Comparison of Trajectories of Depressive Symptom Dimensions through Index Electroconvulsive Therapy in Major Depressive Disorder

doi:10.21203/rs.3.rs-1608425/v1

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Comparison of Trajectories of Depressive Symptom Dimensions through Index Electroconvulsive Therapy in Major Depressive Disorder

https://doi.org/10.21203/rs.3.rs-1608425/v1

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Backgrounds

Studies to date detailing trajectories of depressive symptom dimensions in patients undergoing index electroconvulsive therapy (ECT) have been small in number; many studies have focused on the total score of the rating scale. This Study aimed to investigate the trajectories of depressive symptom dimensions and the time point when the difference in improvement of depressive symptom dimensions between the remitters and non-remitters appeared.

Methods

A retrospective analysis was performed on 80 patients with major depressive disorder who underwent index ECT. The Hamilton Depression Rating Scale-17 was used, and each item was clustered into four dimensions (depression, anxiety, insomnia, and somatic symptoms). Dimensions were standardized to a T-score and assessed at five time points (pre-ECT, and after the third, sixth, ninth, and twelfth ECT session). The data were analyzed using the generalized estimating equations method.

Results

In the total sample, the T-scores of all dimensions continued to reduce significantly until the sixth session. The reduction of the depression dimension T-score was prolonged until the ninth session. Significant differences in the amount of improvement between remitters and non-remitters appeared after the sixth session. The depression dimension showed a greater reduction in T-score than the other dimensions throughout the entire index ECT course.

Conclusions

The depression dimension improved more than other dimensions in patients undergoing ECT. It may be beneficial to administer at least six treatments to avoid early termination of ECT and relapse. Managing other depressive symptoms, such as insomnia, could play a significant role in improving therapeutic effect. Further studies examining depression symptoms using more accurate scales and specifying the neuronal circuits associated with each dimension are necessary.

Major depressive disorder

Electroconvulsive therapy

Symptom dimensions

Trajectory

Generalized estimating equations

Since Ugo Cerletti and Lucio Bini introduced electroconvulsive therapy (ECT) for the treatment of schizophrenia in 1938, it has been one of the most effective treatments for severe mental disorders such as major depressive disorder and schizophrenia for more than 80 years [1, 2]. However, there was a time of decline in the administration of ECT due to the anti-psychiatric movement, fear of electricity, and concerns about side effects such as cognitive impairment and cardio-cerebrovascular disease [2–4]. Furthermore, the development of numerous pharmacologic therapies may have contributed to the limited use of ECT [4, 5]. Since then, efforts have been made to minimize the side effects of ECT, including the application of general anesthesia, using sine waves and right unilateral electrodes (RUL) in addition to bitemporal (BT) electrodes, and adjusting parameters (e.g., pulse width) for each patient. Indeed, the importance of ECT is again highlighted, as numerous studies have shown that it is a safe treatment with a low mortality rate (e.g., 2$-$10 per 100,000 treatments) [6, 7].

Major depression is the primary indication for ECT. Remission and response rates are above 50% and 70%, respectively [8]. In particular, index ECT is considered when a patient has severe depressive symptoms in an acute episode with a high level of suicide risk or psychotic symptoms [9, 10]. The selection and treatment of a patient who is expected to respond positively to ECT the early course of an episode is critical to achieving remission, preventing relapse, and improving quality of life [11, 12]. As mentioned above, in addition to the shorter duration of the episode, several studies have explored the predictive factors of ECT response in major depression. Predictors that have been relatively repeated thus far include old age, accompanying psychotic symptoms or catatonia, and absence of medication failure [13–15].

Meanwhile, many ECT studies, including studies on ECT response predictors, have used the total score of depressive symptom scales such as the Hamilton Depression Rating Scale (HDRS) or Montgomery and Åsberg Depression Rating Scale (MADRS) as response variables [16]. Recently, studies not only exploring total scores, but also studies examining changes in each depressive symptom dimension have been conducted. Wade et al [17] conducted an ECT study of treatment-resistant depression, reporting that the remitter’s 'core mood/anhedonia' dimension showed significant improvement over the 'somatic disturbance' and 'insomnia' dimension. Similarly, Veltman et al [18] reported significant improvement of the 'mood' dimension over the 'melancholia' and 'suicidal' dimensions through ECT course in elderly patients. Huang et al [19] also demonstrated that during index ECT, a 'core factor' subscale had more prominent improvement compared to an 'anxiety/somatization' subscale. However, the above studies had a different constellation of depressive symptom dimensions, and the number of studies dealing with changes in symptom dimensions is not large.

Despite the growing evidence of the effect of ECT on depressive disorders, ECT has been dismissed as a 'last resort' to be used when other treatments fail. This may be due to patient discomfort compared with medication, concerns about cognitive function, prejudice, and the burden of treatment costs [20, 21]. However, early administration of ECT to patients with a shorter duration of depressive episodes and fewer medication treatment failures may contribute to better clinical outcome [14]. Therefore, research targeting the specific treatment effects of ECT is necessary to provide more precise ECT guidelines, along with studies that reduce stigma against ECT. Broadening the understanding of the effects of ECT can lead to increased information delivery to clinicians and patients, which is a major factor in promoting ECT procedures [22]. Particularly, it is important to clearly identify the therapeutic effects of index ECT aimed at the rapid improvement of various depressive symptoms in patients with severe episodes [23]. However, the therapeutic effect of index ECT on each depressive symptom dimension is not well known, and no consensus on this aspect has been reached thus far. In addition, there have been few studies considering differences in the trajectories of depressive symptom dimensions between remitters and the non-remitters through the index ECT course. Therefore, to understand the specific treatment effect of index ECT on major depression, our study investigated the trajectories of each depressive symptom dimension by treatment course. Our aim was to identify a group of patients with depression who improve most by applying ECT in due course and to help develop future ECT treatment guidelines.

