Objective Cognitive Performance Associated with Electroconvulsive Therapy for Depression: A Systematic Review and Meta-Analysis

Objective Cognitive Performance Associated with Electroconvulsive Therapy for Depression: A Systematic Review and Meta-Analysis Maria Semkovska and Declan M. McLoughlin Background: Electroconvulsive therapy (ECT) is the most acutely effective treatment for depression, but is limited by cognitive side effects. However, research on their persistence, severity, and pattern is inconsistent. We aimed to quantify ECT-associated cognitive changes, specify their pattern, and determine progression. Methods: MEDLINE, EMBASE, PsycArticles, PsychINFO, PsychLIT, and reference lists were systematically searched through January 2009. We included all independent, within-subjects design studies of depressed patients receiving ECT where cognition was assessed using standardized tests. Main outcome was change in performance after ECT relative to pretreatment scores with respect to delay between finishing ECT and cognitive testing. We explored potential moderators’ influence, e.g., electrode placement, stimulus waveform. Results: Twenty-four cognitive variables (84 studies, 2981 patients) were meta-analyzed. No standardized retrograde amnesia tests were identified. Significant decreases in cognitive performance were observed 0 to 3 days after ECT in 72% of variables: effect sizes (ES) ranging from ⫺1.10 (95% confidence interval [CI], ⫺1.53 to ⫺.67) to ⫺.21 (95% CI, ⫺.40 to .01). Four to 15 days post-ECT, all but one CI included zero or showed positive ES. No negative ES were observed after 15 days, with 57% of variables showing positive ES, ranging from .35 (95% CI, .07–.63) to .75 (95% CI, .43–1.08). Moderators did not influence cognitive outcomes after 3 days post-ECT. Conclusions: Cognitive abnormalities associated with ECT are mainly limited to the first 3 days posttreatment. Pretreatment functioning levels are subsequently recovered. After 15 days, processing speed, working memory, anterograde memory, and some aspects of executive function improve beyond baseline levels. Key Words: Cognition, depression, electroconvulsive therapy, memory, meta-analysis, standardized assessment lectroconvulsive therapy (ECT) is the most acutely effective treatment for depression (1). About 100,000 US patients annually receive ECT and 1 million worldwide (2, p.14). However, cognitive impairment is the most significant side effect limiting use (3, p.66). Acute disorientation following individual treatments is well documented but usually brief (4,5). Conversely, extent of short-term and long-term cognitive deficits remains controversial. Current research regarding persistence, severity, and precise pattern is inconsistent. For example, 7 to 8 days after a course of brief-pulse bilateral ECT, memory function relative to pretreatment assessment has been described as impaired (6,7), recovered (8,9), or improved (10,11). Regarding long-term side effects, descriptive reviews agree that after 6 months no deficits persist (4,12); no significant differences are noted between real or simulated ECT, between outmoded sine-wave ECT or contemporary brief-pulse ECT (1), or between ECT or pharmacotherapy (4). However, such conclusions have partial generalizability, as these reviews limited discussion of long-term cognitive effects to just one to two studies. According to a recent systematic review, differences in ECT modalities may explain variations in cognitive impairment, with bilateral ECT producing greater deficits than unilateral, treatment thrice

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From the Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, St. Patrick’s University Hospital, Dublin, Ireland. Address correspondence to Declan M. McLoughlin, Ph.D., Trinity College Dublin, St. Patrick’s University Hospital, Department of Psychiatry, James’s Street, Dublin 8, Ireland; E-mail: [email protected]. Received Feb 26, 2010; revised Jun 4, 2010; accepted Jun 4, 2010.

0006-3223/$36.00 doi:10.1016/j.biopsych.2010.06.009

weekly more than twice weekly, and high-dose more than low-dose ECT (1). Nonetheless, these data have not been systematically analyzed to provide clearer evidence about patterns of cognitive dysfunction and progression following ECT. Indeed, consensus regarding memory following ECT lacks specificity. Distinctions between encoding, learning, retention, and retrieval are rarely addressed, while results from verbal and nonverbal tasks are often amalgamated (12–14). Results derived from objective and subjective assessments have also been jointly reviewed (1) despite consistent demonstration of a poor relationship between self-reported and objectively measured neurocognitive performance in depression (15–17). Discrepancies in reviewing methodology, as well as descriptive rather than quantifying approaches, could account for heterogeneous conclusions regarding cognitive outcomes of ECT. The aims of this meta-analysis are to systematically review cognitive impairments following ECT and provide quantitative estimates of extent; determine pattern of ECT-associated cognitive dysfunctions and posttreatment resolution; and examine contribution of moderator variables.

