- Email: [email protected]
Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in major depression: A systematic review
Accepted Manuscript Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in major depression: A systematic review Karina Karolina Kedzior, Maria Schuchinsky, Imke Gerkensmeier, Colleen Loo PII:
S0022-3956(16)30555-6
DOI:
10.1016/j.jpsychires.2017.03.002
Reference:
PIAT 3084
To appear in:
Journal of Psychiatric Research
Received Date: 24 October 2016 Revised Date:
8 February 2017
Accepted Date: 1 March 2017
Please cite this article as: Kedzior KK, Schuchinsky M, Gerkensmeier I, Loo C, Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in major depression: A systematic review, Journal of Psychiatric Research (2017), doi: 10.1016/j.jpsychires.2017.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in
Authors and affiliations
RI PT
major depression: a systematic review
Karina Karolina Kedziora*; Maria Schuchinskyb; Imke Gerkensmeiera; Colleen Looc a
University of Bremen, Germany; bUniversity of Limerick, Ireland; cUniversity of New South
AC C
EP
TE D
M AN U
*Corresponding author ([email protected])
SC
Wales, Black Dog Institute, and St. George Hospital, Australia
1
ACCEPTED MANUSCRIPT Abstract The present study aimed to systematically compare the cognitive outcomes of highfrequency repetitive transcranial magnetic stimulation (HF-rTMS) and electroconvulsive therapy (ECT) in head-to-head studies with major depression (MDD) patients. A systematic
RI PT
literature search identified six studies with 219 MDD patients that were too heterogeneous to reliably detect meaningful differences in acute cognitive outcomes after ECT vs. HF-rTMS. Cognitive effects of brain stimulation vary depending on the timeframe and methods of
SC
assessment, stimulation parameters, and maintenance treatment. Thus, acute and longer-term differences in cognitive outcomes both need to be investigated at precisely defined
M AN U
timeframes and with similar instruments assessing comparable functions.
Keywords: high-frequency repetitive transcranial magnetic stimulation (HF-rTMS);
AC C
EP
TE D
electroconvulsive therapy (ECT); cognition; major depressive disorder (MDD)
ACCEPTED MANUSCRIPT Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in major depression: A systematic review Introduction
RI PT
Electroconvulsive therapy (ECT) is the oldest non-invasive brain stimulation method utilised in the treatment of major depression (MDD) today. Although clinically effective in unipolar and bipolar MDD (Loo et al., 2011), ECT potentially has detrimental cognitive side-
SC
effects (Sackeim et al., 2007). Such cognitive side-effects, including amnesia and slowing of reaction times, occur immediately after treatment and may persist for 6 months with some
M AN U
forms of ECT (Sackeim et al., 2007). Cognitive impairment after ECT can be influenced by concurrent pharmacotherapy, including antidepressants and lithium (Loo et al., 2011; Pigot et al., 2008; Sackeim et al., 2009) and is minimised with specific stimulation forms and parameters, such as ultrabrief pulse, right unilateral ECT (Tor et al., 2015).
TE D
In contrast to ECT, one of the newer non-invasive brain stimulation methods, namely high-frequency repetitive transcranial magnetic stimulation (HF-rTMS), does not require anaesthesia and tends to have little detrimental cognitive effects (Martin et al., 2016) or may
EP
even enhance cognitive functioning in MDD (Serafini et al., 2015). Patients with treatment-
AC C
resistant MDD can benefit from HF-rTMS in terms of improvement in mood outcomes and cognition, including memory and attention (Serafini et al., 2015). Recent research presented at the 6th International Conference on Transcranial Brain Stimulation (Göttingen, Germany, September 7-10, 2016) suggests that the transcranial brain stimulation methods available today need to be compared using head-to-head designs to develop the most effective treatment protocols for MDD. Systematic reviews of mood outcomes in such head-to-head trials suggest that ECT is more effective at treating MDD acutely than HF-rTMS, particularly in samples with psychotic MDD (Berlim et al., 2013;
1
ACCEPTED MANUSCRIPT Kedzior et al., 2016b; Ren et al., 2014). The aim of the current study was to systematically review the cognitive outcomes of ECT vs. HF-rTMS in head-to-head studies with MDD. Material and methods Systematic search strategy and study selection
RI PT
A systematic literature search of PubMed, PsycInfo, and Medline (up to 16.02.2016)
identified 62 studies (see supplementary materials for study selection, Tables S1, S2; Figure S1). Only 14 studies compared the effects of HF-rTMS vs. ECT empirically. Out of these 14,
SC
k=6 studies (Eranti et al., 2007; Grunhaus et al., 2000; Grunhaus et al., 2003; O'Connor et al., 2003; Rosa et al., 2006; Schulze-Rauschenbach et al., 2005) met the inclusion criteria for the
M AN U
current review (cognitive outcomes assessed in parallel head-to-head studies comparing ECT vs. HF-rTMS with >1 Hz frequency in MDD according to DSM-IV). Data coding and outcome measures
Data were coded by two authors (MS, IG), and any inconsistencies were resolved by
TE D
consensus with the third author (KKK). The coded data included the stimulation parameters (Table S3), demographic and clinical characteristics of patients (Table S4), acute cognitive outcomes assessed using standardised scales (overall cognitive impairment, working,
EP
anterograde, and retrograde memory; Table S5), and acute mood outcomes (Table S6). Acute
AC C
cognitive and mood outcomes were expressed as standardised mean difference scores between ECT (post- vs. pre-treatment) and HF-rTMS (post- vs. pre-treatment) corrected for sample size (Hedges’ g; supplementary materials). Results
Cognitive functioning was assessed in 205 out of 219 patients with treatment-resistant MDD, who received either HF-rTMS (n=111) or ECT (n=94) at baseline in k=6 studies. HFrTMS of the left dorsolateral prefrontal cortex was administered with the frequency of 10 Hz and the resting motor threshold of 90-110% in 5-20 sessions. ECT was most commonly
2
