MAGNETS - NOT DRUGS - Cady on TMS at Deaconess Grand Rounds 5 1 2012

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This is the Grand Rounds presentation given by Dr. Cady at Deaconess Hospital, downtown campus, in Evansville, IN on May 1 2012 on the subject of TMS (transcranial magnetic stimulation). Cady …

This is the Grand Rounds presentation given by Dr. Cady at Deaconess Hospital, downtown campus, in Evansville, IN on May 1 2012 on the subject of TMS (transcranial magnetic stimulation). Cady Wellness Institute is the only provider of TMS services to the TriState area within a 90 mile radius.

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  • Giuseppe Mazzini (22 June 1805 – 10 March 1872), nicknamed "Soul of Italy,"[1] was an Italian politician, journalist and activist for the unification of Italy. His efforts helped bring about the independent and unified Italy[2] in place of the several separate states, many dominated by foreign powers, that existed until the 19th century. He also helped define the modern European movement for popular democracy in a republican state. [ citation needed ] – Source - Wikipedia
  • Hello. My name is Dr._____________, and I am pleased to have the opportunity to speak with you today about the role of TMS Therapy in the treatment of patients in with major depression.   In this presentation, I will cover three major areas:   First, I will describe the current landscape of treatment options for major depression, with a particular focus on the concept of treatment resistance. I will also review the most recent Practice Guidelines for the Treatment of Patients with Major Depressive Disorder that have been promulgated by the American Psychiatric Association, highlighting their conclusions regarding the role of TMS in clinical practice.   Second, I will describe the science behind TMS, explaining what it is and how it is thought to exert its effects as an antidepressant. I will also review the most recent clinical trial evidence for its efficacy and safety.   Third and finally, I will conclude by placing this data in context by specifically describing the role of TMS in the treatment of patients with major depression who have not benefited from initial treatment with antidepressant medications.   At the end of this presentation, we will have time for any questions that you may have.
  • First, let ’s talk about the current landscape of treatment options for major depression.
  • As demonstrated by this chart, psychiatric disorders are prevalent. 1-3 These data are from the National Comorbidity Survey (NCS) and the DSM-IV-TR ™ . The NCS is a collaborative epidemiologic investigation based on household survey data of over 8000 respondents from 1990 to 1992. 4
  • This slide depicts the changing conception of depression and anxiety, and their drug treatments, over the last 40 years. In the 1960s, there was a clear diagnostic distinction between major depressive disorder and GAD, paralleling the drug classification distinction between the antidepressants (eg, TCAs) and the anxiolytics (eg, benzodiazepines). During the 1970s and 1980s, some antidepressants were found to be effective in treating comorbid anxiety and depression, while some TCAs were found to be effective in treating some anxiety disorder subtypes. By the 1990s, SSRIs were the first line treatment for some anxiety disorder subtypes as well as effective antidepressants, while benzodiazepines became second-line or augmentation treatments for anxiety disorder subtypes. As illustrated above, a significant degree of diagnostic and therapeutic overlap is now recognized among depression, GAD, and anxiety disorder subtypes. Recently, venlafaxine XR became the first agent to be approved to treat both depression and GAD; positive nefazadone, mirtazapine, and paroxetine results will be discussed in upcoming slides. Boerner RJ, Moller HJ. The importance of new antidepressants in the treatment of anxiety/depressive disorders. Pharmacopsychiat . 1999; 31: 119-126.
  • In addition to utilizing services related to their depression, patients also tend to be high utilizers of general medical care services. It has been shown that depressed patients utilize all types of healthcare services more often than nondepressed patients and incur overall healthcare costs 1 ½ to 2 times higher than the average nondepressed patient. 27,28 It has also been demonstrated that depressed individuals were hospitalized longer and had significant worsening of physical, social, and role functioning, compared with nondepressed individuals. 28-30
  • The PHQ-9 symptom checklist asks the patients in a self-report format, “ Over the last 2 weeks, how often have you been bothered by the: following problems? Little interest or pleasure in doing things; feeling down, depressed or hopeless; trouble falling or staying asleep or sleeping too much; feeling tired or having little energy; poor appetite or overeating; feeling bad about yourself or that you are a failure; trouble concentrating on things; moving or speaking slowly; thoughts that you might be better off dead. ” These are all depression DSM-IV-TR items. Patients can score for themselves how often they have experienced these individual symptoms. 37
  • Depression can strike anyone at any age, but on average it begins in the late 20s. Depressive illness is a highly prevalent disorder associated with substantial morbidity and mortality. According to the World Health Organization, major depression is the leading cause of disability in the U.S. and worldwide. The annual costs associated with depression (both direct and indirect) in the U.S. were estimated to be $43.7 billion in 1990. Epidemiologic studies suggest that in any 30-day period, 2 to 5 percent of the U.S. population meet criteria for major depression. The lifetime probability of experiencing a major depressive episode has been estimated to be as high as 17 percent. Nearly twice as many women (21%) as men (13%) are affected by a depressive disorder during their lifetimes. References 1. Murray CJL, Lopez AD, eds. Summary: The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge, MA: Published by the Harvard School of Public Health on behalf of the World Health Organization and the World Bank, Harvard University Press; 1996. 2. Regier DA, Boyd JH, Burke JD Jr, Rae DS, Myers JK, Kramer M, Robins LN, George LK, Karno M, Locke BZ. One-month prevalence of mental disorders in the United States: based on five Epidemiologic Catchment Area sites. Arch Gen Psychiatry. 1988; 45:977-986. 3. Blazer DG, Kessler RC, McGonagle KA, Swartz MS. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry . 1994;151:979-986. 4. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry. 1993;50(2):85-94. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29:85-96. Greenberg PE, Stiglin LE, Finkelstein SN, Berndt ER. The economic burden of depression in 1990. J Clin Psychiatry . 1993;54:405-418.
