There is a strong medical need to develop suitable biomarkers to improve the diagnosis and treatment of depression, particularly in predicting response to certain therapeutic approaches such as electroconvulsive therapy (ECT). MicroRNAs are small non-coding RNAs that have the ability to influence the transcriptome as well as proteostasis at the systems level. Here, we investigate the role of circulating microRNAs in depression and response prediction towards ECT. Of the 64 patients with treatment-resistant major depression (MDD) who received ECT treatment, 62.5% showed a response, defined as a reduction of ≥50% in the MADRS total score from baseline. We performed smallRNA sequencing in blood samples that were taken before the first ECT, after the first and the last ECT. The microRNAome was compared between responders and non-responders. Co-expression network analysis identified three significant microRNA modules with reverse correlation between ECT- responders and non-responders, that were amongst other biological processes linked to inflammation. A candidate microRNA, namely miR-223-3p was down-regulated in ECT responders when compared to non-responders at baseline. In line with data suggesting a role of miR-223-3p in inflammatory processes we observed higher expression levels of proinflammatory factors Il-6, Il-1b, Nlrp3 and Tnf-α in ECT responders at baseline when compared to non-responders. ROC analysis of confirmed the diagnostic power of miR-223-3p demarcating ECT-responders from non-responder subjects (AUC = 0.76, p = 0.0031). Our data suggest that miR-223-3p expression and related cytokine levels could serve as predictors of response to ECT in individuals with treatment-resistant depressive disorders.

MicroRNAs (miRNAs) may contribute to the development of depression and its treatment. Here, we used the hypothesis-neutral approach of next-generation sequencing (NGS) to gain comprehensive understanding of the effects of a course of electroconvulsive stimulation (ECS), the animal model equivalent of electroconvulsive therapy (ECT), on rat hippocampal miRNAs. Significant differential expression (p < 0.001) of six hippocampal miRNAs was noted following NGS, after correcting for multiple comparisons. Three of these miRNAs were upregulated (miR-132, miR-212, miR-331) and three downregulated (miR-204, miR-483, miR-301a). qRT-PCR confirmed significant changes in four of the six miRNAs (miR-132, miR-212, miR-204, miR-483). miR-483 was also significantly reduced in frontal cortex, though no other significant alterations were noted in frontal cortex, cerebellum, or whole blood. Assessing the translatability of the results, miR-132 and miR-483 were significantly reduced in whole blood samples from medicated patients with depression (n = 50) compared to healthy controls (n = 45), though ECT had no impact on miRNA levels. Notably, pre-ECT miR-204 levels moderately positively correlated with depression severity at baseline and moderately negatively correlated with mood score reduction post-ECT. miRNAs were also examined in cerebrospinal fluid and serum from a separate cohort of patients (n = 8) treated with ECT; no significant changes were noted post-treatment. However, there was a large positive correlation between changes in miR-212 and mood score post-ECT in serum. Though replication studies using larger sample sizes are required, alterations in miRNA expression may be informative about the mechanism of action of ECS/ECT and in turn might give insight into the neurobiology of depression.

Electroconvulsive therapy (ECT) is a quick-acting and powerful antidepressant treatment considered to be effective in treating severe and pharmacotherapy-resistant forms of depression. Recent studies have suggested that epigenetic mechanisms can mediate treatment response and investigations about the relationship between the effects of ECT and DNA methylation have so far largely taken candidate approaches. In the present study, we examined the effects of ECT on the methylome associated with response in depressed patients (n = 34), testing for differentially methylated CpG sites before the first and after the last ECT treatment. We identified one differentially methylated CpG site associated with the effect of ECT response (defined as >50% decrease in Hamilton Depression Rating Scale score, HDRS), TNKS (q < 0.05; p = 7.15 × 10−8). When defining response continuously (ΔHDRS), the top suggestive differentially methylated CpG site was in FKBP5 (p = 3.94 × 10−7). Regional analyses identified two differentially methylated regions on chromosomes 8 (Šídák’s p = 0.0031) and 20 (Šídák’s p = 4.2 × 10−5) associated with ΔHDRS. Functional pathway analysis did not identify any significant pathways. A confirmatory look at candidates previously proposed to be involved in ECT mechanisms found CpG sites associated with response only at the nominally significant level (p < 0.05). Despite the limited sample size, the present study was able to identify epigenetic change associated with ECT response suggesting that this approach, especially when involving larger samples, has the potential to inform the study of mechanisms involved in ECT and severe and treatment-resistant depression.

