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Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: A pilot study
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Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: a pilot study Jian Wang , Fidel Vila-Rodriguez , Ruiyang Ge , Sherry Gao , Elizabeth Gregory , Wei Jiang , Chunlin Yang , Gang Wang PII: DOI: Reference:
S0165-0327(19)32886-1 https://doi.org/10.1016/j.jad.2019.12.022 JAD 11438
To appear in:
Journal of Affective Disorders
Received date: Revised date: Accepted date:
18 October 2019 12 December 2019 13 December 2019
Please cite this article as: Jian Wang , Fidel Vila-Rodriguez , Ruiyang Ge , Sherry Gao , Elizabeth Gregory , Wei Jiang , Chunlin Yang , Gang Wang , Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: a pilot study, Journal of Affective Disorders (2019), doi: https://doi.org/10.1016/j.jad.2019.12.022
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Highlights MDD patients received accelerated Magnetic Seizure Therapy (aMST) for eight days. aMST was well-tolerated, with no cognitive side effects associated with treatment. Patients showed rapid improvements in depression and anxiety symptoms. Further research is necessary to characterize the long-term effects of aMST.
Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: a pilot study
Jian Wang1, Fidel Vila-Rodriguez2, Ruiyang Ge2, Sherry Gao2, Elizabeth Gregory2, Wei Jiang3, Chunlin Yang3, Gang Wang3,4* 1
Department of psychiatry, Beijing Anzhen Hospital, Capital Medical University, Beijing
100029, China 2
Non-Invasive Neurostimulation Therapies (NINET) Laboratory, Department of
Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada 3
The National Clinical Research Centre for Mental Disorders ＆Beijing Key Laboratory
of Mental Disorders, Beijing Anding Hospital, Capital Medical University, School of Mental Health, Beijing 100088, China 4
Advanced Innovation Center for Human Brain Protection, Capital Medical University,
Beijing, 100069, China
Correspondence to: Gang Wang, [email protected]
Funding information: Funding by National Key Research & Development Program of China (No. 2016YFC1307200); Beijing Municipal Administration of Hospitals’ Ascent Plan (No. DFL20151801); Beijing Municipal Science and Tech Commission (No. Z171100000117004).
Conflicts of Interest: The authors declare no financial interests relative to this work. FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and in-kind equipment support for this investigator-initiated trial from MagVenture. He has received honoraria for participation in advisory board for Janssen.
Keywords: Magnetic seizure therapy; Major depressive disorder; Cognition ABSTRACT Background: Magnetic Seizure therapy (MST) is an emerging treatment for major depressive disorder (MDD) that is associated with fewer cognitive side effects compared to electroconvulsive therapy. The present pilot study sought to investigate whether daily MST treatments were associated to antidepressant effect and assess cognitive side effects associated with an accelerated MST (aMST) treatment schedule. Methods: Fifteen MDD patients underwent a six-day course of MST treatment to the vertex following assessment of symptom severity and neuropsychological testing. The primary outcome was severity on the Hamilton Rating Scale for Depression 17-item (HRSD-17). Patient also underwent neuropsychological assessment with the RBANS and Stroop Colour-Word test. Results: There were no instances of delirium or disturbance of consciousness following aMST sessions. Patients showed significant decreases on indices of depression and anxiety symptoms, with 9 (60%) patients showing a clinical response and 7 (47%) patients experiencing remission. Significant improvements were reported in RBANS total score, as well as indices of immediate memory and delayed memory. No changes at follow-up were reported for visuospatial/constructional, language, and attention RBANS
indices, nor for Stroop Colour/Word performance. Limitations: The results should be interpreted with caution as they are part of a nonrandomized, open-label pilot study. Further, the short duration of the study does not provide longitudinal follow-up to determine whether treatment response lasts a meaningful duration of time. Conclusions: aMST well tolerated without significant evidence of cognitive side effects and rapid improvement in symptoms. Further research is required to fully characterize these changes and replicate them in independent samples.
INTRODUCTION Depression is the leading cause of disability world-wide and is associated with substantial morbidity and mortality (World Health Organization, 2017). Magnetic seizure therapy (MST) is a non-invasive convulsive neurostimulation therapy that relies on the principle of electromagnetic induction to induce an electric field in the brain strong enough to elicit a generalized tonic-clonic seizure under general anesthesia (Lisanby et al., 2003). MST has been shown to be a safe and efficacious treatment for major depressive disorder (MDD) (Lisanby et al., 2001), and is associated with a favourable side effect profile compared to electroconvulsive therapy (ECT) (Moscrip et al., 2006). In contrast to ECT, which elicits a widespread electric field to induce a therapeutic seizure (Deng et al., 2011), the electric field elicited by MST is restricted to the cerebral cortex, where the seizure initiates and secondarily spreads to the rest of the brain (Lee et al.,
2014). Therefore, the electric field spares critical brain areas involved in cognition and may be one of the reasons underlying the favourable side effect profile of MST compared to ECT. Specifically, research has demonstrated shorter reorientation time and lesser cognitive impairment after MST compared to ECT (Kayser et al., 2015). Also, MST is associated with less power in frequency bands above delta (Cycowicz et al., 2018) as well as milder increase in heart rate and blood pressure (White et al., 2006). MST is still in the early stages of clinical investigation, but preliminary data are encouraging. Specifically, several case series (Kosel et al., 2003; Lisanby et al., 2001; Noda et al., 2014) and small sample studies (Fitzgerald et al., 2013; Kayser et al., 2011; Lisanby et al., 2003) have reported significant response and remission rates at approximately 60% and 30%, respectively, in patients with MDD and bipolar depression, as well as a more favorable side effect profile compared to ECT, particularly with regards to fewer cognitive side effects (Kirov et al., 2008; Polster et al., 2015). Daily administration of ECT was explored early during the development of ECT, but was quickly abandoned after it was shown that daily bilateral ECT was associated with prolonged confusion and with delirium (Kalinowsky and Worthing, 1943). However, a recent open label study by Rasmussen and colleagues, in which patients received daily right unilateral ultrabrief (RUL-UB) ECT for 10 treatments, reported commensurate efficacy rates without a significant increase in cognitive side effects (Rasmussen et al., 2016). RUL-UB ECT, similar to MST, is associated with lesser cognitive side effects compared to conventional ECT, however appears to have slower rates of improvement and require more treatments compared to conventional ECT (Milev et al., 2016).
