Early improvement as a predictor of final remission in major depressive disorder: New insights in electroconvulsive therapy

Accepted Manuscript

Early improvement as a predictor of final remission in major depressive disorder: New insights in electroconvulsive therapy. Erika Mart´ınez-Amoros Galvez , ´ , Ximena Goldberg , Veronica ` ´ Aida de Arriba-Arnau , Virginia Soria , Jose´ M. Menchon ´ , Diego J. Palao , Mikel Urretavizcaya , Narc´ıs Cardoner PII: DOI: Reference:

S0165-0327(17)32053-0 10.1016/j.jad.2018.03.014 JAD 9711

To appear in:

Journal of Affective Disorders

Received date: Revised date: Accepted date:

3 October 2017 7 February 2018 27 March 2018

Please cite this article as: Erika Mart´ınez-Amoros Galvez , ´ , Ximena Goldberg , Veronica ` ´ Aida de Arriba-Arnau , Virginia Soria , Jose´ M. Menchon ´ , Diego J. Palao , Mikel Urretavizcaya , Narc´ıs Cardoner , Early improvement as a predictor of final remission in major depressive disorder: New insights in electroconvulsive therapy., Journal of Affective Disorders (2018), doi: 10.1016/j.jad.2018.03.014

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Highlights

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The best definition of early improvement is a reduction of 30% in HAM-D21 at week 2.

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This definition could help in the clinical decision making process during ECT

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course.

Short duration and low severity of depression are also positive remission predictors.

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Lack of early improvement may be a clinical marker of change in treatment

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strategy.

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Early improvement as a predictor of final remission in major depressive disorder: New insights in electroconvulsive therapy.

a

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Erika Martínez-Amorósa,b*, Ximena Goldberga,b*, Verònica Gálvezc, Aida de Arriba-Arnaud, Virginia Soriab,d, José M. Menchónb,d, Diego J. Palaoa,b, Mikel Urretavizcayab,d**, Narcís Cardonera,b**.

Mental Health Department, Parc Taulí University Hospital. Institut d’Investigació i

Innovació Sanitària Parc Taulí (I3PT). Department of Psychiatry and

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Medicine, Universitat Autònoma de Barcelona.

Forensic

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Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III

Health Institute, Spain. c

School of Psychiatry, University of NSW. Black Dog Institute, Sydney, Randwick,

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Australia. d

Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research

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Institute (IDIBELL), Neurosciences Group - Psychiatry and Mental Health. Barcelona, Spain. Department of Clinical Sciences, School of Medicine, Universitat de Barcelona,

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Barcelona, Spain.

Corresponding author: Narcís Cardoner.

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**

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*Contributed equally.

Address: OSAMCAT. Santa Fe Building, 2on floor. Parc del Taulí, 1 - 08208 Sabadell (Barcelona). Spain. E-mail: [email protected] Telephone number: +34 93 724 01 82 Fax number: +34 93 717 50 67 **

Corresponding author: Mikel Urretavizcaya. 2

ACCEPTED MANUSCRIPT Address: Feixa Llarga s/n 08907, L’Hospitalet de Llobregat, Barcelona, Spain E-mail: [email protected] Telephone number: +34 93 2607922

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Fax number: +34 93 2607658

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ACCEPTED MANUSCRIPT ABSTRACT Background: Early improvement to antidepressant drugs predicts remission, but the predictive value of early improvement to electroconvulsive therapy (ECT) is still unclear. The main aim of this study was to determine the optimal definition of early improvement in the treatment of major depressive disorder (MDD) with ECT, by

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analyzing its value as a predictor of remission. Methods: A naturalistic study was conducted in 87 adult MDD patients treated with acute ECT. ROC curves were generated to identify the best time point (week 1 or 2 of treatment) predicted remission. Sensibility, specificity, and predictive values were

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calculated for several definitions of early improvement previously proposed in the literature (20%, 25%, 30%, and 35%).

Complementary, time to remission was

analyzed and a logistic regression model was performed to further characterize the impact of the optimal definition of early improvement on remission while adjusting for

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other clinically relevant variables.

Results: A 30% reduction in the HAM-D score after 2 weeks was identified as the

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optimal definition of early improvement, with acceptable sensitivity (76%), and specificity (67%). Complementary analyses provided further support for this definition

variables.

