nerve

VNS was introduced for treating refractory epilepsy in 1997. In 2005, it became the first FDA-approved implantable device for managing chronic or recurrent treatment-resistant depression.

The vagus nerve is the principal parasympathetic, efferent tract regulating heart rate, intestinal motility, and gastric acid secretion. Information about pain, hunger, and satiety is conveyed by these fibers to the median raphe nucleus and locus coeruleus, brain regions with significant serotonergic and noradrenergic innervation. These neurotransmitters also are believed to play a pivotal role in major depression.

With VNS, a pacemaker-like pulse generator is surgically implanted subcutaneously in the patient’s upper left chest. Wires extend from this device to the left vagus nerve (80% of whose fibers are afferent) located in the neck, to which the pulse generator sends electrical signals every few seconds (Table 3). The right vagus nerve is not used because it provides parasympathetic innervation to the heart. A clinician adjusts stimulation parameters using a computer and a noninvasive handheld device. Common adverse effects include voice alteration or hoarseness, cough, and shortness of breath, which occur during active stimulation because of the proximity of the electrodes to the laryngeal and pharyngeal branches of the vagus nerve. These effects may improve by adjusting stimulation intensity. The device permits a wide range of duty cycles, but preclinical animal studies indicate that >50% activation periods may damage the vagus nerve. If patients become too uncomfortable, they may deactivate the device with a magnet held over the implantation area.

Two open-label studies evaluated VNS to treat major depression. The first involved 10 weeks of stimulation in 59 subjects with chronic or recurrent, nonpsychotic, unipolar or bipolar depression who failed at least 2 adequate antidepressant trials in the current episode.⁸ Stable doses of concomitant antidepressants or mood stabilizers were allowed. After 3 months, 18 (31%) patients responded within an average of 45.5 days, and nearly 15% achieved remission. Response was defined as 50% reduction in baseline Hamilton Depression Rating Scale-28 (HDRS-28) score; remission was defined as HDRS-28 score ≤10. Further, clinical response did not differ between unipolar and bipolar depression patients.

In the second trial, 74 patients with treatment-resistant depression received fixed dose antidepressants and VNS for 3 months, followed by 9 months of flexibly dosed VNS and antidepressants.⁹ At 3 months, response (≥50% reduction in HDRS-28 score) and remission (HDRS-28 score <10) rates were 37% and 17%, respectively, and increased to 53% and 33% at 1 year.

A sham-controlled trial of VNS in 235 depressed patients used similar inclusion and exclusion criteria as in the open-label study by Sackeim et al.^8,10 Two weeks after device implantation, patients were randomized to active treatment (stimulator turned on) or sham control (stimulator left off). At 3 months, the primary outcome measure—response rate based on HDRS-24 score—did not differ significantly between the active and control groups (15% vs 10%, respectively). There was, however, a significantly greater improvement in Inventory of Depressive Symptomatology-Self Report Scale scores with active VNS vs sham VNS.

Patients on sham treatment then were switched to active treatment and both groups were followed for 12 additional months, at which time response and remission rates nearly doubled for both groups.¹¹ In a post-hoc analysis, the same investigators found significant improvement with VNS compared with a naturalistic, matched control group with similar treatment-resistant depression.¹² The FDA considered this adequate to support efficacy and approved the device for chronic or recurrent treatment-resistant depression in an episode not responsive to at least 4 adequate treatment trials with pharmacotherapy or ECT. Perhaps because post-hoc analyses typically are not sufficient to gain FDA approval, most insurance companies do not reimburse for VNS treatment of depression, and VNS is not frequently used for refractory depression.

Table 3

Vagus nerve stimulation treatment parameters

A newer option: TMS

TMS is the most recently FDA-approved therapeutic neuromodulation technique for treating depression. In October 2008, a TMS device became available for patients failing to respond to 1 adequate antidepressant trial during the current episode.

TMS delivers intense, intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The pulse intensity is similar to that produced by MRI. The coil usually is placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC) and pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the adjacent cerebral cortex, as well as distal effects in other relevant neural circuits (Table 4). TMS typically is administered on an outpatient basis. A standard treatment course for depression consists of 5 treatment sessions per week for 4 to 8 weeks, depending on symptom severity and how quickly patients respond.

TMS initially was examined in several small, open-label studies that looked at various treatment parameters and stimulation sites. Several sham-controlled studies generally found TMS efficacious and further refined treatment administration. Its role in treating depression—and possibly other psychiatric disorders—has been supported by 2 recent meta-analyses.^13,14

O’Reardon et al¹⁵ conducted the largest double-blind trial of active vs sham TMS (N=301) for moderately treatment-resistant major depression. This study began with a 4- to 6-week, blinded, randomized phase followed by 6 weeks of open-label TMS for initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressants. This trial utilized the most aggressive treatment parameters to date (ie, 10 Hz; 75 4-second trains; 26-second inter-train interval; 120% motor threshold) delivering 3,000 pulses per treatment over an average of 24 sessions. Compared with the sham procedure, patients who received active TMS showed significantly higher response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, remission rate—defined as a MADRS score <10—was significantly higher in the active treatment group (14%) compared with the sham procedure (6%). A post-hoc analysis found that the most robust benefit occurred in patients with only 1 failed adequate antidepressant trial (effect size=0.83).¹⁶ This administration protocol was well tolerated, with no deaths or seizures and a low rate of discontinuation because of adverse events (5%).¹⁷ The most common adverse effects were application site pain or discomfort and headaches.

Recently, the second largest (N=190) sham-controlled trial of TMS for treatment-resistant major depression was published.¹⁸ This National Institute of Mental Health-sponsored, multiphase study included an initial 2-week, treatment-free period; 3 weeks of daily treatments over the left DLPFC using the same device and parameters as in the O’Reardon study; and an additional 3 weeks of treatment in patients who were improving. Those not responding to initial treatment were crossed over to open-label active TMS. This study advanced TMS development by:

• using a novel somatosensory system that produced similar sensations with sham and active TMS
• assessing the success of maintaining the blind
• establishing a rigorous clinical rating system
• utilizing MRI-guided adjustment of coil placement in a subset of patients.

The authors concluded that active TMS was significantly better than sham treatment in achieving remission (14% vs 5%). In addition, the raters, treaters, and patients were effectively blinded to the treatment condition. MRI-assisted coil placement found that in 33% of the sample, site placement determined by standardized assessment was over the premotor cortex rather than the prefrontal cortex, so the coil was moved 1 additional cm anteriorly in these patients. Similar to those observed by O’Reardon et al, adverse effects of active TMS were generally mild to moderate, did not differ by treatment condition, and led to a low discontinuation rate (5.5%).

Table 4

Treatment parameters of transcranial magnetic stimulation

Deep brain stimulation

DBS is a “functional neurosurgical” procedure that delivers electrical current directly to specific areas within the brain.¹⁹ Its mechanism of action remains uncertain; depolarization blockade, synaptic inhibition, and “neural jamming” are leading hypotheses. In contrast to conventional ablative surgeries, DBS is reversible and adjustable. Implantation involves positioning pacemaker-like battery devices subcutaneously in the left and right upper chest. Electrodes attached to wires are run subcutaneously behind the ears and, with stereotactic guidance, placed through burr holes in the skull into specific CNS areas implicated in the pathophysiology of conditions such as Parkinson’s disease, refractory depression, and severe obsessive-compulsive disorder (OCD).

Antidepressant effects. The FDA recently approved DBS under its humanitarian device exemption program for intractable, severe, disabling OCD based on promising results from open and blind trials that stimulated areas such as the internal capsule and adjacent ventral striatum.^20-22 These studies reported that DBS of the caudate nucleus for OCD and subthalamic nucleus for Parkinson’s disease also produced antidepressant effects. Subsequently, trials targeting the subgenual region (Brodmann’s area 25), the ventral capsule/ventral striatum, and nucleus accumbens demonstrated antidepressant effects.^23-27 Pending the results of ongoing pilot trials, large, multi-center studies using different devices and target areas are being planned to clarify the role of DBS for patients with severe, disabling, refractory depression.

Adverse effects of DBS can be:

• surgical-related (eg, seizure, bleeding, infection)
• device-related (eg, lead breakage, malfunction)
• stimulation-related (eg, paresthesia, dysarthria, memory disruption, cognitive changes, psychiatric symptoms).

The most serious risk is intracranial bleeding, which occurs in 2% to 3% of patients. Clearly, the risk-benefit ratio must be carefully considered.

Cost and reimbursement

Cost of treatment and potential for third-party reimbursement are important considerations for any risk-benefit analysis. Many patients who seek neuromodulation treatments will not have insurance or other coverage entitlements.^28-30 Further, newer treatments are not routinely covered by insurance; however, individual case coverage may be allowed and some device manufacturers have programs to assist providers and patients obtain coverage.^28-30 Even ECT, which has long been a covered treatment for major depression, is still considered investigational for other disorders. Thus, it is important to pre-certify with the patient’s health insurance provider before initiating treatment.

Coverage, however, is not the only consideration when weighing cost effectiveness. Economic studies can assist with clinical and ethical decisions relating to treatment choice.³¹ These studies, however, need to be critically evaluated (eg, what costs were included in the analysis). Although direct costs are easier to evaluate, indirect costs—such as the patient’s ability to continue to work while receiving the treatment, caretaker availability during treatment, and whether treatment is an inpatient or outpatient procedure—are more difficult to evaluate and should be discussed with the patient. Because these specialized options have the potential to further benefit patients with depression and other neuropsychiatric disorders, it is essential to balance the pressures of cost containment with the need for more effective and better tolerated treatments.^32-34

Related Resource

• Brunoni AR, Teng CT, Correa C, et al. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Arq Neuropsiquiatr. 2010;68(3):433-451.

Drug Brand Names

• Lithium • Eskalith, Lithobid
• Nortriptyline • Aventyl, Pamelor

Only 28% to 33% of patients with major depression experience remission after their first antidepressant treatment, according to results of the Sequenced Treatment Alternative to Relieve Depression (STAR*D) trial.¹ Therapeutic options include switching to an alternate antidepressant, augmentation with a second antidepressant, psychotherapy, mood stabilizers, or second-generation antipsychotics.

In October 2008, the FDA approved a new option: transcranial magnetic stimulation (NeuroStar TMS Therapy), a neuro-modulation approach indicated for patients with major depressive disorder (MDD) who failed 1 adequate antidepressant trial in the current episode (Table 1).

Table 1

Transcranial magnetic stimulation: Fast facts

How it works

TMS delivers intense intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The intensity of the pulse is similar to that of MRI (1.5 to 2 tesla); however, in MRI the magnetic field is constantly on, whereas in TMS the field is exceptionally brief (milliseconds).

For depression treatment, the coil is usually placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC). Pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the cerebral cortex and distal effects in other neurocircuits.

For depression, standard outpatient treatment consists of 5 daily sessions per week for up to 6 weeks. Each session takes approximately 40 minutes, and patients typically return to normal daily activities without difficulty. Initially, NeuroStar TMS will be available in a limited number of treatment centers (see Related Resource).

Intensity of treatment is individualized by adjusting parameters that affect delivery of the magnetic pulses. Motor threshold (MT) is the level of stimulation required to produce movement in a contralateral target muscle, such as the abductor pollicis brevis that causes contraction of the thumb. Once this level is determined, pulses are administered at an intensity relative to the MT (such as 120%). Single TMS pulses are used to find the relevant area of the motor cortex, whereas repetitive pulses are applied over the left DLPFC for therapy.

Frequency of stimulation is measured in cycles per second or hertz (Hz). Stimulation train is the duration during which pulses are administered, and the intertrain interval (ITI) is the time between stimulation trains. Other parameters include site of stimulation and number of treatments per day, week, and course. Recommended treatment levels appear in (Table 2).

Table 2

TMS depression treatment parameters

Efficacy

George et al² first reported TMS for depression in 1995. Initial small, open-label studies examined a variety of treatment intensities, durations, and stimulation sites. Several sham-controlled studies further refined treatment parameters. These studies generally found TMS efficacious, but questioned the robustness of the clinical effect.

To better assess the antidepressant effect of TMS, studies employed larger samples and more aggressive treatment parameters. Avery et al³ randomized 68 patients to 15 sessions of active or sham TMS over the left DLPFC. Each treatment consisted of 32 10-Hz, 5-second trains at 110% MT with a 25-second ITI. At 1 and 2 weeks after treatment, 31% of subjects in the active treatment group showed a significant decrease in symptoms—defined as ≥50% reduction in Hamilton Depression Rating Scale (HDRS) score—versus 6% in the sham group. In addition, 20% of subjects in the active TMS group achieved remission (defined as HDRS score

The largest trial of TMS monotherapy (N=301) for moderately treatment-resistant major depression was completed in 2007.⁴ This 3-phase study began with a 4- to 6-week, randomized, double-blind activeversus-sham TMS procedure, followed by 6 weeks of open-label TMS in initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressant medication.

This trial used the most aggressive treatment parameters to date: 75 10-Hz, 4-second trains at 120% MT with a 26-second ITI, delivering 3,000 pulses per treatment over an average of 26 sessions. To maintain an adequate blind, the study utilized sham and active coils with similar appearances, placement, and acoustic properties. The sham coil had an embedded aluminum shield, which limited the magnetic energy reaching the cortex to ≤10% of the active coil. Although there was no assessment of the adequacy of the blind in this trial:

• subjects were naive to TMS in the sham-controlled phase
• TMS operators did not assess efficacy
• TMS operators and subjects did not discuss the treatment experience with the efficacy raters.

