Browsing by Author "Heuser, Isabella"

Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory. For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized. Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo. The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog. After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2-52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the combination regimen or as mono treatment, resulted in a transient decline of the ADAScog score in amnestic MCI of presumed AD etiology, while discontinuation of Memantine did not change the cognitive status. In an interrupted trial with amnestic MCI subjects the combination of galantamine plus memantine were generally well tolerated. In the subgroup of MCI subjects with presumed AD etiology, a cognitive benefit of a short-term combination treatment of galantamine plus memantine was observed, and cognitive decline occurred after discontinuation of galantamine.

Background The aim of this paper is to apply the proposed consensus remission criteria to an acutely ill inpatient sample at admission and evaluate their adaptability in this patient population and pharmaceutical trials Methods The Remission in Schizophrenia Working Group s consensus criteria were applied to 272 acutely ill schizophrenia patients Patients were examined using the PANSS HAMD UKU and SWN-K total scales at admission as well as the GAF, SOFAS and the Strauss-Carpenter Prognostic Scale Sociodemographic and clinical baseline variables were assessed using a standardized documentation system Results 33 patients (12%) fulfilled the symptom severity component of the proposed remission criteria already at baseline Almost no significant differences were found when comparing patients with achieved and failed symptom severity component that would explain the hospitalization of the patients with achieved criteria despite their apparently mild psychopathological symptoms The only explainable difference was that patients with an achieved symptom severity component had received significantly more antipsychotics and had suffered from significantly more life events before admission Conclusion The present results raise the question whether the symptom severity threshold is adequate to identify patients in remission when applied in clinical trials

Patients with first-episode schizophrenia (FES) are known to be notably sensitive for developing extrapyramidal adverse effects, but the relation of akathisia and suicidal ideation has rarely been studied. The current report is an ongoing analysis of an 8-week double-blind randomized controlled multicenter trial in 289 FES, comparing risperidone and haloperidol. Assessments were conducted weekly and included the Hillside Akathisia Scale and 21-item Hamilton Depression Rating Scale ratings. Suicidal ideation was significantly associated with clinician observed akathisia, depressed mood, younger age, and use of propranolol. The allocated treatment, anxiety, and nervousness had no influence. The present findings suggest a promoting effect of akathisia on suicidal ideation can not be ruled out in patients with FES.

We measured concentrations of to peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for A beta 1-42, and 1.8-4.1% for A beta 1-40, inter-assay imprecision for A beta 1-42, A beta 1-40, and A beta 1-42/A beta 1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 42-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n = 193) had significantly lower A beta 1-42 plasma concentrations (p<0.007), and A beta 1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n = 64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma. (C) 2009 Published by Elsevier Inc.

Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer's disease (AD) and has recently been found to modulate disease expression in patients with AD. Objective: To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years. Methods: Subjects converting to AD (n = 63) were compared to a control group with stable mild cognitive impairment (n = 131). Clinical, neuropsychological, and MRI data were obtained by the German Dementia Competence Network. Subgroups of converting and stable APOE E4 carriers and non-carriers were investigated longitudinally with MRI to examine structural correlates of conversion. Voxel-based morphometry was applied to investigate gray matter distribution. Results: At baseline, executive performance correlated with global and bilateral prefrontal gray matter volume and predicted conversion only among non-carriers. Converting carriers and non-carriers presented distinct patterns of brain atrophy on longitudinal analysis, in line with a dissociation between more pronounced occipital atrophy in carriers and more frontoparietal volume loss in non-carriers at follow-up. Conclusions: The current findings suggest that in APOE E4 non-carriers with AD, executive dysfunction is closely linked to frontal gray matter atrophy and predictive of progression to dementia. The results are consistent with APOE genotype-dependent profiles of structural damage and cognitive decline in patients with imminent conversion to AD.

ntroductionWhite matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer’s disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD.MethodsWM hyperintensity volume on fluid-attenuated inversion recovery images of 201 patients with AD (128 carriers and 73 non-carriers of the APOE ε4 risk allele) was determined globally as well as regionally with voxel-based lesion mapping. Clinical, neuropsychological and MRI data were collected from prospective multicenter trials conducted by the German Dementia Competence Network.ResultsWM hyperintensity volume was significantly greater in non-carriers of the APOE ε4 allele. Lesion distribution was similar among ε4 carriers and non-carriers. Only ε4 non-carriers showed a correlation between lesion volume and cognitive performance.ConclusionThe current findings indicate an increased prevalence of WM hyperintensities in non-carriers compared with carriers of the APOE ε4 allele among patients with AD. This is consistent with a possibly more pronounced contribution of heterogeneous vascular risk factors to WM damage and cognitive impairment in patients with AD without APOE ε4-mediated risk.

