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Efficacy of high frequency (rapid) suprathreshold repetitive transcranial magnetic stimulation of right prefrontal cortex in bipolar mania: A randomized sham controlled study
Journal of Affective Disorders 117 (2009) 146–150
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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
Research report
Efficacy of high frequency (rapid) suprathreshold repetitive transcranial magnetic stimulation of right prefrontal cortex in bipolar mania: A randomized sham controlled study Samir Kumar Praharaj a,⁎, Daya Ram a, Manu Arora b a b
Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand, India, 834006 Government Medical College Jammu, Jammu & Kashmir, India
a r t i c l e
i n f o
Article history: Received 26 September 2008 Received in revised form 30 December 2008 Accepted 31 December 2008 Keywords: Bipolar affective disorder Mania rTMS
a b s t r a c t Objective: To examine the efficacy of adjunctive right prefrontal high-frequency suprathreshold rTMS treatment in bipolar affective disorder, mania patients as compared to sham stimulation. Method: 41 right handed bipolar mania patients were randomized to receive daily sessions of active or sham rTMS (20 Hz, 110% of MT, 20 trains, 10 s intertrain interval) over the right dorsolateral prefrontal cortex for 10 days. Mania was rated using Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) at baseline, and after 5th and 10th rTMS. Result: For YMRS scores, repeated measures ANOVA showed a significant effect of treatment over time as shown by interaction effect (F = 12.95, df = 1.51/58.94, p b 0.001, GreenhouseGeisser corrected). For CGI-S, repeated measures ANOVA showed a significant interaction effect of treatment over time (F = 5.34, df = 1.36/53.01, p = 0.016, Greenhouse-Geisser corrected). Conclusion: High-frequency supra-threshold right prefrontal rTMS in bipolar, mania patients was well tolerated and found to be effective as add-on to standard pharmacotherapy. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Bipolar disorder is a severe, chronic and often lifethreatening illness which affects approximately 1–3% of the population causing substantial psychosocial morbidity (Goodwin and Jamison, 1990). The therapeutic options available are limited by variable response, adverse effects and are not adequate for many patients. Transcranial magnetic stimulation (TMS) is a noninvasive method in which magnetic field over the surface of the head depolarizes underlying superficial neurons. Although the depth of penetration is limited, deeper brain structures can be influenced because of massive interconnections and redundant cortical-subcortical loops (George et al., 2002). Repetitive TMS (rTMS) has been found to inhibit or activate cortical areas which is frequency dependent; low-frequency rTMS (b1 Hz) has an inhibitory effect on cortical excitability and ⁎ Corresponding author. Tel.: +91 651 2231689; fax: +91 9431345765. E-mail addresses: [email protected] (S.K. Praharaj), [email protected] (D. Ram), [email protected] (M. Arora). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.12.020
decreases blood flow, whereas high-frequency rTMS (N5 Hz) may lead to activation of cortical areas and increase blood flow (Speer et al., 2000). These effects are being explored in the treatment of various neuropsychiatric disorders involving frontal hypometabolism in depression, mania and schizophrenia. The therapeutic effect of rTMS has been robust in the treatment of depression. Stimulation intensity is calculated as a percentage relative to the motor threshold (MT); when it exceeds MT it is known as suprathreshold rTMS, whereas subthreshold rTMS is designated to stimulation intensities below MT. Studies in depression suggest that more intense magnetic pulses (100–110% of MT) and more pulses per day (1200–1600 pulses/day) had better results than those in which less intense pulses (80–90% of MT) or fewer pulses per day (800–1000 pulses/day) were given (Gershon et al., 2003). An anterior-posterior gradient of blood flow and metabolism, i.e. hypofrontality has been suggested in major depressive disorder, more pronounced on the left side with a relative increase in nondominant hemispheric activity (Goodwin, 1997). Consistent with this hypothesis, there have been several studies suggesting significant antidepressant properties with
S.K. Praharaj et al. / Journal of Affective Disorders 117 (2009) 146–150