Compared with those who received the sham procedure, subjects who received active TMS showed significantly better response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, the remission rate (defined as a MADRS score

A post-hoc analysis found that the greatest benefit occurred in patients who had only 1 failed adequate antidepressant trial (effect size=0.83).⁵

TMS vs ECT. Dowd et al⁶ summarized 8 published trials that compared TMS with electroconvulsive therapy (ECT) for severe depression:

• 5 reported equivalent efficacy
• 1 found unilateral ECT (UL-ECT) and bilateral ECT (BL-ECT) superior to TMS
• 1 reported UL-ECT superior to TMS
• 1 found UL-ECT plus medication superior to TMS monotherapy in patients with psychosis but comparable in efficacy to TMS in the absence of psychosis.

These results need to be interpreted with caution because of the studies’ diverse designs, nonblinded assessments, and small sample sizes.

Tolerability and safety

The most frequently reported adverse effects of TMS are headache and pain at the site of stimulation. Seizures had been reported in early trials, but the extremely low occurrence has been much lower since Wasserman⁷ published consensus guidelines on the safe use of TMS in 1996.

Janicak et al⁸ examined safety data from the 3-phase trial mentioned above, which included >10,000 cumulative treatment sessions. TMS was well-tolerated, with a low discontinuation rate associated with adverse effects: 4.5% in the active treatment group versus 3.4% in the sham TMS procedure group. No deaths, seizures, or cases of treatment-emergent mania occurred. The most commonly reported adverse effects were transient headache and discomfort at the stimulation site. Most patients acclimated to these effects in the first week. No changes were seen in cognitive functioning or auditory thresholds.

As in previous studies, TMS was safely combined with antidepressants in the third phase of this trial; however, patients at risk for seizure or on medications that could lower the seizure threshold were excluded. Thus, risk of seizure may be increased under these conditions. TMS is contraindicated for patients with implanted metallic devices or nonremovable objects in or around the head, except for dental hardware or braces.

Related resource

• For availability information, contact the manufacturer, Neuronetics, at (877) 6000-7555 or www.NeuroStarTMS.com.

Disclosures

Drs. Dowd, Rado, and Janicak receive research support from and are consultants to Neuronetics, Inc.

Dr. Welch receives research support from Neuronetics, Inc.

Only 28% to 33% of patients with major depression experience remission after their first antidepressant treatment, according to results of the Sequenced Treatment Alternative to Relieve Depression (STAR*D) trial.¹ Therapeutic options include switching to an alternate antidepressant, augmentation with a second antidepressant, psychotherapy, mood stabilizers, or second-generation antipsychotics.

In October 2008, the FDA approved a new option: transcranial magnetic stimulation (NeuroStar TMS Therapy), a neuro-modulation approach indicated for patients with major depressive disorder (MDD) who failed 1 adequate antidepressant trial in the current episode (Table 1).

Table 1

Transcranial magnetic stimulation: Fast facts

How it works

TMS delivers intense intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The intensity of the pulse is similar to that of MRI (1.5 to 2 tesla); however, in MRI the magnetic field is constantly on, whereas in TMS the field is exceptionally brief (milliseconds).

For depression treatment, the coil is usually placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC). Pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the cerebral cortex and distal effects in other neurocircuits.

For depression, standard outpatient treatment consists of 5 daily sessions per week for up to 6 weeks. Each session takes approximately 40 minutes, and patients typically return to normal daily activities without difficulty. Initially, NeuroStar TMS will be available in a limited number of treatment centers (see Related Resource).

Intensity of treatment is individualized by adjusting parameters that affect delivery of the magnetic pulses. Motor threshold (MT) is the level of stimulation required to produce movement in a contralateral target muscle, such as the abductor pollicis brevis that causes contraction of the thumb. Once this level is determined, pulses are administered at an intensity relative to the MT (such as 120%). Single TMS pulses are used to find the relevant area of the motor cortex, whereas repetitive pulses are applied over the left DLPFC for therapy.

Frequency of stimulation is measured in cycles per second or hertz (Hz). Stimulation train is the duration during which pulses are administered, and the intertrain interval (ITI) is the time between stimulation trains. Other parameters include site of stimulation and number of treatments per day, week, and course. Recommended treatment levels appear in (Table 2).

Table 2

TMS depression treatment parameters

Efficacy

George et al² first reported TMS for depression in 1995. Initial small, open-label studies examined a variety of treatment intensities, durations, and stimulation sites. Several sham-controlled studies further refined treatment parameters. These studies generally found TMS efficacious, but questioned the robustness of the clinical effect.

To better assess the antidepressant effect of TMS, studies employed larger samples and more aggressive treatment parameters. Avery et al³ randomized 68 patients to 15 sessions of active or sham TMS over the left DLPFC. Each treatment consisted of 32 10-Hz, 5-second trains at 110% MT with a 25-second ITI. At 1 and 2 weeks after treatment, 31% of subjects in the active treatment group showed a significant decrease in symptoms—defined as ≥50% reduction in Hamilton Depression Rating Scale (HDRS) score—versus 6% in the sham group. In addition, 20% of subjects in the active TMS group achieved remission (defined as HDRS score

The largest trial of TMS monotherapy (N=301) for moderately treatment-resistant major depression was completed in 2007.⁴ This 3-phase study began with a 4- to 6-week, randomized, double-blind activeversus-sham TMS procedure, followed by 6 weeks of open-label TMS in initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressant medication.

This trial used the most aggressive treatment parameters to date: 75 10-Hz, 4-second trains at 120% MT with a 26-second ITI, delivering 3,000 pulses per treatment over an average of 26 sessions. To maintain an adequate blind, the study utilized sham and active coils with similar appearances, placement, and acoustic properties. The sham coil had an embedded aluminum shield, which limited the magnetic energy reaching the cortex to ≤10% of the active coil. Although there was no assessment of the adequacy of the blind in this trial:

• subjects were naive to TMS in the sham-controlled phase
• TMS operators did not assess efficacy
• TMS operators and subjects did not discuss the treatment experience with the efficacy raters.

Compared with those who received the sham procedure, subjects who received active TMS showed significantly better response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, the remission rate (defined as a MADRS score

A post-hoc analysis found that the greatest benefit occurred in patients who had only 1 failed adequate antidepressant trial (effect size=0.83).⁵

TMS vs ECT. Dowd et al⁶ summarized 8 published trials that compared TMS with electroconvulsive therapy (ECT) for severe depression:

• 5 reported equivalent efficacy
• 1 found unilateral ECT (UL-ECT) and bilateral ECT (BL-ECT) superior to TMS
• 1 reported UL-ECT superior to TMS
• 1 found UL-ECT plus medication superior to TMS monotherapy in patients with psychosis but comparable in efficacy to TMS in the absence of psychosis.

These results need to be interpreted with caution because of the studies’ diverse designs, nonblinded assessments, and small sample sizes.

Tolerability and safety

The most frequently reported adverse effects of TMS are headache and pain at the site of stimulation. Seizures had been reported in early trials, but the extremely low occurrence has been much lower since Wasserman⁷ published consensus guidelines on the safe use of TMS in 1996.

Janicak et al⁸ examined safety data from the 3-phase trial mentioned above, which included >10,000 cumulative treatment sessions. TMS was well-tolerated, with a low discontinuation rate associated with adverse effects: 4.5% in the active treatment group versus 3.4% in the sham TMS procedure group. No deaths, seizures, or cases of treatment-emergent mania occurred. The most commonly reported adverse effects were transient headache and discomfort at the stimulation site. Most patients acclimated to these effects in the first week. No changes were seen in cognitive functioning or auditory thresholds.

As in previous studies, TMS was safely combined with antidepressants in the third phase of this trial; however, patients at risk for seizure or on medications that could lower the seizure threshold were excluded. Thus, risk of seizure may be increased under these conditions. TMS is contraindicated for patients with implanted metallic devices or nonremovable objects in or around the head, except for dental hardware or braces.

Related resource

• For availability information, contact the manufacturer, Neuronetics, at (877) 6000-7555 or www.NeuroStarTMS.com.

Disclosures

Drs. Dowd, Rado, and Janicak receive research support from and are consultants to Neuronetics, Inc.

Dr. Welch receives research support from Neuronetics, Inc.

Only 28% to 33% of patients with major depression experience remission after their first antidepressant treatment, according to results of the Sequenced Treatment Alternative to Relieve Depression (STAR*D) trial.¹ Therapeutic options include switching to an alternate antidepressant, augmentation with a second antidepressant, psychotherapy, mood stabilizers, or second-generation antipsychotics.

In October 2008, the FDA approved a new option: transcranial magnetic stimulation (NeuroStar TMS Therapy), a neuro-modulation approach indicated for patients with major depressive disorder (MDD) who failed 1 adequate antidepressant trial in the current episode (Table 1).

Table 1

Transcranial magnetic stimulation: Fast facts

How it works

TMS delivers intense intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The intensity of the pulse is similar to that of MRI (1.5 to 2 tesla); however, in MRI the magnetic field is constantly on, whereas in TMS the field is exceptionally brief (milliseconds).

For depression treatment, the coil is usually placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC). Pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the cerebral cortex and distal effects in other neurocircuits.

For depression, standard outpatient treatment consists of 5 daily sessions per week for up to 6 weeks. Each session takes approximately 40 minutes, and patients typically return to normal daily activities without difficulty. Initially, NeuroStar TMS will be available in a limited number of treatment centers (see Related Resource).

Intensity of treatment is individualized by adjusting parameters that affect delivery of the magnetic pulses. Motor threshold (MT) is the level of stimulation required to produce movement in a contralateral target muscle, such as the abductor pollicis brevis that causes contraction of the thumb. Once this level is determined, pulses are administered at an intensity relative to the MT (such as 120%). Single TMS pulses are used to find the relevant area of the motor cortex, whereas repetitive pulses are applied over the left DLPFC for therapy.

Frequency of stimulation is measured in cycles per second or hertz (Hz). Stimulation train is the duration during which pulses are administered, and the intertrain interval (ITI) is the time between stimulation trains. Other parameters include site of stimulation and number of treatments per day, week, and course. Recommended treatment levels appear in (Table 2).

Table 2

TMS depression treatment parameters

Efficacy

George et al² first reported TMS for depression in 1995. Initial small, open-label studies examined a variety of treatment intensities, durations, and stimulation sites. Several sham-controlled studies further refined treatment parameters. These studies generally found TMS efficacious, but questioned the robustness of the clinical effect.

To better assess the antidepressant effect of TMS, studies employed larger samples and more aggressive treatment parameters. Avery et al³ randomized 68 patients to 15 sessions of active or sham TMS over the left DLPFC. Each treatment consisted of 32 10-Hz, 5-second trains at 110% MT with a 25-second ITI. At 1 and 2 weeks after treatment, 31% of subjects in the active treatment group showed a significant decrease in symptoms—defined as ≥50% reduction in Hamilton Depression Rating Scale (HDRS) score—versus 6% in the sham group. In addition, 20% of subjects in the active TMS group achieved remission (defined as HDRS score

The largest trial of TMS monotherapy (N=301) for moderately treatment-resistant major depression was completed in 2007.⁴ This 3-phase study began with a 4- to 6-week, randomized, double-blind activeversus-sham TMS procedure, followed by 6 weeks of open-label TMS in initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressant medication.

This trial used the most aggressive treatment parameters to date: 75 10-Hz, 4-second trains at 120% MT with a 26-second ITI, delivering 3,000 pulses per treatment over an average of 26 sessions. To maintain an adequate blind, the study utilized sham and active coils with similar appearances, placement, and acoustic properties. The sham coil had an embedded aluminum shield, which limited the magnetic energy reaching the cortex to ≤10% of the active coil. Although there was no assessment of the adequacy of the blind in this trial:

• subjects were naive to TMS in the sham-controlled phase
• TMS operators did not assess efficacy
• TMS operators and subjects did not discuss the treatment experience with the efficacy raters.

Compared with those who received the sham procedure, subjects who received active TMS showed significantly better response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, the remission rate (defined as a MADRS score

A post-hoc analysis found that the greatest benefit occurred in patients who had only 1 failed adequate antidepressant trial (effect size=0.83).⁵

TMS vs ECT. Dowd et al⁶ summarized 8 published trials that compared TMS with electroconvulsive therapy (ECT) for severe depression:

• 5 reported equivalent efficacy
• 1 found unilateral ECT (UL-ECT) and bilateral ECT (BL-ECT) superior to TMS
• 1 reported UL-ECT superior to TMS
• 1 found UL-ECT plus medication superior to TMS monotherapy in patients with psychosis but comparable in efficacy to TMS in the absence of psychosis.

These results need to be interpreted with caution because of the studies’ diverse designs, nonblinded assessments, and small sample sizes.

Tolerability and safety

The most frequently reported adverse effects of TMS are headache and pain at the site of stimulation. Seizures had been reported in early trials, but the extremely low occurrence has been much lower since Wasserman⁷ published consensus guidelines on the safe use of TMS in 1996.

Janicak et al⁸ examined safety data from the 3-phase trial mentioned above, which included >10,000 cumulative treatment sessions. TMS was well-tolerated, with a low discontinuation rate associated with adverse effects: 4.5% in the active treatment group versus 3.4% in the sham TMS procedure group. No deaths, seizures, or cases of treatment-emergent mania occurred. The most commonly reported adverse effects were transient headache and discomfort at the stimulation site. Most patients acclimated to these effects in the first week. No changes were seen in cognitive functioning or auditory thresholds.