ACCEPTED MANUSCRIPT administered as brief pulse, right unilateral stimulation at 2.5 times the seizure threshold energy in 2-14 sessions. Cognitive assessment was highly heterogeneous in terms of timing, instruments (scales), and functions studied (Table S5). Instead of meta-analysing such a low volume of highly
RI PT
heterogeneous data, we inspected the standardised effect sizes in individual studies. Except for one study, similar acute cognitive outcomes (overall cognitive impairment, anterograde, retrograde, and working memory) were reported after ECT vs. HF-rTMS (Table 1, Figure
SC
S2). One non-randomised study (O'Connor et al., 2003) showed that anterograde and
retrograde memory were significantly more impaired after ECT (as an add-on therapy in
M AN U
more severely depressed patients) relative to HF-rTMS (as a monotherapy in less severely depressed patients). Based on acute mood outcomes (reduction in HDRS scores, higher remission or response rates), ECT (as an add-on therapy) was favoured over HF-rTMS in three studies (two randomised with psychotic MDD and one non-randomised with non-
TE D
psychotic MDD; Table 1).
INSERT TABLE 1 ABOUT HERE
Discussion
EP
Our review suggests that there is too little and too heterogeneous evidence from six head-
AC C
to-head studies to reliably compare the cognitive outcomes of ECT and HF-rTMS in MDD. It is common in scientific practice to blame the lack of substantial differences in any outcome on small sample sizes or the small number of studies. However, we suspect that apart from the sample size or the number of studies, other key methodological requirements are necessary to identify any meaningful differences in cognitive outcomes after ECT vs. HFrTMS, including precisely defined timing and methods of assessment. Given that the sideeffects of ECT are mainly in the memory domain and have been shown to be short-lived, assessment conducted days after ECT may show the recovery of any potential cognitive
3
ACCEPTED MANUSCRIPT dysfunctions back to baseline or even improvement from pre-ECT scores (Semkovska and McLoughlin, 2010). Unlike ECT, HF-rTMS appears to have either minimal impact on cognition (Martin et al., 2016) or to even enhance some cognitive functions in MDD immediately after treatment (Serafini et al., 2015), although maintenance treatment might be
RI PT
required to prolong the durability of clinical effects of HF-rTMS (Kedzior et al., 2015). Thus, assessment conducted days after the last HF-rTMS may fail to detect transient improvement in cognitive functioning present immediately after the acute treatment course, where
SC
maintenance treatment was not given to sustain benefits. Taken together, it is not surprising that combining studies with heterogeneous assessment times did not produce any meaningful
M AN U
differences in cognitive outcomes of ECT vs. HF-rTMS in the primary studies (Table 1) and also in an exploratory random-effects meta-analysis of this low volume of heterogeneous data (Kedzior et al., 2016a). Future studies carefully controlling the timing of assessment and utilising the same standardized instruments are necessary to compare the cognitive outcomes
TE D
of ECT with other non-invasive brain stimulation methods.
Similar to efficacy, cognitive functioning is also likely to depend on stimulation parameters (Kedzior et al., 2014; Tor et al., 2015). Studies in the current review utilised
EP
similar stimulation protocols. However, the small number of stimulation sessions (as few as
AC C
only two ECT or five HF-rTMS) in some patients may have been inadequate for inducing any measurable cognitive effects. The influence of mood outcomes on cognitive outcomes also needs to be considered in explaining the current results. According to one head-to-head study (O'Connor et al., 2003), more severely ill MDD patients responded better to ECT, but also developed acute concurrent deficits in anterograde and retrograde memory after ECT relative to HF-rTMS. In contrast, ECT was found to produce better efficacy than HF-rTMS in two other randomised studies including psychotic MDD patients (Kedzior et al., 2016b, Figure S3). Thus, it is possible that
4
ACCEPTED MANUSCRIPT greater mood improvement may have had an effect in offsetting direct cognitive impairment from ECT. There are a number of limitations in the current review. First, we searched only two databases for published studies. Although we hand-searched other meta-analyses on this topic
RI PT
(Berlim et al., 2013; Ren et al., 2014), it cannot be ruled out that other unpublished data
regarding the cognitive outcomes of ECT vs. HF-rTMS exist. Second, the studies included in the current review are relatively old (published in 2000-2007). More recent studies might
SC
report lower cognitive side-effects of both methods due to advances in stimulation parameters and protocols. Third, according to the Cochrane risk of bias assessment (Higgins et al., 2011),
M AN U
none of the studies in the current review were completely free from bias (see Table S7). In particular, two studies were non-randomised, sham control groups were not used, patients in all studies and assessors in most studies were not blind to treatment received. These limitations reflect the difficulty of researching in this field. Although randomisation is
TE D
considered as an important criterion of methodological quality in research, both nonrandomised studies showed high ecological validity because they were designed as naturalistic clinical trials. The key weaknesses in this set of studies are the variable timing
EP
and methods of cognitive assessment. Finally, the current review focused on the acute (short-
AC C
term) effects of ECT vs. HF-rTMS on cognitive outcomes, as longer term data were limited. It is possible that the risk-benefit comparison of ECT and HF-rTMS is different for acute versus longer-term outcomes. Thus, more data are required regarding longer-term effects of brain stimulation on cognitive functioning. In conclusion, further empirical evidence from randomised, blinded head-to-head studies is required to directly compare the cognitive outcomes of ECT and HF-rTMS in MDD. Those outcomes should be measured not just immediately after but also beyond the acute treatment phases.
