ECT Has Greater Efficacy Than Fluoxetine in Alleviating the Burden of Illness for Patients with Major Depressive Disorder: A Taiwanese Pooled Analysis

ECT Has Greater Efficacy Than Fluoxetine in Alleviating the Burden of Illness for Patients with... Background: The burden of major depressive disorder includes suffering due to symptom severity, functional impairment, and quality of life deficits. The aim of this study was to compare the differences between electroconvulsive therapy and pharmacotherapy in reducing such burdens. Methods: This was a pooled analysis study including 2 open-label trials for major depressive disorder inpatients receiving either standard bitemporal and modified electroconvulsive therapy with a maximum of 12 sessions or 20 mg/d of fluoxetine for 6 weeks. Symptom severity, functioning, and quality of life were assessed using the 17-item Hamilton Rating Scale for Depression, the Modified Work and Social Adjustment Scale, and SF-36. Side effects following treatment, including subjective memory impairment, nausea/vomiting, and headache, were recorded. The differences between these 2 groups in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, quality of life, side effects, and time to response (at least a 50% reduction of 17-item Hamilton Rating Scale for Depression) and remission (17-item Hamilton Rating Scale for Depression ≤7) following treatment were analyzed. Results: Electroconvulsive therapy (n = 116) sho wed a significantly greater reduction in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, and quality of life deficits and had significantly shorter time to response/remission than fluoxetine (n = 126). However, the electroconvulsive therapy group was more likely to experience subjective memory impairment and headache. Conclusions: Compared with fluoxetine, electroconvulsive therapy was more effective in alleviating the burden of major depressive disorder and had a substantially increased speed of response/remission in the acute phase. Increased education and information about electroconvulsive therapy for clinicians, patients, and their families and the general public is warranted. Keywords: major depressive disorder, electroconvulsive therapy, fluoxetine, response, remission Received: June 26, 2017; Revised: October 21, 2017; Accepted: November 30, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 63 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 64 | International Journal of Neuropsychopharmacology, 2018 Significance Statement The results of research conducted in an Asian country revealed that ECT was more effective in reducing the burden of acute phase depression than fluoxetine. Patients with treatment-resistant depression were excluded from the fluoxetine 20 mg group. ECT had a substantially increased speed of symptomatic response and remission compared with fluoxetine, although the ECT group had a higher rate of treatment-resistant depression (86.2%) and experienced more subjective memory impairment and headache, while other side effects were not systematically evaluated in the pooled analysis. and fluoxetine groups in efficacy in relieving the burden of MDD Introduction and speed of response/remission. We hypothesized that ECT- Major depressive disorder (MDD) is a common mental disorder. treated patients would yield greater improvements in reducing The burden of MDD includes suffering due to symptom severity, symptom severity, functional impairments, and QOL deficits functional impairment, and quality of life (QOL) deficits. Such than the fluoxetine-treated patients, but would be less tolerated. burdens may lead to increased suffering, with negative conse- quences for families as well as for society (Ishak et  al., 2013). Methods MDD is predicted to become the second-leading contributor to the global burden of disease by the year 2020 (Mathers et  al., Subjects 2008). The overall goals of treatment of MDD should focus on achieving symptom resolution and episode remission, in add- The data used in this pooled analysis were drawn from 2 open- ition to alleviating functional impairments and QOL deficits label trials for depressed inpatients receiving ECT (ClinicalTrials. (Gelenberg et al., 2010). gov identifier: NCT02032576; duration: from Jan. 2008 to Oct. In clinical practice, pharmacological treatment and electro- 2013)  (Lin et  al., 2016) or fluoxetine (NCT01075529; from May convulsive therapy (ECT) are used to treat MDD patients. ECT 2007 to Feb. 2010) (Lin et al., 2011). Two trials were conducted at is significantly more effective than pharmacotherapy in treat- the Psychosomatic Ward of the Kai-Syuan Psychiatric Hospital, ing severe and treatment-resistant depression (UK ECT Review Kaohsiung, Taiwan, and were approved by the hospital’s institu- Group, 2003; Kellner et  al., 2012). However, traditional initial tional review board. Patients who satisfied the DSM-IV criteria assessment and outcome measurement of mental disorders has for MDD as confirmed using the Structured Clinical Interview been focused on symptom severity. It is generally assumed that for DSM-IV Axis I (APA, 1994), were aged ≥18 years, had a base- changes in depressive symptoms equal changes in function- line 17-item Hamilton Depression Rating Scale (HAMD-17) ing and QOL. However, numerous studies support that symp- (Hamilton, 1960)≥18, and no diagnosis of schizophrenia or other toms, functioning, and QOL are dissociable domains (McCall psychotic disorders, bipolar disorders, or organic mental disor - et  al., 2001, 2004; Angermeyer et  al., 2002; Mathew et  al., 2007; ders were included in both trials. Formal psychotherapy was not Lam et al., 2011). The American Psychiatric Association practice permitted during the study period. guideline for the treatment of patients with MDD (Gelenberg et  al., 2010) emphasizes the importance of adding functioning Procedure and QOL measures to adequately capture the full burden of de- pression. Functioning refers to an individual’s actual involve- For the ECT group, MDD inpatients were enrolled if they met the indications of ECT (i.e., need for a rapid and definitive response, ment and participation in health and life activities, whereas QOL reflects the patient’s satisfaction with such activities and high suicide risk, severe psychomotor retardation, and treat- ment-resistant depression) (Waite and Easton, 2013) and had psychological well-being (WHO, 1998; IsHak et al., 2011). There are several reasons to replicate and extend the out- no serious medical conditions restricting the use of ECT. The practice of ECT was in accord with the American Psychiatric comes of ECT from traditional symptom severity to function- ing and QOL for depressed patients. First, few studies have Association Task Force on ECT (APA, 2001). Psychotropic agents, including antidepressants, antipsychotics, and mood stabilizers, simultaneously explored the differences in alleviating depres- sive symptoms, improving functioning, and reducing QOL defi- were discontinued for 3 days before initiating ECT if emergency ECT was not required. Patients remained medication free dur - cits between ECT and pharmacotherapy. Second, ECT use in Western countries is much more common than in Asian coun- ing the ECT course, except for anxiolytic or sedative-hypnotic medications as needed for insomnia or severe anxiety. Standard tries. Psychiatrists in Asia seem reluctant to prescribe ECT and patients may hesitate to receive it. Almost all the studies about bitemporal and modified ECT was performed. Modified ECT refers to the administration of anesthesia, muscle relaxant, and ECT outcome for depressed patients are from Western countries. Consequently, data for comparison are limited (Chanpattana seizure-inducing electrical stimulus, in that order. For our ECT protocol, anesthesia was induced by thiopental or thiamylal, et al., 2010). Third, ECT is an “orphan treatment,” as there is no marketing supporting it (Kotzalidis et al., 2015). both at doses of 1.5 to2.0  mg/kg i.v. Neuromuscular blockade was induced by succinylcholine at a dosage of 0.5 to 1.0  mg/kg The aim of this study was to compare existing data from 2 previously published open-label studies in regard to depres- i.v. ECT was conducted using the Thymatron System IV machine with brief-pulse and constant current (pulse width, 0.5 ms; fre- sive symptoms, functioning, QOL, and tolerability. The subjects from the first study (Lin et al., 2016) were 130 MDD patients who quency, 60 Hz; current, 0.9 A). Seizure duration was at least 20 seoncds as measured by electromyogram and 25 seconds meas- received ECT with a maximum of 12 treatments. Subjects from the second study (Lin et al., 2011) were 131 MDD patients with- ured by electroencephalography. Treatment was given 3 times a week before Aug. 2009 and later 2 times a week, with a max- out a history of treatment-resistant depression who were pre- scribed 20 mg/d fluoxetine as monotherapy for a period of up to imum of 12 treatments. The number of ECT treatments was determined by the treating psychiatrist, depending on whether 6 weeks. We hoped to ascertain the differences between the ECT Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Lin et al. | 65 remission (HAMD-17 ≤7) had been reached, if patients could not baseline and at weeks 1, 2, 3, 4, and 6.  