As in previous studies, TMS was safely combined with antidepressants in the third phase of this trial; however, patients at risk for seizure or on medications that could lower the seizure threshold were excluded. Thus, risk of seizure may be increased under these conditions. TMS is contraindicated for patients with implanted metallic devices or nonremovable objects in or around the head, except for dental hardware or braces.

Related resource

• For availability information, contact the manufacturer, Neuronetics, at (877) 6000-7555 or www.NeuroStarTMS.com.

Disclosures

Drs. Dowd, Rado, and Janicak receive research support from and are consultants to Neuronetics, Inc.

Dr. Welch receives research support from Neuronetics, Inc.

In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.^1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.

This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:

• pharmacodynamics and pharmacokinetics
  
• potential efficacy in schizophrenia and for specific patients and symptoms
  
• safety and tolerability.
  

How does paliperidone ER work?

Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).

Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D₂) and serotonin (5-HT_2A) receptors, with additional affinity for histaminic (H₁) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.

Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.^4,5

Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.⁷

Paliperidone has an osmotic controlled-release oral delivery system (OROS^®) for steady medication delivery across 24 hours⁸ (Table 2).^1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.⁶ The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.

Table 1

How paliperidone ER compares with risperidone

Paliperidone ER’s clinical characteristics

Clinical use

Paliperidone ER offers potential therapeutic benefits in treating schizophrenia patients, although not without the risk of adverse events such as extrapyramidal symptoms (EPS) (Table 3).^1-3

Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.

Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.

Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.⁹

For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:

• 6 mg/d for those with creatinine clearance ≥50 to
• 3 mg/d for those with creatinine clearance 10 to 10
  

Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).⁹

EPS. Risk of EPS-related AEs (such as akathisia and parkinsonian symptoms) with 3-mg and 6-mg paliperidone ER doses (13% and 10%, respectively) was similar to placebo (11%) but increased with the 9-mg, 12-mg, and 15-mg doses (25%, 26%, and 24%, respectively). Should EPS occur, reduce the paliperidone ER dose or consider adding antiparkinsonian medications.

Lab values. No clinically relevant changes were noted in blood glucose, insulin, or lipids.¹² Similar to risperidone, paliperidone ER elevated prolactin levels.

Weight gain with paliperidone ER is dose-dependent; in the clinical trials, mean body weight change for all doses was ≤1.9 kg, which is similar to the weight gain seen with risperidone and in the moderate range compared with other SGAs. When using paliperidone ER, follow the American Diabetes Association/American Psychiatric Association guidelines¹³ for monitoring weight gain and metabolic parameters with antipsychotics. Also monitor patients for clinical symptoms of hyperprolactinemia, and—if intolerable—adjust the dose or switch to another SGA.

Tachycardia. Advise patients that they may experience a rapid heart rate while taking paliperidone ER. In clinical trials, tachycardia occurred in ≤14% of patients—twice the rate with placebo—but did not contribute to more serious cardiac rhythm disturbances or to discontinuation. Incidence of prolonged corrected QT interval (QTc) was 3% to 5% in the paliperidone ER group vs 3% in the placebo group.

Patient education. Because of paliperidone ER’s pharmacokinetic properties, counsel patients to:

• take 1 tablet each day in the morning
  
• not chew, split, or crush the tablets but swallow whole to preserve the controlled-release delivery.
  

Table 3

Paliperidone ER’s potential benefits and risks in clinical practice

Efficacy trials in schizophrenia

Three 6-week trials^1-3 examined paliperidone ER’s efficacy in a total of 1,692 patients with chronic schizophrenia who were hospitalized ≥14 days with acute exacerbations. The trials were double-blind, randomized, fixed-dose, parallel-group, and placebo- and active-controlled (compared with olanzapine, 10 mg/d). Patients showed no significant differences in demographic or baseline characteristics or in the use of rescue medications.

The primary outcome measure was mean change in Positive and Negative Syndrome Scale (PANSS) total score, which quantifies positive, negative, and global psychopathologic symptom severity. Secondary outcome measures included:

• PANSS Marder factor scores¹⁴ (derived from PANSS items that reflect positive and negative symptoms, anxiety and depression, hostility, and thought disorganization).
  
• Clinical Global Impressions-Severity (CGI-S) score, which measures overall illness severity.¹⁵
  
• Personal and Social Performance (PSP) scores, which rate socially useful activities, relationships, self-care, and disturbing and aggressive behaviors; improvement by 1 category (10 points) reflects a clinically meaningful change.^16,17
  

A total of 43% of patients completed the study—34% taking placebo; 46% taking paliperidone ER, 6 mg; 48% taking paliperidone ER, 12 mg; and 45% taking olanzapine. Demographic and baseline characteristics of the 432 patients who received ≥1 dose were similar across all groups. Approximately 75% of patients in each group used rescue medications—primarily lorazepam—for agitation, restlessness, or insomnia for a mean of 8 days.

Patients taking either paliperidone ER dose showed statistically significant greater improvement in PANSS total score compared with those taking placebo (6 mg, P = 0.006; 12 mg, P

Clinical response rates were similar with the 6-mg and 12-mg paliperidone ER doses—50% and 51%, respectively—and greater than with placebo (34%). The higher response rates with paliperidone ER were statistically significant compared with placebo (6 mg, P

Discontinuation rates for lack of efficacy were lower with paliperidone ER (6 mg, 23%; 12 mg, 14%) than with placebo (35%). A substantially lower percentage of patients taking this agent remained classified as “marked/severe/extremely severe” on the CGI-S score from baseline to endpoint, compared with the placebo group;

• 6 mg paliperidone ER, 58% to 26%
  
• 12 mg paliperidone ER, 64% to 21%
  
• placebo, 60% to 45%.
  

The second study² included U.S. and international sites and compared 3 fixed doses of paliperidone ER (6-, 9-, and 12-mg) with placebo. Among the 630 patients enrolled, 66% completed the study. Patients were randomly assigned to 6 mg, 9 mg, or 12 mg of paliperidone ER; 10 mg of olanzapine; or placebo. The number of patients who dropped out because of adverse events was comparable across the groups.

Patient groups assigned to paliperidone ER showed significant improvement when compared with placebo (P 30% reduction in PANSS total score from baseline to endpoint included:

• 6 mg paliperidone ER, 56%
  
• 9 mg paliperidone ER, 51%
  
• 12 mg paliperidone ER, 61%
  
• placebo, 30%.
  

• 6 mg paliperidone ER, 63% at baseline to 22% at endpoint
  
• 9 mg paliperidone ER, 58% to 23%
  
• 12 mg paliperidone ER, 64% to 16%
  
• placebo, 60% to 51%.
  

The third study³ was a multicenter international trial that compared 3 fixed doses of paliperidone ER (3, 9, and 15 mg) with placebo. Among the 618 randomized patients, 365 (59%) completed the study: 70 of 127 (55%) on 3-mg paliperidone ER, 78 of 125 (62%) on 9-mg paliperidone ER, 82 of 115 (71%) on 15-mg paliperidone ER, and 47 of 123 (38%) on placebo.

• 3 mg paliperidone ER, 40%
  
• 9 mg paliperidone ER, 46%
  
• 15 mg paliperidone ER, 53%
  
• placebo, 18% (P ≤0.005).
  

• 3 mg paliperidone ER, 54% to 32%
  
• 9 mg paliperidone ER, 52% to 23%
  
• 15 mg paliperidone ER, 57% to 17%
  
• placebo, 56% to 50%.
  

Additional trial evidence

Schizophrenia subpopulations. Post hoc analyses of data reported from the 3 pivotal trials suggest that paliperidone ER may be useful for specific groups of schizophrenia patients, including those who are recently diagnosed, age >65, or severely ill or have predominant negative symptoms or sleep problems (Table 4).^18-23

Efficacy in delaying recurrence. Paliperidone ER’s efficacy in delaying symptom recurrence was examined in a randomized, double-blind, placebo-controlled study of 207 patients who had been stabilized on open-label, flexible-dosed paliperidone ER.²⁴ Time to first recurrence of schizophrenia symptoms was the primary efficacy measure. Starting dose was 9 mg/d (flexible dose range 3 to 15 mg/d).

The study was halted at a planned interim analysis because time-to-recurrence was significantly longer for patients receiving paliperidone ER compared with placebo (P

Final analysis of the 179 patients who completed the study confirmed the interim findings. Ongoing treatment maintained improvement in patients’ acute symptoms, functioning, and quality-of-life measures.

Table 4

Studies of paliperidone ER in schizophrenia subpopulations

• Paliperidone extended release. Prescribing information. www.invega.com.
  
• Johnson & Johnson. U.S. District Court upholds Risperdal^® (risperidone) patent (press release). October 16, 2006. www.jnj.com/news/jnj_news/20061016_094453.htm.
  

• Carbamazepine • Tegretol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Paliperidone ER • Invega
  
• Risperidone • Risperdal
  

Dr. Rado and Dr. Dowd receive research support from Neuronetics, sanofi-aventis, Janssen Pharmaceutica, and Solvay.

Dr. Janicak receives research support from Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, Solvay, and sanofi-aventis. He is a consultant to Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, and Solvay, and a speaker for Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, and Pfizer.

In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.^1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.

This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:

• pharmacodynamics and pharmacokinetics
  
• potential efficacy in schizophrenia and for specific patients and symptoms
  
• safety and tolerability.
  

How does paliperidone ER work?

Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).

Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D₂) and serotonin (5-HT_2A) receptors, with additional affinity for histaminic (H₁) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.

Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.^4,5

Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.⁷

Paliperidone has an osmotic controlled-release oral delivery system (OROS^®) for steady medication delivery across 24 hours⁸ (Table 2).^1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.⁶ The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.

Table 1

How paliperidone ER compares with risperidone

Paliperidone ER’s clinical characteristics

Clinical use

Paliperidone ER offers potential therapeutic benefits in treating schizophrenia patients, although not without the risk of adverse events such as extrapyramidal symptoms (EPS) (Table 3).^1-3

Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.

Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.

Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.⁹

For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:

• 6 mg/d for those with creatinine clearance ≥50 to
• 3 mg/d for those with creatinine clearance 10 to 10
  

Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).⁹

EPS. Risk of EPS-related AEs (such as akathisia and parkinsonian symptoms) with 3-mg and 6-mg paliperidone ER doses (13% and 10%, respectively) was similar to placebo (11%) but increased with the 9-mg, 12-mg, and 15-mg doses (25%, 26%, and 24%, respectively). Should EPS occur, reduce the paliperidone ER dose or consider adding antiparkinsonian medications.

Lab values. No clinically relevant changes were noted in blood glucose, insulin, or lipids.¹² Similar to risperidone, paliperidone ER elevated prolactin levels.

Weight gain with paliperidone ER is dose-dependent; in the clinical trials, mean body weight change for all doses was ≤1.9 kg, which is similar to the weight gain seen with risperidone and in the moderate range compared with other SGAs. When using paliperidone ER, follow the American Diabetes Association/American Psychiatric Association guidelines¹³ for monitoring weight gain and metabolic parameters with antipsychotics. Also monitor patients for clinical symptoms of hyperprolactinemia, and—if intolerable—adjust the dose or switch to another SGA.

Tachycardia. Advise patients that they may experience a rapid heart rate while taking paliperidone ER. In clinical trials, tachycardia occurred in ≤14% of patients—twice the rate with placebo—but did not contribute to more serious cardiac rhythm disturbances or to discontinuation. Incidence of prolonged corrected QT interval (QTc) was 3% to 5% in the paliperidone ER group vs 3% in the placebo group.

Patient education. Because of paliperidone ER’s pharmacokinetic properties, counsel patients to:

• take 1 tablet each day in the morning
  
• not chew, split, or crush the tablets but swallow whole to preserve the controlled-release delivery.
  

Table 3

Paliperidone ER’s potential benefits and risks in clinical practice

Efficacy trials in schizophrenia

Three 6-week trials^1-3 examined paliperidone ER’s efficacy in a total of 1,692 patients with chronic schizophrenia who were hospitalized ≥14 days with acute exacerbations. The trials were double-blind, randomized, fixed-dose, parallel-group, and placebo- and active-controlled (compared with olanzapine, 10 mg/d). Patients showed no significant differences in demographic or baseline characteristics or in the use of rescue medications.

The primary outcome measure was mean change in Positive and Negative Syndrome Scale (PANSS) total score, which quantifies positive, negative, and global psychopathologic symptom severity. Secondary outcome measures included:

• PANSS Marder factor scores¹⁴ (derived from PANSS items that reflect positive and negative symptoms, anxiety and depression, hostility, and thought disorganization).
  
• Clinical Global Impressions-Severity (CGI-S) score, which measures overall illness severity.¹⁵
  
• Personal and Social Performance (PSP) scores, which rate socially useful activities, relationships, self-care, and disturbing and aggressive behaviors; improvement by 1 category (10 points) reflects a clinically meaningful change.^16,17
  

A total of 43% of patients completed the study—34% taking placebo; 46% taking paliperidone ER, 6 mg; 48% taking paliperidone ER, 12 mg; and 45% taking olanzapine. Demographic and baseline characteristics of the 432 patients who received ≥1 dose were similar across all groups. Approximately 75% of patients in each group used rescue medications—primarily lorazepam—for agitation, restlessness, or insomnia for a mean of 8 days.

