Psychiatric Annals

CME Article 

Examining the Safety and Effectiveness of Transcranial Magnetic Stimulation for Depression

Mark A. Demitrack, MD

Abstract

Study methodology and clinical trial design present challenges for researchers.

Major depression remains one of the most common and debilitating of human diseases. Early reports examining the prevalence of this condition worldwide provided a general consensus on the frequency of its occurrence, with previous-month incidence rates ranging from 2% to 6%.1,2 One of the more recent epidemiologic surveys conducted in the United States, the National Comorbidity Survey replication study, estimated the lifetime prevalence of formally diagnosed major depression as 16.2%.3 In that report, when observed over a 12-month interval, in more than half of all cases the clinical significance was independently classified as either severe (38.0%) or very severe (12.9%).3 It is remarkable that only about 10% were seen as clinically mild cases.

One of the most compelling statistics that speaks to the staggering personal consequences of major depression comes from the Global Burden of Disease report, which estimated that by the year 2020, major depression will be second only to heart disease in magnitude of disease burden, as determined by disability-adjusted life years.4 Beyond the morbid burden of the illness, it is often forgotten that major depression is also still a potentially lethal disease. The American Suicide Foundation reports that 30% of all patients with depression attempt suicide in their lifetimes; nearly half of those ultimately succeed in their attempts.5

In this context, it is not surprising that the development of more tolerable and effective treatment options has been of considerable interest to patients and their clinicians and has occupied a substantial amount of time and effort in both the public and private research arenas. Also, perhaps not surprisingly, the preponderance of this work has involved the development of improved pharmacologic interventions. It is useful to recall that, before the current generation of pharmaceutical treatments, the clinical management of major depression was an uncomfortable proposition for all involved. From the patient's perspective, the most commonly used medications, namely the tricyclic antidepressants and the monoamine oxidase inhibitors, though clearly effective, also were poorly tolerated. From the clinician's view, the complexity of the clinical management of these agents, coupled with their lethality in overdose, led to their nearly exclusive use in the context of specialty referral, if at all. For all individuals touched by the disease, the stigma of illness was substantial.

Thus, the transformative effect of the arrival of the selective serotonin reuptake inhibitors (SSRIs) and the successive newer generation oral antidepressant therapies cannot be overstated. What was once an arcane and uncomfortable clinical process, isolated to the specialty consultation office, emerged as a dominant facet of the primary care practitioner's clinical world. These newer medications proved easy to use. For many patients, the first dose was the therapeutic dose. Furthermore, from the viewpoint of safety, there was a vast improvement over the prior generation of agents. Probably of greatest importance, the improved tolerability also was accompanied by an increased awareness of the prevalence of depression, stimulating public dialogue on the topic. While there remains a considerable amount of work to be done, the reduction in stigma associated with depression and its treatment during the past 2 decades has been noteworthy.

The ease of use presented by this newer generation of pharmacotherapy options clearly advanced the case for pharmaceutical management as a dominant element in the standard treatment algorithm for this illness. Interestingly, this occurred even though it is generally felt that the newer agents, if anything, sacrificed a margin of efficacy in exchange for remarkable advances in safety and tolerability. Several investigators have indeed argued that the more complex, broad pharmacology of the prior generation of medications conferred a…

Study methodology and clinical trial design present challenges for researchers.

Major depression remains one of the most common and debilitating of human diseases. Early reports examining the prevalence of this condition worldwide provided a general consensus on the frequency of its occurrence, with previous-month incidence rates ranging from 2% to 6%.1,2 One of the more recent epidemiologic surveys conducted in the United States, the National Comorbidity Survey replication study, estimated the lifetime prevalence of formally diagnosed major depression as 16.2%.3 In that report, when observed over a 12-month interval, in more than half of all cases the clinical significance was independently classified as either severe (38.0%) or very severe (12.9%).3 It is remarkable that only about 10% were seen as clinically mild cases.