Methods and Materials Methodology used follows Meta-Analysis of Observational Studies in Epidemiology guidelines (18). Search Strategy and Selection Criteria We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, PsycArticles, PsychINFO, and PsychLIT from commencement to January 2009, using search terms ECT or electroconvulsive therapy and cognitive, neuropsychology, neuropsychological, memory, attention, executive, spatial, or intellectual. References from reviews and relevant articles were searched for additional studies. Only published reports, including non-English language ones, were searched. BIOL PSYCHIATRY 2010;68:568 –577 © 2010 Society of Biological Psychiatry

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M. Semkovska and D.M. McLoughlin Study inclusion criteria were: 1. Independent sample(s) of subjects ⱖ 18 years diagnosed with major depressive episode (DSM-III, DSM-III-R, DSM-IV, ICD-9, or ICD-10); primary depression according to research diagnostic criteria (19); or for studies before 1980, an operationalized definition of endogenous/primary depressive symptoms without comorbidities, e.g., schizophrenia, mania, and dementia. From studies comparing several diagnostic groups, only depression samples were included. 2. Used at least one cognitive test with results reported as means (SD) or means and t statistic for significance of difference according to within-subjects research design: cognitive data should have been collected at baseline and at least one posttreatment assessment point on the same test(s) used at baseline. Studies that collected only post-ECT measures were therefore excluded. 3. Used standardized cognitive test(s) with established reliability and ecological validity. Only studies that used alternative versions for tests subject to practice effect were included. 4. Provided quantitative information regarding time delay between final ECT and post-ECT assessment. 5. Electrode placement details must be provided: bitemporal, unilateral, or mixed (e.g., switched unilateral to bitemporal ECT). Only studies using bitemporal, right unilateral d’Elia, or Lancaster positions were included. To maintain statistical independence of effect sizes, studies were defined as published reports with no obvious sample and test redundancy with other reports. When redundancy was obvious, the most recent report with the largest sample size was coded. Case reports and self-reported measures were excluded. Data Extraction and Recorded Variables Articles were reviewed and data extracted and cross-checked independently by both authors. Disagreements were resolved by consensus. When reported results were insufficiently detailed but studies fulfilled remaining inclusion criteria, corresponding authors were contacted for missing information and re-contacted if necessary. Cognitive tests were included if they appeared in at least three studies. Different tests assessing same function using same methodology were pooled, e.g., outcomes from all word list learning tests were jointly meta-analyzed. From each study, the following variables were coded for each independent sample in standard fashion: number of participants at each assessment point; diagnosis; cognitive tests used; results for calculating standardized mean pre-ECT and post-ECT differences for each cognitive variable; and delay between final ECT and test administration. To explore effects of potential moderators on cognitive outcomes, when available, the following variables were extracted: age; electrode placement; mean number of ECT sessions; weekly ECT frequency; mean electrical charge dose; and stimulus waveform. Statistical Analysis Analyses were done with SPSS (v15.0; SPSS Inc., Chicago, Illinois). Effect sizes (ES) were computed for each cognitive variable using Cohen’s d index of individual effect: di ⫽ (M2i ⫺ M1i)/SDpi, where d is effect size, i individual sample, M1i pretreatment mean, M2i posttreatment mean, and SDpi pooled standard deviation. Pooled SD was calculated by summing pretreatment and posttreatment SD and dividing by 2. Rarely, where both SD were unreported but means and t statistic were available, pooled SD was calculated using the following formula: t ⫽ (M2i ⫺ M1i)/SDpi✓(1/Ni1) ⫹ (1/Ni2).

Positive ES indicates posttreatment performance was superior to pretreatment performance. Speed and error cognitive variables were recoded to parallel that concept, as higher scores indicate poorer performance, i.e., individual effect was equal to ⫺di. To explore cognitive outcome progression over time, samples derived from all studies were subdivided into three groups with respect to interval between final ECT and post-ECT cognitive testing (4): subacute (delay 0 –3 days); short-term (4 –15 days); and long-term outcomes (⬎15 days). When insufficient samples were available during one time interval, results were pooled with those of the next interval containing enough samples. Effect sizes were adjusted for small sample bias and weighted and pooled by use of Cooper and Hedges (20) fixed-effects model a priori to maximize statistical power because each analysis was applied on an individual uniform cognitive variable. Homogeneity of each weighted average ES was tested with Q statistic (20). As Q has ␹2 distribution, one-sided p value ⱕ .01 was considered significant. When significant heterogeneity was found, we investigated ability of each moderator to explain variability using between-groups homogeneity, Qb for categorical moderators (electrode placement, stimulus waveform, ECT frequency), and fixed-model regression for continuous variables (age, number of ECT sessions, stimulus dose). Weighted average ES were interpreted according to Cohen’s recommended cutoffs of 1.30, .80, .50, and .20 for very large, large, medium, and small ES, respectively (21). When outcomes included data from ⱖ10 samples, funnel graphs (ES vs. study size) were used for visual assessment of publication bias. File drawer analyses were performed to investigate likelihood of unpublished studies negating findings from published studies (22).

Results After deleting duplicates, the search strategy identified 1525 citations from which 84 studies (2981 participants) were metaanalyzed. Eighty-two studies were published in English, one in French, and one in Dutch. We received additional information from authors of 13 studies; authors cited “data no longer available” as the main reason for not providing requested information. Review process is summarized in Figure S1 in Supplement 1. Twenty-two standardized neuropsychological tests were identified (Table 1) (for normative, reliability, and validity data, see [23,24]). For each study and included subsamples, all pre-ECT and post-ECT cognitive results plus information regarding coded variables are in Table S1 in Supplement 1. Some tests provided more than one cognitive variable, e.g., most memory tests produced both learning and delayed recall variables. Outcomes were organized into 24 cognitive variables, each independently meta-analyzed. For clarity, results are presented according to eight familiar cognitive domains (Table 1). Tables 2, 3, and 4 summarize the findings. No retrograde memory tasks were retained for meta-analysis, mainly because of pretreatment data absence (e.g., [25]), using nonstandardized tests lacking normative data, established reliability and validity (e.g., [9]), or data unavailability (e.g., [26]). We also identified three studies that used a standardized test of motor function, the Finger Tapping Test (27–29), but could not meta-analyze results, as they used different scoring systems. They all tested patients during the week following final treatment, used sine-wave ECT, and found significant improvement in motor speed. Global Cognitive Status One variable was identified from one test of the same name used for global cognitive status screening (Mini-Mental State Examwww.sobp.org/journal

