Psychological Medicine (2016), 46, 797–806. doi:10.1017/S0033291715002287

© Cambridge University Press 2015

OR I G I N A L A R T I C L E

The acute and medium-term effects of treatment with electroconvulsive therapy on memory in patients with major depressive disorder N. P. Maric1,2*, Z. Stojanovic3, S. Andric1, I. Soldatovic1, M. Dolic3 and Z. Spiric3,4 1

School of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, Serbia Clinic for Psychiatry Clinical Center of Serbia, Pasterova 2, Belgrade, Serbia 3 Clinic for Psychiatry, Military Medical Academy, Belgrade, Serbia 4 Faculty of Medicine of the Military Medical Academy, University of Defense, Belgrade, Serbia 2

Background. Current literature provides insufficient information on the degree of cognitive impairment during and after electroconvulsive therapy (ECT), mostly due to the fact that applied tests lacked sensitivity and flexibility. Our goal was to evaluate cognitive functioning in adult depressed patients treated with bi-temporal ECT, using tests sensitive for detection of possible acute and medium-term memory changes. Method. Thirty adult patients with major depressive disorder, treated with a course of bi-temporal ECT, underwent clinical and cognitive measurements three times: at baseline, immediately after a course of ECT, and 1 month later. For cognition assessment, we used learning and visual, spatial and figural memory tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Results. Bi-temporal ECT has proven to be an effective treatment. The linear mixed model, used to analyze changes in depression severity and patients’ cognitive performances over time and to assess dynamic correlations between aforementioned features, did not show any significant memory impairment as a potential acute or medium-term ECT effect. However, it yielded significant improvement on visual memory and learning at the follow-up, which positively correlated with the improvement of depression. Conclusion. Good progress is being made in the search for ECT-related acute and medium-term cognitive side-effects by using the tests sensitive to detect memory dysfunction with parallel forms of the tasks (to counter practice effects on repeat testing). Our results on learning and memory in relation to ECT during treatment of depression did not bring forth any prolonged and significant bi-temporal ECT-related memory deficit. Received 23 May 2015; Revised 30 September 2015; Accepted 1 October 2015; First published online 23 October 2015 Key words: CANTAB, depression, electroconvulsive therapy, learning, memory.

Introduction The stigmatization of electroconvulsive therapy (ECT) is partially based on beliefs that it has been associated with significant memory impairments (Payne & Prudic, 2009). These beliefs have remained even after ECT protocols were modified from sine-wave into a brief or ultra-brief stimulation, with more favorable profile of the side-effects (Sackeim, 2004). The brief stimulation with the bilateral electrode placement is a currently worldwide-preferred practice, with trend towards a more frequent unilateral stimulation at some European, Australian and New Zealand sites (Leiknes et al. 2012). Despite the longstanding opinion

* Address for correspondence: N. P. Maric, MD, PhD, School of Medicine, University of Belgrade & Clinic for Psychiatry CCS, Pasterova 2, Belgrade 11000, Serbia. (Email: [email protected])

that bilateral stimulation induces more cognitive side effects, recent data from Sienaert et al. (2010) showed that antidepressant efficacy was reached after both unilateral and bilateral stimulation, with no deleterious effects on cognitive function (at least in the case of ultra-brief pulse ECT with bilateral stimulus and a dose slightly above the seizure threshold). In the extensive literature review that included 84 within-subjects designed studies on ECT-related cognitive changes, Semkovska & McLoughlin (2010) found a short-term decrease in cognitive performance immediately after the ECT course, followed by subsequent recovery to the pretreatment functioning levels noticed at follow-up. Nevertheless, the authors concluded that no standardized retrograde amnesia tests were identified by this meta-analysis. We agree with many authors that improved assessment of the degree of cognitive impairment following ECT treatment has to be based on tests with good sensitivity, flexibility and resolution.

