Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients

Journal Pre-proof Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients Laura Basso, Luisa Bönke, Sabine Aust, Matti Gärtner, Isabella Heuser-Collier, Christian Otte, Katja Wingenfeld, Malek Bajbouj, Simone Grimm PII:

S0022-3956(19)31066-0

DOI:

https://doi.org/10.1016/j.jpsychires.2020.01.002

Reference:

PIAT 3806

To appear in:

Journal of Psychiatric Research

Received Date: 16 September 2019 Revised Date:

13 January 2020

Accepted Date: 13 January 2020

Please cite this article as: Basso L, Bönke L, Aust S, Gärtner M, Heuser-Collier I, Otte C, Wingenfeld K, Bajbouj M, Grimm S, Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients, Journal of Psychiatric Research (2020), doi: https://doi.org/10.1016/ j.jpsychires.2020.01.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.

Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients

Authors: Laura Basso1, 2*, Luisa Bönke1*, Sabine Aust1, Matti Gärtner1, Isabella HeuserCollier1, Christian Otte1, Katja Wingenfeld1, Malek Bajbouj1, Simone Grimm1,2,3

1 Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin 2 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland 3 Department of Psychology, MSB Medical School Berlin, Calandrellistr. 1-9, 12247 Berlin, Germany

* both authors contributed equally to the manuscript Correspondence should be addressed to: Luisa Bönke (M.Sc. Psychology) Centre for Affective Neuroscience (CAN) Department of Psychiatry – Campus Benjamin Franklin Charité - Universitätsmedizin Berlin Hindenburgdamm 30 12203 Berlin email: [email protected] phone: +49 30 450 517 746 fax: +49 30 450 517942

2

Abstract Background: While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine’s impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects. Methods: Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment. Results: ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance. Conclusions: Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT. Limitations: As this research employed a naturalistic study design, patients were not systematically randomized, there was no control group and patients received concurrent and partially changing medications during treatment.

Keywords: Depression; Electroconvulsive Therapy (ECT); Ketamine; Neurocognitive Effects Clinical Trials Registration: Functional and Metabolic Changes in the Course of Antidepressive Treatment, https://clinicaltrials.gov/ct2/show/NCT02099630, NCT02099630

3

Ketamine and ECT: Antidepressant and cognitive effects

1. Introduction Depressive disorder causes the highest overall disease burden of mental and neurological disorders in Europe (Wittchen et al., 2011) as well as worldwide (Collins et al., 2011). Even though various effective treatment options are available, in the treatment of depression a few unmet needs still remain. Firstly, not all patients benefit sufficiently from pharmacological treatment with conventional antidepressants (Gupta et al., 2013). In addition, their effects often do not show as fast as desired (Zarate, Henter, & Mathew, 2016), especially in severe depression. The limited treatment response exacerbates suffering for patients and may lead to higher risk of chronification (Rush et al., 2009), relapse (Judd et al., 1998), and suicide (Schosser et al., 2012). Accordingly, there is a strong need for effective treatment options with a faster onset of action than conventional antidepressants. Secondly, a significant number of depressive patients show wide ranging cognitive deficits (Christensen, Griffiths, MacKinnon, & Jacomb, 1997; Rock, Roiser, Riedel, & Blackwell, 2014; Mohn & Rund, 2016). It is important to note that cognitive impairment is not a consequence of the affective symptoms of depression but rather represents a distinct feature of depression (Averill, Murrough, & Abdallah, 2016; Rock et al., 2014). Cognitive impairment has been related to higher disability and disease burden, suicide risk, and treatment non-compliance (Averill et al., 2016). It often persists even after remission of core symptoms like depressed mood, loss of interest and increased fatigability, especially in the domains of attention and executive functions. Since functional recovery is significantly influenced by the level of cognitive impairment, the improvement of cognitive functioning is a crucial treatment target (Rock et al., 2014; Solé,

Ketamine and ECT: Antidepressant and cognitive effects

4

Jiménez, Martinez-Aran, & Vieta, 2015). Thus, there is a need for treatment options, which improve cognitive impairments in depression alongside with depressive core symptoms. Currently, the gold standard for the acute treatment of treatment-resistant depression is ECT (Merkl, Heuser, & Bajbouj, 2009). In terms of efficacy and onset of action, ECT is superior to conventional antidepressants, but also has several limitations, especially causing transient cognitive impairments, mainly in verbal and visual episodic memory domains and executive functions (Bodnar et al., 2016; Feifel, Malcolm, Boggie, & Lee, 2017; Mohn & Rund, 2019; Semkovska & McLoughlin, 2010). Fear of adverse cognitive effects of ECT is common among patients and many report (short-lasting) post-ECT memory impairment a distressing and troublesome experience (Chakrabarti, Grover, & Rajagopal, 2010). Compared to other available antidepressant interventions, ECT has a relatively fast speed of onset (Husain et al., 2004), however, a new antidepressant intervention, namely treatment with the NMDA receptor antagonist ketamine is even more rapid with antidepressant responses within days (Aust et al., 2019; Berman et al., 2000, Zarate et al., 2016). While recreational ketamine abuse and frequent ketamine use e.g. in chronic pain seem to be associated with impaired neurocognitive functioning and abnormalities of white matter (Liao et al., 2010; Morgan et al., 2010; Morgan et al., 2012), relatively little is known about the neurocognitive effects of ketamine in depression treatment. To the best of our knowledge, apart from one study that reported impaired verbal memory (delayed recall) 40 minutes after a single infusion (Murrough et al., 2014), no negative short-term effects of ketamine on cognition have been found in depressed patients. Improvements were shown in different domains (processing speed/attention, verbal learning and memory, visual learning and memory, and working memory/executive functions (Murrough et al., 2015; Permoda-Osip, Kisielewski,