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Table 1. Cognitive Variables Selected for Meta-Analysis Cognitive Domain Cognitive Status Screening Processing Speed Attention/Working Memory

Verbal Episodic Memory

Visual Episodic Memory

Spatial Problem Solving Executive Functioning

Intellectual Ability

Cognitive Variables

n

k

N

MMSE

30

47

1199

Digit symbol Trail Making Test A (time) Digit span forward Digit span backward Digit span total Mental control Spatial span Word list learning (pooled results from BSRT, RAVLT, CVLT, and HVLT) Word list delayed recall (pooled results from BSRT, RAVLT, CVLT, and HVLT) Story memory immediate recall (pooled results from logical memory and Randt short story) Story memory delayed recall (pooled results from logical memory and Randt short story) Verbal paired associates learning (pooled results from verbal paired associates and Randt paired words) Verbal paired associates delayed recall (pooled results from verbal paired associates and Randt paired words) Figure reproduction immediate recall (pooled results from ROCF, visual reproduction, and Benton Visual Retention Test) Figure reproduction delayed recall (pooled results from ROCF and visual reproduction) Design copy (pooled results from block design and ROCF copy) Trail Making Test B (time) Stroop Color-Word condition (time) Stroop Color-Word condition (errors) Semantic Fluency Letter Fluency Vocabulary IQ index

11 8 13 12 16 4 3 17 13

14 10 21 16 23 5 3 25 21

269 172 435 302 387 78 53 518 500

17

28

457

11

17

374

17

28

465

9

12

255

13

22

415

14

23

599

7 6 8 4 11 14 3 3

11 11 10 6 19 20 5 5

276 134 135 71 322 446 64 59

Cognitive variables were derived from the following tests: Mini-Mental State Examination; vocabulary, digit symbol, block design, and digit span subtests from the Wechsler Adult Intelligence Scale; mental control, spatial span, logical memory, verbal paired associates, and visual reproduction subtests from the Wechsler Memory Scale; Trail Making Test; Stroop Color-Word Test; Buschke Selective Reminding Test; Rey-Osterrieth Auditory Verbal Learning Test; California Verbal Learning Test; Hopkins Verbal Learning Test; Randt short story and Randt paired words subtests from the Randt Memory Tests; Rey-Osterrieth Complex Figure; Benton Visual Retention Test; Semantic Fluency and Letter Fluency (23,24). BSRT, Buschke Selective Reminding Test; CVLT, California Verbal Learning Test; HVLT, Hopkins Verbal Learning Test; k, number of samples; MMSE, Mini-Mental State Examination; n, number of studies; N, number of participants; RAVLT, Rey-Osterrieth Auditory Verbal Learning Test; ROCF, Rey-Osterrieth Complex Figure.

ination [MMSE]). Compared with baseline, results showed small subacute impairment and recovery of pretreatment scores during the short-term period. Regarding long-term outcomes, medium, homogeneous, improvement was observed. Processing Speed We identified two variables from two tests of processing speed (digit symbol, Trail Making Test Part A). Data were homogeneous at all time points for digit symbol. Compared with baseline, mean ES showed small subacute impairment, recovery of pretreatment scores during the following 2 weeks, and small long-term improvement. Studies using Trail Making Test Part A during subacute and short-term periods failed to demonstrate significant change compared with baseline. Regarding long-term outcomes, small improvement relative to baseline was observed. Attention/Working Memory Five variables derived from three tests (digit span, mental control, and spatial span) were identified. Digit span forward and digit www.sobp.org/journal

span backward were analyzed separately, as they measure different functions—attention efficiency (freedom from distractibility) and working memory (mental manipulation of items in short-term memory), respectively (23). They are consistently differentiated in meta-analytical research on depression (30 –32). However, as several studies reported only total score, which is a standardized measure, digit span total variable was also meta-analyzed. Small improvement from baseline was observed on digit span backward at long-term follow-ups. All other digit span results were comparable with pretreatment performance at all three time intervals. Small improvement relative to baseline was observed on mental control variable at both short-term and long-term follow-ups. Mean short-term outcome in spatial span following ECT was not significantly different from baseline. Verbal Episodic Memory Selected studies contained data for six variables derived from eight tests exploring different aspects of verbal memory. Tests were organized into three groups—word lists, story memory, and verbal

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Table 2. Subacute Effects: Meta-Analyses of Standardized Change in Cognitive Variables from Pretreatment at 0 to 3 Days Posttreatment 95% Confidence Interval Cognitive Variables

n

k

N

ES

Lower

Upper

p Value

Q

MMSE Digit Symbol Trail Making Test A (Time) Digit Span Forward Digit Span Backward Digit Span Total Mental Control Spatial Span Word List Learning Word List Delayed Recall Story Memory Immediate Recall Story Memory Delayed Recall Verbal Paired Associates Learning Verbal Paired Associates Delayed Recall Figure Reproduction Immediate Recall Figure Reproduction Delayed Recall Design Copy Trail Making Test B (Time) Stroop Color-Word Condition (Time) Stroop Color-Word Condition (Errors) Semantic Fluency Letter Fluency Vocabulary