One of the most compelling statistics that speaks to the staggering personal consequences of major depression comes from the Global Burden of Disease report, which estimated that by the year 2020, major depression will be second only to heart disease in magnitude of disease burden, as determined by disability-adjusted life years.4 Beyond the morbid burden of the illness, it is often forgotten that major depression is also still a potentially lethal disease. The American Suicide Foundation reports that 30% of all patients with depression attempt suicide in their lifetimes; nearly half of those ultimately succeed in their attempts.5

In this context, it is not surprising that the development of more tolerable and effective treatment options has been of considerable interest to patients and their clinicians and has occupied a substantial amount of time and effort in both the public and private research arenas. Also, perhaps not surprisingly, the preponderance of this work has involved the development of improved pharmacologic interventions. It is useful to recall that, before the current generation of pharmaceutical treatments, the clinical management of major depression was an uncomfortable proposition for all involved. From the patient's perspective, the most commonly used medications, namely the tricyclic antidepressants and the monoamine oxidase inhibitors, though clearly effective, also were poorly tolerated. From the clinician's view, the complexity of the clinical management of these agents, coupled with their lethality in overdose, led to their nearly exclusive use in the context of specialty referral, if at all. For all individuals touched by the disease, the stigma of illness was substantial.

Thus, the transformative effect of the arrival of the selective serotonin reuptake inhibitors (SSRIs) and the successive newer generation oral antidepressant therapies cannot be overstated. What was once an arcane and uncomfortable clinical process, isolated to the specialty consultation office, emerged as a dominant facet of the primary care practitioner's clinical world. These newer medications proved easy to use. For many patients, the first dose was the therapeutic dose. Furthermore, from the viewpoint of safety, there was a vast improvement over the prior generation of agents. Probably of greatest importance, the improved tolerability also was accompanied by an increased awareness of the prevalence of depression, stimulating public dialogue on the topic. While there remains a considerable amount of work to be done, the reduction in stigma associated with depression and its treatment during the past 2 decades has been noteworthy.

The ease of use presented by this newer generation of pharmacotherapy options clearly advanced the case for pharmaceutical management as a dominant element in the standard treatment algorithm for this illness. Interestingly, this occurred even though it is generally felt that the newer agents, if anything, sacrificed a margin of efficacy in exchange for remarkable advances in safety and tolerability. Several investigators have indeed argued that the more complex, broad pharmacology of the prior generation of medications conferred a greater and more reliable clinical outcome than is often seen with the SSRIs.6

It is ironic that, at the same time that these clinical advances in pharmacological intervention were moving forward, the most predictably effective antidepressant known, electroconvulsive therapy (ECT), was receiving comparatively less attention in clinical development. An important series of studies of ECT, however, clarified certain aspects of its optimized treatment parameters, its longer-term efficacy and safety, and have begun to provide important insights into its underlying mechanism of effect.7,8 Nevertheless, despite these critical advances in our understanding of ECT, the further elaboration of the device-based platform of antidepressant therapeutics has lagged our understanding of the role of pharmaceuticals. In other words, we now have an interesting and problematic state of affairs, where the array of available somatic treatments for major depression has evolved in a manner heavily biased toward the simple-to-treat end of the clinical spectrum, in essence producing an “unbalanced” armamentarium of agents, which does not adequately serve the full severity spectrum of depression.

Consistent with this view, recent years have seen a reappraisal of the clinical reality of the treatment of major depression. Despite the remarkable accomplishments alluded to above, the outcome expectations for a patient presenting with major depression are virtually unchanged from a generation ago. In particular, in response to drug of first choice, it is still true that only about one-third of all patients will experience a fully adequate level of efficacy (ie, symptom remission) coupled with an acceptable balance of tolerability and safety. It is an unfortunate reality that partial response or nonresponse to treatment remains the norm in contemporary practice. In fact, it is generally estimated that approximately 15% to 25% of patients remain essentially unserved by currently available interventions.9 Coupled with the reality of available treatment options, the need for a more heterogeneous choice of treatments that can be distributed appropriately across the disease severity spectrum is apparent.