Patients taking either paliperidone ER dose showed statistically significant greater improvement in PANSS total score compared with those taking placebo (6 mg, P = 0.006; 12 mg, P

Clinical response rates were similar with the 6-mg and 12-mg paliperidone ER doses—50% and 51%, respectively—and greater than with placebo (34%). The higher response rates with paliperidone ER were statistically significant compared with placebo (6 mg, P

Discontinuation rates for lack of efficacy were lower with paliperidone ER (6 mg, 23%; 12 mg, 14%) than with placebo (35%). A substantially lower percentage of patients taking this agent remained classified as “marked/severe/extremely severe” on the CGI-S score from baseline to endpoint, compared with the placebo group;

• 6 mg paliperidone ER, 58% to 26%
  
• 12 mg paliperidone ER, 64% to 21%
  
• placebo, 60% to 45%.
  

The second study² included U.S. and international sites and compared 3 fixed doses of paliperidone ER (6-, 9-, and 12-mg) with placebo. Among the 630 patients enrolled, 66% completed the study. Patients were randomly assigned to 6 mg, 9 mg, or 12 mg of paliperidone ER; 10 mg of olanzapine; or placebo. The number of patients who dropped out because of adverse events was comparable across the groups.

Patient groups assigned to paliperidone ER showed significant improvement when compared with placebo (P 30% reduction in PANSS total score from baseline to endpoint included:

• 6 mg paliperidone ER, 56%
  
• 9 mg paliperidone ER, 51%
  
• 12 mg paliperidone ER, 61%
  
• placebo, 30%.
  

• 6 mg paliperidone ER, 63% at baseline to 22% at endpoint
  
• 9 mg paliperidone ER, 58% to 23%
  
• 12 mg paliperidone ER, 64% to 16%
  
• placebo, 60% to 51%.
  

The third study³ was a multicenter international trial that compared 3 fixed doses of paliperidone ER (3, 9, and 15 mg) with placebo. Among the 618 randomized patients, 365 (59%) completed the study: 70 of 127 (55%) on 3-mg paliperidone ER, 78 of 125 (62%) on 9-mg paliperidone ER, 82 of 115 (71%) on 15-mg paliperidone ER, and 47 of 123 (38%) on placebo.

• 3 mg paliperidone ER, 40%
  
• 9 mg paliperidone ER, 46%
  
• 15 mg paliperidone ER, 53%
  
• placebo, 18% (P ≤0.005).
  

• 3 mg paliperidone ER, 54% to 32%
  
• 9 mg paliperidone ER, 52% to 23%
  
• 15 mg paliperidone ER, 57% to 17%
  
• placebo, 56% to 50%.
  

Additional trial evidence

Schizophrenia subpopulations. Post hoc analyses of data reported from the 3 pivotal trials suggest that paliperidone ER may be useful for specific groups of schizophrenia patients, including those who are recently diagnosed, age >65, or severely ill or have predominant negative symptoms or sleep problems (Table 4).^18-23

Efficacy in delaying recurrence. Paliperidone ER’s efficacy in delaying symptom recurrence was examined in a randomized, double-blind, placebo-controlled study of 207 patients who had been stabilized on open-label, flexible-dosed paliperidone ER.²⁴ Time to first recurrence of schizophrenia symptoms was the primary efficacy measure. Starting dose was 9 mg/d (flexible dose range 3 to 15 mg/d).

The study was halted at a planned interim analysis because time-to-recurrence was significantly longer for patients receiving paliperidone ER compared with placebo (P

Final analysis of the 179 patients who completed the study confirmed the interim findings. Ongoing treatment maintained improvement in patients’ acute symptoms, functioning, and quality-of-life measures.

Table 4

Studies of paliperidone ER in schizophrenia subpopulations

• Paliperidone extended release. Prescribing information. www.invega.com.
  
• Johnson & Johnson. U.S. District Court upholds Risperdal^® (risperidone) patent (press release). October 16, 2006. www.jnj.com/news/jnj_news/20061016_094453.htm.
  

• Carbamazepine • Tegretol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Paliperidone ER • Invega
  
• Risperidone • Risperdal
  

Dr. Rado and Dr. Dowd receive research support from Neuronetics, sanofi-aventis, Janssen Pharmaceutica, and Solvay.

Dr. Janicak receives research support from Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, Solvay, and sanofi-aventis. He is a consultant to Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, and Solvay, and a speaker for Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, and Pfizer.

In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.^1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.

This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:

• pharmacodynamics and pharmacokinetics
  
• potential efficacy in schizophrenia and for specific patients and symptoms
  
• safety and tolerability.
  

How does paliperidone ER work?

Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).

Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D₂) and serotonin (5-HT_2A) receptors, with additional affinity for histaminic (H₁) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.

Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.^4,5

Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.⁷

Paliperidone has an osmotic controlled-release oral delivery system (OROS^®) for steady medication delivery across 24 hours⁸ (Table 2).^1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.⁶ The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.

Table 1

How paliperidone ER compares with risperidone

Paliperidone ER’s clinical characteristics

Clinical use

Paliperidone ER offers potential therapeutic benefits in treating schizophrenia patients, although not without the risk of adverse events such as extrapyramidal symptoms (EPS) (Table 3).^1-3

Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.

Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.

Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.⁹

For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:

• 6 mg/d for those with creatinine clearance ≥50 to
• 3 mg/d for those with creatinine clearance 10 to 10
  

Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).⁹

EPS. Risk of EPS-related AEs (such as akathisia and parkinsonian symptoms) with 3-mg and 6-mg paliperidone ER doses (13% and 10%, respectively) was similar to placebo (11%) but increased with the 9-mg, 12-mg, and 15-mg doses (25%, 26%, and 24%, respectively). Should EPS occur, reduce the paliperidone ER dose or consider adding antiparkinsonian medications.

Lab values. No clinically relevant changes were noted in blood glucose, insulin, or lipids.¹² Similar to risperidone, paliperidone ER elevated prolactin levels.

Weight gain with paliperidone ER is dose-dependent; in the clinical trials, mean body weight change for all doses was ≤1.9 kg, which is similar to the weight gain seen with risperidone and in the moderate range compared with other SGAs. When using paliperidone ER, follow the American Diabetes Association/American Psychiatric Association guidelines¹³ for monitoring weight gain and metabolic parameters with antipsychotics. Also monitor patients for clinical symptoms of hyperprolactinemia, and—if intolerable—adjust the dose or switch to another SGA.

Tachycardia. Advise patients that they may experience a rapid heart rate while taking paliperidone ER. In clinical trials, tachycardia occurred in ≤14% of patients—twice the rate with placebo—but did not contribute to more serious cardiac rhythm disturbances or to discontinuation. Incidence of prolonged corrected QT interval (QTc) was 3% to 5% in the paliperidone ER group vs 3% in the placebo group.

Patient education. Because of paliperidone ER’s pharmacokinetic properties, counsel patients to:

• take 1 tablet each day in the morning
  
• not chew, split, or crush the tablets but swallow whole to preserve the controlled-release delivery.
  

Table 3

Paliperidone ER’s potential benefits and risks in clinical practice

Efficacy trials in schizophrenia

Three 6-week trials^1-3 examined paliperidone ER’s efficacy in a total of 1,692 patients with chronic schizophrenia who were hospitalized ≥14 days with acute exacerbations. The trials were double-blind, randomized, fixed-dose, parallel-group, and placebo- and active-controlled (compared with olanzapine, 10 mg/d). Patients showed no significant differences in demographic or baseline characteristics or in the use of rescue medications.

The primary outcome measure was mean change in Positive and Negative Syndrome Scale (PANSS) total score, which quantifies positive, negative, and global psychopathologic symptom severity. Secondary outcome measures included:

• PANSS Marder factor scores¹⁴ (derived from PANSS items that reflect positive and negative symptoms, anxiety and depression, hostility, and thought disorganization).
  
• Clinical Global Impressions-Severity (CGI-S) score, which measures overall illness severity.¹⁵
  
• Personal and Social Performance (PSP) scores, which rate socially useful activities, relationships, self-care, and disturbing and aggressive behaviors; improvement by 1 category (10 points) reflects a clinically meaningful change.^16,17
  

A total of 43% of patients completed the study—34% taking placebo; 46% taking paliperidone ER, 6 mg; 48% taking paliperidone ER, 12 mg; and 45% taking olanzapine. Demographic and baseline characteristics of the 432 patients who received ≥1 dose were similar across all groups. Approximately 75% of patients in each group used rescue medications—primarily lorazepam—for agitation, restlessness, or insomnia for a mean of 8 days.

Patients taking either paliperidone ER dose showed statistically significant greater improvement in PANSS total score compared with those taking placebo (6 mg, P = 0.006; 12 mg, P

Clinical response rates were similar with the 6-mg and 12-mg paliperidone ER doses—50% and 51%, respectively—and greater than with placebo (34%). The higher response rates with paliperidone ER were statistically significant compared with placebo (6 mg, P

Discontinuation rates for lack of efficacy were lower with paliperidone ER (6 mg, 23%; 12 mg, 14%) than with placebo (35%). A substantially lower percentage of patients taking this agent remained classified as “marked/severe/extremely severe” on the CGI-S score from baseline to endpoint, compared with the placebo group;

• 6 mg paliperidone ER, 58% to 26%
  
• 12 mg paliperidone ER, 64% to 21%
  
• placebo, 60% to 45%.
  

The second study² included U.S. and international sites and compared 3 fixed doses of paliperidone ER (6-, 9-, and 12-mg) with placebo. Among the 630 patients enrolled, 66% completed the study. Patients were randomly assigned to 6 mg, 9 mg, or 12 mg of paliperidone ER; 10 mg of olanzapine; or placebo. The number of patients who dropped out because of adverse events was comparable across the groups.

Patient groups assigned to paliperidone ER showed significant improvement when compared with placebo (P 30% reduction in PANSS total score from baseline to endpoint included:

• 6 mg paliperidone ER, 56%
  
• 9 mg paliperidone ER, 51%
  
• 12 mg paliperidone ER, 61%
  
• placebo, 30%.
  

• 6 mg paliperidone ER, 63% at baseline to 22% at endpoint
  
• 9 mg paliperidone ER, 58% to 23%
  
• 12 mg paliperidone ER, 64% to 16%
  
• placebo, 60% to 51%.
  

The third study³ was a multicenter international trial that compared 3 fixed doses of paliperidone ER (3, 9, and 15 mg) with placebo. Among the 618 randomized patients, 365 (59%) completed the study: 70 of 127 (55%) on 3-mg paliperidone ER, 78 of 125 (62%) on 9-mg paliperidone ER, 82 of 115 (71%) on 15-mg paliperidone ER, and 47 of 123 (38%) on placebo.

• 3 mg paliperidone ER, 40%
  
• 9 mg paliperidone ER, 46%
  
• 15 mg paliperidone ER, 53%
  
• placebo, 18% (P ≤0.005).
  

• 3 mg paliperidone ER, 54% to 32%
  
• 9 mg paliperidone ER, 52% to 23%
  
• 15 mg paliperidone ER, 57% to 17%
  
• placebo, 56% to 50%.
  

Additional trial evidence

Schizophrenia subpopulations. Post hoc analyses of data reported from the 3 pivotal trials suggest that paliperidone ER may be useful for specific groups of schizophrenia patients, including those who are recently diagnosed, age >65, or severely ill or have predominant negative symptoms or sleep problems (Table 4).^18-23

Efficacy in delaying recurrence. Paliperidone ER’s efficacy in delaying symptom recurrence was examined in a randomized, double-blind, placebo-controlled study of 207 patients who had been stabilized on open-label, flexible-dosed paliperidone ER.²⁴ Time to first recurrence of schizophrenia symptoms was the primary efficacy measure. Starting dose was 9 mg/d (flexible dose range 3 to 15 mg/d).

The study was halted at a planned interim analysis because time-to-recurrence was significantly longer for patients receiving paliperidone ER compared with placebo (P

Final analysis of the 179 patients who completed the study confirmed the interim findings. Ongoing treatment maintained improvement in patients’ acute symptoms, functioning, and quality-of-life measures.

Table 4

Studies of paliperidone ER in schizophrenia subpopulations

• Paliperidone extended release. Prescribing information. www.invega.com.
  
• Johnson & Johnson. U.S. District Court upholds Risperdal^® (risperidone) patent (press release). October 16, 2006. www.jnj.com/news/jnj_news/20061016_094453.htm.
  

• Carbamazepine • Tegretol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Paliperidone ER • Invega
  
• Risperidone • Risperdal
  

Dr. Rado and Dr. Dowd receive research support from Neuronetics, sanofi-aventis, Janssen Pharmaceutica, and Solvay.

Dr. Janicak receives research support from Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, Solvay, and sanofi-aventis. He is a consultant to Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, and Solvay, and a speaker for Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, and Pfizer.

Ms. H, age 26, is being evaluated for moderate to severe depressive symptoms, including oversleeping and overeating. She has had difficulty adhering to medication in the past and is ambivalent about taking antidepressants. She takes a passive approach to managing her depression, preferring to “wait for it to pass.”

Her psychiatrist prescribes fluoxetine, 20 mg in the morning, and recommends that Ms. H change her coping strategies from napping and snacking to increased physical activity. She encourages Ms. H to think about what activities interest her and to set exercise goals.

Ms. H says she has considered buying exercise equipment (an elliptical machine) and increasing her walking outside. She sets a goal to walk 20 minutes most days and to spend 10 to 15 minutes using the elliptical machine while watching television.

Physical activity’s mental health benefits are less well-known than its well-documented medical benefits—reduced risk of heart disease, hypertension, and diabetes; weight control; bone mass preservation; better sleep, and improved cholesterol levels.¹ By encouraging exercise, you can improve patients’ mood, well-being, and quality of life, independent of medication and psychotherapy. In this article, we:

• explore the relationship between physical activity and mental health
• compare exercise with medication and psychotherapies for easing depression
• discuss counseling strategies shown to be effective in helping sedentary patients become more physically active.