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According to Tsaltas et al. (2011), the degree of cognitive impairment residual to ECT cannot be reliably estimated at present, therefore definitive evaluation of ECT-related cognitive deficits calls for further research. Methodology of the research on memory during ECT treatment of depression has to be based on tests sensitive to detect and differentiate frontal from temporal and amygdalo-hyppocampal dysfunctions, with parallel forms of tasks for countering practice effects on repeat testing. By using the Cambridge Neuropsychological Test Automated Battery (CANTAB), the group led by Professor Ian C. Reid (Falconer et al. 2010) has shown for the first time that selected tests from this battery represent an effective measure of ECT-associated memory impairments. Twenty-four severely depressed patients (aged 26–83 years) were examined before and 1 month after ECT (acute and medium-term effects), cognition was tested with an emphasis on visual and visuo-spatial memory (spatial and pattern recognition memory, visual paired associate learning and delayed matching to sample tests). Their results showed that most of the baseline cognitive impairments had disappeared 1 month following ECT, except for the impairment in spatial recognition memory, which remained present at the last follow-up visit (i.e. 1 month later). The authors emphasized that this was among the few studies which have detected anterograde memory deficits in patients with major depressive disorder (MDD) following ECT. Recently, a group from Aberdeen published the following study, based on the 6-month follow-up of a larger group of patients with depression (mean age 61 years). For the neuropsychological assessment, authors used only the Mini Mental State Examination (MMSE) and SRM. Regarding the long-term post-ECT effects, the SRM task revealed reversible cognitive deficiencies (relative to a pre-ECT baseline) for at least 3 months following ECT, while the MMSE score and patients’ subjective reports only improved over time. Thus, the authors concluded that the CANTAB SRM task is sensitive to detect cognitive deficits, unlike the MMSE and patients’ subjective reports (Fernie et al. 2014). However, this field remains under-investigated. Therefore, the goal of the present study was to evaluate cognitive function in adult depressed patients treated with bilateral ECT, by using the MMSE and computerized neuropsychological tests sensitive to detect possible memory changes related to frontal and temporal lobe function before and after the ECT. Furthermore, the authors intended to analyze the correlation between the severity of depression and the cognitive performance. The authors decided to focus on middle-aged patients (65 years and inability to use tests due to poor eyesight. Upon admission, patients were treated with antidepressants in accordance with their doctor’s choice. Alongside antidepressants, most patients were prescribed benzodiazepine, while some of them used mood stabilizers and/or antipsychotic drugs as an augmentation (for more detailed analysis of local and regional prescribing patterns see Jordanova et al. 2011, and Maric et al. 2012). The patients were adherent to the aforementioned medications for at least 1 month before entering the study, and the treatment did not change significantly during the study period (for detailed information concerning patients’ sociodemographic and clinical characteristics see Table 1). The research was performed in compliance with the International Code of Medical Ethics of the World Medical Association (Declaration of Helsinki) and was approved by Institutional Review Board. Informed consent was obtained for all study participants after an explanation of the research procedures. Instruments Clinical scales The Clinical Global Impression Scale (CGI), a wellestablished research rating tool applicable to all psychiatric disorders (Guy, 1976) was used to assess the overall impression. For the purpose of the present study, severity of psychopathology was recorded by using scores ranging from 1 to 7. The intensity of depressive symptoms was evaluated with the Hamilton Rating Scale for Depression (HAMD-21; Hamilton, 1960). Additionally, subjects completed the self-rating Depression Anxiety Stress Scales (DASS; Lovibond & Lovibond, 1995; Jovanovic et al. 2014). The DASS – Depression subscale assesses dysphoria, hopelessness, devaluation of life, self-deprecation, lack of interest or involvement and anhedonia. The DASS – Anxiety subscale assesses autonomic arousal, skeletal muscle effects, situational anxiety and subjective experience of anxious affect. The DASS – Stress subscale

The effects of ECT treatment on memory in patients with MDD 799 Table 1. Demographic and clinical characteristics of the sample N (%) or mean ± S.D. Sex Age Education (years)

IQ Time elapsed from the first depressive episode (years) Medication (yes/no)

