Age predicts low-frequency transcranial magnetic stimulation efficacy in major depression

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Author's personal copy Journal of Affective Disorders 130 (2011) 466–469

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Journal of Affective Disorders 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 / j a d

Preliminary communication

Age predicts low-frequency transcranial magnetic stimulation efficacy in major depression Iratxe Aguirre a, Blanca Carretero b, Olga Ibarra a, Javier Kuhalainen a, Jesús Martínez a, Alicia Ferrer a, Joan Salva a,c, Miquel Roca c, Margalida Gili c, Pedro Montoya c, Mauro Garcia-Toro b,c,⁎ a b c

Hospital Son Dureta, Mallorca, Spain Hospital Son Llatzer, Mallorca, Spain IUNICS, Universitat Illes Balears, Spain

a r t i c l e

i n f o

Article history: Received 16 July 2010 Received in revised form 15 October 2010 Accepted 23 October 2010 Available online 18 November 2010 Keywords: Depression Transcranial magnetic stimulation Low-frequency TMS Prefrontal cortex

a b s t r a c t Background: Transcranial magnetic stimulation (TMS) effectiveness in major depression has so far been studied mainly with high-frequency (N 1 Hz) administration (HF-TMS). However, some available studies with low-frequency TMS (LF-TMS) have provided similar response rates to HF-TMS with better tolerance, but the evidence is mixed and controversial. Methods: Randomized, controlled, two arm, clinical trial. 34 Major Depression patients were randomly assigned to receive 20 sessions of real or sham TMS of the right dorsolateral prefrontal cortex as adjuvant treatment to pharmacotherapy. The main stimulation parameters were 20 trains at 110% of the motor threshold for 60 s at a frequency of 1 Hz. Blinded external evaluators administered the Hamilton Depression Rating Scale. Results: Both treatment groups significantly improved, although there were no statistical differences between them. In the real TMS group patients age inversely correlated with improvement of depressive symptoms at the end of the study (r = −0683 p = 0.002). The percentage of decrease in scores on the Hamilton Scale was greater in subjects younger than 45 years old vs. others (41.3 +/− 22.6 vs. 15.1 +/− 15.8; t = 2.8 df = 16, p = 0.011). These real TMS subgroups did not differ significantly in their history of previous depressive disorders, or in the refractoriness indicators of the current episode. Limitations: Small size and highly refractory sample. Conclusion: Only younger patients benefited from LF-rTMS as adjuvant treatment to antidepressants in this study. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Major depression is a disabling prevalent disease, prone to chronicity (Schutter, 2009). Current treatments of choice are well established: pharmacotherapy and psychotherapy (Shelton

Abbreviations: HDRS, Hamilton Depression Rating Scale; TMS, transcranial magnetic stimulation. ⁎ Corresponding author. Servicio de Psiquiatría, Hospital Son Llatzer, C/ Ctra de Manacor, Km 4, 07198 Palma de Mallorca, Spain. Tel.: +34 971 259966; fax: +34 871 202354. E-mail address: [email protected] (M. Garcia-Toro). 0165-0327/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2010.10.038

et al., 2010). Nevertheless, an important proportion of patients either does not accept or is resistant to these two first-line treatments (George et al., 2010; Shelton et al., 2010). In such cases, several brain neurostimulation techniques, at different stages of development, are beginning to be proposed as an alternative (Marangell et al., 2007; Brunoni et al., 2010). Transcranial magnetic simulation (TMS) is one of those alternatives with increasingly scientific evidence behind it, although not all studies agree about its clinical usefulness (Herwig et al., 2007; Slotema et al., 2010; Bares et al., 2009). TMS effectiveness has been so far studied mainly with highfrequency (N1 Hz) administration (HF-TMS) (Gershon et al.,

Author's personal copy I. Aguirre et al. / Journal of Affective Disorders 130 (2011) 466–469

