repetitive transcranial magnetic stimulation as treatment for anxiety disorders

1449www.expert-reviews.com ISSN 1473-7175© 2008 Expert Reviews Ltd10.1586/14737175.8.10.1449

Special Report

Anxiety disorders, including generalized anxi-ety disorder, panic disorder, post-traumatic stress disorder (PTSD) and obsessive–compulsive disorder (OCD), are common, with a lifetime prevalence greater than 20% [1]. These disorders can be very debilitating and have high rates of nonresponse to treatment [2]. The conventional treatments for anxiety disorders have been pharmacotherapy, supportive psychotherapy and cognitive–behavior therapy. With recent advances in understanding the neurobiology of these disorders, the prospect of novel treatments has been raised. One such treatment is repeti-tive transcranial magnetic stimulation (rTMS), a noninvasive and generally well-tolerated method of stimulating targeted cortical regions [3].

There are many theoretical arguments for a role for rTMS in anxiety. Foremost of these is the considerable overlap between depression and anxiety, with approximately a 90% rate of lifetime comorbidity between anxiety disor-ders and depression, and depression and anxiety sharing many neurobiological underpinnings [4]. Neuroimaging studies have consistently impli-cated prefrontal limbic circuits, the subgenual cingulate cortex (Cg25) and amygdala in both anxiety and mood disorders [2]. Since rTMS is

purportedly effective as an antidepressant treat-ment, it might arguably have a similar effect in anxiety disorders [5]. It is also true that other treatments, such as serotonin-specific reuptake inhibitors and cognitive–behavior therapy, are effective in both anxiety and depression.

More specifically, in OCD, abnormalities in the neural circuit involving the orbito frontal cortex (OFC), supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC) and caudate nucleus have been implicated [6,7]. Successful treatment of OCD appears to pro-duce predominantly right-sided changes in cortical excitability and metabolism, suggest-ing right-sided pathogenesis in OCD [6,8]. The amygdala, DLPFC, OFC and medial prefron-tal cortex (PFC) are reported to be involved in PTSD [9], with similar right-sided patho-genesis [10]. rTMS is generally either excitatory (at high frequency: >1 Hz) or inhibitory (at low frequency: ≤1 Hz), depending upon the frequency of stimulation [11], and has been used widely to excite or inhibit the cortex. However, cortical excitability has been shown to vary between individuals [12]. Therefore, modulation of neuronal activity in the PFC with rTMS may be a rational treatment of anxiety disorders.

Melissa Pigot Colleen Loo†, and Perminder Sachdev†Author for correspondenceSchool of Psychiatry, University of New South Wales, Black Dog Institute, Prince of Wales Hospital, Randwick, NSW 2031, Australia Tel.: +61 293 823 720 Fax: +61 293 828 151 [email protected]

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive and generally well-tolerated method of focally stimulating brain regions. It has been shown to be efficacious in the treatment for depression, but only to a limited degree. It has also been investigated for the treatment of some anxiety disorders, particularly obsessive–compulsive disorder, post-traumatic stress disorder and panic disorder. While anecdotal reports and open studies have suggested a therapeutic role for rTMS in anxiety disorders, controlled studies, which have varied greatly in terms of rTMS administration, have not shown it to be superior to placebo. Furthermore, reports in animal models of anxiety have not been consistent. Therefore, to date, there is no convincing evidence for the clinical role of rTMS in anxiety disorders. Further research is needed, drawing on advances in our understanding of pathological neurocircuitry in anxiety disorders and the mechanisms of action by which rTMS may alter that neurocircuitry. With advances in neuroimaging technology, this understanding is likely to be more accessible than it has been in the past.

Keywords: anxiety disorders • efficacy • obsessive–compulsive disorder • post-traumatic stress disorder • transcranial magnetic stimulation • treatment

Repetitive transcranial magnetic stimulation as treatment for anxiety disordersExpert Rev. Neurother. 8(10), 1449–1455 (2008)

k.rowland

Text Box

For reprint orders, please contact [email protected]

Expert Rev. Neurother. 8(10), (2008)1450

Special Report Pigot, Loo & Sachdev

This article reviews the literature on the use of rTMS as a treatment of anxiety disorders. The aim of the paper is to provide information on the current position of this research, reporting on efficacy and feasibility, and to identify options for future research in this area.

Method Literature searches were performed in the databases MEDLINE and PUBMED for papers published from 1995 to 2008. Keywords searched included, ‘transcranial magnetic stimulation’ and ‘anxi-ety’, ‘anxiety disorders’, ‘obsessive–compulsive disorder’, ‘post-traumatic stress disorder’, ‘generalized anxiety disorder’ or ‘panic disorder’. Articles were searched for cross-references related to studies of rTMS in anxiety. Owing to the small number of studies identified, all reports including controlled randomized clinical tri-als, open-label trials and case reports were included in this review. The review was limited to published reports only.

