Ketamine or ECT? What Have We Learned From the KetECT and ELEKT-D Trials?

1. Two recent clinical trials, KetECT and ELEKT-D, compared the effectiveness of ketamine and electroconvulsive therapy (ECT) for major depressive disorder. Notably, these trials reported marked differences in ECT's clinical outcomes of, with remission rates of 63% for KetECT and a strikingly lower rate of 22% for ELEKT-D, while the remission rates for ketamine were 46% and 38%, respectively. Considering that the primary objective of both trials was to compare the standard treatment (ECT) with an experimental intervention (ketamine), it is crucial to highlight the pronounced disparities in ECT's clinical outcomes. This article offers a comprehensive comparison of these trials while also exploring how patient characteristics, treatment protocols, and study designs may contribute to such pronounced outcome discrepancies. These differences highlight the heterogeneous nature of depression and underscore the need for personalized treatments. These studies also provide valuable insights into identifying the most suitable candidates for ketamine and ECT.

The Content of Physiotherapy and Factors Impacting on Reablement - A National Study.

Purpose: Reablement is a multidisciplinary intervention aimed at promoting function and independence for people with functional decline. Detailed descriptions of various professions' actions are needed for organization and evaluation of reablement services. This study describes physiotherapy practice in a reablement context in Swedish municipalities, focusing on the content and magnitude of interventions. Methods: Physiotherapists (n=108) from 34 municipalities answered a web-based survey covering the target group, content and duration of their actions, and number of contacts initiated over a 3-week period. Data were analyzed with descriptive statistics and multiple logistic regression. Results: Overall, 1005 cases were reported, with a mean age of 78.9 years (SD: 11.7); about 91% (n=912) were aged ≥65 and 61% (n=612) were women. About 70% were allocated to home care; 16% (n=160) of these had minor functional limitations (eg, needing safety alarms/help with domestic tasks), and 55% (n=550) had major functional limitations (eg, needing help with personal activities of daily living). The most reported actions were providing technical aids (60.8%, n=576), instructions/counseling (41.5%, n=393), walking/climbing stairs (27.6%, n=262), strength training (27.2%, n=258), and fall prevention (25.5%, n=242). Almost half of the cases included one action (n=494) and about 89% (n=890) targeted primary needs (body functions, walking indoors, self-care, or domestic life), mainly in clients with major functional limitations (odds ratio=2.96; 95% confidence interval: 1.95-4.49). About 50% (n=517) of the cases involved 1-2 contacts; about 55% (n=549) were completed within 3 weeks. Exercise was associated with ≥6 visits over ≥7 weeks. Supervision of home care staff was performed in 19.1% (n=181) of cases. Conclusion: Reablement physiotherapy mostly comprises a few actions over a relatively short period. Whether this is a conscious strategy based on the purpose of home-based physiotherapy or clients' needs and wishes, or conversely an expression of limited resources, remains to be investigated.

Further development and evaluation of a questionnaire targeting person-centred outpatient care for persons with long-term conditions.

AIM: To further develop the Person-Centred Care instrument for outpatient care (PCCoc), evaluate its user-friendliness and content validity, and to explore its basic psychometric properties in various outpatient settings for adults with long-term conditions. BACKGROUND: Person-centred care (PCC) has been identified as a key factor to provide high-quality care. However, there is still a lack of instruments that are based on a clearly defined framework for PCC for persons with long-term conditions in an outpatient context. The PCCoc is a patient-reported experience measure under development aiming to fill this gap. METHODS: First, the 35-item PCCoc was reviewed and further developed in collaboration with a user-council. Second, the revised 36-item PCCoc was tested among persons receiving outpatient care for various long-term conditions. A total of 179 persons with long-term conditions from four different specialties participated in the study. User-friendliness and content validity were assessed through structured interviews and relevance ratings of each item. Content validity index (CVI) for individual items (I-CVI) and for the overall scale (S-CVI) were calculated, and basic psychometric properties of the PCCoc using classical test theory were explored. RESULTS: It took a median of 8 min for participants to complete the PCCoc. The majority found items easy to understand, response categories distinct and that no important areas were missing. Results from the CVI analyses suggested that participants found the content of the PCCoc relevant (I-CVI range 0.82-1, S-CVI = 0.95). All psychometric properties examined were satisfactory (e.g., item-total correlations, 0.45-0.75; Cronbach's alpha, 0.96; test-retest stability, 0.83). CONCLUSION: The PCCoc was considered user-friendly and relevant by the intended users, and its psychometric properties were satisfactory. This implies that the PCCoc can be a valuable instrument for evaluating and developing PCC in outpatient care for persons with long-term conditions. However, further studies of the PCCoc are needed to establish its measurement properties in various outpatient settings.

