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Actigraphy in patients with treatment-resistant depression undergoing electroconvulsive therapy
Journal of Psychiatric Research xxx (2014) 1e5
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Actigraphy in patients with treatment-resistant depression undergoing electroconvulsive therapy Dietmar Winkler*, Edda Pjrek, Rupert Lanzenberger, Pia Baldinger, Daniel Eitel, Siegfried Kasper, Richard Frey Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 January 2014 Received in revised form 8 June 2014 Accepted 16 June 2014
Depressive disorder is frequently accompanied by changes in psychomotor activity and disturbances of the sleepewake cycle. The chronobiological effects of electroconvulsive therapy (ECT) in patients with treatment-resistant depression (TRD) are largely unknown. The objective of the current study was to measure the influence of ECT on patients' activity and sleep. 15 patients with unipolar TRD were treated with ECT. Activity levels were measured with wrist actigraphy before and after ECT. Remission rate (score on the 17-item Hamilton Depression Rating Scale lower than 8 points) was 40.0%. Remitters had increases of 56.0% on light activity, 49.8% on total activity, and 70.2% on circadian amplitude, while there was no significant change of these variables in subjects who did not experience remission. The circadian acrophase and actigraphic sleep-parameters were not significantly affected by treatment. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Treatment-resistant depression ECT Activity Sleepewake cycle Chronobiology Actigraphic measurements
1. Introduction Depression is frequently accompanied by changes in psychomotor activity and disturbances of the rest-activity cycle. These symptoms represent key features of depression and have diagnostic, pathophysiological and therapeutic significance (Bunney and Potkin, 2008; Schrijvers et al., 2008). Despite a wide range of available antidepressant treatment strategies, treatment resistant depression (TRD) remains an important clinical phenomenon (Souery et al., 2007; Schlaepfer et al., 2012). Approximately 50e60% of patients do not achieve full remission after adequate antidepressant treatment (Fava, 2003; Nemeroff, 2007). Electroconvulsive therapy (ECT) is one of the most effective treatment strategies in TRD (Kellner et al., 2012) and appears to exceed the short-term efficacy of antidepressant medication with faster onset of action, fewer residual symptoms and higher remission rates (Mathew et al., 2005). However, the mechanism of action and the physiological changes occurring during ECT are still not completely understood (Bolwig, 2011; Lanzenberger et al., 2013; Tendolkar et al.,
* Corresponding author. Department of Psychiatry and Psychotherapy, Medical €hringer Gürtel 18-20, A-1090 Vienna, Austria. Tel.: þ43 1 University of Vienna, Wa 40400 35470; fax: þ43 1 40400 30990. E-mail address: [email protected] (D. Winkler).
2013). Specifically, as of yet, no study has examined chronobiological changes accompanying the use of ECT. Actigraphy is a non-invasive technique which uses a small wristworn device to create a high resolution time series of motor activity, which can be evaluated to assess subjects' sleepewake cycle. In contrast to electrophysiological techniques, wrist actigraphy allows ambulatory measurements for long periods with minimal interference to the subjects' lifestyle (Ancoli-Israel et al., 2003). The American Sleep Disorders Association has proposed actigraphy as “an effective means of demonstrating multiday human rest-activity patterns” (American Sleep Disorders Association, 1995). Actigraphy has repeatedly been employed in research of different psychiatric disorders (Kripke et al., 1978; Satlin et al., 1991; Kasper et al., 2010; Pjrek et al., 2012), and several studies have shown the ability to derive measures of sleep and circadian rhythms from actigraphic data (Lieberman et al., 1989; Brown et al., 1990). The aim of the present study was to examine the effect of ECT on the rest-activity cycle in TRD. Based on prior research with different antidepressant strategies (Raoux et al., 1994; Volkers et al., 2003; Winkler et al., 2005; Berle et al., 2010), we hypothesized an increase of motor activity and improvements in blunted circadian rhythms in patients with remission after ECT as compared to patients not remitting after ECT. Furthermore, we wanted to investigate the effects of ECT on sleep in this sample in an explorative way.