  • Let’s take a closer look at the evidence generated in the STAR*D Study. The design of this study involved four treatment Levels. These Levels were pre-specified by expert consensus, and were intended to reflect the general approach taken in clinical practice at the time STAR*D was constructed, which was about 10 years ago.   Patients treated in STAR*D were either first episode patients, or treatment-responsive patients. To get into the study, the patient could not have previously been treated with and failed to benefit from any of the options offered in either Level 1 or 2. Patients were recruited from both primary care and specialty psychiatric treatment settings in the United States. About 4,000 patients entered into this study.   The first Level results showed that in response to an adequate course of treatment with an SSRI (in this study, citalopram was the option used) only about 28% of patients were able to achieve remission as measured using the 17 Item Hamilton Depression Rating Scale.   At Level 2, the results are shown for those patients who were offered a switch to another antidepressant of the same or a different class (these options included sertraline, bupropion SR, or venlafaxine SR). You can already observe the drop in likelihood of remission, here at about 21% after failure of only one prior adequate antidepressant treatment.   At Level 3, the switch options offered were either mirtazapine or Nortriptyline, and again the remission likelihood degrades further.   Finally, at Level 4, the switch option offered was the MAOI tranylcypromine. Here the likelihood of remission after failure of three prior adequate treatments was 6.9%.   References : Fava, M., A. J. Rush, et al. (2006). "A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A Star*D Report." Am J Psychiatry 163 (7): 1161-1172. McGrath, P. J., J. W. Stewart, et al. (2006). "Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report." Am J Psychiatry 163 (9): 1531-1541. Nierenberg, A. A., M. Fava, et al. (2006). "A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report." Am J Psychiatry 163 (9): 1519-1530. Rush, A. J. (2007). "STAR*D: What have we learned?" Am J Psychiatry 164 (2): 201-204. Rush, A. J., M. H. Trivedi, et al. (2006). "Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report." Am J Psychiatry 163 (11): 1905-1917. Trivedi, M. H., M. Fava, et al. (2006). "Medication Augmentation after the Failure of SSRIs for Depression." New England Journal of Medicine 354 (12): 1243-1252. Trivedi, M. H., A. J. Rush, et al. (2006). "Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D Implications for Clinical Practice." Am J Psychiatry 163 (1): 28-40.
  • What about antidepressant tolerability and treatment adherence? A close look at the reported results of STAR*D reveals some important findings.   We have learned from the STAR*D Study, that the likelihood of a patient dropping out of treatment because of side effects rises dramatically, nearly tripling in the transition from Level 1 ( about 9% ) to Level 2 ( about 23% ). By the time a patient had failed to benefit from three prior treatment attempts, the likelihood of their discontinuing due to adverse events from the next offered antidepressant monotherapy (in this case the MAOI tranylcypromine), was quite notable: slightly greater than 41% .   There are many reasons why the intolerance to treatment rises with progressive levels of treatment resistance, and a full consideration of this is beyond the scope of this presentation. In general, this finding is both a reflection of how physically uncomfortable depression is as a disease, as well as the fact that each next treatment offering in this study brought the potential for an even greater degree of uncomfortable adverse events.   Shown on the right side of this diagram is a list of those adverse events reported in product labels for all contemporary antidepressant medications, including the augmentation agents such as the atypical antipsychotics. The list specifically shows those adverse events that in each product’s labeling were observed to occur at an incidence of at least 5% in the antidepressant-treated group, and occurred at a rate at least twice as high as the incidence of that event reported in the placebo group.   References : Fava, M., A. J. Rush, et al. (2006). "A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A Star*D Report." Am J Psychiatry 163 (7): 1161-1172. McGrath, P. J., J. W. Stewart, et al. (2006). "Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report." Am J Psychiatry 163 (9): 1531-1541. Nierenberg, A. A., M. Fava, et al. (2006). "A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report." Am J Psychiatry 163 (9): 1519-1530. Rush, A. J. (2007). "STAR*D: What have we learned?" Am J Psychiatry 164 (2): 201-204. Rush, A. J., M. H. Trivedi, et al. (2006). "Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report." Am J Psychiatry 163 (11): 1905-1917. Trivedi, M. H., M. Fava, et al. (2006). "Medication Augmentation after the Failure of SSRIs for Depression." New England Journal of Medicine 354 (12): 1243-1252. Trivedi, M. H., A. J. Rush, et al. (2006). "Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D Implications for Clinical Practice." Am J Psychiatry 163 (1): 28-40. Product Labeling for currently marketed antidepressants (Neuronetics, Inc., data on file)
  • I ’ d like to expand a bit on the problem of antidepressant treatment adherence. As indicated on the previous slide, as a patient shows increasing levels of treatment resistance, the likelihood that they will keep taking the prescribed treatment also begins to decline. In fact, the occurrence of intolerable adverse events, and discontinuation of patient adherence to the treatment regimen, can become a major challenge in clinical management when treatment resistance worsens.   The iceberg image on this slide portrays the nature of the problem. Clearly, getting to a defined and effective acute treatment (the tip of the iceberg) is the goal: effective treatment with the prescribed antidepressant at an adequate dose for an adequate length of time.   Unfortunately, for the majority of patients, this does not occur, and is an especially significant challenge for the patient with a treatment resistant form of depression.   Below the water line, are shown some of the potential factors that can confound achieving the goal of treatment adequacy.   When looked at in rigorous research studies, adequate antidepressant treatment occurs in the minority of patients. Typically, only one in every four antidepressant treatments is able to achieve the ‘’ tip of the iceberg ’’ due to lack of efficacy, intolerance and other factors as shown here   An effective and, most important, a tolerable treatment option is a critical goal in the setting of treatment resistance .   References  : Nemeroff CB. Depress Anxiety . 1996/1997;4(4):169-181 Oquendo MA, A, et al. J Clin Psychiatry . 2003;64(7):825-833 Oquendo MA, et. al. Am J Psychiatry . 1999;156(2):190-194 Prudic J, et. al. Psychol Med . 2001;31(5):929-934. Osterberg, L, et. al., NEJM , 2009 ; 353 5): 487-497
  • In 2010, the American Psychiatric Association updated their Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, now in its 3 rd Edition.   This slide depicts the general conclusions in that document for the next treatment steps in patients who have failed initial acute phase antidepressant medication. There are several points that I would like to comment on:   As I mentioned above, the APA notes the progressive sequence of steps along the bottom as the next choice for antidepressant medications. As you can see, these options include both medication switches within and across pharmacologic classes, as well as augmentation options. While these options have some scientific evidence base for their support, very few have actually withstood FDA scrutiny in large, multisite, randomized controlled trials. The few that have been studied in this manner and are approved for use in treatment resistant depression are the atypical antipsychotic medications, as augmentation agents. As is also noted in this diagram and as you are well aware, each medication trial can take up to 2 months to clearly understand its potential benefits. Finally, in many instances, ongoing treatment may involve continuation of multiple antidepressant medications.   TMS is now included as an accepted treatment option for patients who have failed to benefit from first line treatment attempts. As we will discuss later in this presentation, placing TMS at this earlier stage in treatment planning is consistent with the strength of the clinical trial evidence that led to the FDA clearance of the NeuroStar TMS Therapy system device. The NeuroStar TMS system is current the only TMS device in the US which has been cleared by the FDA for use in the treatment of major depression.   A treatment course of TMS, as recommended in product labeling, is usually 4 to 6 weeks in duration, and when effective, has been safely followed by a course of a single antidepressant medication.   References : American Psychiatric Association (2010) (eds: Gelenberg, AJ, Freeman, MP, Markowitz, JC, Rosenbaum, JF, Thase, ME, Trivedi, MH, Van Rhoads, RS). Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, 3 rd Edition.