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showing a shorter time to remission and a significant effect adjusted for the rest of

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Limitations: Relatively small sample size, ECT restricted to brief bilateral treatment. Conclusions: Early improvement, defined as a 30% of reduction in the HAM-D21 score

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at week 2, is a good predictor of remission in MDD patients treated with bilateral ECT, with potential clinical impact. Lack of early improvement could indicate a need for further changes in treatment strategies.

Keywords: electroconvulsive therapy, depression, early improvement, predictors, remission.

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ACCEPTED MANUSCRIPT INTRODUCTION Electroconvulsive therapy (ECT) is a highly effective treatment for severe forms of major depressive disorder (MDD) (APA, 2001; UK ECT Review Group et al., 2003). Clinical improvement after ECT is often observed as soon as after the first treatment (Rich et al., 1984), and clinical remission is regularly obtained after 2 to 4 weeks of

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treatment (APA, 2001). A rapid antidepressant response is an essential goal in all patients suffering from depression, but especially for those suffering from severe forms with psychotic symptoms or high risk of suicide. Conversely, a delay in the response increases premature treatment withdrawals and increase personal, social and

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economic burdens associated with depressive illness (Fava and Davidson, 1996; Judd et al., 2000). Hence, one of the major challenges in clinical practice is determining when to modify a therapeutic strategy in patients with a weak or null response in the first weeks of treatment (Kok et al., 2009).

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Response and remission in MDD is commonly measured by changes in Hamilton Depression Scale (HAM-D, (Hamilton, 1967, 1960)) scores at specific time

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points during the course of treatment. In studies of antidepressant drugs, early improvement has been defined by symptoms reduction of 20%, 25%, 30% and 35% of

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HAM-D score in the early course of acute treatment for patients with MDD and a growing body of evidence suggests that these early reductions in HAM-D score may

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predict final response or remission (Henkel et al., 2009; Kok et al., 2009; Szegedi et al., 2003; Vermeiden et al., 2015).

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Regarding ECT treatment, the reduction of clinical symptoms after the first

sessions appears

greater than during the remaining sessions of the ECT course

(Husain et al., 2004; Rich et al., 1984; Rodger et al., 1994) and could also be a good indicator of full improvement after ECT (Husain et al., 2004; Kho et al., 2004; Lin et al., 2016; Segman et al., 1995). Importantly, the speed of response may help identify a threshold to decide whether to continue or discontinue ECT (Husain et al., 2004). Several time points have been used in combination with reductions in HAM-D scores to 5

ACCEPTED MANUSCRIPT predict outcome after ECT. Some studies support that reductions in HAM-D scores after 3 to 6 sessions (i.e., 1 to 2 weeks of ECT) may be the best predictors of response and/or remission after completion of ECT treatment (Husain et al., 2004; Kho et al., 2004; Lin et al., 2016; Segman et al., 1995). An accurate definition of early improvement is clinically relevant to evaluating

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the course of treatment for patients with MDD at an early stage of the episode. This may lead to earlier modification of variables consistently associated with an enhanced response to ECT, such as electrode placement, treatment schedule, and technical aspects of procedure (Abrams et al., 1983; Cronholm and Ottosson, 1960; Kho et al.,

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2004), or an earlier consideration of others augmentation strategies in ECT.

In all, it seems clear that early improvement with ECT can be a highly sensitive predictor of clinical remission, but to date, there is no consensus on the best definition of early improvement to ECT (Kho et al., 2004). Only one prior study has directly

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examined the performance of different cut-offs of HAM-D scores for classifying early improvement and remission from ECT (Lin et al., 2016). However, no study has

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addressed the best definition of early improvement alongside other clinical variables that may have an effect on symptom remission, such as the presence of psychomotor

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disturbances, severity and duration of illness, and level of previous pharmacotherapy resistance (Haq et al., 2015). The main aim of the present study was to determine the

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optimal definition of early improvement in response to bilateral ECT in the treatment of MDD, by analyzing its value as a predictor of remission in naturalistic conditions. This

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objective was explored by comparing the performance of HAM-D reduction scores in 1 week vs. 2 weeks of ECT treatment. Because specific definitions of early improvement have been previously proposed (i.e. 20%, 25%, 30% and 35% HAM-D reductions) (Henkel et al., 2009; Kok et al., 2009; Lin et al., 2016; Szegedi et al., 2003; Vermeiden et al., 2015), our second aim was to further performed diagnostic tests on these cut-off scores. Two complementary aims of the study were: 1) to assess the impact of early

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ACCEPTED MANUSCRIPT improvement in time to remission, and 2) to assess the impact of clinically relevant variables on the found associations.