16 4 3 9 7 7 0 1 12 8 8 8 8 4 4 10 5 2 2 0 5 9 1

27 5 4 15 9 11 0 1b 19 12 13 13 12 5 6 15 8 4 2 0 8 13 1

810 91 55 335 193 231

⫺.28 ⫺.35 .33 .11 ⫺.11 .14

⫺.38 ⫺.64 ⫺.07 ⫺.05 ⫺.31 ⫺.04

⫺.18 ⫺.05 .72 .26 .09 .33

⬍.001 .018 .094 .163 .278 .136

67.61a 3.04 19.38a 20.82 9.27 7.87

436 334 262 293 248 127 205 451 237 50

⫺.66 ⫺1.12 ⫺.04 ⫺.45 ⫺.57 ⫺.69 ⫺.21 ⫺.60 ⫺.27 ⫺1.10

⫺.80 ⫺1.29 ⫺.21 ⫺.61 ⫺.75 ⫺.95 ⫺.40 ⫺.74 ⫺.46 ⫺1.53

⫺.52 ⫺.95 .13 ⫺.28 ⫺.39 ⫺.43 ⫺.01 ⫺.46 ⫺.09 ⫺.67

⬍.001 ⬍.001 .643 ⬍.001 ⬍.001 ⬍.001 .034 ⬍.001 .004 ⬍.001

70.48a 80.69a 15.32 11.97 30.07a 10.22 3.37 122.13a 15.74 6.61

157 379

⫺.71 ⫺.79

⫺.94 ⫺.96

⫺.48 ⫺.63

⬍.001 ⬍.001

16.46 25.15

ES, effect sizes; k, number of samples; MMSE, Mini-Mental State Examination; n, number of studies; N, number of participants. a p ⬍ .01. b Sample pooled with short-term effects.

paired associates—with each group providing two variables: immediate and delayed recall of learned material. In one study investigating effects of different anesthetics (33), subacute data from one sample (receiving propofol) were excluded as obvious outliers with ES of 6.87 SD below mean ES for word list learning (estimated effect ⫺5.56%, 95% confidence interval [CI] ⫺8.23 to ⫺2.88) and 6.02 SD below mean ES for word list delayed recall (estimated effect ⫺6.35%, 95% CI ⫺8.04 to ⫺4.67). All but one variable showed small to large subacute impairment in verbal memory relative to baseline. Half the variables failed to detect significant differences relative to pretreatment scores during short-term period, while medium improvement in story memory immediate recall was detected. Small impairment in verbal paired associates delayed recall was still observed 4 to 5 days after final ECT. There were insufficient studies for story memory delayed recall variable to be subdivided into short-term and long-term outcomes. Results of five samples providing data for those two periods were therefore meta-analyzed together and showed homogeneous medium improvement in story memory delayed recall relative to baseline when tested 4 days to 6 months after final ECT. Studies providing long-term data showed either small-medium improvement or comparable with pretreatment levels of functioning. Visual Episodic Memory Two variables from three tests measuring ability to learn visual information were identified. Immediate and delayed recalls were grouped, respectively, into figure reproduction immediate and delayed recall variables. Compared with baseline, mean ES for figure reproduction immediate recall showed small subacute impairment with small im-

provements at both short-term and long-term follow-ups. For figure reproduction delayed recall, results showed medium subacute impairment, recovery of pretreatment scores during short-term period, and a medium long-term improvement. Spatial Problem Solving We identified one variable, design copy, derived from two tests measuring visuospatial graphic abilities and problem solving— block design and Rey-Osterrieth Complex Figure Test. Small subacute impairment in performance relative to baseline followed by recovery of pretreatment levels during the long-term period was observed. Executive Functioning The selected studies contained data for five variables from four tests considered sensitive to executive functioning: Trail Making Test Part B for set-shifting abilities; Stroop Color-Word condition for mental flexibility with respect to speed and quality of performance; and Semantic Fluency and Letter Fluency for ability to organize thinking (23). Among studies providing subacute data, the same sample from the study described above (33) was excluded as an obvious outlier with ES at 8.86 SD below mean ES for semantic fluency variable (estimated effect ⫺5.28%, 95% CI ⫺7.76 to ⫺2.81) and at 8.41 SD below mean ES for letter fluency variable (estimated effect ⫺4.2%, 95% CI ⫺10.14 to 1.74). Mean ES showed medium-large subacute impairments with recovery of baseline performance levels during short-term follow-up on all executive functioning variables. Small-medium improvements, or baseline levels, were observed at long-term reassessments. www.sobp.org/journal

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Table 3. Short-Term Effects: Meta-Analyses of Standardized Change in Cognitive Variables from Pretreatment at 4 to 15 Days Posttreatment 95% Confidence Interval Cognitive Variables

n

k

N

ES

Lower

Upper

p Value

Q

MMSE Digit Symbol Trail Making Test A (Time) Digit Span Forward Digit Span Backward Digit Span Total Mental Control Spatial Span Word List Learning Word List Delayed Recall Story Memory Immediate Recall Story Memory Delayed Recall Verbal Paired Associates Learning Verbal Paired Associates Delayed Recall Figure Reproduction Immediate Recall Figure Reproduction Delayed Recall Design Copy Trail Making Test B (Time) Stroop Color-Word Condition (Time) Stroop Color-Word Condition (Errors) Semantic Fluency Letter Fluency Vocabulary

