This open-label between-subjects study (n=49) compared the antidepressant efficacy of serial R(-)ketamine treatment (35mg/70kg) versus electroconvulsive therapy (ECT) for patients with depression. Ketamine produced faster antidepressant effects and improved neurocognitive functioning, especially attention and executive functions, which implicate that it may be a more favorable treatment option in the short-term.
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.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Feifel, D., Malcolm, B., Boggie, D. et al. · Journal of Affective Disorders (2017)
Murrough, J. W., Burdick, K. E., Levitch, C. F. et al. · Neuropsychopharmacology (2014)
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Depressive disorder produces a high disease burden worldwide and many patients do not achieve an adequate or sufficiently rapid response with conventional antidepressants. In addition to mood symptoms, cognitive deficits—particularly in attention and executive function—are common, often persist after mood remission, and are linked to poorer functional recovery. Electroconvulsive therapy (ECT) is the established acute treatment for treatment-resistant depression and is relatively rapid in onset, but it is associated with transient cognitive side effects, particularly in episodic memory. Ketamine, an NMDA receptor antagonist, has emerged as a fast-acting antidepressant, yet its short-term effects on cognition in a clinical treatment context remain incompletely characterised. Earlier clinical studies are limited by small samples, single-infusion designs, and few direct comparisons with ECT, and real-world data are sparse. Basso and colleagues set out to compare clinical efficacy and acute neurocognitive effects of serial ketamine infusions versus ECT in a naturalistic sample of depressed inpatients. A secondary, exploratory aim was to examine whether baseline clinical or cognitive characteristics predict treatment outcome for either intervention. The study therefore addresses both speed and magnitude of antidepressant effect and parallel changes in multiple cognitive domains under conditions closer to routine clinical practice than tightly controlled randomised trials.
This was a naturalistic, non-randomised comparative study of depressed inpatients at the Department of Psychiatry, Charité — Universitätsmedizin Berlin. From April 2014 onwards 56 patients received ketamine in the larger programme; 31 met the study inclusion criteria and were matched by age and gender to 31 patients who had received standard ECT between August 2013 and June 2016. After excluding pairs for very few ketamine infusions (≤3), unusually high numbers of ECT (>16), or missing neurocognitive data, the final analytic sample comprised 50 patients: 25 treated with ketamine and 25 treated with ECT. All participants provided informed consent. The extracted text does not report randomisation or a concurrent control group. Inclusion criteria for ketamine (as reported) excluded lifetime ketamine exposure or recreational ketamine use, recent cardiovascular disease, significant untreated medical conditions (e.g. anaemia, thyroid disorder), increased intracranial pressure or glaucoma, pregnancy, and major psychiatric or neurological comorbidity such as dementia, epilepsy, schizophrenia, psychosis, or PTSD. All patients had a primary diagnosis of major depressive disorder and at least two prior adequate antidepressant trials in the current episode. ECT was administered three times weekly, typically over four weeks, using right unilateral ultra-brief pulse stimulation (0.3 ms) on a MECTA 5000Q device under general anaesthesia (propofol or etomidate) with succinylcholine for muscle relaxation; seizure threshold was titrated at first treatment. Mean number of ECT sessions was 12.36 (SD = 1.75, range 9–16). Ketamine was delivered intravenously three times weekly on the same schedule over two weeks, as R-ketamine 0.5 mg/kg infused over 40 minutes, with monitoring until acute psychotomimetic effects subsided; mean infusions were 6.76 (SD = 1.23, range 6–9). Clinical assessments used the German Montgomery-Åsberg Depression Rating Scale (MADRS). Symptom ratings were performed at baseline (T0), mid-treatment (T1: after six ECT sessions or three ketamine infusions) and at treatment end (T2: after about 12 ECT sessions or six ketamine infusions). Response was defined as ≥50% reduction in MADRS and remission as MADRS ≤10. Neurocognitive testing evaluated attention, immediate verbal short-term memory, verbal memory, visual memory and executive functions; tests were administered at baseline and at treatment end for both groups, and additionally at mid-treatment for the ECT group. Raw cognitive scores were transformed into percentile ranks and a composite cognitive score was constructed by averaging domain scores. Assessors were trained clinical personnel and inter-test intervals were usually about 14 days. Statistical analyses used repeated-measures ANOVA/ANCOVA frameworks in SPSS v24. For symptom change a 2 × 2 (Intervention × Time) repeated-measures ANOVA compared percentage change in MADRS from T0 to T1 and T0 to T2, with baseline MADRS included as a covariate. Cognitive change (percentage change T0 to T2) was compared by ANCOVAs with baseline MADRS as covariate when warranted by correlations; otherwise univariate ANOVAs were used. Effect sizes (Cohen's d) were reported for within- and between-group contrasts. Assumptions (normality, homogeneity of variance, linearity) were tested and parametric tests were used when appropriate or robust.