Study Population

This study retrospectively reviewed the medical records of patients with major depressive disorder aged $\ge$ 12 years who underwent index ECT at the psychiatry department of Keimyung University Dongsan Medical Center between August 2016 and February 2022. Patients who satisfied the diagnostic criteria for major depressive disorder ahead of the index ECT initiation according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were included in the analysis [24]. Patients with at least three times of ECT and at least two assessments using the HDRS-17 including a pretreatment evaluation, were included. Patients who had undergone ECT within the past three months were excluded. Patients with a history of bipolar disorder, schizophrenia spectrum disorder, other psychotic disorders, or major neurological disorders were excluded. Patients with neurodegenerative diseases such as Parkinson's disease were excluded. According to exclusion criteria, 12 patients were excluded in the analysis. Ethical approval was obtained from the institutional review board of Keimyung University Dongsan Medical Center (IRB No. DSMC 2022-03-038).

Depression Symptom Severity Measure

In this study, we used the HDRS-17 to measure depressive symptom severity. The HDRS-17, developed in 1960 with proven validity and reliability in many countries, is a clinician-rating scale. This scale has relatively consistent scoring criteria for severity of depression [25, 26]. In this study, we used the Korean version of the HDRS-17, developed by Yi et al [27]. Internal consistency and inter-rater reliability were 0.76 and 0.94, respectively. Factor validity was derived, which explained 50.4% of the total variance. Assessment using the HDRS-17 was conducted at baseline (before index ECT) and at every three ECT procedures thereafter. The post-ECT HDRS-17 was evaluated within one week of the end of the index ECT course. All assessments were conducted by trained psychiatrists using the HDRS-17. Since multiple comparisons of all questions of HDRS-17 can be susceptible to type I error, our study evaluated the trajectories of depressive symptoms with four factors: 'depression', 'anxiety', 'insomnia', and 'somatic symptoms' using four factor analysis suggested by Shafer [28]. First, the ‘depression’ factor measured the severity of core depression and consisted of depressed mood (Item 1), guilt (Item 2), suicide (Item 3), work and interest (Item 7), and retardation (Item 8). Second, the ‘anxiety’ factor measured the severity of anxiety symptoms, consisting of agitation (Item 9), psychic anxiety (Item 10), somatic anxiety (Item 11), hypochondriasis (Item 15), and insight (Item 17). Third, the ‘insomnia’ factor measured the difficulty of sleep and consisted of initial insomnia (Item 4), middle insomnia (Item 5), and delayed insomnia (Item 6). The fourth factor, ‘somatic symptoms’ factor, measured the severity of physical symptoms and consisted of gastrointestinal somatic symptoms (Item 12), general somatic symptoms (Item 13), genital symptoms (Item 14), and weight loss (Item 16). In this study, referring to previous ECT studies evaluating remission using HDRS-17, a patient's post-ECT HDRS-17 total score of 8 or less was defined as a remission [17, 29].

Electroconvulsive Therapy Procedures

All patients underwent modified ECT 2–3 times per week. The administration of index ECT was based on the American Psychiatric Association Task Force on ECT [30]. A MECTA Spectrum 5000Q device (Oswego, Oregon) with 800mA fixed current was used for ECT. To identify the initial seizure threshold (IST), motor seizures of more than 20 seconds, measured by mounting a blood pressure cuff on the right calf, and seizure for more than 25 seconds via electroencephalogram were set as valid initial stimulus intensities. In the second session, multiple seizure threshold dosing was applied for RUL ECT 6 times the IST, and for bilateral ECT 1.5 times the IST to obtain the therapeutic effect of ECT [8]. Thiopental (2 to 4 mg/kg, i. v.) was applied for general anesthesia, and succinylcholine (0.5 to 1.0 mg/kg, i. v.) was used to prevent muscle pain due to excessive muscle contraction and breathing difficulties due to muscle cramps during convulsion. Glycopyrrolate (0.2 to 0.4mg, i. v.) or atropine (0.4 to 1.0mg, i. v.) was injected 10 minutes before ECT to prevent bradycardia, asystole, or increased of oral secretion that may occur immediately after electrical stimulus. Termination of index ECT was determined 1) when remission (HDRS-17 total score of 8 or less) had been reached, and the status continued for at least one consecutive rating in a week interval, 2) if adverse effects that our patient could not tolerate resulted in the index ECT being stopped, or 3) if patients decided to discontinue ECT.

Statistical Analysis

The analysis was conducted on patients with at least two HDRS-17 evaluations, including pre-ECT time point. In most cases, ECT was performed less than 12 times (75 of 80 patients performed less than 12 times). Therefore, data were analyzed for a total of five time points: pre-ECT and after the third, sixth, ninth, and twelfth sessions of ECT to determine the trajectories of scores. Pre-ECT time point and the third, sixth, ninth, and twelfth sessions of ECT were named Time 1, Time 2, Time 3, Time 4, and Time 5, respectively. In the descriptive analysis, continuous variables were compared across remission status using an independent $t$-test or Mann-Whitney $U$ test depending on whether normality was satisfied; categorical variables were analyzed using the chi-square test. Fisher's exact test was used if the chi-square test was not available because of the small sample size. A paired t-test was used to evaluate the changes in the HDRS-17 total and four dimensions before and after each time point of index ECT.

In the HDRS-17, each item has a different range of scores; some items have a range of 0 to 4, whereas others have a range of 0 to 2. In addition, each symptom dimension comprises differing items. Hence, we standardized the HDRS-17 total score and four symptom dimensions using the T-score unit (average = 50, standard deviation = 10) [31]. The T-scores at Times 1, 2, 3, 4, and 5 were calculated using means and standard deviations of HDRS-17 total score and raw score of each symptom dimension of pre-ECT assessment (Time 1) [32]. The formula for calculating the T-score was as follows.

$${X}_{T}= \left\{\left({X}_{raw}-{\stackrel{-}{X}}_{Pre-ECT}\right)/{SD}_{pre-ECT}\right\} \times 10+50$$

To analyze data from patients in whom a portion of the HDRS-17 assessment was missing, the generalized estimating equations method (GEE), which can be used when there is missing data among the repeated measurement data analysis, was used. GEE, which is known to have a higher power with a relatively small number of samples or missing data, is a statistical method used in studies which use repeated measurement data [33, 34]. The first-order autoregressive model was selected as the most suitable working correlation matrix; this model has been used in other studies [19, 35]. The available independent variable was selected by univariable GEE analysis, starting with the simple model including only remission status (remission), time, and remission $\times$ time interaction. As a result, a mixed effect model (adjusted model) with sex, ECT type (RUL vs. BT), frequency of index ECT sessions (2 times vs. 3 times a week), ECT pulse width (0.3 vs. 1.0 msec), number of the index ECT sessions, and number of previous hospitalizations were used as covariates. We did not include age as a covariate because it did not significantly predict any of the dependent variables and adding age did not change the coefficient (B) or P-value.