2003; George et al., 2010; Schutter, 2009). However, some available studies with low-frequency TMS (LF-TMS) have provided similar response rates to HF-TMS with a better tolerance level, but the evidence is mixed and controversial (Carretero et al., 2009; Pallanti et al., 2010; Schutter, 2010; Brunoni et al., 2010). Response and remission rates of TMS at the moment do not seem comparable to ECT and are highly variable inter-individually (Slotema et al., 2010). Based on the foregoing it is interesting to continue trying to confirm or, if possible, to increase LF-TMS effectiveness and define what type of patient profile may most benefit from the technique (Marangell et al., 2007). Therefore, the aim of this study is to analyze the efficacy of LF-rTMS as a coadjuvant to pharmacological treatment in patients with major depression. We also try to find therapeutic response predictors. 2. Methods The local research and ethics review board approved the study. All patients gave their written informed consent before entering the study, and after the procedure and objectives had been fully explained to them. Main criteria for inclusion were patients older than 18 years, fulfilling DSM-IV criteria for unipolar major depression. They also must have followed at least one adequate trial of antidepressant medication (maximum doses tolerated within the therapeutic range, for at least one month). Patients also were required to take the same medication during the last month before inclusion and to agree to continue doing so during the entire study. Prospective patients were screened for contraindications for TMS, including personal or family history of seizures, past neurosurgical procedures, implanted pacemaker, inner ear prosthesis, medication pumps and unstable medical conditions. Pregnant women or those of childbearing potential lacking an effective contraceptive method were also not included. Likewise, patients with a high suicidal risk were excluded. The study consisted of 4 weeks of treatment and 4 weeks of follow-up. The main characteristics of the clinical trial design were: two arms, randomized, simple-blinded with an external evaluator (patients and raters were blind to the procedure but not the physician who administered it). Stimulation sessions were held daily on working days for as many as 20 sessions with an approximate duration of 30 min per session. Investigators who were masked to the intervention made evaluations at baseline and weeks 2, 4, and 8. The scale used was the 17-item Hamilton Depression Rating Scale. The TMS sessions were carried out using DANTEC equipment (Dantec Medical, Medtronic Inc., Minneapolis, Minnesota, USA), MagPro model. We used a butterfly coil and each wing was 8.5 cm in diameter. The main stimulation parameters were 20 trains at 110% of motor threshold for 60 s at 1 Hz and a 45-s interval between trains. All together we administered a total of 1200 pulses at each of the 20 sessions. The stimulation area was the right dorsolateral prefrontal cortex (DLPC), 5 cm in front of the specular point that triggered a more selective right-thumb abduction response in the left motor cortex. Active LF-TMS was applied with the coil held flat on the scalp, and the handle pointing 45° laterally with respect to the midsagittal line. In the sham sessions, the coil was placed perpendicularly to the cranium at the calculated stimulation point, before being inclined 45° forwards on the axis. The

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magnetic field, therefore, did not significantly penetrate the brain, although the patient did hear the sound produced by the apparatus. At the end of each session patients were asked about possible secondary effects. All statistical analysis was performed at a significant threshold of 0.05, using the SPSS software package version 12.0 for Windows. A two-tailed Student's t test was used to compare independent and matched samples after confirming that distribution was normal. When the application of parametric tests was not possible, the Mann–Whitney test was used. Qualitative variables were compared using the chi-square and Fisher exact test. 3. Results The groups receiving active and sham treatment did not differ significantly in gender, age, baseline scores or other clinical parameters. All subjects were outpatients and non-psychotic. 66 patients were evaluated and 32 were discarded for not meeting all inclusion criteria. Of the 34 patients who began the study 19 were randomized to the real LF-TMS group and 15 to the sham LF-TMS group. There were only two drop-outs. One was in the active treatment group after the second week due to onset of alcohol abuse with irregular attendance at TMS sessions. The other was in the control group after the fourth week due to the emergence of a serious somatic disease (myeloma). Their data have been included in the statistical analysis. Tolerance was good, although 14 patients reported mild headache pain or discomfort associated with treatment (8 in the real stimulation group and 6 in the simulated). Four patients reported less localized discomfort or slight increases in anxiety during the sessions (two in the real TMS group and two in the sham). One patient of the real TMS group experienced a mild and short hypomanic episode when he finished the sessions, and it was the first time he had this experience. The antidepressants taken by the patients were very similar in both groups, with the majority of patients taking selective serotonin reuptake inhibitors. Most patients were also taking benzodiazepines in combination, 13 in the real LFTMS group and 8 in the sham group. The groups receiving real and sham TMS were comparable in all major clinical and sociodemographic parameters. Both groups clearly reduced their scores on the Hamilton Scale, but no statistical significant differences appeared between them. In the 19 patients who received active treatment, there was only one variable, age, which correlated with the decrease in Hamilton Scale scores, both at the end of 20 sessions (r = −0683 p=0.002) and four weeks later (r=−0631 p=0.005). The age of 45 years divided the sample into two similar subgroups (Table 1). They differed in the percentage of decrease in the score of the Hamilton Scale at week four (41.3+/− 22.6 vs. 15.1+/− 15.8, t=2 8 df=16, p=0.011) and at week eight (46.6+/− 22.7 vs. 8.1+/− 25.4, t=3.3, df=16, p=0.005). These real TMS subgroups did not differ significantly in their history of previous depressive disorders, nor in the refractoriness indicators of the current episode. 4. Discussion LF-TMS has been shown to decrease cortical excitability while the opposite is true for HF-TMS (Brunoni et al., 2010).