The low rates of cognitive side effects associated with MST make this intervention a potential candidate for increasing the frequency of treatments to accelerate the time to clinical response. We recently reported preliminary data from three patients in this pilot study (Wang et al., 2018), and we report here the complete pilot open-label study to test the feasibility and tolerability of delivering 6 consecutive daily MST sessions to treat MDD. MATERIALS AND METHODS All study procedures were approved by the Anding Hospital of Capital Medical University Ethics Committee and registered on Chinese Clinical Trial Registry site (http://www.chictr.org, number ChiCTR-RNC-17014100)(Wang et al., 2018). All participants provided informed consent. Participants Inclusion criteria were assessed by a physical examination, including a routine blood test and electrocardiogram before MST. Inclusion criteria were: (1) aged between 18 and 60 years old, (2) Hamilton Rating Scale for Depression 17-item (HRSD-17) score of 18 or greater, (3) convulsive therapy clinically indicated, (4) right-handed, and (5) able to provide informed consent. Exclusion criteria included: (1) not suitable for ECT, (2) had any history of schizophrenia, schizoaffective disorder, or bipolar disorder, (3) were pregnant or planning on getting pregnant, (4) were allergic to anesthetics or muscle relaxants, (5) had any devices that could be affected by MST or were deemed unsuitable for magnetic resonance scanning, or (6) had received ECT in the past 6 months or had failed to respond to an adequate course of ECT in the past. Clinical Outcome Measures
Psychiatric diagnoses were made on the basis of the Diagnostic and Statistical Manual of Mental Disorders 5 (American Psychiatric Association, 2013). Clinical assessments were included the HRSD-17 as the primary outcome measure (Hamilton, 1960), and the Hamilton Anxiety Rating Scale (HAMA, (Hamilton, 1959). Response was defined as a ≥ 50% reduction in HRSD-17 from baseline, and remission was defined as a HRSD-17 score ≤ 7. The Chinese version of the Repeatable Battery for the Assessment of Neuropsychological status (RBANS), as well as the Stroop Colour/word test (Golden version), were used to assess neuropsychological functioning. The RBANS provides standardized scores of performances in immediate memory, delayed memory, visuospatial/constructional functions, language, and attention, while the Stroop color/word test is a measure of inhibitory function (Strauss et al., 2006). The RBANS shows sensitivity to impairments associated with depression (Faust et al., 2017). In healthy subjects, the Chinese version of the RBANS demonstrates high internal reliability for total score (Cronbachs’ α = 0.90) and subtest scores (Cronbachs’ α = 0.67 – 0.86). Test-retest reliability is similarly high for total score (ICC = 0.90) and subtest scores (ICC = 0.53 – 0.80). The Chinses version of the RBANS also demonstrates construct validity, showing positive correlations with more extensive neuropsychological assessments (e.g. Wechsler tests, r = 0.21-0.59; Zhang et al., 2008). Clinical rating scales and neuropsychological testing assessments were performed at baseline and within three days of their last MST treatment by trained raters. MST Treatment The MST treatments were administered under general anesthesia using a
stimulator (MagStim, UK) with a circular coil (diameter of the coil: 130 mm). Stimulation was delivered over the vertex, as measured following the international EEG 10-20 system. Vertex stimulation was chosen because stimulation of this area reliably induces seizures (Kayser et al., 2011; Kirov et al., 2008). Stimulation duration was up to 10 seconds, with a frequency of 100 Hz and 100% of maximum stimulator output. As per standard procedures described in the literature, the seizure-threshold titration procedure was employed throughout the treatment sessions, wherein stimulation duration is adjusted to modify stimulus strength (Lisanby et al., 2003). A total of 6 sessions were administered on 6 consecutive week-days early in the morning. Due to lack of a priori data regarding the efficacy of aMST, all patients were treated with serotonin/norepinephrine reuptake inhibitors. This systematic approach was adopted to minimize the confounding effect of having patients on different antidepressant medications. Patients remained on stable doses of antidepressant during the MST treating process (see supplemental table 1), benzodiazepines were not administered for 12hrs before the treatment. Benzodiazepine dose equivalents were calculated using previously defined ratios from the literature and reported in supplemental table 1 ( U.M.I. (UKMi) pharmacists for N. healthcare, 2018). General anesthesia was induced with propofol (1.52 mg/kg) and muscle relaxation with succinylcholine (0.5-1 mg/kg). Statistical Analyses: Paired t-tests were performed to compare changes between pre and post treatment assessments of HRSD, HAMA, RBANS, and Stroop Colour-Word test scores, as well as to assess the change in stimulation duration and seizure length over the six treatments. All score changes were correlated with demographic and clinical variables to determine
any potentially relevant associations. Analyses were computed using R, version 3.5.1. RESULTS Demographic and clinical characteristics Demographic and clinical characteristics are summarized in Table 1. The sample comprised of younger adults, the majority female. Patients were severely depressed as measured by HRSD mean scores and showed moderate to severe symptoms of anxiety according HAMA scores at baseline. Illness course was non-lengthy, although there was considerable variability within the sample, as the majority were experiencing recurrent MDD and some MDD single episode. Average current episode duration was less than one year. All patients were taking antidepressants, with 14 patients taking duloxetine (4060mg BID) and 1 patient taking venlafaxine (150mg qD). Thirteen patients started medication within one day of MST treatment initiation, while two patients had been taking antidepressants for three weeks prior to MST treatment with no improvement in symptoms. The majority of patients were taking low doses of benzodiazepines (see supplemental Table 1). Clinical and Neuropsychological Outcomes Outcome variables are summarized in Table 2. Overall, 9 patients (60%) showed response to aMST treatment and 7 (47%) met remission criterion. Patients experienced a 57% mean reduction of depressive symptoms (17.3 point reduction on HDRS, t=-10.4; p<.001), and 62% mean reduction of anxiety symptoms (17 point reduction on HAMA, t=-7.7; p<.001). Patients showed statistically significant improvements in RBANS total score (16% improvement; p<.001), immediate memory index (34% improvement; p<.001), and
delayed memory index (18% improvement; p<.01). Performance on the visuospatial/constructional index, the language index, and the attention index, did not change significantly, although scores increased marginally over time. Performance remained unchanged for the Stroop Colour/Word task, both in measures of speed and number of total errors, although the number of errors was reduced at follow-up. Age was associated with a lesser increase in the immediate memory index over time (r=-.55, p=.03). No other demographic or clinical characteristic was associated with changes in neuropsychological performance, nor was treatment response. Treatment Characteristics and Side Effects Mean (SD) seizure length at the first treatment was 41.5 seconds (18.7) and decreased steadily over the course of the six treatments (p<.001), with a seizure length of 25.7 seconds (17.4) by the last (6th) treatment. Mean stimulation duration increased over the course of the six treatments, starting at a mean of 7.4 seconds (1.6) at the first treatment, and increasing to a mean of 9.7 seconds (0.8) at the final treatment (p<.001). T-tests for both variables (seizure length and stimulation duration) showed no significant differences between responders and non-responders across treatment sessions. Changes in seizure length and stimulation duration over time are illustrated in Figure 1. No serious adverse events were recorded in the 15 patients during MST treatment. Eight cases (53%) reported transient mild dizziness, 6 cases (40%) reported transient mild muscle soreness, 3 cases reported moderate dry mouth, 2 cases (13%) reported transient lisp, and 1 case (7%) reported transient fever, the highest 38.6℃. None of the patients experienced post-MST delirium or disturbance of consciousness. No patients dropped out, with all 15 patients completing the six treatments and study visits.