Table 1

Why physical activity may improve mental health

Mental benefits of exercise

Adults who exercise regularly report lower levels of depressive and anxiety disorders than the overall U.S. population.² As a therapeutic intervention, exercise has been studied primarily in depressed individuals, although some data also support its efficacy in:

• reducing anxiety symptoms in panic disorder³
• reducing disruptive behavior in developmentally disabled patients⁴
• alleviating chronic fatigue symptoms⁵
• improving body esteem in patients with body image disturbance⁶
• increasing function in chronic pain⁷
• reducing urges to smoke and improving smoking abstinence among nicotine-dependent individuals.⁸

Why exercise helps. Mechanisms that would explain exercise’s positive effect on mood are not well understood.⁹ Physiologic and psychological hypotheses have been suggested (Table 1),^10,11 and researchers are attempting to elucidate them by using animal models.¹³

Case report: Feeling more energetic

At follow-up 6 weeks later, Ms. H. reported a substantial reduction in depressive symptoms. She noted increased energy, improved sleep, decreased overeating, higher self-esteem, and greater confidence in her ability to manage her depression.

Exercising also helped structure her day. She noticed that on days she did not exercise she was more likely to take a nap, miss her medication, or feel pessimistic about her depression.

Exercise as an antidepressant

Exercise vs psychotherapy. Exercise has been shown to be more effective at reducing depressive symptoms than no treatment, occupational therapy, cognitive therapy, health seminars, routine care, or meditation. Interventions used in these meta-analyses ranged from nonaerobic exercise training several times a week to 1 hour of supervised running 4 times a week.¹² Literature reviews also have concluded that exercise training compares favorably with individual or group psychotherapy and with cognitive therapy for treating depression.⁷

Exercise vs medication. Exercise training has also been compared with drug therapy in treating depression.

In a randomized, controlled trial, 156 men and women over age 50 with major depression received exercise training, sertraline, or exercise plus sertraline. Subjects in the exercise groups completed 40 minutes of aerobic exercise (biking or brisk walking/ jogging) 3 times a week. Subjects treated with sertraline received 50 to 200 mg/d, depending on response.

After 16 weeks, all three groups were significantly improved, with no clinically or statistically significant differences in depressive symptoms, as measured with the Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory.¹³

In a follow-up study 6 months later,¹⁴ the exercise group had significantly lower rates of relapse (defined as HRSD scores >15 and meeting diagnostic criteria) than did the medication group. Combining exercise with medication did not provide an added benefit in preventing relapse.

Exercise as monotherapy. Some studies have investigated using exercise instead of medication and psychotherapy. Many of these trials, however, were limited by methodologic weaknesses such as nonrandomized samples or lack of appropriate control groups.¹²

To address the need for higher-quality evidence, the Depression Outcomes Study of Exercise (DOSE) is investigating the dose-continued from page 12 response effects of exercise as monotherapy for major depressive disorder (MDD).⁵ The 12-week trial included 80 men and women ages 20 to 45 diagnosed with mild-to-moderate MDD using the Structured Clinical Interview for Depression. They were randomly assigned to one of five supervised exercise regimens:

• 7.0 kcal/kg/week in 3 days/week
• 7.0 kcal/kg/week in 5 days/week
• 17.5 kcal/kg/week in 3 days/week
• 17.5 kcal/kg/week in 5 days/week
• 3 days/week of stretching and flexibility exercises for 15 to 20 min/session.

Table 2

How much physical activity is recommended for adults?

Depressive symptoms were measured with the HRSD and Inventory of Depressive Symptoms (clinician and self-report). Other outcome measures included cardiorespiratory fitness, self-efficacy, and quality of life. Results are being prepared for publication and will likely help clarify the role of physical activity in treating patients with MDD.

Table 3

Why patients don’t exercise: Common barriers they perceive

How much exercise is therapeutic?

In the absence of physical activity guidelines specific to mental health, we suggest using standard public health guidelines (Table 2):

• 30 minutes or more of moderate-intensity physical activity (brisk walking, swimming, dancing, cycling) most days of the week (recommended by the Centers for Disease Control and Prevention and American College of Sports Medicine)¹
• 60 minutes of moderate-intensity physical activity daily for weight loss and maintenance (recommended by the Institute of Medicine).¹⁶

A recent study investigated the effects of exercise duration and intensity on weight loss in overweight, sedentary women. These researchers recommended setting the initial intervention target at 150 minutes or more of moderate-intensity exercise per week and progressing to 60 minutes per day as appropriate.¹⁶

Increasing the number of steps taken per day, as measured by a pedometer, also can be beneficial. Encourage patients to obtain a baseline measure of daily steps and to gradually increase toward a moderate goal of 10,000 steps per day.¹⁷

Case report: Accentuating the positive

On follow-up, Ms. H was quick to report the many barriers to exercise she had experienced and the times she did not meet her goal. Rather than dwell on shortcomings, the psychiatrist redirected her to examine the many positive actions she had taken to manage her depression.

As she considered how to overcome barriers to exercise, she reported increased confidence that she could stick with her medication and exercise regimen. She continues to exercise regularly and adheres to her fluoxetine. Her depressive symptoms remain well-controlled.

Overcoming barriers to exercise

Patient obstacles. Many patients acknowledge that regular exercise makes them feel physically and emotionally healthier but have difficulty exercising long term. Less than one-half of those who start an exercise program stick with it beyond 6 months.¹⁸ Drop-out reasons include injuries, lack of time, and low motivation (Table 3).^19,20

Depressive symptoms—fatigue, loss of interest, low self-esteem, feelings of helplessness, and psychomotor retardation—make exercise adherence even more difficult.

Physician obstacles. The U.S. Preventive Services Task Force recommends that physicians advise all patients to increase physical activity, but the national rate of physician counseling about exercise is low. In a population-based survey of more than 9,000 patients, 34% said their physicians counseled them about exercise at their most recent visit within the past year.²¹

Physician-reported barriers to exercise counseling include:

• competing demands for limited clinical time
• perceived ineffectiveness of advice to exercise
• lack of training and knowledge about exercise counseling and prescription.^22,23

Patients are more likely to become active and continue exercising when their physicians help them set achievable goals.

Project PACE. Physicians can overcome barriers to counseling patients about exercise. Those who participated in Project PACE (Physician-based Assessment and Counseling for Exercise)²⁴ said they felt more confident that they could counsel patients about physical activity in 1 to 5 minutes.

In a controlled study of 212 sedentary adults, patients who received PACE counseling from their physicians significantly increased their minutes of weekly walking compared with a control group. Also, 52% of patients who received PACE counseling adopted some physical activity, compared with 12% of controls.²⁵

Though modest initial goals are not sufficient for achieving the full benefits of exercise, success with a small goal is a powerful motivator. Rather than giving up, patients feel encouraged and are more likely to set a subsequent, more ambitious goal.

Recommendations. To help patients start exercising, determine how motivated and ready they are. Start by asking them to describe their current activities. Ask if they were ever more active and what they liked about it. Did they experience any benefits? Establish which of increased activity’s benefits—improved sleep, reduced depression, increased energy—would most benefit the patient, based on his or her symptoms.

Discuss barriers to physical activity and encourage problem-solving to overcome them and incorporate physical activity into their lives. Encourage patients to seek support from family, friends, coworkers, and exercise groups.

Help them set realistic, achievable goals. Even a modest 10 minutes of activity has been shown to enhance mood,²⁶ and a 10-minute brisk walk is one-third of the day’s public health guideline. Suggest that patients choose a variety of activities they enjoy.

During follow-up visits, reinforce any progress toward change. When patients’ exercise efforts fall short, explain that the process of becoming more active often includes setbacks. Advise them to seek support and to consider adopting more-achievable goals.

Related resources

• Getting started. Resources on nutrition and physical activity from the National Center for Chronic Disease Prevention and Health Promotion. http://www.cdc.gov/nccdphp/dnpa/physical/starting/index.htm
• Marcus B, Forsyth L. Motivating people to be physically active. Champaign, IL: Human Kinetics, 2002.

Drug brand names

• Fluoxetine • Prozac
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. H, age 26, is being evaluated for moderate to severe depressive symptoms, including oversleeping and overeating. She has had difficulty adhering to medication in the past and is ambivalent about taking antidepressants. She takes a passive approach to managing her depression, preferring to “wait for it to pass.”

Her psychiatrist prescribes fluoxetine, 20 mg in the morning, and recommends that Ms. H change her coping strategies from napping and snacking to increased physical activity. She encourages Ms. H to think about what activities interest her and to set exercise goals.

Ms. H says she has considered buying exercise equipment (an elliptical machine) and increasing her walking outside. She sets a goal to walk 20 minutes most days and to spend 10 to 15 minutes using the elliptical machine while watching television.

Physical activity’s mental health benefits are less well-known than its well-documented medical benefits—reduced risk of heart disease, hypertension, and diabetes; weight control; bone mass preservation; better sleep, and improved cholesterol levels.¹ By encouraging exercise, you can improve patients’ mood, well-being, and quality of life, independent of medication and psychotherapy. In this article, we:

• explore the relationship between physical activity and mental health
• compare exercise with medication and psychotherapies for easing depression
• discuss counseling strategies shown to be effective in helping sedentary patients become more physically active.

Table 1

Why physical activity may improve mental health

Mental benefits of exercise

Adults who exercise regularly report lower levels of depressive and anxiety disorders than the overall U.S. population.² As a therapeutic intervention, exercise has been studied primarily in depressed individuals, although some data also support its efficacy in:

• reducing anxiety symptoms in panic disorder³
• reducing disruptive behavior in developmentally disabled patients⁴
• alleviating chronic fatigue symptoms⁵
• improving body esteem in patients with body image disturbance⁶
• increasing function in chronic pain⁷
• reducing urges to smoke and improving smoking abstinence among nicotine-dependent individuals.⁸

Why exercise helps. Mechanisms that would explain exercise’s positive effect on mood are not well understood.⁹ Physiologic and psychological hypotheses have been suggested (Table 1),^10,11 and researchers are attempting to elucidate them by using animal models.¹³

Case report: Feeling more energetic

At follow-up 6 weeks later, Ms. H. reported a substantial reduction in depressive symptoms. She noted increased energy, improved sleep, decreased overeating, higher self-esteem, and greater confidence in her ability to manage her depression.

Exercising also helped structure her day. She noticed that on days she did not exercise she was more likely to take a nap, miss her medication, or feel pessimistic about her depression.

Exercise as an antidepressant

Exercise vs psychotherapy. Exercise has been shown to be more effective at reducing depressive symptoms than no treatment, occupational therapy, cognitive therapy, health seminars, routine care, or meditation. Interventions used in these meta-analyses ranged from nonaerobic exercise training several times a week to 1 hour of supervised running 4 times a week.¹² Literature reviews also have concluded that exercise training compares favorably with individual or group psychotherapy and with cognitive therapy for treating depression.⁷

Exercise vs medication. Exercise training has also been compared with drug therapy in treating depression.

In a randomized, controlled trial, 156 men and women over age 50 with major depression received exercise training, sertraline, or exercise plus sertraline. Subjects in the exercise groups completed 40 minutes of aerobic exercise (biking or brisk walking/ jogging) 3 times a week. Subjects treated with sertraline received 50 to 200 mg/d, depending on response.

After 16 weeks, all three groups were significantly improved, with no clinically or statistically significant differences in depressive symptoms, as measured with the Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory.¹³

In a follow-up study 6 months later,¹⁴ the exercise group had significantly lower rates of relapse (defined as HRSD scores >15 and meeting diagnostic criteria) than did the medication group. Combining exercise with medication did not provide an added benefit in preventing relapse.

Exercise as monotherapy. Some studies have investigated using exercise instead of medication and psychotherapy. Many of these trials, however, were limited by methodologic weaknesses such as nonrandomized samples or lack of appropriate control groups.¹²

To address the need for higher-quality evidence, the Depression Outcomes Study of Exercise (DOSE) is investigating the dose-continued from page 12 response effects of exercise as monotherapy for major depressive disorder (MDD).⁵ The 12-week trial included 80 men and women ages 20 to 45 diagnosed with mild-to-moderate MDD using the Structured Clinical Interview for Depression. They were randomly assigned to one of five supervised exercise regimens:

• 7.0 kcal/kg/week in 3 days/week
• 7.0 kcal/kg/week in 5 days/week
• 17.5 kcal/kg/week in 3 days/week
• 17.5 kcal/kg/week in 5 days/week
• 3 days/week of stretching and flexibility exercises for 15 to 20 min/session.

Table 2

How much physical activity is recommended for adults?

Depressive symptoms were measured with the HRSD and Inventory of Depressive Symptoms (clinician and self-report). Other outcome measures included cardiorespiratory fitness, self-efficacy, and quality of life. Results are being prepared for publication and will likely help clarify the role of physical activity in treating patients with MDD.

Table 3

Why patients don’t exercise: Common barriers they perceive

How much exercise is therapeutic?

In the absence of physical activity guidelines specific to mental health, we suggest using standard public health guidelines (Table 2):

• 30 minutes or more of moderate-intensity physical activity (brisk walking, swimming, dancing, cycling) most days of the week (recommended by the Centers for Disease Control and Prevention and American College of Sports Medicine)¹
• 60 minutes of moderate-intensity physical activity daily for weight loss and maintenance (recommended by the Institute of Medicine).¹⁶

A recent study investigated the effects of exercise duration and intensity on weight loss in overweight, sedentary women. These researchers recommended setting the initial intervention target at 150 minutes or more of moderate-intensity exercise per week and progressing to 60 minutes per day as appropriate.¹⁶

Increasing the number of steps taken per day, as measured by a pedometer, also can be beneficial. Encourage patients to obtain a baseline measure of daily steps and to gradually increase toward a moderate goal of 10,000 steps per day.¹⁷

Case report: Accentuating the positive

On follow-up, Ms. H was quick to report the many barriers to exercise she had experienced and the times she did not meet her goal. Rather than dwell on shortcomings, the psychiatrist redirected her to examine the many positive actions she had taken to manage her depression.