http://dx.doi.org/10.1016/j.jpsychires.2014.06.006 0022-3956/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Winkler D, et al., Actigraphy in patients with treatment-resistant depression undergoing electroconvulsive therapy, Journal of Psychiatric Research (2014), http://dx.doi.org/10.1016/j.jpsychires.2014.06.006
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D. Winkler et al. / Journal of Psychiatric Research xxx (2014) 1e5
2. Method 2.1. Subjects 15 inpatients (10 women, 5 men; age: 47.9 ± 10.4 years, range: 22.1e64.6 years) with an episode of (recurrent) major depressive disorder according to the diagnostic criteria of the DSM-IV-TR (American Psychiatric Association, 2000) and the ICD-10 (World Health Organization, 1991) were recruited at the Department of Psychiatry and Psychotherapy (Medical University of Vienna, Austria). Only treatment-resistant patients, i. e. after a failure of treatment of at least two adequate trials with antidepressants of different pharmacological classes were selected (Bauer et al., 2013). Subjects had to be eligible for electroconvulsive therapy (ECT) after having been medically cleared. Patients completed the Structured Clinical Interview for DSM-IV (SCID; First et al., 2002) and had to obtain a total score of 23 or higher on the 17-item Hamilton Depression Rating Scale (HAM-D; Hamilton, 1960) on inclusion. The psychopharmacological medication of the subjects (Table 1), with the exception of occasional doses of benzodiazepines, was kept stable throughout the study starting at least 10 days before inclusion. Patients with a history of substance abuse, schizophrenia, schizoaffective disorder or bipolar disorder as well as incompliant patients, pregnant females, and subjects involuntarily hospitalized according to the Austrian Hospitalization Act (Bundesgesetzblatt € für die Republik Osterreich, 1990) were not included. Patients with a history of past ECT treatments were also not enrolled. Subjects had to be in good overall physical health without somatic or neurological illnesses, that could have potentially influenced activity levels or circadian rhythms. The study was approved by the local institutional review board, the Ethics Committee of the Medical University of Vienna (project number EK 556/2008); all subjects provided written informed consent before any study procedures were performed. 2.2. Study procedures ECT was performed using a Thymatron System IV device (Somatics Inc.: Lake Bluff, IL, USA) according to national and international guidelines and consensus statements for ECT (Conca et al.,
Table 1 Medication (substance name and daily dose) of 15 inpatients suffering from TRD at baseline. Patient no.
Medication
1 2 3 4 5
Olanzapine 15 mg, Lorazepam 2.5 mg Escitalopram 10 mg, Alprazolam 1 mg Sertraline 100 mg, Prothipendyl 160 mg, Lorazepam 6.25 mg Duloxetine 120 mg, Oxazepam 30 mg Duloxetine 120 mg, Mirtazapine 60 mg, Amisulpride 500 mg, Prothipendyl 40 mg, Lithium carbonate 450 mg Escitalopram 20 mg, Mirtazapine 30 mg, Olanzapine 10 mg, Prothipendyl 80 mg, Lorazepam 3 mg, Zolpidem 10 mg Sertraline 200 mg, Venlafaxine XR 300 mg, Lorazepam 2.5 mg Duloxetine 120 mg, Bupropion XR 450 mg Milnacipran 100 mg, Prothipendyl 160 mg, Lorazepam 3.75 mg, Lamotrigine 100 mg, Oxcarbazepine 300 mg Escitalopram 20 mg, Bupropion XR 300 mg, Prothipendyl 160 mg Venlafaxine XR 300 mg, Solian 400 mg, Prothipendyl 320 mg, Lorazepam 5 mg, Zoldem 10 mg Citalopram 60 mg, Mirtazapine 60 mg, Prothipendyl 80 mg, Lorazepam 4 mg Venlafaxine XR 300 mg, Mirtazapine 60 mg, Alprazolam 0.5 mg, Zolpidem 10 mg, Lamotrigine 50 mg Duloxetine 120 mg, Mirtazapine 30 mg, Pregabalin 300 mg Fluoxetine 40 mg, Triazolam 0.25 mg
6 7 8 9 10 11 12 13 14 15
2004; Lisanby, 2007; Bauer et al., 2013). Treatment was performed three times per week under general anesthesia with methohexital and muscle relaxation with succinylcholine. Seizure duration was measured by simultaneous electroencephalography (EEG) and electromyography (EMG). At each patient's first treatment, repeated stimuli of increasing intensity were administered until a seizure occurred and the lowest stimulus intensity able to induce an epileptic seizure was defined as the threshold (Frey et al., 2001). In the following treatment, the charge was set at three times the seizure threshold. The intensity was further increased in the absence of seizure activity or in case of inadequate seizures (i. e. <20sec; Peterchev et al., 2010). In all patients, ECT was started with unilateral stimulation using an electrode placement in the right frontotemporal position (d'Elia and Raotma, 1975). Bilateral stimulation was used after 5 ECT sessions in the case of insufficient clinical response. The number of administered ECT sessions was 9.8 ± 2.4 (range: 4e14). Study participants were instructed to wear activity monitors (Actiwatch Plus by Cambridge Neurotechnology Ltd., Cambridgeshire, UK) on their non-dominant wrist. Subjects were told to only remove the actigraphs when showering or bathing during the study period. The device contains a piezo-electric accelerometer that records the intensity and duration of all movements over 0.05 g. Recording epoch was adjusted to 60 s. Altogether, we were able to obtain 4.1 ± 4.7 days of actigraphic measurement before ECT and 3.6 ± 2.1 days after ECT. At the end of the study, patients had a second clinical evaluation, and treatment outcome was measured using