ResultsObsessive–compulsive disorderWe identified six published studies on the therapeutic effect of rTMS in patients with OCD. The first study assessed the efficacy of right and left PFC rTMS (80% of motor threshold [MT] at 20 Hz frequency for 20 min) in comparison to a control site (midoc-cipital region) in 12 OCD patients [13]. Each participant had one rTMS session at each of the three stimulation sites on separate days. Compulsive symptoms were significantly improved up to 8 h after rTMS when given to the right PFC and significantly improved, only during rTMS, when given to the left PFC. Compulsions also improved, although not significantly, in the control group. Mood tended to improve after right PFC stimulation, but no effect was reported in relation to obsessive thoughts. Response between stimu-lation sites was not reported, suggesting the moderate but signifi-cant effects found may not have differed significantly between sites. This study provides preliminary support of the potential of rTMS as a treatment for OCD.

In a treatment trial, the efficacy of high-frequency rTMS was assessed in 12 treatment-resistant OCD patients assigned to receive stimulation to the left or right DLPFC over ten rTMS sessions [14]. Patients in both groups had a significant improvement on both the obsessions and compulsions subscales and the total score of the Yale–Brown Obsessive Compulsive Scale (Y-BOCS) after 2 weeks of rTMS. Improvement on the obsessions subscale was still significant at a 1-month follow-up. Given that rTMS has been reported to be an efficacious treatment for depression, the authors used a measure of change in depressive symptoms as a covariate in the study [5,15]. The improvement in obsessive symptoms still tended toward significance (p = 0.062) after controlling for changes in depression.

While this study suggested that prefrontal rTMS might be use-ful in OCD, without a sham rTMS-control group it is possible that positive findings could be accounted for by placebo effects. Second, the results did not distinguish between left and right high-frequency prefrontal stimulation, providing little guidance about the differing effects of lateralized treatment. Theoretically, it is unlikely that high-frequency rTMS would have the same effect in the right and left hemisphere [11].

It has been suggested that repetitive behaviors in OCD are caused by reduced cortical–subcortical inhibition and cortical hyperexcit-ability [16]. Using this knowledge, Mantovani and colleagues used rTMS to bilaterally stimulate the SMA [8]. Ten participants with either OCD and/or Tourette’s syndrome (TS) received ten sessions (daily) of 1-Hz rTMS at 100% MT (1200 pulses) over the left and right SMA. Participants with OCD without TS (n = 5) showed a significant reduction in Y-BOCS scores (subscale scores were not reported). This reduction increased progressively over time. A total of 60% of the group maintained clinically significant effects for 3 months after the end of treatment. This clinical change was mir-rored by a reduction in motor cortex excitability in the right hemi-sphere (but not the left), providing some support for hyperactivity, particularly in the right hemisphere, in OCD. Changes in motor cortex excitability were only reported at the end of treatment.

Three subsequent studies have assessed both right and left pre-frontal rTMS in sham-controlled studies. All three used different stimulation parameters: right low frequency [17], left low fre-quency [18] and left high frequency [19]. None reported beneficial effects for OCD symptoms.

Alonso et al. administered 18 sessions of rTMS (three-times per week for 6 weeks) to 18 OCD patients (ten active and eight placebo), with rTMS administered at 110% MT, 1-Hz frequency for 20 min (1200 pulses) [17]. A slightly greater reduction in obses-sions was reported in the active group, but a significant difference between groups was not reported on any of the scores of inter-est: the obsessions or compulsions subscale scores and the total score on the Y-BOCS and the Hamilton Depression Rating Scale (HDRS) score.

The study by Prasko et al. examined low-frequency rTMS of the left DLPFC in a sham-controlled study [18]. A total of 30 par-ticipants completed the trial of ten rTMS sessions, administered daily over 2 weeks (1800 pulses/day). While both the sham and active rTMS groups improved significantly on measures of anxiety (Hamilton Rating Scales for Anxiety [HAMA]) and Y-BOCS, there was no difference between the groups, suggesting the rTMS did not influence reported changes.