METHOD Sample and data collection

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Inpatients with unipolar MDD requiring ECT were recruited from the Psychiatry Department of Bellvitge University Hospital between May 2006 and December 2009. Inclusion criteria were as follows: 1) age over 18 years old, 2) DSM-IV-TR (American Psychiatric Association, 2000) diagnostic criteria for MDD. Patients were excluded if they presented comorbid axis I or II disorders (except nicotine dependence) or neurological

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pathology. A total of 89 patients were included in the study. Two cases were dropped due to missing data for analysis. The total sample size analyzed was 87 patients. Written informed consent was obtained from all patients or their relatives. The

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study was approved by the Bellvitge University Hospital Ethics Committee, and all

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procedures were carried out according to the Declaration of Helsinki.

ECT protocol

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ECT was applied according to the APA Task Force on ECT (APA, 2001) and the Spanish Consensus on ECT (Bernardo et al., 1999). Psychotropic treatment prescribed

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by the treating psychiatrist was not discontinued before ECT. In line with the naturalistic design of our study, inclusion in this study did not influence the pharmacological treatment

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choice, and changes in the psychotropic strategy were allowed according to clinical criteria. The practice of ECT was based on the standard protocol of the Hospital. Anesthesia was induced with intravenous thiopental (2-2.5 mg/kg), and succinylcholine (0.5-1 mg/kg) was used for muscle relaxation. Patients were preoxygenated and then manually ventilated using a valve mask and 100% oxygen when they showed adequate muscle relaxation. ECT was administered using a brief pulse constant-current device (ThymatronTM DGx and System IV, Somatics, Inc., Lake Bluff, IL, USA) with a pulse width 7

ACCEPTED MANUSCRIPT of 1 ms in 90.8% of patients and 0.5 ms in the rest of the patients. Bilateral (bifrontotemporal) electrode placement was used. The stimulus charge was set up according to the “half age method” (Petrides and Fink, 1996; APA, 2001). Treatment was given three times a week. The length of the seizure, measured by motor seizure and EEG, was sustained longer than 20 seconds. If seizure duration fell to less than 20

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seconds, the stimulus charge was raised at the next session (to 10% of machine output). ECT was stopped on the basis of the clinical judgment of the treating psychiatrist, until the patient was asymptomatic (i.e., met remission criteria) or until a plateau in benefits had been reached. No maximum number of ECT sessions was pre-established. All patients

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received more than 6 sessions before being considered non-remitters.

Measures

Symptom severity was assessed by an expert clinical rater specifically trained for this study at baseline, weekly during the course of ECT, and after the last ECT session

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using the 21-item HAM-D (HAM-D21). Assessment was conducted at least 24 hours after

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treatment. Scores ranged from 0 to 66 on the HAM-D scale, with higher scores indicating more severe symptoms. The Spanish version of the scale that was used in this study has

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good internal consistency (Cronbach’s alpha = 0.78) and test-retest reliability (0.92) (Bobes et al., 2003; Ramos-Brieva and Cordero, 1986).

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For the exploration of our main analysis, we used HAM-D reductions after 1 and 2

weeks of ECT sessions as predictors. For our second aim, we defined early improvement

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as proposed in previous studies (Henkel et al., 2009; Kok et al., 2009; Lin et al., 2016; Szegedi et al., 2003; Vermeiden et al., 2015): a reduction in HAM- D21 of 20%, 25%, 30% and 35% at the best point of treatment (1 or 2 weeks). Response was defined as a reduction of at least 50% from the baseline HAM-D21 score in 2 consecutive assessments. Patients were considered non-responders when by the end of the assessment did not meet response criteria. Remission was defined as an end point HAM-D21 score of 7 in 2 consecutive assessments (Frank et al., 1991). 8

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Clinical variables Functional status was assessed using the Spanish version of the Global Assessment of Function (GAF; (American Psychiatric Association, 1987)). Furthermore, data were collected regarding i) age at onset, with the presence of the first complete

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episode as the onset starting point; ii) duration of current episode; iii) total duration of illness; iv) presence of melancholic and psychotic symptoms using DSM-IV-TR major depression specifiers; v) psychomotor disturbance measured by the CORE system (Parker G, 1996; Soria et al., 2016); vi) treatment-resistant depression as assessed by the

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Thase and Rush staging method (Thase and Rush, 1997), with patients scoring 3 (stage II resistance + failure of adequate trial of TCA) or higher (stage IV and V) were defined as having a high level of pharmacotherapy treatment resistance (Okazaki et al., 2010); and vii) concomitant medication during ECT course. Data regarding ECT course were also

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collected, including the number of ECT sessions administered in the index episode and

Statistical Analysis

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ECT parameters (pulse-width, duration of seizure and charge).