Among the more promising advances in somatic treatments for depression are the newer options being explored in the previously neglected arena of device-based approaches (Figure 1, see page 122). For purposes of this article, we will refer to this class of interventions in the broad sense as representing a novel platform of “brain stimulation” therapies. It should be emphasized that they represent a striking diversity of technical approaches. As shown in Figure 1, they can be considered in terms of whether they produce a seizure and whether they are invasive or interventional in their administration. Accordingly, these varying clinical features result in an equally varied range of clinical outcomes, both from an efficacy and safety perspective.

Brain stimulation therapies as a novel platform of antidepressant treatment.

Figure 1.

Brain stimulation therapies as a novel platform of antidepressant treatment.

Figure 2 (see page 122) graphically portrays a potential future reality of the clinical treatment portfolio for patients with major depression. As will be addressed by articles elsewhere in this issue, it is argued that the potential opportunities emerging in the next generation of brain stimulation therapies represent a credible opportunity to “rebalance” the existing portfolio of available treatments.

A continuum of care for treatment planning for major depression.

Figure 2.

A continuum of care for treatment planning for major depression.

The principal focus of this article is to explore the challenge represented by these novel interventions from a clinical development perspective, using as an example the development of transcranial magnetic stimulation (TMS) as a treatment for major depression. The discussion will summarize some of the more pertinent issues in clinical development for the platform of brain stimulation therapies and outline some of the priorities for further study.

Brain Stimulation Using rTMS

TMS is a well-known method of using powerful, rapidly alternating (or pulsed) magnetic fields to induce electrical currents directed at a specific target location. The basic mechanism of action derives from a fundamental principle of physics, first described by Michael Faraday in 1831.10 He observed that a time-varying magnetic field produces an electrical current in a conductive substance, this current traveling in a path orthogonal to the direction of the magnetic field. The contemporary era of central nervous system TMS studies generally is credited as originating with the report from Barker and colleagues11 in 1985; they described the direct stimulation of human motor cortex.

TMS can be applied in single pulses, paired pulses, or rapidly repeated trains. The last method is referred to as repetitive transcranial magnetic stimulation, or rTMS. Single-pulse and paired-pulse administration are used primarily for diagnostic purposes, such as in the examination of central motor conduction time or to map specific areas of cortical function.

From a clinical and methodological perspective, the use of TMS as a method of delivering an electrical stimulation to the brain is of particular interest because, unlike the direct application of electric current as occurs with ECT, the magnetic field travels relatively unperturbed through the scalp and skull, delivering the induced electrical current in a more discrete manner than can be achieved with ECT. This attribute allows for a more focal application of electrical stimulation to a specific targeted brain region of interest. TMS also has introduced the potential of answering a critical scientific question: is a method of focal electrical stimulation which is capable of altering nervous tissue function without the induction of a seizure of therapeutic merit in the treatment of psychiatric illness?

A large and growing literature has established a number of key features about rTMS that are circumstantially relevant to its putative therapeutic effects. There is no doubt that brain functional activity can be altered by the application of rTMS stimulation to various cortical structures. It is also clear that the available methods of rTMS stimulation produce evidence of discrete metabolic effects in the location of the induced electrical field (ie, directly under the magnetic coil) and are accompanied by regional alterations in brain metabolism that argue for a broad, transsynaptic functional action of locally applied rTMS.12,13

In addition, it has been shown that the effects of rTMS are mediated by the specific choice of stimulation parameters.14 In general, higher frequency pulse administration — “fast rTMS,” at greater than 1 hertz — results in excitation of neuronal function. Low frequency stimulation — “slow rTMS,” at less than 1 hertz — appears generally inhibitory at the same target. Some authors have suggested that the magnetic field intensity, the total number of pulses, and the duration of exposure to an acute course of rTMS stimulation are critical variables in the determination of an effective dose in the treatment of patients with depression,15 and each appears to show a relatively linear dose-effect relationship.