11 6 4 3 4 8 3 3 6 7 9 5 8 4 8 5 1 3 6 4 6 5 1

17 8 5 6 7 11 3 3b 6 11 14 5c 12 6 14 10 1d 4 8 6 9 6 1d

306 158 97 90 99 136 49 53 74 228 176 85 188 120 179 207

.46 .14 ⫺.06 .11 .08 .15 .45 .15 .15 .10 .51 .61 .02 ⫺.36 .28 .04

.30 ⫺.08 ⫺.34 ⫺.18 ⫺.20 ⫺.09 .04 ⫺.23 ⫺.18 ⫺.08 .29 .25 ⫺.19 ⫺.62 .07 ⫺.16

.62 .36 .22 .41 .36 .39 .85 .53 .47 .29 .72 .97 .22 ⫺.10 .49 .23

⬍.001 .209 .671 .459 .571 .216 .025 .428 .358 .287 ⬍.001 .001 .847 .006 .009 .686

55.18a 3.75 .61 .68 7.19 2.66 .25 .51 5.59 12.17 27.97a 8.24 12.56 9.61 5.89 21.62

40 95 71 137 109

.10 .28 .06 ⫺.06 ⫺.07

⫺.34 ⫺.01 ⫺.28 ⫺.30 ⫺.34

.54 .56 .40 .18 .19

.646 .051 .725 .621 .601

2.40 4.04 8.13 5.79 .88

ES, effect sizes; k, number of samples; MMSE, Mini-Mental State Examination; n, number of studies; N, number of participants. a p ⬍ .01. b Includes sample from subacute effects. c Includes two samples from long-term effects. d Sample pooled with long-term effects.

Intellectual Ability We identified two variables generally used to estimate intellectual ability—vocabulary subtest and intellectual quotient index, both from the Wechsler Adult Intelligence Scale. Three studies that assessed intellectual quotient index were meta-analyzed together, as insufficient samples were available to test ES separately with respect to individual time intervals. Mean weighted ES was ⫺.11, with 95% CI ⫺.39 to .17 with nonsignificant Q statistic (1.43, p ⫽ .98). At long-term follow-ups, vocabulary was also comparable with baseline performance. Moderators Most variables showed homogeneous ES, suggesting that once sampling error was removed, no substantive differences remained between studies contributing to weighted mean ES. Heterogeneity in variables assessing cognitive change was concentrated in subacute outcomes (0 –3 days post-ECT) with 6 of 18 variables having significant Q statistics (Table 2). Only 2 of 21 variables showed evidence for heterogeneity at short-term and long-term periods (Tables 3 and 4). Overall, heterogeneous results were found in memory variables, global cognition (MMSE), and processing speed (Trail Making Test Part A). Tables 5 and 6 show influence of potential moderator categorical variables. Electrode placement affected cognitive performance in three of six heterogeneous subacute variables with bitemporal placement associated with significantly more impairment (large to very large ES) than unilateral placement (small to large ES) (Table 5). Interestingly, bitemporal ECT was associated with significantly greater imwww.sobp.org/journal

provement in MMSE (medium ES) from baseline than unilateral ECT at short-term follow-ups and also with improved digit span backward (medium ES) in long-term period. For stimulus waveform, there were insufficient data to compare brief-pulse with sine-wave for 5 of 10 heterogeneous variables. Therefore, for these variables, we analyzed only studies reporting results with brief-pulse ECT. Regarding subacute and short-term changes in MMSE, ES remained heterogeneous with Q statistics of, respectively, 66.40 for 26 samples and 54.58 for 14 samples. Heterogeneity remained also for subacute outcomes on word list learning—Q ⫽ 66.07 for 17 samples. When the unique sample receiving sine-wave ECT was removed from meta-analysis of subacute change in Trail Making Test Part A, mean ES for brief-pulse studies showed comparable with baseline— estimated ES of ⫺.04 (95% CI: ⫺.47 to .39) with a nonsignificant Q statistic (1.50, p ⫽ .47). When comparing brief-pulse with sine-wave was possible (Table 6), stimulus waveform reduced heterogeneity only in two subacute variables: brief-pulse was associated with significantly more impairment (very large ES) in word list delayed recall than found in the single study using sine-wave (nonsignificant ES); and sine-wave was associated with more impairment (large ES) in figure reproduction delayed recall than brief-pulse (medium ES). Frequency of administration contributed significantly in explaining heterogeneity of only one primary outcome result. Patients receiving ECT twice weekly showed significantly greater short-term improvement in global cognitive status (medium ES) than did patients receiving ECT thrice weekly (small ES).