5
ACCEPTED MANUSCRIPT References Berlim, M.T., Van den Eynde, F., Daskalakis, Z.J., 2013. Efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive
randomized trials. Depress. Anxiety 30(7), 614-623.
RI PT
therapy (ECT) for major depression: a systematic review and meta-analysis of
Eranti, S., Mogg, A., Pluck, G., Landau, S., Purvis, R., Brown, R.G., Howard, R., Knapp, M., Philpot, M., Rabe-Hesketh, S., Romeo, R., Rothwell, J., Edwards, D., McLoughlin, D.M.,
SC
2007. A randomized, controlled trial with 6-month follow-up of repetitive transcranial
Psychiatry 164(1), 73-81.
M AN U
magnetic stimulation and electroconvulsive therapy for severe depression. Am. J.
Grunhaus, L., Dannon, P.N., Schreiber, S., Dolberg, O.H., Amiaz, R., Ziv, R., Lefkifker, E., 2000. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: An open study. Biol.
TE D
Psychiatry 47(4), 314-234.
Grunhaus, L., Schreiber, S., Dolberg, O.T., Polak, D., Dannon, P.N., 2003. A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic
AC C
324-331.
EP
stimulation in severe and resistant nonpsychotic major depression. Biol. Psychiatry 53(4),
Higgins, J.P.T., Altman, D.G., Gøtzsche, P.C., Jüni, P., Moher, D., Oxman, A.D., Savović, J., Schulz, K.F., Weeks, L., Sterne, J.A.C., 2011. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 343, doi: 10.1136/bmj.d5928. Kedzior, K.K., Azorina, V., Reitz, S.K., 2014. More female patients and fewer stimuli per session are associated with the short-term antidepressant properties of repetitive transcranial magnetic stimulation (rTMS): a meta-analysis of 54 sham-controlled studies published between 1997-2013. Neuropsychiatr. Dis. Treat. 10, 727-756.
6
ACCEPTED MANUSCRIPT Kedzior, K.K., Reitz, S.K., Azorina, V., Loo, C., 2015. Durability of the antidepressant effect of the high-frequency repetitive transcranial magnetic stimulation (rTMS) in the absence of maintenance treatment in major depression. A systematic review and meta-analysis of 16 double-blind, randomised, sham-controlled trials. Depress. Anxiety 32(3), 193-203.
RI PT
Kedzior, K.K., Schuchinsky, M., Gerkensmeier, I., Loo, C., 2016a. Cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) and
electroconvulsive therapy (ECT) in the treatment of major depression: A systematic
SC
review and meta-analysis, 6th International Conference on Transcranial Brain Stimulation. Göttingen, Germany (September 7-10, 2016).
M AN U
Kedzior, K.K., Schuchinsky, M., Müller, C., Engelhardt, T.-C., Kappen, C., Loo, C., 2016b. Clinical outcomes of high-frequency repetitive transcranial magnetic stimulation (HFrTMS) and electroconvulsive therapy (ECT) in the treatment of major depression. An overview of findings from meta-analyses, 6th International Conference on Transcranial
TE D
Brain Stimulation. Göttingen, Germany (September 7-10, 2016). Loo, C., Katalinic, N., Mitchell, P.B., Greenberg, B., 2011. Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain
EP
stimulation techniques. J. Affect. Disord. 132(1-2), 1-13.
AC C
Martin, D.M., McClintock, S.M., Forster, J., Loo, C.K., 2016. Does therapeutic repetitive transcranial magnetic stimulation cause cognitive enhancing effects in patients with neuropsychiatric conditions? A systematic review and meta-analysis of randomised controlled trials. Neuropsychol. Rev. 26(3), 295-309. O'Connor, M., Brenninkmeyer, C., Morgan, A., Bloomingdale, K., Thall, M., Vasile, R., Leone, A.P., 2003. Relative effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy on mood and memory: a neurocognitive risk-benefit analysis. Cogn. Behav. Neurol. 16(2), 118-127.