the HAM-D. 2.3. Data collection and statistical analysis Data were downloaded to a computer and processed subjectwise with the Actiwatch software (Cambridge Neurotechnology Ltd., 2001). Data were carefully reviewed and checked for missing values and outliers. A nonparametric circadian rhythm analysis (Van Someren et al., 1999) of the data and cosinor analysis (assuming that a sinusoidal curve can be fitted to the 24-h activity rhythm) were performed (Nelson et al., 1979). A sleep analysis (Kushida et al., 2001) was conducted with the sensitivity of the algorithm set to “medium” (an activity score of 40 or more during an epoch will designate that epoch as being awake) to estimate actigraphic sleep parameters. We calculated a percentage change between measurements before and after ECT for our outcome variables to account for intraindividual differences in baseline activity. Resulting data were further analyzed with IBM SPSS Statistics (IBM Corporation, 1989e2010) for differences before and after ECT in remitters (HAM-D 7) and non-remitters. We preferred to group our data by remission rather than by response to treatment because frequent residual symptoms such as daytime fatigue, lack of drive or sleep disturbances (Zajecka et al., 2013) would inevitably obscure changes in actigraphic variables. Light activity (activity between 08:00 a.m. and 22:00 p.m.) was selected as the primary outcome measure of our analysis. Total activity, amplitude, cosine peak (acrophase of the circadian rhythm), sleep efficiency, sleep latency, and fragmentation index (during sleep) were considered as secondary actigraphic outcome parameters. The use of these parameters has been previously validated (Oakley, 1997; Van Someren et al., 1999; Kushida et al., 2001; Lichstein et al., 2006; Thomas and Burr, 2008). KolmogoroveSmirnov test was used to check for deviations from normal distribution in our variables. Student's t test, Wilcoxon signed rank test and Pearson's correlation coefficient were used for hypothesis testing. Effect sizes (Cohen's d) were calculated from t-statistics and sample sizes using the following formula: d¼(t*(n1 þ n2))/SQRT((n1 þ n2-2)(n1*n2)) (Rosenthal and Rosnow, 2008). The p 0.05 level of significance (two-tailed) was
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adopted. Data are either presented as arithmetic mean ± standard deviation or in the case of percentage change values together with 95% confidence intervals in square brackets. 3. Results Prior to ECT no significant differences on any actigraphic variable between remitters (6 of 15 subjects e 40%) and non-remitters were observed. Bilateral ECT was employed in 9 patients of the total sample (60.0%), but only in 2 of 6 remitters (33.3%). Scores on the HAM-D decreased significantly with ECT in the total sample (before ECT: 24.3 ± 3.2, after ECT: 10.2 ± 6.6; Z ¼ 3.409, p ¼ 0.001) as well as in patients who did (25.2 ± 3.1 vs. 4.7 ± 2.0; Z ¼ 2.207, p ¼ 0.027) or did not (23.8 ± 3.3 vs. 13.9 ± 6.0; Z ¼ 2.668, p ¼ 0.008) achieve remission. Raw activity scores by time of day before and after ECT as well as in patients with and without remission after ECT are shown in Figs. 1 and 2, respectively. After ECT, there was a 24.2% [2.8e45.7%] increase in light activity in the total sample (t ¼ 2.217, df ¼ 14, p ¼ 0.044; Cohen's d ¼ 0.838), 56.0% [17.5e94.4%] in remitters (t ¼ 2.855, df ¼ 5, p ¼ 0.036; Cohen's d ¼ 1.806), and no significant change (3.1% [10.6 to 16.8%]) in non-remitters (t ¼ 0.444, df ¼ 8, p ¼ 0.669). The difference in light activity scores after ECT between patients with and without remission was statistically significant (t ¼ 2.946, df ¼ 13, p ¼ 0.011; Cohen's d ¼ 1.668; Fig. 3). There was also a significant correlation between the pre/post difference on HAM-D scores and the percentage change in light activity (r ¼ 0.540, p ¼ 0.038). A significant correlation was also seen between the change in the HAM-D item “activities” and the actigraphic parameter light activity (r ¼ 0.559, p ¼ 0.030). Total activity likewise increased in the total sample (21.8% [2.2e41.4%]; t ¼ 2.183, df ¼ 14, p ¼ 0.047) and in remitters (49.8% [16.2e83.5%]; t ¼ 2.902, df ¼ 5, p ¼ 0.034), but not in non-remitters (3.1% [11.9 to 18.2%]; t ¼ 0.407, df ¼ 8, p ¼ 0.695; test for difference between remitters/ non-remitters: t ¼ 2.793, df ¼ 13, p ¼ 0.015). The circadian amplitude in remitters increased by 70.2% [21.6e118.8%] (t ¼ 2.831, df ¼ 5, p ¼ 0.037), while this parameter
Fig. 2. Activity scores (number of movements per minute) by time of day after ECT in 6 patients with and 9 patients without remission from depression. Moving average: 60 min.
remained unchanged in non-remitters (0.4% [10.9 to 10.1%]; t ¼ 0.080, df ¼ 8, p ¼ 0.938; test for difference between the two groups: t ¼ 3.374, df ¼ 13, p ¼ 0.005; Fig. 4). The cosine peak did not shift significantly with ECT (remitter: -62.5 ± 111.9 min; t ¼ 1.368, df ¼ 5, p ¼ 0.230; non-remitter: 0.0 ± 95.2 min; t ¼ 0.000, df ¼ 8, p ¼ 1.000). We found no significant change in sleep efficacy, sleep latency or fragmentation index after ECT in patients with or without remission. 4. Discussion
Fig. 1. Actigraphic measurements in a sample of 15 inpatients suffering from TRD. Shown are the raw activity scores (number of wrist movements per minute) for the measurement days before and after ECT by time of day (x-axis). Data are smoothed by applying a moving average of 60 min.