  • As I noted previously, TMS is now incorporated as an accepted treatment option for patients who have failed to benefit from initial antidepressant medication treatment for their illness.   This is reflected in a growing body of published consensus. I mentioned earlier the recent publication of the APA Practice Guidelines, and you can read the quote from the Executive Summary of that document on this slide.   Several other organizations have also acknowledged the scientific evidence for the safety and efficacy of TMS, including the World Federation of Societies for Biological Psychiatry (2009), and the Canadian Network for Mood and Anxiety Treatments (CANMAT, 2009).   References : American Psychiatric Association (2010) (eds: Gelenberg, AJ, Freeman, MP, Markowitz, JC, Rosenbaum, JF, Thase, ME, Trivedi, MH, Van Rhoads, RS). Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, 3 rd Edition. Kennedy, SH, Milev, R, Giacobbe, P, Ramasubbu, R, Lam, RW, Parikh, SV, Patten, SB, Ravindran, AV. (2009) Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. IV. Neurostimulation therapies. J Aff Disorders 117:S44-S53. Schlaepfer, TE, George, MS, Mayberg, H. (2009) WFSBP Guidelines on Brain Stimulation Treatments in Psychiatry. World J Biol Psychiatry Aug 26:1-7.
  • In the following section of my talk, I ’d like to discuss TMS in more detail. I will review its mechanism of action, and then discuss some of the most recent randomized clinical trial evidence supporting its efficacy and safety. I will also discuss recent outcomes in real-world practice settings obtained from an ongoing large, prospective outcomes study.
  • Capacitors of the day did not permit high intensity or rapid frequency use. The “ phosphenes ” were either generate from effects on the occipital cortex or directly on the retina of the eye. 1959 – Kolin et al – first to demonstrate magnetic field could stimulation a peripheral frog muscle preparation.
  • The underlying rationale for the use of TMS exploits the fact that neurons are electrochemical cells. This means that neuronal activity can be affected either chemically, via the use of drugs, or electrically, via interventions like TMS.   Unlike drug action, whose effects tend to be anatomically diffuse, the effects of TMS are anatomically focused, and by design are non-invasive and non-systemic in action. Under normal conditions of use, TMS therefore incurs far fewer adverse events, and is devoid of undesired systemic adverse events commonly observed with antidepressant medications. The TMS device is a powerful electromagnet, which is turned on and off in a rapid fashion, producing a pattern of “pulsed” magnetic fields. When pulsed magnetic fields are positioned close to an electrical conductor, like neurons, a local electrical current is produced in that conductor. This electric current is powerful enough right under the magnetic coil to elicit action potentials, which then travel down the neuron, ultimately causing the release of neurotransmitters at the synapse (Post 2001, p. 193A) . References : Post A, Keck ME. Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms? J Psychiatric Research. 2001;35: 193-215.
  • When the pulsed magnetic fields from the TMS coil are applied to the left dorsolateral prefrontal cortex, there are a series of events that are thought to underlie the therapeutic effects of TMS in the treatment of major depression: First, direct neuronal depolarization under the coil leads to local action potentials in neurons and the local release of neurotransmitters in the cortex. In addition to these local effects, neuronal depolarization of cortical pyramidal neurons is thought to occur (as represented by the blue neural pathway), reaching to deeper brain regions that lie outside the direct action of the pulsed magnetic fields. Activation of these deeper brain regions is then presumed to lead to secondary activation of brainstem neurotransmitter centers, which are then presumed to result in upward influences on the remaining brain regions involved in mood regulation (represented by the purple neural pathway). As a result, dopamine (Kanno 2004, pp. 75A, 76A, 77A) and serotonin (Juckel 1999, pp. 393A, 394A) activity are increased in areas of the brain whose low neurotransmitter activity have been linked to depression. The activity may be increased both in the short term by increasing release of neurotransmitters and in the long term by modulating expression of proteins involved in neurotransmitters signaling (Post 2001, p. 200A,B). Presumably, as a result of these changes, depression lifts (Slotema 2010, p. 876A). The net action of TMS is therefore targeted on the specific brain areas known to be involved in the regulation of mood, and is comprehensive in that its action has both direct effects on local neurons in the cerebral cortex, and then results in deeper actions on brain regions that are distant from the site of stimulation, but neurally connected to these cortical areas. These effects can be demonstrated in human neuroimaging studies of patients who have undergone treatment with TMS for their depression, as shown in the SPECT (single photon emission computed tomography) scan on the right (Kito, et al, 2008). In this image, the TMS coil has been positioned over the dorsolateral prefrontal cortex on the left side of the head. The area just underneath the coil is showing increased metabolic activity as a direct result of the magnetic stimulation. You can also see that the increase in metabolism reaches secondarily the deeper brain regions, in this case the regions of the cingulate cortex also show increased activation. References : Kanno M, Matsumoto M, et al. Effects of acute repetitive transcranial magnetic stimulation on dopamine release in rat dorsolateral striatum. J Neurological Sciences. 2004;217:73-81. Juckel G, Mendlin MA, et al. Electrical Stimulation of Rat Medial Prefrontal Cortex Enhances Forebrain Serotonin Output: Implications for Electroconvulsive Therapy and Transcranial Magnetic Stimulation in Depression. Neuropsychopharmacology. 1999;21(3):391-398. Slotema CW, Blom JD, et al. Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry. 2010;71(7):873-884. Kito, S, Fujita, K, Koga, Y. Changes in Regional Cerebral Blood Flow After Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Treatment-Resistant Depression . J Neuropsychiatry Clin Neurosci. 2008; 20(1):74-80.
  • The NeuroStar TMS Therapy system is the only FDA-cleared TMS device for the treatment of adult patients with major depression who have failed to benefit from initial treatment.   In clinical practice, TMS Therapy is:   An outpatient procedure, It is non-invasive and non-systemic in action, Shows a safety profile of few side effects, Is typically performed in an outpatient setting, without need for sedation or anesthesia, A standard treatment session is 37 minutes long, and a treatment course consists of daily (5 days per week) treatments for 4 to 6 weeks, A physician or other clinical professional is in attendance during the treatment session, which facilitates adherence with the prescribed treatment   References : NeuroStar TMS Therapy System User Manual. Neuronetics, Inc: Malvern, PA; 2008.