left prefrontal rapid rTMS (Burt et al., 2002) and less so with right prefrontal slow rTMS (Feinsod et al., 1998; Padberg et al., 1999; Klein et al.,1999, Isenberg et al., 2005). The opposite trend has been hypothesized in mania, i.e. the decreased anterior metabolism is more pronounced on the right side and a relative increase in metabolism on the left side (Grisaru et al., 1998). Furthermore, there is a reversal of hypofrontality with pharmacotherapy (Kumar et al., 1993) or with a switch from depression to hypomania or mania. On the basis of ECT-like effects of left prefrontal rTMS, Grisaru et al. (1998) conducted a double-blind controlled trial of right versus left prefrontal rapid rTMS in 16 bipolar mania patients. 20 Hz rTMS (2 s duration/train, 20 trains/session for 10 days; intertrain interval was 1 min) was delivered through a Cadwell high-speed magnetic stimulator with a 9-cm diameter circular coil at 80% of motor threshold. Right prefrontal rTMS was associated with significant improvement in YMRS scores as compared to left, with which worsening of mania was noted. This study indicated that the therapeutic effect of rTMS in mania may show laterality effect opposite to its effect in depression. Another double-blind sham-controlled study by Kaptsan et al. (2003) using right prefrontal rapid rTMS in 19 bipolar mania patients with same rTMS parameters as that of Grisaru et al. (1998), reported lack of therapeutic effect. Michael and Erfurth (2004) reported therapeutic efficacy of right prefrontal rapid rTMS in an open study on 9 patients with either bipolar mania or mixed episodes. In another open label study, Saba et al. (2004) reported significant improvement in manic symptoms with add-on right prefrontal rTMS (10-Hz, at 80% of MT,10 sessions, 5 trains of 15 s, intertrain interval of 20 s). These studies were limited by small sample size, subthreshold rTMS and lack of sham controls, except for the study by Kaptsan et al. (2003). Based on the earlier promising results by Grisaru et al. (1998), we planned to study the efficacy of adjunctive rapid right prefrontal suprathreshold rTMS in bipolar mania patients using a larger sample size, using suprathreshold stimuli and sham controls. 2. Materials and methods This was a prospective, hospital-based, single-blind, randomized, sham-controlled rTMS study carried out during September 2005 to August 2006 at the Centre of Cognitive Neurosciences Department of Central Institute of Psychiatry, Ranchi, India. The study was approved by the institutional review board. In this study 44 right handed, normotensive patients of either sex, aged between 18–60 years with a diagnosis of bipolar disorder, mania according to Diagnostic Criteria for Research of ICD-10 (WHO, 1992) were included in the study. Written informed consent was obtained from the patients prior to the study. Subjects with current neurological or any comorbid psychiatric disorders or history of drug abuse, past history of epilepsy, significant head injury or any neurosurgical procedure, with cardiac pacemakers or other metal parts in the body, or who have received ECT in past 6 months were excluded from the study. Patients were either drug-naïve or drug-free for at least 2 months prior to the current study. Three patients dropped out from the study as they did not cooperate during estimation of motor threshold due to manic hyperactivity. The selected 41 patients were alternatively assigned to receive either active rTMS (n = 21)
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or sham stimulation (n = 20) with first patient receiving active treatment. A semi-structured pro-forma was used for recording demographic and clinical details. The Hindi version of Handedness Preference Schedule (Mandal et al., 1992) which has 15 items was used to assess hand preference. The 11-item clinician administered Young Mania Rating Scale (YMRS; Young et al., 1978) and 21-item Structured Interview Guide for the Hamilton Depression Scale (SIGH-D; Janet and Williams, 1988) was used to assess severity of manic and depressive symptoms respectively. Clinical Global Impression (CGI; Guy, 1976) was used to assess overall illness severity and response to treatment. The MT for the right abductor pollicis brevis (APB) was determined using a figure-of-eight shaped coil at 1 Hz frequency according to Rossini-Rothwell algorithm (Rothwell et al., 1999). According to this algorithm, MT was defined as the lowest intensity, which produced 5 motor evoked potential (MEP) responses of at least 50 µV in 10 trials. The right prefrontal cortex rTMS stimulation site was determined by measuring 5 cm anterior and in a parasagittal line from the point of maximum stimulation of contralateral APB muscle (Rollnik et al., 2002). Patients were started on medications as decided by the treating team. Daily sessions of 20 Hz rTMS (at 110% of MT, 2 s/train, 20 trains/session, 10 s intertrain interval, 800 pulses/day) was administered after one week using Magstim Rapid device over the right dorsolateral prefrontal cortex (DLPFC) for 10 