To our best knowledge, this is the first study using actigraphy to investigate patients with TRD undergoing ECT. As hypothesized we observed an increase in light activity and circadian amplitude in patients with remission after ECT, which was not seen in nonremitters. Since it has been shown that actigraphic light activity correlates best with the HAM-D item “activities” (Razavi et al., 2011), this is most likely due to an increase of drive in remitters. Given the decrease of HAM-D scores, it is, however, surprising that the group of patients without remission did not show a trend towards increases of motor activity: Therefore, in our sample of treatment-resistant patients, residual depressive symptoms still seem to have a profound impact on activity. Furthermore, it is important to recognize the specific properties of our sample: When comparing mean raw light activity levels of our patients (before ECT: 169.1 ± 53.6; after ECT: 213.0 ± 120.3) with a subset of healthy controls from a prior study (Winkler et al., 2005: 748.5 ± 387.5; N ¼ 10; mean age: 45.9 ± 15.5 years), it is apparent that our TRD patients had markedly diminished activity levels even after ECT. This might be owing to the rather severe and chronic nature of their depressive illness e many of these patients had more than two treatment trials with antidepressants and could also be characterized as treatment refractory (Kasper and Akimova, 2013), but may also have been aggravated by a lack of activities during hospitalization. Therefore, it would be interesting to evaluate follow-up data aquired from the same patients with stable remission in an outpatient setting.
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Fig. 3. Percental change from baseline in light activity (08:00e22:00) in 15 inpatients with TRD after ECT. Presented are means ± 95% confidence intervals.*p < 0.05.
80% at baseline) and (pre)treatment with sleep promoting medication might have contributed to this negative finding. Our study is limited by the small sample size, the lack of a control group and the open, non-randomized nature of this study. However, it is unlikely that actigraphic measurements in a sample of treatment resistant patients would have induced a large bias due to placebo effects. Furthermore, we did our best to rule out drug effects by keeping the medication of our patients stable. To conclude, we have shown that ECT improves attenuated circadian rhythms, while having minimal effect on sleep. From our results it is still unclear, whether ECT possesses phase-shifting properties. Our findings should therefore be replicated in a larger sample. Furthermore, it would be interesting to directly compare ECT with other antidepressant treatments regarding their chronobiological effects. Finally, we found no actigraphic predictors for remission to ECT, although this study was not adequately powered for this analysis. However, future studies may aim to take early actigraphic changes during ECT into account and to combine these data with electrophysiologic techniques or functional neuroimaging to allow prediction of treatment effect. Role of the funding source
The acrophase of the circadian rhythm was numerically advanced by slightly more than 1 h in remitters after ECT, while this was not seen in non-remitters. Due to a large interindividual variability of the cosine peak in our data this difference did not reach statistical significance. If our results reflected a true treatment effect of ECT, the magnitude of the phase advance would be comparable to other studies in depression. Indeed, other nonpharmacological biological treatments, such as total sleep deprivation and bright light therapy (Winkler et al., 2005; Benedetti et al., 2007) and antidepressants like agomelatine (Krauchi et al., 1997) and possibly also trazodone (Suzuki et al., 2002) have been shown to mediate a phase advance. During this study we were not able to ascertain effects of ECT on sleep. Apart from one case series (Zarcone et al., 1967), which focused on sleep stages in a mixed patient population and found a trend-wise increase in total sleep time, treatment with ECT has not been systematically investigated for its impact on sleep. Rather, our results stand in line with the clinical observation that ECT does not have a substantial influence on sleep. However, our specific sample with a low rate of insomnia (only 5 of 15 subjects had sleep efficiency below
None. Contributors Dietmar Winkler and Edda Pjrek designed the study with support from Rupert Lanzenberger and Richard Frey. Dietmar Winkler, Pia Baldinger and Richard Frey carried out the study-related procedures. Dietmar Winkler and Daniel Eitel performed the statistical evaluation together with Edda Pjrek and Siegfried Kasper. Rupert Lanzenberger and Siegfried Kasper provided administrative support for this study. Dietmar Winkler, Pia Baldinger and Daniel Eitel drafted the article. All co-authors contributed substantially to the final version of this article. Conflict of interest Dr. Frey has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb, and Eli Lilly. Dr. Kasper has received grant/ research support from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, Sepracor, and Servier; has served as a consultant or on advisory boards for AstraZeneca, Austrian Sick Found, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Novartis, Organon, Pfizer, and Sepracor; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Janssen, Lundbeck, Sepracor, and Servier. Dr. Lanzenberger has received travel grants and/or conference speaker honoraria from AstraZeneca, Lundbeck and Roche. Dr. Winkler has received lecture fees from Bristol-Myers Squibb, CSC Pharmaceuticals, Novartis, Pfizer, and Servier. The other authors report no financial or other relationship possibly relevant to the subject of this article. Acknowledgment € flich and Dr. Zoltan The authors are grateful to Dr. Anna Ho Micskei for their medical support. We thank Dr. Marie Spies for proofreading. References
Fig. 4. Percental change (mean ± 95% CI) from baseline in circadian amplitude after ECT in 15 depressed inpatients. *p < 0.05, **p < 0.01.