Male/female 8–12 12–16 >16

Benzodiazepines Antidepressants Antipsychotics Mood stabilizers

Number of ECT sessions received by the participants

captures feelings of nervous tension, difficulty relaxing and irritability. In accordance with the recommendations of McClintock et al. (2014), both observer-rated and selfrated instruments were used to obtain a sufficiently clear view of the current emotional state. Neuropsychological testing The MMSE is a widely used test for general assessment of cognitive impairment (Pangman et al. 2000). It measures several cognitive domains, including orientation for time, orientation for place, attention and calculation, registration, recall, repetition and ability to follow simple commands. The highest overall score is 30. IQ was assessed by the Wechsler Adult Intelligence Scale – Revised (WAIS-R; Wechsler, 1981). The scale consists of six verbal (Information, Comprehension, Arithmetic, Digit Span, Similarities, Vocabulary) and five performance subtests (Picture Arrangement, Picture Completion, Block Design, Object Assembly, Digit Symbol). A verbal IQ, performance IQ and fullscale IQ were obtained. CANTAB tests The Pattern Recognition Memory (PRM) is a visual memory test, primarily sensitive to dysfunction in the medial temporal brain areas and relatively insensitive to frontal lobe dysfunction. In the first phase of the test, participants need to memorize presented series of 12 colored visual patterns. Afterwards, they are presented with 12 paired new and old patterns and are required to identify the pattern they have already seen during the presentation phase. The mean percentage of correct answers served as the main outcome parameter. The Delayed Matching to Sample (DMS) test is primarily sensitive to impairments in the medial temporal

13 (43.3)/17 (56.7) 47.3 ± 10.3 6 (20.1) 16 (53.3) 8 (26.6) 97.8 ± 11.9 7.8 ± 6.0 26 (86.7)/4 (13.3) 30 (100)/0 (0) 22 (73.3)/8 (26.7) 18 (60.0)/12 (40.0) 9.6 ± 3.8

lobe area, with some input from the frontal lobe. The participants are presented with one target (complex visual pattern) and four different patterns simultaneously or 0, 4 and 12 s after the target presentation. Afterwards, the participants are required to identify the pattern which exactly matches the target. The main performance indications were mean percentages of correct answers in all time intervals. The Paired Associates Learning (PAL) test assesses visual memory and new learning. The test is primarily sensitive to changes in the medial temporal lobe functioning. The participants are presented with randomly opened boxes, of which one or more contain a pattern. Afterwards, the patterns are one by one displayed in the middle of the screen and participants are required to identify the box where the pattern was originally located. As the task progresses, the number of patterns is gradually increasing up to eight. The total number of errors served as a main outcome parameter. The Spatial Recognition Memory (SRM) test is primarily sensitive to dysfunction in the frontal lobe, and relatively insensitive to the temporal lobe damage. In the first phase of the test, a white square is displayed at five different locations on the screen and participants are required to memorize the locations on the screen. Afterwards, participants are presented with a series of five pairs of squares and they have to choose the square which was presented to them previously, in the presentation phase. The mean percentage of correct answers was used as outcome parameter for this test.

Procedure Ratings for clinical scales, as well as neuropsychological testing, were made at three time points: Baseline (T0), 1–3 days before ECT; Post-ECT (T1), 1 day after