First, to determine whether there was a significant change in the HDRS-17 total score and four dimensions over the index ECT course (time), GEE analysis was performed using five assessment time points as the with-subject effect for the total sample, remitters, and non-remitters. By doing so, we investigated whether time as a main effect significantly changed each factor score. In addition, the difference (estimate) in each factor’s T-score compared to the previous time was identified to investigate the time point when significant improvement was maintained. Second, the differences in each T-score at Times 2, 3, 4, and 5 compared to Time 1 were compared between the remitters and non-remitters groups to identify the time point at which significant differences in improvement between remitters and non-remitters began to appear. Finally, to compare the improvement speed of the four dimensions at each time point, the difference in the amount of change between the two factors at time points of Time 2, 3, 4, and 5 from Time 1 (as a reference time) was examined. Since two factors were paired to compare each factor, six comparisons were made: depression vs. anxiety, depression vs. insomnia, depression vs. somatic symptoms, anxiety vs. insomnia, anxiety vs. somatic symptoms, insomnia vs. somatic symptoms. In other words, the amount of change at Times 2, 3, 4, and 5 with reference to Time 1 was measured for each factor. Next, the difference in the change between the two factors was compared at each time point. Post-hoc tests using Bonferroni correction were performed to adjust for multiple comparisons. All analyses were conducted using Statistical Package for the Social Sciences (SPSS) ver. 21.0 (SPSS Inc., Chicago, IL, USA), and statistical significance was defined as P < 0.05.

Sociodemographic and Clinical Characteristics

The total sample consisted of eighty patients, twenty-four were men (30.0%), and fifty-six were women (70.0%). There was very little difference in the number of remitters and non-remitters between men and women, forty-one (51.3%) and thirty-nine (48.7%), respectively. The average age of the total sample was 41.95 ± 20.2 years old, with a minimum age of 14 years (1 person) and a maximum age of eighty-two (1 person). Age and gender did not show a significant relationship with remission status (P = 0.09 and 0.884, respectively). The proportion of remitters was significantly higher in married patients (χ² = 4.01, $df$=1, P=0.045). Sixty-six patients (82.5%) underwent ECT three times a week, and 14 (17.5%) twice a week. Eleven patients (13.8%) had previous ECT experience, and there was no significant relationship between remission status and the frequency of ECT per week (P = 0.918) or previous ECT experience (P = 0.387). The average duration of depressive episodes before index ECT was 13.71±9.79 weeks, and the average number of ECT sessions was 8.04±3.14 in the total sample with 7.92±3.18 in the RUL group, and 9.13±2.75 in the BT group (Table 1).

Table 1

Characteristics of Study Population
		Total (N = 80)	Remitter (N = 41)	Non-remitter (N = 39)	P
Sociodemographics
Age, yr, mean$\pm$SD		41.95 ± 20.20	45.68 ± 19.85	38.03 ± 20.07	0.090
Male/Female		24/56	12/29	12/27	0.884
Marriage Yes/No		46/34	28/13	18/21	0.045
BMI, kg/m², mean$\pm$SD		24.02 ± 5.00	23.93 ± 5.24	24.12 ± 4.79	0.868
Education level, yr, mean$\pm$SD		12.16 ± 3.86	12.29 ± 3.43	12.03 ± 4.30	0.759
Clinical information
Prior ECT history, Yes/No		11/69	4/37	7/32	0.387
Current episode duration, weeks, mean$\pm$SD		13.71 ± 9.79	13.22 ± 9.26	14.23 ± 10.42	0.647
Prior number of admissions, mean$\pm$SD		1.26 ± 2.73	1.32 ± 3.48	1.21 ± 1.66	0.856
ECT information
Frequency
Twice a week/Thrice a week		14/66	7/34	7/32	0.918
RUL/BT		72/8	39/2	33/6	0.150^*
Number of ECT treatments, mean$\pm$SD	Total	8.04 ± 3.14	8.32 ± 3.02	7.74 ± 3.28	0.418
	RUL	7.92 ± 3.18	8.23 ± 3.04	7.55 ± 3.35	0.366
	BT	9.13 ± 2.75	10.00 ± 2.83	8.83 ± 2.93	0.737^†
Pulse width, 0.3msec/1.0msec	RUL	34/38	19/20	15/18	0.782
Pulse width, 0.3msec/1.0msec	BT	2/6	0/2	2/4	1.000^*
ECT pulse amplitude, mA		800
IST, mC, mean$\pm$SD	RUL	59.64 ± 42.55	60.98 ± 47.76	58.06 ± 36.09	0.774
IST, mC, mean$\pm$SD	BT	75.55 ± 33.14	112.00 ± 22.63	63.40 ± 26.96	0.088^†
BMI indicates body mass index; SD, standard deviation; RUL, right unilateral; BT, bitemporal; IST, initial seizure threshold; HDRS-17, 17-item Hamilton Depression Rating Scale; mA, milliampere; mC, millicoulombs. Remitter: Post-ECT HDRS-17 score ≦ 8. Non-remitter: post-ECT HDRS-17 score ≧ 9. ^*: Fisher’s exact test. ^†: Mann-Whitney U test.