  • This slide describes some of the major demographic and clinical characteristics of the patients studied in the registration clinical trials that led to FDA clearance for the NeuroStar TMS Therapy system.   All patients had a diagnosis of unipolar, non-psychotic major depression, with moderate to severe symptoms at entry to the study. About a third of all patients had a concurrent secondary diagnosis of an anxiety disorder.   All patients received a rigorous characterization of their antidepressant medication treatment history in the current illness episode. Most patients had received numerous medication treatment attempts, with one of these treatment attempts being administered at an adequate daily dose and for at least four weeks without clinical benefit. The average number of overall treatment attempts (which includes all antidepressant medications administered in the current episode, regardless of whether they reached an adequate dose and duration) was 4, with a range across the study population from 1 to as many as 23 treatment attempts.   Consistent with the data that I reviewed earlier in this presentation, about 75% of the time, these antidepressant treatment attempts were unable to achieve this minimum level of exposure adequacy (usually because of treatment intolerance, or failure to adhere to the recommended treatment regimen).   References : Demitrack, MA , Thase, ME,. (2009) Clinical significance of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant depression: synthesis of recent data. Psychopharm Bulletin 42(2) :5-38
  • Subsequent to the FDA clearance of the NeuroStar TMS system, the second-largest, randomized, sham-controlled clinical trial examining the safety and efficacy of TMS in major depression has now been reported.   This study has been referred to as the Optimization of TMS Study, or ‘OPT-TMS’ by its investigators. It is a very important study for several reasons:   It was conducted independent of industry, and was funded and sponsored by the NIMH, It studied patients similar in inclusion and exclusion criteria to those studied in the Neuronetics trial, It used the same device as was used in the Neuronetics trial, the NeuroStar TMS Therapy System, It incorporated several additional innovations, including the use of an active sham condition to address questions of adequacy of the study blind in TMS trials, and The results were published in the Archives of General Psychiatry.   The main results of this study confirmed the observations of the earlier Neuronetics trial, and showed a statistically and clinically significant outcome on the primary efficacy measure of remission.   For those patients on sham treatment who did not improve, an open-label extension study was also offered. In that open-label extension, about 30% of patients were able to achieve remission after treatment with TMS.   This study also confirmed the safety and tolerability of TMS Therapy observed in prior studies, with a similar adverse event profile and with nearly 90% of patients fully adherent to the prescribed acute phase treatment course.   References : George, MS, Lisanby, SH, Avery, D, McDonald, WM, Durkalski, V, Pavlicova, M, Anderson, B, Nahas, Z, Bulow, P, Zarkowski, P, Holtzheimer, P, Schwartz, T, Sackeim, HA. (2010) Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial. Archives of General Psychiatry 67(5) :507-516
  • The published scientific evidence supporting the antidepressant effect of TMS is substantial, and now spans nearly twenty years of scientific research, involving more than 30 published studies, and over 2000 patients.   There are twelve published meta-analyses or qualitative reviews of this research. The most recent and comprehensive of these was reported by Slotema and colleagues last year. They analyzed the results of 34 studies involving 1,383 patients. They computed an effect size of 0.55 (P < 0.001), which represents a moderate to large clinical effect of TMS in the treatment of depression.   In their conclusion, they noted that “…rTMS deserves a place in the standard toolbox of psychiatric treatment methods, as it is effective for depression…and has a mild side effect profile…”.   References: Slotema, CW, Blom, JD, Hoek, HW, Sommer, IEC. (2010) Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A Meta-analysis of the efficacy of rTMS in psychiatric disorders. Journal of Clinical Psychiatry 71(7) :873-84. Schutter, DJLG. (2009) Antidepressant Efficacy of High-Frequency Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex in Double-Blind Sham-Controlled Designs: A Meta-Analysis. Psychol Medicine , 39 :65-75.
  • All of the research I have reviewed to this point was obtained prior to the introduction of NeuroStar TMS Therapy into routine clinical practice. In the following slides, I would like to describe the results of an ongoing research study that is designed to characterize the outcomes of TMS in real world clinical practice settings.
  • The goal of this study was to define real-world outcomes associated with NeuroStar TMS Therapy across a broad spectrum of patients and practitioners as well as to follow patient outcomes for one-year after TMS treatment. This study involves 307 unipolar non-psychotic major depressive disorder patients enrolled within the acute phase. The study enrolled patients at 42 sites, comprised of both institutions and private practices with the vast majority being private practices. The study is currently on-going with the duration ultimately lasting two years. We recently closed the acute phase of the study during which enrolled patients received a full course of acute treatment of NeuroStar TMS Therapy as determined by their treating psychiatrist. Following the acute TMS treatment course, patient outcomes are being measured and followed for twelve months. The patient treatments during the follow-up period consisted of clinical care as usual with six clinical assessments made at seven time points. References : Neuronetics, Inc., data on file.
  • Among the 307 patients,   About two thirds were women, The average age was about 49 years old, Most patients (over 90%) had a recurrent course of illness prior to this episode, Almost half of all patients had been hospitalized at some point for their depression, On average, patients had received 2.5 antidepressant treatments of adequate dose and duration in the current episode without receiving clinical benefit from these treatments   On average, the course of TMS treatment spanned about 5 to 6 weeks, and reflected an average of 28 TMS sessions.   References : Neuronetics, Inc. data on file.
  • This slide shows the outcome from baseline to end of acute treatment on the major clinician and patient rated scales.   On the left hand side are the results of the CGI-Severity of Illness scale, a global illness outcome scale of disease severity rated by the psychiatrist. On the right hand side are the results of the PHQ-9 scale, a nine-item depression scale rated by the patient. The distribution of scores on these scales are shown at baseline, prior to NeuroStar TMS treatment, and then at the conclusion of the acute treatment course. The distribution of scores in terms of illness severity is shown in a three-tiered grouping for each scale. For the CGI-Severity of Illness scale, the category of Markedly Ill or worse reflects either a score of 5 (markedly ill), 6 (severely ill) or 7 (among the most extremely ill patients). The category of Moderately ill reflects those patients rated as 4 (moderately ill), and the Mildly ill or better category reflects those patients rated as either a score of 3 (mildly ill), 2 (borderline mentally ill), or 1 (normal, not at all ill). For the PHQ-9, the category of Markedly Ill or worse reflects a total score of 15 or more (moderately severe or severe depression). The category of Moderately ill reflects those patients rated as a total score between 10 and 15 (moderate depression), and the Mildly ill or better category reflects those patients rated as a score of less than 10 (mild depression or no depression). With these illness severity groupings, it can be seen that from both the clinician’s and the patient’s perspective, the majority of patients at baseline were seen as markedly ill or worse (nearly three quarters of the patients were rated at this severity level), while by the end of about 5-6 weeks of acute treatment with the NeuroStar device, more than half of patients had reached a substantial improvement at a level rated as only mildly ill or no symptoms. On the CGI-Severity of Illness scale, 58% of patients were rated by the clinicians in this category, while on the PHQ-9 scale, 56.4% of patient rated themselves at this level of improvement.   References : Neuronetics, Inc. data on file.
  • The end of treatment categories for the CGI-Severity of Illness and PHQ-9 scales shown on the preceding slide demonstrate a substantial response among patients. However, the goal of depression treatment is remission of symptoms. This slide shows how many patients achieve this definitive level of wellness at the end of acute treatment with the NeuroStar TMS system. On the left, it can be seen that 37.1% of patients are rated by the clinician as having remitted on CGI-S (an endpoint score of 1 or 2 on this scale), which represents more than half of the 58% of responding patients. Similarly, on the PHQ-9 scale, 28.7% of patient self-report a score of less than 5 (remission), representing about half of the total group of responding patients. References : Neuronetics, Inc. data on file.