Sachdev et al. also found a course of rTMS to be ineffective in treating OCD [19]. A total of 18 OCD participants (ten active and eight sham rTMS) were initially given ten sessions of high-frequency rTMS (10 Hz, 110% MT; 1500 pulses) daily over the left DLPFC; all participants were unblinded at the end of ten sessions and offered continued treatment for up to 20 sessions of active treatment. After 2 weeks (sham-controlled period) there was no difference between groups on the total Y-BOCS score (including the obsessions and compulsions subscales). After 4 weeks of rTMS treatment (open phase), there was a significant difference reported on total Y-BOCS score (owing to a reduction in obsessive but not compulsive symp-toms). However, the aforementioned findings were no longer sig-nificant when changes in depressive symptoms (measured by the Montgomery–Asberg Depression Rating Scale [MADRS]) were added as a covariate in the ana lysis. These results suggest that the initial reduction in obsessive symptoms may have been due to a pla-cebo effect and that benefits from continued treatment over several weeks may have been secondary to antidepressant effects.

www.expert-reviews.com 1451

Special ReportRepetitive transcranial magnetic stimulation as treatment for anxiety disorders

In conclusion, the published results do not support that rTMS, as hitherto applied, is effective in the treatment of OCD, given that the three sham-controlled studies were all negative [17–19].

There are a few main limitations of this literature:

The treatment courses could have been inadequate. The litera-•ture of the therapeutic effects of rTMS in depression clearly suggests that 4 weeks (20 sessions) of rTMS, administered on consecutive weekdays, is necessary for consistent antidepressant effects [5]. Only the Alonso et al. study assessed the effects of rTMS compared with a sham control over at least 4 weeks [17]. However, rTMS was only administered three-times per week in this study;

At least two of these studies may have been underpowered, sug-•gesting results may be attributed to a type II error [17,18]. The low placebo response reported in patients with OCD supports this conclusion [20]. However, Sachdev and colleagues note that, given the effect size of their study, a very large sample would have been required to demonstrate a group difference [19]. All sham-controlled studies used methods that are recognized to provide adequate blinding (active coil, 90° to the head or inactive coil on the head with active coil discharged 1 m away);

Only two of these studies controlled for antidepressant effects •[18,19]. This is important given that rTMS to the PFCs has anti-depressant effects [15,21] and that comorbid depression is com-mon in OCD [22]. As such, it is very difficult to assess the effects of rTMS on OCD independently of depression;

The neural circuitry implicated in the pathogenesis of OCD is •not exclusively cortical. Given that rTMS is a focal treatment that is known to result in cortical depolarization up to a depth of 2 cm, it is possible that prefrontal rTMS is insufficient to modify abnormal subcortical circuitry in OCD, despite known trans-synaptic effects [3].

Post-traumatic stress disorder Neuroimaging studies have demonstrated that PTSD is associ-ated with hyperactivity of the amygdala and hypoactivity in the PFC [9,23]. The suggested abnormalities involve the PFC, particularly the OFC and DLPFC, and limbic and paralimbic regions, especially in the right hemisphere [10]. Based on this knowledge, prefrontal rTMS has been hypothesized as a possible therapeutic tool for the treatment of PTSD. Two preliminary studies (one open and one sham controlled) and case reports have assessed this hypothesis.

Ten PTSD patients were given one session of rTMS (0.3 Hz, 15 trains of 30 pulses, with a 1-min interval between trains) to each side of the motor cortex [24]. Results suggested a significant reduction in avoidance and somatization (measured by the Impact of Events Scale and the Symptoms Checklist [SCL]-90) in the 24 h following rTMS. Anxiety, measured by SCL-90, was also significantly reduced 24 h after rTMS and 28 days later. This preliminary result was intended to inform primarily on the safety, tolerability and potential efficacy of rTMS in PTSD patients. However, the rTMS protocol is extremely conservative, and provided little information regarding the safety and tolerability of rTMS in a therapeutic sense.

McCann et al. reported a reduction in the frequency of PTSD symptoms in two treatment-resistant PTSD patients [25]. Both patients (female, aged 29 and 42 years) were treated with right pre-frontal rTMS, 1 Hz at 80% MT, initially three-times per week, but increased to four- to five-times per week over a 4–6-week period. A reduction in the frequency of PTSD symptoms was reported in both cases, with the greatest improvement in symptom subjectively reported when the frequency of treatment sessions was increased. The effects were reported to last up to 1 month. Interestingly, both participants showed normalization of pretreatment hypermetabo-lism, particularly in the right hemisphere, measured by PET, after the course of rTMS. This is consistent with the hypothesis of right hemi-sphere hyperactivity in PTSD. In addition, in an open-treatment study comparing left DLPFC rTMS at 1 or 5 Hz, ten sessions (daily), was reported to improve mood, anxiety and sleep disturbances in 12 people with comorbid depression and PTSD [26].

The aforementioned results prompted a sham-controlled study [10]. Both high- (10 Hz) and low-frequency (1 Hz) rTMS (80% MT) over the right DLPFC were compared with each other and with sham rTMS in 24 PTSD patients. For sham treatment, an active coil was held at 90° to the head in the vertical position. After ten daily sessions, 10-Hz rTMS was significantly better than sham and 1-Hz rTMS in reducing PTSD symptoms, as measured by the PTSD Checklist and Treatment Outcome for PTSD scale. Additionally, levels of anxiety were significantly reduced in the high-frequency group when compared with both the sham and 1-Hz rTMS groups. The effects were stable for at least 14 days after treatment.