When paired $t$-test with raw scores were used, the HDRS-17 total score decreased from 22.44 ± 4.61 (before ECT) to 9.41 ± 5.21 (after ECT, $t$=17.97, P<0.001). The depression dimensions changed from 10.70±2.48 to 4.50±2.70 ($t$=16.59, P<0.001), the anxiety dimension from 6.05±2.59 to 2.89±1.90 ($t$=10.40, P<0.001), the insomnia dimension from 2.74±1.62 to 1.00±1.23 ($t$=9.20, P < 0.001), and the somatic symptoms dimension from 2.95±1.37 to 1.03±1.17 ($t$=10.57, P<0.001). The T-scores of the HDRS-17 total score and the four dimensions showed significant differences before and after ECT (data not shown in the table).

Overall Changes Of Hdrs-17 And Symptom Dimensions During Index Ect Course

The total sample, remitters, and non-remitters all improved significantly during index ECT course in both HDRS-17 total score and four symptom dimensions in the GEE mixed effect model ('time' main effect P < 0.001) (Table 2, Fig. 1). When comparing the degree of improvement to the previous time point in the total sample, the T-score of the HDRS-17 total score maintained a significant decrease until twelfth ECT session (P in Times 1–2, 2–3, 3–4, 4–5 < 0.001, < 0.001, 0.001, 0.006, respectively). The degree of reduction (estimate, B) between Times 1–2 and Times 2–3 was greater than that in Times 3–4 and Times 4–5 (B in Times 1–2, 2–3 = 12.44, -12.22 vs. B in Times 3–4, 4–5=$-$3.74, $-$3.52). Similar to the HDRS-17 total score, the estimate until Time 3 was larger than thereafter in the depression dimension (B in Time 1–2, 2–3=$-$11.21, $-$10.91 vs B in Time 3–4, 4–5=$-$2.85, $-$3.43 in the total sample). Notably, in the total sample, the depression dimension maintained a significant reduction until Time 4 (B in Time 4=$-$2.85, P=0.008), whereas the other three dimensions had significant reductions only until Time 3. In addition, the T-score of depression dimension was significantly reduced from the third session of the ECT and maintained the decrease until the sixth session in the non-remitter group, but other three dimensions did not. In particular, the anxiety and insomnia dimensions showed no significant decline in T-score until the third session of the ECT (B of anxiety dimension in Time 1–2=$-$3.31, P=0.032; B of insomnia dimension in Time 1–2=$-$3.18, P=0.054). The somatic symptoms dimension showed a significant reduction up to the third ECT session (B in time 1–2=$-$4.59, P=0.001), but no significant reduction in T-score continued from the sixth ECT session (Table 3). Figure 1 illustrates the T-score trajectories of the total sample, remitter, and non-remitter groups for the HDRS-17 total score and the four dimensions.

Table 2

Trajectories of HDRS-17 and Symptom Dimensions T-score during Index ECT using GEE Method
Dimension		Time 1 (N = 80)	Time 2 (N = 74)	Time 3 (N = 62)	Time 4 (N = 46)	Time 5 (N = 26)	P^*
HDRS-17^a estimate mean (SE)	total	51.11 (8.28)	38.68 (8.37)	26.45 (8.26)	22.72 (8.08)	19.19 (7.81)	< 0.001
	Remitter	48.63 (8.14)	33.72 (8.41)	18.45 (8.31)	14.24 (8.15)	10.67 (7.74)	< 0.001
	Non-remitter	53.60 (8.54)	43.63 (8.47)	34.46 (8.34)	31.19 (8.22)	27.71 (8.13)	< 0.001
Depression^b estimate mean (SE)	Total	50.28 (8.04)	39.07 (8.19)	28.16 (8.06)	25.31 (7.83)	21.88 (7.70)	< 0.001
	Remitter	48.67 (7.96)	36.69 (8.18)	22.80 (8.21)	19.05 (8.06)	15.32 (8.12)	< 0.001
	Non-remitter	51.89 (8.27)	41.45 (8.38)	33.51 (8.06)	31.57 (7.79)	28.43 (7.60)	< 0.001
Anxiety^c estimate mean (SE)	Total	51.19 (7.19)	46.00 (7.10)	40.17 (7.18)	39.04 (7.05)	37.14 (6.72)	< 0.001
	Remitter	50.48 (6.94)	43.41 (7.12)	35.20 (6.96)	34.94 (6.89)	32.56 (6.65)	< 0.001
	Non-remitter	51.91(7.58)	48.60 (7.23)	45.13 (7.51)	43.14 (7.32)	41.71 (6.95)	< 0.001
Insomnia^d estimate mean (SE)	Total	50.02 (7.03)	45.23 (7.25)	41.25 (7.01)	38.83 (6.81)	38.05 (6.45)	< 0.001
	Remitter	47.36 (6.91)	40.87 (7.13)	38.38 (7.01)	34.89 (6.74)	33.62 (6.40)	< 0.001
	Non-remitter	52.69 (7.32)	49.59 (7.51)	44.11 (7.16)	42.76 (7.02)	42.48 (6.70)	< 0.001
Somatic symptoms^e estimate mean (SE)	Total	51.15 (8.67)	45.15 (8.76)	39.43 (8.64)	36.94 (8.48)	34.68 (8.61)	< 0.001
	Remitter	50.18 (8.77)	42.79 (8.82)	34.97 (8.93)	32.07 (8.48)	30.73 (8.57)	< 0.001
	Non-remitter	52.12 (8.69)	47.51 (8.80)	43.90 (8.45)	41.79 (8.72)	38.63 (8.88)	< 0.001
GEE indicates generalized estimating equations; SE, standardized error ^a: HDRS-17 = The total score of HDRS-17 ^b: Depression dimension = HDRS-17 items 1 (depressed mood), 2 (feelings of guilt), 3 (suicide), 7 (work and interests), and 8 (retardation). ^c: Anxiety dimension = HDRS-17 items 9 (agitation), 10 (anxiety psychic), 11 (anxiety somatic), 15 (hypochondriasis), and 17 (insight loss). ^d: Insomnia dimension = HDRS-17 items 4 (initial insomnia), 5 (middle insomnia), and 6 (delayed insomnia). ^e: Somatic symptoms dimension = HDRS-17 items 12 (gastrointestinal somatic symptoms), 13 (general somatic symptoms), 14 (libido loss), and 16 (weight loss). ^*: P of effect of time.

