rTMS for adolescents: Safety and efficacy considerations

Psychiatry Research 177 (2010) 280–285

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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s

Review article

rTMS for adolescents: Safety and efficacy considerations Douglas D'Agati a, Yuval Bloch b, Yechiel Levkovitz b, Irving Reti a,⁎ a b

Department of Psychiatry and Behavioral Sciences, The School of Medicine, Johns Hopkins University, 600 N. Wolfe St. Baltimore, MD 21287, United States Shalvata Mental Health Center, Hod Hasharon, Israel

a r t i c l e

i n f o

Article history: Received 4 November 2009 Received in revised form 1 March 2010 Accepted 9 March 2010 Keywords: Transcranial magnetic stimulation Seizure Children Depression

a b s t r a c t In light of both the FDA's clearance of repetitive transcranial magnetic stimulation (rTMS) for adult major depressive disorder and concerns about safety and efficacy of existing antidepressant therapies for adolescent depression, there is increasing interest in rTMS as a novel treatment for adolescent depression. We reviewed English-language studies using rTMS in persons under the age of 18, yielding 6 published reports. Because rTMS is typically delivered at or above 1 Hz for psychiatric indications, our search was confined to these frequencies. Also included are studies involving rTMS above 1 Hz for non-psychiatric indications. Articles were retrieved from the MEDLINE database. There were 19 reported subjects under age 18 who have been administered rTMS at a frequency above 1 Hz: 10 for major depression, 5 for spastic cerebral palsy and 4 for epilepsia partialis continua. We found that most subjects responded favorably to rTMS and no adverse events have been reported. However data are insufficient for drawing firm conclusions about safety and efficacy. Further studies of rTMS as a treatment for adolescent depression are warranted. © 2010 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . 4.1. Efficacy . . . . . . . . . . . . . . . . . . 4.2. Safety considerations . . . . . . . . . . . 4.2.1. Seizure . . . . . . . . . . . . . . 4.2.2. Concurrent medications and seizure 4.2.3. Hypomania and mania . . . . . . 4.2.4. Neurocardiogenic syncope . . . . . 4.2.5. Auditory threshold . . . . . . . . 4.2.6. Neuropsychological performance . . 4.2.7. Electromagnetic radiation . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . 6. Disclosures . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Since Barker et al. (1985) first introduced the procedure, transcranial magnetic stimulation (TMS) has emerged as a promising ⁎ Corresponding author. Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Meyer 3-181, Baltimore, MD 21205, United States. Tel.: + 1 410 955 1484; fax: + 1 410 955 0152. E-mail address: [email protected] (I. Reti). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.03.004

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diagnostic and therapeutic tool, with applications in psychiatry, neurology and rehabilitation medicine. The procedure relies on the principle of electromagnetic induction: electric pulses in a coil induce a changing magnetic field which permeates the skull and induces an electric field in the brain, focally and non-invasively depolarizing neurons. A train of TMS pulses – repetitive TMS (rTMS) – can provoke long-lasting up- or down-regulation of brain activity, including in regions that can regulate emotion and movement (Huang et al., 2004). These features – the ability to focally and non-invasively stimulate the