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Actigraphy in patients with treatment-resistant depression undergoing electroconvulsive therapy Dietmar Winkler*, Edda Pjrek, Rupert Lanzenberger, Pia Baldinger, Daniel Eitel, Siegfried Kasper, Richard Frey Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 January 2014 Received in revised form 8 June 2014 Accepted 16 June 2014
Depressive disorder is frequently accompanied by changes in psychomotor activity and disturbances of the sleepewake cycle. The chronobiological effects of electroconvulsive therapy (ECT) in patients with treatment-resistant depression (TRD) are largely unknown. The objective of the current study was to measure the influence of ECT on patients' activity and sleep. 15 patients with unipolar TRD were treated with ECT. Activity levels were measured with wrist actigraphy before and after ECT. Remission rate (score on the 17-item Hamilton Depression Rating Scale lower than 8 points) was 40.0%. Remitters had increases of 56.0% on light activity, 49.8% on total activity, and 70.2% on circadian amplitude, while there was no significant change of these variables in subjects who did not experience remission. The circadian acrophase and actigraphic sleep-parameters were not significantly affected by treatment. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Treatment-resistant depression ECT Activity Sleepewake cycle Chronobiology Actigraphic measurements
1. Introduction Depression is frequently accompanied by changes in psychomotor activity and disturbances of the rest-activity cycle. These symptoms represent key features of depression and have diagnostic, pathophysiological and therapeutic significance (Bunney and Potkin, 2008; Schrijvers et al., 2008). Despite a wide range of available antidepressant treatment strategies, treatment resistant depression (TRD) remains an important clinical phenomenon (Souery et al., 2007; Schlaepfer et al., 2012). Approximately 50e60% of patients do not achieve full remission after adequate antidepressant treatment (Fava, 2003; Nemeroff, 2007). Electroconvulsive therapy (ECT) is one of the most effective treatment strategies in TRD (Kellner et al., 2012) and appears to exceed the short-term efficacy of antidepressant medication with faster onset of action, fewer residual symptoms and higher remission rates (Mathew et al., 2005). However, the mechanism of action and the physiological changes occurring during ECT are still not completely understood (Bolwig, 2011; Lanzenberger et al., 2013; Tendolkar et al.,
* Corresponding author. Department of Psychiatry and Psychotherapy, Medical €hringer Gürtel 18-20, A-1090 Vienna, Austria. Tel.: þ43 1 University of Vienna, Wa 40400 35470; fax: þ43 1 40400 30990. E-mail address: [email protected] (D. Winkler).
2013). Specifically, as of yet, no study has examined chronobiological changes accompanying the use of ECT. Actigraphy is a non-invasive technique which uses a small wristworn device to create a high resolution time series of motor activity, which can be evaluated to assess subjects' sleepewake cycle. In contrast to electrophysiological techniques, wrist actigraphy allows ambulatory measurements for long periods with minimal interference to the subjects' lifestyle (Ancoli-Israel et al., 2003). The American Sleep Disorders Association has proposed actigraphy as “an effective means of demonstrating multiday human rest-activity patterns” (American Sleep Disorders Association, 1995). Actigraphy has repeatedly been employed in research of different psychiatric disorders (Kripke et al., 1978; Satlin et al., 1991; Kasper et al., 2010; Pjrek et al., 2012), and several studies have shown the ability to derive measures of sleep and circadian rhythms from actigraphic data (Lieberman et al., 1989; Brown et al., 1990). The aim of the present study was to examine the effect of ECT on the rest-activity cycle in TRD. Based on prior research with different antidepressant strategies (Raoux et al., 1994; Volkers et al., 2003; Winkler et al., 2005; Berle et al., 2010), we hypothesized an increase of motor activity and improvements in blunted circadian rhythms in patients with remission after ECT as compared to patients not remitting after ECT. Furthermore, we wanted to investigate the effects of ECT on sleep in this sample in an explorative way.
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Please cite this article in press as: Winkler D, et al., Actigraphy in patients with treatment-resistant depression undergoing electroconvulsive therapy, Journal of Psychiatric Research (2014), http://dx.doi.org/10.1016/j.jpsychires.2014.06.006
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2. Method 2.1. Subjects 15 inpatients (10 women, 5 men; age: 47.9 ± 10.4 years, range: 22.1e64.6 years) with an episode of (recurrent) major depressive disorder according to the diagnostic criteria of the DSM-IV-TR (American Psychiatric Association, 2000) and the ICD-10 (World Health Organization, 1991) were recruited at the Department of Psychiatry and Psychotherapy (Medical University of Vienna, Austria). Only treatment-resistant patients, i. e. after a failure of treatment of at least two adequate trials with antidepressants of different pharmacological classes were selected (Bauer et al., 2013). Subjects had to be eligible for electroconvulsive therapy (ECT) after having been medically cleared. Patients completed the Structured Clinical Interview for DSM-IV (SCID; First et al., 2002) and had to obtain a total score of 23 or higher on the 17-item Hamilton Depression Rating Scale (HAM-D; Hamilton, 1960) on inclusion. The psychopharmacological medication of the subjects (Table 1), with the exception of occasional doses of benzodiazepines, was kept stable throughout the study starting at least 10 days before inclusion. Patients with a history of substance abuse, schizophrenia, schizoaffective disorder or bipolar disorder as well as incompliant patients, pregnant females, and subjects involuntarily hospitalized according to the Austrian Hospitalization Act (Bundesgesetzblatt € für die Republik Osterreich, 1990) were not included. Patients with a history of past ECT treatments were also not enrolled. Subjects had to be in good overall physical health without somatic or neurological illnesses, that could have potentially influenced activity levels or circadian rhythms. The study was approved by the local institutional review board, the Ethics Committee of the Medical University of Vienna (project number EK 556/2008); all subjects provided written informed consent before any study procedures were performed. 2.2. Study procedures ECT was performed using a Thymatron System IV device (Somatics Inc.: Lake Bluff, IL, USA) according to national and international guidelines and consensus statements for ECT (Conca et al.,
Table 1 Medication (substance name and daily dose) of 15 inpatients suffering from TRD at baseline. Patient no.
