Electroconvulsive therapy in children and adolescents in Europe-a systematic review of the literature complemented by expert information and guideline recommendations.

The first documented pediatric use of Electroconvulsive therapy (ECT) occurred in Europe in 1941. Since then, predominantly successful treatments and reasonable side effects have been reported in severely ill minors. Nevertheless, a shy reluctance determines the controversy about ECT in young patients. This study describes the use of ECT in children and adolescents in Europe. We systematically searched the literature concerning the practice of ECT in minors in all 53 European countries. In addition, we surveyed European experts about national practices and compared guidelines for ECT in minors. The search yielded 79 publications from 18 European countries, mainly from Western Europe, Israel, and Turkey. National data were available from eight countries. These showed an interestingly high relationship between the number of minors treated with ECT and the general use of ECT. No persistent deficits or deaths were reported. On the other hand, no randomized clinical trial was found, and many publications lacked relevant information. Accordingly, the appraisal of the evidence in the guidelines varies considerably. Experts from 13 European countries consistently reported infrequent and unsystematic use of ECT in minors. ECT has been used successfully in minors in Europe with reasonable complications and side effects. Adverse effects on the developing brain, as often suspected, have not been scientifically supported in eight decades. Nevertheless, the use of ECT in Europe is sparse and dependent on accidental circumstances. High-quality evidence is needed, as well as improved knowledge and training of child and adolescent psychiatrists.

Electroconvulsive Therapy in Switzerland: A Survey on Contemporary Practice in Remembrance of a Historical Meeting.

OBJECTIVES: The prevalence and use of electroconvulsive therapy (ECT) varies widely across Europe. Historically, Switzerland played an important role in the worldwide spread of ECT. Nevertheless, an overview of current ECT practice in Switzerland is still lacking. The present study aims to fill this gap. METHODS: A cross-sectional study was conducted in 2017 using a standardized questionnaire to investigate current ECT practice in Switzerland. Fifty-one Swiss hospitals were contacted by email and followed up by telephone. In early 2022, we updated the list of facilities that offer ECT. RESULTS: Thirty eight of the 51 hospitals (74.5%) provided feedback to the questionnaire, 10 of them claimed to offer ECT. They reported 402 treated patients, which corresponds to an ECT-treated person rate of 4.8 persons per 100,000 inhabitants. Depression was the most frequent indication. All hospitals reported an increase in ECT treatments between 2014 and 2017 except for one with constant numbers. The number of facilities offering ECT almost doubled between 2010 and 2022. Most ECT facilities performed the treatment predominantly on an outpatient rather than an inpatient basis. CONCLUSIONS: Historically, Switzerland relevantly contributed to the worldwide spread of ECT. In an international comparison, the treatment frequency is in the lower middle range. The outpatient treatment rate is high compared with other countries in Europe. The supply and spread of ECT in Switzerland have increased over the past decade.

Provision of Electroconvulsive Therapy During the COVID-19 Pandemic: A Survey Among Clinics in Germany, Austria, and Switzerland.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic has had a marked impact on psychiatry. Capacity reductions also affected electroconvulsive therapy (ECT), even though ECT is an essential rather than an elective procedure. We sent a survey to all 197 clinics in Germany, Austria, and Switzerland with an ECT service between March and May 2021 to provide an overview of the changes made to ECT services in these countries during the acute phase of the COVID-19 pandemic. More than a quarter of the clinics (27.0%) reported a temporary suspension of all ECT treatments, and 28.2% of the clinics reported reductions of up to 75%. Maintenance ECT was suspended in 46.7% of the clinics and reduced by up to 75% in 30.6% of the clinics. At the time of the survey, 40.8% of the clinics still reported lower numbers of ECT treatments compared with the prepandemic situation. Reasons for the reduced number of ECT treatments included patient safety and testing measures, personnel shortages in the anesthesiology departments, and limited availability of rooms. The COVID-19 pandemic had and continues to have a marked negative impact on the provision of ECT in clinics in Germany, Austria, and Switzerland. To avoid negative consequences for patients, ECT clinics should urgently take steps to provide ECT services without disruptions.

Electroconvulsive Therapy in Germany: Development Over 8 Years With a Background of 4 Decades.