days. The sham group was administered rTMS after the first week of admission using same parameters with one wing of the coil at 45°angle with the head; in this position TMS does not produce MEPs but does produce scalp sensations (Speer et al., 2000; Rollnik et al., 2002). The stimulation sessions were performed as ‘addon’ to the ongoing medications as decided by the treating team. YMRS, SIGH-D and CGI were administered at baseline (on day 7) and after 5th and 10th rTMS sessions by SKP. The investigators were blind to the medications received by the patients during the study period which were solely decided by the treating team, who were blind to the treatment condition. The patients were blind to the treatment condition. 2.1. Statistical analyses The data was analyzed using the computer software program, Statistical Package for Social Sciences-version 14.0 for Windows. Socio-demographic and clinical variables were compared using independent t-test and chi-square test wherever applicable. To see the effect of treatment, the mean YMRS and CGI-S scores were compared between active and sham group using two way repeated measures ANOVA. Greenhouse-Geiser correction was applied considering violation of sphericity assumption. Effect sizes were calculated for the effect of treatment. The proportion of patients in each group that achieved remission was determined using chisquare test. Remission was defined as a score of 12 or less in YMRS as used by Tohen et al. (2000). 3. Results The socio-demographic and clinical profile of the active and sham group was comparable (Table 1). Males were
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Table 1 Socio-demographic and clinical profile of experimental groups. Variables
Active group N = 21 (Mean/N ± SD/%)
Sham group N = 20 (Mean/N ± SD/%)
χ2/t
df
p
Age (in years) Education (in years) Sex
29.76 ± 6.80 8.80 ± 4.91 18 (43.9%) 3 (7.3%) 9 (22%) 12 (29.3%) 5 (12.2%) 16 (39%) 20.71 ± 5.85 4.23 ± 2.84 3.80 ± 2.60 0.42 ± 0.67 49.52 ± 54.29 24.76 ± 7.52 359.35 ± 159.98
30.50 ± 7.99 8.80 ± 4.38 17 (41.5%) 3 (7.3%) 11 (26.8%) 9 (22%) 6 (14.6%) 14 (34.1%) 21.00 ± 5.98 4.05 ± 2.16 3.90 ± 2.22 0.15 ± 0.36 47.6 ± 46.32 26.05 ± 7.49 341.96 ± 166.61
− 0.32 0.08 0.01
39 39 1
0.752 0.995 0.948
0.61
1
0.437
0.20
1
0.655
− 0.15 0.24 − 0.12 1.63 0.12 − 0.55 0.34
39 39 39 39 39 39 39
0.878 0.814 0.905 0.112 0.904 0.586 0.735
10 (24.4%) 9 (22%) 2 (4.9%) 1069 ± 124.21 672.22 ± 90.59 1264.28 ± 373.75
13 (31.7%) 4 (9.8%) 3 (7.3%) 1078.84 ± 155.22 621.42 ± 112.63 1066.66 ± 115.47
− 0.16 0.87 0.73
21 11 3
0.875 0.403 0.589
Male Female Lower Middle Unmarried Married
Socioeconomic status Marital status Age of onset (in years) Total number of episodes Number of manic episodes Number of depressive episodes Duration of current episode (in days) Age at first hospitalization Dose of chlorpromazine equivalent (mg/day) Mood stabilizer
Dose of mood stabilizer (mg/day)
Lithium Carbamazepine Valproate Lithium Carbamazepine Valproate
⁎Significance at p b 0.05 (2-tailed).
overrepresented in the study (85.4%). Except one patient in the sham group, all other patients had psychotic symptoms, which were mood congruent. All the patients had received antipsychotic medications, which were converted to chlorpromazine equivalent per day (CPZ equivalent/day). The active group had received 359.35 ± 159.98 mg CPZ equivalent/day and sham group 341.96 ± 166.61 mg CPZ equivalent/ day during the study period, with no significant difference between two groups. More than half (56.1%) received lithium as mood stabilizer, followed by carbamazepine (31.8%), and the rest received sodium valproate. The mean dose of lithium, carbamazepine or sodium valproate between the active and sham groups was not statistically different. Motor threshold ranged from 60 to 85% (mean 67%) in the active group and 54 to 72% (mean 64%) in the sham group. The effect of rTMS on YMRS and CGI-S scores is shown in Table 2. For YMRS scores, repeated measures ANOVA showed a significant effect of treatment over time as shown by interaction effect (F = 12.95, df = 1.51/58.94, p b 0.001, Greenhouse-Geisser corrected). The effect size for treatment with time interaction for YMRS scores was .249 (eta squared). For CGI-S, repeated measures ANOVA showed a significant interaction effect of treatment over time (F = 5.34, df = 1.36/ 53.01, p = 0.016, Greenhouse-Geisser corrected). The effect Table 2 Effect of rTMS on YMRS and CGI-S in mania. Variables
YMRS Active Sham CGI-S Active Sham
Baseline
After 5th rTMS
After 10th rTMS
Mean ± SD
Mean ± SD
Mean ± SD
20.85 ± 5.21 19.35 ± 7.32
11.38 ± 5.05 14.70 ± 7.35
5.76 ± 3.26 11.05 ± 6.86
4.19 ± 0.60 4.20 ± 0.76
3.23 ± 0.62 3.55 ± 0.75
2.42 ± 0.59 3.10 ± 1.00
YMRS: Young Mania Rating Scale; CGI-S: Clinical Global Impression–Severity.