7
ACCEPTED MANUSCRIPT Pigot, M., Andrade, C., Loo, C., 2008. Pharmacological attenuation of electroconvulsive therapy--induced cognitive deficits: theoretical background and clinical findings. J. ECT. 24(1), 57-67. Ren, J., Li, H., Palaniyappan, L., Liu, H., Wang, J., Li, C., Rossini, P.M., 2014. Repetitive
RI PT
transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a systematic review and meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 51, 181-189.
SC
Rosa, M.A., Gattaz, W.F., Pascual-Leone, A., Fregni, F., Rosa, M.O., Rumi, D.O.,
Myczkowski, M., Silva, M.F., Mansur, C., Rigonatti, S.P., Jacobsen Teixeira, M.,
M AN U
Marcolin, M.A., 2006. Comparison of repetitive transcranial magnetic stimulation and electroconvulsive therapy in unipolar non-psychotic refractory depression: a randomized, single-blind study. Int. J. Neuropsychoph. 9(6), 667-676.
Sackeim, H.A., Dillingham, E.M., Prudic, J., Cooper, T., McCall, W.V., Rosenquist, P.,
TE D
Isenberg, K., Garcia, K., Mulsant, B.H., Haskett, R.F., 2009. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch. Gen. Psychiatry 66(7), 729-737.
EP
Sackeim, H.A., Prudic, J., Fuller, R., Keilp, J., Lavori, P.W., Olfson, M., 2007. The cognitive
AC C
effects of electroconvulsive therapy in community settings. Neuropsychopharmacology 32(1), 244-254.
Schulze-Rauschenbach, S.C., Harms, U., Schlaepfer, T.E., Maier, W., Falkai, P., Wagner, M., 2005. Distinctive neurocognitive effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy in major depression. Br. J. Psychiatry 186(5), 410-416. Semkovska, M., McLoughlin, D.M., 2010. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol. Psychiatry 68(6), 568-577.
8
ACCEPTED MANUSCRIPT Serafini, G., Pompili, M., Belvederi Murri, M., Respino, M., Ghio, L., Girardi, P., Fitzgerald, P.B., Amore, M., 2015. The effects of repetitive transcranial magnetic stimulation on cognitive performance in treatment-resistant depression. A systematic review. Neuropsychobiology 71(3), 125-139.
RI PT
Tor, P.C., Bautovich, A., Wang, M.J., Martin, D., Harvey, S.B., Loo, C., 2015. A systematic review and meta-analysis of brief versus ultrabrief right unilateral electroconvulsive
AC C
EP
TE D
M AN U
SC
therapy for depression. J. Clin. Psychiatr. 76(9), e1092-1098.
9
ACCEPTED MANUSCRIPT
Table 1. Summary of cognitive and mood outcomes following acute HF-rTMS vs. ECT relative to baseline in k=6 studies Favoured method (HF-rTMS or ECT)
Treatment strategy (monotherapy or add-on to antidepressants)
Primary diagnosis
Unipolar MDD Psychotic
Randomised Open-label
Unipolar MDD
Randomised Single-blind
ECT: Add-on HF-rTMS: Monotherapy
Unipolar MDD
Non-randomised (MDD severity ECT>HF-rTMS) Open-label
Add-on
Unipolar MDD
Non-randomised Open-label
Unipolar MDD
Randomised Single-blind
RI PT
Study
Mood outcomes
Grunhaus et al., 2000
Neither
ECT ↓ HDRS scores ↑ response
ECT: Add-on HF-rTMS: Monotherapy
Grunhaus et al., 2003
Neither
Neither
Monotherapy
O’Connor et al., 2003a
HF-rTMS ↑ anterograde/ retrograde memory
ECT ↓ HDRS scores
SchulzeRauschenbach et al., 2005
Neither
Neither
Rosa et al., 2006
Neither
Neither
Eranti et al., 2007
Neither
TE D
M AN U
SC
Cognitive outcomes
EP
Monotherapy
Design
AC C
ECT Add-on Unipolar/Bipolar MDD Randomised ↓ HDRS scores Psychotic Single-blind ↑ remission ↑ response Note. Cognitive outcomes include the overall cognitive impairment, working, anterograde, and retrograde memory. Mood outcomes include standardised HDRS change scores (post – pre-treatment baseline), response, and remission rates. Neither means that cognitive or mood
10
ACCEPTED MANUSCRIPT
outcomes were similar (did not differ statistically) after HF-rTMS vs. ECT. aAnterograde memory (verbal learning) and retrograde memory (free
RI PT
recall) worsened after ECT vs. HF-rTMS; all functions improved back to baseline at the two-week follow-up in the ECT group. Abbreviations: ECT, electroconvulsive therapy; HDRS, Hamilton Depression Rating Scale; HF-rTMS, high-frequency repetitive transcranial
AC C
EP
TE D
M AN U
SC
magnetic stimulation; MDD, major depressive disorder.
11
ACCEPTED MANUSCRIPT Highlights ECT and HF-rTMS have similar cognitive outcomes in six head-to-head studies.
•
These results might be due to heterogeneous timing and assessment methods.
•
Cognitive effects need to be assessed in longer-term after brain stimulation.