Table 3

Degree (= Estimate) of T-Score Improvement Compared to the Previous Time Point using GEE method
Dimension	Group	Time 1	Time 2	Time 3	Time 4	Time 5
Dimension	Group	Estimate mean (SE)	Estimate (SE) P^*	Estimate (SE) P^*	Estimate (SE) P^*	Estimate (SE) P^*
HDRS-17	Total	51.11 (8.28)	-12.44 (1.27) < 0.001	-12.22 (1.25) < 0.001	-3.74 (1.15) 0.001	-3.52 (1.30) 0.006
	Remitter	48.63 (8.14)	-14.85 (1.80) < 0.001	-15.33 (1.72) < 0.001	-4.26 (1.02) < 0.001	-3.63 (2.09) 0.083
	Non-remitter	53.60 (8.54)	-10.00 (1.79) < 0.001	-9.30 (1.84) < 0.001	-2.98 (2.04) 0.144	-3.28 (1.67) 0.049
Depression	Total	50.28 (8.04)	-11.21 (1.24) < 0.001	-10.91 (1.31) < 0.001	-2.85 (1.08) 0.008	-3.43 (1.48) 0.02
	Remitter	48.67 (7.96)	-11.95 (1.96) < 0.001	-14.03 (2.10) < 0.001	-3.97 (1.22) 0.001	-3.97 (2.02) 0.05
	Non-remitter	51.89 (8.27)	-10.46 (1.52) < 0.001	-7.92 (1.56) < 0.001	-1.38 (1.71) 0.418	-2.55 (2.16) 0.238
Anxiety	Total	51.19 (7.19)	-5.19 (1.11) < 0.001	-5.83 (0.97) < 0.001	-1.13 (1.01) 0.265	-1.91 (1.40) 0.172
	Remitter	50.48 (6.94)	-7.06 (1.58) < 0.001	-8.07 (1.47) < 0.001	-0.31 (1.45) 0.833	-2.32 (1.93) 0.230
	Non-remitter	51.91 (7.58)	-3.31 (1.55) 0.032	-3.64 (1.30) 0.005	-1.94 (1.42) 0.174	-1.62 (2.02) 0.423
Insomnia	Total	50.02 (7.03)	-4.80 (1.21) < 0.001	-3.98 (1.14) < 0.001	-2.42 (1.13) 0.032	-0.78 (0.94) 0.412
	Remitter	47.36 (6.91)	-6.48 (1.74) < 0.001	-2.64 (0.97) 0.007	-3.43 (1.17) 0.003	-1.12 (1.26) 0.374
	Non-remitter	52.69 (7.32)	-3.18 (1.65) 0.054	-5.33 (2.05) 0.009	-1.18 (1.97) 0.548	0.03 (1.51) 0.985
Somatic symptoms	Total	51.15 (8.67)	-6.00 (0.88) <0.001	-5.71 (1.01) < 0.001	-2.49 (1.43) 0.082	-2.26 (1.06) 0.033
	Remitter	50.18 (8.77)	-7.38 (1.26) <0.001	-7.86 (1.38) < 0.001	-2.95 (1.35) 0.028	-1.48 (1.26) 0.239
	Non-remitter	52.12 (8.69)	-4.59 (1.24) 0.001	-3.71 (1.47) 0.047	-1.93 (2.53) 1.000	-3.07 (1.71) 0.289
GEE indicated generalized estimating equations; SE, standardized error ^*: Bonferroni correction = P/4 = 0.0125

Table 4. Difference (= Estimate) of Improvement from Time 1 Between Remitters and Non-remitters using GEE Method

Time

HDRS-17

Estimate (SE)

P^*

[95% CI]

Depression

Estimate (SE)

P^*

[95% CI]

Anxiety

Estimate (SE)

P^*

[95% CI]

Insomnia

Estimate (SE)

P^*

[95% CI]

Somatic

symptoms

Estimate (SE)

P^*

[95% CI]

Time 2

-4.93 (2.54)

0.052

[-9.90 ~ 0.04]

-1.54 (2.49)

0.536

[-6.41 ~ 3.34]

-3.76 (2.21)

0.09

[-8.09 ~ 0.58]

-3.40 (2.41)

0.158

[-8.11 ~ 1.32]

-2.78 (1.77)

0.116

[-6.25 ~ 0.69]

Time 3

-11.04 (2.95)

< 0.001

[-16.83~-5.26]

-7.48 (3.16)

0.018

[-13.68~-1.29]

-8.50 (2.24)

< 0.001

[-12.89~-4.10]

-0.41 (2.55)

0.872

[-5.41 ~ 4.58]

-6.98 (2.42)

0.004

[-11.72~-2.24]

Time 4

-11.98 (3.41)

< 0.001

[-18.66~-5.30]

-9.30 (3.26)

0.004

[-15.69~-2.92]

-6.77 (2.31)

0.003

[-11.30~-2.24]

-2.55 (2.70)

0.345

[-7.84 ~ 2.74]

-7.77 (3.52)

0.028

[-14.67~-0.86]

Time 5

-12.06 (3.61)

0.001

[-19.14~-4.99]

-9.88 (3.80)

0.009

[-17.33~-2.43]

-7.71 (2.96)

0.009

[-13.52~-1.91]

-3.52 (3.10)

0.256

[-9.60 ~ 2.56]

-5.96 (3.49)

0.087

[-12.79 ~ 0.87]

GEE indicates generalized estimating equations; SE, standardized error; CI, confidence interval

^*: Bonferroni correction = P/4 = 0.0125

Time Point When Significant Difference In Reduction Appears Between Remitters And Non-remitters