DISCUSSION Our pilot study is the first to report the use of aMST for depression (i.e. daily administration, excluding weekends). The patients hence received only 6 treatments in a span of 8 days, which is half the number of treatments, and three times shorter span of time, usually delivered with ECT (i.e. ECT takes ~30 days to deliver 12 sessions at 3 sessions/week). Using this accelerated and abbreviated protocol, 9 of the 15 patients showed response (and 7 remitted), while the remaining 6 patients showed some improvement in their HRSD scores but did not achieve response criterion. All patients showed decrease in HAMA scores, although responders showed significantly greater improvement in anxiety symptoms. Although these results are encouraging for such a brief and intensive intervention, it is important to draw attention to the fact the patients in the sample had a relatively short mean duration of illness of 12 months. A portion of them were MDD single episode therefore limiting the potential generalization of results to clinical samples of higher severity and refractoriness. The fact that all but two initiated antidepressant treatment at the same time as they started their course of MST opens more questions, as an additive or a synergistic effect of MST and antidepressants are both plausible hypotheses. A future definite trial must carefully consider the timeline between antidepressant introduction or changes and initiation of MST to increase the degree of certainty regarding attribution of the effect to MST. In addition to antidepressants, all patients were on low doses of benzodiazepines, a factor that has been associated to worse outcomes in the context of both ECT (Delamarre et al., 2019) and repetitive transcranial magnetic stimulation (Kaster et al., 2019). It will remain an open question as to whether a larger therapeutic effect may be observed in the absence of benzodiazepine use.
Neurocognitive assessments showed no detrimental effects to cognition, with scores on visuospatial/construction, language, and attention indices, as well as the Stroop Colour/Word task, remaining unchanged. Promisingly, patients showed improvements in RBANS overall scores with a mean improvement of 16.2% (13.9 point increase), as well as in immediate and delayed memory indices, with mean improvements of 33.7% (26.2 point increase) and 18.5% (15.4 point increase), respectively. These changes in neurocognitive performance were not associated with treatment response. Change scores on the RBANS of 15 points or greater are generally thought to be clinically significant (Strauss et al., 2006). While the lack of a control group in this current study does not allow for the discounting of any practice effects, especially given the short window between neuropsychological testing sessions, improvements in cognitive performance, especially in domains of memory (which often show detrimental side effects of ECT), are encouraging (Verwijk et al., 2012). Daskalakis and colleagues recently reported similar improvements in neurocognitive performance, with improvements in visuospatial memory and delayed recall following MST treatment (Daskalakis et al, 2019). Similar to our study, there was no comparator group, however given the convergence of results, investigation of the potential cognitive gains from MST treatment is warranted. In terms of tolerability it is important to note that there were no episodes of delirium or prolonged confusion after any of the treatments. No serious adverse events were recorded, and all patients were able to complete the six treatments, demonstrating that aMST appears to be a safe and tolerable treatment for MDD. Although large randomized clinical trials have yet to definitively establish the efficacy and tolerability of MST for depression, available data show that MST might have similar efficacy to some
forms of ECT (Cretaz et al., 2015; Lee et al., 2016), but with fewer cognitive side effects. It would appear the significantly weaker and more focal E-field that MST generates might be associated with the differential cognitive side effects seen in MST compared to ECT (Kayser et al., 2015). Changes in seizure and stimulation duration, specifically shorter seizures and longer duration of stimulation, suggest that aMST is able to cause changes in neural excitability in a manner similar to ECT even over a short period of time (Bajbouj et al., 2006). Daily administration of ECT has been previously reported both using bilateral placement (Kalinowsky et al., 1943) and right unilateral (RUL) (Abrams, 1967; Rasmussen et al., 2016). Kalinowsky and colleagues treated only 18 patients with psychosis and bitemporal placement for 7-10 days and reported the development of a transient confusional state with no advantage on outcomes. On the other hand, Abrams reported the use of RUL in patients with schizophrenia comparing daily vs three times a week administration for a total of 20 treatments in both groups, revealing no differences in rates of confusion or neuropsychological assessment using the Wechsler memory form (Abrams, 1967). More recently, Rasmussen and colleagues reported on a pilot open label study comparing RUL ultrabrief ECT for 10 treatments comparing daily administration (Mon-Fri) to three times per week (Rasmussen et al., 2016). Outcomes and rates of side effects were similar in both groups providing preliminary evidence for the safe use of accelerated convulsive therapy in depression. Our results align with those of Rasmussen and colleagues, as we found good outcomes and even improvement in neuropsychological tests indexing memory function. While preliminary, our findings encourage the study of aMST as a tool for the
rapid relief of depressive symptoms. Currently, ketamine is the only established therapeutic intervention to produce a meaningful response in a brief window of time (Schwartz et al., 2016). Future investigation of aMST is thus of great importance as this may provide patients with another option to rapidly treat depressive symptoms. Limitations Our results should be interpreted with caution as they are part of a pilot study with a small sample size, with inherent limitations such as non-randomization, the lack of a comparator group, and the open-label design. Importantly, the sample investigated in the current study is not a typical treatment-resistant sample: Patients showed relatively short illness durations, with many experiencing first-episode depression. Furthermore, all participants were initiated on antidepressant treatment at the same time as the aMST. It is therefore difficult to separate the effects of the antidepressants from the effects of aMST, although clinical response within 8 days would not be expected for treatment with antidepressants (Jakubovski et al., 2019). A definite trial on aMST should control for this confounding variable by either using aMST in monotherapy or having patients on a stable number and doses of medications for 4 to 8 weeks before starting aMST. In addition, the aMST protocol only lasted 8 days, leaving a very short span of time in between cognitive and mood assessments. Therefore, the possibility of practice effects as a potential explanation for the improvement noted in cognitive performance should be considered. However, even the possibility of a practice effect is encouraging in the context of convulsive therapies as possibly the most consistent and burdensome side effects are short-term memory and learning deficits (Verwijk et al., 2012).