AC C
EP
TE D
M AN U
SC
RI PT
•
1
S0022-3956(16)30555-6
DOI:
10.1016/j.jpsychires.2017.03.002
Reference:
PIAT 3084
To appear in:
Journal of Psychiatric Research
Received Date: 24 October 2016 Revised Date:
8 February 2017
Accepted Date: 1 March 2017
Please cite this article as: Kedzior KK, Schuchinsky M, Gerkensmeier I, Loo C, Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in major depression: A systematic review, Journal of Psychiatric Research (2017), doi: 10.1016/j.jpsychires.2017.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in
Authors and affiliations
RI PT
major depression: a systematic review
Karina Karolina Kedziora*; Maria Schuchinskyb; Imke Gerkensmeiera; Colleen Looc a
University of Bremen, Germany; bUniversity of Limerick, Ireland; cUniversity of New South
AC C
EP
TE D
M AN U
*Corresponding author ([email protected])
SC
Wales, Black Dog Institute, and St. George Hospital, Australia
1
ACCEPTED MANUSCRIPT Abstract The present study aimed to systematically compare the cognitive outcomes of highfrequency repetitive transcranial magnetic stimulation (HF-rTMS) and electroconvulsive therapy (ECT) in head-to-head studies with major depression (MDD) patients. A systematic
RI PT
literature search identified six studies with 219 MDD patients that were too heterogeneous to reliably detect meaningful differences in acute cognitive outcomes after ECT vs. HF-rTMS. Cognitive effects of brain stimulation vary depending on the timeframe and methods of
SC
assessment, stimulation parameters, and maintenance treatment. Thus, acute and longer-term differences in cognitive outcomes both need to be investigated at precisely defined
M AN U
timeframes and with similar instruments assessing comparable functions.
Keywords: high-frequency repetitive transcranial magnetic stimulation (HF-rTMS);
AC C
EP
TE D
electroconvulsive therapy (ECT); cognition; major depressive disorder (MDD)
ACCEPTED MANUSCRIPT Challenges in comparing the acute cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) vs. electroconvulsive therapy (ECT) in major depression: A systematic review Introduction
RI PT
Electroconvulsive therapy (ECT) is the oldest non-invasive brain stimulation method utilised in the treatment of major depression (MDD) today. Although clinically effective in unipolar and bipolar MDD (Loo et al., 2011), ECT potentially has detrimental cognitive side-
SC
effects (Sackeim et al., 2007). Such cognitive side-effects, including amnesia and slowing of reaction times, occur immediately after treatment and may persist for 6 months with some
M AN U
forms of ECT (Sackeim et al., 2007). Cognitive impairment after ECT can be influenced by concurrent pharmacotherapy, including antidepressants and lithium (Loo et al., 2011; Pigot et al., 2008; Sackeim et al., 2009) and is minimised with specific stimulation forms and parameters, such as ultrabrief pulse, right unilateral ECT (Tor et al., 2015).
TE D
In contrast to ECT, one of the newer non-invasive brain stimulation methods, namely high-frequency repetitive transcranial magnetic stimulation (HF-rTMS), does not require anaesthesia and tends to have little detrimental cognitive effects (Martin et al., 2016) or may
EP
even enhance cognitive functioning in MDD (Serafini et al., 2015). Patients with treatment-
AC C
resistant MDD can benefit from HF-rTMS in terms of improvement in mood outcomes and cognition, including memory and attention (Serafini et al., 2015). Recent research presented at the 6th International Conference on Transcranial Brain Stimulation (Göttingen, Germany, September 7-10, 2016) suggests that the transcranial brain stimulation methods available today need to be compared using head-to-head designs to develop the most effective treatment protocols for MDD. Systematic reviews of mood outcomes in such head-to-head trials suggest that ECT is more effective at treating MDD acutely than HF-rTMS, particularly in samples with psychotic MDD (Berlim et al., 2013;
1
ACCEPTED MANUSCRIPT Kedzior et al., 2016b; Ren et al., 2014). The aim of the current study was to systematically review the cognitive outcomes of ECT vs. HF-rTMS in head-to-head studies with MDD. Material and methods Systematic search strategy and study selection
RI PT
A systematic literature search of PubMed, PsycInfo, and Medline (up to 16.02.2016)
identified 62 studies (see supplementary materials for study selection, Tables S1, S2; Figure S1). Only 14 studies compared the effects of HF-rTMS vs. ECT empirically. Out of these 14,
SC
k=6 studies (Eranti et al., 2007; Grunhaus et al., 2000; Grunhaus et al., 2003; O'Connor et al., 2003; Rosa et al., 2006; Schulze-Rauschenbach et al., 2005) met the inclusion criteria for the
M AN U
current review (cognitive outcomes assessed in parallel head-to-head studies comparing ECT vs. HF-rTMS with >1 Hz frequency in MDD according to DSM-IV). Data coding and outcome measures
Data were coded by two authors (MS, IG), and any inconsistencies were resolved by
TE D
consensus with the third author (KKK). The coded data included the stimulation parameters (Table S3), demographic and clinical characteristics of patients (Table S4), acute cognitive outcomes assessed using standardised scales (overall cognitive impairment, working,
EP
anterograde, and retrograde memory; Table S5), and acute mood outcomes (Table S6). Acute
AC C
cognitive and mood outcomes were expressed as standardised mean difference scores between ECT (post- vs. pre-treatment) and HF-rTMS (post- vs. pre-treatment) corrected for sample size (Hedges’ g; supplementary materials). Results
Cognitive functioning was assessed in 205 out of 219 patients with treatment-resistant MDD, who received either HF-rTMS (n=111) or ECT (n=94) at baseline in k=6 studies. HFrTMS of the left dorsolateral prefrontal cortex was administered with the frequency of 10 Hz and the resting motor threshold of 90-110% in 5-20 sessions. ECT was most commonly
2
ACCEPTED MANUSCRIPT administered as brief pulse, right unilateral stimulation at 2.5 times the seizure threshold energy in 2-14 sessions. Cognitive assessment was highly heterogeneous in terms of timing, instruments (scales), and functions studied (Table S5). Instead of meta-analysing such a low volume of highly