UKU, a clinician-rating tolerate the side effects, or if patients decided to discontinue scale with 48 items, contains a Likert scale of 0 to 3 for degree of ECT (APA, 2001). severity. A score of 1, 2, or 3 on any UKU item that first occurred For the fluoxetine group, physically healthy inpatients who or worsened during treatment indicated a “case” (E.Dal J.  y et al., required acute treatment of MDD were enrolled. Patients with 2011). To compare the ECT group with the fluoxetine group, only treatment-resistant depression or substance dependence/abuse subjective memory impairment (Item 1.4), nausea/vomiting were excluded. Treatment-resistant depression was defined as a (Item 3.4), and headache (Item 4.17) were selected. lack of response to 2 or more adequate trials of different classes of antidepressants (Souery et al., 1999). An adequate trial was 4 Statistical Analysis to 6 weeks of treatment with an antidepressant at a dosage con- Analysis was on a modified intent-to-treat basis for subjects sidered therapeutic. After a washout period of at least 72 hours, reporting at least one post-baseline assessment. Data were patients received open-label fluoxetine treatment at a fixed analyzed using the SPSS version 17.0 for Windows (SPSS Inc.). dose of 20 mg/d for 6 weeks. No other psychotropic agents were Statistical significance was defined as P < .05. Pearson χ test or administered during the treatment period, except for anxiolytic Fisher’s exact test was used to compare categorical variables, or sedative-hypnotic medications as needed for insomnia or se- and independent t test was used for continuous variables. vere anxiety. Judgment of treatment adherence was based on In the first step, 2 groups at baseline were compared in terms the nursing staff’s observations. Both sets of subjects, receiving of sex, age, age at onset, baseline HAMD-17, baseline MWSAS, either ECT or fluoxetine, would complete their trials within 6 baseline PCS, baseline MCS, anxiolytic/sedative-hypnotic weeks. medications used during the trial period, employment in the 6 months before the trial, and side effects following treatment. Outcome Measures Age at onset was defined as the age at which the first major de- Symptom severity was assessed by independent board-certified pressive episode occurred. Employment was defined as working psychiatrists using HAMD-17. Higher HAMD-17 scores (ranging for pay in the 6 months before the trial (Lerner et al., 2004). from 0 to 52)  indicate more severe depression. The Work and In the second step, the median pre-post differences in the Social Adjustment Scale (WSAS) (Mundt et al., 2002) is a 5-item HAMD-17 and MWSAS scores in both groups were calculated. self-rating scale designed to measure functional impairment. The generalized estimating equations (GEE) method with the Each item is scored from 0 (not affected at all) to 8 (severely first-order autoregressive working correlation structure (AR affected). Item 1 assesses work ability, but it may be difficult 1)  (Liang and Zeger, 1986) was applied to examine the differ - for patients to demonstrate a high level of work functioning ences in HAMD-17 and MWSAS scores between the 2 groups while in the hospital when their jobs are outside of the hos- during the course of acute treatment, after adjusting for sex, pital, or for those patients who have retired. Therefore, Item 1 age, age at onset, and baseline severity (baseline HAMD-17 or has been omitted. We renamed the Work and Social Adjustment MWSAS). Analyses of group differences in PCS and MCS were Scale, without Item 1, the Modified Work and Social Adjustment performed by ANCOVA, with treatment (ECT vs fluoxetine) as Scale (MWSAS) (ranging from 0 to 32) to assess functioning. The a fixed factor and sex, age, age at onset, and the baseline value Medical Outcomes Study Short-Form 36 (SF-36) (Brazier et  al., (baseline PCS or MCS) as covariates. 1992), a self-rating scale with 2 primary-factor analytic compo- In the last step, the treating psychiatrists, patients, and their nents, the physical component summary (PCS) and the mental families need to know the onset of a meaningful benefit of treat- component summary (MCS), was used to measure QOL. Lower ment, such as symptomatic response or remission. Response PCS and MCS scores reflect worse QOL. was defined as an at least 50% reduction of the baseline HAMD- For the ECT group, symptom severity and functioning were 17 score. Kaplan-Meier survival analysis was used to deter - assessed using HAMD-17 and MWSAS before ECT, after every mine the differences in speed of response/remission between 3 ECT treatments, and after the final ECT treatment. QOL was 2 groups. assessed before ECT. A study by Daly et al. (J. JDal .  y et al., 2001) In contrast to the fluoxetine trial, which is typically of fixed found that an average of 6 ECT treatments is needed to reach duration and involves fixed time points for assessment (i.e., initial response. Therefore, if patients received at least 6 ECT weeks 0, 1, 2, 3, 4, and 6), ECT is administered over a brief period treatments, QOL was reassessed after the final ECT. To prevent (i.e., 2 or 3 times weekly) with considerable variability in the post-ECT confusion from influencing the assessment, all meas- time points of clinical assessment (i.e., before ECT, after every 3 ures were conducted 1 to 2 days after treatment. ECT treatments, and after the final ECT treatment). We therefore For the fluoxetine group, symptom severity and function- used the exact number of days since the baseline assessment ing were assessed using HAMD-17 and MWSAS at baseline, and as the time variable in both the GEE and Kaplan-Meier survival again at weeks 1, 2, 3, 4, and 6. QOL as determined by SF-36 was analysis. This method has been used previously (Schoeyen et al., assessed at baseline and reassessed if patients completed the 2015). 6-week fluoxetine treatment. Results Side Effects Subjects For the ECT group, side effects not present before ECT, including subjective memory impairment, nausea/vomiting, and headache, A flow chart of the participant selection process is shown in either first observed by the psychiatrist at each visit or first reported Figure 1. In the ECT group, 130 patients treated with ECT (n = 113 spontaneously by the patient indicated side effects “cases.” due to treatment-resistant depression, n = 15 due to high sui - For the fluoxetine group, side effects were assessed using the cide risk, and n= 2 due to severe psychomotor retardation) par - Utvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) ticipated in the study. One-hundred sixteen patients receiving (Lingjaerde et al., 1987) and by the registration of side effects at at least 3 ECT treatments (n = 100 due to tr eatment-resistant Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 66 | International Journal of Neuropsychopharmacology, 2018 depression, n = 14 due to high suicide risk, and n= 2 due to significantly lower employment rates than the fluoxetine group. severe psychomotor retardation) were included in the analysis. In the ECT group, 105 patients completed the SF-36 assessment Twelve of the 116 discontinued ECT prematurely; the remainder before ECT, and 95 of 105 once again after ECT. In the fluoxetine (n = 104) completed the course of ECT. In the fluoxetine group, group, 119 patients completed the SF-36 assessment at baseline, 131 patients were enrolled. One hundred twenty-six who had at and 106 of 119 once again after the 6-week fluoxetine trial. least one post-baseline assessment at week 1 entered the ana- lysis. Fourteen of the 126 discontinued the fluoxetine trial pre- Premature Discontinuation maturely; the remainder (n = 112) completed the 6-week trial. In The clinical baseline characteristics of dropout patients did not the ECT group, the mean number of treatments was 8.9 ± 2.5. One differ significantly between the ECT group (n= 26) and the flu- hundred (86.2%) were diagnosed as having treatment-resistant oxetine group (n= 19) with respect to sex (P = .487), age (P = .944), depression, and 103 received ECT twice weekly.T able  1 reveals age at onset (P= .869), baseline HAMD-17 (P = .135), and base- that the clinical variables at baseline did not significantly dif- line MWSAS (P= .169) (data not shown in the table). There fer between the treatment groups. However, the ECT group had Figure 1. Study design for patients with major depressive disorder treated with electroconvulsive therapy or fluoxetine. Table 1. Baseline Clinical Characteristics and Side Effects Comparing Patients Receiving ECT and Those Receiving Fluoxetine ECT Fluoxetine P Variables n n Sex, female, n (%) 116 82 (70.7) 126 96 (76.2) .332 Age, mean (SD), year 116 46.9 (12.3) 126 45.3 (11.0) .286 Age at onset, mean (SD), year 116 38.1 (12.8) 126 38.9 (11. 