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brain with long-lasting effects – have made rTMS the focus of active study for the treatment of psychiatric disorders, including major depression, schizophrenia, obsessive compulsive disorder and Tourette's syndrome, as well as for the treatment of neurologic conditions, such as epilepsy, dystonia and Parkinson's disease. To date, there have been over 30 controlled studies, involving more than 1100 subjects, investigating the safety and efficacy of rTMS for adult depression (Rachid and Bertschy, 2006; Gross et al., 2007; Mantovani and Lisanby, 2007; Padberg et al., 2007). Among them, the large, multisite, randomized controlled trial by O'Reardon et al. (2007) prompted the U.S. Food and Drug Administration (FDA) to clear the NeuroStar TMS System in October of 2008 as a treatment for major depressive disorder (MDD)—the first such clearance of rTMS for any condition. The clearance, however, is restricted to the treatment of MDD in adults, due to a paucity of data from children. Adolescent MDD is a recurrent and potentially life-threatening illness, affecting as much as 8% of the adolescent population in the United States (SAMHSA, 2008). Furthermore, it is estimated that at least 40% of adolescents with MDD do not show an adequate clinical response to a trial of medication, psychotherapy or a medicationpsychotherapy combination, and only one third experience complete remission (March et al., 2004; Brent et al., 2008). In addition, reviews of prior studies suggest a significant rise in suicidal thinking in adolescent patients treated with selective serotonin reuptake inhibitors (SSRIs) in comparison to placebo (Hammad et al., 2006). The FDA responded in 2007 by mandating the addition of a black box warning highlighting this risk of treatment with antidepressant medications. Accordingly, there is increasing interest in developing new treatments for adolescent MDD such as rTMS, particularly in light of evidence suggesting younger adult subjects with MDD respond better to the treatment than older subjects (Fregni et al., 2006). In this article we review published English-language articles involving the use of rTMS in children and adolescents aged 17 and under. As rTMS protocols for psychiatric indications typically utilize a pulse frequency of at least 1 Hz (Fitzgerald et al., 2009), we confine our report to rTMS cases at or above this frequency. We also discuss safety issues pertaining to rTMS in this younger population. Single and paired pulse TMS are not reviewed here, as both are regarded as minimal risk in children and neither is studied as a treatment for psychiatric disorders (Gilbert et al., 2004).

2. Methods A computerized literature search of the MEDLINE database was conducted to find all English-language studies involving rTMS in persons younger than 18 years of age. The keywords “transcranial magnetic stimulation” and “TMS” were initially used, and later crossed with the following additional keywords, either alone or in various combinations: depressi*, safe*, adverse, deep, seizure, epilep*, mania, hypomania, hear*, auditory, histo*, MRI, volumetric*, pain, young adult, adolescent and child. Material unavailable on MEDLINE was retrieved from the Welch Medical Library at Johns Hopkins. In addition to reporting all cases of rTMS administered for a psychiatric condition – which were administered with pulses above 1 Hz – we also include reports of rTMS being used for neurological indications at frequencies above 1 Hz. As rTMS at or below 1 Hz transiently decreases cortical excitability (Chen et al., 1997a), it has been used experimentally to treat epilepsy in medication-resistant subjects.

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3. Results There are 6 published reports, containing 19 adolescent cases of rTMS, meeting our criteria: 10 received rTMS for MDD, 5 for spastic cerebral palsy and 4 for epilepsia partialis continua (EPC) with a frequency greater than 1 Hz. Despite active study in adults, no controlled trials of rTMS in children or adolescents have been performed for psychiatric indications. In fact, the recent publication by Bloch et al. (2008) is the first case series in adolescents. The youngest child to receive rTMS was 5-years old (Valle et al., 2007), though single-pulse TMS has been administered to children as young as 2 weeks to examine the development of motor control (Muller et al., 1991). The 19 cases of rTMS administered to adolescents under the age of 18 (in 6 published reports) are summarized below and in the accompanying table (Table 1): 1) Walter et al. (2001) published the first report of the use of rTMS in persons younger than 18 with psychiatric disorders. Three adolescent patients younger than 18 with MDD were described (together with four 18-year-old patients). Two of these 3 patients improved by the conclusion of rTMS treatment, administered daily at 10 Hz, 5 times per week for 2 weeks. All patients received 1600 stimuli per session. None of the adolescent patients reported adverse effects (though one 18-year-old experienced a headache during 2 treatment sessions). 2) Loo et al. (2006) evaluated the safety and efficacy of rTMS for two 16year-old depressed adolescents. rTMS was administered at 110% MT, 10 Hz, forty 5 s trains with 25 s ITI (2000 stimuli per session). One patient continued on venlafaxine (225 mg/day) and methylphenidate (20 mg/day) during rTMS treatment. Both subjects improved to a clinically significant degree, and the improvement was sustained at 1-month follow-up. Neither patient reported an adverse event. 3) Bloch et al. (2008) reported rTMS to be safe and moderately effective in a case series of 9 subjects, aged 16–18, suffering from treatmentresistant MDD. Five of the 9 subjects were younger than 18, and all remained on their pre-existing pharmacotherapy and psychotherapy regimes throughout the study. rTMS was administered over 14 sessions, with twenty 2 s trains at 10 Hz and 80% motor threshold for a total of 400 pulses per session. As determined by the Child Depression Rating Scale (CDRS), 3 out of 9 satisfied the primary outcome measure of a reduction of greater than 30% from their CDRS baseline. All 3 responders were under the age of 18. Overall, rTMS was well-tolerated with 4 of the 5 adolescent participants reporting mild headache, but no other significant adverse effects. There are also 2 reports of rTMS above 1 Hz being used to treat intractable seizure disorders: 4) Graff-Guerrero et al. (2004) described 2 cases of rTMS administered to the left frontal cortex for EPC, one in an 11-year-old male, the other in a 7-year-old female. Each received 1 rTMS session of 20 Hz and 600 stimuli. Both children had reduced perfusion at the stimulated site, though only one experienced a significant clinical benefit. No adverse effects were reported in either case.