RI PT
heterogeneous data, we inspected the standardised effect sizes in individual studies. Except for one study, similar acute cognitive outcomes (overall cognitive impairment, anterograde, retrograde, and working memory) were reported after ECT vs. HF-rTMS (Table 1, Figure
SC
S2). One non-randomised study (O'Connor et al., 2003) showed that anterograde and
retrograde memory were significantly more impaired after ECT (as an add-on therapy in
M AN U
more severely depressed patients) relative to HF-rTMS (as a monotherapy in less severely depressed patients). Based on acute mood outcomes (reduction in HDRS scores, higher remission or response rates), ECT (as an add-on therapy) was favoured over HF-rTMS in three studies (two randomised with psychotic MDD and one non-randomised with non-
TE D
psychotic MDD; Table 1).
INSERT TABLE 1 ABOUT HERE
Discussion
EP
Our review suggests that there is too little and too heterogeneous evidence from six head-
AC C
to-head studies to reliably compare the cognitive outcomes of ECT and HF-rTMS in MDD. It is common in scientific practice to blame the lack of substantial differences in any outcome on small sample sizes or the small number of studies. However, we suspect that apart from the sample size or the number of studies, other key methodological requirements are necessary to identify any meaningful differences in cognitive outcomes after ECT vs. HFrTMS, including precisely defined timing and methods of assessment. Given that the sideeffects of ECT are mainly in the memory domain and have been shown to be short-lived, assessment conducted days after ECT may show the recovery of any potential cognitive
3
ACCEPTED MANUSCRIPT dysfunctions back to baseline or even improvement from pre-ECT scores (Semkovska and McLoughlin, 2010). Unlike ECT, HF-rTMS appears to have either minimal impact on cognition (Martin et al., 2016) or to even enhance some cognitive functions in MDD immediately after treatment (Serafini et al., 2015), although maintenance treatment might be
RI PT
required to prolong the durability of clinical effects of HF-rTMS (Kedzior et al., 2015). Thus, assessment conducted days after the last HF-rTMS may fail to detect transient improvement in cognitive functioning present immediately after the acute treatment course, where
SC
maintenance treatment was not given to sustain benefits. Taken together, it is not surprising that combining studies with heterogeneous assessment times did not produce any meaningful
M AN U
differences in cognitive outcomes of ECT vs. HF-rTMS in the primary studies (Table 1) and also in an exploratory random-effects meta-analysis of this low volume of heterogeneous data (Kedzior et al., 2016a). Future studies carefully controlling the timing of assessment and utilising the same standardized instruments are necessary to compare the cognitive outcomes
TE D
of ECT with other non-invasive brain stimulation methods.
Similar to efficacy, cognitive functioning is also likely to depend on stimulation parameters (Kedzior et al., 2014; Tor et al., 2015). Studies in the current review utilised
EP
similar stimulation protocols. However, the small number of stimulation sessions (as few as
AC C
only two ECT or five HF-rTMS) in some patients may have been inadequate for inducing any measurable cognitive effects. The influence of mood outcomes on cognitive outcomes also needs to be considered in explaining the current results. According to one head-to-head study (O'Connor et al., 2003), more severely ill MDD patients responded better to ECT, but also developed acute concurrent deficits in anterograde and retrograde memory after ECT relative to HF-rTMS. In contrast, ECT was found to produce better efficacy than HF-rTMS in two other randomised studies including psychotic MDD patients (Kedzior et al., 2016b, Figure S3). Thus, it is possible that
4
ACCEPTED MANUSCRIPT greater mood improvement may have had an effect in offsetting direct cognitive impairment from ECT. There are a number of limitations in the current review. First, we searched only two databases for published studies. Although we hand-searched other meta-analyses on this topic
RI PT
(Berlim et al., 2013; Ren et al., 2014), it cannot be ruled out that other unpublished data
regarding the cognitive outcomes of ECT vs. HF-rTMS exist. Second, the studies included in the current review are relatively old (published in 2000-2007). More recent studies might
SC
report lower cognitive side-effects of both methods due to advances in stimulation parameters and protocols. Third, according to the Cochrane risk of bias assessment (Higgins et al., 2011),
M AN U
none of the studies in the current review were completely free from bias (see Table S7). In particular, two studies were non-randomised, sham control groups were not used, patients in all studies and assessors in most studies were not blind to treatment received. These limitations reflect the difficulty of researching in this field. Although randomisation is
TE D
considered as an important criterion of methodological quality in research, both nonrandomised studies showed high ecological validity because they were designed as naturalistic clinical trials. The key weaknesses in this set of studies are the variable timing
EP
and methods of cognitive assessment. Finally, the current review focused on the acute (short-
AC C
term) effects of ECT vs. HF-rTMS on cognitive outcomes, as longer term data were limited. It is possible that the risk-benefit comparison of ECT and HF-rTMS is different for acute versus longer-term outcomes. Thus, more data are required regarding longer-term effects of brain stimulation on cognitive functioning. In conclusion, further empirical evidence from randomised, blinded head-to-head studies is required to directly compare the cognitive outcomes of ECT and HF-rTMS in MDD. Those outcomes should be measured not just immediately after but also beyond the acute treatment phases.