5

Ketamine and ECT: Antidepressant and cognitive effects

Bartkowska-Sniatkowska, & Rybakowski, 2015; Shiroma et al., 2014) although only Murrough et al. 2015 conducted a randomized controlled trial. Moreover, these studies examined relatively small samples and in some studies patients only received a single infusion of ketamine. Furthermore, there is a lack of studies examining ketamine administration in clinical real-life settings (Feifel et al., 2017). One previous study by Ghasemi et al. (2014) compared antidepressant effects of ketamine and ECT. However, sample size was limited, patients received only a short course of ECT (3 ECTs) and impact on neurocognitive functioning was not assessed. Thus, this study aims to compare both clinical efficacy and neurocognitive functioning in depressed patients treated either with ketamine or ECT in a naturalistic sample. Previous findings indicate that baseline cognitive functioning might be a predictor for treatment response (Murrough et al., 2014; Murrough et al., 2015; Shiroma et al., 2014). Thus, as an exploratory analysis, we aim to examine whether clinical or neurocognitive characteristics can predict treatment outcome of ECT or ketamine administration. The identification of such predictors is of high clinical relevance, as it might help to guide future treatment choices.

2. Material and Methods 2.1. Participants

The sample consisted of depressed patients hospitalized at Department of Psychiatry, Charité – Universitätsmedizin Berlin, who were either treated with a 4-week course of ECT or a 2week series of ketamine infusions. While all patients had a clinical indication for ECT, some choose treatment with ketamine infusions as an alternative. Ketamine administration was integrated in a larger study that was carried out in accordance with the Declaration of Helsinki and was approved by the Institutional Review

Ketamine and ECT: Antidepressant and cognitive effects

6

Board of Charité- Universitätsmedizin Berlin. All patients gave written informed consent. Since April 2014, a total of 56 patients were treated with ketamine. 31 of them met the following inclusion criteria (see also Aust et al., 2019): primary diagnosis of major depressive disorder, two or more sufficient antidepressant treatment trials during the current episode without achieving remission, no lifetime antidepressant treatment with ketamine, no lifetime recreational use of ketamine, no cardiovascular diseases in the past six months, no insufficiently treated anemia, hyper- or hypothyroidism, no lifetime increased intracranial pressure or glaucoma, no chronic physical diseases, no current pregnancy, no relevant psychiatric or neurological comorbidity (in particular dementia, epileptic seizures, schizophrenia, psychosis, or post-traumatic stress disorder). Thirty-one age and gender matched patients were selected who had received the standard treatment ECT in the period from August 2013 to June 2016. Their data was collected from the medical records of standard clinical and neurocognitive assessments of the Department of Psychiatry. Of this sample with a total of 62 patients, patients who received a very small number of ketamine infusions (three or less; N = 4) or a very high number of ECT sessions (more than 16; N = 1), and patients with missing neurocognitive data (N = 1) and their respective matched patient from the other group were excluded. As 6 patients and their respective matches were excluded, a total of 12 patients from the original sample of 62 patients were excluded which led to the final sample of 50 patients, 25 patients treated with ketamine and 25 patients treated with ECT. Reasons for the small number of ketamine infusions were a subjective lack of efficacy after two or three infusions for 3 patients and full remission after three infusions for one patient (see Aust et al., 2019). General reasons for stopping ketamine or ECT treatment earlier (before 12 ECT treatments or 6 ketamine infusions) were full remission of the patients, lack of efficacy or adverse side effects.

7

Ketamine and ECT: Antidepressant and cognitive effects

A significant proportion of patients had psychiatric and/or medical comorbidities and received antidepressant medication in addition to the aforementioned treatment intervention. Demographic and basic clinical characteristics can be found in Table 1; additional clinical data with respect to comorbidities and medication are described in the supplement (S1-S3). Table 1 Comparison of Demographic and Clinical Characteristics between Treatment Groups Variable M

Ketamine SD Range

n

M

ECT SD Range

F

p

n

Age

49.08

10.45

30-70

25

49.96

11.82

20-71

25

0.08

.782

Education (years) a

15.58

2.30

13-19

24

14.83

2.81

10-20

23

1.03

.316

5.71

3.51

1–16

24

5.12

2.98

2–13

24

.39

.538

5.76

4.46

1–15

25

4.45

4.58

1–20

20

.94

.339

0.26

1.25

0–6

23

0.29

0.91

0–4

24

.01

.923

30.30

22.24

5–72

25

15.05

11.20

1–34

19

7.46

.009

26.40 28.59

4.94 6.24

19–38 20–44

25 23

31.17 24.55

7.28 3.89

17–48 17–32

23 24

7.17 7.16 χ2 0.72 5.52

.010 .010 p .396 .336

4.84

.094

Number of psychiatric hospitalizations a Number of depressive episodes a Number of manic episodes a Duration of current episode (months) a, b Baseline MADRS score BMI Gender (F:M) Marital status c

15:10 40% single (10) 12% cohabiting (3) 24% married (6) 8% separated (2) 16% divorced (4) 0% widowed (0)

Living arrangement c

48% alone (12) 36% with a partner (9) 16% with relatives (4)

Note. Census data in parentheses. N/A = not available. BMI = Body Mass Index. a Assumption of normality violated (Shapiro-Wilk: p< .05). b Assumption of equality of error variances violated (Levene's test: p< .05). c Fisher's exact test.