Introduction A burst suppression pattern in the electroencephalogram represents a down-regulated brain state, which also occurs in the postictal phase of electroconvulsive therapy (ECT). Suppressive actions of the brain to terminate the seizure are thought to be necessary for the efficacy of ECT. On the other hand, recent studies showed an association of burst suppression in general anesthesia or sedation with (postprocedural) cognitive complications. Methods We retrospectively examined the length of postictal burst suppression and reorientation time in 49 ECT sessions of 25 consecutive patients. Burst suppression duration was determined by bispectral index monitoring and defined as the time with a bispectral index value of less than 20%. The association between duration of burst suppression and reorientation time was analyzed with multivariate logistic and linear regression analysis controlling for several covariates. Results The reorientation time showed a statistically significant association with the duration of burst suppression, but with no other variable. Longer phase of postictal burst suppression predicted longer reorientation time in the recovery room (P = 0.046). Conclusions The association between the duration of postictal burst suppression and reorientation time after ECT in this sample suggests that (not only the efficacy but also the) cognitive adverse effects of ECT might be related to the extent of postictal central inhibition after the termination of the seizure.

During the rapid rise of the COVID-19 pandemic, a reduction of the numbers of patients presenting to emergency departments has been observed. We present an early study from a German psychiatric hospital to assess the dynamics of mental health emergency service utilization rates during the COVID-19 pandemic. Our results show that the numbers of emergency presentations decreased, and a positive correlation between these numbers and mobility of the general public suggests an impact of extended measures of social distancing. This finding underscores the necessity of raising and sustaining awareness regarding the threat to mental health in the context of the pandemic.

Objectives: Evidence points towards an important relationship between the antidepressant effects of electroconvulsive therapy (ECT) and the modulation of the immune system. To further elucidate this interplay, we performed a study on the effects of the antidepressant treatment by ECT on 25 cytokines in patients with depression.Methods: We measured 25 different cytokines (interleukin (IL)-1β, IL-1RA, Il-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17, tumor necrosis factor-α, interferon (IFN)-α, IFN-γ, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein (MIP)-1α, MIP-1β, IFN-γ-induced protein 10 (IP-10), monokine induced by IFN-γ, Eotaxin, Rantes and monocyte chemoattractant protein 1) in the cerebrospinal fluid (CSF) and blood of 12 patients with a severe and treatment-resistant depressive episode before and after a course of ECT.Results: CSF levels of IP-10, IL-5 and IL-8 were elevated after ECT and more ECT sessions were associated with the differences of CSF levels before and after ECT of IFN-γ, IL-2RA, Rantes, IL-6 and IL-1β. Responders and/or remitters had a decrease of CSF levels of IL-17, MIP-1α, Rantes and IL-2R during ECT. CSF IP-10 levels increased less during ECT in patients who had a remission.Conclusions: Although the sample size was small, we found different effects of the ECT treatment per se and of the antidepressant action induced by ECT in CSF and blood.

Objective Preclinical evidence suggests a role for brain-derived neurotrophic factor (BDNF) in the mode of action of electroconvulsive therapy (ECT). Clinical data regarding BDNF levels in serum or plasma are more inconsistent. We measured BDNF levels from the cerebrospinal fluid (CSF) in patients with major depression before and shortly after a course of ECT. Methods Cerebrospinal fluid and serum BDNF levels were determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Results We included 9 patients with a severe depressive episode within a major depressive disorder into the study. The CSF BDNF concentrations at baseline were lower compared with those CSF BDNF levels after the complete ECT treatment (P = 0.042), whereas no such a constellation was found for serum BDNF. No associations between the BDNF levels and the amount of individual ECT sessions or the reduction of the depressive symptoms were found. Conclusions For the first time, it has been shown that CSF BDNF concentrations increase during a course of ECT in patients with a severe unipolar depressive episode, which is in line with the neurotrophin hypothesis as a mode of action of ECT, although it was not possible to demonstrate either a dose-effect relation or a relationship with the actual antidepressant effects in our small sample. Major limitation is the small sample size.