Participant flow and baseline characteristics: After exclusions the study analysed 25 patients in the ketamine arm and 25 in the ECT arm. The groups were similar in age, gender, education and most demographic variables, but differed on clinical variables: ketamine-treated patients had lower baseline MADRS scores (less severe depression) and longer current episode durations (on average twice as long) than ECT patients. Baseline cognitive performance did not differ between groups, and baseline MADRS was not associated with baseline cognition except for verbal memory (moderate negative correlation, r = -0.315, p = .029, N = 48). Antidepressant efficacy: Both interventions produced clinically meaningful symptom reductions. At mid-treatment (T1) mean MADRS was 13.38 (SD = 5.27, N = 24) in the ketamine group versus 19.52 (SD = 7.07, N = 25) in the ECT group. At treatment end (T2) mean MADRS was 13.40 (SD = 6.89, N = 25) for ketamine and 13.75 (SD = 7.69, N = 24) for ECT. A significant Treatment Group × Time interaction was observed, F(1,43) = 6.93, p = .012, partial η2 = 0.139, indicating a faster antidepressant response with ketamine; between-group effect size for this interaction was d = 0.80. Specifically, percentage MADRS reduction from T0 to T1 was greater for ketamine (mean = -47.45%, SD = 23.43, n = 24) than for ECT (mean = -34.86%, SD = 21.29, n = 22). By T2, symptom reduction did not differ significantly between groups, indicating comparable end-of-treatment efficacy. Neurocognitive outcomes: Cognitive domain results varied by treatment. For ECT, a significant decline was observed in verbal memory (large effect sizes reported), whereas visual memory unexpectedly improved (small to moderate effect), possibly reflecting practice effects on that specific test. Executive functions remained relatively stable in the ECT group. In the ketamine group, performance improved significantly in attention (small effect), visual memory (small to moderate effect) and executive functions (small to moderate effect); however, one measure of verbal memory (delayed recall) showed a small but significant decline. Across domains, differences with p ≤ .05 had effect sizes generally greater than d = 0.5; the overall composite cognitive score difference reflected a smaller effect (d ≈ 0.38–0.40). When baseline MADRS was included as a covariate, the composite score comparison favoured ketamine (ECT: mean change -1.84%, SD = 20.34, n = 24; ketamine: mean change 4.07%, SD = 8.35, n = 24), but excluding MADRS from the model rendered the composite difference non-significant (F(1,46) = 1.73, p = .194, n = 48). Relationship between cognition and clinical response: Baseline cognitive performance did not predict symptom change to T2 in either treatment group. Change in cognitive performance and change in MADRS scores were not correlated, suggesting that cognitive improvements were not simply secondary to mood improvement. No systematic associations were found between baseline MADRS and baseline cognition except for the verbal memory correlation noted above. Other reported details: Mean number of ECT sessions was 12.36 (SD = 1.75, range 9–16); mean number of ketamine infusions was 6.76 (SD = 1.23, range 6–9). The extracted text does not provide a detailed adverse-event table or long-term follow-up outcomes.