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the final ECT application; Follow-up (T2), 4 weeks after the final treatment. Testing was completed within approximately 60 min. The multi-domain cognitive assessment was feasible and well-tolerated. Description of the ECT intervention Similarly to most sites worldwide (Leiknes et al. 2012), our site has been using bilateral (bi-temporal) ECT for all patients referred to our specialized unit. Bilateral ECT has been chosen for several reasons. Previous data has shown reduced efficiency of unilateral v. bilateral electrode placement during ECT in depression (most recent analysis was published by McCormick et al. 2009). Moreover, patients referred for ECT course are all in-patients with high hospital costs and limited length of stay. Thus, following risks and benefits calculation, a consensus was made that bilateral ECT should be the first line choice of electrode placement and patients were treated accordingly. In line with the local guidelines, pre-treatment investigations included: blood test, hepatic and renal function tests, ECG, EEG and medical, neurological and ophthalmological consultation. All patients were required to sign a separate informed consent forms for ECT and anesthesia. The ECT was administered three times a week. In all cases and all sessions, the Thymatron System IV machine and brief pulses (0.5 ms pulsewidth) with bilateral (bi-temporal) electrode placement and atropine premedication (dose 0.5 mg) were used. Anesthesia was induced with propofol (2–2.5 mg/kg) combined with the muscle relaxant succinylcholine (1 mg/kg). (For detailed description on ECT practice in Serbia, see Spiric et al. 2014.) For the first treatment, stimulus dose was based on the ‘half-age’ method (Petrides & Fink, 1996), with pulse amplitude of 900 mA during the therapy. The first and the final delivered treatment charges were 140.26 ± 45.23 and 227.15 ± 38.07 mC (1.6 first stimulus dose), respectively. The first and the last stimulus durations were 6.2 ± 0.6 and 7.6 ± 0.3 s, respectively. The minimum seizure duration of 20 s was considered acceptable. Statistical analyses The data were analyzed using SPSS v. 20.0 (IBM Corp., USA) statistical software. Socio-demographic and clinical data were displayed using absolute and relative numbers, mean and standard deviation (S.D.). Neurocognitive data were presented as mean ± standard error (S.E.). Initially, all data were tested for normality, and some of them (i.e. total DASS score, DASS Depression subscale) were log-transformed prior to analysis in order to address skewed data. Linear mixed model was used to analyze changes in depressive symptom severity and patients’ cognitive

performances over time, and to assess dynamic correlations between aforementioned features. Age and gender (random effects) adjustment was applied, when applicable. An overall test of the fixed effect for the examined time points was obtained, along with the pairwise comparisons of interest (the comparison of the baseline scores with the scores obtained at T1 and T2). A mixed model was used for analysis, as it exhibited a number of advantages when repeated measurements on the same subject were performed, had great flexibility to model time effects, and adequately handled missing data. Effect size (ES) was measured using Cohen’s d (repeated measurements). Baseline and the last observation score were used to calculate ES. In order to constrain the risk of type I error, Bonferroni correction was applied. After applying the correction for multiple comparisons (two pairwise comparisons), p level was set at 0.025.

Results Severity of depression Severity of depressive symptoms, as measured by both clinician-rated and self-rated instruments, was significantly reduced over time (F2,50.48 = 134.73, p < 0.01, Cohen’s d = 2.92). When compared to the baseline (T0), HAMD scores were significantly reduced at T1 (mean difference −13.37, S.E. = 0.87, df = 47.31, p < 0.01, 95% CI −15.39 to −11.34) and T2 (mean difference 14.99, S.E. = 1.09, df = 75.75, p < 0.01, 95% CI −17.49 to −12.50). Similarly, significant decrease in DASS scores was also observed throughout time (total DASS score: F2,53.31 = 47.91, p < 0.01, Cohen’s d = 1.93; DASS subscales – Depression: F2,28.26 = 44.38, p < 0.01, Cohen’s d = 2.37; Anxiety: F2,27.71 = 44.19, p < 0.01, Cohen’s d = 1.54; Stress: F2,27.25 = 34.31, p < 0.01, Cohen’s d = 1.41). Continuous decline in DASS scores was evident at T1 (total DASS score: mean difference −0.31, S.E. = 0.04, df = 50.67, p < 0.01, 95% CI −0.39 to −0.23; DASS subscales – Depression: mean difference −0.32, S.E. = 0.04, df = 29.00, p < 0.01, 95% CI −0.41 to −0.24; Anxiety: mean difference −0.35, S.E. = 0.05, df = 29.00, p < 0.01, 95% CI −0.45 to −0.24; Stress: mean difference −14.23, S.E. = 1.82, df = 29.00, p < 0.01, 95% CI −18.53 to −9.93) as well as at T2 (total DASS score: mean difference −0.41, S.E. = 0.05, df = 75.36, p < 0.01, 95% CI −0.51 to −0.30; DASS subscales – Depression: mean difference −0.45, S.E. = 0.06, df = 28.77, p < 0.01, 95% CI −0.59 to −0.31; Anxiety: mean difference −0.47, S.E. = 0.06, df = 27.38, p < 0.01, 95% CI −0.62 to −0.32; Stress: mean difference 14.48, S.E. = 2.13, df = 27.67, p < 0.01, 95% CI −19.54 to −9.42) in comparison to T0 (see Fig. 1).