The result is in contrast to theories of right hemisphere hyper-activity in PTSD. High-frequency rTMS is reported to have an excitatory effect on cortical activity [27], which would theoreti-cally increase right hemisphere hyperactivity, exacerbating rather than reducing symptoms. For example, to this effect, feeling more emotional or anxious and spontaneously tearful was reported with bilateral DLPFC rTMS treatment at a frequency of 15 Hz [28].

The authors suggest the positive effect of high-frequency right rTMS may be related to re-establishing connectivity between an underactive PFC, which is theorized to mediate amygdala activity and amygdala hyperactivity in PTSD by increasing PFC activity. Alternatively, the result could be associated with increased acti-vation of the hypothalamic–pituitary–adrenal (HPA) axis, sug-gesting an association between right prefrontal hypoactivity and hypoactivity of the HPA axis [10]. Given the effects of rTMS in depression, high-frequency right stimulation would, theoretically, worsen depressive symptoms (often comorbid in PTSD) as hyper-activity of the HPA axis is commonly implicated in the patho-genesis of depression [29]. Another possible explanation is that of interindividual differences in cortical excitability with rTMS; such differences have been reported to be substantial [12]. Therfore, data on PTSD are too preliminary to make an informed decision on the role of rTMS in its treatment, and more definitive work is needed.

Other anxiety disordersEvidence for rTMS as a treatment option for other anxiety disor-ders, such as panic disorder (PD) and generalized anxiety disorder (GAD), is sparse and most of the literature is based on single case



reports. After a comprehensive literature search, only one sham-controlled, double-blind clinical trial was found assessing rTMS as a treatment for PD [30].

Two case reports have found that treatment with high-frequency (20 Hz) rTMS to the left PFC had a beneficial effect in treatment-resistant patients with PD [31,32]. Both reports used different treat-ment regimes. Guaiana and Robertson gave a 34-year-old female with PD and agoraphobia a course of 20 sessions (administered three-times per week) [31]. Significant improvement in panic symp-toms and agoraphobia was reported, which remained at remis-sion level 6 months after treatment. Interestingly, high-frequency left-sided rTMS was administered only after nine sessions of 1-Hz right-sided rTMS had failed. With 30 sessions of rTMS given twice daily (on weekdays) for 3 weeks, Sakkas et al. reported a clinically significant improvement in depression and panic symptoms in a 55-year-old male with comorbid depression and PD after a myo-cardial infarction [32]. This change was apparent immediately after the treatment course. Weekly treatment was then administered for 1 month and initial treatment response was maintained for 3 months after rTMS.

Using the alternative approach of 1-Hz right DLPFC rTMS, Garcia-Toro et al. treated three patients with PD [33]. After 2 weeks (ten sessions) of treatment, all patients experienced a modest, par-tial improvement in symptoms that, according to the authors, was not clinically relevant. Of the patients, two participated in a fur-ther ‘add-on’ study that alternated treatment between left 10-Hz rTMS and right 1-Hz rTMS, both to the prefrontal cortices. This additional treatment offered no further clinical benefit.

However, low-frequency righted-sided rTMS has also been reported to be effective. A case study reported that a 2-week course (ten sessions) of 1-Hz right-sided rTMS was effective for PD in a 52-year-old woman; between a 40 and 78% reduction in symptoms of anxiety and panic were reported [34]. An open trial assessed the efficacy of the same rTMS schedule in six patients with PD and comorbid major depression [35]. Clinical improve-ment was reported after the first week and, by the end of ten sessions, five had shown improvements in panic and anxiety, and four in depression. A significant difference between pre- and post-treatment scores on HAMA, HDRS and Panic Disorder Severity Scale (PDSS) was also reported.

In the only sham-controlled trial to date, Prasko and colleagues gave low-frequency (1 Hz) right DLPDC rTMS to 15 participants with PD resistant to treatment with selective serotonin-reuptake inhibitors (SSRIs) [30]. Participants were randomly allocated to receive ten sessions (on consecutive weekdays) of sham (active coil held at 90° to the head at the same intensity as real rTMS) or active rTMS in a double-blind, parallel-design trial. All partici-pants remained on SSRI treatment (to which they had previously failed to respond to) for the duration of the trial. Results showed all participants had a reduction in anxiety and PD symptoms (mea-sured by HAMA, PDSS, Beck Anxiety Inventory and the Clinical Global Impression scale) regardless of treatment condition.