Basso and colleagues interpret their findings as showing that serial ketamine administration and ECT are both effective acute treatments for depression in a naturalistic inpatient sample, but ketamine produces a faster initial antidepressant effect. Symptom reduction after one week of ketamine (three infusions) was greater than after one week of ECT (six sessions), whereas by the end of the respective courses (two weeks of ketamine versus four weeks of ECT) both groups had similar levels of symptom improvement. The investigators highlight the clinical relevance of a rapid onset of action for situations requiring urgent symptom reduction, such as high suicide risk, and note that additional ketamine infusions after the first week produced little further symptom reduction in their sample. With regard to cognition, the authors report divergent patterns: ECT was associated with a decline in verbal memory but relatively preserved executive function and even improvement in visual memory (which they suggest may reflect practice effects). Ketamine was associated with improvements in attention, visual memory and executive function but a small decline in delayed verbal recall. Overall, ketamine-treated patients showed better short-term global cognitive outcomes than those who received ECT (moderate effect size on the composite), leading the authors to characterise serial ketamine administration as having a small procognitive effect in the short term and a preferable cognitive profile compared with ECT. The study authors caution several limitations that temper interpretation. The design was naturalistic and non-randomised: patients chose treatment, no control group was included, and participants received concurrent and partially changing medications; these factors introduce potential selection and expectation biases. The ketamine group had less severe baseline depression but a longer episode duration; baseline MADRS was included as a covariate and did not materially alter key domain findings, but residual confounding cannot be excluded. The sample was heterogeneous with psychiatric and medical comorbidities, and the requirement to complete neurocognitive testing excluded patients with severe functional impairment, limiting generalisability. Assessments took place 1–3 days after treatment end, so longer-term cognitive and clinical trajectories were not assessed. The authors also note that practice effects may explain some cognitive improvements and that prior literature on ketamine's cognitive effects is mixed; one prior study found transient verbal memory impairment shortly after a single infusion, which may be consistent with their small verbal memory decline. In terms of implications, the investigators suggest that for middle-aged, chronic non-psychotic depressed patients—particularly those with treatment-related cognitive impairment—serial ketamine could be a favourable acute option because it combines rapid mood improvement with better short-term cognitive outcomes than ECT. They recommend randomised controlled trials with larger samples and longer-term follow-up (e.g. 6–12 months) to confirm these findings and to address maintenance strategies given known relapse rates after both ECT and ketamine.
Depressive disorder causes the highest overall disease burden of mental and neurological disorders in Europeas well as worldwide. 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. In addition, their effects often do not show as fast as desired, especially in severe depression. The limited treatment response exacerbates suffering for patients and may lead to higher risk of chronification, relapse, and suicide. Accordingly, there is a strong need for effective treatment options with a faster onset of action than conventional antidepressants. Received 16 September 2019; Received in revised form 13 January 2020; Accepted 13 January 2020 Secondly, a significant number of depressive patients show wide ranging cognitive deficits. 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. Cognitive impairment has been related to higher disability and disease burden, suicide risk, and treatment non-compliance. 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. 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 treatmentresistant depression is ECT. 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. Fear of adverse cognitive effects of ECT is common among patients and many report (shortlasting) post-ECT memory impairment a distressing and troublesome experience. Compared to other available antidepressant interventions, ECT has a relatively fast speed of onset, however, a new antidepressant intervention, namely treatment with the NMDA receptor antagonist ketamine is even more rapid with antidepressant responses within days. 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, 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 min after a single infusion, 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 functionsalthough onlyconducted 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. One previous study bycompared 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. 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.
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 2-week 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 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: 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, hyperor 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. 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. 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; additional clinical data with respect to comorbidities and medication are described in the supplement (S1-S3).
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 Fig.. Clinical assessments were part of the clinical routine and conducted by trained professionals. A German version of the Montgomery-Åsberg Depression Rating Scale (MADRS;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. 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 Tablefor a detailed description of the utilized measures and the respective cognitive domains. For the VLMT (verbal memory) parallel test versions were used. The cognitive assessment followed the same order of testing for each patient. The assessment was generally completed within 40-55 min 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).