As she considered how to overcome barriers to exercise, she reported increased confidence that she could stick with her medication and exercise regimen. She continues to exercise regularly and adheres to her fluoxetine. Her depressive symptoms remain well-controlled.

Overcoming barriers to exercise

Patient obstacles. Many patients acknowledge that regular exercise makes them feel physically and emotionally healthier but have difficulty exercising long term. Less than one-half of those who start an exercise program stick with it beyond 6 months.¹⁸ Drop-out reasons include injuries, lack of time, and low motivation (Table 3).^19,20

Depressive symptoms—fatigue, loss of interest, low self-esteem, feelings of helplessness, and psychomotor retardation—make exercise adherence even more difficult.

Physician obstacles. The U.S. Preventive Services Task Force recommends that physicians advise all patients to increase physical activity, but the national rate of physician counseling about exercise is low. In a population-based survey of more than 9,000 patients, 34% said their physicians counseled them about exercise at their most recent visit within the past year.²¹

Physician-reported barriers to exercise counseling include:

• competing demands for limited clinical time
• perceived ineffectiveness of advice to exercise
• lack of training and knowledge about exercise counseling and prescription.^22,23

Patients are more likely to become active and continue exercising when their physicians help them set achievable goals.

Project PACE. Physicians can overcome barriers to counseling patients about exercise. Those who participated in Project PACE (Physician-based Assessment and Counseling for Exercise)²⁴ said they felt more confident that they could counsel patients about physical activity in 1 to 5 minutes.

In a controlled study of 212 sedentary adults, patients who received PACE counseling from their physicians significantly increased their minutes of weekly walking compared with a control group. Also, 52% of patients who received PACE counseling adopted some physical activity, compared with 12% of controls.²⁵

Though modest initial goals are not sufficient for achieving the full benefits of exercise, success with a small goal is a powerful motivator. Rather than giving up, patients feel encouraged and are more likely to set a subsequent, more ambitious goal.

Recommendations. To help patients start exercising, determine how motivated and ready they are. Start by asking them to describe their current activities. Ask if they were ever more active and what they liked about it. Did they experience any benefits? Establish which of increased activity’s benefits—improved sleep, reduced depression, increased energy—would most benefit the patient, based on his or her symptoms.

Discuss barriers to physical activity and encourage problem-solving to overcome them and incorporate physical activity into their lives. Encourage patients to seek support from family, friends, coworkers, and exercise groups.

Help them set realistic, achievable goals. Even a modest 10 minutes of activity has been shown to enhance mood,²⁶ and a 10-minute brisk walk is one-third of the day’s public health guideline. Suggest that patients choose a variety of activities they enjoy.

During follow-up visits, reinforce any progress toward change. When patients’ exercise efforts fall short, explain that the process of becoming more active often includes setbacks. Advise them to seek support and to consider adopting more-achievable goals.

Related resources

• Getting started. Resources on nutrition and physical activity from the National Center for Chronic Disease Prevention and Health Promotion. http://www.cdc.gov/nccdphp/dnpa/physical/starting/index.htm
• Marcus B, Forsyth L. Motivating people to be physically active. Champaign, IL: Human Kinetics, 2002.

Drug brand names

• Fluoxetine • Prozac
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. H, age 26, is being evaluated for moderate to severe depressive symptoms, including oversleeping and overeating. She has had difficulty adhering to medication in the past and is ambivalent about taking antidepressants. She takes a passive approach to managing her depression, preferring to “wait for it to pass.”

Her psychiatrist prescribes fluoxetine, 20 mg in the morning, and recommends that Ms. H change her coping strategies from napping and snacking to increased physical activity. She encourages Ms. H to think about what activities interest her and to set exercise goals.

Ms. H says she has considered buying exercise equipment (an elliptical machine) and increasing her walking outside. She sets a goal to walk 20 minutes most days and to spend 10 to 15 minutes using the elliptical machine while watching television.

Physical activity’s mental health benefits are less well-known than its well-documented medical benefits—reduced risk of heart disease, hypertension, and diabetes; weight control; bone mass preservation; better sleep, and improved cholesterol levels.¹ By encouraging exercise, you can improve patients’ mood, well-being, and quality of life, independent of medication and psychotherapy. In this article, we:

• explore the relationship between physical activity and mental health
• compare exercise with medication and psychotherapies for easing depression
• discuss counseling strategies shown to be effective in helping sedentary patients become more physically active.

Table 1

Why physical activity may improve mental health

Mental benefits of exercise

Adults who exercise regularly report lower levels of depressive and anxiety disorders than the overall U.S. population.² As a therapeutic intervention, exercise has been studied primarily in depressed individuals, although some data also support its efficacy in:

• reducing anxiety symptoms in panic disorder³
• reducing disruptive behavior in developmentally disabled patients⁴
• alleviating chronic fatigue symptoms⁵
• improving body esteem in patients with body image disturbance⁶
• increasing function in chronic pain⁷
• reducing urges to smoke and improving smoking abstinence among nicotine-dependent individuals.⁸

Why exercise helps. Mechanisms that would explain exercise’s positive effect on mood are not well understood.⁹ Physiologic and psychological hypotheses have been suggested (Table 1),^10,11 and researchers are attempting to elucidate them by using animal models.¹³

Case report: Feeling more energetic

At follow-up 6 weeks later, Ms. H. reported a substantial reduction in depressive symptoms. She noted increased energy, improved sleep, decreased overeating, higher self-esteem, and greater confidence in her ability to manage her depression.

Exercising also helped structure her day. She noticed that on days she did not exercise she was more likely to take a nap, miss her medication, or feel pessimistic about her depression.

Exercise as an antidepressant

Exercise vs psychotherapy. Exercise has been shown to be more effective at reducing depressive symptoms than no treatment, occupational therapy, cognitive therapy, health seminars, routine care, or meditation. Interventions used in these meta-analyses ranged from nonaerobic exercise training several times a week to 1 hour of supervised running 4 times a week.¹² Literature reviews also have concluded that exercise training compares favorably with individual or group psychotherapy and with cognitive therapy for treating depression.⁷

Exercise vs medication. Exercise training has also been compared with drug therapy in treating depression.

In a randomized, controlled trial, 156 men and women over age 50 with major depression received exercise training, sertraline, or exercise plus sertraline. Subjects in the exercise groups completed 40 minutes of aerobic exercise (biking or brisk walking/ jogging) 3 times a week. Subjects treated with sertraline received 50 to 200 mg/d, depending on response.

After 16 weeks, all three groups were significantly improved, with no clinically or statistically significant differences in depressive symptoms, as measured with the Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory.¹³

In a follow-up study 6 months later,¹⁴ the exercise group had significantly lower rates of relapse (defined as HRSD scores >15 and meeting diagnostic criteria) than did the medication group. Combining exercise with medication did not provide an added benefit in preventing relapse.

Exercise as monotherapy. Some studies have investigated using exercise instead of medication and psychotherapy. Many of these trials, however, were limited by methodologic weaknesses such as nonrandomized samples or lack of appropriate control groups.¹²

To address the need for higher-quality evidence, the Depression Outcomes Study of Exercise (DOSE) is investigating the dose-continued from page 12 response effects of exercise as monotherapy for major depressive disorder (MDD).⁵ The 12-week trial included 80 men and women ages 20 to 45 diagnosed with mild-to-moderate MDD using the Structured Clinical Interview for Depression. They were randomly assigned to one of five supervised exercise regimens:

• 7.0 kcal/kg/week in 3 days/week
• 7.0 kcal/kg/week in 5 days/week
• 17.5 kcal/kg/week in 3 days/week
• 17.5 kcal/kg/week in 5 days/week
• 3 days/week of stretching and flexibility exercises for 15 to 20 min/session.

Table 2

How much physical activity is recommended for adults?

Depressive symptoms were measured with the HRSD and Inventory of Depressive Symptoms (clinician and self-report). Other outcome measures included cardiorespiratory fitness, self-efficacy, and quality of life. Results are being prepared for publication and will likely help clarify the role of physical activity in treating patients with MDD.

Table 3

Why patients don’t exercise: Common barriers they perceive

How much exercise is therapeutic?

In the absence of physical activity guidelines specific to mental health, we suggest using standard public health guidelines (Table 2):

• 30 minutes or more of moderate-intensity physical activity (brisk walking, swimming, dancing, cycling) most days of the week (recommended by the Centers for Disease Control and Prevention and American College of Sports Medicine)¹
• 60 minutes of moderate-intensity physical activity daily for weight loss and maintenance (recommended by the Institute of Medicine).¹⁶

A recent study investigated the effects of exercise duration and intensity on weight loss in overweight, sedentary women. These researchers recommended setting the initial intervention target at 150 minutes or more of moderate-intensity exercise per week and progressing to 60 minutes per day as appropriate.¹⁶

Increasing the number of steps taken per day, as measured by a pedometer, also can be beneficial. Encourage patients to obtain a baseline measure of daily steps and to gradually increase toward a moderate goal of 10,000 steps per day.¹⁷

Case report: Accentuating the positive

On follow-up, Ms. H was quick to report the many barriers to exercise she had experienced and the times she did not meet her goal. Rather than dwell on shortcomings, the psychiatrist redirected her to examine the many positive actions she had taken to manage her depression.

As she considered how to overcome barriers to exercise, she reported increased confidence that she could stick with her medication and exercise regimen. She continues to exercise regularly and adheres to her fluoxetine. Her depressive symptoms remain well-controlled.

Overcoming barriers to exercise

Patient obstacles. Many patients acknowledge that regular exercise makes them feel physically and emotionally healthier but have difficulty exercising long term. Less than one-half of those who start an exercise program stick with it beyond 6 months.¹⁸ Drop-out reasons include injuries, lack of time, and low motivation (Table 3).^19,20

Depressive symptoms—fatigue, loss of interest, low self-esteem, feelings of helplessness, and psychomotor retardation—make exercise adherence even more difficult.

Physician obstacles. The U.S. Preventive Services Task Force recommends that physicians advise all patients to increase physical activity, but the national rate of physician counseling about exercise is low. In a population-based survey of more than 9,000 patients, 34% said their physicians counseled them about exercise at their most recent visit within the past year.²¹

Physician-reported barriers to exercise counseling include:

• competing demands for limited clinical time
• perceived ineffectiveness of advice to exercise
• lack of training and knowledge about exercise counseling and prescription.^22,23

Patients are more likely to become active and continue exercising when their physicians help them set achievable goals.

Project PACE. Physicians can overcome barriers to counseling patients about exercise. Those who participated in Project PACE (Physician-based Assessment and Counseling for Exercise)²⁴ said they felt more confident that they could counsel patients about physical activity in 1 to 5 minutes.

In a controlled study of 212 sedentary adults, patients who received PACE counseling from their physicians significantly increased their minutes of weekly walking compared with a control group. Also, 52% of patients who received PACE counseling adopted some physical activity, compared with 12% of controls.²⁵

Though modest initial goals are not sufficient for achieving the full benefits of exercise, success with a small goal is a powerful motivator. Rather than giving up, patients feel encouraged and are more likely to set a subsequent, more ambitious goal.

Recommendations. To help patients start exercising, determine how motivated and ready they are. Start by asking them to describe their current activities. Ask if they were ever more active and what they liked about it. Did they experience any benefits? Establish which of increased activity’s benefits—improved sleep, reduced depression, increased energy—would most benefit the patient, based on his or her symptoms.

Discuss barriers to physical activity and encourage problem-solving to overcome them and incorporate physical activity into their lives. Encourage patients to seek support from family, friends, coworkers, and exercise groups.

Help them set realistic, achievable goals. Even a modest 10 minutes of activity has been shown to enhance mood,²⁶ and a 10-minute brisk walk is one-third of the day’s public health guideline. Suggest that patients choose a variety of activities they enjoy.

During follow-up visits, reinforce any progress toward change. When patients’ exercise efforts fall short, explain that the process of becoming more active often includes setbacks. Advise them to seek support and to consider adopting more-achievable goals.

Related resources

• Getting started. Resources on nutrition and physical activity from the National Center for Chronic Disease Prevention and Health Promotion. http://www.cdc.gov/nccdphp/dnpa/physical/starting/index.htm
• Marcus B, Forsyth L. Motivating people to be physically active. Champaign, IL: Human Kinetics, 2002.

Drug brand names

• Fluoxetine • Prozac
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Using magnets to improve health is sometimes hawked in dubious classified ads and “infomercials.” However, a legitimate use of magnetism—repetitive transcranial magnetic stimulation (rTMS)—is showing promise in treating severe depression (Box) ^1-4 and other psychiatric disorders.

Patients or their families are likely to ask psychiatrists about rTMS as more becomes known about this investigational technology. Drawing from our experience and the evidence, we offer an update on whether rTMS may be an alternative for treating depression and address issues that must be resolved before it could be used in clinical practice.

WHAT IS RTMS?

rTMS consists of a series of magnetic pulses produced by a stimulator, which can be adjusted for:

• coil type and placement
• stimulation site, intensity, frequency, and number
• amount of time between stimulations
• treatment duration.