Using Time 1 (before ECT) as a reference, the differences (estimate, B) in the T-score change between remitters and non-remitters at Time 2 (pre-ECT), 3 (sixth ECT), 4 (ninth ECT), and 5 (twelfth ECT) were identified (e.g., T-score of HDRS-17 total score change from Time 1 to Time 2 of the remitter group – that of the non-remitter group). First, the total HDRS-17 scores began to show a significant difference between the two groups from Time 3 (B=$-$11.04, P < 0.001), and a significant difference was continued until the twelfth ECT session (B in Time 4=$-$11.98, P<0.001; B in Time 5=$-$12.06, P = 0.001). As for symptom dimensions, significant differences occurred at Times 3 and 4 for anxiety and depression dimensions, respectively (B of depression dimension at Time 4 depression factors=$-$9.30, P = 0.004; B of anxiety dimension at Time 3=$-$8.50, P<0.001). This significant difference persisted throughout the index ECT period. On the other hand, the insomnia dimension showed no significant difference between remitters and non-remitters throughout the entire time point from Time 2 to Time 5 (B in Time 2=$-$3.40, P=0.158; Time 3=$-$0.41, P=0.872; Time 4 =$-$2.55, P=0.345; Time 5 =$-$3.52, P=0.256). The somatic symptoms dimension showed a significant difference between the two groups only at Time 3 (B=$-$6.98, P=0.004), and there was no significant difference in the amount of change thereafter (Table 4).

Comparison Of Improvements Between Four Symptom Dimensions

Figure 2 illustrates the trajectories of four depressive symptom dimensions throughout the index ECT. To compare the speed of improvement of each dimension, we examined the T-score differences of each dimension at Times 2, 3, 4, and 5 (time 1 as a reference). Each difference was then compared in pairs (e.g., depression vs. anxiety at Time 2). The decrease in the depression factor T-score was significantly greater than the decrease in anxiety, insomnia, and somatic symptom dimensions through Time 2, 3, 4, and 5 (e.g., in Time 2, the decrease in the depression dimension from Time 1 was greater by 6.08 points of T- score than that of anxiety factor, P < 0.001). No significant differences in T-score reduction between anxiety, insomnia, and somatic symptoms dimensions were observed at Times 2, 3, 4, and 5 (Table 5).

Table 5

Comparison of Difference (= Estimate) in T-score Reduction of Symptom Dimensions using GEE Method
Time	Depression vs. Anxiety	Depression vs. Insomnia	Depression vs. Somatic symptoms	Anxiety vs. Insomnia	Anxiety vs. Somatic symptoms	Insomnia vs. Somatic symptoms
	Estimate (SE) P^*	Estimate (SE) P^*	Estimate (SE) P^*	Estimate (SE) P^*	Estimate (SE) P^*	Estimate (SE) P^*
Time 2	-6.08 (1.42) < 0.001	-6.35 (1.48) < 0.001	-5.30 (1.35) < 0.001	-0.26 (1.60) 0.871	0.79 (1.34) 0.555	1.04 (1.50) 0.485
Time 3	-11.11 (1.68) < 0.001	-13.73 (1.98) < 0.001	-10.38 (1.62) < 0.001	-2.59 (1.64) 0.115	0.69 (1.63) 0.672	3.30 (1.52) 0.03
Time 4	-12.97 (1.59) < 0.001	-14.55 (2.01) < 0.001	-10.75 (2.13) < 0.001	-1.57 (1.69) 0.354	2.17 (1.94) 0.264	3.81 (2.02) 0.059
Time 5	-14.31 (2.26) < 0.001	-17.14 (2.29) < 0.001	-12.53 (2.26) < 0.001	-2.73 (2.26) 0.227	1.88 (2.59) 0.467	4.65 (2.13) 0.029
Time 1 (pre-ECT) as a reference in the total sample SE indicates standardized error; GEE, generalized estimating equations ^*: Bonferroni correction = $\frac{P}{4\times 6}= P/24$ ≒ 0.002

Our study specifically investigated the therapeutic effects of index ECT on major depression, focusing on the temporal changes in symptom dimensions. As with previous studies, there was a rapid improvement of depressive symptoms in the early course of the index ECT course (by about the third session) [9]. Our main findings are as follows: First, the depression dimension had a longer duration of significant improvement than the other dimensions. Second, it took at least six ECT sessions before a significant difference in the amount of improvement between the remitter and non-remitter groups began to appear and continued, only in the depression and anxiety dimensions. Third, the depression dimension continued to show a greater amount of reduction of the T-score from baseline than the other three dimensions through to the twelfth session of ECT.

We used the four-factor classification (depression, anxiety, insomnia, and somatic symptoms) of HDRS-17 suggested by Shafer to identify and compare the trajectories of depressive symptoms throughout the index ECT course [28] more clearly. Our four-factor structures are consistent with those of previous studies. In the meta-analysis of HDRS factors by Bagby et al [36], 'general depression factor' including 'depressive mood', 'guilty', and 'suicide' items were identified, which were very similar to the depression dimension in our study. Our study categorized early, middle, and delayed insomnia into the insomnia dimension, which was replicated in other studies [37]. The 'anxiety/agitation factor' composed of agitation, psychic anxiety, and somatic anxiety was also used in a number of studies, and our study regarded this factor as the anxiety dimension [38]. Lastly, our study selected gastrointestinal somatic symptoms, general somatic symptoms, genital symptoms, and weight loss as somatic symptoms dimension to examine the trajectory of somatic symptoms during the index ECT course. This grouping of symptoms is consistent with the meta-analysis by Bagby et al., in which gastrointestinal somatic symptoms, general somatic symptoms, and genital symptoms were the same factor in two studies, and gastrointestinal symptoms and weight loss were the same factor in 11 out of 15 studies [36]. By categorizing the four depressive symptom dimensions, the patterns of change between symptom dimensions in the index ECT could be carefully explored.