8) .636 Baseline HAMD-17 score, mean (SD) 116 30.9 (7.0) 126 31.3 (6.5) .602 Baseline MWSAS score, mean (SD) 116 23.5 (7.3) 126 23. 8 (7.9) .747 Baseline SF-36 PCS, mean (SD), 105 42.4 (9.1) 119 40.1 (10.6) .088 Baseline SF-36 MCS, mean (SD), 105 20.5 (7.7) 119 21.5 (9.0) .396 Employment in the 6 months before the trial, n (%) 116 19 (16.4) 126 46 (36.5) <.001 Anxiolytic/sedative-hypnotic medication used, n (%) 116 105 (90.5) 126 113 (89.7) .828 Side effects following treatment 116 48 (41.4) 126 21 (16.7) <.001 0.332 Subjective memory impairment, n (%) 116 24 (20.7) 126 20 (15.9) <.001 Nausea/vomiting n (%) 116 70 (60.3) 126 21 (16.7) Headache n (%) Abbreviations: ECT, electroconvulsive therapy; HAMD-17, 17-item Hamilton Rating Scale for Depression; MCS, mental component summary, lower scores of PCS reflect worse quality of life; MWSAS, Modified Work and Social Adjustment Scale = Work and Social Adjustment Scale (WSAS) without Item 1; PCS, physical component summary, lower scores of PCS reflect worse quality of life; SF-36, Medical Outcomes Study Short-Form 36. Bold, statistically significant. a 2 Pearson’s χ test Independent t test. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Lin et al. | 67 were no significantly different dropout rates between the ECT response between the 2 groups, and Figure 4 compares the time group (20.0%= 26/130) and the fluoxetine group (14.5% = 19/131) to remission between the 2 groups. (χ = 1.31, df = 1, P = .240). Thirteen (13/26 = 50%) patients did not complete the ECT course due to side effects: complaints of pain Discussion (n = 6), confusion or memory problems (n = 2), hypoxia after ECT (n = 3), and a high frequency of ventricular premature contrac- This pooled analysis study revealed 3 main findings: (1) ECT tion, lasting for a long duration, which occurred after ECT (n = 2). alleviated the burden of MDD more than fluoxetine in the Nineteen patients did not complete the fluoxetine trial due to acute phase (Tables 2 and 3); (2) compared to fluoxetine-treated lack of efficacy (n = 3), premature discharge (n= 14), and with- patients, ECT-treated patients had a more rapid onset of re- drawal of consent (n = 2). In contrast to the patients treated with sponse/remission. Our results may be comparable with the find- ECT, none of fluoxetine-treated patients dropped out due to side ings by a randomized study that showed ECT is superior to effects (Fisher’s exact test, < P .001). paroxetine in treatment-resistant depression in terms of both degree and speed of response (Folkerts et  al., 1997). (3) The ECT group had a dropout rate comparable with the fluoxetine Efficacy and Side Effects group. One-half of the dropout patients in the ECT group dis- The ECT group had greater median pre-post differences continued treatment due to side effects, whereas none of the than the fluoxetine group, regardless of rating by HAMD-17 patients in the fluoxetine group dropped out of the trial because (23.0 vs 16.0) or MWSAS (12.0 vs 4.0) (data not shown in the of side effects. Patients treated with ECT were likely to experi- table). After adjusting for sex, age, age at onset, and base- ence subjective memory impairment and headache more often line severity (baseline HAMD-17 or MWSAS) using GEE, the than fluoxetine following treatment (Table ). 1 This indicates ECT group had significantly decreased posttreatment HAMD- that fluoxetine is better tolerated than ECT. Even though un- 17 and MWSAS scores compared with the fluoxetine group pleasant side effects are widely believed to impair the patient’s during the course of acute treatment, on average by 4.29 and QOL (Wisniewski et al., 2007), ECT still improved QOL more than 3.59 points, respectively (Table )2 . Figure 2 shows the HAMD- fluoxetine (Table 3). 17 scores between the ECT group and the fluoxetine group The patients in the ECT or fluoxetine groups represented during the course of acute treatment. Similarly, score gains a relatively severely ill population who had not responded in PCS and MCS for the ECT group were significantly greater adequately to outpatient treatment and needed hospitaliza- than those for the fluoxetine group, as analyzed by ANCOVA, tion (Gelenberg et  al., 2010). Previous studies have found that with sex, age, age at onset, and baseline values (baseline patients with severe depression are associated with signifi- PCS or MCS) as covariates (Table ). 3 However, the ECT group cant functional impairment and poor QOL (Coryell et al., 1993; experienced significantly higher rates of subjective memory Thase, 2000; Trivedi et  al., 2006). Both groups had comparable impairment and headache than did the fluoxetine group fol- symptom severity (Table 1 ), even though 86% of the patients in lowing treatment (Table 1). the ECT group were treatment-resistant. It is reasonable that there were no statistically significant differences between these 2 groups with respect to functional impairment and QOL deficit Remission and Response at baseline (Table  1 ). Compared with the fluoxetine group, the Among the patients who completed treatment, the response ECT group showed significantly lower employment rates in the rate of 92.3% (96/104) in the ECT group was significantly higher 6  months before the trial (Table).   1 There was a distinct possi- 2 = than the 58.9% (66/112) in the fluoxetine group (χ 32.04, bility that a high percentage of the patients in the ECT group df = 1, P < .001). The ECT group (71.2%= 74/104) also had a sig- were treatment-resistant, because patients with treatment- nificantly higher remission rate than the fluoxetine group resistant depression have been reported to experience lower 2 = (27.7% = 31/112) (χ 40.80, df = 1, P < .001). Patients treated with employment rates than those without (Souery et al., 2007). This ECT (mean time± SE = 19.3 ± 0.9  days) also had a significantly may be associated with longer durations of current episodes shorter time to response than those treated with fluoxet- and longer stays in hospital after several ineffective treatment ine (mean time ± SE = 24.3 ± 1.3  days) (log rank = 13.48, df = 1, options (Souery et al., 2007; Zaninotto et al., 2013). P < .001). Time to remission for ECT-treated patients (mean Although the ECT can be superior to antidepressant drugs time± SE = 29.9 ± 1.0  days) was also significantly shorter than in reducing the burden of depression for patients, it is gen- for fluoxetine-treated patients (mean time ± SE = 35.2 ± 1.0 days) erally applied as the treatment of last resort. There is still (log rank = 36.48, df = 1, P < .001). Figure  3 compares the time to a majority of MDD patients with an indication for ECT who Table  2. Effects of Sex, Treatment (ECT vs Fluoxetine), Treatment Duration, Age, Age at Onset, and Baseline Severity (Baseline HAMD-17 or MWSAS) over Time on the HAMD-17 Score or MWSAS Score Using the Generalized Estimating Equations HAMD-17 MWSAS Variable Estimate SE P Estimate SE P Male vs female -0.30 0.55 .583 -0.97 0.68 .150 ECT vs fluoxetine -4.29 0.53 <.001 -3.59 0.62 <.001 Treatment duration (1-day increments) -0.52 0.02 <.001 -0.25 0.02 <.001 Age (1-year increments) 0.04 0.04 .249 -0.01 0.04 .771 Age at onset (1-year increments) -0.05 0.04 .193 -0.03 0.04 .513 Baseline HAMD-17 or MWSAS (1-point increments) 0.59 0.04 <.001 0.74 0.04 <.001 Bold, statistically significant. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 68 | International Journal of Neuropsychopharmacology, 2018 Figure 2. Error bars showing the 17-item Hamilton Rating Scale for Depression (HAMD-17) scores between the electroconvulsive therapy (ECT) group and the fluoxetine group during the course of acute treatment. Table  3. Changes of PCS and MCS before and after Treatment for The ECT group was treated with bi-temporal ECT. Unilateral Patients Receiving ECT and Fluoxetine electrode placement might have reduced the observed incidence of subjective memory impairment (Waite and Easton, 2013). ECT Fluoxetine P Therefore, whether the present findings can be extrapolated to those treated with right unilateral ECT requires additional study. Variables n n However, one study (Prudic et al., 1996) has concluded that ECT SF-36 PCS change, 95 6.1 (9.4) 106 1.3 (9.3) <.001 outcome appears to be independent of electrode placement. mean (SD) Treatment with a fixed dose of 20 mg/d of fluoxetine treat- SF-36 MCS change, 95 12.0 (11.2) 106 6.4 (11.6) .013 ment might be considered insufficient to demonstrate response, mean (SD) as in clinical practice individuals vary in their dosage for op- timal treatment response. However, earlier fixed-dose studies aP values were determined by ANCOVA, with sex, age, age at onset, (Schweizer et  al., 1990; Stokes, 1993) have demonstrated that and baseline value as a covariate. 20 mg of fluoxetine daily is the optimal dose for most patients. Bold, statistically significant. A  meta-analysis study by Beasley et  al. (Beasley et  al., 2000) also found that fluoxetine therapy at 20  mg daily is a critical have not received ECT. One possible reason is that side effects factor for adequate therapy and has good treatment tolerance. Berney (Berney, 2005) concluded that a flat dose-response curve may compromise adherence to ECT, even though most side effects are transient (Fink, 2014). Psychiatrists must help is a class phenomenon for selective serotonin reuptake inhibi- tors, regardless of whether patients have mild or moderate-to- patients reduce their fear and manage such side effects. For example, prophylaxis with antiemetic agents and analgesics severe depression. Therefore, the poor outcome of the fluoxetine group did not appear to be due to the 20  mg/d of fluoxetine. to relieve nausea/vomiting and headache might be consid- ered before undergoing ECT (Payne and Prudic, 2009). Some Additionally, because plasma levels were not analyzed in the fluoxetine group, the 20 mg/d of fluoxetine prescribed might be strategies recommended to decrease memory impairment include setting the ECT machine with brief pulse waveform, criticized as to whether the therapeutic plasma levels could be reached. However, previous studies reported no evidence of a re- unilateral nondominant stimulus electrode placement, and ultra-brief pulse stimuli. Also, decreasing stimulus intensity lationship between fluoxetine plasma concentrations and clin- ical response (Kelly et al., 1989 Norman et  ; al., 1993; Amsterdam and decreasing the frequency and number of treatments may prove beneficial (Payne and Prudic, 2009; Mankad, 2010). On et al., 1997). Several strengths of this study should be addressed. First, the other hand, more professional education about ECT and related mental health laws for psychiatrists may increase the to our knowledge, this is the first study to focus on symptom severity, functioning, QOL, side effects, and the speed of symp- numbers of ECT prescriptions or referrals (Finch et  al., 1999; Dauenhauer et al., 2011). tomatic response/remission when simultaneously comparing Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Lin et al. | 69 Figure 3. Time to response (log rank = 13.48, df = 1, P < .001) for patients with major depressive disorder receiving ECT or fluoxetine. Figure 4. Time to remission (log rank = 36.48, df = 1, P < .001) for patients with major depressive disorder receiving ECT or fluoxetine. the results of ECT and antidepressant medication in depressed it permits examination of the relationships between variables patients. Symptom severity reflects only a portion of the bur - at all time points, adjusts for the within-subject dependence den of major depressive disorder (Cohen et al., 2013). Both func- effect, and allows for the inclusion of subjects with missing data tioning and QOL assessed by self-rating scales (i.e., MWSAS and (Liang and Zeger, 1986; Twisk, 2003; Madhoo and Levine, 2015). SF-36) may reflect patients’ perspectives on ECT. Second, the GEE Third, survival analysis may display the greatest sensitivity in offers advantages over standard regression techniques in that detecting treatment group differences in speed of symptomatic Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 70 | International Journal of Neuropsychopharmacology, 2018 response/remission (Nobler et  al., 1997). Fourth, our results improvement. Thus, some initial improvement may be due to could be generalized to a clinical setting (Nierenberg et al., 1995). the sedating effects of anxiolytics/sedative-hypnotic medication The present study was also subject to certain limitations. rather than the ECT or fluoxetine (Roose and Nobler, 2001Smith ; First, this pooled analysis study was nonrandomized and et  al., 2002). However, no significant difference existed in the unblinded, which could contribute to major bias. The pooled rates of anxiolytics/sedative-hypnotic medication used between analysis study came from 2 short-term and open-label studies. the ECT and fluoxetine groups (Table 1). The impact on outcome We did not know how long such outcome differences between or tolerability of each group should therefore be comparable. 2 groups could last. Additionally, it was difficult to estimate the In conclusion, the current results revealed that bi-temporal degree to which clinical improvements were due to treatments, ECT was more effective in reducing the burden of acute phase placebo effect, or other psychiatric interventions. For example, depression than fluoxetine. Bi-temporal ECT had a substantially depressed patients in hospital do obtain relief from milieu increased speed of symptomatic response and remission com- approaches (Rasmussen, 2009). Patients and clinicians both pared to fluoxetine, although the ECT group had a higher rate know the treatments and both may anticipate the outcomes. of treatment-resistant depression (86.2%) and experienced more These anticipations may contribute to a placebo effect. However, unpleasant side effects. Increased education and information it is unlikely the clinical response was solely attributable to pla-about ECT for clinicians, patients and their family, and the gen- cebo effects for the following reasons: first, the response rates of eral public is indispensable. the ECT (92.3%) and the fluoxetine groups (58.9%) were too high to be accountable by the typical placebo effect, i.e., around 30 %, Funding as estimated from past clinical placebo-controlled antidepres- sant trials (Walsh et al., 2002); second, it has been demonstrated This study was supported by the Kaohsiung Municipal that patients with severe depression and with treatment-resist- Kai-Syuan Psychiatric Hospital (KSPH-2007-16, KSPH-2008-12) ant depression present a lower placebo response (Khan et  al., and the Ministry of Science and Technology, Taiwan (MOST-103- 2002; Brunoni et al., 2009). However, both trials were open-label. 2314-B-280-001-MY3). The placebo effect might not be comparable in the 2 groups and must not be underestimated. Acknowledgments Second, the 6-week treatment with fluoxetine might also be criticized as being of too short a duration for the stability of the We would like to thank all the participants for this study. result to be verified, as longer treatment durations may lead to further improvement in depressive symptoms and functioning (Kocsis et al., 2002; Rush et al., 2006). Therefore, prolonged fluox- Statement of interest etine treatment may yield greater improvement, thereby less- None. ening the difference between fluoxetine and ECT. However, the 6-week period was relatively long and sufficient for inpatient trials to detect initial responses to antidepressant medication. 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ECT Has Greater Efficacy Than Fluoxetine in Alleviating the Burden of Illness for Patients with Major Depressive Disorder: A Taiwanese Pooled Analysis