In regards to the cognitive assessment, it is important to note that the RBANS, which is not typically used as a measure in seizure therapy studies, was used as the assessment measure in the current study. The few ECT studies that cite the use of RBANS note no changes in cognitive symptoms over time, bringing into question its sensitivity to detect potential detrimental effects (Bayless et al., 2010; Abbott et al., 2013). However, memory impairments are the most common cognitive side effect of ECT, and we instead report significant cognitive gains, thus suggesting that undetected cognitive side effects are not a concern in the current sample. Finally, the short duration of the study gives little insight into the long-term effects of aMST; at present, there are no longitudinal follow-up data to determine whether the mood and cognition improvements seen last for a meaningful duration of time. Further investigation into the long-term effects of aMST is therefore warranted. In any case, our pilot study generates relevant hypotheses for the field that merit further research as the speed of response in only 8 days and the lack of confusion or severe cognitive side effects is promising to provide rapid, safe and well-tolerated, and effective symptomatic relief in MDD.
Conflicts of Interest: The authors declare no financial interests relative to this work. FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and in-kind equipment support for this investigator-initiated trial from MagVenture. He has received honoraria for participation in advisory board for Janssen. Contributors JW, WJ, CY, and GW conceived and designed the study. FVR, RG, SG, and EG developed the plan for statistical analyses and drafted the manuscript. All authors made revisions to the manuscript. Roles of the Funding Source None. Acknowledgements None.
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Figure 1. Change in seizure length (in log seconds) and stimulation duration (in seconds) over the course of 6 MST treatments.
Table 1. Demographic and clinical characteristics All patients (n = Responders (n = 15) 9) Age, years, mean 31.9 (10.9) 29.6 (9.2) (SD)
Non-responders (n = 6) 35.5 (13.1)
p values* 0.32
Sex, female/male (% female)
11/4 (73%)
5/4 (55%)
6/0 (100%)
0.06
Education, years, mean (SD)
13.1 (3.4)
14.1 (3.6)
11.5 (2.6)
0.15
Age at onset, years, mean (SD)
29.1 (8.9)
31.8 (10.1)
25.2 (5.2)
0.36
Disease duration, months, median (1st, 3rd quartile)
12.0 (6.0, 48.0)
8.0 (2.5, 84.0)
15.0 (10.5, 51.0)
0.60
Duration current episode, months, mean (SD)
5.2 (4.1)
6.9 (4.4)
2.7 (2.2)
0.05
AD equivalent dose, mean (SD)
27.9 (5.4)
26.7 (0.0)
29.7 (8.6)
0.05
BDZ equivalent dose, mean (SD)
1.1 (1.2)
1.1 (1.3)
1.1 (1.1)
0.74
HRSD (baseline), mean (SD)
30.4 (5.4)
29.8 (5.0)
31.3 (6.3)
0.60
HRSD (endpoint), mean (SD)
13.1 (8.3)
7.9 (3.48)
20.8 (7.33)
<.01
HAM-A (baseline, mean (SD)
28.3 (8.4)
28.0 (8.8)
28.8 (8.6)
0.86
HAMA (endpoint), 10.6 (6.9) 6.6 (1.8) 16.7 (7.5) mean (SD) HRSD: 17-item Hamilton Rating Scale for Depression; HAM-A: Hamilton Anxiety Rating Scale.AD: Antidepressant; BZD: Benzodiazepine. *The p values report the significance levels for the t-tests (as applicable) comparing responders and nonresponders.
<.01
Table 2. Clinical and neuropsychological outcome variables Outcome Before After MST mean difference* measure MST HRSD-17 mean (SD) HAMA mean (SD)
-17.3 (t=-10.42, p< .001) -17.7 (t=-7.72, p< .001)
Change (%)
30.4 (5.4)
13.1(8.3)
-57%
28.3 (8.4)
10.6 (6.9)
RBANS total 85.8 (16.2) score mean (SD)
99.7 (16.5)
13.9 (t=5.80, p<.001)
16.20%
(1)Immediate memory index mean (SD)
77.5 (17.4) 103.7 (22.4)
26.2 (t=8.95, p<.001)
33.70%
(2)Delayed memory index mean (SD)
83.5 (16.8)
98.9 (17.1)
15.4 (t=3.34, p< .01)
18.50%
(3)Visuospatial/ constructional 99.8 (18.3) index mean (SD)
101 (14.7)
1.2 (t= .30, p= .76)
1.20%
(4)Language 86.9 (12.9) index mean (SD)
94.9 (9.8)
8.1 (t= 2.10, p= .054)
9.30%
(5)Attention 98.5 (16.2) index mean (SD)
99.4 (18.6)
0.9 (t= .63, p= .54)
0.90%
-62.60%
Stroop colorword condition 101.3 0.6 101.9 (36.3) 0.60% (time) mean (32.1) (t= .17, p= .86) (SD) Stroop colorword condition -0.9 1.3 (1.9) 0.4 (1.1) -68.40% (error) mean (t=-1.78, p= .096) (SD) HRSD: 17-item Hamilton Rating Scale for Depression; HAM-A: Hamilton Anxiety Rating Scale RBANS: Repeatable Battery for the Assessment of Neuropsychological Status. *p values report the two-tailed significance of paired ttests for the baseline and follow-up scores.
Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: a pilot study Jian Wang , Fidel Vila-Rodriguez , Ruiyang Ge , Sherry Gao , Elizabeth Gregory , Wei Jiang , Chunlin Yang , Gang Wang PII: DOI: Reference:
S0165-0327(19)32886-1 https://doi.org/10.1016/j.jad.2019.12.022 JAD 11438
To appear in:
Journal of Affective Disorders
Received date: Revised date: Accepted date:
18 October 2019 12 December 2019 13 December 2019
Please cite this article as: Jian Wang , Fidel Vila-Rodriguez , Ruiyang Ge , Sherry Gao , Elizabeth Gregory , Wei Jiang , Chunlin Yang , Gang Wang , Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: a pilot study, Journal of Affective Disorders (2019), doi: https://doi.org/10.1016/j.jad.2019.12.022
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Highlights MDD patients received accelerated Magnetic Seizure Therapy (aMST) for eight days. aMST was well-tolerated, with no cognitive side effects associated with treatment. Patients showed rapid improvements in depression and anxiety symptoms. Further research is necessary to characterize the long-term effects of aMST.
Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: a pilot study
Jian Wang1, Fidel Vila-Rodriguez2, Ruiyang Ge2, Sherry Gao2, Elizabeth Gregory2, Wei Jiang3, Chunlin Yang3, Gang Wang3,4* 1
Department of psychiatry, Beijing Anzhen Hospital, Capital Medical University, Beijing
100029, China 2
Non-Invasive Neurostimulation Therapies (NINET) Laboratory, Department of
Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada 3
The National Clinical Research Centre for Mental Disorders ＆Beijing Key Laboratory
of Mental Disorders, Beijing Anding Hospital, Capital Medical University, School of Mental Health, Beijing 100088, China 4
Advanced Innovation Center for Human Brain Protection, Capital Medical University,
Beijing, 100069, China
Correspondence to: Gang Wang, [email protected]
Funding information: Funding by National Key Research & Development Program of China (No. 2016YFC1307200); Beijing Municipal Administration of Hospitals’ Ascent Plan (No. DFL20151801); Beijing Municipal Science and Tech Commission (No. Z171100000117004).
Conflicts of Interest: The authors declare no financial interests relative to this work. FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and in-kind equipment support for this investigator-initiated trial from MagVenture. He has received honoraria for participation in advisory board for Janssen.
Keywords: Magnetic seizure therapy; Major depressive disorder; Cognition ABSTRACT Background: Magnetic Seizure therapy (MST) is an emerging treatment for major depressive disorder (MDD) that is associated with fewer cognitive side effects compared to electroconvulsive therapy. The present pilot study sought to investigate whether daily MST treatments were associated to antidepressant effect and assess cognitive side effects associated with an accelerated MST (aMST) treatment schedule. Methods: Fifteen MDD patients underwent a six-day course of MST treatment to the vertex following assessment of symptom severity and neuropsychological testing. The primary outcome was severity on the Hamilton Rating Scale for Depression 17-item (HRSD-17). Patient also underwent neuropsychological assessment with the RBANS and Stroop Colour-Word test. Results: There were no instances of delirium or disturbance of consciousness following aMST sessions. Patients showed significant decreases on indices of depression and anxiety symptoms, with 9 (60%) patients showing a clinical response and 7 (47%) patients experiencing remission. Significant improvements were reported in RBANS total score, as well as indices of immediate memory and delayed memory. No changes at follow-up were reported for visuospatial/constructional, language, and attention RBANS
indices, nor for Stroop Colour/Word performance. Limitations: The results should be interpreted with caution as they are part of a nonrandomized, open-label pilot study. Further, the short duration of the study does not provide longitudinal follow-up to determine whether treatment response lasts a meaningful duration of time. Conclusions: aMST well tolerated without significant evidence of cognitive side effects and rapid improvement in symptoms. Further research is required to fully characterize these changes and replicate them in independent samples.
INTRODUCTION Depression is the leading cause of disability world-wide and is associated with substantial morbidity and mortality (World Health Organization, 2017). Magnetic seizure therapy (MST) is a non-invasive convulsive neurostimulation therapy that relies on the principle of electromagnetic induction to induce an electric field in the brain strong enough to elicit a generalized tonic-clonic seizure under general anesthesia (Lisanby et al., 2003). MST has been shown to be a safe and efficacious treatment for major depressive disorder (MDD) (Lisanby et al., 2001), and is associated with a favourable side effect profile compared to electroconvulsive therapy (ECT) (Moscrip et al., 2006). In contrast to ECT, which elicits a widespread electric field to induce a therapeutic seizure (Deng et al., 2011), the electric field elicited by MST is restricted to the cerebral cortex, where the seizure initiates and secondarily spreads to the rest of the brain (Lee et al.,
2014). Therefore, the electric field spares critical brain areas involved in cognition and may be one of the reasons underlying the favourable side effect profile of MST compared to ECT. Specifically, research has demonstrated shorter reorientation time and lesser cognitive impairment after MST compared to ECT (Kayser et al., 2015). Also, MST is associated with less power in frequency bands above delta (Cycowicz et al., 2018) as well as milder increase in heart rate and blood pressure (White et al., 2006). MST is still in the early stages of clinical investigation, but preliminary data are encouraging. Specifically, several case series (Kosel et al., 2003; Lisanby et al., 2001; Noda et al., 2014) and small sample studies (Fitzgerald et al., 2013; Kayser et al., 2011; Lisanby et al., 2003) have reported significant response and remission rates at approximately 60% and 30%, respectively, in patients with MDD and bipolar depression, as well as a more favorable side effect profile compared to ECT, particularly with regards to fewer cognitive side effects (Kirov et al., 2008; Polster et al., 2015). Daily administration of ECT was explored early during the development of ECT, but was quickly abandoned after it was shown that daily bilateral ECT was associated with prolonged confusion and with delirium (Kalinowsky and Worthing, 1943). However, a recent open label study by Rasmussen and colleagues, in which patients received daily right unilateral ultrabrief (RUL-UB) ECT for 10 treatments, reported commensurate efficacy rates without a significant increase in cognitive side effects (Rasmussen et al., 2016). RUL-UB ECT, similar to MST, is associated with lesser cognitive side effects compared to conventional ECT, however appears to have slower rates of improvement and require more treatments compared to conventional ECT (Milev et al., 2016).