Box

Coil type and placement. Initial studies involved stimulation—typically low-frequency—over the vertex, but most subsequent rTMS trials in depression have stimulated the left dorsolateral prefrontal cortex. Neuroimaging studies have shown prefrontal functioning abnormalities in depressed subjects, and it is hypothesized that stimulating this area (plus possible distal effects) may produce an antidepressant effect.⁵

Various configurations have been used, but circular and figure-eight-shaped coils are most common. These flat coils are made of tightly wound ferromagnetic material such as copper, enclosed in a heavy plastic cover. With the figure-eight coil, the intersection of the two loops produces the strongest magnetic field.

Stimulation site. Stimulation intensity depends on the individual’s motor threshold, and the site can be determined visually or electrophysiologically.

• With the visual method, the motor threshold over the left primary motor cortex site for the first dorsal interosseous muscle (FDI) or the abductor pollius brevis (APB) is determined by iteration. This involves placing the coil at a progression of sites and increasing stimulation intensity until reliable (in 5 of 10 stimulations) contractions are seen in the right FDI or APB.
• Similarly, the electrophysiologic method uses 5 of 10 motorevoked potentials of 50 microvolts to locate the site.

The only small trial that compared visual and electrophysiologic site determination showed similar results with both methods.⁶ The most common stimulation site is the left dorsolateral prefrontal cortex, 5 cm anterior and parasagittal to the FDI or APB motor cortex. Alternately, frameless stereotactic systems or the international 10-20 proportional system used in EEG labs have been recommended to target sites more accurately.

Stimulus intensity. Each individual’s motor threshold determines stimulus intensity. Using functional MRI studies, researchers from the Medical University of South Carolina concluded that higher stimulation intensity relative to the motor threshold may have a more robust effect, as the magnetic field declines with distance from the coil.⁷ However, intensities >120% of the motor threshold are generally avoided because of possible increased seizure risk.⁹

Frequency of stimulation. Most researchers apply frequencies of 1 to 20 Hz over the left dorsolateral prefrontal cortex, but also use lower frequencies (<1 Hz) over the right dorsolateral prefrontal cortex. Using higher frequencies in major depression is attractive in theory because of:

• the reported association of decreased regional cerebral blood flow with hypometabolism in the left dorsolateral prefrontal cortex
• higher-frequency stimulation’s ability to produce temporary excitation and neuronal depolarization.

Number of stimulations. The number of stimulations is determined by frequency (Hz) and stimulation train duration (for example, 10 Hz for 5 seconds equals 50 stimulations). A typical treatment session incorporates 10 to 30 stimulation trains several seconds apart (the inter-train interval). Thus, a typical session delivers 1,000 to 1,200 stimulations. In studies of unmedicated depressed patients, the total number of stimulations has varied from 8,000 to 32,000 per treatment course.

Duration between two stimulation trains. Chen et al have demonstrated that shorter (<1 second) inter-train intervals increase seizure risk with higher frequencies (such as 20 Hz) and intensities (>100% of motor threshold) of stimulation.⁹ Based on their studies with healthy volunteers, they recommended several “safe” ranges (such as 5 seconds at 110% of motor threshold). Most trials use 30- to 60-second inter-train intervals.

Most treatments continue 2 to 4 weeks, Monday through Friday, although more frequent treatments are being studied.

EFFICACY FOR DEPRESSION

Most studies of rTMS in depression have compared real rTMS to a sham control or electroconvulsive therapy (ECT).

In earlier studies, the sham procedure typically involved tilting the coil away from the skull. This method has been questioned, however, because of evidence of neuronal depolarization.¹⁰

More recent sham coils mimic the real coils’ sound and sensation, without magnetic stimulation.

Despite these methodologic problems and some mixed results, depressed patients receiving rTMS show more favorable results than those receiving sham rTMS.^11,12 Several meta-analyses have attempted to quantify rTMS’ efficacy for depression:

• Holtzheimer et al concluded that rTMS was statistically superior to sham rTMS, but the clinical significance of these findings was modest in a population of mostly outpatients with less-severe depression.¹³
• Burt et al found a statistically strong antidepressant effect, but its magnitude varied and few of the studies yielded a substantial clinical response or remission. The team also noted that rTMS’ long-term efficacy or adverse effects are unknown.¹⁴
• Kozel et al concluded that left prefrontal rTMS rendered a significant antidepressant effect with measurable clinical improvement.¹⁵
• Gershon et al¹⁶ supported an antidepressant effect for rTMS when compared with sham rTMS or ECT.

Ongoing rTMS research includes subjects with many types of mild to severe psychiatric illnesses, including major depression, obsessive-compulsive disorder, and psychosis. Typically, patients referred for experimental approaches have not responded to or tolerated available treatments. Exclusion criteria used by most rTMS studies are listed in the Table.

Table

Medical conditions that preclude use of rTMS

rTMS vs. ECT. Four randomized, controlled trials have compared rTMS with ECT for treating severely ill, often medication-resistant patients.^17-20 Although their methodologies differed, all four studies concluded that rTMS and ECT offer similar efficacy, except that rTMS may be less effective for treating psychotic depression.

One study found ECT more effective than rTMS for psychotic depression, although the patients who received ECT were also treated with antipsychotics and/or antidepressants.¹⁷ Our study,¹⁹ which did not use these agents, has not corroborated this observation. Preliminary data also indicate comparable relapse rates following acute ECT and rTMS when subjects are followed on maintenance medication.²¹

ADVERSE EFFECTS

The potential adverse effects of new treatments must always be considered. Thus far, rTMS appears to produce minimal, relatively benign complications, including:

• mild discomfort at the stimulation site
• localized muscle twitching during stimulation
• mild post-treatment headaches—believed caused by muscle contractions—which usually respond to aspirin or acetaminophen
• treatment stimulation-related seizures (rarely).⁸

The rTMS device makes a loud clicking noise, and subjects wear protective ear plugs during treatment.

Patient experience. The first rTMS session—during which the patient’s motor threshold is determined—can last up to 45 minutes. Subsequent sessions are usually 15 to 20 minutes. Patients are typically apprehensive before the first session but become more relaxed with experience and tolerate the treatments easily.

During the procedure, many patients describe a tapping sensation on the forehead, and some experience slight muscle twitching around the eye or corner of the mouth. As the coil warms, the skin it touches sometimes flushes pink, although this does not seem to bother our patients. They can return to their daily routines immediately after a session.

rTMS for major depression. In our experience, rTMS may help patients with major depression. For example, one patient diagnosed with a major depressive episode with psychotic features was referred to our study comparing rTMS with ECT.¹⁹ Her depression had lasted several months, with partial response to ECT treatments. She signed informed consent and was randomly assigned to receive rTMS treatment.

At study admission, the patient’s Hamilton Depression Rating Scale (HDRS) score was 48, indicating moderate to severe depression. Following 10 rTMS sessions, her HDRS score had dropped to 2, with remission of symptoms. No follow-up results were documented.

Cognitive effects. Whereas mood disorders are associated with medication-independent neuropsychological deficits, most studies have found no adverse cognitive effects with rTMS.²² Indeed, some of our rTMS patients have improved in certain cognitive tests, although this may be explained by test-retest effects or better attention and concentration associated with mood improvement.

Figure Potential roles for rTMS in treating major depression

Solid lines represent current standards of practice. Dotted lines represent hypothetical roles for rTMS.

Source: Adapted and reprinted with permission from Dowd et al. Is repetitive transcranial magnetic stimulation an alternative to ECTfor the treatment of depression? Contemp Psychiatry 2002;1:1-10.

POTENTIAL ROLE FOR rTMS

Today’s standard treatment of major depressive episodes begins with an antidepressant (plus an antipsychotic, if necessary) and proceeds to augmentation strategies if response is insufficient. rTMS may one day become an augmentation or monotherapy option for patients who do not respond sufficiently to standard treatments (Figure).

ECT treatment may be initiated if a patient has had a prior good response to ECT, is intolerant to medication, or prefers ECT. In that case, rTMS may be used as an alternate initial treatment or with ECT. Thus, rTMS may be used:

• to augment antidepressants
• as an alternative to antidepressants or ECT
• or sequentially with ECT.

Before that can happen, however, optimal treatment parameters need to be clarified by larger, well-designed, controlled studies comparing rTMS to a valid sham treatment, antidepressants, and ECT.

Related resources

• International Society for Transcranial Stimulation. www.ists.unibe.ch/
• Repetitive Transcranial Magnetic Stimulation Research Clinic at Yale-New Haven Psychiatric Hospital.

Disclosure

The authors report that they have no proprietary interest in the technology discussed in this article.

Using magnets to improve health is sometimes hawked in dubious classified ads and “infomercials.” However, a legitimate use of magnetism—repetitive transcranial magnetic stimulation (rTMS)—is showing promise in treating severe depression (Box) ^1-4 and other psychiatric disorders.

Patients or their families are likely to ask psychiatrists about rTMS as more becomes known about this investigational technology. Drawing from our experience and the evidence, we offer an update on whether rTMS may be an alternative for treating depression and address issues that must be resolved before it could be used in clinical practice.

WHAT IS RTMS?

rTMS consists of a series of magnetic pulses produced by a stimulator, which can be adjusted for:

• coil type and placement
• stimulation site, intensity, frequency, and number
• amount of time between stimulations
• treatment duration.

Box

Coil type and placement. Initial studies involved stimulation—typically low-frequency—over the vertex, but most subsequent rTMS trials in depression have stimulated the left dorsolateral prefrontal cortex. Neuroimaging studies have shown prefrontal functioning abnormalities in depressed subjects, and it is hypothesized that stimulating this area (plus possible distal effects) may produce an antidepressant effect.⁵

Various configurations have been used, but circular and figure-eight-shaped coils are most common. These flat coils are made of tightly wound ferromagnetic material such as copper, enclosed in a heavy plastic cover. With the figure-eight coil, the intersection of the two loops produces the strongest magnetic field.

Stimulation site. Stimulation intensity depends on the individual’s motor threshold, and the site can be determined visually or electrophysiologically.

• With the visual method, the motor threshold over the left primary motor cortex site for the first dorsal interosseous muscle (FDI) or the abductor pollius brevis (APB) is determined by iteration. This involves placing the coil at a progression of sites and increasing stimulation intensity until reliable (in 5 of 10 stimulations) contractions are seen in the right FDI or APB.
• Similarly, the electrophysiologic method uses 5 of 10 motorevoked potentials of 50 microvolts to locate the site.

The only small trial that compared visual and electrophysiologic site determination showed similar results with both methods.⁶ The most common stimulation site is the left dorsolateral prefrontal cortex, 5 cm anterior and parasagittal to the FDI or APB motor cortex. Alternately, frameless stereotactic systems or the international 10-20 proportional system used in EEG labs have been recommended to target sites more accurately.

Stimulus intensity. Each individual’s motor threshold determines stimulus intensity. Using functional MRI studies, researchers from the Medical University of South Carolina concluded that higher stimulation intensity relative to the motor threshold may have a more robust effect, as the magnetic field declines with distance from the coil.⁷ However, intensities >120% of the motor threshold are generally avoided because of possible increased seizure risk.⁹

Frequency of stimulation. Most researchers apply frequencies of 1 to 20 Hz over the left dorsolateral prefrontal cortex, but also use lower frequencies (<1 Hz) over the right dorsolateral prefrontal cortex. Using higher frequencies in major depression is attractive in theory because of:

• the reported association of decreased regional cerebral blood flow with hypometabolism in the left dorsolateral prefrontal cortex
• higher-frequency stimulation’s ability to produce temporary excitation and neuronal depolarization.

Number of stimulations. The number of stimulations is determined by frequency (Hz) and stimulation train duration (for example, 10 Hz for 5 seconds equals 50 stimulations). A typical treatment session incorporates 10 to 30 stimulation trains several seconds apart (the inter-train interval). Thus, a typical session delivers 1,000 to 1,200 stimulations. In studies of unmedicated depressed patients, the total number of stimulations has varied from 8,000 to 32,000 per treatment course.

Duration between two stimulation trains. Chen et al have demonstrated that shorter (<1 second) inter-train intervals increase seizure risk with higher frequencies (such as 20 Hz) and intensities (>100% of motor threshold) of stimulation.⁹ Based on their studies with healthy volunteers, they recommended several “safe” ranges (such as 5 seconds at 110% of motor threshold). Most trials use 30- to 60-second inter-train intervals.

Most treatments continue 2 to 4 weeks, Monday through Friday, although more frequent treatments are being studied.

EFFICACY FOR DEPRESSION

Most studies of rTMS in depression have compared real rTMS to a sham control or electroconvulsive therapy (ECT).

In earlier studies, the sham procedure typically involved tilting the coil away from the skull. This method has been questioned, however, because of evidence of neuronal depolarization.¹⁰

More recent sham coils mimic the real coils’ sound and sensation, without magnetic stimulation.

Despite these methodologic problems and some mixed results, depressed patients receiving rTMS show more favorable results than those receiving sham rTMS.^11,12 Several meta-analyses have attempted to quantify rTMS’ efficacy for depression:

• Holtzheimer et al concluded that rTMS was statistically superior to sham rTMS, but the clinical significance of these findings was modest in a population of mostly outpatients with less-severe depression.¹³
• Burt et al found a statistically strong antidepressant effect, but its magnitude varied and few of the studies yielded a substantial clinical response or remission. The team also noted that rTMS’ long-term efficacy or adverse effects are unknown.¹⁴
• Kozel et al concluded that left prefrontal rTMS rendered a significant antidepressant effect with measurable clinical improvement.¹⁵
• Gershon et al¹⁶ supported an antidepressant effect for rTMS when compared with sham rTMS or ECT.