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Rates of response and remission were determined as frequencies in percentages (%). Potential group demographic and clinical differences were tested for

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responders vs. non-responders and remitters vs. non-remitters by either the Chisquared test or Fisher’s exact test (for qualitative variables), and the Student’s T test or

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Mann-Whitney U test (for quantitative variables). Nonparametric test (Mann-Whitney U test) was used for the variables that were not normally distributed. The data are presented as mean for continuous variables, or the median where necessary and as percentages for categorical variables (number/total number). Group differences in percentage of improvement in HAM-D21 at week 1 and week 2 were tested to identify the time point measure that best predicted remitter patients.

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ACCEPTED MANUSCRIPT To achieve our main aim, analyses were run that allowed to quantify the ability of the time point for identifying remitters from non-remitters. This was performed by entering the percentage of improvement in HAM-D21 at week 1 and week 2 into a receiver operating characteristic (ROC) curve. The area under the curve (AUC) was obtained and analyzed.

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To achieve our second aim, several definitions of early improvement as defined in previous studies were used (20%, 25%, 30%, and 35% reduction in HAM-D21 baseline total score) and studied in relation to the following indices: sensitivity (S= proportion of remitters who were correctly classified as early improvers), specificity (E=

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proportion of non-remitters who were correctly classified as early non-improvers), positive predictive value (PPV= proportion of early improvers who finally remitted), negative predictive value (NPV= proportion of early non-improvers who finally did not remit), and proportion of correctly classified patients (CCP). The exploration of these

those previously proposed.

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indices allowed to identify the best predictor of remission after ECT treatment among

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Finally, two complementary analyses were run to obtain a more comprehensive description of the identified best predictor of remission: 1) A Kaplan-Meier survival

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curve and log-rank comparisons were used to provide an estimate of the time to remission among early improvers compared to early non-improvers. 2) A logistic

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regression model was conducted to explore the putative impact of clinically relevant variables on the association between the predictor and the outcome (i.e., remission).

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The choice of the candidate variables was done in the basis of our previous results (bivariate analysis) and previous literature (Haq et al., 2015). All data were analyzed using SPSS for Windows, v. 19.0 (SPSS, Chicago).

Statistical significance was defined as p< .05 (bilateral).

RESULTS Sample characteristics 10

ACCEPTED MANUSCRIPT The demographic and clinical characteristics of the sample are summarized in Table 1. In summary, our sample was composed of inpatients with severe MDD: the mean HAM-D21 score at recruitment was 28.8 (6.79), psychotic symptoms were present in 52.9% of patients in the context of psychotic MDD (schizoaffective disorders were not included in the study), melancholic features were found in 95.4% of patients,

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48.3% had received ECT in prior episodes and 58.6% of them had a high level of pharmacotherapy treatment resistance. The median duration of current episode was 81 days. Median HAM-D21 and GAF at hospital discharge were 4 (range: 0-21) and 70 (range: 50-90), respectively. Table 2 shows the psychopharmacological treatment

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characteristics received by the patients during the course of ECT. Regarding ECT parameters, the patients received a mean charge of 242.2 (108.8) mC and the mean EEG seizure duration was 29.39 (7.79) seconds.

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Response and Remission

In our sample, almost all patients (95.4%, n=83/87) achieved sustained

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response. Responders did not differ from non-responders in age or in clinical characteristics, with the exception of duration of current episode, which showed

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marginal statistical significance and percent improvement in HAM-D21 in week 2. All non-responders were men (p = 0.03).