  • In summary, the data demonstrating the efficacy of NeuroStar TMS Therapy has been established in two, large, multisite randomized, sham-controlled clinical trials, both of which have shown clinically significant antidepressant effects of TMS. The research studies have been confirmed in the clinical outcomes in a multisite, real world clinical practice setting observational study.   In real world clinical practice settings, the results of the outcomes study show that over 1 in 2 patients achieve clinical response to treatment, and 1 in 3 reach full remission. This data is consistent with open-label clinical trial data that was collected in the Neuronetics and OPT-TMS clinical trials.    Adherence to treatment in a real world setting is also good, with over 80% of patients completing their prescribed course of TMS.   References : Neuronetics, Inc. data on file.
  • I’d like to also revisit the Treatment Algorithm that I presented earlier. Based on the information I have reviewed in this talk, I hope I have provided you sufficient scientific support to validate the conclusions about where TMS fits in the spectrum of potential antidepressant options as articulated in the Depression Treatment Guideline pictured here.   As I mentioned earlier, TMS is now included as an appropriate treatment option for patients who have failed to benefit from first line treatment attempts. As I have shown, placing TMS at this earlier stage in treatment planning is consistent with the strength of the clinical trial evidence that led to the FDA clearance of the NeuroStar TMS Therapy system device. NeuroStar TMS offers patients an effective treatment alternative, without the systemic side effects associated with medication antidepressants.   References : American Psychiatric Association (2010) (eds: Gelenberg, AJ, Freeman, MP, Markowitz, JC, Rosenbaum, JF, Thase, ME, Trivedi, MH, Van Rhoads, RS). Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, 3 rd Edition.
  • In the following slides, we will review some important aspects of the safety data of the NeuroStar TMS system obtained in the registration clinical trials.
  • An overall summary of the main safety findings are shown on this slide:   As I discussed earlier in reviewing its mechanism of action, TMS showed no systemic side effects, There were no adverse effects on cognition as measured by formal cognitive testing using the Mini Mental Status Examination (a measure of global cognitive function), the Buschke Selective Reminding Test (a measure of short-term memory), and the Autobiographical Memory Interview Short Form (a measure of long-term memory), The most commonly reported device-related adverse event was scalp pain or discomfort in about a third of all patients, Only about 5% of patients discontinued due to adverse events, and for the majority of patients, the device-related adverse events subsided substantially after the first week of treatment Long term safety was confirmed in a six month period of follow up after benefit from acute treatment   Seizure is the major, medically significant potential safety risk of TMS. During clinical trials, no seizures were observed with the NeuroStar TMS system. In post-market use, the risk of seizure is rare. Since market introduction and based on current usage, an estimated risk of seizure is approximately 0.003% per treatment exposure, and <0.1% per acute treatment course. To date, over 150,000 treatments and more than 5,000 patients have been treated with the NeuroStar TMS Therapy system which confirms its safe use in the treatment of depression.   References : Janicak, PG, O’Reardon, JP, Sampson, SM, Husain, MM, Lisanby, SH, Rado, JT, Demitrack, MA. (2008) Transcranial Magnetic Stimulation (TMS) in the Treatment of Major Depression: A Comprehensive Summary of Safety Experience from Acute and Extended Exposure and During Reintroduction Treatment. J Clin Psychiatry 69(2) :222-232. Janicak, PG, Nahas, Z, Lisanby, SH, Sovason, HB, Sampson, SM, McDonald, WM, Marangell, LB, Rosenquist, PB, McCall, WV, Kimball, J, O’Reardon, J, Loo, C, Husain, MH, Krystal, A, Gilmer, W, Dowd, SM, Demitrack, MA, Schatzberg, AF: (2010) Long-Term Durability of Acute Response to Transcranial Magnetic Stimulation (TMS) in the Treatment of Pharmacoresistant Major Depression. Brain Stimulation 3 :187-199.
  • This slide shows another important safety observation. The risk of emergent suicidal ideation is a concern with any antidepressant treatment.   In the analysis shown on this slide, Item 3 of the Hamilton Depression Rating Scale (the Suicidal Ideation item), which ranges from 0 to 4, was used. The slide depicts the proportion of patients in either the active TMS or sham TMS treatment group in the randomized controlled trial who came in with no suicidal ideation (an Item 3 score of 0 or 1) at baseline, and who later experienced an abrupt emergence of suicidal ideation (a score of 3 or 4) at any later time point.   It can be seen that virtually all of these instances occurred only in the sham treatment condition. This indicates that TMS is not associated with provoking emergent suicidal ideation during acute treatment in the indicated patient population.   References : Neuronetics, Inc., data on file. Janicak, PG, O’Reardon, JP, Sampson, SM, Husain, MM, Lisanby, SH, Rado, JT, Demitrack, MA. (2008) Transcranial Magnetic Stimulation (TMS) in the Treatment of Major Depression: A Comprehensive Summary of Safety Experience from Acute and Extended Exposure and During Reintroduction Treatment. J Clin Psychiatry 69(2) :222-232.
  • TMS employs the same type of pulsed magnetic field technology used in modern MR imaging equipment. While the safety of this medical technology in short and long term exposure is well established, Neuronetics also characterized the long-term safety outcomes of patients treated with TMS during six months of follow up after cessation of acute treatment.   The design of this open-label follow up study is shown in this diagram. Following completion of acute treatment with TMS alone, all patients were transitioned during a 3 week Taper Phase off of TMS and onto single antidepressant medication maintenance.   The choice of medication was based on clinician and patient preference, but could not include use of a medication to which the patient had previously been non-responsive. The most commonly used medications in this study in long-term follow up were duloxetine and bupropion.   During the 6 months of follow up, patients were not permitted to modify or add to the single medication regimen in any way. TMS treatment was permitted if the patient experienced symptom recurrence, as measured by the protocol rating scales.   References : Janicak, PG, Nahas, Z, Lisanby, SH, Sovason, HB, Sampson, SM, McDonald, WM, Marangell, LB, Rosenquist, PB, McCall, WV, Kimball, J, O’Reardon, J, Loo, C, Husain, MH, Krystal, A, Gilmer, W, Dowd, SM, Demitrack, MA, Schatzberg, AF: (2010) Long-Term Durability of Acute Response to Transcranial Magnetic Stimulation (TMS) in the Treatment of Pharmacoresistant Major Depression. Brain Stimulation 3 :187-199.