2.3. Procedure

11:14 24% single (6) 8% cohabiting (2) 40% married (10) 0% separated (0) 16% divorced (4) 8% widowed (2) 4% N/A (1) 28% alone (7) 64% with a partner (16) 4% with relatives (1) 4% N/A (1)

Ketamine and ECT: Antidepressant and cognitive effects

8

2.3.1. Design Clinical assessments were performed before the first treatment intervention (ECT session or ketamine infusion, baseline T0), after 50% of the interventions had been administered (six ECT sessions or three ketamine infusions, mid-treatment T1), and after the last treatment intervention (generally after 12 ECT sessions or six ketamine infusions, treatment end T2), see Figure 1.

Figure 1. Flowchart displaying course of study. Dots represent treatment interventions (ECT sessions or ketamine infusions).

9

Ketamine and ECT: Antidepressant and cognitive effects

Clinical assessments were part of the clinical routine and conducted by trained professionals. A German version of the Montgomery-Åsberg Depression Rating Scale (MADRS; Montgomery & Åsberg, 1979) was used as a measure of symptom severity. Reduction of MADRS score of 50 % or more is defined as response, MADRS score ≤ 10 as remission (Maust et al., 2012). Cognitive assessments were performed routinely with patients receiving ECT before the first ECT session, after the sixth and after the twelfth or last ECT session (1–3 days). Patients treated with ketamine were assessed before the first and after the sixth or last ketamine infusion. No assessments were performed after 50% of ketamine administrations (after the third infusion) because the inter-testing interval would have been too brief for valid outcomes due to learning effects. Post treatment neurocognitive testing was performed on the day after the last treatment with ECT or ketamine. The following cognitive domains were assessed: attention, immediate verbal short-term memory, verbal memory, visual memory and executive functions. See Table 2 for a detailed description of the utilized measures and the respective cognitive domains. For the VLMT (verbal memory) parallel test versions were used.

Table 2 List of Test Measures and Corresponding Cognitive Domains Domains

Tests/Subtests

Attention

TMT-A FWIT/Stroop Test: - reading color words - naming color patches Digit span forward* VLMT/RAVLT: supra-span (1st trial) VLMT/RAVLT: - learning sum - recall after interference - recall after delay - recognition Visual reproduction* - immediate recall - delayed recall

Immediate (verbal) short-term memory Verbal memory

Visual memory

10

Ketamine and ECT: Antidepressant and cognitive effects

Executive functions (cognitive flexibility, cognitive inhibition, and working memory)

TMT-B FWIT/Stroop Test: interference condition Digit span backward

Note. TMT = Trail Making Test (e.g. in CERAD-Plus, Morris et al., 1988). FWIT = Farbe-Wort-Interferenztest (Baeumler, 1985). VLMT = Verbaler Lern- und Merkfähigkeitstest (Helmstaedter, Lendt, & Lux, 2001). RAVLT = Rey Auditory Verbal Learning Test (Helmstaedter, Lendt, & Lux, 2001. * (Wechsler, 1987)

The cognitive assessment followed the same order of testing for each patient. The assessment was generally completed within 40–55 minutes and inter-testing intervals were usually 14 days. For convenience, the raw test scores were additionally transformed into percentile ranks and a composite score combining all cognitive domains was calculated by computing mean values of the domain scores. Thus, this study has a mixed factorial design with symptom severity and neurocognitive performance as within-subject variables with three (baseline, mid-treatment, treatment end) and two levels (baseline and treatment end) respectively, and one between-subjects variable (treatment) with two levels (ECT and ketamine).

2.3.2. Treatment ECT was administered three times a week mostly over the course of four weeks. The procedure followed standard clinical protocols at the Department of Psychiatry which had been adapted to minimize cognitive impairment (another description of the same ECT procedure can be found in: Brakemeier et al., 2014; Roepke et al 2011). A MECTA 5000Q device (Somatics, Belleville, Illinois) was used to deliver ultrabrief pulse stimuli (0.3 ms) for right unilateral ECT. Patients were anesthetized either with propofol (approximately 1.5 mg/kg) or etomidate (approximately 0.75 mg/kg). Succinylcholine (approximately 0.75 mg/kg) was used for muscular relaxation. In order to control for adequate duration, motor and electroencephalogram seizure duration were monitored. During the first ECT treatment seizure threshold was titrated and voltage was

Ketamine and ECT: Antidepressant and cognitive effects

11

only modified if patients did not respond clinically or showed insufficient seizures during the course of ECT (i.e., motor response < 20 sec or electroencephalogram seizure activity < 30 sec). The mean number of administered ECT sessions in this sample was 12.36 (SD = 1.75, n = 25), ranging from 9 to 16 ECT sessions. Ketamine was administered intravenously at a subanesthetic dose also three times a week, on the same days and in the same room as ECT. Patients received R-ketamine infusions of 0.5 mg per kg of body weight over a period of 40 minutes. Patients were monitored and kept under surveillance after the infusions until psychotomimetic effects ceased. The mean number of administered infusions was 6.76 (SD = 1.23, n = 25), ranging from 6 to 9 infusions.