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Table 4. Long-Term Effects: Meta-Analyses of Standardized Change in Cognitive Variables from Pretreatment at More Than 15 Days Posttreatment 95% Confidence Interval Cognitive Variables MMSE Digit Symbol Trail Making Test A (Time) Digit Span Forward Digit Span Backward Digit Span Total Mental Control Spatial Span Word List Learning Word List Delayed Recall Story Memory Immediate Recall Story Memory Delayed Recall Verbal Paired Associates Learning Verbal Paired Associates Delayed Recall Figure Reproduction Immediate Recall Figure Reproduction Delayed Recall Design Copy Trail Making Test B (Time) Stroop Color-Word Condition (Time) Stroop Color-Word Condition (Errors) Semantic Fluency Letter Fluency Vocabulary

Delay (In Days)

n

k

N

ES

Lower

Upper

p Value

Q

28–365 30–730 183–730 28–365 28–91 21–365 21–365

9 7 3 6 6 5 3 0 4 4 6 2 5 3 5 2 2 2 3 2 6 4 3

10 10 4 9 9 9 4 0 6 6 10 2b 9 4 12 4 4c 3 5 4 10 5 5c

236 173 87 141 145 127 71

.51 .40 .37 .08 .37 .24 .45

.33 .18 .06 ⫺.15 .13 ⫺.01 .11

.70 .61 .69 .32 .60 .49 .78

⬍.001 ⬍.001 .020 .501 .002 .057 .007

10.04 5.83 25.89a 9.98 22.09a 10.37 .22

80 115 156

.40 .35 .50

.09 .07 .27

.71 .63 .73

.010 .013 ⬍.001

1.26 13.76 15.24

137 41 181 75 54 46 78 66 169 95 64

.22 .18 .45 .62 .02 .46 .75 .33 .17 .11 .004

⫺.02 ⫺.25 .24 .29 ⫺.36 .04 .43 ⫺.02 ⫺.05 ⫺.18 ⫺.34

.46 .62 .66 .95 .39 .88 1.08 .67 .38 .39 .35

.070 .403 ⬍.001 ⬍.001 .915 .027 ⬍.001 .056 .119 .443 .982

4.69 .88 8.11 2.37 .21 5.23 2.15 2.26 7.41 5.74 .53

30–365 28–365 21–365 30–183 21–365 21–183 21–365 28–183 14–31 183–365 30–365 183–365 30–365 30–730 14–91

ES, effect sizes; k, number of samples; MMSE, Mini-Mental State Examination; n, number of studies; N, number of participants. a p ⬍ .01. b Samples pooled with short-term effects. c Includes one sample from short-term effects.

No significant relationships were found between weighted ES and age, total number of ECT sessions, or stimulus dose, following fixed-model meta-regression analyses to explore moderator effects on the above heterogeneous results. The p values for estimated regression coefficients ranged .18 to .99. Regarding stimulus dose, meta-regressions were used only for two, subacute, heterogeneous variables (MMSE, figure reproduction delayed recall), as insufficient data were available to test its influence on remaining heterogeneous variables. Publication Bias Data were available to analyze funnel plots for 35% of metaanalyzed outcomes (see Tables 2– 4 for variables including ⬎ 10 samples). However, neither these nor Begg Rank Correlation Tests (all nonsignificant, p ⬎ .21) revealed evidence of publication bias.

Discussion Our meta-analysis showed that ECT for depression is associated with significant cognitive impairment evident within days of finishing an ECT course. However, compared with baseline performance, deficits resolve during the subsequent 2 weeks and the majority of cognitive functions analyzed improve thereafter. Extent of impairment, recovery, and improvement from baseline over time differed for individual cognitive variables across cognitive domains. Up to 3 days after finishing an ECT course, medium-large deficits can be expected in episodic memory and executive functioning. Delayed recall was consistently more affected than immediate recall with verbal episodic memory appearing more disturbed than visual episodic memory. For verbal memory, learning and retrieval

of unstructured information (i.e., word list tests) showed higher impairment than ability to acquire and retrieve organized and contextualized information (i.e., story memory tests). In fact, during this subacute period, capacity to immediately recall a newly heard story was not affected by ECT. A surprising finding was that all executive functioning measures showed medium-large impairment, while this was not so for all episodic memory outcomes. Thus, tasks requiring set shifting and planning one’s own thinking appear more consistently impaired during the subacute period. Processing speed, spatial problem solving, and global cognition showed small subacute deficits, while tests of attention/working memory were not different from baseline. Electroconvulsive therapy had no demonstrable effect upon intellectual ability at any time point. Only one variable, verbal paired associates delayed recall, showed persisting small deficit during short-term follow-up (4 –15 days after ECT). However, as all but one of the analyzed samples for that variable at this time period included patients receiving sinewave ECT, this result cannot be generalized to contemporary briefpulse ECT. All other cognitive variables demonstrating subacute deficits showed recovery of baseline functioning, i.e., processing speed, episodic memory, and executive functioning. Results showed a medium improvement in ability to learn and spontaneously recall new organized and contextualized verbal information. Small improvement relative to pre-ECT scores was evident in global cognition and working memory. Our meta-analysis did not demonstrate persisting cognitive deficits in any studied variable beyond 15 days after ECT. For the majority of variables, there was small-medium improvement beyond baseline. However, for episodic memory, two variables recovered only to baseline performance at long-term follow-up; again, www.sobp.org/journal

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Table 5. Analyses of Electrode Placement as a Potential Moderator of Heterogeneous Effect Sizes in Studies of Cognitive Change Following ECT

Variable Subacute Effects MMSE Bitemporal Unilateral Mixed Word List Learning Bitemporal Unilateral Mixed Word List Delayed Recall Bitemporal Unilateral Mixed Verbal Paired Associates Learning Bitemporal Unilateral Figure Reproduction Delayed Recall Bitemporal Unilateral Short-Term Effects MMSE Bitemporal Unilateral or mixed Story Memory Immediate Recall Bitemporal Unilateral Mixed Long-Term Effects Digit Span Backward Bitemporal Unilateral