Transformation of Rasch model logits for enhanced interpretability.

BACKGROUND: The Rasch model allows for linear measurement based on ordinal item responses from rating scales commonly used to assess health outcomes. Such linear measures may be inconvenient since they are expressed as log-odds units (logits) that differ from scores that users may be familiar with. It can therefore be desirable to transform logits into more user-friendly ranges that preserve their linear properties. In addition to user-defined ranges, three general transformations have been described in the literature: the least measurable difference (LMD), the standard error of measurement (SEM) and the least significant difference (LSD). The LMD represents the smallest possible meaningful unit, SEM relates the transformed scale values to measurement uncertainty (one unit on the transformed scale represents roughly one standard error), and LSD represents a lower bound for how coarse the transformed scale can be without loss of valid information. However, while logit transformations are relatively common in the health sciences, use of LMD, SEM and LSD transformations appear to be uncommon despite their potential role. METHODS: Logit transformations were empirically illustrated based on 1053 responses to the Epworth Sleepiness Scale. Logit measures were transformed according to the LMD, SEM and LSD, and into 0-10, 0-100, and the original raw score (0-24) ranges. These transformations were conducted using a freely available Excel tool, developed by the authors, that transforms logits into user-defined ranges along with the LMD, SEM and LSD transformations. RESULTS: Resulting LMD, SEM and LSD transformations ranged 0-34, 0-17 and 0-12, respectively. When considering these relative to the three user-defined ranges, it is seen that the 0-10 range is narrower than the LSD range (i.e., loss of valid information), and a 0-100 range gives the impression of better precision than there is, since it is considerably wider than the LMD range. However, the 0-24 transformation appears reasonable since it is wider than the LSD, but narrower than the LMD ranges. CONCLUSIONS: It is suggested that LMD, SEM and LSD transformations are valuable for benchmarking in deciding appropriate ranges when transforming logit measures. This process can be aided by the Excel tool presented and illustrated in this paper.

Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized, Open-Label, Non-Inferiority Trial (KetECT).

BACKGROUND: Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression. METHODS: Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale score ≤10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session. RESULTS: In total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52). CONCLUSION: Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.

The effect of electroconvulsive therapy on neuroinflammation, behavior and amyloid plaques in the 5xFAD mouse model of Alzheimer's disease.

Microglial cells are affected in Alzheimer's disease (AD) and interact with amyloid-beta (Aß) plaques. Apart from memory loss, depression is common in patients with AD. Electroconvulsive therapy (ECT) is an anti-depressive treatment that may stimulate microglia, induce neuroinflammation and alter the levels of soluble Aß, but the effects of ECT on microglia and Aß aggregation in AD are not known. We investigated the short- and long-term effects of ECT on neuroinflammation and Aß accumulation. 5xFAD mice received either electroconvulsive stimulation (ECS n = 26) or sham treatment (n = 25) for 3 weeks. Microglia and Aß were analyzed in samples collected 24 h, 5 weeks, or 9 weeks after the last treatment. Aß plaques and microglia were quantified using immunohistochemistry. The concentration of soluble Aß and cytokines was quantified using ELISA and levels of Aß aggregates were measured with Western Blot. Microglial phagocytosis of Aß in the hippocampus was evaluated by flow cytometry in Methoxy-X04 injected mice 24 h following the last ECS treatment. Y-maze and Elevated plus maze were performed to study behavior after 5 weeks. We could not detect any significant short- or long-term effects of ECS on Aß pathology or neuroinflammation, but ECS reduced abnormal behavior in the Elevated Plus maze.

A Naturalistic, European Multi-Center Clinical Study of Electrodermal Reactivity and Suicide Risk Among Patients With Depression.