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A large percentage of patients (75.9%, n=66/87) attained remission. Before

starting treatment with ECT, remitters and non-remitters did not differ on the severity of

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MDD, showing no significant differences at baseline in terms of treatment resistance, use of ECT in prior episodes, psychotic symptoms, psychomotor disturbance, HAM-D21 and GAF scores, and pharmacological regimen. Remitters were more frequently women (p = 0.03), had a current episode of < 1 year’s duration (p = 0.01) and received fewer ECT sessions in the index episode (p = 0.001). No differences were found regarding other ECT parameters (pulse width, mean charge, and mean EEG seizure

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ACCEPTED MANUSCRIPT duration) or with respect to psychopharmacological treatment during the course of ECT. Importantly, the results showed that the percentage of improvement in HAM-D21 score differed only at week 2 of treatment, with no differences found at week 1 between

------ Table 1 here -------------- Table 2 here ---------

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remitters and non-remitters.

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Main analysis: Ability of the time point for predicting remission (AUC)

For our main objective, the percentages of improvement in HAM-D21 at week 1 and week 2 were entered into ROC curve analysis to determine the ability of the measures to predict remission (Figure DS1 in data supplement). AUC at week 1 was 0.654 (95%

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CI 0.516 – 0.793, p = 0.034), while AUC at week 2 was 0.765 (95% CI 0.652 – 0.878, p<0.001). Hence, the measure at week 2 showed a larger discriminative capacity than

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the measure at week 1. This supported the group comparison findings shown in Table 1. Sensitivity, specificity, and positive and negative values of different cut-off points

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(percentage improvement in HAM-D21 total score) for predicting remission are shown in Table DS1 in data supplement. In our sample, a cut-off point of 30% showed the

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highest score for sensitivity (76%) and specificity (67%); the PPV was 88% and the

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NPV 47%.

Other definitions of early improvement as predictors of remission For our second objective, we analyzed the sensitivity, specificity, positive

predictive value, negative predictive value, and percentage of correctly classified patients for the 4 definitions of early improvement (20%, 25%, 30% and 35% reduction in HAM-D21 baseline total score) at week 2. The results are presented in Table 3.

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ACCEPTED MANUSCRIPT The highest sensitivity was observed for the 20% and 25% reduction definitions, but these definitions also showed low specificity values (38.10% and 47.62%, respectively). The highest score for sensitivity (77.27%) and specificity (66.67%) were observed for the 30% reduction definition. In contrast with the 35% reduction definition, 30% reduction showed a similar estimate of PPV, and higher estimates of NPV

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(48.28%), and CCP (74.71%).

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Complementary analyses: time to remission and impact of clinically relevant variables Taken together, the results of the main and secondary analysis were indicative that a 30% reduction of HAM-D21 score in week 2 of ECT treatment was the best predictor of remission in our sample. Hence, the complementary analyses were run

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using this measure as predictor.

Fifty-eight patients (66.7%) in our sample fulfilled criteria for early improvement

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as operationalized by a 30% decrease in HAM-D21 score at week 2. No significant differences between early improvers and non-early improvers were observed in

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demographic or clinical variables at baseline (Table DS2 in data supplement). Fifty-one of these patients were remitters (87.9%).

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Regarding patients who did not achieved early improvement, 51.7% (15/29)

ultimately attained remission. Patients with early improvement had significantly fewer

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residual symptoms and better functionality after the ECT course than patients without early improvement (median score of HAM-D21 = 3 vs. 7, p = 0.001; median score of the Core system = 1 vs. 5, p = 0.001; and median score of GAF 75 vs. 70, p = 0.008). This occurred despite the fact that patients without early improvement received more ECT sessions (14 vs. 10, p = 0.000) and had higher mean ECT stimulus (227.21 (89.15) vs. 281.18 (134.79) mC, p = 0.028) during the acute course. Log-rank tests (Kaplan-Meier survival analyses) showed significantly shorter time to remission in patients with early 13

ACCEPTED MANUSCRIPT improvement (29 (95% CI: 27.22 - 30.78) vs. 47 (95% CI: 36.90 - 57.04) days, X2 = 21.522, p < 0.001; Figure DS2 in data supplement). A logistic regression model was used to test the impact of the proposed measure of early improvement on remission independent of other clinically relevant variables. Early improvement, sex, age, duration of current episode of < 1 year,

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baseline HAM-D21, resistant depression, concomitant pharmacological strategy, presence of psychomotor disturbance (CORE system), and presence of psychotic symptoms were entered into the model. As shown in Table 4, early improvement emerged as a predictor of remission. Among other variables, only duration of current

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episode of < 1 year and relatively lower HAM-D21 score at baseline were significantly associated with remission.