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Abstract

Background: The burden of major depressive disorder includes suffering due to symptom severity, functional impairment, and quality of life deficits. The aim of this study was to compare the differences between electroconvulsive therapy and pharmacotherapy in reducing such burdens. Methods: This was a pooled analysis study including 2 open-label trials for major depressive disorder inpatients receiving either standard bitemporal and modified electroconvulsive therapy with a maximum of 12 sessions or 20 mg/d of fluoxetine for 6 weeks. Symptom severity, functioning, and quality of life were assessed using the 17-item Hamilton Rating Scale for Depression, the Modified Work and Social Adjustment Scale, and SF-36. Side effects following treatment, including subjective memory impairment, nausea/vomiting, and headache, were recorded. The differences between these 2 groups in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, quality of life, side effects, and time to response (at least a 50% reduction of 17-item Hamilton Rating Scale for Depression) and remission (17-item Hamilton Rating Scale for Depression ≤7) following treatment were analyzed. Results: Electroconvulsive therapy (n = 116) sho wed a significantly greater reduction in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, and quality of life deficits and had significantly shorter time to response/remission than fluoxetine (n = 126). However, the electroconvulsive therapy group was more likely to experience subjective memory impairment and headache. Conclusions: Compared with fluoxetine, electroconvulsive therapy was more effective in alleviating the burden of major depressive disorder and had a substantially increased speed of response/remission in the acute phase. Increased education and information about electroconvulsive therapy for clinicians, patients, and their families and the general public is warranted. Keywords: major depressive disorder, electroconvulsive therapy, fluoxetine, response, remission Received: June 26, 2017; Revised: October 21, 2017; Accepted: November 30, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 63 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 64 | International Journal of Neuropsychopharmacology, 2018 Significance Statement The results of research conducted in an Asian country revealed that ECT was more effective in reducing the burden of acute phase depression than fluoxetine. Patients with treatment-resistant depression were excluded from the fluoxetine 20 mg group. ECT had a substantially increased speed of symptomatic response and remission compared with fluoxetine, although the ECT group had a higher rate of treatment-resistant depression (86.2%) and experienced more subjective memory impairment and headache, while other side effects were not systematically evaluated in the pooled analysis. and fluoxetine groups in efficacy in relieving the burden of MDD Introduction and speed of response/remission. We hypothesized that ECT- Major depressive disorder (MDD) is a common mental disorder. treated patients would yield greater improvements in reducing The burden of MDD includes suffering due to symptom severity, symptom severity, functional impairments, and QOL deficits functional impairment, and quality of life (QOL) deficits. Such than the fluoxetine-treated patients, but would be less tolerated. burdens may lead to increased suffering, with negative conse- quences for families as well as for society (Ishak et  al., 2013). Methods MDD is predicted to become the second-leading contributor to the global burden of disease by the year 2020 (Mathers et  al., Subjects 2008). The overall goals of treatment of MDD should focus on achieving symptom resolution and episode remission, in add- The data used in this pooled analysis were drawn from 2 open- ition to alleviating functional impairments and QOL deficits label trials for depressed inpatients receiving ECT (ClinicalTrials. (Gelenberg et al., 2010). gov identifier: NCT02032576; duration: from Jan. 2008 to Oct. In clinical practice, pharmacological treatment and electro- 2013)  (Lin et  al., 2016) or fluoxetine (NCT01075529; from May convulsive therapy (ECT) are used to treat MDD patients. ECT 2007 to Feb. 2010) (Lin et al., 2011). Two trials were conducted at is significantly more effective than pharmacotherapy in treat- the Psychosomatic Ward of the Kai-Syuan Psychiatric Hospital, ing severe and treatment-resistant depression (UK ECT Review Kaohsiung, Taiwan, and were approved by the hospital’s institu- Group, 2003; Kellner et  al., 2012). However, traditional initial tional review board. Patients who satisfied the DSM-IV criteria assessment and outcome measurement of mental disorders has for MDD as confirmed using the Structured Clinical Interview been focused on symptom severity. It is generally assumed that for DSM-IV Axis I (APA, 1994), were aged ≥18 years, had a base- changes in depressive symptoms equal changes in function- line 17-item Hamilton Depression Rating Scale (HAMD-17) ing and QOL. However, numerous studies support that symp- (Hamilton, 1960)≥18, and no diagnosis of schizophrenia or other toms, functioning, and QOL are dissociable domains (McCall psychotic disorders, bipolar disorders, or organic mental disor - et  al., 2001, 2004; Angermeyer et  al., 2002; Mathew et  al., 2007; ders were included in both trials. Formal psychotherapy was not Lam et al., 2011). The American Psychiatric Association practice permitted during the study period. guideline for the treatment of patients with MDD (Gelenberg et  al., 2010) emphasizes the importance of adding functioning Procedure and QOL measures to adequately capture the full burden of de- pression. Functioning refers to an individual’s actual involve- For the ECT group, MDD inpatients were enrolled if they met the indications of ECT (i.e., need for a rapid and definitive response, ment and participation in health and life activities, whereas QOL reflects the patient’s satisfaction with such activities and high suicide risk, severe psychomotor retardation, and treat- ment-resistant depression) (Waite and Easton, 2013) and had psychological well-being (WHO, 1998; IsHak et al., 2011). There are several reasons to replicate and extend the out- no serious medical conditions restricting the use of ECT. The practice of ECT was in accord with the American Psychiatric comes of ECT from traditional symptom severity to function- ing and QOL for depressed patients. First, few studies have Association Task Force on ECT (APA, 2001). Psychotropic agents, including antidepressants, antipsychotics, and mood stabilizers, simultaneously explored the differences in alleviating depres- sive symptoms, improving functioning, and reducing QOL defi- were discontinued for 3 days before initiating ECT if emergency ECT was not required. Patients remained medication free dur - cits between ECT and pharmacotherapy. Second, ECT use in Western countries is much more common than in Asian coun- ing the ECT course, except for anxiolytic or sedative-hypnotic medications as needed for insomnia or severe anxiety. Standard tries. Psychiatrists in Asia seem reluctant to prescribe ECT and patients may hesitate to receive it. Almost all the studies about bitemporal and modified ECT was performed. Modified ECT refers to the administration of anesthesia, muscle relaxant, and ECT outcome for depressed patients are from Western countries. Consequently, data for comparison are limited (Chanpattana seizure-inducing electrical stimulus, in that order. For our ECT protocol, anesthesia was induced by thiopental or thiamylal, et al., 2010). Third, ECT is an “orphan treatment,” as there is no marketing supporting it (Kotzalidis et al., 2015). both at doses of 1.5 to2.0  mg/kg i.v. Neuromuscular blockade was induced by succinylcholine at a dosage of 0.5 to 1.0  mg/kg The aim of this study was to compare existing data from 2 previously published open-label studies in regard to depres- i.v. ECT was conducted using the Thymatron System IV machine with brief-pulse and constant current (pulse width, 0.5 ms; fre- sive symptoms, functioning, QOL, and tolerability. The subjects from the first study (Lin et al., 2016) were 130 MDD patients who quency, 60 Hz; current, 0.9 A). Seizure duration was at least 20 seoncds as measured by electromyogram and 25 seconds meas- received ECT with a maximum of 12 treatments. Subjects from the second study (Lin et al., 2011) were 131 MDD patients with- ured by electroencephalography. Treatment was given 3 times a week before Aug. 2009 and later 2 times a week, with a max- out a history of treatment-resistant depression who were pre- scribed 20 mg/d fluoxetine as monotherapy for a period of up to imum of 12 treatments. The number of ECT treatments was determined by the treating psychiatrist, depending on whether 6 weeks. We hoped to ascertain the differences between the ECT Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Lin et al. | 65 remission (HAMD-17 ≤7) had been reached, if patients could not baseline and at weeks 1, 2, 3, 4, and 6.  