Background: Electrodermal hyporeactivity has been proposed as a marker of suicidal risk. The EUDOR-A study investigated the prevalence of electrodermal hyporeactivity among patients with depression and its association with attempted and completed suicide. Methods: Between August 2014 and March 2016, 1,573 in- and outpatients with a primary diagnosis of depression (active or remission phase) were recruited at 15 European psychiatric centers. Each patient was followed-up for 1 year. Electrodermal activity was assessed at baseline with the ElectroDermal Orienting Reactivity Test. Data on the sociodemographic characteristics, clinical diagnoses, and treatment of the subjects were also collected. The severity of the depressive symptoms was assessed through the Montgomery-Asberg Depression Rating Scale. Information regarding number, time, and method of suicide attempts was gathered at baseline and at the end of the 1-year follow-up. The same data were collected in case of completed suicide. Results: Hyporeactive patients were shown to be significantly more at risk of suicide attempt compared to reactive patients, both at baseline and follow-up. A sensitivity of 29.86% and a positive predictive value (PPV) of 46.77% were found for attempted suicide at baseline, while a sensitivity of 35.36% and a PPV of 8.92% were found for attempted suicide at follow-up. The sensitivity and PPV for completed suicide were 25.00 and 0.61%, respectively. However, when controlled for suicide attempt at baseline, the association between hyporeactivity and follow-up suicide attempt was no longer significant. The low number of completed suicides did not allow any analysis.

Self-Reported Needs for Care, Support and Treatment of Persons Who Frequently Visit Psychiatric Emergency Rooms in Sweden.

AIM: To investigate self-reported needs for care, support and treatment among persons who frequently visit psychiatric emergency rooms (PERs). DESIGN: A cross-sectional design. Qualitative and quantitative data were collected using an interview-based manual. Qualitative data were analysed using content analysis, whereas quantitative data were analysed using descriptive, non-parametric statistical tests. RESULTS: Persons who frequently visit PERs self-reported unmet needs for care, support and treatment in life domains such as health, socialisation, daytime activities, and emotional and financial security. CONCLUSION: To meet the needs of persons who frequently visit PERs, close cooperation between concerned welfare actors should be implemented.

Clinical profiles and temporal patterns of psychiatric emergency room visitors in Sweden.

AIMS: To describe persons visiting the psychiatric emergency room (PER) in Sweden and to compare persons who frequently (PFV) and infrequently (PIFV) visit PERs in terms of group size, age, gender, PER location inside versus outside the home municipality, diagnosis (ICD 10), temporal patterns of visits and hospital admissions. METHODS: This register study included all visits to PERs in one Swedish county over 3 years, 2013-2015 (N = 67,031 visits). The study employed descriptive statistics as well as Chi-square tests combined with Bonferroni correction to compare PFV with PIFV. RESULTS: Of the total of 27,282 visitors, 2201 (8.1%) were identified as PFV (five or more visits within 12 months) and they accounted for 38.1% of the total visits. The study found differences between PFV and PIFV in gender, diagnostic profile, hospital admissions and temporal patterns. Differences were also detected with regard to distance between PERs and home municipalities. However, no age-related differences were found between the two groups. CONCLUSIONS: PFV and PIFV have different clinical profiles and temporal patterns. These results may be important when planning, developing and evaluating interventions targeting the needs of each group, which is in accordance with a person-centred approach. Such an approach might eventually result in fewer visits to PERs.

Spatial memory impairment in Morris water maze after electroconvulsive seizures.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most efficient treatments for severe major depression, but some patients suffer from retrograde memory loss after treatment. Electroconvulsive seizures (ECS), an animal model of ECT, have repeatedly been shown to increase hippocampal neurogenesis, and multiple ECS treatments cause retrograde amnesia in hippocampus-dependent memory tasks. Since recent studies propose that addition of newborn hippocampal neurons might degrade existing memories, we investigated whether the memory impairment after multiple ECS treatments is a cumulative effect of repeated treatments, or if it is the result of a delayed effect after a single ECS. METHODS: We used the hippocampus-dependent memory task Morris water maze (MWM) to evaluate spatial memory. Rats were exposed to an 8-day training paradigm before receiving either a single ECS or sham treatment and tested in the MWM 24 h, 72 h, or 7 days after this treatment, or multiple (four) ECS or sham treatments and tested 7 days after the first treatment. RESULTS: A single ECS treatment was not sufficient to cause retrograde amnesia whereas multiple ECS treatments strongly disrupted spatial memory in the MWM. CONCLUSION: The retrograde amnesia after multiple ECS is a cumulative effect of repeated treatments rather than a delayed effect after a single ECS.

Embedded Ultrathin Cluster Electrodes for Long-Term Recordings in Deep Brain Centers.