Thus, although early case reports were encouraging in sug-gesting that either high-frequency left prefrontal rTMS or low-frequency (1 Hz) right prefrontal rTMS may be useful in the

treatment of anxiety disorders, particularly PD, the efficacy of these treatment approaches has not been confirmed by sham-con-trolled data. Furthermore, given the high comorbidity between anxiety disorders and depression, it is unclear how much of the improvement reported in some patients can be attributed to mood improvement secondary to rTMS, rather than direct effects on anxiety. Future adequately powered sham-controlled studies, con-trolling for mood changes, are needed to investigate the efficacy of rTMS in treating anxiety disorders.

The literature on the efficacy of rTMS in anxiety disorders has tended to look at a small subsection of anxiety disorders (OCD and PTSD) and failed to address the most prevalent anxiety disorder, general anxiety disorder (GAD). There have been no clinical trials of rTMS in patients with GAD. This is important when assessing the efficacy of rTMS in other disorders, as GAD contributes significantly to the high rate of comorbidity between anxiety disorders and depression [4].

Animal studies of the effects of rTMS on anxietyDespite a growing body of clinical research, very few studies have examined the effects of rTMS in animal models of anxiety. In line with clinical work, animal research has shown inconsistency in design and results. A handful of studies have used the elevated plus-maze (EPM) tests to assess the anxiolytic effects of rTMS in rats. Chronic rTMS treatment has been shown not to affect anxi-ety on the EPM test [36,37]. Furthermore, selectively bred, highly anxious rats did not benefit from 5 weeks of rTMS treatment, and anxiety was increased in a low-anxiety strain [38]. Anxiolytic effects have, however, been reported on the forced swim test, but the same animals failed to show an effect on the EPM [39]. Kanno and colleagues found some evidence for anxiolytic effects of rTMS on the EPM when administered at 25 Hz, suggesting the frequency of the stimulation is critical to anxiolytic effects [40]. By contrast, it has been reported that high-frequency (15 Hz) rTMS increases anxiety in normal rats after ten sessions [41]. It is important to note that replication of human anxiety disorders, particularly OCD, in valid animal models has proved difficult [42].

Expert commentary On review of the aforementioned literature, the evidence is not conclusive for the use of rTMS as treatment for anxiety disorders. While positive results have generally been reported in open studies and case reports, a variety of treatment parameters (location, fre-quency, intensity and duration) have been used, making the inter-pretation of results difficult and providing little guidance on what treatment parameters (i.e., stimulus location and frequency) may be the most useful in anxiety disorders. Sham-controlled research has often reported symptom improvement in all participants and has been unable to distinguish between response to active rTMS and sham treatment [18,19,30], suggesting that response may be attributed to a placebo effect (Table 1).

It is possible that the efficacy of rTMS in treating anxiety disor-ders is limited by the focal nature of the stimulation, with only the superficial layers of the cortex likely to be affected. With currently available TMS technology, it is not possible to directly stimulate



more distant cortical (e.g., orbitofrontal) and sub cortical (e.g., amygdala, hippocampus and striatum) regions, which are most likely to be relevant to the pathogenesis of anxiety disorders [2]. Effects on subcortical regions are thought to be indirect, via trans-synaptic connections [3]. In addition, the underlying neuro biological disturbance in anxiety disorders may be too diffuse to be easily targeted with TMS technology.

Second, rTMS may act in concert with the brain’s reparative processes in reversing mental disorders. It is likely that, since depression is self-remitting in many cases, rTMS works as an adjunct for this spontaneous process. Anxiety disorders on the other hand, do not have the clinical picture of self-remitting disorders, and rTMS may, therefore, be less likely to produce a lasting remission. With the caveat that different mechanisms are involved, electroconvulsive therapy is an effective treatment for depression but not for anxiety disorders, including OCD.

With the evidence equivocal, if not negative, it is difficult to recommend further studies that will clearly determine the role of rTMS in anxiety disorders. We think that more theoretical justification, as well as evidence in animal models, will assist in planning future studies. Key advances in rTMS and neuroimaging technology may also make its further study in anxiety disorders an imperative.

Five-year viewWe think that rTMS in its current form is not likely to emerge as an effective treatment of any of the anxiety disorders. It is likely that there will be technological advances in the delivery of TMS in the next few years, for example, z-burst stimula-tion and development of coils capable of stimulation at depth (H-coil), which are likely to result in more efficient stimulation parameters and the ability to deliver TMS to deeper cerebral

Table 1. Summary of open and controlled studies of repetitive transcranial magnetic stimulation as a treatment of anxiety in OCD, PTSD and PD.

Study Design n rTMS protocol Efficacy Ref.