  • The major results of this long-term, open-label safety follow up are shown here.   No new safety observations related to TMS were reported.   Approximately 37% of patients experienced symptom recurrence requiring reintroduction of TMS. For those patients, about 85% benefited from reintroduction of TMS given in addition to their ongoing antidepressant medication.   Over 6 months of follow up, the net incidence of illness relapse (ie, those patients who deteriorated without receiving TMS and exited the study, or those patients for whom TMS reintroduction was not effective) was about 11%. This compares favorably to the long-term relapse reported in open-label naturalistic follow up in the STAR*D study, where 6 month relapse rates in Level 2 or 3 patients ranged as high as 35-50% despite continued best efforts at treatment as usual.   References : Janicak, PG, Nahas, Z, Lisanby, SH, Sovason, HB, Sampson, SM, McDonald, WM, Marangell, LB, Rosenquist, PB, McCall, WV, Kimball, J, O’Reardon, J, Loo, C, Husain, MH, Krystal, A, Gilmer, W, Dowd, SM, Demitrack, MA, Schatzberg, AF: (2010) Long-Term Durability of Acute Response to Transcranial Magnetic Stimulation (TMS) in the Treatment of Pharmacoresistant Major Depression. Brain Stimulation 3 :187-199. Rush, A. J., M. H. Trivedi, et al. (2006). "Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report." Am J Psychiatry 163 (11): 1905-1917.

Transcript

  • 1. MAGNETS, NOT PILLS: Transcranial Magnetic Stimulation - : A New Depression TreatmentLouis B. Cady, MD – CEO & Founder – Cady Wellness Institute Adjunct Professor – University of Southern Indiana Adjunct Professor – Indiana University School of Medicine For Deaconess Hospital Grand Rounds Evansville, IN May 1, 2012
  • 2. “Slumber not in thetents of your fathers.The world is advancing.Advance with it.” - Giuseppe Mazzine
  • 3. Topics we will cover in this talk Major – DiagnosisDepression – Unmet medical needs TMS – How it works – Safety and tolerability – Where it fits in the “Treatment Algorithm” for Major Depression
  • 4. Major Depression Unmet Medical Needs
  • 5. *ACCURATE MEDICAL diagnosis a malpractice suit Depression & Anxiety & “mood disorder due to a in 1 Easy Lesson general medical condition” AND r/o bipolar disorderDEPRESSION Gen. ANXIETY D.O. SIG: E- CAPS! •Somatic Sx (“energy”,etc.)• Sleep •WORRY• Sadness •Irritability• Interest loss •Concentration• Guilt •Keyed up• *Energy •Insomnia (“sleep”)• Concentration •Restlessness• Appetite BEWARE BEWARE – “too much”• Psychomotor Sx energy• Suicidal thinking SWICKIR is Quicker: Worry + 3 = GAD (Baughman)5of 9 with 1 of 2 x 2 weeks
  • 6. Lifetime Prevalence ofCommon Psychiatric Disorders Major depressive disorder 17.1% Alcohol dependence 14.1% Social anxiety disorder 13.3% PTSD 7.8% Generalized anxiety d.o 5.1% PMDD 5%* Panic disorder 3.5% OCD 2.5% 0 2 4 6 8 10 12 14 16 18 Lifetime prevalence (%)*In menstruating women. Kessler 1994; Kessler 1995; DSM-IV-TR™ 2000.
  • 7. Conceptual Evolution of Depression/Anxiety Comorbidity 10.5% 67.8% 10.4% of all psychological of all disorders psychological disorders67.8% of patients diagnosed with depression also fulfill the criteria for an anxiety disorder.Boerner and Möller, 1999.
  • 8. Depression—Impact on the Healthcare System• Compared with those without depression, depressed individuals: – Utilize all types of healthcare services more often – Incur 1½ to 2 times greater healthcare costs – increased length of hospital stay – significant worsening of physical, social, and role functioningSimon 1995; Luber 2000; Verbosky 1993; Wells 1989.
  • 9. PHQ-9 Symptom Checklist More Nearly 1. Over the last 2 weeks, how often have you Not Several than half every been bothered by the following problems? at all days the days day 0 1 2 3 a. Little interest or pleasure in doing things     b. Feeling down, depressed, or hopeless     c. Trouble falling or staying asleep, or sleeping too much     d. Feeling tired or having little energy     e. Poor appetite or overeating     f. Feeling bad about yourself, or that you are a failure…     g. Trouble concentrating on things, such as reading…     h. Moving or speaking so slowly…     i. Thoughts that you would be better off dead…     Subtotals: 3 4 9 TOTAL: 16Kroenke 2001.
  • 10. Epidemiology of DepressionPrevalence of Major Depression 20 point prevalence (30 day) 15 lifetime prevalence Percent 10 of Patients 5 0 Epidemiologic National Comorbidity Catchment Area (ECA) Survey (NCS) Regier et al., 1988; Blazer et al., 1994
  • 11. STAR*D Study demonstrates that current treatments have limited effectivenessTrivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry
  • 12. Likelihood of discontinuing treatment increases with each new medication attempt Systemic Drug Side Effects  Weight Gain  Fatigue  Constipation  Headache/ Migraine  Diarrhea  Abnormal  Nausea Ejaculation  Drowsiness  Impotence  Insomnia  Sweating  Decreased  Tremor Libido  Treatment  Nervous Discontinuation Anxiety Side Effects  Increased  Weakness Appetite  Dry Mouth  Decreased Appetite  DizzinessTrivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) AmJ Psychiatry; Neuronetics, Inc. (data on file)
  • 13. Adequate Treatment Is Difficult to Achieve • Adequacy of Adequate Adequate treatment = C. Dosage Duration 18% Factors contributing to inadequate • (regardless of treatment include: agent) Lack of Poor adherence to tolerability • The ratio of recommended treatment Medical and inadequate-to- Lack of efficacy Psychiatric Comorbiditie adequate s treatment attempts is 4:1 …adequate treatment in depression is the exception, not the normNemeroff (1996/1997) Depress Anxiety; Oquendo (2003) J Clin Psychiatry; Oquendo (1999) Am J Psychiatry. 13
  • 14. Best Practices Treatment Guideline for Depression Based on 2010 APA guidelines and NeuroStar TMS Therapy® indication for use. Unmet Medical Needs Adapted from: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd Edition, APA (2010)
  • 15. TMS is Included in Practice Guidelines Following Failure of Initial Treatment Guideline Sources American Psychiatric Association (2010) “…Acute phase treatment may include pharmacotherapy, depression- focused psychotherapy, the combination of medications and psychotherapy, or other somatic therapies such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or light therapy…” World Federation of Societies Canadian Network for Mood for Biological Psychiatry and Anxiety Treatments (2009) (2009)Schlaepfer, et al. World J Biol Psychiatry (2009); Kennedy, et al J Aff Disorders (2009); AmericanPsychiatric Association (2010)
  • 16. A quick look back in historyThe Interpretation of Ugo Cerletti 1935 Prozac - 1987Dreams – 1885 - 1890
  • 17. The Therapeutic Trifecta of Psychiatry: Shrinking Shocking or Drugging [Supposedly] the only three things you could do to a patient’s brain…]
  • 18. ECT – origins• Origin in 1700’s – Middlesex Hospital – machine with weak electrical current used for range of illnesses. – John Birch, English neurosurgeon, used it to shock the brains of depressed patients – Benjamin Franklin, after shocked, recommended electric shock for tx of mental illness• Ugo Cerletti – 1935 – noted (incorrectly) that epilepsy and schizophrenia didn’t occur in same patient• Problems with ECT – memory loss, anesthesia risk• Cost of $6400 for eight treatments• 80% improvement• 33,000 hospitalized Americans – ECT in 1980, last year for NIMH figures – http://www.faqs.org/health/topics/19/Electroconvulsive-therapy.html
  • 19. "The Shock Shop,Mr. McMurphy, mightbe said to do the work ofthe sleeping pill, theelectric chair and thetorture rack. Its a cleverlittle procedure, simple,quick, nearly painless ithappens so fast, but noone ever wants anotherone. Ever.”