size for treatment with time interaction for CGI-S scores was .120 (eta squared). Patients receiving add-on active rTMS had higher remission rates (100%) as compared to 65% patients receiving sham rTMS (χ2 = 8.863, p = .003, Cramer's V = .465). One of the patients receiving active rTMS developed mild depression during the study period with SIGH-D score 10 after 10th rTMS, whereas none from the sham group developed clinical depression. There was no report of any serious adverse effect of rTMS or sham treatment. The most common complaint of the patients receiving active treatment was pain during stimulation which improved spontaneously after completion of the session. Transient headache was reported by 6 patients (28.57%) receiving active treatment following rTMS session, which lasted from less than an hour to four h. Of them three patients required simple analgesics such as paracetamol to control headache. Anxiety was reported by five patients during first rTMS session which decreased after reassurance. One patient reported dizziness after first rTMS session, which subsided spontaneously after one hour. 4. Discussion The patients who received active rTMS were comparable to the sham group with respect to age, sex, education, marital and socioeconomic status. The mean age of patients was 29.76 ± 6.80 years in active group and 30.50 ± 7.99 years in the sham group, which is less than that of Grisaru et al. (1998) and Kaptsan et al. (2003). Both the groups had similar age of onset of first episode, total number of episodes, number of manic and depressive episodes, duration of the current episode and age of first hospitalization. The mean age of onset of first episode was 19.42 ± 6.63 years in active group and 21.00 ± 5.98 years which is similar to that reported in the literature (Kessler et al., 1994). In our study, the pharmacological profile was comparable between both the groups
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which eliminate the confounding effect of medications on psychopathology as in Kaptsan et al. (2003). In previous controlled studies (Grisaru et al., 1998; Kaptsan et al., 2003) examining efficacy of rTMS in mania included no more than 20 patients. The dropout rates in previous studies have been higher, 11% in Grisaru et al. (1998) and 24% in Kaptsan et al. (2003) as compared to 7% in the present study. In the patients receiving active rTMS, the improvement in psychopathology as reflected in YMRS and CGI-S score was significantly greater than those who received sham treatment which suggests that right prefrontal rapid rTMS is effective as add-on in the treatment of bipolar disorder, manic episodes. Previous case reports (Erfurth et al., 2000), open studies (Michael and Erfurth, 2004; Saba et al., 2004) and one controlled study comparing left and right prefrontal stimulation (Grisaru et al., 1998) had reported similar findings. In our study the mean MT was 67% in active and 64% in sham group, which was similar to that of the sham-controlled study by Kaptsan et al. (2003) (63% in active and 65% in the sham group) in which rTMS was found to be ineffective. It is possible that subthreshold rTMS (80% of MT) in the study by Kaptsan et al. (2003) could have contributed to the lack of efficacy. Whereas, suprathreshold rTMS that was used in the present study has been reported to produce larger and more widespread regional cerebral blood flow changes (Nahas et al., 2001). This could possibly result in correcting the altered metabolism or blood flow that is associated with mania. Moreover, in a recent study (Knoch et al., 2006) it was demonstrated that right prefrontal rTMS induces a different pattern of rCBF changes than left prefrontal rTMS (i.e. a laterality effect), whereas high-frequency and low frequency rTMS lead to diverse frontal and remote area CBF changes (i.e. a frequency effect). The CBF changes were not restricted to the stimulated area but involved a range of areas of the frontolimbic circuits: when left-sided stimulation was applied, low frequency rTMS affected more areas in the fronto-limbic network than high-frequency stimulation, whereas in applying right-sided stimulation the high-frequency rTMS condition was associated with CBF changes in a larger number of remote areas compared to low-frequency rTMS. As the TMS parameters have not yet been optimized, a shorter intertrain interval could also contribute to the efficacy of rTMS observed in our study. The effect sizes for reduction in YMRS and CGI-S score was small accounting for only 6.2% and 1.44% of the total variance, respectively. All patients receiving add-on active rTMS achieved remission as defined by Tohen et al. (2000) as compared to 65% receiving sham stimulation. The effect size for achieving remission was moderate. Kaptsan et al. (2003) has argued that a higher number of psychotic mania cases in their sample (84.21%) might have led to lack of efficacy. Similar findings were reported in a previous study by Grunhaus et al. (2003), who argued that absence of psychosis may be a predictor of treatment success. Interestingly, in our sample 97.56% of patients had psychotic symptoms. Similar result was reported by previous studies in which both psychotic and non psychotic depression responded better to rTMS than sham stimulation (PascualLeone et al., 1996; Ray et al., 2005). One of the patients who received active rTMS developed clinical depression after 10th rTMS. It can be hypothesized that in this patient rTMS overcorrected the underlying
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pathophysiology so as to produce a clinical state opposite to mania. Nevertheless, spontaneous switch to depression cannot be ruled out, as it is known to occur during the clinical course of manic episodes. Also, the effect of medications might contribute to production of similar state. In the present study rTMS was found to be tolerated well by the patients with benign adverse effect profile; most common were pain during the procedure, transient headache, dizziness and anxiety. The limitations of the study included lack of double blinding which could lead to rater bias during the assessment of psychopathology. Alternative assignment of the patients to either treatment group does not represent true randomization is another limitation. The DLPFC of patients was located using the “5 cm rule”, which does not take into consideration the shape and size of a person's head (George et al., 1997). This may result in some variations in the exact site of stimulation in the prefrontal cortex. Although the use of sham rTMS by tilting the coil reduces cortical stimulation, still it may involve low level of cortical stimulation (Loo et al., 2000). Alternative methods used in recent studies (e.g. Rumi et al., 2005) involve placebo or inactive coils that do not produce cortical stimulation. Females were underrepresented in the study group. It will be helpful to study rTMS as monotherapy, initially in hypomania and less severe mania cases where this will be ethically possible. Further studies are required to optimize TMS parameters. The period of TMS to maintain the gains produced need to be examined with longer follow up studies. Furthermore, studies using low frequency left prefrontal rTMS need to be done to examine its efficacy in mania, which would further support that the laterality effect of rTMS in mania, similar to that of studies in depression. Neurophysiological variables such as quantitative EEG, evoked potentials, frontal activation tasks should be measured along with rTMS in mania for more comprehensive assessment of the treatment effect. Studies that combine SPECT or PET scan along with rTMS might be required to demonstrate the brain regions that are implicated. 5. Conclusion Rapid supra-threshold right prefrontal rTMS in bipolar, mania patients was well tolerated and found to be effective as add-on to standard pharmacotherapy. Role of funding source Nothing declared. Conflict of Interest No conflict declared.