OCD

Greenberg et al. (1997)

RCT Intra-individual crossover 3 sessions

12 DLPFC-R 20 Hz 80% MT and DLPFC-L 20 Hz 80% MT and midoccipital 20 Hz 80% MT (control)

Reduction of OCD symptoms with R-sided treatment*

[12]

Sachdev et al. (2001)

RCT/parallel 10 sessions (daily)

12 DLPFC-R 10 Hz 110% MT or DLPFC-L 10 Hz 110% MT

Reduction of OCD symptoms in both groups*

[13]

Alonso et al. (2001)

RCT/parallel 18 sessions (2nd daily)

18 DLPFC-R 1 Hz 110% MT or sham rTMS

No change of OCD symptoms in either group

[16]

Prasko et al. (2006)


30 DLPFC-L 1 Hz 110% MT or sham rTMS

Reduction of OCD and anxiety symptoms in both groups*

[17]

Mantovani et al. (2006)

Open 10 sessions (daily)

10 SMA R & L 1 Hz 100% MT Reduction of OCD and anxiety symptoms*

[8]

Sachdev et al. (2007)


18 DLPFC-L 10 Hz 110% MT or sham rTMS

No difference between rTMS and sham groups

[18]

PTSD

Grisaru et al. (1998)

Open 1 session

10 Motor cortex R and L 100% machine output

Reduction of anxiety, somatization and avoidance*

[22]

Rosenberg et al. (2002)

Open/parallel 10 sessions (daily)

15 DLPFC-L 1 Hz 90% MT or DLPFC-L 5 Hz 90% MT

Reduction in anxiety in both groups*; no group differences

[24]

Cohen et al. (2004)


24 DLPFC-R 1 Hz 80% MT or DLPFC-R 10 Hz 80% MT or sham rTMS

Reduction in PTSD and anxiety in R 10-Hz group in comparison to R 1-Hz and sham*

[10]

PD

Garcia-Toro et al. (2002)


3 DLPFC-R 1 Hz 110% MT Moderate reduction in PD symptoms [30]

Mantovani et al. (2007)


6 DLPFC–R 1 Hz 100% MT Reduction in anxiety, depression and panic symptoms*

[32]

Prasko et al. (2007)


15 DLPFC-R 1 Hz 110% MT or sham rTMS

Reduction in anxiety and PD in both groups; no group differences

[27]

*Significant at 0.05 level. DLPFC: Dorsolateral prefrontal cortex; L: Left; MT: Motor threshold; OCD: Obsessive–compulsive disorder; PD: Panic disorder; PTSD: Post-traumatic stress disorder; R: Right; RCT: Randomized clinical trial; rTMS: Repetitive transcranial magnetic stimulation; SMA: Supplementary motor area.



structures. If this occurs, the role of rTMS will be revisited in the future with further controlled studies.

Financial & competing interests disclosureThe authors received a National Health and Medical Research Council (Australia) Program Grant 510135. The authors have no other relevant affilia-tions or financial involvement with any organization or entity with a financial interest in or financial con-flict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the produc-tion of this manuscript.

ReferencesPapers of special note have been highlighted as:•ofinterest••ofconsiderableinterest

Greenberg PE, Sisitsky T, Kessler RC1 et al. The economic burden of anxiety disorders in the 1990s. J. Clin. Psychiatry 60(7), 427–435 (1999).

Ressler KJ, Mayberg HS. Targeting 2

abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat. Neurosci. 10(9), 1116–1124 (2007).

George MS, Wassermann EM, Post RM. 3

Transcranial magnetic stimulation: a neuropsychiatric tool for the 21st Century. J. Neuropsychiatry Clin. Neurosci. 8(4), 373–382 (1996).

Gorman JM. Comorbid depression and 4

anxiety spectrum disorders. Depress. Anxiety 4(4), 160–168 (1996).

Loo CK, Mitchell PB. A review of 5

the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. J. Affect. Disord. 88(3), 255–267 (2005).

Saxena S, Brody AL, Ho ML6 et al. Differential cerebral metabolic changes with paroxetine treatment of obsessive–compulsive disorder vs major depression. Arch. Gen. Psychiatry 59(3), 250–261 (2002).

Sheppard DM, Bradshaw JL, Purcell R7 et al. Tourette’s and comorbid syndromes: obsessive compulsive and attention deficit hyperactivity disorder. A common etiology? Clin. Psychol. Rev. 19(5), 531–552 (1999).

Mantovani A, Lisanby SH, Pieraccini F8 et al. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive–compulsive disorder (OCD) and Tourette’s syndrome (TS). Int. J. Neuropsychopharmcol. 9(1), 95–100 (2006).

Shin LM, Rauch SL, Pitman RK. 9

Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann. NY Acad. Sci. 1071, 67–79 (2006).

Cohen H, Kaplan Z, Kotler M10 et al. Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study. Am. J. Psychiatry 161(3), 515–524 (2004).

Provides a sophisticated review of the •evidence for repetitive transcranial magnetic stimulation (rTMS) as a potential treatment for post-traumatic stress disorder (PTSD) and presents a placebo-controlled study.