  • 20. But even before these guys…• Electromagneitc induction – 1831 (Faraday & Joseph Henry)• 1st demonstrated by Faraday August 29, 1831
  • 21. Faraday’s law• “The induced electromotive force (EMF) in any closed circuit is equal to the time rate of change of the magnetic flux through the circuit.”• Discovered by Michael Faraday and Joseph Henry in 1831 – Faraday first to publish. 
  • 22. Faraday’s Law of Induction TMS Induced neuronal Magnetic current field
  • 23. From electricity to magnetism• Bartholow, R (1874) – Stimulation of human brain (exposed cortex) of patient with cranial defect.• d’Arsonval – “Phosphenes and vertigo” induced inside powerful magnetic coil• Silvanus P. Thomson, Ph.D. – new type of magnetic Thompson, SP. “A Physiological Effect of an Alternating Magnetic stimulation (1910) Field.” Proceedings of the Royal Society of London B82:396-399, 1910
  • 24. First patent application for magnetic therapy:• 1902 Adrian Pollacsek and Berthold Beer – Vienna, Austria for a “therapeutical apparatus”• Electromagnetic coil, placed over the skull was noted to “pass vibrations into the skull” and “treat depression and neuroses.”
  • 25. First modern TMS:• Barker AT, et al. “Non- invasive magnetic stimulation of the human motor cortex. The Lancet 1:1106-1107, 1985.• 1st device – designed by Barker – Univ. of Sheffield, England. – 100 microsecond, 2 T pulse
  • 26. Coil types and rationaleFrom Matt Edwardson, MD – Research Fellow and ActingInstructor, Dept. of Neurology, Univ. of WA 10/16/2011
  • 27. TMS Targeted Effects on Local and Distant Regional Blood FlowNahas Z et al. Brain Effects of TMS Delivered Over Pefrontal Cortex in DepressedAdults. Journal of Neuropsychiatry and Clinical Neurosciences 2001:13:459-460.
  • 28. Nahas Z et al. Brain Effects of TMS Delivered Over Pefrontal Cortex in DepressedAdults. Journal of Neuropsychiatry and Clinical Neurosciences 2001:13:459-460.
  • 29. An unusual side effect of imaging (2004)…• CONCLUSIONS: “These preliminary data suggest that the EP-MRSI scan induces electric field that are associated with reported mood improvement in subjects with bipolar disorder.”
  • 30. NeuroStar Directly Depolarizes Cortical Neurons Neuron Pulsed magnetic fields from NeuroStar: •induce a local electric current in the cortex which depolarizes neurons Neurons are •eliciting action potentials “electrochemical •causing the release of cells” and respond to chemical either electrical or neurotransmitters chemical stimulation
  • 31. NeuroStar Releases Neurotransmitters in the Brain Depolarization of neurons in the DLPFC causes local neurotransmitter release These effects Dorsolateral are associated prefrontal cortex with improvements in Anterior cingulate depressive cortex symptoms Kito (2008) J Neuropsychiatry Clin Neurosci Depolarization of pyramidal neurons in the DLPFC also Activation of deeper braincauses neurotransmitter release neurons then exerts secondary in deeper brain neurons effects on remaining portions of targeted mood circuits
  • 32. ECT TMSAnesthesia, LOC ECT vs. TMS No YesInduction of seizure Yes NoSystemic effects Anesthetic drugs, none increase HRTreatment schedule 3X/ week (8 -15 tx) Daily, M-F, six weeks (30 tx)Rapidity of onset 2 – 3 treatments 2 – 3 weeksMechanism of action SEIZURE. Massive NT Reactivation of neural release; rise in sz circuits. Precise, LOCAL threshold release of NT’s.Side effects Memory loss, confusion Essentially none (mild HA 1st week)Psychosocial impact can’t work Drive to and from tx’s, work improvedAfter-effects Mild (usually transient) None. Pro-cognitive memory lossInsurance coverage Almost always Rare. Improving
  • 33. NeuroStar TMS in Clinical Practice at CWI• Outpatient 37-minute daily procedure (3000 pulses)• 4-6 week treatment course• “Antidepressant medication monotherapy” may be used for maintenance – we use multiple both during and after.• At CWI – multiple medications thyroid balancing, NT balancing, and psychotherapy (during treatment)
  • 34. Does it work?• Original registration trial – 307 major depressed patients • 67% women • 93% recurrent depressives • 43% had been hospitalized already – 42 sites – Treatment per label• Results: ½ patients responded; 1/3 of patients remitted.• 80% patients completed the treatment.
  • 35. Who Was Studied? • Primary diagnosis: DSM-IV Major Depressive Disorder – Unipolar type, non-psychotic – Moderate to severe symptoms at baseline – Approximately one-third of patients had a co-morbid anxiety disorder (OCD excluded) • Antidepressant Treatment History: – Average number of antidepressant medication trials in current episode = 4 (range: 1 to 23 attempts) • Majority of treatment attempts were unable to achieve adequate dose and duration of treatment due to intolerance – In the indicated patient population, all patients failed to achieve satisfactory benefit from one antidepressant medication at an adequate dose and duration in current episode 39Demitrack and Thase (2009) Psychopharm Bulletin
  • 36. O’Reardon, JP, et al. (2007) Efficacy and Safety of Transcranial Magnetic Stimulation inthe Acute Treatment of Major Depression: A Multi-Site Randomized Controlled Trial.Biol Psychiatry 62:1208-1216.