Neural interfaces which allow long-term recordings in deep brain structures in awake freely moving animals have the potential of becoming highly valuable tools in neuroscience. However, the recording quality usually deteriorates over time, probably at least partly due to tissue reactions caused by injuries during implantation, and subsequently micro-forces due to a lack of mechanical compliance between the tissue and neural interface. To address this challenge, we developed a gelatin embedded neural interface comprising highly flexible electrodes and evaluated its long term recording properties. Bundles of ultrathin parylene C coated platinum electrodes (N = 29) were embedded in a hard gelatin based matrix shaped like a needle, and coated with Kollicoat™ to retard dissolution of gelatin during the implantation. The implantation parameters were established in an in vitro model of the brain (0.5% agarose). Following a craniotomy in the anesthetized rat, the gelatin embedded electrodes were stereotactically inserted to a pre-target position, and after gelatin dissolution the electrodes were further advanced and spread out in the area of the subthalamic nucleus (STN). The performance of the implanted electrodes was evaluated under anesthesia, during 8 weeks. Apart from an increase in the median-noise level during the first 4 weeks, the electrode impedance and signal-to-noise ratio of single-units remained stable throughout the experiment. Histological postmortem analysis confirmed implantation in the area of STN in most animals. In conclusion, by combining novel biocompatible implantation techniques and ultra-flexible electrodes, long-term neuronal recordings from deep brain structures with no significant deterioration of electrode function were achieved.

Effect of electroconvulsive seizures on cognitive flexibility.

Electroconvulsive seizures (ECS), an animal model of electroconvulsive therapy, strongly stimulate hippocampal neurogenesis, but it is not known how this relates to the therapeutic effect or to the unwanted cognitive side effects. Recent findings suggest that neurogenesis might be important for flexible learning in changing environments. We hypothesize that animals receiving ECS treatment, which induces hippocampal neurogenesis, will show enhanced cognitive flexibility compared with controls. We have utilized a touch screen-based cognitive test (location discrimination (LD) task) to assess how five consecutive ECS treatments affect cognitive flexibility (measured as reversal of cognitive strategy) as well as spatial pattern separation ability. ECS-treated animals performed more reversals in the LD task earlier than controls over the 9 experimental weeks irrespective of spatial separation of visual stimuli, indicating an enhanced cognitive flexibility but unaffected pattern separation ability after ECS. We observed no correlation between hippocampal neurogenesis and the number of performed reversals during the last experimental week. This is the first study to elucidate the effect of ECS on cognitive flexibility. Our results indicate that ECS improves cognitive flexibility without affecting spatial pattern separation ability. Whether cognitive flexibility is enhanced via neurogenesis or other ECS-modulated processes, remains unknown. © 2016 Wiley Periodicals, Inc.

Effect of electroconvulsive seizures on pattern separation.

Strategies employing different techniques to inhibit or stimulate neurogenesis have implicated a role for adult-born neurons in the therapeutic effect of antidepressant drugs, as well as a role in memory formation. Electroconvulsive seizures (ECS), an animal model of electroconvulsive therapy, robustly stimulate hippocampal neurogenesis, but it is not known how this relates to either therapeutic efficacy or unwanted cognitive side effects. We hypothesized that the ECS-derived increase in adult-born neurons would manifest in improved pattern separation ability, a memory function that is believed to be both hippocampus-dependent and coupled to neurogenesis. To test this hypothesis, we stimulated neurogenesis in adult rats by treating them with a series of ECS and compared their performances in a trial-unique delayed nonmatching-to-location task (TUNL) to a control group. TUNL performance was analyzed over a 12-week period, during which newly formed neurons differentiate and become functionally integrated in the hippocampal neurocircuitry. Task difficulty was manipulated by modifying the delay between sample and choice, and by varying the spatial similarity between target and distracter location. Although animals learned the task and improved the number of correct responses over time, ECS did not influence spatial pattern separation ability.

Environmental enrichment, exercise and corticosterone affect endothelial cell proliferation in adult rat hippocampus and prefrontal cortex.

Stress and environmental enrichment have opposing effects on cerebral cellular plasticity. Stress-induced disturbances in neuronal and glial plasticity have been implicated in the pathophysiology of affective disorders. Patients with depression often show volume reductions in specific brain regions. The mechanisms behind these changes are not well understood, but animal studies have indicated that increased levels of glucocorticoids and stress have negative impact on the neuronal and glial cell populations. On the contrary, enriched environment and physical activity have positive effects. In this study we have examined the effect of corticosterone (CORT), environmental enrichment (EE) and running on angiogenesis in hippocampus and prefrontal cortex (PFC). We demonstrate a dramatic inhibition in endothelial cell proliferation in these brain regions in CORT-treated rats. Environmental enrichment had the opposite effect and stimulated endothelial cell proliferation both in the hippocampus and in the PFC. Running had a stimulatory effect in hippocampus, but not in the PFC. We suggest that the angiostatic effect of CORT demonstrated in this study might be paralleled in human subjects exposed to high levels of stress hormones for prolonged periods of time. Raised cortisol levels in depressed or old patients could, by reducing endothelial cell formation/turnover, lead to rarefaction and aging of the vascular bed, and as a result, neuronal function could be impaired. It is tempting to speculate that a physically and intellectually active life may protect against stress-induced vascular changes. Therapeutic agents also targeting the cerebral vasculature could consequently constitute a new tool in the combat of stress-related disorders.