OBJECTIVES: The use of electroconvulsive therapy (ECT) in Europe varies broadly between the extremes of Sweden on one side and Italy on the other. Here, we document the frequency, practice and standards of ECT in Germany in 2016, compare it with a survey of 2008, and describe the historical background. METHODS: A questionnaire was sent electronically to the 396 psychiatric institutions in Germany. Repeated follow-up calls yielded a complete list of hospitals performing ECT and a high rate of detailed responses. RESULTS: Forty-five percent (178/396) of the psychiatric hospitals performed ECT. Of those, 73.6% (131/178) completed the questionnaire. Based on 2 procedures, we estimated an incidence of 60,000 single treatments and 5700 patients treated, with a rate of 6.9 patients per 105 inhabitants. As in 2008, regional differences proved to be significant. The rate at which patients are referred to ECT hospitals from other clinics for the special purpose of ECT has increased since 2008. Maintenance treatments and the use of ketamine for anesthesia have gone up considerably while fewer hospitals offered outpatient treatments. CONCLUSIONS: The application of ECT has increased markedly in the last 8 years, showing an exponential growth over the last 4 decades in Germany. The accessibility to the treatment seems to have improved and some global trends have been well received. Electroconvulsive therapy has become a modern, increasingly used medical intervention.

Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy and concomitant lithium therapy remain a matter of debate because of increased rates of adverse events. Current recommendations include monitoring lithium levels and reducing lithium to minimally effective dose. We present a report on protracted effects of lithium intoxication as electroconvulsive therapy 8 days after intoxication and under normal lithium serum levels resulted in a prolonged seizure. Electroencephalogram recordings before stimulation showed electroencephalogram correlates of subsiding lithium intoxication most likely due to protracted lithium influx and efflux of the central nervous system.

[Electroconvulsive therapy in a female patient with a cavernous malformation in the medulla oblongata]. / Elektrokonvulsionstherapie bei einer Patientin mit Kavernom in der Medulla oblongata.

The implementation of ECT treatment should not be ruled out in principle even if there is a cavernoma of the medulla oblongata with previous bleeding, but it requires appropriate conditions such as neurosurgical consultation, strict blood pressure monitoring and special information from the patient.

Electroconvulsive Therapy in Italy-Current Dissemination of Treatment and Determining Factors of the Past.

OBJECTIVES: The history of electroconvulsive therapy (ECT) spans eight decades, over which period this method of treatment has been modernized. At the same time, however, the conflict between acceptance and rejection of ECT therapy remains unresolved today. This ambivalence is particularly noticeable in Italy, where the number of uses of ECT has been declining for several years. The aim of the present study is to examine the distribution and use of ECT in Italy today in comparison to 2009 and to analyze the factors that have influenced this downward development. METHODS: A cross-sectional study using a standardized Italian-language questionnaire was conducted in 2017 to investigate the dissemination and practice of ECT in Italy. The study was addressed to all public and private hospitals providing ECT as a treatment. RESULTS: Of the 145 mental health facilities in Italy, only 9 offered ECT. A total of 293 patients were treated with ECT within 1 year (mainly for depression). Rates for 3-year treatments in the centers yielded an uneven picture: 4 centers showed an increase in cases and just as many a decline. A north-south divide existed in terms of geographical distribution: centers were mainly located in the north in 2017. CONCLUSIONS: The study shows that the dissemination and use of ECT have reached a historical low in Italy. It further documents the extent to which the use of ECT declined after 2009. Three factors that have accompanied this development are discussed. If this downward trend is to be reversed, it will be necessary to develop a new approach so as to engender a perception of ECT as a viable treatment option.

[Electroconvulsive Therapy - A beneficial and well tolerated therapy in children and adolescents with schizophrenia]. / Elektrokonvulsionstherapie ­ bei Kindern und Jugendlichen mit Schizophrenie wirksam und gut verträglich.

We report four cases of 12- to 17-year-old patients with schizophrenia, two of them suffering from catatonia, which were treated by ECT. Under a combined treatment with either ziprasidone or clozapine, and electroconvulsive therapy (ECT), they improved markedly. Severity and course of acute schizophrenia were evaluated by the Brief Psychiatric rating Scale (BPRS), severity and course of catatonia were evaluated with the Bush-Francis Catatonia Rating Scale (BFCRS). This article underlines the benefit, the safety and the tolerability of ECT in younger patients with schizophrenic disorders.

Cardiac stress after electroconvulsive therapy and spontaneous generalized convulsive seizures: A prospective echocardiographic and blood biomarker study.