Table 1 Summary of studies with patients under 18 years of age treated with rTMS. Author, year

Country

Age of patients

No. of patients

Disorder

Outcome

Adverse events/side effects

Walter et al. (2001)

U.S.A.

3

Depression

2/3 improved

None, mild headache (1)

Loo et al. (2006) Bloch et al. (2008)

Australia Israel

2 5

Depression Depression

2/2 improved 3/5 improved

none None except mild headache (1)

Graff-Guerrero et al. (2004) Morales et al. (2005) Valle et al. (2007)

Mexico U.S.A. Brazil

16 (1) 17 (2) 16 (2) 16 (2) 17 (3) 7, 11 8, 16 Avg age 9.8 yrs

2 2 5

Epilepsia partialis continua (EPC) EPC Spasticity

1/2 improved 0/2 improved Mild improvement

None None None

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5) Morales et al. (2005) reported the use of rTMS on 2 patients (8 and 16 years old) for EPC. Each received 2 trials of rTMS to the left motor cortex. On day 1, each patient received 2 sessions of rTMS (1st session: 1 Hz; 2nd session: 6 Hz followed immediately by 1 Hz). The 8-year-old female also received an rTMS session of 1 Hz the following day. No adverse effects occurred, though the treatment was ineffective.

children. Quintana (2005) reviewed 48 studies involving TMS (single-pulse, paired and repetitive) in persons younger than 18 years, comprising a total of 1036 children and adolescents. No seizures or any other major adverse effects were reported in any child or adolescent who underwent TMS, including in children with conditions predisposing them to seizure, such as epilepsy and cerebral palsy.

Finally, there is a single report of rTMS above 1 Hz used to treat spasticity:

4.2.2. Concurrent medications and seizure Concurrent psychotropic medication has been implicated as a risk factor in some of the seizures reported above (Conca et al., 2000; Bernabeu et al., 2004; Tharayil et al., 2005); however, thousands of other patients have received rTMS while taking psychotropic medications without ill effect. The medications that arouse greatest concern are those which can lower seizure threshold. Antidepressants with the highest risk appear to be bupropion, clomipramine and maprotiline, while neuroleptics with the highest risk appear to be chlorpromazine and clozapine (Edwards et al., 1986; Rosenstein et al., 1993; Garcia and Alldredge, 1994; Franson et al., 1995; Alldredge, 1999; Pisani et al., 2002; Lee et al., 2003). There is also evidence that methylphenidate, commonly prescribed in childhood for ADHD, may lower seizure threshold and cause seizure in children with seizure history, prior electroencephalogram (EEG) abnormalities, or – extremely rarely – in children without seizure history or EEG abnormalities (Hemmer et al., 2001).