The low rates of cognitive side effects associated with MST make this intervention a potential candidate for increasing the frequency of treatments to accelerate the time to clinical response. We recently reported preliminary data from three patients in this pilot study (Wang et al., 2018), and we report here the complete pilot open-label study to test the feasibility and tolerability of delivering 6 consecutive daily MST sessions to treat MDD. MATERIALS AND METHODS All study procedures were approved by the Anding Hospital of Capital Medical University Ethics Committee and registered on Chinese Clinical Trial Registry site (http://www.chictr.org, number ChiCTR-RNC-17014100)(Wang et al., 2018). All participants provided informed consent. Participants Inclusion criteria were assessed by a physical examination, including a routine blood test and electrocardiogram before MST. Inclusion criteria were: (1) aged between 18 and 60 years old, (2) Hamilton Rating Scale for Depression 17-item (HRSD-17) score of 18 or greater, (3) convulsive therapy clinically indicated, (4) right-handed, and (5) able to provide informed consent. Exclusion criteria included: (1) not suitable for ECT, (2) had any history of schizophrenia, schizoaffective disorder, or bipolar disorder, (3) were pregnant or planning on getting pregnant, (4) were allergic to anesthetics or muscle relaxants, (5) had any devices that could be affected by MST or were deemed unsuitable for magnetic resonance scanning, or (6) had received ECT in the past 6 months or had failed to respond to an adequate course of ECT in the past. Clinical Outcome Measures
Psychiatric diagnoses were made on the basis of the Diagnostic and Statistical Manual of Mental Disorders 5 (American Psychiatric Association, 2013). Clinical assessments were included the HRSD-17 as the primary outcome measure (Hamilton, 1960), and the Hamilton Anxiety Rating Scale (HAMA, (Hamilton, 1959). Response was defined as a ≥ 50% reduction in HRSD-17 from baseline, and remission was defined as a HRSD-17 score ≤ 7. The Chinese version of the Repeatable Battery for the Assessment of Neuropsychological status (RBANS), as well as the Stroop Colour/word test (Golden version), were used to assess neuropsychological functioning. The RBANS provides standardized scores of performances in immediate memory, delayed memory, visuospatial/constructional functions, language, and attention, while the Stroop color/word test is a measure of inhibitory function (Strauss et al., 2006). The RBANS shows sensitivity to impairments associated with depression (Faust et al., 2017). In healthy subjects, the Chinese version of the RBANS demonstrates high internal reliability for total score (Cronbachs’ α = 0.90) and subtest scores (Cronbachs’ α = 0.67 – 0.86). Test-retest reliability is similarly high for total score (ICC = 0.90) and subtest scores (ICC = 0.53 – 0.80). The Chinses version of the RBANS also demonstrates construct validity, showing positive correlations with more extensive neuropsychological assessments (e.g. Wechsler tests, r = 0.21-0.59; Zhang et al., 2008). Clinical rating scales and neuropsychological testing assessments were performed at baseline and within three days of their last MST treatment by trained raters. MST Treatment The MST treatments were administered under general anesthesia using a
stimulator (MagStim, UK) with a circular coil (diameter of the coil: 130 mm). Stimulation was delivered over the vertex, as measured following the international EEG 10-20 system. Vertex stimulation was chosen because stimulation of this area reliably induces seizures (Kayser et al., 2011; Kirov et al., 2008). Stimulation duration was up to 10 seconds, with a frequency of 100 Hz and 100% of maximum stimulator output. As per standard procedures described in the literature, the seizure-threshold titration procedure was employed throughout the treatment sessions, wherein stimulation duration is adjusted to modify stimulus strength (Lisanby et al., 2003). A total of 6 sessions were administered on 6 consecutive week-days early in the morning. Due to lack of a priori data regarding the efficacy of aMST, all patients were treated with serotonin/norepinephrine reuptake inhibitors. This systematic approach was adopted to minimize the confounding effect of having patients on different antidepressant medications. Patients remained on stable doses of antidepressant during the MST treating process (see supplemental table 1), benzodiazepines were not administered for 12hrs before the treatment. Benzodiazepine dose equivalents were calculated using previously defined ratios from the literature and reported in supplemental table 1 ( U.M.I. (UKMi) pharmacists for N. healthcare, 2018). General anesthesia was induced with propofol (1.52 mg/kg) and muscle relaxation with succinylcholine (0.5-1 mg/kg). Statistical Analyses: Paired t-tests were performed to compare changes between pre and post treatment assessments of HRSD, HAMA, RBANS, and Stroop Colour-Word test scores, as well as to assess the change in stimulation duration and seizure length over the six treatments. All score changes were correlated with demographic and clinical variables to determine
any potentially relevant associations. Analyses were computed using R, version 3.5.1. RESULTS Demographic and clinical characteristics Demographic and clinical characteristics are summarized in Table 1. The sample comprised of younger adults, the majority female. Patients were severely depressed as measured by HRSD mean scores and showed moderate to severe symptoms of anxiety according HAMA scores at baseline. Illness course was non-lengthy, although there was considerable variability within the sample, as the majority were experiencing recurrent MDD and some MDD single episode. Average current episode duration was less than one year. All patients were taking antidepressants, with 14 patients taking duloxetine (4060mg BID) and 1 patient taking venlafaxine (150mg qD). Thirteen patients started medication within one day of MST treatment initiation, while two patients had been taking antidepressants for three weeks prior to MST treatment with no improvement in symptoms. The majority of patients were taking low doses of benzodiazepines (see supplemental Table 1). Clinical and Neuropsychological Outcomes Outcome variables are summarized in Table 2. Overall, 9 patients (60%) showed response to aMST treatment and 7 (47%) met remission criterion. Patients experienced a 57% mean reduction of depressive symptoms (17.3 point reduction on HDRS, t=-10.4; p<.001), and 62% mean reduction of anxiety symptoms (17 point reduction on HAMA, t=-7.7; p<.001). Patients showed statistically significant improvements in RBANS total score (16% improvement; p<.001), immediate memory index (34% improvement; p<.001), and
delayed memory index (18% improvement; p<.01). Performance on the visuospatial/constructional index, the language index, and the attention index, did not change significantly, although scores increased marginally over time. Performance remained unchanged for the Stroop Colour/Word task, both in measures of speed and number of total errors, although the number of errors was reduced at follow-up. Age was associated with a lesser increase in the immediate memory index over time (r=-.55, p=.03). No other demographic or clinical characteristic was associated with changes in neuropsychological performance, nor was treatment response. Treatment Characteristics and Side Effects Mean (SD) seizure length at the first treatment was 41.5 seconds (18.7) and decreased steadily over the course of the six treatments (p<.001), with a seizure length of 25.7 seconds (17.4) by the last (6th) treatment. Mean stimulation duration increased over the course of the six treatments, starting at a mean of 7.4 seconds (1.6) at the first treatment, and increasing to a mean of 9.7 seconds (0.8) at the final treatment (p<.001). T-tests for both variables (seizure length and stimulation duration) showed no significant differences between responders and non-responders across treatment sessions. Changes in seizure length and stimulation duration over time are illustrated in Figure 1. No serious adverse events were recorded in the 15 patients during MST treatment. Eight cases (53%) reported transient mild dizziness, 6 cases (40%) reported transient mild muscle soreness, 3 cases reported moderate dry mouth, 2 cases (13%) reported transient lisp, and 1 case (7%) reported transient fever, the highest 38.6℃. None of the patients experienced post-MST delirium or disturbance of consciousness. No patients dropped out, with all 15 patients completing the six treatments and study visits.