Medication
1 2 3 4 5
Olanzapine 15 mg, Lorazepam 2.5 mg Escitalopram 10 mg, Alprazolam 1 mg Sertraline 100 mg, Prothipendyl 160 mg, Lorazepam 6.25 mg Duloxetine 120 mg, Oxazepam 30 mg Duloxetine 120 mg, Mirtazapine 60 mg, Amisulpride 500 mg, Prothipendyl 40 mg, Lithium carbonate 450 mg Escitalopram 20 mg, Mirtazapine 30 mg, Olanzapine 10 mg, Prothipendyl 80 mg, Lorazepam 3 mg, Zolpidem 10 mg Sertraline 200 mg, Venlafaxine XR 300 mg, Lorazepam 2.5 mg Duloxetine 120 mg, Bupropion XR 450 mg Milnacipran 100 mg, Prothipendyl 160 mg, Lorazepam 3.75 mg, Lamotrigine 100 mg, Oxcarbazepine 300 mg Escitalopram 20 mg, Bupropion XR 300 mg, Prothipendyl 160 mg Venlafaxine XR 300 mg, Solian 400 mg, Prothipendyl 320 mg, Lorazepam 5 mg, Zoldem 10 mg Citalopram 60 mg, Mirtazapine 60 mg, Prothipendyl 80 mg, Lorazepam 4 mg Venlafaxine XR 300 mg, Mirtazapine 60 mg, Alprazolam 0.5 mg, Zolpidem 10 mg, Lamotrigine 50 mg Duloxetine 120 mg, Mirtazapine 30 mg, Pregabalin 300 mg Fluoxetine 40 mg, Triazolam 0.25 mg
6 7 8 9 10 11 12 13 14 15
2004; Lisanby, 2007; Bauer et al., 2013). Treatment was performed three times per week under general anesthesia with methohexital and muscle relaxation with succinylcholine. Seizure duration was measured by simultaneous electroencephalography (EEG) and electromyography (EMG). At each patient's first treatment, repeated stimuli of increasing intensity were administered until a seizure occurred and the lowest stimulus intensity able to induce an epileptic seizure was defined as the threshold (Frey et al., 2001). In the following treatment, the charge was set at three times the seizure threshold. The intensity was further increased in the absence of seizure activity or in case of inadequate seizures (i. e. <20sec; Peterchev et al., 2010). In all patients, ECT was started with unilateral stimulation using an electrode placement in the right frontotemporal position (d'Elia and Raotma, 1975). Bilateral stimulation was used after 5 ECT sessions in the case of insufficient clinical response. The number of administered ECT sessions was 9.8 ± 2.4 (range: 4e14). Study participants were instructed to wear activity monitors (Actiwatch Plus by Cambridge Neurotechnology Ltd., Cambridgeshire, UK) on their non-dominant wrist. Subjects were told to only remove the actigraphs when showering or bathing during the study period. The device contains a piezo-electric accelerometer that records the intensity and duration of all movements over 0.05 g. Recording epoch was adjusted to 60 s. Altogether, we were able to obtain 4.1 ± 4.7 days of actigraphic measurement before ECT and 3.6 ± 2.1 days after ECT. At the end of the study, patients had a second clinical evaluation, and treatment outcome was measured using the HAM-D. 2.3. Data collection and statistical analysis Data were downloaded to a computer and processed subjectwise with the Actiwatch software (Cambridge Neurotechnology Ltd., 2001). Data were carefully reviewed and checked for missing values and outliers. A nonparametric circadian rhythm analysis (Van Someren et al., 1999) of the data and cosinor analysis (assuming that a sinusoidal curve can be fitted to the 24-h activity rhythm) were performed (Nelson et al., 1979). A sleep analysis (Kushida et al., 2001) was conducted with the sensitivity of the algorithm set to “medium” (an activity score of 40 or more during an epoch will designate that epoch as being awake) to estimate actigraphic sleep parameters. We calculated a percentage change between measurements before and after ECT for our outcome variables to account for intraindividual differences in baseline activity. Resulting data were further analyzed with IBM SPSS Statistics (IBM Corporation, 1989e2010) for differences before and after ECT in remitters (HAM-D 7) and non-remitters. We preferred to group our data by remission rather than by response to treatment because frequent residual symptoms such as daytime fatigue, lack of drive or sleep disturbances (Zajecka et al., 2013) would inevitably obscure changes in actigraphic variables. Light activity (activity between 08:00 