6) In a study by Valle et al. (2007), 5 children (average age 9.8 years) with cerebral palsy and spastic quadriplegia received five 1-min trains of 5 Hz rTMS with an intensity of 90% motor threshold (1500 pulses per session). No adverse events occurred. The therapeutic effects of 5 Hz rTMS on spasicity were modest. 4. Discussion 4.1. Efficacy As with many other treatments studied extensively in adults, little data are available on the therapeutic effects of rTMS in children and adolescents (just 19 cases). The dearth of data might also be explained by concerns about safety – particularly as it relates to seizure risk and effects on the developing brain – although major adverse effects have not been reported in this age group. Larger case series and eventually controlled trials of rTMS as a treatment for depression need to be conducted in adolescents, particularly given the paucity of existing data and concerns about suicidality and poor response associated with antidepressants. In light of the recent FDA clearance of rTMS for adult depression, we are hopeful there will be increased interest in such trials. 4.2. Safety considerations Safety considerations for the use of rTMS in adults have been extensively reviewed elsewhere (Chen et al., 1997b; Wassermann, 1998; Rachid and Bertschy, 2006; George et al., 2007; Padberg et al., 2007; Janicak et al., 2008; Loo et al., 2008). The most common adverse effects are mild headache and scalp pain, resulting from activation of muscles and nerves beneath the TMS coil. In this discussion we review significant adverse effects, briefly summarizing available data for patients of all ages but with particular emphasis on adolescents where possible. 4.2.1. Seizure While no rTMS-induced seizures have been reported in persons under 18, the risk of seizure remains the primary safety concern with rTMS. Prior to 1998, 6 cases of seizure in adults were reported out of several thousand rTMS sessions (Wassermann, 1998), leading to the adoption of safe stimulation parameters recommended by Chen et al. (1997b) and Wassermann (1998). Since the implementation of these safety guidelines, 5 cases of grand mal seizure (Bernabeu et al., 2004; Prikryl and Kucerova, 2005; Tharayil et al., 2005; Nowak et al., 2006; Rosa et al., 2006), and one possible case each of absence (Conca et al., 2000) and focal motor seizure (Figiel et al., 1998) have been reported. These seizures were associated either with stimulation parameters outside the recommended guidelines and/or occurred in conjunction with other risk factors such as certain antidepressant medications or stimulation to the motor cortex. None of these subjects suffered lasting physical sequelae. Still, seizure risk is of particular concern with the adolescent population because seizure threshold may be lower in reference to TMS stimulation in this age group—as is the case with ECT stimulation (Sackeim et al., 1987; Coffey et al., 1995). Moreover, there are no established rTMS safety guidelines for

4.2.3. Hypomania and mania Although there is evidence rTMS may be useful as a treatment for bipolar disorder (Dolberg et al., 2002; Nahas et al., 2003) – as well as for mania (Grisaru et al., 1998; Erfuth et al., 2000) – several studies report switching to hypomania and mania in bipolar subjects (GarciaToro, 1999; Dolberg et al., 2001; Ella et al., 2002; Fitzgerald et al., 2003, 2006; Sakkas et al., 2003; Huang et al., 2004; Su et al., 2005), as well as new onset of the disorder in patients previously thought to have unipolar illness (George et al., 1995; Ella et al., 2002; Zwanzger et al., 2002; Sakkas et al., 2003; Hausmann et al., 2004; Rachid and Bertschy, 2006). In all of these studies except those by Sakkas et al. (2003) and Hausmann et al. (2004) stimulation parameters were within recommended safety guidelines, although concomitant antidepressant medication may increase the risk (Xia et al., 2007). As the incidence rate for onset of bipolar disorder is highest in adolescents and young adults (Kennedy et al., 2005), the chance of a depressed subject presenting with first episode bipolar depression is also higher than in older cohorts. Accordingly, rTMS-triggered switching to hypomania or mania could be more frequent in adolescence than in adulthood. 4.2.4. Neurocardiogenic syncope Kirton et al. (2008) reported the occurrence of neurocardiogenic syncope in 2 adolescents (ages 14 and 16 years) with chronic stroke who had received single-pulse TMS to the nonlesional motor cortex. Ten children in total received TMS in the study. The authors concluded that the combination of anxiety with a “novel, mildly noxious stimulus” is a common precipitant of syncope. Both adolescents had risk factors rendering them more vulnerable, including prior presyncope with venipuncture or micturition, and situational variables, such as stress and hunger. Neither of the subjects suffered any lasting consequence from the adverse events. One syncopal episode has also been reported in a healthy adult receiving rTMS for depression (Figiel et al., 1998), although causation is unclear. 4.2.5. Auditory threshold Much like MRI machines, TMS machines produce a loud clicking noise due to minute expansions and contractions of the coil itself (caused by the switching of field gradients). The FDA-cleared NeuroStar Therapy system produces 92 dB of sound at its peak,