Electroconvulsive therapy (ECT) is an effective treatment for depressive disorders. In certain cases, ECT-associated anaesthesia can be improved by the use of ketofol (i.e., S-ketamine + propofol). We aimed to evaluate the empirical mixing ratio of ketofol in these cases for better clinical implementation. We retrospectively investigated n = 52 patients who received 919 ECT sessions with S-ketamine plus propofol as anaesthetic agents. Several anaesthesia and ECT-related parameters including doses of S-ketamine and propofol were analysed. The mean empirically determined S-ketamine/propofol ratio was 1.38 (SD ± 0.57) for 919 individual ECT sessions and 1.52 (SD ± 0.62) for 52 patients, respectively. The mean relative dose was 0.72 (± 0.18) mg/kg S-ketamine and 0.54 (± 0.21) mg/kg propofol. Higher propofol dose was associated with poorer seizure quality. Seizure quality and time in recovery room were significantly influenced by age. Ketofol could be an option to exploit the advantageous qualities of S-ketamine and propofol, if both doses are reduced compared with single use of S-ketamine or propofol. Patients with poor seizure quality may benefit from lower propofol doses, which are applicable by the addition of ketamine. An empirically determined mixing ratio in favour of ketamine turned out to be preferable in a clinical setting. Recovery time was primarily prolonged by higher age rather than by ketamine dose, which had previously often been associated with a prolonged monitoring time in the recovery room. These new findings could improve electroconvulsive therapy and should be replicated in a prospective manner.

Carolin Hoyer Hanna Luise Schmidt Laura Kranaster Angelika Alonso 1Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany; 2Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany Background and purpose: The comorbidity of psychiatric disorders and cerebrovascular disease appears to be complex with underlying bidirectional influences. Hitherto, research has focused mainly on the evaluation of stroke risk in particular psychiatric disorders; only a few studies have assessed their role in the acute natural history of stroke. The aim of this study was to provide a perspective on psychiatric premorbidity and its impact on stroke severity, psychiatric complications during the initial treatment phase, and the short-term functional outcome of stroke. Patients and methods: We retrospectively studied the impact of a predocumented psychiatric diagnosis (PDPD) on stroke severity, short-term functional outcome, and psychiatric complications in a sample of 798 patients consecutively admitted for acute ischemic or hemorrhagic stroke by performing a chart review. Group comparisons (PDPD vs non-PDPD) with adjustment for covariates were carried out either using multivariate analysis of variance or logistic regression analysis. Results: More severe strokes (ie, mean National Institute of Health Stroke Scale score on admission 10.1±7.9 vs 7.5±7.4; F(10,796)=18.5, p<0.0001) and higher prevalence of poor outcome (73.7 vs 54.9%; OR: 2.6, standard error: 0.5, z=4.82, p<0.0001) was found in patients with a documented psychiatric diagnosis at the time of stroke, as well as a higher rate of psychiatric complications during the initial treatment phase (46.7 vs 28.9%; OR: −0.78, z=4.59, p<0.0001). Conclusion: Our data have clinical implications in that they call for identification of psychiatric premorbidity or comorbidity through careful history-taking and particularly close monitoring for psychiatric complications with respect to their potentially negative impact on outcome after stroke.

Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associated with accelerated cellular aging as well as aging-related phenotypes and comorbidity observed in Klotho deficiency. Soluble α-Klotho (sKlotho) serum levels in patients with a major depressive episode and either undergoing electroconvulsive therapy (n = 16) or a monotherapy with an antidepressant (n = 37) were investigated. We measured the sKlotho serum levels in those patients before and after treatment and compared the baseline levels with those of age-matched healthy controls (n = 39). No group differences were found between the baseline sKlotho levels of patients and controls (573.5 pg/ml vs. 563.8 pg/ml; p = 0.80) and between pre- and post-treatment in the patients with depression (563.8 pg/ml vs. 561.8 pg/ml; p = 0.15), when treated either with electroconvulsive therapy or antidepressant. The major limitation of our study might be that peripheral material such as serum might not reliably reflect processes in the central nervous system. In sum, this first study on peripheral sKlotho levels in a clinical sample cannot confirm a global Klotho dysregulation in depression as it has been already suggested by others. Nonetheless, further preclinical and clinical studies on the involvement of Klotho in affective disorders should be carried out.