2.4. Statistical Analyses All analyses were conducted using SPSS statistical software, version 24 (IBM Corp., USA), for Mac OS X. The statistical analyses focus on three different aspects: (1) group differences in demographic and clinical data before the beginning of treatment, (2) change in clinical and neurocognitive data over the course of treatment, and (3) the relationship between clinical and neurocognitive data. In order to compare changes in clinical and neurocognitive data between groups (2) change scores (change of raw data in percentage) were computed. For the between-group analysis of clinical data, a 2 × 2 (Intervention [ECT, ketamine] × Time [change in percentage from T0 to T1, change in percentage from T0 to T2] repeated measures ANOVA was conducted to compare the reduction in MADRS scores from T0 to T1 and from T0 to T2 between treatment groups; MADRS baseline scores were included as covariate. Change in percentage of cognitive performance (from T0 to T2) on test measures, domains and the composite score was compared using ANCOVAs with intervention as the between-subjects factor and

12

Ketamine and ECT: Antidepressant and cognitive effects

MADRS baseline score as a covariate; or univariate ANOVAs when no relationship between baseline MADRS scores and the dependent variable could be detected by correlations and scatterplots. Z-values for neurocognitive data as well as their comparison can be found in the supplement, see Table S6 and S7. The effect size d (Cohen, 1988) was calculated for within-group (paired-samples ttests) and between-group analyses (ANOVAs/ANCOVAs). Pooled standard deviation was adjusted in case of unequal sample sizes (due to missing data). Absolute p-values are presented for all conducted tests. Parametric tests were only used if all assumptions of the respective tests were satisfied or when it was reasonable to conclude that the tests were robust against the respective violations. Normality of distribution was tested with the Shapiro-Wilk test (Shapiro & Wilk, 1965), equality of error variances was tested with Levene’s test, linearity and strength of relationships was assessed by scatterplots and correlations, homogeneity of regression slopes was tested with interaction terms.

3. Results 3.1. Group differences in demographic and baseline clinical and neurocognitive data The two treatment groups did not differ regarding age, gender, education, or other demographic variables, see Table 1. Concerning clinical variables, the groups differed with regard to the duration of their current episode and their baseline MADRS scores. Patients treated with ketamine were less severely depressed at the start of the intervention than those treated with ECT (d = 0.77), yet their current episode had on average been lasting twice as long (d = 0.83; see Table 1). MADRS baseline scores were included as a covariate in the following between-group analyses. The two treatment groups did not differ regarding baseline cogni-

Ketamine and ECT: Antidepressant and cognitive effects

13

tive performance (p > .05; see Table S4 in the supplement) and baseline MADRS scores were not related to baseline cognitive performance, except for verbal memory (r = -.315, p = .029, N = 48, effect size moderate with d = 0.66).

3.2.

Change in clinical data

Mean MADRS scores at T1 were M = 13.38, SD = 5.27 (N = 24) in the ketamine group and M = 19.52, SD = 7.07 in the ECT group (N = 25). Mean MADRS scores at T2 were M = 13.40, SD = 6.89 (N = 25) in the ketamine group and M = 13.75, SD = 7.69 in the ECT group (N = 24). A significant Treatment Group × Time interaction was found, F(1,43) = 6.93, p = .012, partial η2 = .139, n = 46, d = 0.80. MADRS scores were more strongly reduced from T0 to T1 for patients treated with ketamine (M = -47.45%, SD = 23.43, n = 24) than for those treated with ECT (M = -34.86%, SD = 21.29, n = 22), whereas symptom reduction until T2 was not significantly different between groups (ECT: M = -55.70%, SD = 23.63, n = 22; ketamine: M = -49.88%, SD = 27.30, n = 24). Symptom reduction over the course of treatment is depicted in Figure 2. Treatment response could neither be significantly predicted by baseline MADRS scores in the ketamine (β = .188, p = .083, n = 25) nor in the ECT group (β = -.038, p = .530, n = 22).

14

Ketamine and ECT: Antidepressant and cognitive effects

*

Mean reduction in MADRS scores (%)

70

ECT

**

Ketamine

60

* 50 40 30 20 10 Until mid-treatment

Until treatment end

Figure 2. Mean reduction (%) in symptom severity (MADRS scores) until mid-treatment (T1-T0) and treatment end (T2-T0) in both treatment groups (controlled for MADRS baseline scores). Error bars represent standard errors. * p< .05. ** p< .01.

3.3. Change in neurocognitive data Change in performance (%) on the individual test measures and their comparison between groups can be found in Table S5, supplementary material. Changes in the different cognitive domains and the composite score are displayed in Figure 3 for both treatment groups. All differences with p ≤ 0.05 that were found in the different domains (attention, verbal memory, and executive functions) were characterized by large effect sizes (all d >.5), whereas the difference regarding change on the composite score reflected a small effect (d = 0.40). Including or excluding MADRS baseline scores as a covariate did not change results with respect to the different domains. For the composite score, however, excluding MADRS baseline score as a covariate from the model did lead to a considera-

15

Ketamine and ECT: Antidepressant and cognitive effects

bly higher p-value, F(1,46) = 1.73, p = .194, n = 48 (ECT: M = -1.84%, SD = 20.34, n = 24; ketamine: M = 4.07%, SD = 8.35, n = 24); d = 0.38. No significant between-group differences were found for immediate and visual memory.