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Table 1 Age

b/=45

N45

No. Males No previous depressive episodes Depressive episode duration (months) Antidepressant treatment in present episode (months) HDRS baseline HDRS percentage decrement 2 week (SD) HDRS percentage decrement 4 week (SD) HDRS percentage decrement 8 week (SD) HDRS reduction over 25% HDRS reduction over 50% Respondent HDRS b8

10 3 2.8 (2.0) 13.2 (12.4) 6.1 (6.4)

9 5 4.3 (4.0) 12.0 (6.2) 4.8 (6.0)

23.1 25.5 41.3 46.6 8 6 3

(4.0) 19.4 (2.9) (21.6) 13.4 (4.3) (22.6) 15.1 (15.8)* (22.7) 8.1 (25.4)* 2 1 0

*Statistical difference.

Both actions have been correlated with major depression improvement, but applied to different hemispheres: LF-TMS to right DLPC and HF-TMS to left DLPC (Gershon et al., 2003). In this study we could not prove the effectiveness of applying 1 Hz-TMS in the right DLPC, despite having increased the number of sessions and intensity (20 sessions and 110% of motor threshold, respectively). Most previous LF-TMS studies used only 10 sessions and b100% of motor threshold intensity, and the majority of them were positive (Gross et al., 2007; Schutter, 2010). Enhancing the LF-TMS dose might not improve the results, despite what has been previously suggested (Gershon et al., 2003; Gross et al., 2007; Schutter, 2010). On the other hand, methodology limitations of this study could explain this negative result. The main limitation of this study is the lack of statistical power due to the relatively small sample size. In addition, the sample refractoriness to treatment is also another possible explanation: the majority of patients had been treated for more than four months with more than two prior antidepressant treatment attempts. There were also some other methodological limitations concerning the lack of measures to specifically locate the stimulation site, aside from moving 5 cm anterior to the location of motor response (Schönfeldt-Lecuona et al., 2010). Despite the previous limitations we found an inverse correlation between age and LF-TMS response. Refractoriness to previous treatment trials is a well established predictor of TMS response (Fregni et al., 2006; Brakemeier et al., 2007). In this study age and therapy response correlation could not be explained by a greater therapeutic refractoriness of older patients. Nor do we think that younger patients have a greater placebo response as previous studies have found no such association (Brunoni et al., 2009). To our knowledge this is the first time age has been a response predictor in LF-TMS. Younger depressed patients usually respond better to any antidepressant treatment, perhaps because of better brain plasticity. In HF-TMS research, age has also frequently been a predictor of therapeutic response to TMS, but not in all studies (Fregni et al., 2006; Herwig et al., 2007; Lisanby et al., 2009). The rationale of this finding has also been explained by a greater prefrontal cortical atrophy in older patients which limits HF-TMS magnetic field capability to reach the prefrontal cortex (Kozel et al., 2000). It is very likely that in the case of right DLPC LF-TMS elderly patients would also respond unsatisfactorily because of their incipient cortical atrophy.

This is the reason why, for patients with frontal atrophy, higher intensity and prolonged TMS have been suggested (Brunoni et al., 2010). It has previously been suggested that the action mechanism of LF- TMS in major depression and other mental and neurologic disorders is associated with the capability to revert an unbalance in cerebral activity (Hoffman and Cavus, 2002; Garcia-Toro et al., 2009). This study suggests that it could be easier to restore the balance of brain activity through LF-TMS in younger patients. Role of funding source Funding for this study was provided by the IUNICS Research Institute and the Mateu Orfila Foundation. Both Institutions had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest All authors declare that they have no conflicts of interests.

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