AIM: Knowledge about cardiac stress related to seizures in electroconvulsive therapy (ECT) and spontaneously occurring generalized convulsive seizures (GCS) is limited. The aim of the present study was to analyze cardiac function and circulating markers of cardiac stress in the early postictal period after ECT and GCS. METHODS: Patients undergoing ECT in the Department of Psychiatry, Psychotherapy and Psychosomatics and patients undergoing diagnostic video-EEG monitoring (VEM) in the Department of Neurology were prospectively enrolled between November 2017 and November 2018. Cardiac function was examined twice using transthoracic echocardiography within 60 min and >4 h after ECT or GCS. Established blood markers (troponin T high-sensitive, N-terminal pro brain natriuretic peptide) of cardiac stress or injury were collected within 30 min, 4 to 6 h, and 24 h after ECT or GCS. In the ECT group, the troponin T values were also correlated with periprocedural heart rate and blood pressure values. Because of organizational or technical reasons, the measurement was not performed in all patients. RESULTS: Twenty patients undergoing ECT and 6 patients with epilepsy with a GCS during VEM were included. Postictal echocardiography showed no wall motion disorders and no change in left ventricular and right ventricular functions. Four of 17 patients displayed a transient increase in high-sensitive cardiac troponin T 4-6 h after the seizure (3 patients with ECT-induced seizure). None of these 4 patients had signs of an acute cardiac event, and periprocedural blood pressure or heart rate peaks during ECT did not significantly differ in patients with and without troponin T elevation. CONCLUSIONS: Signs of mild cardiac stress can occur in some patients following ECT or GCS without clinical complications, probably related to excessive catecholamine release during the seizure.

Brief vs. ultrabrief pulse ECT: focus on seizure quality.

The effect of electroconvulsive therapy (ECT) performed with ultrabrief pulse (UBP) stimulation has been found inferior to brief pulse (BP) ECT in various studies. We reinvestigated this issue using a new dosing strategy that is based on seizure quality instead of seizure threshold. There is a long history of studies associating ictal characteristics of ECT with the clinical outcome. Accordingly, we used the clinical status of the patient and the quality of the prior seizure to determine the dosage for the upcoming treatment-referred to as Clinical and Seizure Based Stimulation (CASBAS). This approach aims at continuously providing high-quality seizures to optimize the outcome. While this dosing strategy was applied in our department, the pulse width was changed for a period of time from BP to UBP. It was hypothesized that the procedure would: (1) maintain seizure quality and clinical outcome under both conditions and would; and (2) compensate the lesser clinical efficacy of UBP by an increase in stimulus intensity. 245 patients received an ECT course according to the dosing strategy described, 162 with brief pulse (BP) and 83 with ultrabrief pulse ECT (UBP). In a retrospective evaluation, seizure quality and clinical outcome (available in a 20% subgroup of patients) did not differ between both groups in most of the examined parameters, while stimulus intensity was found to be significantly higher in the UBP group. As hypothesized, UBP was less efficient than BP in providing comparable ictal quality and clinical outcome. In a first test of concept the dosing strategy CASBAS seemed suitable to continuously adjust the stimulus intensity in ECT and maintain the seizure quality.

[Determinants of relapse after electroconvulsive therapy in depressed patients]. / Risikofaktoren für Rückfall nach Elektrokonvulsionstherapie bei depressiven Erkrankungen.

BACKGROUND: Maintaining remission after successful acute treatment remains a challenge in the use of electroconvulsive therapy (ECT). For this purpose, the concept of gradually tapered continuation ECT (C-ECT) has been increasingly propagated. The present study is aimed at identifying factors that contribute to relapse after ECT in depressed patients. METHODS: After successful acute treatment of a depressive episode with ECT, all patients were offered a fixed schedule of C-ECT. The number of C-ECT sessions varied in this naturalistic setting depending on compliance. All patients with follow-up data of at least 6 months were included (n = 82). Survival analyses with time to relapse as dependent variable were used to estimate the risk of relapse. RESULTS: 34.1 % of the patients relapsed within 6 months. Factors associated with a decreased relapse rate were: 1. C-ECT treatment, especially within the first three month; 2. higher mean charge during I-ECT; 3. switch from unilateral to bilateral electrode placement during I-ECT, and 4. male sex. However, the sensitivity analyses suggest that the influence of sex on relapse was limited to the first three months of the continuation phase. CONCLUSION: As expected, C-ECT reduced relapse rates, especially when performed early after I-ECT. Besides, increased charge and a change of electrode placement from unilateral to bilateral during the index series were associated with a lower risk of relapse. Compared to men, there was a higher rate of relapse in women.