For patients with depression treated with electroconvulsive therapy (ECT), the novel seizure quality index (SQI) can predict the risk of non-response (and non-remission)—as early as after the second ECT session—based the extent of several ictal parameters of the seizure. We aim to test several CSF markers on their ability to predict the degree of seizure quality, measured by the SQI to identify possible factors, that could explain some variability of the seizure quality. Baseline CSF levels of metabolites from the kynurenine pathway, markers of neurodegeneration (tau proteins, β-amyloids and neurogranin), elements of the innate immune system, endocannabinoids, sphingolipids, neurotrophic factors (VEGF) and Klotho were measured before ECT in patients with depression (n = 12) to identify possible correlations with the SQI by Pearson's partial correlation. Negative, linear relationships with the SQI for response were observed for CSF levels of T-tau (rpartial = − 0.69, p = 0.019), phosphatidylcholines (rpartial = − 0.52, p = 0.038) and IL-8 (rpartial = − 0.67, p = 0.047). Regarding the SQI for remission, a negative, linear relationship was noted with CSF levels of the endocannabinoid AEA (rpartial = − 0.70, p = 0.024) and CD163 (rpartial = − 0.68, p = 0.029). In sum, CSF Markers for the innate immune system, for neurodegeneration and from lipids were found to be associated with the SQI for response and remission after adjusting for age. Consistently, higher CSF levels of the markers were always associated with lower seizure quality. Based on these results, further research regarding the mechanism of seizure quality in ECT is suggested.

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BACKGROUND AND PURPOSE:The comorbidity of psychiatric disorders and cerebrovascular disease appears to be complex with underlying bidirectional influences. Hitherto, research has focused mainly on the evaluation of stroke risk in particular psychiatric disorders; only a few studies have assessed their role in the acute natural history of stroke. The aim of this study was to provide a perspective on psychiatric premorbidity and its impact on stroke severity, psychiatric complications during the initial treatment phase, and the short-term functional outcome of stroke. PATIENTS AND METHODS:We retrospectively studied the impact of a predocumented psychiatric diagnosis (PDPD) on stroke severity, short-term functional outcome, and psychiatric complications in a sample of 798 patients consecutively admitted for acute ischemic or hemorrhagic stroke by performing a chart review. Group comparisons (PDPD vs non-PDPD) with adjustment for covariates were carried out either using multivariate analysis of variance or logistic regression analysis. RESULTS:More severe strokes (ie, mean National Institute of Health Stroke Scale score on admission 10.1±7.9 vs 7.5±7.4; F(10,796)=18.5, p<0.0001) and higher prevalence of poor outcome (73.7 vs 54.9%; OR: 2.6, standard error: 0.5, z=4.82, p<0.0001) was found in patients with a documented psychiatric diagnosis at the time of stroke, as well as a higher rate of psychiatric complications during the initial treatment phase (46.7 vs 28.9%; OR: -0.78, z=4.59, p<0.0001). CONCLUSION:Our data have clinical implications in that they call for identification of psychiatric premorbidity or comorbidity through careful history-taking and particularly close monitoring for psychiatric complications with respect to their potentially negative impact on outcome after stroke.

Background: Several lines of evidence are pointing towards an involvement of the vascular endothelial growth factor (VEGF) in the pathophysiology of depression. There are studies analyzing blood levels of VEGF in patients with depression compared to controls, but a data on cerebrospinal fluid (CSF) levels of VEGF in patients with depression are lacking. Method: CSF VEGF levels were measured in patients (n = 12) with a severe, treatment-resistant depressive episode before and after the antidepressant treatment by a course of electroconvulsive therapy (ECT) and compared to age- and sex-matched controls (n = 20). Results: The patients with depression showed lower mean VEGF levels in the CSF prior to ECT than the controls (p = 0.041). Regarding the patients, CSF VEGF concentration at baseline and after the complete ECT treatment did not differ from each other (p = 0.78). Limitations: Major limitations of this study are the small sample size and that data from corresponding serum levels cannot be provided. Another limitation is that the controls were not completely healthy, as they were recruited from a memory clinic with subjective complaints. The timing of the second sample might have been suboptimal, when taking into account that there might be an on-going phase of re-equilibrating after ECT. Conclusions: CSF VEGF concentrations were lower in a clinical sample of patients with treatment-resistant depression compared with matched controls. Additionally, no change in CSF VEGF levels during a course of ECT could be detected.

The novel Seizure Quality Index (SQI) could predict the risk of non-response and non-remission as early as after the second electroconvulsive therapy (ECT) session based the extent of several ictal parameters of the seizure in patients with depression. The association between those indices with the peripheral serum levels of brain-derived neurotrophic factor (BDNF) was evaluated in this study. It was proposed that seizure quality reflected by the SQI will be positively correlated with the levels of serum BDNF after ECT in patients with depression. We included 36 patients with a full data set, a completed course of ECT and BDNF levels before and after that ECT course. Baseline serum BDNF levels (2838.9 pg/ml +/- 1659.9) were lower compared to the mean BDNF levels after ECT (3206.3 pg/ml +/- 1532.3), but the statistical test did not reach significance (z = 1.96, p = 0.051, r = 0.23). In a sub-group analysis, the BDNF levels after ECT were positively correlated with the SQI sum score for response (r(s) = 0.62, p = 0.018) and for remission (r(s) = 0.57, p = 0.033) in patients younger than 65 years, the group, for whom the SQI has been built and validated. This suggests that one link between seizure quality and antidepressant response to ECT could be BDNF.