Attention **

Immediate memory

Verbal memory **

Visual memory

Executive functions **

Composite score *

Mean change in performance (%)

20 10 0 -10 -20 -30 -40 ECT -50

Ketamine

Figure 3. Mean performance change (%) in cognitive domains and the composite score (T2-T0) in both treatment groups (controlled for MADRS baseline scores). Error bars represent standard errors. * p< .05. ** p< .01. *** p< .001.

3.4. Relationship between clinical and neurocognitive data Correlations revealed that MADRS baseline scores were not systematically associated with cognitive performance at baseline in any domain except for verbal memory (r = .315, p = .029, N = 48, effect size moderate with d = 0.66). In both groups, no significant correlation between baseline cognitive performance and change in symptom severity (%) until T2 was found. Moreover, change in cognitive

16

Ketamine and ECT: Antidepressant and cognitive effects

performance (%) and change in MADRS scores (%) were not correlated. Baseline cognitive performance could not predict treatment response for any of the two groups.

4. Discussion We compared effects of ECT and serial ketamine administration with regard to treatment efficacy and acute neurocognitive effects in a naturalistic sample of depressed patients. In addition, we examined whether clinical or neurocognitive characteristics predict treatment outcome of ECT or ketamine administration. Our study demonstrated that both ECT and ketamine are effective treatments for depression. However, ketamine showed a faster onset of action than ECT. Furthermore, symptom reduction was stronger at mid-treatment for patients treated with ketamine (after 1 week) compared to patients treated with ECT (after 2 weeks). At the end of treatment (4 weeks of ECT/2 weeks of ketamine infusions) both treatments were equally effective. Yet, it is important to note that the same antidepressant effects that were achieved within four weeks of ECT treatment could be achieved within two weeks of ketamine administration. Therefore, ketamine appears to be an especially useful treatment option when there is an urgent need for symptom improvement, e.g. in the case of high suicide risk (Ballard & Price, 2016). Already a single ketamine infusion seems to rapidly reduce suicidal ideation (Wilkinson et al., 2018). As there was no significant additional symptom reduction from T1 to T2 in the ketamine group, one might question the necessity for three more ketamine infusions after the first treatment week with three infusions. Regarding neurocognitive functioning findings generally matched our expectations, yet also some surprising findings were made. For patients treated with ECT, performance was expected to decline. However, in this sample, only performance in verbal

Ketamine and ECT: Antidepressant and cognitive effects

17

memory was significantly reduced after ECT (with generally large effect sizes), which is in line with previous findings (Bodnar et al., 2016; Semkovska & McLoughlin, 2010). However, these previous studies also report a decline in executive functions after ECT, which was not observed in this sample. Remarkably, for visual memory, performance improved after ECT, with a small effect size for immediate and a moderate effect size for delayed recall. In a healthy sample, learning effects on the test used for the assessment of visual memory have been observed over short periods (similar to the one used in this study; Theisen, Rapport, Axelrod, & Brines, 1998). Thus, learning effects might be a possible explanation for the improvement in visual memory in our sample, too. Other improvements in the ketamine group and relatively stable executive functions in the ECT group might also be due to learning effects. Furthermore, a meta-analysis by Semkovska and McLoughlin (2010) found that for episodic memory, post-ECT disturbances are generally greater in delayed recall than in immediate recall and that impairment in verbal episodic memory is greater than in visual episodic memory. Thus, our findings are only partially in line with their observations. For the ketamine group, results indicate that performance significantly increased in the domains of attention (small effect sizes), visual memory (small to moderate effect sizes), and executive functions (small to moderate effect sizes). Yet surprisingly, a significant decrease in one measure of verbal memory (delayed recall; small effect) was found. The improvements concerning attention, visual memory, and executive functions after ketamine treatment are line with previous findings (Murrough et al., 2015; Permoda-Osip et al., 2015; Shiroma et al., 2014). However, as stated before, practice effects cannot be ruled out as an explanation for these effects. An unexpected finding was the decline in verbal memory performance within the ketamine group. Based on the literature, no change or even improvement was expected. One previous study by Mur-

Ketamine and ECT: Antidepressant and cognitive effects

18

rough et al. (2014) also found impaired verbal memory performance after ketamine treatment, and interestingly they also found impairment in delayed recall. In contrast to our study, their assessment took place 40 minutes after a single ketamine infusion. A possible explanation for these results might be that ketamine induces selective and temporary impairment in verbal memory some minutes up to several days after treatment (as found in this study), which changes into improvement later on (e.g., 7 days after a single infusion; Murrough et al., 2015). An alternative explanation is that repeated infusions might be related to more extended impairments compared to single infusions. Nonetheless, at treatment end, patients treated with ketamine showed significantly better overall cognitive performance than those treated with ECT (moderate effect size). These results indicate that serial ketamine administration has a small pro-cognitive effect and a better overall cognitive (short-term) outcome than ECT treatment. Regarding treatment choices, this might suggest that ketamine constitutes the more favorable treatment option over ECT for patients with preexisting cognitive impairments. In contrast to previous studies (Murrough et al., 2015; Murrough et al., 2014; Shiroma et al., 2014), no association between baseline cognitive performance and treatment response was found for any of the groups. Two of the three studies that found a relationship between treatment response and baseline cognition only administered a single ketamine infusion (Murrough et al., 2015; Murrough et al., 2014). Therefore, it is possible that baseline symptom severity is predictive of (initial) treatment response to one or few ketamine infusions, but not necessarily of the clinical response to a series of infusions. However, Shiroma et al. (2014) found such an association after six infusions, which is in conflict with this explanation. Moreover, in our sample change in cognitive performance was not related to change in symptom severity. Thus, improvement in cognitive performance could not be explained by the reduction in symptom severity in the ketamine