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DISCUSSION

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The aim of our study was to define the most useful indicator of early improvement for predicting clinical remission in MDD patients treated with bilateral ECT

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under naturalistic conditions. We found that a 30% reduction in the baseline HAM-D21 score during the second week of bilateral ECT treatment constituted the best operative

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definition of early improvement. The exploration of previously defined cut-off scores supported this finding and provided evidence to further test this indicator in relation to

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other variables of interest. Additionally, this definition of early improvement was found to be significantly associated with lower number of days to achieve remission, and its effect was significant after adjustment for other clinically relevant variables. In our sample, the percentage of improvement in HAM-D21 score between remitters and non-remitters differed only at week 2 and not in week 1. Likewise, ROC curves in the second week were associated with the best predictive value profile. These findings are consistent with a recent study on predictors of outcome in MDD 14

ACCEPTED MANUSCRIPT patients treated with bilateral ECT (Lin et al., 2016) and existing findings on patients treated with drugs (Henkel et al., 2009; Vermeiden et al., 2015). A variety of definitions of early improvement (different percentages of HAM-D reduction from 2 to 4 weeks) have been used in previous drug studies but early improvement has usually been defined as a symptom reduction from baseline of at least 20% after two weeks of

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treatment (Helmreich et al., 2015). In the analysis conducted in our sample, the best definition of early improvement was a 30% of reduction in HAM-D21 at week 2. This means a greater reduction of symptoms at two weeks and could be explained by the greater efficacy and faster onset of action of ECT than is generally reported for

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antidepressant drugs (Husain et al., 2004; Segman et al., 1995; Uk and Review, 2003). Using this criterion (30% of reduction in HAM-D21 at week 2), a higher number of patients were correctly classified, showing acceptable sensitivity (76%) and specificity (67%). These results are similar to other work carried out in

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pharmacotherapy (Henkel et al., 2009). The only previous study that proposed a cut-off point for ECT treatment, by Lin et al. (2016), also considered a reduction of 30% after 6

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ECT sessions (with high sensitivity (98.6%) and high NPV (83.3%), but with limited specificity (16.1%)), and similar to our findings, a higher cut-off point tended to

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decrease sensitivity and increase specificity (table 3). In a study of the predictors of speed of response, Kho et al. (2004) chose a HAM-D score reduction of 35%, but this

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choice was based on methodological reasons and was not compared to other cut-offs points. Our results were also consistent with those of Segman et al. (1995), who

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proposed a definition of symptom improvement as a HAM-D score reduction of ≥ 30% after 6 bilateral ECT sessions. They found that this definition correctly identified 33 of 34 final responders and 11 of 13 non-responders. Our complementary analyses further supported a 30% cut-off score as a useful indicator of early improvement. Patients with early improvement needed a significantly fewer days to achieve remission than patients without early improvement. This is clinically relevant because it implies fewer days of depression. In this line, several 15

ACCEPTED MANUSCRIPT studies support that the persistence of depression (more days with depressive symptoms) exerts a neurotoxic effect with a negative impact on prognosis of the illness (Gorwood et al., 2008; Serra-Blasco et al., 2013). Furthermore, a faster remission also lessens the suffering of patients and caregivers and could reduce healthcare costs. In line with this, we also found that early improvement was associated with fewer residual

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symptoms of depression after a course of ECT. This finding is consistent with other studies which suggest that a rapid response predicts the absence of residual symptoms of depression after the ECT course (Kho et al., 2004). This fact is also relevant because the presence of residual symptoms is the main predictor of relapses

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in MDD (Judd et al., 1998).

Regarding other clinical variables that could influence MDD remission, the results of studies into predictors for ECT efficacy are not consistent (Haq et al., 2015; Kho et al., 2005). We found that a shorter duration of the current episode of depression

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was associated with a better ECT outcome, similar to other studies (Haq et al., 2015; Kho et al., 2005; Loo et al., 2011; Nordenskjöld et al., 2012). We also found that

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relatively lower HAM-D21 baseline score (pre-ECT) could predict a shorter time to remission, unlike the study by Kho et al. (2004). However, our result is congruent with

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others that suggest that responsiveness to ECT decreases with increasing severity of depression (Buchan et al., 1992; Hickie et al., 1996, 1990). These findings would

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support the recommendation to evaluate ECT as a therapeutic strategy in previous

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stages and not as a last treatment option. Other clinical variables often classically considered as predictors of ECT response or remission, such as age (Nordenskjöld et al., 2012; O’Connor et al., 2001), pharmacological resistance (De Vreede et al., 2005; Dombrovski et al., 2005; Loo et al., 2011; Prudic et al., 1996) or psychotic symptoms (Birkenhäger et al., 2003; Petrides et al., 2001) were not associated with ECT outcome in our sample, similar to what was reported in a recent meta-analysis (Haq et al., 2015).