In-depth analysis of cost structure for electroconvulsive therapy in a performance-based hospital budget.

OBJECTIVE: New medical guideline recommendations for the treatment of major depressive disorders and regulative changes in the payment system of the German mental health care system warrant a revision of the framework in which electroconvulsive therapies (ECT) are offered. METHODS: A cost structure analysis of the clinical resources essential for the ECT procedure was conducted and economically validated, exemplified at a German inpatient ECT treatment center. RESULTS: The identification of directly attributable costs to the ECT intervention presupposes an accurate assessment of personnel engagement time and material consumption as well as an inclusion of overhead costs for the operational readiness of the hospital. CONCLUSION: The increasing importance of ECT in the clinical portfolio of therapy options demands an adequate refunding to support the expansion of this highly effective treatment. For the calculation of an appropriate reimbursement for ECT and ascertaining an acceptable contribution, a detailed knowledge of personnel costs and infrastructure settings of the respective hospitals is required.

Are morphological changes necessary to mediate the therapeutic effects of electroconvulsive therapy?

The neurotrophic hypothesis has become the favorite model to explain the antidepressant properties of electroconvulsive therapy (ECT). It is based on the assumption that a restoration of previously defective neural networks drives therapeutic effects. Recent data in rather young patients suggest that neurotrophic effects of ECT might be detectable by diffusion tensor imaging. We here aimed to investigate whether the therapeutic response to ECT necessarily goes along with mesoscopic effects in gray matter (GM) or white matter (WM) in our patients in advanced age. Patients (n = 21, 15 males and 7 females) suffering from major depressive disorder were treated with ECT. Before the start of treatment and after the completion of the index series, they underwent magnetic resonance imaging, including a diffusion-weighed sequence. We used voxel-based morphometry to assess GM changes and tract-based spatial statistics and an SPM-based whole-brain analysis to detect WM changes in the course of treatment. Patients significantly improved clinically during the course of ECT. This was, however, not accompanied by GM or WM changes. This result challenges the notion that mesoscopic brain structure changes are an obligatory prerequisite for the antidepressant effects of ECT.

Electroconvulsive therapy as viewed by german psychiatrists: a comparison of 3 subgroups.

OBJECTIVES: Electroconvulsive therapy (ECT) is a stigmatized treatment even among doctors. This restrains the accessibility of ECT for patients in need of this treatment. In Germany, the utilization of ECT is low as compared with other Western industrialized countries. However, increasing application rates of ECT in Germany indicate some degree of support from psychiatrists. Therefore, the present study examined the current attitudes among 3 subgroups of psychiatrists toward ECT. METHODS: A questionnaire was sent through e-mail to 423 psychiatric hospitals in the Federal Republic of Germany and through facsimile to 2550 specialists working in private practice. One hundred eighty-three (43%) of the institutions applied ECT (ECT facilities) and 240 (57%) institutions did not apply (non-ECT facilities). RESULTS: Nine hundred eighty-three answers could be evaluated. One hundred fifteen (63%) of the 183 ECT facilities, 118 (49%) of the 240 non-ECT facilities, and 751 (30%) of the 2500 specialists working in private practice responded. The general attitude toward ECT was favorable: most of the participants agreed that ECT is used less often than it should be to best serve patients' interests (61%-89%) and that it should be applied more often (54%-79%). Most of the participants thought that the image of ECT has improved among psychiatrists (61%-74%) but has not changed among fellow physicians, patients, and the general population. CONCLUSIONS: A surprisingly positive attitude toward ECT was found in our study among all 3 groups of German psychiatrists, which might further help improve patients' access to this treatment.

Effects of electroconvulsive therapy on cerebral A1 adenosine receptor availability: a PET study in patients suffering from treatment-resistant major depressive disorder.