Studies in preclinical models predictive of potential antidepressant action show apparent efficacy of rTMS.16,17 It should be cautioned, however, that because of the constraints of magnetic coil geometry, the interpretation of these animal studies is confounded by questions of the precise location and amount of direct stimulation delivered, as a larger volume of brain is directly stimulated in these animal models compared with the local area of direct activation achieved in the human brain. Arguably the more compelling evidence is the sizable human literature of the potential therapeutic effects of rTMS administration in psychiatric disease. More than 20 controlled trials of the use of rTMS in the treatment of major depression have been reported in the peer-reviewed literature, most showing a consistent, statistically significant improvement of mood when active rTMS is compared with sham treatment in patients with medication-resistant major depression.18–22

Study Design Issues

While there is compelling evidence in favor of an antidepressant action of rTMS, at the same time, these studies have raised a number of clinical development issues that must be addressed in future work. For example, rTMS as a device-based intervention represents an innovative advance among the therapeutic choices for the treatment of depression. Indeed, its sheer novelty in form and method of application in comparison to the familiar pharmacotherapy paradigm also raises critical methodological questions. This new treatment process and the questions raised by it are not only relevant in the interpretation of the clinical research observations reported to date but also essential to consider in the design of any future studies of rTMS.

For example, whether we should employ identical approaches to the clinical development of rTMS as have been used in the study of new pharmacotherapies for this illness; demand unique and different strategies; or blend elements of the two approaches are dilemmas which must be considered. To this point, the literature has grappled largely with fundamental technical issues largely related to the machine stimulation parameters or the method of sham control. The remainder of this article will summarize some of these key methodologic issues in the clinical development of rTMS for the treatment of major depression, and provide recommendations for future study.

Challenges and Considerations

The consistency with which a beneficial effect of rTMS on mood in patients with major depression has been observed is all the more remarkable given the methodologic variability across these individual studies. Some of the more critical sources of variability are summarized in Figure 3 (see page 124). While these issues are essential to address in the next stage of development, it is nonetheless reasonable to state that these early studies have established a strong case that rTMS has a potential clinical antidepressant effect. Stated another way, using the parallel context from clinical drug development, rTMS has emerged with promising evidence from Phase I studies sufficient to bring it forward as a candidate for middle to later stage development and more definitively establish the magnitude of its clinical potential. To do that, consensus must be achieved on a number of critical clinical development assumptions for future studies of rTMS.

Critical sources of variability in the clinical development of rTMS.

Figure 3.

Critical sources of variability in the clinical development of rTMS.

The Sidebar addresses these assumptions as a set of questions to consider in any future study designs. As suggested earlier in this article, device-based treatments in general, and rTMS in particular, represent a paradigm shift in the treatment planning for patients with major depression. Given that all the potential members of this class require a level of hands-on technical complexity in comparison to the use of pharmaceuticals, it is unlikely that, at least in the near term, they will be employed as first-line monotherapies for the treatment of major depression. On the other hand, it is highly likely that, as portrayed in Figure 2, these various interventions will move forward in a differential manner in the treatment planning process depending on the levels of disease severity and clinical complexity of the specific patient population needing intervention. For example, it is likely that rTMS would be considered as a clinical intervention in advance of the use of deep brain stimulation. These positions in the decision-making process can be considered critical guides for the nature of the population to be examined in clinical trials for a particular intervention.

Sidebar.

Questions to Consider in Planning Clinical Development Strategy

  • What is the intended use of the device in clinical practice?
  • How will the study population be defined?
  • How will treatment resistance be determined?
  • What are the critical features of the study design?
    • Dose (ie, stimulation parameters)?

    • Method of blinding?

    • Visit frequency?

    • Duration of treatment?

    • Entry and exit phases?

    • Extension studies?

    • Training methods (for rating, for device itself)?

  • How will outcome be defined in terms of:
    • Symptoms?

    • Functional status?

    • Economic effects/benefits?

  • What method of safety assessment will be used?
  • What will be the potential conclusions of the study? Will they provide meaningful information for future work?

Questions to Consider in Planning Clinical Development Strategy

Further, it is important to consider whether the intervention should more appropriately be standalone or an add-on or adjunctive treatment modality as a first priority of study. With this end in mind, the definition of the population to be studied with a particular intervention must be stated clearly and unambiguously. Unfortunately, in the existing literature, the study population recruited has shown a significant degree of diagnostic heterogeneity, including a wide range of major depression types (eg, bipolar depression, melancholia, atypical depression, psychotic depression, and geriatric depression). While this may be useful for early identification of more treatment responsive subgroups, in later stages of development, such population heterogeneity can impede the identification of an effective treatment. In addition, a substantial degree of diagnostic comorbidity was allowed in the prior work, both on Axis I and Axis II.