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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
Research report
Efficacy of high frequency (rapid) suprathreshold repetitive transcranial magnetic stimulation of right prefrontal cortex in bipolar mania: A randomized sham controlled study Samir Kumar Praharaj a,⁎, Daya Ram a, Manu Arora b a b
Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand, India, 834006 Government Medical College Jammu, Jammu & Kashmir, India
a r t i c l e
i n f o
Article history: Received 26 September 2008 Received in revised form 30 December 2008 Accepted 31 December 2008 Keywords: Bipolar affective disorder Mania rTMS
a b s t r a c t Objective: To examine the efficacy of adjunctive right prefrontal high-frequency suprathreshold rTMS treatment in bipolar affective disorder, mania patients as compared to sham stimulation. Method: 41 right handed bipolar mania patients were randomized to receive daily sessions of active or sham rTMS (20 Hz, 110% of MT, 20 trains, 10 s intertrain interval) over the right dorsolateral prefrontal cortex for 10 days. Mania was rated using Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) at baseline, and after 5th and 10th rTMS. Result: For YMRS scores, repeated measures ANOVA showed a significant effect of treatment over time as shown by interaction effect (F = 12.95, df = 1.51/58.94, p b 0.001, GreenhouseGeisser corrected). For CGI-S, repeated measures ANOVA showed a significant interaction effect of treatment over time (F = 5.34, df = 1.36/53.01, p = 0.016, Greenhouse-Geisser corrected). Conclusion: High-frequency supra-threshold right prefrontal rTMS in bipolar, mania patients was well tolerated and found to be effective as add-on to standard pharmacotherapy. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Bipolar disorder is a severe, chronic and often lifethreatening illness which affects approximately 1–3% of the population causing substantial psychosocial morbidity (Goodwin and Jamison, 1990). The therapeutic options available are limited by variable response, adverse effects and are not adequate for many patients. Transcranial magnetic stimulation (TMS) is a noninvasive method in which magnetic field over the surface of the head depolarizes underlying superficial neurons. Although the depth of penetration is limited, deeper brain structures can be influenced because of massive interconnections and redundant cortical-subcortical loops (George et al., 2002). Repetitive TMS (rTMS) has been found to inhibit or activate cortical areas which is frequency dependent; low-frequency rTMS (b1 Hz) has an inhibitory effect on cortical excitability and ⁎ Corresponding author. Tel.: +91 651 2231689; fax: +91 9431345765. E-mail addresses: [email protected] (S.K. Praharaj), [email protected] (D. Ram), [email protected] (M. Arora). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.12.020
decreases blood flow, whereas high-frequency rTMS (N5 Hz) may lead to activation of cortical areas and increase blood flow (Speer et al., 2000). These effects are being explored in the treatment of various neuropsychiatric disorders involving frontal hypometabolism in depression, mania and schizophrenia. The therapeutic effect of rTMS has been robust in the treatment of depression. Stimulation intensity is calculated as a percentage relative to the motor threshold (MT); when it exceeds MT it is known as suprathreshold rTMS, whereas subthreshold rTMS is designated to stimulation intensities below MT. Studies in depression suggest that more intense magnetic pulses (100–110% of MT) and more pulses per day (1200–1600 pulses/day) had better results than those in which less intense pulses (80–90% of MT) or fewer pulses per day (800–1000 pulses/day) were given (Gershon et al., 2003). An anterior-posterior gradient of blood flow and metabolism, i.e. hypofrontality has been suggested in major depressive disorder, more pronounced on the left side with a relative increase in nondominant hemispheric activity (Goodwin, 1997). Consistent with this hypothesis, there have been several studies suggesting significant antidepressant properties with