Ketamine and ECT: Antidepressant and cognitive effects

19

group. This finding is in line with others (Murrough et al., 2015; Permoda-Osip et al., 2015) that found no such association. Consequently, changes in cognition are likely to reflect direct effects of ketamine itself and not secondary effects which were caused by the clinical improvement.

Some limitations of this work need to be mentioned. First of all, as our study employed a naturalistic design, patients could choose between ketamine and ECT. Ketamine is a new and easy to apply treatment option whereas ECT in contrast may often be stigmatized or perceived as the ultimate treatment. As our study is missing a control group, potential confounding effects of this circumstance cannot be ruled out. Thus, the faster and stronger effect of ketamine found in our study could be partly due to this effect. On the other hand it is well know that e.g. in pharmacotherapy and psychotherapy expected effectiveness is a predictor of treatment success, so a presumably positive image of ketamine might also be seen as a general advantage and not only as a confounding factor. Our sample mostly consists of middle-aged patients, so questions concerning the effects for younger or older patients remain open. In general, the present sample is very heterogeneous with regard to clinical characteristics such as severity of depression, diagnosis (unipolar, bipolar), psychiatric and medical comorbidities, and the use of antidepressant medication. None of the patients who received ketamine suffered from a severe depressive episode with psychotic symptoms, whereas in the ECT group 16% of the patients were diagnosed with RDD with psychotic symptoms. Patients in the ketamine group were more chronic yet less severely depressed. The difference between treatment groups in baseline symptom severity was controlled for, but generally did not have an impact on results regarding efficacy and changes in the different cognitive domains. Furthermore, the diversity of the sample can also be seen as an advantage. In clinical trials, exclusion criteria are relatively strict and patients meeting these criteria are poorly representative of depressed patients (Feifel et al., 2017; Zimmerman, Mattia, &

Ketamine and ECT: Antidepressant and cognitive effects

20

Posternak, 2002). Because the present sample is a naturalistic sample acquired in a clinical setting, it is more representative of depressed patients than those usually included in randomized control trials and therefore might prove very enlightening for clinical everyday work. However, it also needs to be considered that the ability to perform neurocognitive testing was a prerequisite of this study; patients with severe functional impairment therefore could not be included.

Patients were assessed a few days (1–3) after the end of treatment. It would be of high clinical interest how symptoms and cognitive performance change in the weeks or months following treatment. For ECT, it is known that after short-lived cognitive impairments during treatment, cognitive performance improves again (Bodnar et al., 2016; Mohn & Rund, 2019; Semkovska & McLoughlin, 2010) and no long-term cognitive impairments are reported (Vasavada, 2017). For ketamine, no negative effects on neurocognitive performance have been found 7 days post-treatment (Diamond et al., 2014; Murrough et al., 2015), or over a 4-week follow up period (Shiroma et al., 2014). Considering the antidepressant effect of ECT, a response rate of 70-80% can be assumed

(van Djermen, 2018), however after 6 months without any continuation treatment relapse rates are high (up to 80 %; Ferrier, 2019). Murrough et al. (2013) reported a response rate of 70 % after a series of up to six ketamine infusions, median time to

relapse after treatment end was 18 days. Thus, especially as the antidepressant effect of ketamine seems to be rather short-lived (e.g. Wolf Fourcade & Lapidus, 2016) and studies for long-term cognitive effects of ketamine are missing future studies are needed. Considering the above named relapse rates, another crucial topic for future research should be the maintenance of achieved antidepressant effects, with e.g. psychotherapeutic programs as proposed by Brakemeier et al. (2014). To sum up, a randomized con-

21

Ketamine and ECT: Antidepressant and cognitive effects

trolled trial with a large sample including long-term follow up measurements (e.g. after 6 months and after 12 months) seems advisable. In conclusion, in this naturalistic sample of depressed patients, serial ketamine administration was related to a better short-term cognitive outcome than ECT treatment, while simultaneously achieving faster symptom reduction. Therefore, this study might suggest that for middle-aged, rather chronic non-psychotic depressed patients with strong depression-related cognitive impairment, ketamine could constitute a more beneficial acute treatment option than ECT, as it seems to improve both affective and cognitive symptoms relatively quick and thus might help to reduce patients’ suffering rapidly and effectively.

5. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

6. Conflict of Interest Prof. Dr. Bajbouj was involved in a clinical trial by Johnson and Johnson investigating the antidepressant effects of ketamine. Prof. Dr. Otte has received honoraria from Lundbeck and Neuraxpharm. All other authors reported no biomedical, financial or potential conflicts of interest.