In the analysis of the period of significant improvement, the reduction of the HDRS-17 total score was more evident until the sixth ECT session, and the depression dimension continued to ameliorate significantly longer than the other three dimensions. The rapid decrease in the HDRS-17 total score in the early phases of index ECT (about third to sixth session) is consistent with previous studies [39]. Indeed, there have been numerous studies examining changes in the total scores of depression rating scales (e.g., HDRS and MADRS) through ECT, and some studies have recently investigated the trajectories of specific depressive symptoms in the index ECT period [17–19]. However, to date, very few studies have identified the period during which a significant reduction remains in each dimension of depressive symptoms. The T-score of the depression dimension started to decline significantly from the third session, and the improvement lasted longer than the other three dimensions, until the ninth session of the ECT. Even in the non-remitter group, the decrease in the depression dimension persisted longer than the other dimensions until the sixth session.

In addition, we have provided the results of when the difference in degrees of the T-score changes between the remitter and non-remitter groups becomes significant. Only depression and anxiety dimensions showed a significant difference between the two groups from the sixth to ninth sessions of the index ECT, and this difference persisted until the twelfth session of ECT. The HDRS-17 total score also revealed a significant difference between the two groups after the sixth ECT session. Taken together, significant differences between the remitter and non-remitter groups were observed at least from the sixth session of the index ECT course. In addition, our finding that all four dimensions showed significant improvement after at least six sessions of ECT (ninth session for depression dimension) coincides with the previous demonstration that early termination of ECT could increase the likelihood of relapse [40, 41]. Considering the guidelines that have suggested six to twelve treatments in the typical index ECT course, at least six ECT sessions may be required for significant therapeutic benefit [42, 43].

Meanwhile, the insomnia dimension showed no significant difference in change between the remitter and non-remitter groups at times 2, 3, 4, and 5. McCall et al [44] suggested that ECT might have a modest effect on insomnia. Although an improvement in insomnia was observed in both remitters and non-remitters in our study, no significant difference in the amount of change was observed between the two groups. According to McCall's findings, sleep improvement might also have occurred due to effects other than ECT (e.g., use of hypnotics), but ECT itself might have had less of an effect on insomnia. Therefore, managing residual symptoms, such as insomnia, that may remain after the middle phases of index ECT course (sixth to ninth session) could help improve the overall treatment effect.

Our finding that the core depressive symptoms ('depression' dimension), including depressed mood and loss of interest, have a greater degree of improvement than other dimensions has been repeated in previous studies. Huang et al [19] used the GEE method to analyze longitudinal data, as in our study, and reported that the improvement of this core factor subscale was consistently greater than that of the anxiety/somatization subscale of the HDRS-17 during the index ECT course. Wade et al [17] also suggested that the degree of improvement of core mood/anhedonia factor was larger than that of insomnia and somatic disturbance factors in remitters. In addition, Veltman et al [18] demonstrated that the mood dimension improved faster than the melancholic and suicidality dimensions in the early course of ECT (after one week). Our study repeatedly assessed the HDRS-17, the most used scale, every three ECT sessions, and compared depression, anxiety, insomnia, and somatic symptom dimensions.

Based on these results, understanding the disproportionate effects of ECT on core mood symptom dimension compared with other dimensions plays an important role in expanding our knowledge of the therapeutic mechanisms of ECT in depression. First, at the neurotransmitter level, depressive mood, loss of interest, and psychomotor retardation, which belong to the 'depression' dimension of our study, might be caused by dopamine deficiency or reduced reactivity of the post-synaptic dopamine receptor [45]. It is known that the changes in D1 and D2 receptor function in the early phases of index ECT, especially the downregulation of D2 receptors, can lead to symptom improvement. These mechanisms may affect the amelioration of core depressive symptoms in the early stages of ECT [46, 47]. In addition to dopamine, serotonin-related effects induced by ECT can affect mood symptoms and suicidality. The 5-HT2A receptor is thought to be a major receptor involved in the pathophysiology of depression. There have been several studies which have suggested that upregulation of this receptor is linked to suicide, reduction of intracellular signaling pathways, and melancholic depression [48–50]. Thus, we considered the possibility that the 5-HT2A receptor and emotion-related symptoms might be correlated. Based on the results that ECT leads to downregulation of 5-HT2A receptors in humans, we suggest that the downregulation of 5-HT2A receptors by ECT may have affected suicidality and depressed mood [47, 51].

Second, we considered the association between the brain structural changes induced by ECT and depression dimensions. Referring to the meta-analysis of Wilkinson et al [52], which suggested that ECT increases the volume of the hippocampus, and the study of Zhu et al [53], which studied the association between the hippocampus and emotional processing, we considered that the volume increase of the hippocampus induced by ECT can contribute to the improvement of core mood symptoms. However, there is a multi-site study in which there was no positive correlation between hippocampal volume changes and clinical outcomes. Therefore, the correlation between ECT-induced hippocampal volume changes and core mood symptoms requires further studies [54].

A change in the activity of the subgenual anterior cingulate cortex (sgACC) could be another hypothesis for the disproportionate reduction mechanism of depressive symptoms following ECT. The sgACC, a part of the anterior cingulate cortex, plays a major role in unpleasant emotion regulation. The relationship between sgACC and depression has been a prominent topic in mood disorder and neuromodulation studies [55, 56]. Although the effect of ECT on sgACC is estimated to influence the reduction of the depression dimension, the direction of this effect is inconsistent. Liu et al [57] reported increased regional activity of the sgACC and connectivity of the sgACC with other brain regions (i.e., the parahippocampal gyrus, middle temporal gyrus, and orbitofrontal codex) with eight ECT sessions. In contrast, Hamani et al [58] suggested increased sgACC activity in depressed individuals which was reversed by antidepressant therapy. Taken together, although the effect of ECT on sgACC has not been clearly identified, it could be a possible mechanism for the specific improvement in core mood symptoms by ECT.