5
ACCEPTED MANUSCRIPT References Berlim, M.T., Van den Eynde, F., Daskalakis, Z.J., 2013. Efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive
randomized trials. Depress. Anxiety 30(7), 614-623.
RI PT
therapy (ECT) for major depression: a systematic review and meta-analysis of
Eranti, S., Mogg, A., Pluck, G., Landau, S., Purvis, R., Brown, R.G., Howard, R., Knapp, M., Philpot, M., Rabe-Hesketh, S., Romeo, R., Rothwell, J., Edwards, D., McLoughlin, D.M.,
SC
2007. A randomized, controlled trial with 6-month follow-up of repetitive transcranial
Psychiatry 164(1), 73-81.
M AN U
magnetic stimulation and electroconvulsive therapy for severe depression. Am. J.
Grunhaus, L., Dannon, P.N., Schreiber, S., Dolberg, O.H., Amiaz, R., Ziv, R., Lefkifker, E., 2000. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: An open study. Biol.
TE D
Psychiatry 47(4), 314-234.
Grunhaus, L., Schreiber, S., Dolberg, O.T., Polak, D., Dannon, P.N., 2003. A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic
AC C
324-331.
EP
stimulation in severe and resistant nonpsychotic major depression. Biol. Psychiatry 53(4),
Higgins, J.P.T., Altman, D.G., Gøtzsche, P.C., Jüni, P., Moher, D., Oxman, A.D., Savović, J., Schulz, K.F., Weeks, L., Sterne, J.A.C., 2011. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 343, doi: 10.1136/bmj.d5928. Kedzior, K.K., Azorina, V., Reitz, S.K., 2014. More female patients and fewer stimuli per session are associated with the short-term antidepressant properties of repetitive transcranial magnetic stimulation (rTMS): a meta-analysis of 54 sham-controlled studies published between 1997-2013. Neuropsychiatr. Dis. Treat. 10, 727-756.
6
ACCEPTED MANUSCRIPT Kedzior, K.K., Reitz, S.K., Azorina, V., Loo, C., 2015. Durability of the antidepressant effect of the high-frequency repetitive transcranial magnetic stimulation (rTMS) in the absence of maintenance treatment in major depression. A systematic review and meta-analysis of 16 double-blind, randomised, sham-controlled trials. Depress. Anxiety 32(3), 193-203.
RI PT
Kedzior, K.K., Schuchinsky, M., Gerkensmeier, I., Loo, C., 2016a. Cognitive outcomes of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) and
electroconvulsive therapy (ECT) in the treatment of major depression: A systematic
SC
review and meta-analysis, 6th International Conference on Transcranial Brain Stimulation. Göttingen, Germany (September 7-10, 2016).
M AN U
Kedzior, K.K., Schuchinsky, M., Müller, C., Engelhardt, T.-C., Kappen, C., Loo, C., 2016b. Clinical outcomes of high-frequency repetitive transcranial magnetic stimulation (HFrTMS) and electroconvulsive therapy (ECT) in the treatment of major depression. An overview of findings from meta-analyses, 6th International Conference on Transcranial
TE D
Brain Stimulation. Göttingen, Germany (September 7-10, 2016). Loo, C., Katalinic, N., Mitchell, P.B., Greenberg, B., 2011. Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain
EP
stimulation techniques. J. Affect. Disord. 132(1-2), 1-13.
AC C
Martin, D.M., McClintock, S.M., Forster, J., Loo, C.K., 2016. Does therapeutic repetitive transcranial magnetic stimulation cause cognitive enhancing effects in patients with neuropsychiatric conditions? A systematic review and meta-analysis of randomised controlled trials. Neuropsychol. Rev. 26(3), 295-309. O'Connor, M., Brenninkmeyer, C., Morgan, A., Bloomingdale, K., Thall, M., Vasile, R., Leone, A.P., 2003. Relative effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy on mood and memory: a neurocognitive risk-benefit analysis. Cogn. Behav. Neurol. 16(2), 118-127.