7. Acknowledgments Assistance provided by Prof. Dr. rer. nat. Lutz Jäncke (University of Zurich, Department of Psychology, Professorship of Neuropsychology) was greatly appreciated.

22

Ketamine and ECT: Antidepressant and cognitive effects

8. References Aust S, Gärtner M, Basso L, Otte C, Wingenfeld K, Chae WR, et al. Anxiety during ketamine infusions is associated with negative treatment responses in major depressive disorder. European Neuropsychopharmacology. 2019. Averill LA, Murrough JW, Abdallah CG. Ketamine’s mechanism of rapid antidepressant activity: Evidence gleaned from clinical studies. In Mathew SJ, Zarate CA, editors. Ketamine for Treatment-Resistant Depression: The First Decade of Progress. Switzerland: Adis; 2016. Baeumler, G. (1985). Farbe-Wort-Interferenztest (FWIT) nach J. R. Stroop: Handanwei sung. Göttingen: Hogrefe Ballard ED, Price RB. Ketamine and suicide risk. In: Mathew JS, Zarate AC, editors. Ketamine for Treatment-Resistant Depression: The First Decade of Progress. Switzerland: Adis; 2016. p. 43–56. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000; 47(4): 351–354. Bodnar A, Krzywotulski M, Lewandowska A, Chlopocka-Wozniak M, BartkowskaSniatkowska A, Michalak M, et al. Electroconvulsive therapy and cognitive functions in treatment-resistant depression. The World Journal of Biological Psychiatry. 2016; 17(2):159–164. Brakemeier EL, Merkl A, Wilbertz G, Quante A, Regen F, Bührsch N, et al. Cognitivebehavioral therapy as continuation treatment to sustain response after electroconvulsive therapy in depression: A randomized controlled trial. Biological Psychiatry. 2014; 76(3): 194–202.

Ketamine and ECT: Antidepressant and cognitive effects

23

Chakrabarti S, Grover S, Rajagopal R. Electroconvulsive therapy: A review of knowledge, experience and attitudes of patients concerning the treatment. The World Journal of Biological Psychiatry. 2010; 11(3): 525–537. Christensen H, Griffiths K, MacKinnon A, Jacomb P. A quantitative review of cognitive deficits in depression and Alzheimer-type dementia. Journal of the International Neuropsychological Society. 1997; 3(6): 631–651. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd edition. Lawrence Erlbaum Associates: Hillsdale, NJ; 1988. Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS. Grand challenges in global mental health. Nature. 2011; 475(7354): 27–30. Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, et al. Ketamine infusions for treatment resistant depression: A series of 28 patients treated weekly or twice weekly in an ECT clinic. Journal of Psychopharmacology. 2014; 28(6): 536– 544. Feifel D, Malcolm B, Boggie D, Lee K. Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. Journal of Affective Disorders. 2017; 221(Suppl. C): 283–288. Ferrier, I. N. (2019). ECT in the Treatment of Depression. In The ECT Handbook, Waite J, & Easton,A. (Eds.). RCPsych Publications. Ghasemi M, Kazemi MH, Yoosefi A, Ghasemi A, Paragomi P, Amini H, Afzali M. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Research. 2014; 215(2): 355–361. Gupta M, Holshausen K, Best MW, Jokic R, Milev R, Bernard T, et al. Relationships among neurocognition, symptoms, and functioning in treatment-resistant depression. Archives of Clinical Neuropsychology. 2013; 28(3): 272–281.

Ketamine and ECT: Antidepressant and cognitive effects

24

Helmstaedter, C., Lendt, M., & Lux, S. (2001). VLMT: Verbaler Lern- und Merkfähigkeits test. Göttingen: Beltz Test GmbH. Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): A consortium for research in ECT (CORE) report. The Journal of Clinical Psychiatry. 2004; 65(44): 85–491. Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, et al. Major depressive disorder: A prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. Journal of Affective Disorders. 1998; 50(2–3): 97–108. Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, ... & Hao W. Frontal white matter abnorma lities

following chronic ketamine use: a diffusion tensor imaging study. Brain. 2010;

133(7), 2115- 2122. Maust D, Cristancho M, Gray L, Rushing S, Tjoa C, Thase ME. Psychiatric rating scales. In Aminoff MJ, Boller F, Swaab DF, editors. Handbook of Clinical Neurology. Amsterdam: Elsevier; 2012. p. 227–237 Merkl A, Heuser I, Bajbouj M. Antidepressant electroconvulsive therapy: Mechanism of action, recent advances and limitations. Experimental Neurology. 2009; 219(1): 20–26. Mohn C, Rund BR. Neurocognitive profile in major depressive disorders: Relationship to symptom level and subjective memory complaints. BMC Psychiatry. 2016; 16: 108. Mohn C, Rund BR. Neurocognitive function and symptom remission 2 years after ECT in major depressive disorders. Journal of Affective Disorders. 2019; 246: 368–375. Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. British Journal of Psychiatry. 1979; 134(4): 382–389.

Morgan CJ, Muetzelfeldt L & Curran HV. Consequences of chronic ketamine self‐ admi nistration upon neurocognitive function and psychological wellbeing: a 1‐year lon gitudinal study. Addiction. 2010; 105(1), 121-133.