Background: Electroconvulsive therapy (ECT) and depression have been associated with brain volume changes, especially in the hippocampus and the amygdala. Methods: In this retrospective study we collected data from individual pre-post ECT whole brain magnetic resonance imaging scans of depressed patients from six German university hospitals. Gray matter volume (GMV) changes were quantified via voxel-based morphometry in a total sample of 92 patients with major depressive episodes (MDE). Additionally, 43 healthy controls were scanned twice within a similar time interval. Results: Most prominently longitudinal GMV increases occurred in temporal lobe regions. Within specific region of interests we detected significant increases of GMV in the hippocampus and the amygdala. These results were more pronounced in the right hemisphere. Decreases in GMV were not observed. GMV changes did not correlate with psychopathology, age, gender or number of ECT sessions. We ruled out white matter reductions as a possible indirect cause of the detected GMV increase. Conclusion: The present findings support the notion of hippocampus and amygdala modulation following an acute ECT series in patients with MDE. These results corroborate the hypothesis that ECT enables primarily unspecific and regionally dependent neuroplasticity effects to the brain.

Electroconvulsive therapy (ECT) is a remarkably safe procedure. However, there might exist a subgroup of patients with an increased risk for cardiovascular events. The cardiac-specific enzymes high-sensitive cardiac troponin I (hscTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured before and after ECT in 23 patients. No relevant increase of hscTnI after ECT was found. Mean NT-proBNP levels were higher after ECT and in three patients a new NT-proBNP elevation after ECT was identified. In conclusion, our small study did not find any evidence for myocardial damage due to ECT by measuring hsTnI, but an increase of NT-proBNP, whose clinical relevance could only be speculated, yet.

BACKGROUND:No candidate biomarkers based on cerebrospinal fluid (CSF) have been identified as prognostic factors in patients with major depression treated with electroconvulsive therapy (ECT), yet. METHOD:Following different underlying hypotheses, we analysed baseline CSF levels of markers of neurodegeneration (tau proteins, β-amyloids and neurogranin), elements of the innate immune system (interleukin [IL]-6, neopterin, soluble CD14, soluble CD163, migration inhibitory factor and monocyte chemotactic protein 1), endocannabinoids, sphingolipids and Klotho before ECT in patients with depression (n = 12) to identify possible correlations with the clinical antidepressant response to ECT. RESULTS:Correlation with the reduction of the depressive symptoms could be observed especially for markers of neurodegeneration and elements of the innate immune system. Differences for CSF levels of several markers were found between the groups of responders and non-responders at the trend level. LIMITATIONS:The sample size is small and the -distribution of responders and non-responders is uneven. CONCLUSIONS:It is this first study on CSF biomarkers for antidepressant efficacy of ECT warrants further research regarding the mechanism of ECT and personalized antidepressant therapy.

Early identification of patients who are at a high risk for an unfavorable outcome to ECT during the treatment course might be beneficial because it provides an opportunity for timely intensification or optimization of stimulus conditions. We aimed to validate a previously developed seizure quality index (SQI) that delivers a clinically relevant outcome prediction early in the treatment course and can be used within common clinical setting. Therefore, a prospective study was conducted. Patients (n = 26) below the age of 65 years with a depressive episode and the clinical decision for ECT (right unilateral, brief pulse) were included and several ictal parameters, the SQI for non-response and non-remission, and the clinical outcome of the patients were documented. Logistic regression analysis revealed a statistically significant association between the SQI and non-response (p = 0.035). A significant association between the clinical outcome of non-response and the classified outcome of non-response was detected (p = 0.041). The overall classification accuracy regarding response/non-response was 71.3%, and the model revealed a sensitivity of 84.6% and a specificity of 61.5% for non-response. In this study, we could validate the SQI for the clinical outcome of non-response, but not for non-remission. Based on our data, the SQI might become an interesting clinical tool for early outcome prediction for ECT in patients with depression.