Pascual-Leone A, Catala MD, 11

Pascual-Leone Pascual A. Lateralized effect of rapid-rate transcranial magnetic stimulation of the prefrontal cortex on mood. Neurology 46(2), 499–502 (1996).

Maeda F, Keenan JP, Tormos JM, Topka 12

H, Pascual-Leone A. Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp. Brain Res. 133(4), 425–430 (2000).

Greenberg BD, George MS, Martin JD13 et al. Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study. Am. J. Psychiatry 154(6), 867–869 (1997).

Sachdev PS, McBride R, Loo CK14 et al. Right versus left prefrontal transcranial magnetic stimulation for obsessive–compulsive disorder: a preliminary investigation. J. Clin. Psychiatry 62(12), 981–984 (2001).

O’Reardon JP, Solvason HB, Janicak PG15 et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol. Psychiatry 62(11), 1208–1216 (2007).

Rossi S, Bartalini S, Ulivelli M16 et al. Hypofunctioning of sensory gating mechanisms in patients with obsessive–compulsive disorder. Biol. Psychiatry 57(1), 16–20 (2005).

Alonso P, Pujol J, Cardoner N17 et al. Right prefrontal repetitive transcranial magnetic stimulation in obsessive–compulsive disorder: a double-blind, placebo-controlled study. Am. J. Psychiatry 158(7), 1143–1145 (2001).

Prasko J, Paskova B, Zalesky R18 et al. The effect of repetitive transcranial magnetic stimulation (rTMS) on symptoms in obsessive compulsive disorder. A randomized, double blind, sham controlled study. Neuro. Endocrinol. Lett. 27(3), 327–332 (2006).

Presents a negative placebo-controlled •trial of rTMS in obsessive–compulsive disorder (OCD), outlining stimulus intensity, placement and the number of sessions as possible limitations.

Sachdev PS, Loo CK, Mitchell PB, 19

McFarquhar TF, Malhi GS. Repetitive transcranial magnetic stimulation for the treatment of obsessive compulsive disorder: a double-blind controlled investigation. Psychol. Med. 37(11), 1645–1649 (2007).

Key issues

Anxiety disorders are common, sometimes debilitating and often nonresponsive to • extant treatments.

The neurobiology of anxiety disorders is becoming increasingly clearer, and • abnormalities in prefrontal and limbic circuits are generally implicated.

Repetitive transcranial magnetic stimulation (rTMS) has been found to a have • therapeutic effects in another psychiatric disorder, (i.e., depression, with altered prefrontal and limbic circuitry).

rTMS has been studied as a treatment for obsessive–compulsive disorder, post-• traumatic stress disorder and panic disorder, but research has been limited by varied rTMS protocols, a lack of sham-controlled studies and small numbers.

Evidence for the efficacy of rTMS as treatment for anxiety disorders in controlled • studies is lacking.

Future research should address the issue of laterality in anxiety disorders and the ability • of rTMS to affect subcortical pathology in anxiety disorders.



Placebo-controlled trial using rTMS in ••OCD subjects. No clinical benefit was reported beyond an antidepressant effect (known to occur with the type of stimulation used).

Huppert JD, Schultz LT, Foa EB20 et al. Differential response to placebo among patients with social phobia, panic disorder, and obsessive-compulsive disorder. Am. J. Psychiatry 161(8), 1485–1487 (2004).

Herrmann LL, Ebmeier KP, Herrmann LL, 21

Ebmeier KP. Factors modifying the efficacy of transcranial magnetic stimulation in the treatment of depression: a review. J. Clin. Psychiatry 67(12), 1870–1876 (2006).

Abramowitz JS, Storch EA, Keeley M, 22

Cordell E. Obsessive–compulsive disorder with comorbid major depression: what is the role of cognitive factors? Behav. Res. Ther. 45(10), 2257–2267 (2007).

Bremner JD, Staib LH, Kaloupek D23 et al. Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study. Biol. Psychiatry 45(7), 806–816 (1999).

Grisaru N, Amir M, Cohen H, Kaplan Z. 24

Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study. Biol. Psychiatry 44(1), 52–55 (1998).

McCann UD, Kimbrell TA, Morgan CM25 et al. Repetitive transcranial magnetic stimulation for posttraumatic stress disorder. Arch. Gen. Psychiatry 55(3), 276–279 (1998).

Reports on two case studies where rTMS •was given for PTSD. Both cases reported improved symptoms, which were mirrored by decreases in cerebral metabolism in the right hemisphere.

Rosenberg PB, Mehndiratta RB, 26

Mehndiratta YP et al. Repetitive transcranial magnetic stimulation treatment of comorbid posttraumatic stress disorder and major depression.[see comment]. J. Neuropsychiatry Clin. Neurosci. 14(3), 270–276 (2002).