While there is obvious interest in establishing the generalizability of the proposed treatment intervention, the practical reality is that in a randomized clinical trial, the greater the population heterogeneity, the greater the sources that may contribute to general measurement variation, hence obscuring the signal of interest. For rTMS in particular, it is noted that until further data accumulates, there is some indication that psychotic forms of depression may respond less favorably to rTMS than other subtypes of illness.23 In addition, Kozel and colleagues24 have noted that distance to the surface of the cortex from the coil face may contribute to decreasing the efficacy of rTMS, raising the question of whether patients who may be presumed at risk for clinically significant cortical atrophy should be excluded from study.

In addition to a more phenomenologically homogeneous approach to the categorical definition of the diagnosis itself, other attributes of the clinical illness should be considered. As noted above, it is highly likely that the initial clinical context for use of rTMS will be in patients who have received little benefit from, or who have been unable to tolerate, drug treatment. It is therefore crucial to agree on the minimal level of medication resistance or intolerance present in the study sample.

Few studies to date have employed a methodologically valid approach to defining and measuring treatment resistance. The most direct approach would be to demonstrate this phenomenon by prospectively documenting this clinical feature in the study population. While attractive in theory, the practical reality is that the burden upon patients, the time for the participating members of the study team, and implications for patient attrition, study cost, and timing demand an alternative approach. The most rigorously tested alternatives have involved various approaches to semistructured interview, record retrieval, and formal documentation of retrospective treatment.

The most promising, and the only prospectively validated approach, used in the literature is the Antidepressant Treatment History Form (ATHF).25,26 This scheme involves an organized method of staging resistance to recognized somatic treatments based on dose and duration, accompanied by objective verification of historical report and categorical appraisal of clinical outcome to treatment. Although this latter approach is a considerable improvement over gross historical report as used in most of the existing clinical studies of rTMS, there are still considerable problems in the definition of treatment resistance. For example, even with the ATHF methodology, while a detailed appraisal of the resistance “floor” is relatively easy to obtain (ie, the number of failed or intolerant trials in the current or most recent episode), it is extremely difficult to establish the precise location of the resistance “ceiling.” This latter clinical attribute is an important contributor to constraining treatment response overall, making it harder to demonstrate a positive effect when actually present (ie, producing an unacceptably high number of false negatives).

The vast majority of rTMS studies for the treatment of major depression have been designed as 2-week endpoint studies, using a “per session” study design model rather than an “interval of treatment exposure” model in their conceptual starting point. The former approach is reminiscent of the study design and treatment context for the use of ECT. This approach was used because ECT carries with it such poor tolerability, a high degree of medical complexity and service utilization, and potential toxicity with prolonged treatment exposure. Thus, it is understandable that the goal would be aimed at optimizing treatment outcome at the earliest time with the minimal dose needed.

In contrast, the “interval of treatment exposure” approach is the preferred design strategy in the clinical development of pharmaceuticals - that is, assuring an adequate dose and duration of exposure to the treatment of interest and recognizing that in virtually all instances, acute efficacy accumulates with treatment duration. Typically, this necessitates a minimum of 6 weeks of acute treatment to optimally describe a valid signal.

As a novel potential treatment, rTMS shares some similarity to both of these existing approaches. However, its major advance from the perspective of device-based interventions is its promise to provide a significant degree of improvement in clinical tolerability and safety over ECT, the only other device-based intervention available. In fact, rTMS allows the first opportunity with a device to explore beyond the limitations of the “per-treatment” model and more flexibly explore response across a standard duration of antidepressant treatment, hence establishing a more accurate appraisal of the full clinical potential of this acute treatment intervention. Considered from this vantage point, it is all the more remarkable that an efficacy signal from rTMS treatment has been observed in prior work, since these study designs are not dissimilar from a hypothetical study proposing to examine an initial dose of a drug treatment and then attempting to draw a definitive conclusion regarding efficacy after only 2 weeks of drug exposure.