a.m. and 22:00 p.m.) was selected as the primary outcome measure of our analysis. Total activity, amplitude, cosine peak (acrophase of the circadian rhythm), sleep efficiency, sleep latency, and fragmentation index (during sleep) were considered as secondary actigraphic outcome parameters. The use of these parameters has been previously validated (Oakley, 1997; Van Someren et al., 1999; Kushida et al., 2001; Lichstein et al., 2006; Thomas and Burr, 2008). KolmogoroveSmirnov test was used to check for deviations from normal distribution in our variables. Student's t test, Wilcoxon signed rank test and Pearson's correlation coefficient were used for hypothesis testing. Effect sizes (Cohen's d) were calculated from t-statistics and sample sizes using the following formula: d¼(t*(n1 þ n2))/SQRT((n1 þ n2-2)(n1*n2)) (Rosenthal and Rosnow, 2008). The p 0.05 level of significance (two-tailed) was
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adopted. Data are either presented as arithmetic mean ± standard deviation or in the case of percentage change values together with 95% confidence intervals in square brackets. 3. Results Prior to ECT no significant differences on any actigraphic variable between remitters (6 of 15 subjects e 40%) and non-remitters were observed. Bilateral ECT was employed in 9 patients of the total sample (60.0%), but only in 2 of 6 remitters (33.3%). Scores on the HAM-D decreased significantly with ECT in the total sample (before ECT: 24.3 ± 3.2, after ECT: 10.2 ± 6.6; Z ¼ 3.409, p ¼ 0.001) as well as in patients who did (25.2 ± 3.1 vs. 4.7 ± 2.0; Z ¼ 2.207, p ¼ 0.027) or did not (23.8 ± 3.3 vs. 13.9 ± 6.0; Z ¼ 2.668, p ¼ 0.008) achieve remission. Raw activity scores by time of day before and after ECT as well as in patients with and without remission after ECT are shown in Figs. 1 and 2, respectively. After ECT, there was a 24.2% [2.8e45.7%] increase in light activity in the total sample (t ¼ 2.217, df ¼ 14, p ¼ 0.044; Cohen's d ¼ 0.838), 56.0% [17.5e94.4%] in remitters (t ¼ 2.855, df ¼ 5, p ¼ 0.036; Cohen's d ¼ 1.806), and no significant change (3.1% [10.6 to 16.8%]) in non-remitters (t ¼ 0.444, df ¼ 8, p ¼ 0.669). The difference in light activity scores after ECT between patients with and without remission was statistically significant (t ¼ 2.946, df ¼ 13, p ¼ 0.011; Cohen's d ¼ 1.668; Fig. 3). There was also a significant correlation between the pre/post difference on HAM-D scores and the percentage change in light activity (r ¼ 0.540, p ¼ 0.038). A significant correlation was also seen between the change in the HAM-D item “activities” and the actigraphic parameter light activity (r ¼ 0.559, p ¼ 0.030). Total activity likewise increased in the total sample (21.8% [2.2e41.4%]; t ¼ 2.183, df ¼ 14, p ¼ 0.047) and in remitters (49.8% [16.2e83.5%]; t ¼ 2.902, df ¼ 5, p ¼ 0.034), but not in non-remitters (3.1% [11.9 to 18.2%]; t ¼ 0.407, df ¼ 8, p ¼ 0.695; test for difference between remitters/ non-remitters: t ¼ 2.793, df ¼ 13, p ¼ 0.015). The circadian amplitude in remitters increased by 70.2% [21.6e118.8%] (t ¼ 2.831, df ¼ 5, p ¼ 0.037), while this parameter
Fig. 2. Activity scores (number of movements per minute) by time of day after ECT in 6 patients with and 9 patients without remission from depression. Moving average: 60 min.
remained unchanged in non-remitters (0.4% [10.9 to 10.1%]; t ¼ 0.080, df ¼ 8, p ¼ 0.938; test for difference between the two groups: t ¼ 3.374, df ¼ 13, p ¼ 0.005; Fig. 4). The cosine peak did not shift significantly with ECT (remitter: -62.5 ± 111.9 min; t ¼ 1.368, df ¼ 5, p ¼ 0.230; non-remitter: 0.0 ± 95.2 min; t ¼ 0.000, df ¼ 8, p ¼ 1.000). We found no significant change in sleep efficacy, sleep latency or fragmentation index after ECT in patients with or without remission. 4. Discussion
Fig. 1. Actigraphic measurements in a sample of 15 inpatients suffering from TRD. Shown are the raw activity scores (number of wrist movements per minute) for the measurement days before and after ECT by time of day (x-axis). Data are smoothed by applying a moving average of 60 min.