7
ACCEPTED MANUSCRIPT Pigot, M., Andrade, C., Loo, C., 2008. Pharmacological attenuation of electroconvulsive therapy--induced cognitive deficits: theoretical background and clinical findings. J. ECT. 24(1), 57-67. Ren, J., Li, H., Palaniyappan, L., Liu, H., Wang, J., Li, C., Rossini, P.M., 2014. Repetitive
RI PT
transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a systematic review and meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 51, 181-189.
SC
Rosa, M.A., Gattaz, W.F., Pascual-Leone, A., Fregni, F., Rosa, M.O., Rumi, D.O.,
Myczkowski, M., Silva, M.F., Mansur, C., Rigonatti, S.P., Jacobsen Teixeira, M.,
M AN U
Marcolin, M.A., 2006. Comparison of repetitive transcranial magnetic stimulation and electroconvulsive therapy in unipolar non-psychotic refractory depression: a randomized, single-blind study. Int. J. Neuropsychoph. 9(6), 667-676.
Sackeim, H.A., Dillingham, E.M., Prudic, J., Cooper, T., McCall, W.V., Rosenquist, P.,
TE D
Isenberg, K., Garcia, K., Mulsant, B.H., Haskett, R.F., 2009. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch. Gen. Psychiatry 66(7), 729-737.
EP
Sackeim, H.A., Prudic, J., Fuller, R., Keilp, J., Lavori, P.W., Olfson, M., 2007. The cognitive
AC C
effects of electroconvulsive therapy in community settings. Neuropsychopharmacology 32(1), 244-254.
Schulze-Rauschenbach, S.C., Harms, U., Schlaepfer, T.E., Maier, W., Falkai, P., Wagner, M., 2005. Distinctive neurocognitive effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy in major depression. Br. J. Psychiatry 186(5), 410-416. Semkovska, M., McLoughlin, D.M., 2010. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol. Psychiatry 68(6), 568-577.
8
ACCEPTED MANUSCRIPT Serafini, G., Pompili, M., Belvederi Murri, M., Respino, M., Ghio, L., Girardi, P., Fitzgerald, P.B., Amore, M., 2015. The effects of repetitive transcranial magnetic stimulation on cognitive performance in treatment-resistant depression. A systematic review. Neuropsychobiology 71(3), 125-139.
RI PT
Tor, P.C., Bautovich, A., Wang, M.J., Martin, D., Harvey, S.B., Loo, C., 2015. A systematic review and meta-analysis of brief versus ultrabrief right unilateral electroconvulsive
AC C
EP
TE D
M AN U
SC
therapy for depression. J. Clin. Psychiatr. 76(9), e1092-1098.
9
ACCEPTED MANUSCRIPT
Table 1. Summary of cognitive and mood outcomes following acute HF-rTMS vs. ECT relative to baseline in k=6 studies Favoured method (HF-rTMS or ECT)
Treatment strategy (monotherapy or add-on to antidepressants)
Primary diagnosis
Unipolar MDD Psychotic
Randomised Open-label
Unipolar MDD
Randomised Single-blind
ECT: Add-on HF-rTMS: Monotherapy
Unipolar MDD
Non-randomised (MDD severity ECT>HF-rTMS) Open-label
Add-on
Unipolar MDD
Non-randomised Open-label
Unipolar MDD
Randomised Single-blind
RI PT
Study
Mood outcomes
Grunhaus et al., 2000
Neither
ECT ↓ HDRS scores ↑ response
ECT: Add-on HF-rTMS: Monotherapy
Grunhaus et al., 2003
Neither
Neither
Monotherapy
O’Connor et al., 2003a
HF-rTMS ↑ anterograde/ retrograde memory
ECT ↓ HDRS scores
SchulzeRauschenbach et al., 2005
Neither
Neither
Rosa et al., 2006
Neither
Neither
Eranti et al., 2007
Neither
TE D
M AN U
SC
Cognitive outcomes
EP
Monotherapy
Design
AC C
ECT Add-on Unipolar/Bipolar MDD Randomised ↓ HDRS scores Psychotic Single-blind ↑ remission ↑ response Note. Cognitive outcomes include the overall cognitive impairment, working, anterograde, and retrograde memory. Mood outcomes include standardised HDRS change scores (post – pre-treatment baseline), response, and remission rates. Neither means that cognitive or mood
10
ACCEPTED MANUSCRIPT
outcomes were similar (did not differ statistically) after HF-rTMS vs. ECT. aAnterograde memory (verbal learning) and retrograde memory (free
RI PT
recall) worsened after ECT vs. HF-rTMS; all functions improved back to baseline at the two-week follow-up in the ECT group. Abbreviations: ECT, electroconvulsive therapy; HDRS, Hamilton Depression Rating Scale; HF-rTMS, high-frequency repetitive transcranial
AC C
EP
TE D
M AN U
SC
magnetic stimulation; MDD, major depressive disorder.
11
ACCEPTED MANUSCRIPT Highlights ECT and HF-rTMS have similar cognitive outcomes in six head-to-head studies.
•
These results might be due to heterogeneous timing and assessment methods.
•
Cognitive effects need to be assessed in longer-term after brain stimulation.
AC C
EP
TE D
M AN U
SC
RI PT
•
1