DISCUSSION Our pilot study is the first to report the use of aMST for depression (i.e. daily administration, excluding weekends). The patients hence received only 6 treatments in a span of 8 days, which is half the number of treatments, and three times shorter span of time, usually delivered with ECT (i.e. ECT takes ~30 days to deliver 12 sessions at 3 sessions/week). Using this accelerated and abbreviated protocol, 9 of the 15 patients showed response (and 7 remitted), while the remaining 6 patients showed some improvement in their HRSD scores but did not achieve response criterion. All patients showed decrease in HAMA scores, although responders showed significantly greater improvement in anxiety symptoms. Although these results are encouraging for such a brief and intensive intervention, it is important to draw attention to the fact the patients in the sample had a relatively short mean duration of illness of 12 months. A portion of them were MDD single episode therefore limiting the potential generalization of results to clinical samples of higher severity and refractoriness. The fact that all but two initiated antidepressant treatment at the same time as they started their course of MST opens more questions, as an additive or a synergistic effect of MST and antidepressants are both plausible hypotheses. A future definite trial must carefully consider the timeline between antidepressant introduction or changes and initiation of MST to increase the degree of certainty regarding attribution of the effect to MST. In addition to antidepressants, all patients were on low doses of benzodiazepines, a factor that has been associated to worse outcomes in the context of both ECT (Delamarre et al., 2019) and repetitive transcranial magnetic stimulation (Kaster et al., 2019). It will remain an open question as to whether a larger therapeutic effect may be observed in the absence of benzodiazepine use.
Neurocognitive assessments showed no detrimental effects to cognition, with scores on visuospatial/construction, language, and attention indices, as well as the Stroop Colour/Word task, remaining unchanged. Promisingly, patients showed improvements in RBANS overall scores with a mean improvement of 16.2% (13.9 point increase), as well as in immediate and delayed memory indices, with mean improvements of 33.7% (26.2 point increase) and 18.5% (15.4 point increase), respectively. These changes in neurocognitive performance were not associated with treatment response. Change scores on the RBANS of 15 points or greater are generally thought to be clinically significant (Strauss et al., 2006). While the lack of a control group in this current study does not allow for the discounting of any practice effects, especially given the short window between neuropsychological testing sessions, improvements in cognitive performance, especially in domains of memory (which often show detrimental side effects of ECT), are encouraging (Verwijk et al., 2012). Daskalakis and colleagues recently reported similar improvements in neurocognitive performance, with improvements in visuospatial memory and delayed recall following MST treatment (Daskalakis et al, 2019). Similar to our study, there was no comparator group, however given the convergence of results, investigation of the potential cognitive gains from MST treatment is warranted. In terms of tolerability it is important to note that there were no episodes of delirium or prolonged confusion after any of the treatments. No serious adverse events were recorded, and all patients were able to complete the six treatments, demonstrating that aMST appears to be a safe and tolerable treatment for MDD. Although large randomized clinical trials have yet to definitively establish the efficacy and tolerability of MST for depression, available data show that MST might have similar efficacy to some
forms of ECT (Cretaz et al., 2015; Lee et al., 2016), but with fewer cognitive side effects. It would appear the significantly weaker and more focal E-field that MST generates might be associated with the differential cognitive side effects seen in MST compared to ECT (Kayser et al., 2015). Changes in seizure and stimulation duration, specifically shorter seizures and longer duration of stimulation, suggest that aMST is able to cause changes in neural excitability in a manner similar to ECT even over a short period of time (Bajbouj et al., 2006). Daily administration of ECT has been previously reported both using bilateral placement (Kalinowsky et al., 1943) and right unilateral (RUL) (Abrams, 1967; Rasmussen et al., 2016). Kalinowsky and colleagues treated only 18 patients with psychosis and bitemporal placement for 7-10 days and reported the development of a transient confusional state with no advantage on outcomes. On the other hand, Abrams reported the use of RUL in patients with schizophrenia comparing daily vs three times a week administration for a total of 20 treatments in both groups, revealing no differences in rates of confusion or neuropsychological assessment using the Wechsler memory form (Abrams, 1967). More recently, Rasmussen and colleagues reported on a pilot open label study comparing RUL ultrabrief ECT for 10 treatments comparing daily administration (Mon-Fri) to three times per week (Rasmussen et al., 2016). Outcomes and rates of side effects were similar in both groups providing preliminary evidence for the safe use of accelerated convulsive therapy in depression. Our results align with those of Rasmussen and colleagues, as we found good outcomes and even improvement in neuropsychological tests indexing memory function. While preliminary, our findings encourage the study of aMST as a tool for the
rapid relief of depressive symptoms. Currently, ketamine is the only established therapeutic intervention to produce a meaningful response in a brief window of time (Schwartz et al., 2016). Future investigation of aMST is thus of great importance as this may provide patients with another option to rapidly treat depressive symptoms. Limitations Our results should be interpreted with caution as they are part of a pilot study with a small sample size, with inherent limitations such as non-randomization, the lack of a comparator group, and the open-label design. Importantly, the sample investigated in the current study is not a typical treatment-resistant sample: Patients showed relatively short illness durations, with many experiencing first-episode depression. Furthermore, all participants were initiated on antidepressant treatment at the same time as the aMST. It is therefore difficult to separate the effects of the antidepressants from the effects of aMST, although clinical response within 8 days would not be expected for treatment with antidepressants (Jakubovski et al., 2019). A definite trial on aMST should control for this confounding variable by either using aMST in monotherapy or having patients on a stable number and doses of medications for 4 to 8 weeks before starting aMST. In addition, the aMST protocol only lasted 8 days, leaving a very short span of time in between cognitive and mood assessments. Therefore, the possibility of practice effects as a potential explanation for the improvement noted in cognitive performance should be considered. However, even the possibility of a practice effect is encouraging in the context of convulsive therapies as possibly the most consistent and burdensome side effects are short-term memory and learning deficits (Verwijk et al., 2012).