To our best knowledge, this is the first study using actigraphy to investigate patients with TRD undergoing ECT. As hypothesized we observed an increase in light activity and circadian amplitude in patients with remission after ECT, which was not seen in nonremitters. Since it has been shown that actigraphic light activity correlates best with the HAM-D item “activities” (Razavi et al., 2011), this is most likely due to an increase of drive in remitters. Given the decrease of HAM-D scores, it is, however, surprising that the group of patients without remission did not show a trend towards increases of motor activity: Therefore, in our sample of treatment-resistant patients, residual depressive symptoms still seem to have a profound impact on activity. Furthermore, it is important to recognize the specific properties of our sample: When comparing mean raw light activity levels of our patients (before ECT: 169.1 ± 53.6; after ECT: 213.0 ± 120.3) with a subset of healthy controls from a prior study (Winkler et al., 2005: 748.5 ± 387.5; N ¼ 10; mean age: 45.9 ± 15.5 years), it is apparent that our TRD patients had markedly diminished activity levels even after ECT. This might be owing to the rather severe and chronic nature of their depressive illness e many of these patients had more than two treatment trials with antidepressants and could also be characterized as treatment refractory (Kasper and Akimova, 2013), but may also have been aggravated by a lack of activities during hospitalization. Therefore, it would be interesting to evaluate follow-up data aquired from the same patients with stable remission in an outpatient setting.
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Fig. 3. Percental change from baseline in light activity (08:00e22:00) in 15 inpatients with TRD after ECT. Presented are means ± 95% confidence intervals.*p < 0.05.
80% at baseline) and (pre)treatment with sleep promoting medication might have contributed to this negative finding. Our study is limited by the small sample size, the lack of a control group and the open, non-randomized nature of this study. However, it is unlikely that actigraphic measurements in a sample of treatment resistant patients would have induced a large bias due to placebo effects. Furthermore, we did our best to rule out drug effects by keeping the medication of our patients stable. To conclude, we have shown that ECT improves attenuated circadian rhythms, while having minimal effect on sleep. From our results it is still unclear, whether ECT possesses phase-shifting properties. Our findings should therefore be replicated in a larger sample. Furthermore, it would be interesting to directly compare ECT with other antidepressant treatments regarding their chronobiological effects. Finally, we found no actigraphic predictors for remission to ECT, although this study was not adequately powered for this analysis. However, future studies may aim to take early actigraphic changes during ECT into account and to combine these data with electrophysiologic techniques or functional neuroimaging to allow prediction of treatment effect. Role of the funding source
The acrophase of the circadian rhythm was numerically advanced by slightly more than 1 h in remitters after ECT, while this was not seen in non-remitters. Due to a large interindividual variability of the cosine peak in our data this difference did not reach statistical significance. If our results reflected a true treatment effect of ECT, the magnitude of the phase advance would be comparable to other studies in depression. Indeed, other nonpharmacological biological treatments, such as total sleep deprivation and bright light therapy (Winkler et al., 2005; Benedetti et al., 2007) and antidepressants like agomelatine (Krauchi et al., 1997) and possibly also trazodone (Suzuki et al., 2002) have been shown to mediate a phase advance. During this study we were not able to ascertain effects of ECT on sleep. Apart from one case series (Zarcone et al., 1967), which focused on sleep stages in a mixed patient population and found a trend-wise increase in total sleep time, treatment with ECT has not been systematically investigated for its impact on sleep. Rather, our results stand in line with the clinical observation that ECT does not have a substantial influence on sleep. However, our specific sample with a low rate of insomnia (only 5 of 15 subjects had sleep efficiency below
None. Contributors Dietmar Winkler and Edda Pjrek designed the study with support from Rupert Lanzenberger and Richard Frey. Dietmar Winkler, Pia Baldinger and Richard Frey carried out the study-related procedures. Dietmar Winkler and Daniel Eitel performed the statistical evaluation together with Edda Pjrek and Siegfried Kasper. Rupert Lanzenberger and Siegfried Kasper provided administrative support for this study. Dietmar Winkler, Pia Baldinger and Daniel Eitel drafted the article. All co-authors contributed substantially to the final version of this article. Conflict of interest Dr. Frey has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb, and Eli Lilly. Dr. Kasper has received grant/ research support from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, Sepracor, and Servier; has served as a consultant or on advisory boards for AstraZeneca, Austrian Sick Found, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Novartis, Organon, Pfizer, and Sepracor; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Janssen, Lundbeck, Sepracor, and Servier. Dr. Lanzenberger has received travel grants and/or conference speaker honoraria from AstraZeneca, Lundbeck and Roche. Dr. Winkler has received lecture fees from Bristol-Myers Squibb, CSC Pharmaceuticals, Novartis, Pfizer, and Servier. The other authors report no financial or other relationship possibly relevant to the subject of this article. Acknowledgment € flich and Dr. Zoltan The authors are grateful to Dr. Anna Ho Micskei for their medical support. We thank Dr. Marie Spies for proofreading. References
Fig. 4. Percental change (mean ± 95% CI) from baseline in circadian amplitude after ECT in 15 depressed inpatients. *p < 0.05, **p < 0.01.
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Please cite this article in press as: Winkler D, et al., Actigraphy in patients with treatment-resistant depression undergoing electroconvulsive therapy, Journal of Psychiatric Research (2014), http://dx.doi.org/10.1016/j.jpsychires.2014.06.006