Ongoing rTMS research includes subjects with many types of mild to severe psychiatric illnesses, including major depression, obsessive-compulsive disorder, and psychosis. Typically, patients referred for experimental approaches have not responded to or tolerated available treatments. Exclusion criteria used by most rTMS studies are listed in the Table.

Table

Medical conditions that preclude use of rTMS

rTMS vs. ECT. Four randomized, controlled trials have compared rTMS with ECT for treating severely ill, often medication-resistant patients.^17-20 Although their methodologies differed, all four studies concluded that rTMS and ECT offer similar efficacy, except that rTMS may be less effective for treating psychotic depression.

One study found ECT more effective than rTMS for psychotic depression, although the patients who received ECT were also treated with antipsychotics and/or antidepressants.¹⁷ Our study,¹⁹ which did not use these agents, has not corroborated this observation. Preliminary data also indicate comparable relapse rates following acute ECT and rTMS when subjects are followed on maintenance medication.²¹

ADVERSE EFFECTS

The potential adverse effects of new treatments must always be considered. Thus far, rTMS appears to produce minimal, relatively benign complications, including:

• mild discomfort at the stimulation site
• localized muscle twitching during stimulation
• mild post-treatment headaches—believed caused by muscle contractions—which usually respond to aspirin or acetaminophen
• treatment stimulation-related seizures (rarely).⁸

The rTMS device makes a loud clicking noise, and subjects wear protective ear plugs during treatment.

Patient experience. The first rTMS session—during which the patient’s motor threshold is determined—can last up to 45 minutes. Subsequent sessions are usually 15 to 20 minutes. Patients are typically apprehensive before the first session but become more relaxed with experience and tolerate the treatments easily.

During the procedure, many patients describe a tapping sensation on the forehead, and some experience slight muscle twitching around the eye or corner of the mouth. As the coil warms, the skin it touches sometimes flushes pink, although this does not seem to bother our patients. They can return to their daily routines immediately after a session.

rTMS for major depression. In our experience, rTMS may help patients with major depression. For example, one patient diagnosed with a major depressive episode with psychotic features was referred to our study comparing rTMS with ECT.¹⁹ Her depression had lasted several months, with partial response to ECT treatments. She signed informed consent and was randomly assigned to receive rTMS treatment.

At study admission, the patient’s Hamilton Depression Rating Scale (HDRS) score was 48, indicating moderate to severe depression. Following 10 rTMS sessions, her HDRS score had dropped to 2, with remission of symptoms. No follow-up results were documented.

Cognitive effects. Whereas mood disorders are associated with medication-independent neuropsychological deficits, most studies have found no adverse cognitive effects with rTMS.²² Indeed, some of our rTMS patients have improved in certain cognitive tests, although this may be explained by test-retest effects or better attention and concentration associated with mood improvement.

Figure Potential roles for rTMS in treating major depression

Solid lines represent current standards of practice. Dotted lines represent hypothetical roles for rTMS.

Source: Adapted and reprinted with permission from Dowd et al. Is repetitive transcranial magnetic stimulation an alternative to ECTfor the treatment of depression? Contemp Psychiatry 2002;1:1-10.

POTENTIAL ROLE FOR rTMS

Today’s standard treatment of major depressive episodes begins with an antidepressant (plus an antipsychotic, if necessary) and proceeds to augmentation strategies if response is insufficient. rTMS may one day become an augmentation or monotherapy option for patients who do not respond sufficiently to standard treatments (Figure).

ECT treatment may be initiated if a patient has had a prior good response to ECT, is intolerant to medication, or prefers ECT. In that case, rTMS may be used as an alternate initial treatment or with ECT. Thus, rTMS may be used:

• to augment antidepressants
• as an alternative to antidepressants or ECT
• or sequentially with ECT.

Before that can happen, however, optimal treatment parameters need to be clarified by larger, well-designed, controlled studies comparing rTMS to a valid sham treatment, antidepressants, and ECT.

Related resources

• International Society for Transcranial Stimulation. www.ists.unibe.ch/
• Repetitive Transcranial Magnetic Stimulation Research Clinic at Yale-New Haven Psychiatric Hospital.

Disclosure

The authors report that they have no proprietary interest in the technology discussed in this article.

Using magnets to improve health is sometimes hawked in dubious classified ads and “infomercials.” However, a legitimate use of magnetism—repetitive transcranial magnetic stimulation (rTMS)—is showing promise in treating severe depression (Box) ^1-4 and other psychiatric disorders.

Patients or their families are likely to ask psychiatrists about rTMS as more becomes known about this investigational technology. Drawing from our experience and the evidence, we offer an update on whether rTMS may be an alternative for treating depression and address issues that must be resolved before it could be used in clinical practice.

WHAT IS RTMS?

rTMS consists of a series of magnetic pulses produced by a stimulator, which can be adjusted for:

• coil type and placement
• stimulation site, intensity, frequency, and number
• amount of time between stimulations
• treatment duration.

Box

Coil type and placement. Initial studies involved stimulation—typically low-frequency—over the vertex, but most subsequent rTMS trials in depression have stimulated the left dorsolateral prefrontal cortex. Neuroimaging studies have shown prefrontal functioning abnormalities in depressed subjects, and it is hypothesized that stimulating this area (plus possible distal effects) may produce an antidepressant effect.⁵

Various configurations have been used, but circular and figure-eight-shaped coils are most common. These flat coils are made of tightly wound ferromagnetic material such as copper, enclosed in a heavy plastic cover. With the figure-eight coil, the intersection of the two loops produces the strongest magnetic field.

Stimulation site. Stimulation intensity depends on the individual’s motor threshold, and the site can be determined visually or electrophysiologically.

• With the visual method, the motor threshold over the left primary motor cortex site for the first dorsal interosseous muscle (FDI) or the abductor pollius brevis (APB) is determined by iteration. This involves placing the coil at a progression of sites and increasing stimulation intensity until reliable (in 5 of 10 stimulations) contractions are seen in the right FDI or APB.
• Similarly, the electrophysiologic method uses 5 of 10 motorevoked potentials of 50 microvolts to locate the site.

The only small trial that compared visual and electrophysiologic site determination showed similar results with both methods.⁶ The most common stimulation site is the left dorsolateral prefrontal cortex, 5 cm anterior and parasagittal to the FDI or APB motor cortex. Alternately, frameless stereotactic systems or the international 10-20 proportional system used in EEG labs have been recommended to target sites more accurately.

Stimulus intensity. Each individual’s motor threshold determines stimulus intensity. Using functional MRI studies, researchers from the Medical University of South Carolina concluded that higher stimulation intensity relative to the motor threshold may have a more robust effect, as the magnetic field declines with distance from the coil.⁷ However, intensities >120% of the motor threshold are generally avoided because of possible increased seizure risk.⁹

Frequency of stimulation. Most researchers apply frequencies of 1 to 20 Hz over the left dorsolateral prefrontal cortex, but also use lower frequencies (<1 Hz) over the right dorsolateral prefrontal cortex. Using higher frequencies in major depression is attractive in theory because of:

• the reported association of decreased regional cerebral blood flow with hypometabolism in the left dorsolateral prefrontal cortex
• higher-frequency stimulation’s ability to produce temporary excitation and neuronal depolarization.

Number of stimulations. The number of stimulations is determined by frequency (Hz) and stimulation train duration (for example, 10 Hz for 5 seconds equals 50 stimulations). A typical treatment session incorporates 10 to 30 stimulation trains several seconds apart (the inter-train interval). Thus, a typical session delivers 1,000 to 1,200 stimulations. In studies of unmedicated depressed patients, the total number of stimulations has varied from 8,000 to 32,000 per treatment course.

Duration between two stimulation trains. Chen et al have demonstrated that shorter (<1 second) inter-train intervals increase seizure risk with higher frequencies (such as 20 Hz) and intensities (>100% of motor threshold) of stimulation.⁹ Based on their studies with healthy volunteers, they recommended several “safe” ranges (such as 5 seconds at 110% of motor threshold). Most trials use 30- to 60-second inter-train intervals.

Most treatments continue 2 to 4 weeks, Monday through Friday, although more frequent treatments are being studied.

EFFICACY FOR DEPRESSION

Most studies of rTMS in depression have compared real rTMS to a sham control or electroconvulsive therapy (ECT).

In earlier studies, the sham procedure typically involved tilting the coil away from the skull. This method has been questioned, however, because of evidence of neuronal depolarization.¹⁰

More recent sham coils mimic the real coils’ sound and sensation, without magnetic stimulation.

Despite these methodologic problems and some mixed results, depressed patients receiving rTMS show more favorable results than those receiving sham rTMS.^11,12 Several meta-analyses have attempted to quantify rTMS’ efficacy for depression:

• Holtzheimer et al concluded that rTMS was statistically superior to sham rTMS, but the clinical significance of these findings was modest in a population of mostly outpatients with less-severe depression.¹³
• Burt et al found a statistically strong antidepressant effect, but its magnitude varied and few of the studies yielded a substantial clinical response or remission. The team also noted that rTMS’ long-term efficacy or adverse effects are unknown.¹⁴
• Kozel et al concluded that left prefrontal rTMS rendered a significant antidepressant effect with measurable clinical improvement.¹⁵
• Gershon et al¹⁶ supported an antidepressant effect for rTMS when compared with sham rTMS or ECT.

Ongoing rTMS research includes subjects with many types of mild to severe psychiatric illnesses, including major depression, obsessive-compulsive disorder, and psychosis. Typically, patients referred for experimental approaches have not responded to or tolerated available treatments. Exclusion criteria used by most rTMS studies are listed in the Table.

Table

Medical conditions that preclude use of rTMS

rTMS vs. ECT. Four randomized, controlled trials have compared rTMS with ECT for treating severely ill, often medication-resistant patients.^17-20 Although their methodologies differed, all four studies concluded that rTMS and ECT offer similar efficacy, except that rTMS may be less effective for treating psychotic depression.

One study found ECT more effective than rTMS for psychotic depression, although the patients who received ECT were also treated with antipsychotics and/or antidepressants.¹⁷ Our study,¹⁹ which did not use these agents, has not corroborated this observation. Preliminary data also indicate comparable relapse rates following acute ECT and rTMS when subjects are followed on maintenance medication.²¹

ADVERSE EFFECTS

The potential adverse effects of new treatments must always be considered. Thus far, rTMS appears to produce minimal, relatively benign complications, including:

• mild discomfort at the stimulation site
• localized muscle twitching during stimulation
• mild post-treatment headaches—believed caused by muscle contractions—which usually respond to aspirin or acetaminophen
• treatment stimulation-related seizures (rarely).⁸

The rTMS device makes a loud clicking noise, and subjects wear protective ear plugs during treatment.

Patient experience. The first rTMS session—during which the patient’s motor threshold is determined—can last up to 45 minutes. Subsequent sessions are usually 15 to 20 minutes. Patients are typically apprehensive before the first session but become more relaxed with experience and tolerate the treatments easily.

During the procedure, many patients describe a tapping sensation on the forehead, and some experience slight muscle twitching around the eye or corner of the mouth. As the coil warms, the skin it touches sometimes flushes pink, although this does not seem to bother our patients. They can return to their daily routines immediately after a session.

rTMS for major depression. In our experience, rTMS may help patients with major depression. For example, one patient diagnosed with a major depressive episode with psychotic features was referred to our study comparing rTMS with ECT.¹⁹ Her depression had lasted several months, with partial response to ECT treatments. She signed informed consent and was randomly assigned to receive rTMS treatment.

At study admission, the patient’s Hamilton Depression Rating Scale (HDRS) score was 48, indicating moderate to severe depression. Following 10 rTMS sessions, her HDRS score had dropped to 2, with remission of symptoms. No follow-up results were documented.

Cognitive effects. Whereas mood disorders are associated with medication-independent neuropsychological deficits, most studies have found no adverse cognitive effects with rTMS.²² Indeed, some of our rTMS patients have improved in certain cognitive tests, although this may be explained by test-retest effects or better attention and concentration associated with mood improvement.

Figure Potential roles for rTMS in treating major depression

Solid lines represent current standards of practice. Dotted lines represent hypothetical roles for rTMS.

Source: Adapted and reprinted with permission from Dowd et al. Is repetitive transcranial magnetic stimulation an alternative to ECTfor the treatment of depression? Contemp Psychiatry 2002;1:1-10.

POTENTIAL ROLE FOR rTMS

Today’s standard treatment of major depressive episodes begins with an antidepressant (plus an antipsychotic, if necessary) and proceeds to augmentation strategies if response is insufficient. rTMS may one day become an augmentation or monotherapy option for patients who do not respond sufficiently to standard treatments (Figure).

ECT treatment may be initiated if a patient has had a prior good response to ECT, is intolerant to medication, or prefers ECT. In that case, rTMS may be used as an alternate initial treatment or with ECT. Thus, rTMS may be used:

• to augment antidepressants
• as an alternative to antidepressants or ECT
• or sequentially with ECT.

Before that can happen, however, optimal treatment parameters need to be clarified by larger, well-designed, controlled studies comparing rTMS to a valid sham treatment, antidepressants, and ECT.

Related resources

• International Society for Transcranial Stimulation. www.ists.unibe.ch/
• Repetitive Transcranial Magnetic Stimulation Research Clinic at Yale-New Haven Psychiatric Hospital.

Disclosure

The authors report that they have no proprietary interest in the technology discussed in this article.