Within-Category Homogeneity Statistic

Between-Category Homogeneity Statistic

p Value

n

k

N

d

95% Confidence Interval

8 8 3

10 11 6

275 225 310

⫺.35 ⫺.13 ⫺.33

⫺.52 to ⫺.18 ⫺.32 to .05 ⫺.49 to ⫺.17

22.26a 13.69 28.25a

3.41

.18

3 6 4

4 9 6

77 286 73

⫺.27 ⫺.75 ⫺.77

⫺.59 to .05 ⫺.92 to ⫺.57 ⫺1.12 to ⫺.42

6.05 37.02a 20.40a

7.01

.03

3 5 2

3 7 2

83 223 28

⫺1.51 ⫺1.10 ⫺.29

⫺1.86 to ⫺1.16 ⫺1.31 to ⫺.90 ⫺.82 to .24

1.65 64.24a .44

14.36a

⬍.001

5 5

6 5

116 109

⫺.91 ⫺.33

⫺1.18 to ⫺.64 ⫺.60 to ⫺.06

12.84a 6.51

8.89a

.003

3 8

4 11

115 336

⫺1.46 ⫺.40

⫺1.77 to ⫺1.14 ⫺.55 to ⫺.25

75.15a 12.58

34.40a

⬍.001

7 4

12 5

161 145

.73 .20

.50 to .96 ⫺.03 to .43

43.85a 1.30

10.03a

.002

3 2 4

6 3 5

64 31 81

.88 .41 .29

.50 to 1.25 ⫺.11 to .93 ⫺.02 to .60

13.98 7.14 .96

5.89

.05

4 4

5 4

76 69

.66 .07

.33 to 1.00 ⫺.27 to .40

12.60 3.45

6.04

.01

d, mean weighted effect size; ECT, electroconvulsive therapy; k, number of samples; MMSE, Mini-Mental State Examination; n, number of studies; N, number of participants. a p ⬍ .01.

these were the verbal paired associates variables for which half the long-term samples included patients receiving sine-wave ECT. In addition, for executive functioning, fluency variables remained restored to baseline levels, although there was a trend for progressive improvement. Several meta-analyses have already established that major depression is associated with a range of cognitive deficits (30,34,35). An effective treatment, therefore, could be expected to improve cognition concurrently with affective state. However, persisting cognitive impairment is consistently described in middle-aged and elderly remitted patients (36 –38) and to lesser extent in young adults (39). Defective performance has been shown in attention, processing speed, visuospatial abilities, executive functioning, and episodic memory, while no significant relationship has consistently been found between changes in cognition and depressive symptoms (36 –38). Levels of cognitive function at long-term follow-ups, found in our meta-analysis to be similar to baseline, may thus reflect persisting cognitive impairment in depressive remitters rather than ECT-induced cognitive deficits. Improved long-term performance relative to baseline was found on several cognitive functions after ECT, i.e., processing speed, verbal working memory, and executive function. Interestingly, ES for these improvements were of similar magnitude to ES of impairments on same functions in depressed patients compared www.sobp.org/journal

with healthy control subjects (30,31,35). One interpretation of these results is that, while treating depression, ECT may also improve cognitive performance, possibly due to upregulation of cerebral trophic factors (40). Practice effects on executive tests without alternate forms (e.g., Stroop Color-Word) cannot be excluded as possible contributors to these improvements. Cognitive change data were heterogeneous for a third of studied subacute variables but mostly homogeneous for short-term and long-term cognitive outcomes of ECT. This suggests that differences in techniques, parameters, or patient characteristics have little contribution to those short-term and long-term outcomes. However, subacute heterogeneity indicates that magnitude and pattern of identified cognitive impairments differ because of different study characteristics (moderators). Of potential moderators, only electrode placement, stimulus waveform, and, to a lesser extent, weekly frequency of ECT administration affected strength of some ES and reduced significantly within-groups heterogeneity. Where significant differences were found, bitemporal ECT was associated with more deficits in verbal and visual episodic memory than unilateral ECT. Similarly, brief-pulse caused less impairment on visual episodic memory than sine-wave ECT. Consistent with the United Kingdom Electroconvulsive Therapy Review Group metaanalysis (1), stimulus waveform did not contribute significantly to ES heterogeneity, with just one exception.

BIOL PSYCHIATRY 2010;68:568 –577 575

M. Semkovska and D.M. McLoughlin

Table 6. Analyses of (A) Stimulus Waveform and (B) Treatment Frequency as Potential Moderators of Heterogeneous Effect Sizes in Studies of Cognitive Change Following ECT

Variable (A) Stimulus Waveform Subacute Effects Word List Delayed Recall Brief pulse Sine wave Verbal Paired Associates Learning Brief pulse Sine wave Figure Reproduction Delayed Recall Brief pulse Sine wave Short-Term Effects Story Memory Immediate Recall Brief pulse Sine wave Long-Term Effects Digit Span Backward Brief pulse Sine wave (B) Treatment Frequency Subacute effects MMSE Twice weekly Thrice weekly Verbal Paired Associates Learning Twice weekly Thrice weekly Short-Term Effects MMSE Twice weekly Thrice weekly Story Memory Immediate Recall Twice weekly Thrice weekly Long-Term Effects Digit Span Backward Twice weekly Thrice weekly