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ACCEPTED MANUSCRIPT Finally, the course of the treatment response among non-early improvers is clinically relevant. Lin et al. (2016) considered that patients without early improvement after 6 ECT sessions were unlikely to reach remission. In our sample, 51.7% (15/29) of patients who did not achieve early improvement ultimately attained final remission, although they did so later than patients with early improvement. This is relevant

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because ECT could be prematurely discontinued in a subgroup of patients who might attain remission with a prolonged ECT course. Therefore, in cases without early improvement, continuing the ECT course could be considered, in addition to assessing if it is being done under optimal condition. Furthermore, at this stage, issues such as

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treatment schedule, technical aspects of procedure (suprathreshold dosing, pulse width, and pulse frequency), and strategies of combination or augmentation for ECT with psychotropic medications could be considered.

The following strengths and limitations should be considered. Our work was an

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uncontrolled, naturalistic study. This design allowed us to have a comprehensive picture of the real-life course of the treatment, but the use of concomitant psychotropic

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medication during ECT course - although it is the usual practice in our context (Vera et al., 2016) - could have been a source of bias. To overcome this limitation, we controlled

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for the effect of the concomitant pharmacological strategy in the analysis. Second, the rates of response (95.4%) in our sample were high. This was attributed to the fact that

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only severe MDD inpatients are referred to ECT in our center, which made the studied group highly homogeneous in terms of diagnosis and severity of the depressive

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symptoms. Also, patients with a good response to ECT may be overrepresented in a naturalistic study provided that the decision to administrate ECT is guided by specific criteria such as a history of response to previous ECT course. It is important to note that other studies have reported similar response rates, both in bilateral and unilateral ECT. For example, the group of Husain (2004) reports a rate of 79% and Lin (2016) a rate of 85.7% in depressed patients treated with bilateral ECT. While in a recent study using ultrabrief pulse right unilateral ECT, Kellner (Kellner et al., 2016) reports a 17

ACCEPTED MANUSCRIPT response rate of 70% in a large sample of patients with severe geriatric depression. Regarding other potential limitations, the sample size was limited to 87, and only bilateral ECT was assessed; therefore further studies should be performed in both bilateral and unilateral ECT, with distinct pulse width and larger sample sizes. In summary, our findings corroborate the scarce data on early improvement as

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a predictor of remission in major depressive patients treated with bilateral ECT. The best definition of early improvement was a 30% of reduction in HAM-D21 at week 2. This definition may be used as a guidance during the treatment course to help in clinical decisions. Shorter episode duration and relatively lower severity of depression

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would also predict remission, so ECT should not be considered as a last resort in treatment algorithms for MDD patients. Lack of early improvement could be a putative indicator to contemplate further changes in treatment strategies. Other robust clinical and biological predictors of ECT response and remission are needed for a better

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ROLE OF FUNDING SOURCES

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approach to patients with severe MDD.

XG was supported by a Sara Borrell grant (CD13/00282). No funding was

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required for this study.

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CONTRIBUTORS

All authors of this research paper have directly participated in the planning,

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execution, analysis or discussion of results of the study, and have read and fully approved the final version here submitted.

ACKNOWLEDGMENTS The authors thank Dr. Joan Carles Oliva for his contribution to the statistical analysis, Dra. Marta Subirà for her contribution, and all of the study subjects as well as the staff from the Department of Psychiatry of Bellvitge University Hospital. 18

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CONFLICT OF INTEREST

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The authors state they have no conflicts of interest to declare.