  • 37. Optimization of TMS (‘OPT-TMS’) Study Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD; Martina Pavlicova, Phd; Berry Anderson, Phd, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD; Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PHD Major Findings:• NIMH-funded, independent of industry • MADRS total score decreased:16.6%• N=190 patients, 4 premier academic sites (Active) vs 6.9% (Sham) p=0.01• Primary outcome measure: (Effect size: 0.51) % Remission - Active 15% vs Sham 4% (P = • 30% of patients achieved remission 0.015); Odds Ratio of achieving remission: in open-label extension phase 4.2 (95%CI, 1.3-13.2) • Excellent safety and adherenceConclusion: “Daily left prefrontal rTMS as monotherapy produced statisticallysignificant and clinically meaningful antidepressant therapeutic effects greater thansham.”
  • 38. Recent TMS Literature Review• Roughly 30 controlled clinical research studies to date• Most recent meta-analysis (Slotema, et al, 2010): – Included analysis of 34 studies involving 1,383 patients – Estimated standardized effect size = 0.55 (P < 0.001) Conclusion: “…rTMS deserves a place in the standard toolbox of psychiatric treatment methods, as it is effective for depression…and has a mild side effect profile….” 1.Slotema, CW, Blom, JD, Hoek, HW, Sommer, IEC. (2010) Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)J Clin Psych 71(7):873-84. 2.Schutter, DJLG. (2009) Antidepressant Efficacy of High-Frequency Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex in Double-Blind Sham-Controlled Designs: A Meta-Analysis. Psychol Medicine, 39:65-75.
  • 39. NeuroStar TMS Therapy:Acute Efficacy Outcomes in Real-World Clinical Practice
  • 40. Treatment Utilization and Outcomes Study ( Protocol No. 19-50001-000) • Goal – Define real world outcomes associated with NeuroStar TMS Therapy across a broad spectrum of patients and practitioners • Patient Population & Sites – 307 evaluable unipolar, non-psychotic MDD patients in acute phase – 42 sites comprised of institutions and private practice • Study Design Phases – Acute phase (clinician determined care based on clinical progress) – Long-term outcomes at 12 months (study ongoing at present) • Patient Treatment – Clinical care initiated per current labeled guidelines 44Neuronetics, Inc. (data on file) ; clinicaltrials.gov listing number NCT 01114477
  • 41. Patient and Treatment Characteristics (N=307) N (%) Female 205 (66.8) Age in years, mean (SD) 48.6 (14.2) Disease and Treatment History N(%) - Recurrent Major Depression 285 (92.8) - Comorbid Anxiety Disorder 46 (15.0) Psychiatric Treatment History N(%) - History of Inpatient Hospitalization 133 (43.3) - History of ECT Treatment 15 (4.9) Prior Antidepressant Medication Treatment mean(SD) 2.5 (2.3) - Avg # of Adequate Treatments in Current Episode Mean (SD) Number of TMS Sessions During Acute Treatment 45 28 (10.1)Neuronetics, Inc. (data on file) ; clinicaltrials.gov listing number NCT 01114477
  • 42. Comparison of End of Acute Treatment Clinical Status: Clinician- and Patient-Assessed Outcomes Clinician Rating Patient Rating (CGI-Severity of Illness) (PHQ-9 Scale) % of Patients (N=307) Markedly ill or worse Moderately ill Mildly ill or betterOCF Analysis of intent-to-treat population
  • 43. Comparison of End of Acute Treatment Clinical Status: Clinician- and Patient-Assessed Outcomes Clinician Rating Patient Rating (CGI-Severity of Illness) (PHQ-9 Scale) % of Patients (N=307) Responders (CGI-S <3, PHQ-9 <10) Remitters (CGI-S <2, PHQ-9 <5)LOCF Analysis of intent-to-treat population
  • 44. Summary of Clinical Outcomes• In research settings, two large, multisite, randomized controlled trials demonstrated clinically significant antidepressant effect of TMS• Prospective, naturalistic study confirms these results in real-world practice settings• Overall, 1 in 2 patients respond and 1 in 3 patients achieve remission• High level of treatment adherence , >80% of patients completed acute treatment in both research setting and in clinical practice 48
  • 45. Best Practices Treatment Guideline for DepressionBased on 2010 APA guidelines and NeuroStar TMS Therapy® indication for use.Adapted from: Practice Guideline for the Treatment of Patients with Major 50Depressive Disorder, 3rd Edition, APA (2010)
  • 46. Safety andTolerability ofNeuroStar TMS Therapy
  • 47. NeuroStar TMS Therapy: Safety Overview • No systemic side effects • No adverse effect on cognition • Most common adverse event associated with treatment was scalp pain or discomfort – < 5% of patients discontinued due to adverse events • No seizures with NeuroStar device during clinical studies (over 10,000 treatments) • Rare risk of seizure with NeuroStar TMS in post-market use (0.003% per treatment, <0.1% per acute treatment course) (>150,000 treatments in post-marketing experience to date) • Long term safety demonstrated in 6 months follow-upJanicak, et al. J Clin Psychiatry, 2008; Janicak, et al. Brain Stimulation, 2010.
  • 48. No Evidence of Emergent Suicidal Ideation 4.0 NeuroStar TMS Therapy (n=155) HAMD Item 3 Suicidal Ideation 3.5 Sham TMS (n=146) 3.0 Shift Score (%)* 2.5 2.0 1.5 1.0 0.5 0.0 Baseline Week 2 Week 4 Week 6 * Shift Score indicates the percent of subjects who experienced a change in HAMD Item 3 score from 0 or 1 at baseline to 3 or 4 at later point in time.Janicak (2008) J Clinical Psychiatry.
  • 49. Long Term Follow Up After Acute Treatment RCT or Open-Label Extension Study Long-Term Follow-Up Study ACUTE TAPER LONG TERM OUTCOME BENEFIT (3 Weeks) ASSESSMENT (6 Weeks) (6 Months) Transition from Antidepressant medication TMS to monotherapy w/TMS rescue as pharmacotherapy add-on if needed through 6 MonthsJanicak, et al. Brain Stimulation, 2010.
  • 50. Long Term Follow Up After Acute Treatment • Safety confirmed during long term, open-label 6 month follow up period • During open-label follow up on antidepressant medication monotherapy, – ~37% of patients required TMS reintroduction – ~85% of patients who received TMS reintroduction benefited • Net incidence of illness relapse under these open-label follow up conditions: 11% – Six-month relapse with antidepressant treatment alone in STAR*D study was 35-50% (Level 2 and 3 range)Janicak, et al. Brain Stimulation, 2010.
  • 51. “But my patients don’t know about this and aren’t asking for it….” “It’s not the consumers’ job to know what they want.” - Steve Jobs
  • 52. Perhaps the ability not only to acquirethe confidence of the patient, but todeserve it, to see what the patientdesires and needs, comes through thesixth sense we call intuition, which inturn comes from wide experience anddeep sympathy for and devotion tothe patient, giving to the possessorremarkable ability to achieve results. ...William J. Mayo, 1935