Speer AM, Kimbrell TA, Wassermann EM27 et al. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol. Psychiatry 48(12), 1133–1141 (2000).

Loo CK, Mitchell PB, Croker VM28 et al. Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychol. Med. 33(1), 33–40 (2003).

Thomson F, Craighead M. Innovative 29

approaches for the treatment of depression: targeting the HPA axis. Neurochem. Res. 33(4), 691–707 (2008).

Prasko J, Zalesky R, Bares M30 et al. The effect of repetitive transcranial magnetic stimulation (rTMS) add on serotonin reuptake inhibitors in patients with panic disorder: a randomized, double blind sham controlled study. Neuro. Endocrinol. Lett. 28(1), 33–38 (2007).

Negative sham-controlled clinical trial of ••rTMS for panic disorder. Both sham and rTMS treatment improved anxiety and panic symptoms when given with concurrent selective serotonin-reuptake inhibitor treatment.

Guaiana G, Mortimer AM, Robertson C. 31

Efficacy of transcranial magnetic stimulation in panic disorder: a case report. Aust. NZ J. Psychiatry 39(11–12), 1047 (2005).

Sakkas P, Psarros C, Papadimitriou GN, 32

Theleritis CG, Soldatos CR. Repetitive transcranial magnetic stimulation (rTMS) in a patient suffering from comorbid depression and panic disorder following a myocardial infarction. Prog. Neuropsychopharmacol. Biol. Psychiatry 30(5), 960–962 (2006).

Garcia-Toro M, Salva Coll J, Crespi Font M33 et al. Panic disorder and transcranial magnetic stimulation. Actas Esp. Psiquiatr. 30(4), 221–224 (2002).

Zwanzger P, Minov C, Ella R34 et al. Transcranial magnetic stimulation for panic. Am. J. Psychiatry 159(2), 315–316 (2002).

Mantovani A, Leckman JF, Grantz H35 et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in the treatment of Tourette syndrome: report of two cases. Clin. Neurophysiol. 118(10), 2314–2315 (2007).

Hargreaves GA, McGregor IS, Sachdev PS. 36

Chronic repetitive transcranial magnetic stimulation is antidepressant but not anxiolytic in rat models of anxiety and depression. Psychiatry Res. 137(1–2), 113–121 (2005).

An animal model of rTMS reported that ••rTMS had no effect on levels of anxiety, but an antidepressant effect was produced. This paper suggests the benefits noted in anxiety patients with rTMS treatment may be due to relief of symptoms of depression rather than anxiety.

Hedges DW, Higginbotham BJ, Salyer DL, 37

Lund TD. Transcranial magnetic stimulation effects on one-trial learning and response to anxiogenic stimuli in adult male rats. J. ECT 21(1), 25–30 (2005).

Keck ME, Welt T, Post A38 et al. Neuroendocrine and behavioral effects of repetitive transcranial magnetic stimulation in a psychopathological animal model are suggestive of antidepressant-like effects. Neuropsychopharmacology 24(4), 337–349 (2001).

Keck ME, Engelmann M, Muller MB39 et al. Repetitive transcranial magnetic stimulation induces active coping strategies and attenuates the neuroendocrine stress response in rats. J. Psychiatr. Res. 34(4–5), 265–276 (2000).

Kanno M, Matsumoto M, Togashi H40 et al. Effects of repetitive transcranial magnetic stimulation on behavioral and neurochemical changes in rats during an elevated plus-maze test. J. Neurol. Sci. 211(1–2), 5–14 (2003).

Isogawa K, Fujiki M, Akiyoshi J41 et al. Anxiolytic suppression of repetitive transcranial magnetic stimulation-induced anxiety in the rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 29(5), 664–668 (2005).

Joel D. Current animal models of obsessive 42

compulsive disorder: a critical review. Prog. Neuropsychopharmacol. Biol. Psychiatry 30(3), 374–388 (2006).

AffiliationsMelissa Pigot •School of Psychiatry, University of New South Wales; Black Dog Institute, Prince of Wales Hospital, Randwick, NSW 2031, Australia Tel.: +61 293 823 720 Fax: +61 293 828 151 [email protected]

Colleen Loo •School of Psychiatry, University of New South Wales; Black Dog Institute, Prince of Wales Hospital, Randwick, NSW 2031, Australia Tel.: +61 291 132 039 Fax: +61 291 133 734 [email protected]

Perminder Sachdev •Neuropsychiatric Institute; School of Psychiatry, University of New South Wales, Euroa Centre, Prince of Wales Hospital, Randwick, NSW 2031, Australia Tel.: +61 293 823 763 Fax: +61 293 823 772 [email protected]

repetitive transcranial magnetic stimulation as treatment for anxiety disorders

Documents