Our study has several limitations. First, as a retrospective study, it is possible that medication use might have functioned as a confounding variable because patients were given psychopharmacologic treatment during the index ECT process. However, there are many combinations of ECT and pharmacotherapy in contemporary clinical settings, and it is not easy to discontinue all medications abruptly [59]. Indeed, this was similar to other studies in that the comparison of remitters and non-remitters was performed under the same condition where all patients received medication. This study, using concomitant pharmacotherapy, may be used to determine the specific effect of index ECT on various depressive symptoms in actual clinical practice. The second limitation of this study was that some patients had missing data. For the analysis including missing data, we used the GEE method, which maintains relatively high power in longitudinal measurements with missing data and has the advantage of identifying overall average effects. Third, our study did not assess anxiety, insomnia, and somatic symptoms with additional validated scales (e.g., Pittsburgh Sleep Quality Index, Beck Anxiety Inventory, and Depression and Somatic Symptoms Scale) in addition to the HDRS-17. However, the HDRS is the most widely used assessment measure in depression studies. In this study, standardization was performed with a T-score for comparison between each depressive symptom dimension. In future, it will be necessary to apply an assessment scale that can more precisely evaluate each symptom.

In conclusion, our study showed that index ECT for major depression may induce improvements in all four depressive symptom dimensions. Among the dimensions, the depression dimension had a longer period of improvement and a greater amount of improvement than the other dimensions. Additionally, we examined when a significant difference in improvement was observed between remitters and non-remitters. Our study is expected to help identify the symptoms that might specifically improve with ECT. Further neuromodulation research, including ECT, is needed to specify brain regions or neural circuits related to symptom dimensions and explore neurobiological changes that might appear in each part of the brain in detail. Moreover, future studies investigating the time point and type of pharmacotherapy after index ECT and the use of maintenance treatment to prevent relapse, such as maintenance ECT, are needed to reduce burden of disease in patients and maintain remission.

ECT: Electroconvulsive therapy; HDRS-17: Hamilton Depression Rating Scale-17; GEE: Generalized estimating equations; RUL: Right unilateral; BT: Bitemporal; MADRS: Montgomery and Åsberg Depression Rating Scale; IST: Initial seizure threshold; SPSS: Statistical Package for the Social Sciences; sgACC: subgenual anterior cingulate cortex

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of Keimyung University Dongsan Medical Center, Daegu, Republic of Korea. IRB number DSMC 2022-03-038 on March 18, 2022.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

None of authors received funding in the current study.

Authors’ contributions

Conceptualization: JWY, HL, SWJ. Data acquisition: JWY, YTK, SWJ. Formal analysis: JWY, HL. Writing original draft: JWY, HL. Review & editing: SWJ, HL, YTK. All authors have read and approved the final manuscript.

Acknowledgments

Not applicable.

Authors information

¹Department of Psychiatry, Keimyung University Dongsan Medical Center, 1035, Dalgubeol-daero, Dalseo-gu, Daegu, Republic of Korea

²Department of Psychiatry, School of Medicine, Keimyung University, 1095, Dalgubeol-daero, Dalseo-gu, Daegu, Republic of Korea

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No competing interests reported.

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Comparison of Trajectories of Depressive Symptom Dimensions through Index Electroconvulsive Therapy in Major Depressive Disorder

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Abstract

Figures

Background

Methods

Study Population

Depression Symptom Severity Measure

Electroconvulsive Therapy Procedures

Statistical Analysis

Results

Sociodemographic and Clinical Characteristics

Overall Changes Of Hdrs-17 And Symptom Dimensions During Index Ect Course

Time Point When Significant Difference In Reduction Appears Between Remitters And Non-remitters

Comparison Of Improvements Between Four Symptom Dimensions

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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		Total (N = 80)	Remitter (N = 41)	Non-remitter (N = 39)	P
Sociodemographics
Age, yr, mean\(\pm\)SD		41.95 ± 20.20	45.68 ± 19.85	38.03 ± 20.07	0.090
Male/Female		24/56	12/29	12/27	0.884
Marriage Yes/No		46/34	28/13	18/21	0.045
BMI, kg/m², mean\(\pm\)SD		24.02 ± 5.00	23.93 ± 5.24	24.12 ± 4.79	0.868
Education level, yr, mean\(\pm\)SD		12.16 ± 3.86	12.29 ± 3.43	12.03 ± 4.30	0.759
Clinical information
Prior ECT history, Yes/No		11/69	4/37	7/32	0.387
Current episode duration, weeks, mean\(\pm\)SD		13.71 ± 9.79	13.22 ± 9.26	14.23 ± 10.42	0.647
Prior number of admissions, mean\(\pm\)SD		1.26 ± 2.73	1.32 ± 3.48	1.21 ± 1.66	0.856
ECT information
Frequency
Twice a week/Thrice a week		14/66	7/34	7/32	0.918
RUL/BT		72/8	39/2	33/6	0.150^*
Number of ECT treatments, mean\(\pm\)SD	Total	8.04 ± 3.14	8.32 ± 3.02	7.74 ± 3.28	0.418
	RUL	7.92 ± 3.18	8.23 ± 3.04	7.55 ± 3.35	0.366
	BT	9.13 ± 2.75	10.00 ± 2.83	8.83 ± 2.93	0.737^†
Pulse width, 0.3msec/1.0msec	RUL	34/38	19/20	15/18	0.782
Pulse width, 0.3msec/1.0msec	BT	2/6	0/2	2/4	1.000^*
ECT pulse amplitude, mA		800
IST, mC, mean\(\pm\)SD	RUL	59.64 ± 42.55	60.98 ± 47.76	58.06 ± 36.09	0.774
IST, mC, mean\(\pm\)SD	BT	75.55 ± 33.14	112.00 ± 22.63	63.40 ± 26.96	0.088^†
BMI indicates body mass index; SD, standard deviation; RUL, right unilateral; BT, bitemporal; IST, initial seizure threshold; HDRS-17, 17-item Hamilton Depression Rating Scale; mA, milliampere; mC, millicoulombs. Remitter: Post-ECT HDRS-17 score ≦ 8. Non-remitter: post-ECT HDRS-17 score ≧ 9. ^*: Fisher’s exact test. ^†: Mann-Whitney U test.