Introduction: Sleep deprivation and electroconvulsive therapy (ECT) effectively ameliorate symptoms in major depressive disorder (MDD). In rodents, both are associated with an enhancement of cerebral adenosine levels, which in turn likely influence adenosinergic receptor expression. The aim of the current study was to investigate cerebral A1 adenosine receptor (A1AR) availability in patients with MDD as a potential mediating factor of antidepressant effects of ECT using [18F]CPFPX and positron emission tomography (PET). Methods: Regional A1AR availability was determined before and after a series of ECT applications (mean number ± SD 10.4 ± 1.2) in 14 subjects (4 males, mean age 49.5 ± 11.8 years). Clinical outcome, measured by neuropsychological testing, and ECT parameters were correlated with changes in A1AR availability. Results: ECT had a strong antidepressive effect (p < 0.01) while on average cerebral A1AR availability remained unaltered between pre-and post-ECT conditions (F = 0.65, p = 0.42, mean difference ± SD 3.93% ± 22.7%). There was no correlation between changes in clinical outcome parameters and regional A1AR availability, although individual patients showed striking bidirectional alterations of up to 30-40% in A1AR availability after ECT. Solely, for the mean seizure quality index of the applied ECTs a significant association with changes in A1AR availability was found (rs = -0.6, p = 0.02). Discussion: In the present study, therapeutically effective ECT treatment did not result in coherent changes of A1AR availability after a series of ECT treatments. These findings do not exclude a potential role for cerebral A1ARs in ECT, but shift attention to rather short-termed and adaptive mechanisms during ECT-related convulsive effects.

Baseline levels of miR-223-3p correlate with the effectiveness of electroconvulsive therapy in patients with major depression.

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.

Impaired pitch identification as a potential marker for depression.

BACKGROUND: Impaired auditory performance has been considered as marker for depression. The present study tested whether pitch perception is affected in depression and whether the impairment is task-specific or reflects global dysfunction. METHODS: Twelve depressive in-patients and 12 non-depressive participants, half of the sample women, volunteered. The participants performed pitch identification using a four-choice reaction task, pitch contour perception, and pitch discrimination. RESULTS: During pitch identification but not during pitch contour perception or pitch discrimination, depressive patients responded less accurate than non-depressive participants (F = 3.3, p = 0.047). An analysis of covariates revealed that only female but not male depressive patients identified pitches poorly (Z = -2.2, p = 0.025) and inaccurate pitch identification correlated with high scores in the Beck Depression Inventory in women (r = -0.8, p = 0.001) but not in men (r = -0.1, p = 0.745). Patients did not differ from controls in reaction time or responsiveness. CONCLUSIONS: Impaired pitch perception in depression is task-specific. Therefore, cognitive deficits in depression are circumscribed and not global. Reduced pitch identification in depression was associated with female sex. We suggest that impaired pitch identification merits attention as a potential marker for depression in women.

Cerebral oxygen saturation in the prefrontal cortex during electroconvulsive therapy and its relation with the postictal reorientation time.

The therapeutic effect of Electroconvulsive Therapy (ECT) has been attributed to generalised seizure. Although patients are well oxygenated prior to and during treatment, critics have associated ECT with brain tissue hypoxemia. In this study, the regional oxygen saturation (rSO2) was measured continuously during ECT in the prefrontal cortex (PFC) of both hemispheres using 2-channel Near Infrared Spectroscopy (NIRS). Additionally, the postictal reorientation time (PRT) was determined and related to the rSO2 course. We evaluated 72 ECT treatments in 22 adult patients who were treated for a therapy-resistant depressive syndrome. The therapy was performed according to our standard clinical procedures deploying right unilateral (RUL) and left anterior versus right temporal (LART) electrode placements. According to our results, the rSO2 courses showed an increase during hyperventilation, a sharp drop immediately after the stimulus, and a long recovery period with values far exceeding the baseline. In 55,6% of treatments the rSO2 course stayed above the baseline. In the others, the drop fell below it for an average of 12.6 s. According to a cardio surgical standard no signs of hypoxemia occurred during ECT treatments. The rSO2 drop at seizure onset was the only parameter of the oxygen course related to the PRT in the multivariate analysis and might therefore be a characteristic feature of the seizure. It could reflect its physiological intensity and thereby be involved in the mechanism of action of ECT. NIRS seems to be an interesting non-invasive tool for monitoring and studying ECT.

Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Insufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD. Objective: To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD. Design, Setting, and Participants: The study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020. Interventions: Participants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks. Main Outcomes and Measures: Primary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-to-treat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales. Results: Of 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of treatment (1.46 [-1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically significant effect on secondary outcomes. Conclusions and Relevance: In this large randomized clinical trial with minocycline at a dose of 200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD. Trial Registration: EU Clinical Trials Register Number: EudraCT 2015-001456-29.