Repetitive transcranial magnetic stimulation (rTMS), defined as the administration of a series of magnetic stimuli to the brain for the purpose of altering brain function, is an experimental medical intervention. rTMS currently is used to probe various aspects of brain function in the context of research studies approved by local ethics committees. rTMS also is under investigation as a potential treatment for various neurologic and psychiatric disorders. In light of the growing interest in using rTMS in a variety of experimental and therapeutic settings, the International Society for Transcranial Stimulation has recognized the need to formulate a consensus statement to assist the field in developing guidelines for its safe application. Whether the intended use is experimental or therapeutic, certain principles regarding the safety of rTMS apply. This statement is not aimed at guiding the therapeutic use of rTMS in any given condition or its application in any research paradigm, but rather is meant to apply broadly wherever rTMS is used.

rTMS has significant risks, most importantly that of producing epileptic seizures. The degree of risk varies with the dosing parameters and individual subject factors. Therefore, rTMS should be administered only under a licensed physician's orders (ie, by prescription or through some other mechanism that makes a physician directly responsible for its administration to the individual patient or research subject). Because rTMS has potential behavior-changing effects, undesirable side effects, and therapeutic impact, careful assessment of the risk and appropriateness of rTMS in each clinical or scientific context is critical and can only be made by, or in consultation with, a physician knowledgeable and experienced in the use of rTMS and fully trained in neurology, psychiatry, or another appropriate specialty.

One of the key messages of the Sequenced Treatment Alternatives to Relieve Depression study was that only one third of patients with a diagnosis of major depressive disorder (MDD) achieve remission after the first treatment with an antidepressant. Management of most patients after one or more failed trials moves beyond the currently available evidence base and therefore represents a significant clinical challenge. Over the course of the four treatment steps, the cumulative remission rate was 67% and remission was more likely to occur during the first two treatment levels (20% to 30%) rather than during levels 3 and 4 (10% to 20%). These finding suggest that after two consecutive unsuccessful antidepressant trials a change in pharmacologic mode of action has a low probability to affect the likelihood of remission from MDD. The switch to a third antidepressant treatment resulted in an even lower remission rate than the one achieved in the first two levels. Furthermore, the discontinuation rates due to treatment intolerance was shown to rise across sequenced levels. At this point, the search for effective and tolerable alternative options to pharmacotherapy is essential.

New findings regarding the mechanisms of action of electroconvulsive therapy (ECT) have led to novel developments in treatment technique to further improve this highly effective treatment for major depression. These new approaches include novel electrode placements, optimization of electrical stimulus parameters, and new methods for inducing more targeted seizures (eg, magnetic seizure therapy [MST]). MST is the use of transcranial magnetic stimulation to induce a seizure. Magnetic fields pass through tissue unimpeded, providing more control over the site and extent of stimulation than can be achieved with ECT. This enhanced control represents a means of focusing the treatment on target cortical structures thought to be essential to antidepressant response and reducing spread to medial temporal regions implicated in the cognitive side effects of ECT. MST is at an early stage of development. Preliminary results suggest that MST may have some advantages over ECT in terms of subjective side effects and acute cognitive functioning. Studies designed to address the antidepressant efficacy of MST are underway. As with all attempts to improve convulsive therapy technique, the clinical value of MST will need to be established through controlled clinical trials. This article reviews the experience to date with MST, and places this work in the broader context of other means of optimizing convulsive therapy in the treatment of depression.

The latest and most generative biological theories of major depression center on two major hypotheses. The first focuses on the concept that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis leads to many of the pathological changes in the brain that accompany major depression. The second posits that neurogenesis leads to the repair of depression-related injuries. These two hypotheses are complementary: the former alludes to the etiology or consequences of depression, while the latter suggests mechanisms of antidepressant action. Significant crosstalk occurs between these two systems at many levels. Protein kinase A (PKA) may play an important role in this crosstalk at the intracellular level of signaling cascades. PKA is involved in the formation of long-term potentiation and fear conditioning in response to stress. Chronic stress leads to the suppression of hippocampal activity, which may cause the hyperactivity of the HPA axis during melancholic depression. PKA is also involved in the stimulation of hippocampal neurogenesis after antidepressant treatment. In theory, neurogenesis may lead to the restoration of hippocampal function, and this may be the mechanism that leads to antidepressant-mediated normalization of HPA hyperactivity. Thus, PKA is active during processes that potentially lead to depression and other processes that lead to the resolution of the illness. These opposing processes may be mediated by separate PKA isozymes that activate two distinct pathways. This review highlights the dual role of this enzyme in two biological hypotheses pertaining to depression and its treatment.

BRAIN STIMULATION IN THE TREATMENT OF MAJOR DEPRESSION

Repetitive transcranial magnetic stimulation (rTMS) is an experimental medical procedure that is currently under investigation for its potential therapeutic value in major depression and other psychiatric and neurological disorders (Wassermann & Lisanby, 2001). The idea of using brain stimulation to treat depression dates back to the origins of ECT, and includes more recently developed techniques such as deep brain stimulation and vagus nerve stimulation. The value of brain stimulation in psychiatry is still most clearly seen in the, as yet, unparalleled efficacy of ECT in treating severe depression (American Psychiatric Association, 2001). While ECT is the most effective and most rapidly acting treatment for depression, it also causes a variable degree of undesirable cognitive side effects that limit its clinical utility and prevent many patients who could benefit from receiving this often life-saving treatment (McElhiney et al. 1995; Lisanby et al. 2000b). The search for an effective somatic treatment for medication resistant depression with fewer cognitive side effects than ECT has motivated much of the work with rTMS in psychiatry.