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directly below the coil (personal communication, Karen Heart, Neuronetics). The level at which sustained exposure may result in hearing loss is 85–90 dB, and pain begins at 140 dB (NIOSH, 1998). Several cases of temporary hearing loss were described by PascualLeone et al. (1993) in subjects not wearing ear protection, but no ill effects were reported when earplugs were worn. Another study examining acoustic trauma in children (without ear protection) failed to find adverse effects on hearing as a result of single-pulse TMS (Collado-Corona et al., 2001). There is, however, one report of transient increases in auditory threshold following 4–6 week courses of rTMS in 2 patients wearing ear protection (Loo et al., 2001). Both subjects' hearing returned to normal by 1-month follow-up. Zangen et al. (2005) reported the occurrence of permanent hearing loss in a subject whose hearing protection fell out transiently while receiving 1 Hz of rTMS using the H-coil at 120% of motor threshold. The loudness of the H-coil is not different from that of other coils according to the authors. In sum, there have been no reports of permanent hearing loss as a result of rTMS if ear protection is worn properly. 4.2.6. Neuropsychological performance The effect of rTMS treatment on neuropsychologic performance has been examined across a wide range of neuropsychological domains, using different stimulation parameters and a variety of neuropsychological tests. In the reviews by Loo et al. (2008) and Padberg et al. (2007), 39 and 16 studies were analyzed and compared, respectively. Although in isolated studies a mild worsening of a specific cognitive test has been reported (George et al., 2000; Loo et al., 2003), most studies report improvements in cognitive test results as depression is treated, though in sham-controlled trials differences are rarely significant (Loo et al., 2008). Both reviews reach the conclusion that significant neuropsychological impairment from an rTMS course is unlikely. Additionally, Bloch et al. (2008) found no ill effects on neuropsychological testing in 9 subjects, 16–18 years old, who received rTMS; in fact, improvements were recorded in two areas, planning and reaction time. 4.2.7. Electromagnetic radiation There is widespread community concern about the effects of electromagnetic radiation on the brain, especially amongst children who might be more susceptible as their rate of cellular activity and division is more rapid (Carpenter and Sage, 2008). Electromagnetic radiation from rTMS is comparable to radiation from MRI in frequency, field switching time and strength (Bourland et al., 1999; personal communication, Karen Heart, Neuronetics). However, pulses are continuous during MRI unlike during rTMS and, accordingly, total pulse number experienced during a session of TMS is far less (perhaps 1000-fold) than during an MRI scan. Anatomical exposure is also much smaller with rapid decay of the magnetic field just a couple of centimeters from the coil. Moreover, there is no evidence that MRI exposure is associated with adverse effects such as tumorigenesis, nor is there any evidence of risk from TMS either to the subject or the TMS administrator, including at up to 12960 TMS pulses per session (Anderson et al., 2006). Nonetheless, apart from two follow-up studies, one involving 10 patients receiving maintenance rTMS over as long as 6 years and another of 16 patients over 4 years (O'Reardon et al., 2005; Demirtas-Tatlided et al., 2008), there are no long-term follow-up studies of rTMS, especially of patients who have received the treatment chronically. 5. Conclusion In the adult population, rTMS is a well-tolerated, relatively safe procedure for treating depression, with minimal – mostly mild and transient – side effects. Of the thousands of subjects who have undergone rTMS, few have experienced major adverse events, such as

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seizure and hypomania. Moreover, the occurrence of such events is substantially lower when stimulation is applied within recommended TMS parameter guidelines (Chen et al., 1997b; Wassermann, 1998) and when subjects are screened for potential risk factors. However, more work is needed in the child and adolescent populations, as only 19 reports exist of rTMS above 1 Hz in this age group. While no major adverse events have occurred in any child or adolescent subject receiving any form of TMS, safety standards must be established and controlled trials must be conducted before rTMS can emerge as a viable treatment option for children and adolescents. 6. Disclosures Dr. Levkovitz serves as a consultant to Brainsway. Dr. Reti has research projects sponsored by Brainsway and Neuronetics. All other authors declare that they have no conflicts of interest. Acknowledgement This review was kindly supported by a grant from the Hope for Depression Research Foundation (Reti).

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