Differential inhibition of neurogenesis and angiogenesis by corticosterone in rats stimulated with electroconvulsive seizures.

Antidepressant drugs and electroconvulsive seizure (ECS)-treatment, an animal model of electroconvulsive therapy, induce neurogenesis in adult rats. Stress and high levels of corticosterone (CORT) on the contrary inhibit neurogenesis. Hippocampal neurogenesis has been described to occur in an angiogenic niche where proliferation of neural progenitors takes place in an environment with active vascular growth. Here we investigate the effect of ECS-treatment on the proliferation of endothelial cells and neuronal precursors in hippocampus of CORT-treated rats. Bromodeoxyuridine (BrdU) was used to identify dividing cells. The number of newborn neuronal precursors and endothelial cells was quantified in the subgranular zone (SGZ) and the molecular layer (ML) of the dentate gyrus. The increase in neuronal precursor proliferation in the SGZ following ECS-treatment was not inhibited by elevated levels of CORT despite CORT strongly inhibiting ECS-induced endothelial cell proliferation. Also in the ML CORT-treatment inhibited the ECS-induced angiogenic response. We conclude that despite common factors regulating neurogenesis and angiogenesis, ECS-induced proliferation of neuronal precursors can take place even if the angiogenic response is blunted. Whether inhibition of angiogenesis affects other steps in the chain of events leading to the formation of fully integrated granule neurons remains to be elucidated.

Corticosterone-induced inhibition of gliogenesis in rat hippocampus is counteracted by electroconvulsive seizures.

BACKGROUND: Volumetric changes and glial pathology have been reported in the central nervous system (CNS) of patients with depressive disorder, an illness often associated with elevated glucocorticoid levels. Glucocorticoids reduce gliogenesis in the adult rat CNS. Electroconvulsive seizure (ECS)-treatment, an animal model for the antidepressant treatment electroconvulsive therapy, can enhance proliferation of glial cells. This study examined glial cell proliferation in response to ECS in rats whose glucocorticoid levels were elevated to mimic the conditions seen in depression. METHODS: Rats were injected daily for seven days with either corticosterone or vehicle. ECS- or sham- treatment was given once daily during the first five days. Proliferating cells in the hippocampus were labeled with bromodeoxyuridine and analyzed for co-labeling with the glial cell markers NG2, Ox42, S-100beta and Rip. RESULTS: ECS counteracted the glucocorticoid-induced inhibition of NG2+, Ox42+ and Rip+ cell proliferation, and the gliogenesis rate was restored to baseline levels. Volumetric changes in rats treated with ECS were detected. CONCLUSIONS: Our results show that ECS-treatment affects the proliferation of glial cells even in the presence of elevated levels of glucocorticoids. This result adds to an increasing number of studies suggesting that antidepressant treatment can counteract degenerative processes associated with major depression.

Electroconvulsive seizures induce angiogenesis in adult rat hippocampus.

BACKGROUND: Electroconvulsive seizure (ECS)-treatment, a model for electroconvulsive therapy (ECT) has been shown to induce proliferation of endothelial cells in the dentate gyrus (DG) of adult rats. Here we quantified the net angiogenic response after chronic ECS-treatment in the molecular layer (ML) of the dentate gyrus. Patients undergoing ECT are routinely oxygenated to prevent hypoxia, a known inducer of angiogenesis. Therefore we also examined the effect of oxygenation on ECS-induced proliferation of endothelial cells. METHODS: Total endothelial cell numbers and vessel length were estimated utilizing design based stereological analysis methods. Endothelial cell proliferation in the DG after ECS with or without oxygenation was assessed using bromodeoxyuridine. RESULTS: The total number of endothelial cells and total vessel length was increased. Oxygenation did not abolish the ECS-induced proliferation of endothelial cells in the DG. CONCLUSIONS: ECS-treatment induces a dramatic increase in endothelial cell proliferation leading to a 30% increase in the total number of endothelial cells. The increase in cell number resulted in a 16% increase in vessel length. These findings raise the possibility that similar vascular growth is induced by clinically administered ECT.