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left prefrontal rapid rTMS (Burt et al., 2002) and less so with right prefrontal slow rTMS (Feinsod et al., 1998; Padberg et al., 1999; Klein et al.,1999, Isenberg et al., 2005). The opposite trend has been hypothesized in mania, i.e. the decreased anterior metabolism is more pronounced on the right side and a relative increase in metabolism on the left side (Grisaru et al., 1998). Furthermore, there is a reversal of hypofrontality with pharmacotherapy (Kumar et al., 1993) or with a switch from depression to hypomania or mania. On the basis of ECT-like effects of left prefrontal rTMS, Grisaru et al. (1998) conducted a double-blind controlled trial of right versus left prefrontal rapid rTMS in 16 bipolar mania patients. 20 Hz rTMS (2 s duration/train, 20 trains/session for 10 days; intertrain interval was 1 min) was delivered through a Cadwell high-speed magnetic stimulator with a 9-cm diameter circular coil at 80% of motor threshold. Right prefrontal rTMS was associated with significant improvement in YMRS scores as compared to left, with which worsening of mania was noted. This study indicated that the therapeutic effect of rTMS in mania may show laterality effect opposite to its effect in depression. Another double-blind sham-controlled study by Kaptsan et al. (2003) using right prefrontal rapid rTMS in 19 bipolar mania patients with same rTMS parameters as that of Grisaru et al. (1998), reported lack of therapeutic effect. Michael and Erfurth (2004) reported therapeutic efficacy of right prefrontal rapid rTMS in an open study on 9 patients with either bipolar mania or mixed episodes. In another open label study, Saba et al. (2004) reported significant improvement in manic symptoms with add-on right prefrontal rTMS (10-Hz, at 80% of MT,10 sessions, 5 trains of 15 s, intertrain interval of 20 s). These studies were limited by small sample size, subthreshold rTMS and lack of sham controls, except for the study by Kaptsan et al. (2003). Based on the earlier promising results by Grisaru et al. (1998), we planned to study the efficacy of adjunctive rapid right prefrontal suprathreshold rTMS in bipolar mania patients using a larger sample size, using suprathreshold stimuli and sham controls. 2. Materials and methods This was a prospective, hospital-based, single-blind, randomized, sham-controlled rTMS study carried out during September 2005 to August 2006 at the Centre of Cognitive Neurosciences Department of Central Institute of Psychiatry, Ranchi, India. The study was approved by the institutional review board. In this study 44 right handed, normotensive patients of either sex, aged between 18–60 years with a diagnosis of bipolar disorder, mania according to Diagnostic Criteria for Research of ICD-10 (WHO, 1992) were included in the study. Written informed consent was obtained from the patients prior to the study. Subjects with current neurological or any comorbid psychiatric disorders or history of drug abuse, past history of epilepsy, significant head injury or any neurosurgical procedure, with cardiac pacemakers or other metal parts in the body, or who have received ECT in past 6 months were excluded from the study. Patients were either drug-naïve or drug-free for at least 2 months prior to the current study. Three patients dropped out from the study as they did not cooperate during estimation of motor threshold due to manic hyperactivity. The selected 41 patients were alternatively assigned to receive either active rTMS (n = 21)
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or sham stimulation (n = 20) with first patient receiving active treatment. A semi-structured pro-forma was used for recording demographic and clinical details. The Hindi version of Handedness Preference Schedule (Mandal et al., 1992) which has 15 items was used to assess hand preference. The 11-item clinician administered Young Mania Rating Scale (YMRS; Young et al., 1978) and 21-item Structured Interview Guide for the Hamilton Depression Scale (SIGH-D; Janet and Williams, 1988) was used to assess severity of manic and depressive symptoms respectively. Clinical Global Impression (CGI; Guy, 1976) was used to assess overall illness severity and response to treatment. The MT for the right abductor pollicis brevis (APB) was determined using a figure-of-eight shaped coil at 1 Hz frequency according to Rossini-Rothwell algorithm (Rothwell et al., 1999). According to this algorithm, MT was defined as the lowest intensity, which produced 5 motor evoked potential (MEP) responses of at least 50 µV in 10 trials. The right prefrontal cortex rTMS stimulation site was determined by measuring 5 cm anterior and in a parasagittal line from the point of maximum stimulation of contralateral APB muscle (Rollnik et al., 2002). Patients were started on medications as decided by the treating team. Daily sessions of 20 Hz rTMS (at 110% of MT, 2 s/train, 20 trains/session, 10 s intertrain interval, 800 pulses/day) was administered after one week using Magstim Rapid device over the right dorsolateral prefrontal cortex (DLPFC) for 10 days. The sham group was administered rTMS after the first week of admission using same parameters with one wing of the coil at 45°angle with the head; in this position TMS does not produce MEPs but does produce scalp sensations (Speer et al., 2000; Rollnik et al., 2002). The stimulation sessions were performed as ‘addon’ to the ongoing medications as decided by the treating team. YMRS, SIGH-D and CGI were administered at baseline (on day 7) and after 5th and 10th rTMS sessions by SKP. The investigators were blind to the medications received by the patients during the study period which were solely decided by the treating team, who were blind to the treatment condition. The patients were blind to the treatment condition. 