Within-Category Homogeneity Statistic

Between-Category Homogeneity Statistic

p Value

n

k

n

d

95% Confidence Interval

7 1

10 2

285 49

⫺1.38 .08

⫺1.56 to ⫺1.19 ⫺.32 to .48

35.54a 3.30

41.85a

⬍.001

3 5

3 9

87 161

⫺.36 ⫺.70

⫺.66 to ⫺.05 ⫺.92 to ⫺.47

3.92 23.04a

3.11

.08

7 3

11 4

349 102

⫺.51 ⫺1.06

⫺.66 to ⫺.36 ⫺1.40 to ⫺.73

12.30 101.15a

8.68a

.003

8 3

11 3

141 35

.45 .78

5.53 21.23a

1.21

.27

5 1

7 2

110 35

.35 .42

.08 to .62 ⫺.05 to .90

21.90a .12

.07

.79

2 12

2 22

62 709

.01 ⫺.27

⫺.35 to .36 ⫺.38 to ⫺.16

1.24 39.15

2.14

.14

1 5

2 7

16 196

⫺1.34 ⫺.59

⫺2.18 to ⫺.50 ⫺.80 to ⫺.39

10.70a 10.15

2.84

.09

6 4

10 4

163 116

.65 .29

.42 to .88 .03 to .54

49.27a .68

4.18

.04

7 2

11 2

139 21

.60 .15

.35 to .84 ⫺.47 to .78

20.45 5.05a

1.69

.19

1 3

2 4

35 64

.42 .01

⫺.05 to .90 ⫺.33 to .36

.12 2.39

1.86

.17

.21 to .69 .25 to 1.30

d, mean weighted effect size; ECT, electroconvulsive therapy; k, number of samples; MMSE, Mini-Mental State Examination; n, number of studies; N, number of participants. a p ⬍ .01.

No relation was found between cognitive change ES and age, total number of ECTs, or mean electrical charge dose. Unfortunately, no final conclusion can be made regarding relative contributions of these moderators, as they may interact differently with the first three moderators. For example, high-dose bitemporal ECT could cause greater cognitive impairment than both high-dose unilateral and low-dose bitemporal ECT. However, insufficient data were available to test more complex hypothetical models. Limitations A potential source of bias in any meta-analysis is failure to retrieve a comprehensive sample of primary studies. Our search was rigorous, while funnel plots and rank correlations did not suggest publication bias. However, insufficient studies were available to complete funnel graphs for all cognitive outcomes and rank correlations for small components outcomes have only moderate power to detect publication bias (22).

Several uncertainties about ECT cognitive outcomes merit further investigation. First, current evidence does not provide an estimate of the degree of retrograde amnesia that is often described. This is mainly due to lack of within-subjects studies to explore its progression over time and insufficient systematic use of reliable assessments. This is remarkable, as retrograde amnesia has been reported by patients as a major concern following ECT (41), while researchers have indicated that it persists longer than other deficits (26,42). However, a recent systematic review reported that subjective measures of autobiographical amnesia are associated with depressive symptom intensity (i.e., improved mood correlated with fewer memory complaints) and subjective complaints persisted longer than objective measures of performance (42). The situation is compounded by technical difficulties of accurately testing retrospective memory function. For example, a consistent finding of autobiographical memory research in normal populations is that www.sobp.org/journal

576 BIOL PSYCHIATRY 2010;68:568 –577 personal memories lose specificity over time, especially those acquired after early adulthood (43). Despite this, in the ECT literature, retrograde amnesia is estimated by tasks developed for the purpose of particular research projects but without previous collection of normative data with appropriate time intervals to allow assessment of memory change as occurs normally. Standardized and validated measures of ability to recall events learned before onset of depression or beginning ECT would be useful in future studies. Second, with regard to anterograde memory after ECT, the current evidence is insufficient to determine if delayed recall impairments are due to deficits in retaining material or retrieving it spontaneously. Therefore, it remains unclear if patients are able to learn new information during the subacute period but unable to use it without cues or if, on the contrary, new information cannot be consolidated during the first 3 days following ECT. Studies aiming to differentiate between those aspects of memory would be useful to inform clinical expectations following ECT. Third, the contribution of other possible moderators, such as post-ECT persisting depressive symptoms (42) or anesthesia (33), could not be estimated mainly because subgroup data are rarely available. Further studies are needed to explore their impact on cognitive effects of ECT. Finally, there is little evidence on effects of ECT on several cognitive domains known to be dysfunctional in depression, e.g., visual attention, visual working memory, visuospatial abilities, planning, and problem solving. Further studies are needed to circumscribe fully the cognitive profile of successfully treated patients—are these particular functions improving or staying at baseline after ECT? However, for the cognitive functions we analyzed, there is a reasonable evidence base that impairments associated with ECT are limited to the first 3 days after ending treatment and that afterward most improve beyond baseline. This is important information to help patients in deciding to have ECT and adapt activities upon finishing a treatment course. The research was supported by awards from the Health Research Board and the Friends of St. Patrick’s University Hospital. These organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors, MS and DMM, had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of data analysis. We are grateful to corresponding authors for sending us further information on their studies. The authors report no biomedical financial interests or potential conflicts of interest.

M. Semkovska and D.M. McLoughlin

7.

8.

9.

10.

11.

12. 13. 14.

15.

16.

17.

18.

19.

20. 21. 22. 23. 24.

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