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Table 1. Patients and Demographic, Clinical and ECT Characteristics. Remission Total sample (n=87)

Remitters (n=66)

Non-remitters (n=21)

p-Value

58.6 (51)

65.2 (43)

38.1 (8)

0.03a

Age, mean (SD), years

66.01 (13.06)

66.74 (13.41)

63.71 (11.89)

0.36b

Age at onset, mean (SD),

45.66 (16.85)

45.50 (16.86)

46.14 (17.2)

0.88b

Sex (female), % (n)

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15 (5 – 51)

19 (0 – 51)

0.19c

Duration of current episode < 1 year, % (n)

74.7% (65)

81.8% (54)

52.4% (11)

0.01 a

Psychotic symptoms, % (n)

52.9% (46)

50% (33)

61.9% (13)

0.34 a

Baseline HAM-D21, mean (SD)

28.8 (6.79)

28.17 (6.17)

30.81 (8.29)

0.12b

35.34 (11.53)

35 (10.99)

36.43 (13.34)

0.62b

19.16 (9)

19.07 (8.66)

19.45 (10.21)

0.87b

58.6% (51)

59.1% (39)

57.1% (12)

0.88 a

Baseline Core system, mean (SD) Treatment-resistant 1 depression , % (n) Number of ECT sessions in the index episode, median (min-max)*

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Baseline GAF, mean (SD)

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Duration of illness, median (min-max), years*

11 (4-22)

16 (7-25)

<0.01c

Percent improvement in HAMD21 at week 1 of treatment, mean (SD)

22.14 (22.15)

24.43 (22.85)

14.91 (18.47)

0.09b

Percent improvement in HAMD21 at week 2 of treatment, mean (SD)

43.67 (26.72)

49.42 (25.56)

25.6 (22.25)

<0.01b

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12 (4-25)

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ECT= electroconvulsive therapy, GAF= Global Assessment of Function, HAM-D21= Hamilton Depression Rating Scale 21 items. 1 Treatmentresistant depression as assessed by the Thase and Rush staging method (Thase and Rush, 1997), which consists of five stages: I: Failure of at least 1 adequate trial of 1 major class of antidepressant; II: Stage I resistance + failure of an adequate trial of an antidepressant in a different class from that used in stage I; III: Stage II resistance + failure of adequate trial of TCA. IV: Stage III resistance + failure of adequate trial of MAOI. V: Stage IV resistance + failure of a course of bilateral ECT. Patients were considered to be resistant if they reached Thase and Rush staging 3 or higher. The data are presented as mean (standard deviation) for continuous variables, or the median (min-max) where necessary* and as percentages for categorical variables (number). ap value, 2 test; bp value, Student’s T test; cp value, MannWhitney U. Bold, statistically significant.

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Table 2. Concomitant medication during ECT course (n=87) Type of medication

% (n)

98.9 (86)

Antipsychotics

62.1 (54)

Benzodiazepines

59.8 (52)

Lithium

8 (7)

Strategy Unmodified

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Antidepressant (AD)

35.6 (31) 10.3 (9)

Dose optimization

17.2 (15)

Substitution of AD

18.4 (16)

Combination of AD

10.3 (9)

Augmentation

8 (7)

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AD introduction

Table 3. Estimates of early improvement at week 2 for prediction of remission. Sensitivity (%) Specificity (%) PPV (%) NPV (%) CCP (%)

20% reduction 89.39

25% reduction 81.82

30% reduction 77.27

35% reduction 66.67

38.10

47.62

66.67

71.43

81.94 53.33 77.01

83.08 45.45 73.56

87.93 48.28 74.71

88.00 40.54 67.81

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Positive

predictive

value,

NPV=

Negative

predictive value, CCP= Correctly classified patients,

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AUC= Area under the curve.

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Sex

1.111

3.038

Age

0.019

1.019

Duration of current episode of < 1 year

1.409

4.091

HAM-D21 pre-ECT*

0.286

0.751

Early improvement

1.917

6.800

Resistant depression pre-ECT Concomitant pharmacological strategy Psychomotor disturbance

-0080

0.923

0.732

0.481

Psychotic symptoms

0.005 0.486

0.995 0.615

95% CI 1.1008.391 0.9821.057 1.41711.814 0.5211.083 2.32219.914 0.3422.494 0.1571.472 0.9411.053 0.2251.680

p value

Β

Odds Ratio

95% CI

p value

0.032

---

---

---

---

0.317

---

---

---

---

0.009

2.090

8.081

2.05031.861

0.003

0.126

0.539

0.584

0.3650.933

0.025

<0.001

2.040

7.691

2.31425.567

0.001

0.875

---

---

---

---

0.200

---

---

---

---

0.868

---

---

---

---

0.343

---

---

---

---

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Odds Ratio

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*Indicates change in the outcome for every 5 points in HAM-D21 for greater clinical utility.

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