2.1. Statistical analyses The data was analyzed using the computer software program, Statistical Package for Social Sciences-version 14.0 for Windows. Socio-demographic and clinical variables were compared using independent t-test and chi-square test wherever applicable. To see the effect of treatment, the mean YMRS and CGI-S scores were compared between active and sham group using two way repeated measures ANOVA. Greenhouse-Geiser correction was applied considering violation of sphericity assumption. Effect sizes were calculated for the effect of treatment. The proportion of patients in each group that achieved remission was determined using chisquare test. Remission was defined as a score of 12 or less in YMRS as used by Tohen et al. (2000). 3. Results The socio-demographic and clinical profile of the active and sham group was comparable (Table 1). Males were
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Table 1 Socio-demographic and clinical profile of experimental groups. Variables
Active group N = 21 (Mean/N ± SD/%)
Sham group N = 20 (Mean/N ± SD/%)
χ2/t
df
p
Age (in years) Education (in years) Sex
29.76 ± 6.80 8.80 ± 4.91 18 (43.9%) 3 (7.3%) 9 (22%) 12 (29.3%) 5 (12.2%) 16 (39%) 20.71 ± 5.85 4.23 ± 2.84 3.80 ± 2.60 0.42 ± 0.67 49.52 ± 54.29 24.76 ± 7.52 359.35 ± 159.98
30.50 ± 7.99 8.80 ± 4.38 17 (41.5%) 3 (7.3%) 11 (26.8%) 9 (22%) 6 (14.6%) 14 (34.1%) 21.00 ± 5.98 4.05 ± 2.16 3.90 ± 2.22 0.15 ± 0.36 47.6 ± 46.32 26.05 ± 7.49 341.96 ± 166.61
− 0.32 0.08 0.01
39 39 1
0.752 0.995 0.948
0.61
1
0.437
0.20
1
0.655
− 0.15 0.24 − 0.12 1.63 0.12 − 0.55 0.34
39 39 39 39 39 39 39
0.878 0.814 0.905 0.112 0.904 0.586 0.735
10 (24.4%) 9 (22%) 2 (4.9%) 1069 ± 124.21 672.22 ± 90.59 1264.28 ± 373.75
13 (31.7%) 4 (9.8%) 3 (7.3%) 1078.84 ± 155.22 621.42 ± 112.63 1066.66 ± 115.47
− 0.16 0.87 0.73
21 11 3
0.875 0.403 0.589
Male Female Lower Middle Unmarried Married
Socioeconomic status Marital status Age of onset (in years) Total number of episodes Number of manic episodes Number of depressive episodes Duration of current episode (in days) Age at first hospitalization Dose of chlorpromazine equivalent (mg/day) Mood stabilizer
Dose of mood stabilizer (mg/day)
Lithium Carbamazepine Valproate Lithium Carbamazepine Valproate
⁎Significance at p b 0.05 (2-tailed).
overrepresented in the study (85.4%). Except one patient in the sham group, all other patients had psychotic symptoms, which were mood congruent. All the patients had received antipsychotic medications, which were converted to chlorpromazine equivalent per day (CPZ equivalent/day). The active group had received 359.35 ± 159.98 mg CPZ equivalent/day and sham group 341.96 ± 166.61 mg CPZ equivalent/ day during the study period, with no significant difference between two groups. More than half (56.1%) received lithium as mood stabilizer, followed by carbamazepine (31.8%), and the rest received sodium valproate. The mean dose of lithium, carbamazepine or sodium valproate between the active and sham groups was not statistically different. Motor threshold ranged from 60 to 85% (mean 67%) in the active group and 54 to 72% (mean 64%) in the sham group. The effect of rTMS on YMRS and CGI-S scores is shown in Table 2. For YMRS scores, repeated measures ANOVA showed a significant effect of treatment over time as shown by interaction effect (F = 12.95, df = 1.51/58.94, p b 0.001, Greenhouse-Geisser corrected). The effect size for treatment with time interaction for YMRS scores was .249 (eta squared). For CGI-S, repeated measures ANOVA showed a significant interaction effect of treatment over time (F = 5.34, df = 1.36/ 53.01, p = 0.016, Greenhouse-Geisser corrected). The effect Table 2 Effect of rTMS on YMRS and CGI-S in mania. Variables
YMRS Active Sham CGI-S Active Sham
Baseline
After 5th rTMS
After 10th rTMS
Mean ± SD
Mean ± SD
Mean ± SD
20.85 ± 5.21 19.35 ± 7.32
11.38 ± 5.05 14.70 ± 7.35
5.76 ± 3.26 11.05 ± 6.86
4.19 ± 0.60 4.20 ± 0.76
3.23 ± 0.62 3.55 ± 0.75
2.42 ± 0.59 3.10 ± 1.00
YMRS: Young Mania Rating Scale; CGI-S: Clinical Global Impression–Severity.