Two additional intrinsic features of a device-based intervention such as rTMS introduce other important contextual factors that have implications for study design and implementation, compared with the standard pharmaceutical development model. These include the approach to maintaining the study blind and the visit frequency mandated based on current understanding of effective clinical dosing with rTMS. Until recently, the standard method of blinding in clinical study designs for rTMS has essentially been a single-blind model, with the use of fully blinded clinical raters who remain independent from the treatment session itself. This has been done because technical limitations necessitated the use of a placebo procedure created simply by physically orienting the magnetic coil to direct most of the magnetic field external to the head (ie, a 45- or 90-degree tilt tangential to the head).27 As remarkable as it might seem, where adequacy of the clinical blind has been queried, there is little evidence that a treatment-naïve subject can differentiate active from placebo treatment delivered in this manner.28,29 On the other hand, criticism has been directed at the conclusions that can be drawn from this preliminary work because of this issue.

Recent innovations now permit an enhancement of the study blind through the development of coils that do not demand physical reorientation for placebo treatment, and therefore improve the potential for the treater to remain blinded. Nevertheless, because of the potential for the differing magnetic field shapes under active and placebo conditions to produce observable differences in cutaneous sensation and scalp muscle artifact, it is considered standard to maintain a clear differentiation of treater staff from rater staff in any well-designed clinical study.

Regarding the frequency of treatment in assessment of acute efficacy, the best understanding of the dosing schedule for rTMS suggests that optimization of acute response may be achieved with daily dosing during an acute phase trial. The consequences from a study design perspective are that this increases the overall clinical contact time, and hence enhances the potential risk for non-specific treatment effects to inflate both the treatment and the placebo responses. A standard approach that limits the nonessential treater-subject interaction and formally scripts allowable procedures during the treatment session is highly recommended.

Given these considerations, a final mention should be made of the critical importance of other general standards of study implementation such as a standardized program of efficacy rater performance monitoring.30 Furthermore, unique to a study of a device-based treatment intervention, there is an additional need for the development of a set of standardized training materials accompanied by a formalized didactic program and practical follow-up schedule of on-site visits to ensure adequacy and reproducibility of device administration.

The last issue for study design concerns both the choice of outcome measures and the proper characterization of efficacy and safety. What are the most appropriate measures and methods for declaring efficacy and identifying safety for the study of rTMS? With regard to efficacy outcome, the literature to date has relied primarily upon assessment of symptom change using the Hamilton Depression Rating Scale (HDRS). A long history of tradition and methodologic query has continually returned to the use of this scale in depression research31 and, more recently, the Montgomery-Asberg Depression Rating Scale (MADRS).32 It is also a notable peculiarity of the published efficacy studies of rTMS in depression that few have summarized the results of these measures in the most standard method of report, using as a primary outcome the change in total score as a continuous measure and as a key secondary outcome the percentage of subjects who achieve a categorical score above the standard thresholds of response (ie, greater than 50% reduction in baseline score), or remission (eg, with the 17-item HDRS, most commonly quantified as a score less than 8).

It is of interest that almost no studies have reported on the pattern of individual item change on these scales, nor have they reported the outcome results on the standard repertoire of symptom subscales for either the HDRS or the MADRS. This is unfortunate, as a key question remaining to be addressed is whether these scales, developed primarily for the assessment of pharmaceutical efficacy, are the most appropriate and sensitive measures of clinical change to study a novel intervention such as rTMS. Similarly, with regard to safety, in the few instances where the methodology is described in any specific detail, formal assessment has been concerned with targeted areas of interest such as cognitive function or potential changes in auditory threshold. Future studies should combine these targeted domain approaches with a broader based assessment of spontaneous adverse event reporting.

Although it is beyond the scope of this article, the available published studies have employed a variety of different device forms, with accordingly different types of manufacturing and performance specifications. Future studies should comprehensively detail the known performance characteristics of the specific machine employed, and any modifications in construction or method of use from the parent product design.