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:. A MECTA 5000Q device (Somatics, Belleville, Illinois) was used to deliver ultra-brief 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 only modified if patients did not respond clinically or showed insufficient seizures during the course of ECT (i.e., motor response < 20 s or electroencephalogram seizure activity < 30 s). 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 min. 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.
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 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 Tablesand. The effect size dwas calculated for within-group (paired-samples t-tests) and between-group analyses (ANOVAs/AN-COVAs). 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, 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.
The two treatment groups did not differ regarding age, gender, education, or other demographic variables, see Table. 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). MADRS baseline scores were included as a covariate in the following between-group analyses. The two treatment groups did not differ regarding baseline cognitive performance (p > .05; see Tablein the supplement) and baseline MADRS scores were not related to baseline cognitive performance, except for verbal memory (r = -0.315, p = .029, N = 48, effect size moderate with d = 0.66).
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 η 2 = 0.139, 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 Note. TMT = Trail Making Test (e.g. in CERAD-Plus,. FWIT = Farbe-Wort-Interferenztest. VLMT = Verbaler Lern-und Merkfähigkeitstest. RAVLT = Rey Auditory Verbal Learning Test. a.
Change in performance (%) on the individual test measures and their comparison between groups can be found in Table, supplementary material. Changes in the different cognitive domains and the composite score are displayed in Fig.for both treatment groups. All differences with p ≤ .05 that were found in the different domains (attention, verbal memory, and executive functions) were characterized by large effect sizes (all d > 0.5), 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 considerably 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 betweengroup differences were found for immediate and visual memory.
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 performance (%) and change in MADRS scores (%) were not correlated. Baseline cognitive performance could not predict treatment response for any of the two groups.
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 midtreatment 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. Already a single ketamine infusion seems to rapidly reduce suicidal ideation. 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 memory was significantly reduced after ECT (with generally large effect sizes), which is in line with previous findings). 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;. 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 byfound 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. 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 byalso 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 min 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;. 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 procognitive 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, 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. 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,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 group. This finding is in line with othersthat 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 known 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 middleaged 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, 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. 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 againand no longterm cognitive impairments are reported. For ketamine, no negative effects on neurocognitive performance have been found 7 days post-treatment, or over a 4-week follow up period. 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%;.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 and 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. To sum up, a randomized controlled 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.
Create a free account to open full-text PDFs.
Permoda-Osip, A., Kisielewski, J., Bartkowska- Sniatkowska, A. et al. · Pharmacopsychiatry (2014)
Wilkinson, S. T., Ballard, E. D., Bloch, M. H. et al. · American Journal of Psychiatry (2017)
Papers in Blossom that reference this study
Lan, X-F., Wang, C-Y., Zhang, F. et al. · Child and Adolescent Psychiatry (2023)
Zavaliangos-Petropulu, A., Mcclintock, S. M., Khalil, J. et al. · Journal of Affective Disorders (2023)
Rhee, T. G., Shim, S. R., Forester, B. P. et al. · JAMA Psychiatry (2022)
Luppi, A. I., Hansen, J. Y., Adapa, R. et al. · Biorxiv (2022)
Albott, C. S., Lim, K. O., Erbes, C. et al. · Journal of Affective Disorders (2022)
Shiroma, P. R., Velit-Salazar, M. R., Vorobyov, Y. · Clinical Drug Investigation (2022)
Beaudequin, D. A., Can, A. T., Jones, M. et al. · Psychiatry Research (2021)
Zhou, Y-L., Wang, C., Lan, X-F. et al. · Journal of Psychiatric Research (2021)
Haarsma, J., Harmer, C. J., Tamm, S. · Brain and Neuroscience Advances (2021)
Davis, M. T., Dellagiogia, N., Maruff, P. et al. · Translational Psychiatry (2021)
Nichols, D. E., Walter, H. · Pharmacopsychiatry (2020)
Veraart, J. K. E., Smith-Apeldoorn, S. Y., Spaans, H. P. et al. · Journal of Affective Disorders (2020)