Ketamine and ECT: Antidepressant and cognitive effects

25

Morgan CJ, Curran HV & Independent Scientific Committee on Drugs (ISCD). Ketamine use: a review. Addiction. 2012; 107(1), 27-38. Morris JC, Mohs RC, Rogers H, Fillenbaum G, Heyman A. The Consortium to Establish a Registry for Alzheimer’ s Disease (CERAD): clinical and neuropsychological asses sment of Alzheimer ’ s disease . Psychopharmacolical Bulletin. 1988 ; 4 : 642 – 52 . Murrough JW, Burdick KE, Levitch CF, Perez AM, Brallier JW, Chang LC, et al. Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: A randomized controlled trial. Neuropsychopharmacology. 2015; 40(5): 1084–1090.

Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, ... & Iosifescu DV. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological psychiatry. 2013; 74(4), 250-256. Murrough JW, Soleimani L, DeWilde KE, Collins KA, Lapidus KA, Iacoviello BM, ... & Price R.B. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychological medicine. 2015; 45(16), 3571-3580. Murrough JW, Wan LB, Iacoviello B, Collins KA, Solon C, Glicksberg B, et al. Neurocognitive effects of ketamine in treatment-resistant major depression: Association with antidepressant response. Psychopharmacology. 2014; 231(3): 481–488. Permoda-Osip A, Kisielewski J, Bartkowska-Sniatkowska A, Rybakowski JK. Single ketamine infusion and neurocognitive performance in bipolar depression. Pharmacopsychiatry. 2015; 48(2): 78–79. Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: A systematic review and meta-analysis. Psychological Medicine. 2014; 44(10): 2029–2040. Roepke S, Luborzewski A, Schindler F, Quante A, Anghelescu I, Heuser I, Bajbouj M. Stimulus pulse-frequency-dependent efficacy and cognitive adverse effects of ultrabrief-

26

Ketamine and ECT: Antidepressant and cognitive effects

pulse electroconvulsive therapy in patients with major depression. The Journal of ECT. 2011; 27(2): 109–113. Rush AJ, Warden D, Wisniewski SR, Fava M, Trivedi MH, Gaynes BN, Nierenberg AA. STAR*D: Revising conventional wisdom. CNS Drugs. 2009; 23(8): 627–647. Schosser A, Serretti A, Souery D, Mendlewicz J, Zohar J, Montgomery S, Kasper S. European Group for the Study of Resistant Depression (GSRD)—where have we gone so far: Review of clinical and genetic findings. European Neuropsychopharmacology 2012; 22(7): 453–468 Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: A systematic review and meta-analysis. Biological Psychiatry. 2010; 68(6): 568–577. Shapiro SS, Wilk MB. An analysis of variance test for normality (complete samples). Biometrika. 1965; 52(3/4): 591–611. Shiroma PR, Albott CS, Johns B, Thuras P, Wel, J, Lim KO. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. International Journal of Neuropsychopharmacology. 2014; 17(11): 1805–1813. Solé B, Jiménez E, Martinez-Aran A, Vieta E. Cognition as a target in major depression: New developments. European Neuropsychopharmacology. 2015; 25(2): 231–247. Theisen ME, Rapport LJ, Axelrod BN, Brines DB. Effects of practice in repeated administrations of the Wechsler Memory Scale-Revised in normal adults. Assessment. 1998; 5(1): 85–92.

Vasavada, M. M., Leaver, A. M., Njau, S., Joshi, S. H., Ercoli, L., Hellemann, G., ... & E spinoza, R.

Short-and Long-term Cognitive Outcomes in Patients With Major De

pression Treated With 33(4), 278-285.

Electroconvulsive Therapy. The journal of ECT. 2017;

Ketamine and ECT: Antidepressant and cognitive effects

27

Wechsler, D. (1987). Wechsler Memory Scale-Revised: Manual. San Antonio, TX: Psycho logical Corporation. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis. American Journal of Psychiatry. 2018; 175(2): 150–158. Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson, B, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology. 2011; 21(9): 655–679. Wolf Fourcade E, Lapidus KAB. The basic and clinical pharmacology of ketamine. In Mathew SJ, Zarate CA, editors. Ketamine for Treatment-Resistant Depression: The First Decade of Progress. 2016. p. 13–29. Zarate CA, Henter I, Mathew SJ. (2016). Commentary. In Mathew SJ, Zarate CA, editorsKetamine for Treatment-Resistant Depression: The First Decade of Progress. 2016. p. v–ix. Zimmerman M, Mattia JI, Posternak, MA. Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice? American Journal of Psychiatry. 2002; 159(3): 469–473.

28

Ketamine and ECT: Antidepressant and cognitive effects

9. Figure Legends

Figure 2. Flowchart displaying course of study. Dots represent treatment interventions (ECT sessions or ketamine infusions).

Figure 2. Mean reduction (%) in symptom severity (MADRS scores) until mid-treatment and treatment end in both treatment groups. Error bars represent standard errors.

Figure 3. Mean performance change (%) in cognitive domains and the composite score in both treatment groups. Error bars represent standard errors. p < .05. **p < .01. ***p < .001.

Ketamine and ECT: Antidepressant and cognitive effects

29

Conflict of Interest Prof. Dr. Bajbouj was involved in a clinical trial by Johnson and Johnson investigating the antidepressant effects of ketamine. Prof. Dr. Otte has received honoraria from Lundbeck and Neuraxpharm. All other authors reported no biomedical, financial or potential conflicts of interest.