size for treatment with time interaction for CGI-S scores was .120 (eta squared). Patients receiving add-on active rTMS had higher remission rates (100%) as compared to 65% patients receiving sham rTMS (χ2 = 8.863, p = .003, Cramer's V = .465). One of the patients receiving active rTMS developed mild depression during the study period with SIGH-D score 10 after 10th rTMS, whereas none from the sham group developed clinical depression. There was no report of any serious adverse effect of rTMS or sham treatment. The most common complaint of the patients receiving active treatment was pain during stimulation which improved spontaneously after completion of the session. Transient headache was reported by 6 patients (28.57%) receiving active treatment following rTMS session, which lasted from less than an hour to four h. Of them three patients required simple analgesics such as paracetamol to control headache. Anxiety was reported by five patients during first rTMS session which decreased after reassurance. One patient reported dizziness after first rTMS session, which subsided spontaneously after one hour. 4. Discussion The patients who received active rTMS were comparable to the sham group with respect to age, sex, education, marital and socioeconomic status. The mean age of patients was 29.76 ± 6.80 years in active group and 30.50 ± 7.99 years in the sham group, which is less than that of Grisaru et al. (1998) and Kaptsan et al. (2003). Both the groups had similar age of onset of first episode, total number of episodes, number of manic and depressive episodes, duration of the current episode and age of first hospitalization. The mean age of onset of first episode was 19.42 ± 6.63 years in active group and 21.00 ± 5.98 years which is similar to that reported in the literature (Kessler et al., 1994). In our study, the pharmacological profile was comparable between both the groups
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which eliminate the confounding effect of medications on psychopathology as in Kaptsan et al. (2003). In previous controlled studies (Grisaru et al., 1998; Kaptsan et al., 2003) examining efficacy of rTMS in mania included no more than 20 patients. The dropout rates in previous studies have been higher, 11% in Grisaru et al. (1998) and 24% in Kaptsan et al. (2003) as compared to 7% in the present study. In the patients receiving active rTMS, the improvement in psychopathology as reflected in YMRS and CGI-S score was significantly greater than those who received sham treatment which suggests that right prefrontal rapid rTMS is effective as add-on in the treatment of bipolar disorder, manic episodes. Previous case reports (Erfurth et al., 2000), open studies (Michael and Erfurth, 2004; Saba et al., 2004) and one controlled study comparing left and right prefrontal stimulation (Grisaru et al., 1998) had reported similar findings. In our study the mean MT was 67% in active and 64% in sham group, which was similar to that of the sham-controlled study by Kaptsan et al. (2003) (63% in active and 65% in the sham group) in which rTMS was found to be ineffective. It is possible that subthreshold rTMS (80% of MT) in the study by Kaptsan et al. (2003) could have contributed to the lack of efficacy. Whereas, suprathreshold rTMS that was used in the present study has been reported to produce larger and more widespread regional cerebral blood flow changes (Nahas et al., 2001). This could possibly result in correcting the altered metabolism or blood flow that is associated with mania. Moreover, in a recent study (Knoch et al., 2006) it was demonstrated that right prefrontal rTMS induces a different pattern of rCBF changes than left prefrontal rTMS (i.e. a laterality effect), whereas high-frequency and low frequency rTMS lead to diverse frontal and remote area CBF changes (i.e. a frequency effect). The CBF changes were not restricted to the stimulated area but involved a range of areas of the frontolimbic circuits: when left-sided stimulation was applied, low frequency rTMS affected more areas in the fronto-limbic network than high-frequency stimulation, whereas in applying right-sided stimulation the high-frequency rTMS condition was associated with CBF changes in a larger number of remote areas compared to low-frequency rTMS. As the TMS parameters have not yet been optimized, a shorter intertrain interval could also contribute to the efficacy of rTMS observed in our study. The effect sizes for reduction in YMRS and CGI-S score was small accounting for only 6.2% and 1.44% of the total variance, respectively. All patients receiving add-on active rTMS achieved remission as defined by Tohen et al. (2000) as compared to 65% receiving sham stimulation. The effect size for achieving remission was moderate. Kaptsan et al. (2003) has argued that a higher number of psychotic mania cases in their sample (84.21%) might have led to lack of efficacy. Similar findings were reported in a previous study by Grunhaus et al. (2003), who argued that absence of psychosis may be a predictor of treatment success. Interestingly, in our sample 97.56% of patients had psychotic symptoms. Similar result was reported by previous studies in which both psychotic and non psychotic depression responded better to rTMS than sham stimulation (PascualLeone et al., 1996; Ray et al., 2005). One of the patients who received active rTMS developed clinical depression after 10th rTMS. It can be hypothesized that in this patient rTMS overcorrected the underlying
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pathophysiology so as to produce a clinical state opposite to mania. Nevertheless, spontaneous switch to depression cannot be ruled out, as it is known to occur during the clinical course of manic episodes. Also, the effect of medications might contribute to production of similar state. In the present study rTMS was found to be tolerated well by the patients with benign adverse effect profile; most common were pain during the procedure, transient headache, dizziness and anxiety. The limitations of the study included lack of double blinding which could lead to rater bias during the assessment of psychopathology. Alternative assignment of the patients to either treatment group does not represent true randomization is another limitation. The DLPFC of patients was located using the “5 cm rule”, which does not take into consideration the shape and size of a person's head (George et al., 1997). This may result in some variations in the exact site of stimulation in the prefrontal cortex. Although the use of sham rTMS by tilting the coil reduces cortical stimulation, still it may involve low level of cortical stimulation (Loo et al., 2000). Alternative methods used in recent studies (e.g. Rumi et al., 2005) involve placebo or inactive coils that do not produce cortical stimulation. Females were underrepresented in the study group. It will be helpful to study rTMS as monotherapy, initially in hypomania and less severe mania cases where this will be ethically possible. Further studies are required to optimize TMS parameters. The period of TMS to maintain the gains produced need to be examined with longer follow up studies. Furthermore, studies using low frequency left prefrontal rTMS need to be done to examine its efficacy in mania, which would further support that the laterality effect of rTMS in mania, similar to that of studies in depression. Neurophysiological variables such as quantitative EEG, evoked potentials, frontal activation tasks should be measured along with rTMS in mania for more comprehensive assessment of the treatment effect. Studies that combine SPECT or PET scan along with rTMS might be required to demonstrate the brain regions that are implicated. 5. Conclusion Rapid supra-threshold right prefrontal rTMS in bipolar, mania patients was well tolerated and found to be effective as add-on to standard pharmacotherapy. Role of funding source Nothing declared. Conflict of Interest No conflict declared.
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