The effects of ECT treatment on memory in patients with MDD 801

Fig. 1. Depressive symptom severity and CANTAB tests performance trajectory. HAMD, Hamilton Rating Scale for Depression; DASS-D, Depression subscale of the Depression Anxiety Stress Scales; SRM, Spatial Recognition Memory task; DMS, Delayed Matching to Sample task; PAL, Paired Associates Learning task; T0, baseline, before ECT; T1, 1 day after the final ECT; T2, 1 month after the final treatment.

Clinical global impression was significantly improved over the course of time (F2,27.77 = 105.07, p < 0.01, Cohen’s d = 2.88) pointing to a satisfactory response to the treatment. CGI scores were significantly lower at T1 (mean difference −1.97, S.E. = 0.15, df = 29.00, p < 0.01, 95% CI −2.32 to −1.62) and T2 (mean difference −2.55, S.E. = 0.20, df = 28.02, p < 0.01, 95% CI −3.03 to 2.08) compared to T0. Cognition MMSE The MMSE scores varied significantly across the examined time points (F2,27.01 = 9.14, p < 0.01, Cohen’s d = 1.01). More precisely, when compared to T0, general cognition improved at T1 (mean difference 0.80, S.E. = 0.19, df = 29.00, p < 0.01, 95% CI 0.35–1.24) and T2 (mean difference 0.84, S.E. = 0.20, df = 29.08, p < 0.01, 95% CI 0.38–1.31). Nevertheless, clinical importance of that finding is questionable, since the size of the change was within one unit of the scale (see Table 2). CANTAB tests Visual, spatial and figural memory The mixed model showed no significant difference in SRM (F2,53.64 = 2.69, p = 0.08) nor PRM (F2,51.39 = 0.08,

p = 0.92) across the examined time points (see Table 3), suggesting that participants’ visuo-spatial memory did not differ across the treatment period. Likewise, patients’ delayed matching to sample scores did not differ between baseline, 1 day after the final ECT application and 4 weeks following the treatment completion (F2,55.22 = 1.44, p = 0.25). On the other side, we found a statistically significant difference in the simultaneous matching to sample over time (F2,28.82 = 5.16, p = 0.01, Cohen’s d = 0.51), but this finding lacked clinical importance since there was no difference between T0 and T2. Initial improvement in simultaneous matching observed at T1 returned to baseline values at T2 (see Table 3).

Visual memory and learning There was a significant difference in the total number of errors in PAL task throughout the examined time period (F2,26.51 = 3.90, p = 0.03, Cohen’s d = 2.46). More precisely, significant reduction of total errors in PAL was observed between T0 and T2 (mean difference −0.21, S.E. = 0.08, df = 25.23, p = 0.03, 95% CI −0.41 to −0.02), while there was no significant difference between T0 and T1. Patients’ intermediate achievement in PAL at T1 was suggestive of a gradual improvement in learning ability over time (see Fig. 1).

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Table 2. The clinical assessment Measure

T0 (n = 30)a

T1 (n = 30)b

T2 (n = 26)c

p

CGI HAMD DASS Total score Depression Anxiety Stress MMSE

5.57 ± 0.50 28.40 ± 3.65

3.60 ± 0.77 15.03 ± 3.17

2.88 ± 1.11 13.31 ± 6.27

The acute and medium-term effects of treatment with electroconvulsive therapy on memory in patients with major depressive disorder.

Current literature provides insufficient information on the degree of cognitive impairment during and after electroconvulsive therapy (ECT), mostly du...
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