UKU, a clinician-rating tolerate the side effects, or if patients decided to discontinue scale with 48 items, contains a Likert scale of 0 to 3 for degree of ECT (APA, 2001). severity. A score of 1, 2, or 3 on any UKU item that first occurred For the fluoxetine group, physically healthy inpatients who or worsened during treatment indicated a “case” (E.Dal J.  y et al., required acute treatment of MDD were enrolled. Patients with 2011). To compare the ECT group with the fluoxetine group, only treatment-resistant depression or substance dependence/abuse subjective memory impairment (Item 1.4), nausea/vomiting were excluded. Treatment-resistant depression was defined as a (Item 3.4), and headache (Item 4.17) were selected. lack of response to 2 or more adequate trials of different classes of antidepressants (Souery et al., 1999). An adequate trial was 4 Statistical Analysis to 6 weeks of treatment with an antidepressant at a dosage con- Analysis was on a modified intent-to-treat basis for subjects sidered therapeutic. After a washout period of at least 72 hours, reporting at least one post-baseline assessment. Data were patients received open-label fluoxetine treatment at a fixed analyzed using the SPSS version 17.0 for Windows (SPSS Inc.). dose of 20 mg/d for 6 weeks. No other psychotropic agents were Statistical significance was defined as P < .05. Pearson χ test or administered during the treatment period, except for anxiolytic Fisher’s exact test was used to compare categorical variables, or sedative-hypnotic medications as needed for insomnia or se- and independent t test was used for continuous variables. vere anxiety. Judgment of treatment adherence was based on In the first step, 2 groups at baseline were compared in terms the nursing staff’s observations. Both sets of subjects, receiving of sex, age, age at onset, baseline HAMD-17, baseline MWSAS, either ECT or fluoxetine, would complete their trials within 6 baseline PCS, baseline MCS, anxiolytic/sedative-hypnotic weeks. medications used during the trial period, employment in the 6 months before the trial, and side effects following treatment. Outcome Measures Age at onset was defined as the age at which the first major de- Symptom severity was assessed by independent board-certified pressive episode occurred. Employment was defined as working psychiatrists using HAMD-17. Higher HAMD-17 scores (ranging for pay in the 6 months before the trial (Lerner et al., 2004). from 0 to 52)  indicate more severe depression. The Work and In the second step, the median pre-post differences in the Social Adjustment Scale (WSAS) (Mundt et al., 2002) is a 5-item HAMD-17 and MWSAS scores in both groups were calculated. self-rating scale designed to measure functional impairment. The generalized estimating equations (GEE) method with the Each item is scored from 0 (not affected at all) to 8 (severely first-order autoregressive working correlation structure (AR affected). Item 1 assesses work ability, but it may be difficult 1)  (Liang and Zeger, 1986) was applied to examine the differ - for patients to demonstrate a high level of work functioning ences in HAMD-17 and MWSAS scores between the 2 groups while in the hospital when their jobs are outside of the hos- during the course of acute treatment, after adjusting for sex, pital, or for those patients who have retired. Therefore, Item 1 age, age at onset, and baseline severity (baseline HAMD-17 or has been omitted. We renamed the Work and Social Adjustment MWSAS). Analyses of group differences in PCS and MCS were Scale, without Item 1, the Modified Work and Social Adjustment performed by ANCOVA, with treatment (ECT vs fluoxetine) as Scale (MWSAS) (ranging from 0 to 32) to assess functioning. The a fixed factor and sex, age, age at onset, and the baseline value Medical Outcomes Study Short-Form 36 (SF-36) (Brazier et  al., (baseline PCS or MCS) as covariates. 1992), a self-rating scale with 2 primary-factor analytic compo- In the last step, the treating psychiatrists, patients, and their nents, the physical component summary (PCS) and the mental families need to know the onset of a meaningful benefit of treat- component summary (MCS), was used to measure QOL. Lower ment, such as symptomatic response or remission. Response PCS and MCS scores reflect worse QOL. was defined as an at least 50% reduction of the baseline HAMD- For the ECT group, symptom severity and functioning were 17 score. Kaplan-Meier survival analysis was used to deter - assessed using HAMD-17 and MWSAS before ECT, after every mine the differences in speed of response/remission between 3 ECT treatments, and after the final ECT treatment. QOL was 2 groups. assessed before ECT. A study by Daly et al. (J. JDal .  y et al., 2001) In contrast to the fluoxetine trial, which is typically of fixed found that an average of 6 ECT treatments is needed to reach duration and involves fixed time points for assessment (i.e., initial response. Therefore, if patients received at least 6 ECT weeks 0, 1, 2, 3, 4, and 6), ECT is administered over a brief period treatments, QOL was reassessed after the final ECT. To prevent (i.e., 2 or 3 times weekly) with considerable variability in the post-ECT confusion from influencing the assessment, all meas- time points of clinical assessment (i.e., before ECT, after every 3 ures were conducted 1 to 2 days after treatment. ECT treatments, and after the final ECT treatment). We therefore For the fluoxetine group, symptom severity and function- used the exact number of days since the baseline assessment ing were assessed using HAMD-17 and MWSAS at baseline, and as the time variable in both the GEE and Kaplan-Meier survival again at weeks 1, 2, 3, 4, and 6. QOL as determined by SF-36 was analysis. This method has been used previously (Schoeyen et al., assessed at baseline and reassessed if patients completed the 2015). 6-week fluoxetine treatment. Results Side Effects Subjects For the ECT group, side effects not present before ECT, including subjective memory impairment, nausea/vomiting, and headache, A flow chart of the participant selection process is shown in either first observed by the psychiatrist at each visit or first reported Figure 1. In the ECT group, 130 patients treated with ECT (n = 113 spontaneously by the patient indicated side effects “cases.” due to treatment-resistant depression, n = 15 due to high sui - For the fluoxetine group, side effects were assessed using the cide risk, and n= 2 due to severe psychomotor retardation) par - Utvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) ticipated in the study. One-hundred sixteen patients receiving (Lingjaerde et al., 1987) and by the registration of side effects at at least 3 ECT treatments (n = 100 due to tr eatment-resistant Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 66 | International Journal of Neuropsychopharmacology, 2018 depression, n = 14 due to high suicide risk, and n= 2 due to significantly lower employment rates than the fluoxetine group. severe psychomotor retardation) were included in the analysis. In the ECT group, 105 patients completed the SF-36 assessment Twelve of the 116 discontinued ECT prematurely; the remainder before ECT, and 95 of 105 once again after ECT. In the fluoxetine (n = 104) completed the course of ECT. In the fluoxetine group, group, 119 patients completed the SF-36 assessment at baseline, 131 patients were enrolled. One hundred twenty-six who had at and 106 of 119 once again after the 6-week fluoxetine trial. least one post-baseline assessment at week 1 entered the ana- lysis. Fourteen of the 126 discontinued the fluoxetine trial pre- Premature Discontinuation maturely; the remainder (n = 112) completed the 6-week trial. In The clinical baseline characteristics of dropout patients did not the ECT group, the mean number of treatments was 8.9 ± 2.5. One differ significantly between the ECT group (n= 26) and the flu- hundred (86.2%) were diagnosed as having treatment-resistant oxetine group (n= 19) with respect to sex (P = .487), age (P = .944), depression, and 103 received ECT twice weekly.T able  1 reveals age at onset (P= .869), baseline HAMD-17 (P = .135), and base- that the clinical variables at baseline did not significantly dif- line MWSAS (P= .169) (data not shown in the table). There fer between the treatment groups. However, the ECT group had Figure 1. Study design for patients with major depressive disorder treated with electroconvulsive therapy or fluoxetine. Table 1. Baseline Clinical Characteristics and Side Effects Comparing Patients Receiving ECT and Those Receiving Fluoxetine ECT Fluoxetine P Variables n n Sex, female, n (%) 116 82 (70.7) 126 96 (76.2) .332 Age, mean (SD), year 116 46.9 (12.3) 126 45.3 (11.0) .286 Age at onset, mean (SD), year 116 38.1 (12.8) 126 38.9 (11. 