In regards to the cognitive assessment, it is important to note that the RBANS, which is not typically used as a measure in seizure therapy studies, was used as the assessment measure in the current study. The few ECT studies that cite the use of RBANS note no changes in cognitive symptoms over time, bringing into question its sensitivity to detect potential detrimental effects (Bayless et al., 2010; Abbott et al., 2013). However, memory impairments are the most common cognitive side effect of ECT, and we instead report significant cognitive gains, thus suggesting that undetected cognitive side effects are not a concern in the current sample. Finally, the short duration of the study gives little insight into the long-term effects of aMST; at present, there are no longitudinal follow-up data to determine whether the mood and cognition improvements seen last for a meaningful duration of time. Further investigation into the long-term effects of aMST is therefore warranted. In any case, our pilot study generates relevant hypotheses for the field that merit further research as the speed of response in only 8 days and the lack of confusion or severe cognitive side effects is promising to provide rapid, safe and well-tolerated, and effective symptomatic relief in MDD.
Conflicts of Interest: The authors declare no financial interests relative to this work. FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and in-kind equipment support for this investigator-initiated trial from MagVenture. He has received honoraria for participation in advisory board for Janssen. Contributors JW, WJ, CY, and GW conceived and designed the study. FVR, RG, SG, and EG developed the plan for statistical analyses and drafted the manuscript. All authors made revisions to the manuscript. Roles of the Funding Source None. Acknowledgements None.
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Figure 1. Change in seizure length (in log seconds) and stimulation duration (in seconds) over the course of 6 MST treatments.
Table 1. Demographic and clinical characteristics All patients (n = Responders (n = 15) 9) Age, years, mean 31.9 (10.9) 29.6 (9.2) (SD)
Non-responders (n = 6) 35.5 (13.1)
p values* 0.32
Sex, female/male (% female)
11/4 (73%)
5/4 (55%)
6/0 (100%)
0.06
Education, years, mean (SD)
13.1 (3.4)
14.1 (3.6)
11.5 (2.6)
0.15
Age at onset, years, mean (SD)
29.1 (8.9)
31.8 (10.1)
25.2 (5.2)
0.36
Disease duration, months, median (1st, 3rd quartile)
12.0 (6.0, 48.0)
8.0 (2.5, 84.0)
15.0 (10.5, 51.0)
0.60
Duration current episode, months, mean (SD)
5.2 (4.1)
6.9 (4.4)
2.7 (2.2)
0.05
AD equivalent dose, mean (SD)
27.9 (5.4)
26.7 (0.0)
29.7 (8.6)
0.05
BDZ equivalent dose, mean (SD)
1.1 (1.2)
1.1 (1.3)
1.1 (1.1)
0.74
HRSD (baseline), mean (SD)
30.4 (5.4)
29.8 (5.0)
31.3 (6.3)
0.60
HRSD (endpoint), mean (SD)
13.1 (8.3)
7.9 (3.48)
20.8 (7.33)
<.01
HAM-A (baseline, mean (SD)
28.3 (8.4)
28.0 (8.8)
28.8 (8.6)
0.86
HAMA (endpoint), 10.6 (6.9) 6.6 (1.8) 16.7 (7.5) mean (SD) HRSD: 17-item Hamilton Rating Scale for Depression; HAM-A: Hamilton Anxiety Rating Scale.AD: Antidepressant; BZD: Benzodiazepine. *The p values report the significance levels for the t-tests (as applicable) comparing responders and nonresponders.
<.01
Table 2. Clinical and neuropsychological outcome variables Outcome Before After MST mean difference* measure MST HRSD-17 mean (SD) HAMA mean (SD)
-17.3 (t=-10.42, p< .001) -17.7 (t=-7.72, p< .001)
Change (%)
30.4 (5.4)
13.1(8.3)
-57%
28.3 (8.4)
10.6 (6.9)
RBANS total 85.8 (16.2) score mean (SD)
99.7 (16.5)
13.9 (t=5.80, p<.001)
16.20%
(1)Immediate memory index mean (SD)
77.5 (17.4) 103.7 (22.4)
26.2 (t=8.95, p<.001)
33.70%
(2)Delayed memory index mean (SD)
83.5 (16.8)
98.9 (17.1)
15.4 (t=3.34, p< .01)
18.50%
(3)Visuospatial/ constructional 99.8 (18.3) index mean (SD)
101 (14.7)
1.2 (t= .30, p= .76)
1.20%
(4)Language 86.9 (12.9) index mean (SD)
94.9 (9.8)
8.1 (t= 2.10, p= .054)
9.30%
(5)Attention 98.5 (16.2) index mean (SD)
99.4 (18.6)
0.9 (t= .63, p= .54)
0.90%
-62.60%
Stroop colorword condition 101.3 0.6 101.9 (36.3) 0.60% (time) mean (32.1) (t= .17, p= .86) (SD) Stroop colorword condition -0.9 1.3 (1.9) 0.4 (1.1) -68.40% (error) mean (t=-1.78, p= .096) (SD) HRSD: 17-item Hamilton Rating Scale for Depression; HAM-A: Hamilton Anxiety Rating Scale RBANS: Repeatable Battery for the Assessment of Neuropsychological Status. *p values report the two-tailed significance of paired ttests for the baseline and follow-up scores.