Summary

The design of a clinical development program for a novel antidepressant intervention such as rTMS must build upon the established methodology employed in the general evaluation of any antidepressant treatment. At the same time, there is a need to attend to the specific contextual differences associated with this unique form of treatment. In some instances, these contextual differences require new design modifications or the provision for subsequent analysis of the chosen interventions to determine their adequacy of performance as implemented in the study itself. Given these considerations, a general model for clinical development of these novel treatment interventions can be proposed and is summarized in the Table (see page 127). The key design features that should be considered are outlined in the left column, and a preferred set of recommendations for each are shown in the right column.

General Recommendations for a Clinical Development Plan for rTMS Studies

Table.

General Recommendations for a Clinical Development Plan for rTMS Studies

Based on the long legacy of work for pharmaceutical interventions to treat major depression, we are in possession of a considerable array of tools that can help clarify questions about the manner and degree of efficacy seen with novel interventions such as rTMS. However, we should not lose sight of the fact that these new interventions bring with them new methodological questions which must be critically appraised in concert with the efficacy and safety results themselves to refine our skills and capabilities for future clinical development work.

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General Recommendations for a Clinical Development Plan for rTMS Studies

Issue Recommended approaches
Diagnostic assessment <list-item>

Use of a structured interview (eg, Structured Clinical Interview for DSM-IV-TR)

</list-item>
<list-item>

Clarification of allowable comorbidities

</list-item>
Definition of treatment resistance <list-item>

Retrospective interview (eg, ATHF)

</list-item><list-item>

Specify method of support documentation required

</list-item>
Efficacy measures <list-item>

Disease-specific measure (eg, HAMD, MADRS)

</list-item><list-item>

Primary outcome continuous variable preferred

</list-item><list-item>

Secondary outcomes should include categorical measures(eg, response, remission) and key rating subscales (eg, HAMD Core, Sleep, Anxiety factors

</list-item><list-item>

Patient-rated outcome (eg, PGI, IDS-SR)

</list-item>
Functional outcome measures <list-item>

Quality of life (eg, Q-LES-Q)

</list-item><list-item>

General functional status (eg, Sheehan Disability Scale, MOS SF-20, MOS SF-36)

</list-item>
Health care system effects <list-item>

Employment or equivalent status

</list-item><list-item>

Resource utilization (at least baseline assessment)

</list-item>
Safety assessment <list-item>

True spontaneous adverse event collection

</list-item><list-item>

Targeted safety assessment for relevant considerations (eg, cognitive function)

</list-item>

Sidebar.

Questions to Consider in Planning Clinical Development Strategy

  • What is the intended use of the device in clinical practice?
  • How will the study population be defined?
  • How will treatment resistance be determined?
  • What are the critical features of the study design?
    • Dose (ie, stimulation parameters)?

    • Method of blinding?

    • Visit frequency?

    • Duration of treatment?

    • Entry and exit phases?

    • Extension studies?

    • Training methods (for rating, for device itself)?

  • How will outcome be defined in terms of:
    • Symptoms?

    • Functional status?

    • Economic effects/benefits?

  • What method of safety assessment will be used?
  • What will be the potential conclusions of the study? Will they provide meaningful information for future work?

Questions to Consider in Planning Clinical Development Strategy

Educational Objectives

  1. Discuss advantages and drawbacks of the therapeutic armamentarium for the treatment of major depression and the relevance of the emerging platform of brain stimulation therapeutics.

  2. Explain methodological challenges in the study of repetitive transcranial magnetic stimulation (rTMS).

  3. Describe a framework for the design of a clinical development program to evaluate the efficacy of rTMS.

Authors

Dr. Demitrack is vice president and chief medical officer, Neuronetics Inc., Malvern, PA.

Address reprint requests to: Mark A. Demitrack, MD, Neuronetics Inc., One Great Valley Parkway, Suite 2, Malvern, PA 19355; or e-mail mdemitrack@neuronetics.com.

Dr. Demitrack serves as a consultant for Bristol-Myers Squibb.

10.3928/00485713-20050201-04

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