8) .636 Baseline HAMD-17 score, mean (SD) 116 30.9 (7.0) 126 31.3 (6.5) .602 Baseline MWSAS score, mean (SD) 116 23.5 (7.3) 126 23. 8 (7.9) .747 Baseline SF-36 PCS, mean (SD), 105 42.4 (9.1) 119 40.1 (10.6) .088 Baseline SF-36 MCS, mean (SD), 105 20.5 (7.7) 119 21.5 (9.0) .396 Employment in the 6 months before the trial, n (%) 116 19 (16.4) 126 46 (36.5) <.001 Anxiolytic/sedative-hypnotic medication used, n (%) 116 105 (90.5) 126 113 (89.7) .828 Side effects following treatment 116 48 (41.4) 126 21 (16.7) <.001 0.332 Subjective memory impairment, n (%) 116 24 (20.7) 126 20 (15.9) <.001 Nausea/vomiting n (%) 116 70 (60.3) 126 21 (16.7) Headache n (%) Abbreviations: ECT, electroconvulsive therapy; HAMD-17, 17-item Hamilton Rating Scale for Depression; MCS, mental component summary, lower scores of PCS reflect worse quality of life; MWSAS, Modified Work and Social Adjustment Scale = Work and Social Adjustment Scale (WSAS) without Item 1; PCS, physical component summary, lower scores of PCS reflect worse quality of life; SF-36, Medical Outcomes Study Short-Form 36. Bold, statistically significant. a 2 Pearson’s χ test Independent t test. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Lin et al. | 67 were no significantly different dropout rates between the ECT response between the 2 groups, and Figure 4 compares the time group (20.0%= 26/130) and the fluoxetine group (14.5% = 19/131) to remission between the 2 groups. (χ = 1.31, df = 1, P = .240). Thirteen (13/26 = 50%) patients did not complete the ECT course due to side effects: complaints of pain Discussion (n = 6), confusion or memory problems (n = 2), hypoxia after ECT (n = 3), and a high frequency of ventricular premature contrac- This pooled analysis study revealed 3 main findings: (1) ECT tion, lasting for a long duration, which occurred after ECT (n = 2). alleviated the burden of MDD more than fluoxetine in the Nineteen patients did not complete the fluoxetine trial due to acute phase (Tables 2 and 3); (2) compared to fluoxetine-treated lack of efficacy (n = 3), premature discharge (n= 14), and with- patients, ECT-treated patients had a more rapid onset of re- drawal of consent (n = 2). In contrast to the patients treated with sponse/remission. Our results may be comparable with the find- ECT, none of fluoxetine-treated patients dropped out due to side ings by a randomized study that showed ECT is superior to effects (Fisher’s exact test, < P .001). paroxetine in treatment-resistant depression in terms of both degree and speed of response (Folkerts et  al., 1997). (3) The ECT group had a dropout rate comparable with the fluoxetine Efficacy and Side Effects group. One-half of the dropout patients in the ECT group dis- The ECT group had greater median pre-post differences continued treatment due to side effects, whereas none of the than the fluoxetine group, regardless of rating by HAMD-17 patients in the fluoxetine group dropped out of the trial because (23.0 vs 16.0) or MWSAS (12.0 vs 4.0) (data not shown in the of side effects. Patients treated with ECT were likely to experi- table). After adjusting for sex, age, age at onset, and base- ence subjective memory impairment and headache more often line severity (baseline HAMD-17 or MWSAS) using GEE, the than fluoxetine following treatment (Table ). 1 This indicates ECT group had significantly decreased posttreatment HAMD- that fluoxetine is better tolerated than ECT. Even though un- 17 and MWSAS scores compared with the fluoxetine group pleasant side effects are widely believed to impair the patient’s during the course of acute treatment, on average by 4.29 and QOL (Wisniewski et al., 2007), ECT still improved QOL more than 3.59 points, respectively (Table )2 . Figure 2 shows the HAMD- fluoxetine (Table 3). 17 scores between the ECT group and the fluoxetine group The patients in the ECT or fluoxetine groups represented during the course of acute treatment. Similarly, score gains a relatively severely ill population who had not responded in PCS and MCS for the ECT group were significantly greater adequately to outpatient treatment and needed hospitaliza- than those for the fluoxetine group, as analyzed by ANCOVA, tion (Gelenberg et  al., 2010). Previous studies have found that with sex, age, age at onset, and baseline values (baseline patients with severe depression are associated with signifi- PCS or MCS) as covariates (Table ). 3 However, the ECT group cant functional impairment and poor QOL (Coryell et al., 1993; experienced significantly higher rates of subjective memory Thase, 2000; Trivedi et  al., 2006). Both groups had comparable impairment and headache than did the fluoxetine group fol- symptom severity (Table 1 ), even though 86% of the patients in lowing treatment (Table 1). the ECT group were treatment-resistant. It is reasonable that there were no statistically significant differences between these 2 groups with respect to functional impairment and QOL deficit Remission and Response at baseline (Table  1 ). Compared with the fluoxetine group, the Among the patients who completed treatment, the response ECT group showed significantly lower employment rates in the rate of 92.3% (96/104) in the ECT group was significantly higher 6  months before the trial (Table).   1 There was a distinct possi- 2 = than the 58.9% (66/112) in the fluoxetine group (χ 32.04, bility that a high percentage of the patients in the ECT group df = 1, P < .001). The ECT group (71.2%= 74/104) also had a sig- were treatment-resistant, because patients with treatment- nificantly higher remission rate than the fluoxetine group resistant depression have been reported to experience lower 2 = (27.7% = 31/112) (χ 40.80, df = 1, P < .001). Patients treated with employment rates than those without (Souery et al., 2007). This ECT (mean time± SE = 19.3 ± 0.9  days) also had a significantly may be associated with longer durations of current episodes shorter time to response than those treated with fluoxet- and longer stays in hospital after several ineffective treatment ine (mean time ± SE = 24.3 ± 1.3  days) (log rank = 13.48, df = 1, options (Souery et al., 2007; Zaninotto et al., 2013). P < .001). Time to remission for ECT-treated patients (mean Although the ECT can be superior to antidepressant drugs time± SE = 29.9 ± 1.0  days) was also significantly shorter than in reducing the burden of depression for patients, it is gen- for fluoxetine-treated patients (mean time ± SE = 35.2 ± 1.0 days) erally applied as the treatment of last resort. There is still (log rank = 36.48, df = 1, P < .001). Figure  3 compares the time to a majority of MDD patients with an indication for ECT who Table  2. Effects of Sex, Treatment (ECT vs Fluoxetine), Treatment Duration, Age, Age at Onset, and Baseline Severity (Baseline HAMD-17 or MWSAS) over Time on the HAMD-17 Score or MWSAS Score Using the Generalized Estimating Equations HAMD-17 MWSAS Variable Estimate SE P Estimate SE P Male vs female -0.30 0.55 .583 -0.97 0.68 .150 ECT vs fluoxetine -4.29 0.53 <.001 -3.59 0.62 <.001 Treatment duration (1-day increments) -0.52 0.02 <.001 -0.25 0.02 <.001 Age (1-year increments) 0.04 0.04 .249 -0.01 0.04 .771 Age at onset (1-year increments) -0.05 0.04 .193 -0.03 0.04 .513 Baseline HAMD-17 or MWSAS (1-point increments) 0.59 0.04 <.001 0.74 0.04 <.001 Bold, statistically significant. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 68 | International Journal of Neuropsychopharmacology, 2018 Figure 2. Error bars showing the 17-item Hamilton Rating Scale for Depression (HAMD-17) scores between the electroconvulsive therapy (ECT) group and the fluoxetine group during the course of acute treatment. Table  3. Changes of PCS and MCS before and after Treatment for The ECT group was treated with bi-temporal ECT. Unilateral Patients Receiving ECT and Fluoxetine electrode placement might have reduced the observed incidence of subjective memory impairment (Waite and Easton, 2013). ECT Fluoxetine P Therefore, whether the present findings can be extrapolated to those treated with right unilateral ECT requires additional study. Variables n n However, one study (Prudic et al., 1996) has concluded that ECT SF-36 PCS change, 95 6.1 (9.4) 106 1.3 (9.3) <.001 outcome appears to be independent of electrode placement. mean (SD) Treatment with a fixed dose of 20 mg/d of fluoxetine treat- SF-36 MCS change, 95 12.0 (11.2) 106 6.4 (11.6) .013 ment might be considered insufficient to demonstrate response, mean (SD) as in clinical practice individuals vary in their dosage for op- timal treatment response. However, earlier fixed-dose studies aP values were determined by ANCOVA, with sex, age, age at onset, (Schweizer et  al., 1990; Stokes, 1993) have demonstrated that and baseline value as a covariate. 20 mg of fluoxetine daily is the optimal dose for most patients. Bold, statistically significant. A  meta-analysis study by Beasley et  al. (Beasley et  al., 2000) also found that fluoxetine therapy at 20  mg daily is a critical have not received ECT. One possible reason is that side effects factor for adequate therapy and has good treatment tolerance. Berney (Berney, 2005) concluded that a flat dose-response curve may compromise adherence to ECT, even though most side effects are transient (Fink, 2014). Psychiatrists must help is a class phenomenon for selective serotonin reuptake inhibi- tors, regardless of whether patients have mild or moderate-to- patients reduce their fear and manage such side effects. For example, prophylaxis with antiemetic agents and analgesics severe depression. Therefore, the poor outcome of the fluoxetine group did not appear to be due to the 20  mg/d of fluoxetine. to relieve nausea/vomiting and headache might be consid- ered before undergoing ECT (Payne and Prudic, 2009). Some Additionally, because plasma levels were not analyzed in the fluoxetine group, the 20 mg/d of fluoxetine prescribed might be strategies recommended to decrease memory impairment include setting the ECT machine with brief pulse waveform, criticized as to whether the therapeutic plasma levels could be reached. However, previous studies reported no evidence of a re- unilateral nondominant stimulus electrode placement, and ultra-brief pulse stimuli. Also, decreasing stimulus intensity lationship between fluoxetine plasma concentrations and clin- ical response (Kelly et al., 1989 Norman et  ; al., 1993; Amsterdam and decreasing the frequency and number of treatments may prove beneficial (Payne and Prudic, 2009; Mankad, 2010). On et al., 1997). Several strengths of this study should be addressed. First, the other hand, more professional education about ECT and related mental health laws for psychiatrists may increase the to our knowledge, this is the first study to focus on symptom severity, functioning, QOL, side effects, and the speed of symp- numbers of ECT prescriptions or referrals (Finch et  al., 1999; Dauenhauer et al., 2011). tomatic response/remission when simultaneously comparing Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Lin et al. | 69 Figure 3. Time to response (log rank = 13.48, df = 1, P < .001) for patients with major depressive disorder receiving ECT or fluoxetine. Figure 4. Time to remission (log rank = 36.48, df = 1, P < .001) for patients with major depressive disorder receiving ECT or fluoxetine. the results of ECT and antidepressant medication in depressed it permits examination of the relationships between variables patients. Symptom severity reflects only a portion of the bur - at all time points, adjusts for the within-subject dependence den of major depressive disorder (Cohen et al., 2013). Both func- effect, and allows for the inclusion of subjects with missing data tioning and QOL assessed by self-rating scales (i.e., MWSAS and (Liang and Zeger, 1986; Twisk, 2003; Madhoo and Levine, 2015). SF-36) may reflect patients’ perspectives on ECT. Second, the GEE Third, survival analysis may display the greatest sensitivity in offers advantages over standard regression techniques in that detecting treatment group differences in speed of symptomatic Downloaded from https://academic.oup.com/ijnp/article-abstract/21/1/63/4708251 by Ed 'DeepDyve' Gillespie user on 16 March 2018 70 | International Journal of Neuropsychopharmacology, 2018 response/remission (Nobler et  al., 1997). Fourth, our results improvement. Thus, some initial improvement may be due to could be generalized to a clinical setting (Nierenberg et al., 1995). the sedating effects of anxiolytics/sedative-hypnotic medication The present study was also subject to certain limitations. rather than the ECT or fluoxetine (Roose and Nobler, 2001Smith ; First, this pooled analysis study was nonrandomized and et  al., 2002). However, no significant difference existed in the unblinded, which could contribute to major bias. The pooled rates of anxiolytics/sedative-hypnotic medication used between analysis study came from 2 short-term and open-label studies. the ECT and fluoxetine groups (Table 1). The impact on outcome We did not know how long such outcome differences between or tolerability of each group should therefore be comparable. 2 groups could last. Additionally, it was difficult to estimate the In conclusion, the current results revealed that bi-temporal degree to which clinical improvements were due to treatments, ECT was more effective in reducing the burden of acute phase placebo effect, or other psychiatric interventions. For example, depression than fluoxetine. Bi-temporal ECT had a substantially depressed patients in hospital do obtain relief from milieu increased speed of symptomatic response and remission com- approaches (Rasmussen, 2009). Patients and clinicians both pared to fluoxetine, although the ECT group had a higher rate know the treatments and both may anticipate the outcomes. of treatment-resistant depression (86.2%) and experienced more These anticipations may contribute to a placebo effect. However, unpleasant side effects. Increased education and information it is unlikely the clinical response was solely attributable to pla-about ECT for clinicians, patients and their family, and the gen- cebo effects for the following reasons: first, the response rates of eral public is indispensable. the ECT (92.3%) and the fluoxetine groups (58.9%) were too high to be accountable by the typical placebo effect, i.e., around 30 %, Funding as estimated from past clinical placebo-controlled antidepres- sant trials (Walsh et al., 2002); second, it has been demonstrated This study was supported by the Kaohsiung Municipal that patients with severe depression and with treatment-resist- Kai-Syuan Psychiatric Hospital (KSPH-2007-16, KSPH-2008-12) ant depression present a lower placebo response (Khan et  al., and the Ministry of Science and Technology, Taiwan (MOST-103- 2002; Brunoni et al., 2009). However, both trials were open-label. 2314-B-280-001-MY3). The placebo effect might not be comparable in the 2 groups and must not be underestimated. Acknowledgments Second, the 6-week treatment with fluoxetine might also be criticized as being of too short a duration for the stability of the We would like to thank all the participants for this study. result to be verified, as longer treatment durations may lead to further improvement in depressive symptoms and functioning (Kocsis et al., 2002; Rush et al., 2006). Therefore, prolonged fluox- Statement of interest etine treatment may yield greater improvement, thereby less- None. ening the difference between fluoxetine and ECT. However, the 6-week period was relatively long and sufficient for inpatient trials to detect initial responses to antidepressant medication. 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International Journal of NeuropsychopharmacologyOxford University Press

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