SORL1 gene variants were described as risk factor of Alzheimer's disease (AD) additionally SORL1 gene variants were associated with altered A beta(42) CSF levels in AD patients. In the present study we investigated the association of SORL1 gene variants (rs2070045 (SNP19), SORL1-18ex26 (SNP21), rs3824968 (SNP23), rs1010159 (SNP25)) with AD risk by using Cox proportional hazard model and Kaplan-Meier survival analysis in 349 AD patients and 483 controls, recruited from a multicenter study of the German Competence Network Dementias. The SNP21G-allele and a SORL1 haplotype consisting of the SNP19 T-allele, SNP21 G-allele and SNP23 A-allele (T/G/A) were associated with increased hazard ratios and an earlier age at onset of AD (SNP21: p = 0.002; T/G/A haplotype: p = 0.007). This effect was most pronounced in carriers of an additional APOE4 allele (SNP21: p = 0.003; T/G/A haplotype: p = 0.005). In conclusion, we found SORL1 gene variants located in the 3' region of the gene to be associated with increased AD risk and an earlier age at onset of AD in our Central-European population. Thus, our data support a role of SORL1 polymorphisms in AD. (C) 2009 Elsevier B.V. All rights reserved.

Structural MRI markers may serve as surrogate endpoints in clinical trials on disease modification in Alzheimer's disease (AD). Here, we used a longitudinal MRI data set of total brain and cortical grey matter volumes from 66 patients with AD recruited across seven centres of the German Dementia Competence Network. We compared effect size estimates for the detection of a 25% reduction of atrophy progression between a priori segmentation of brain tissue, implementing an anatomical model of brain tissue distribution, and a posteriori segmentation that was not informed by an anatomical model. Additionally, we compared effect size estimates between fixed effects analysis and a mixed effects model, implementing a random effects term to account for variable spacing of observation times. A priori segmentation reduced the required sample size by 50%. Introducing a random effects term for time led to an additional 50% reduction of required samples sizes compared to fixed effects analysis. In summary, using a priori segmentation with mixed effects analysis reduced the sample size to detect clinically relevant treatment effects more than fourfold. The implementation of mixed effects models will enhance the power to detect treatment effects also with other classes of biological endpoints including molecular biomarkers of disease.

Background: Purpose of the present study was to assess the attitude towards adherence at discharge and to verify its predictability using anamnestic and sociodemographic variables. factors influencing clinical treatment as well as the medical treatment applied. Methods: Attitude towards adherence was evaluated in 369 inpatients with schizophrenic spectrum disorders within a naturalistic multicenter trial using the Compliance Rating Scale (CRS) by Kemp. Biweekly ratings of the PANSS, UKU and the Subjective Well-being under Neuroleptic Treatment Scale (SWN-K) were applied. Logistic regression and CART analyses were used to determine significant predictor variables for the attitude towards adherence at discharge. Results: Sixty-seven percent of the patients were rated to have an attitude of active participation and moderate participation (=positive attitude towards adherence) and 33% of the patients to have an attitude of passive acceptance, occasional or permanent reluctance towards treatment as well as refusing treatment (=negative attitude towards adherence). A significant correlation was found between patients with a positive attitude towards adherence and course of all PANSS subscales. Statistical analyses revealed a reduction in PANSS general psychopathology subscore, employment status, greater illness insight and treatment with atypical antipsychotics to be significantly predictive for a positive attitude towards adherence at discharge. Conclusions: The importance of an adequate antipsychotic treatment as a precondition for a favourable adherence attitude and the need to incorporate adherence-focused psychotherapy and psychoeducation into daily clinical practice are highlighted. (C) 2009 Elsevier Ltd. All rights reserved.

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1–42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

Significant changes of schizophrenia patients during inpatient treatment were evalutaed and compared to established outcome criteria. The concept of reliable and clinically significant change methods was applied to three hundred and ninety-six patients suffering from a schizophrenia spectrum disorder. First, information on whether or not the change of the patient's condition is sufficient in order to declare that it is beyond a measurement error or random effect (= reliable change) was evaluated and in a second step it was observed if the reliable change was clinically meaningful (= clinically significant change). Different Positive and Negative Syndrome Scale for Schizophrenia (PANSS) thresholds were applied to define the clinically significant change (40, 45 and 50 points). These changes were then compared to established outcome criteria such as response and remission. Seventy-nine of the 396 patients (20%) showed a reliable improvement of symptoms, whereas 70% improved without achieving a reliable change of their condition. Of the 79 patients achieving a reliable change during treatment 8-15% concurrently showed a clinically significant change depending on the respective PANSS threshold. In contrast, 56% of the patients achieved response and 60% were in remission at discharge when applying established outcome criteria. Our results showed that a rather small number of schizophrenia patients were found to reliably change during inpatient treatment, with even less patients achieving a clinically significant change. The concept of reliable and clinically significant changes revealed to be a lot more stringent than today's established outcome criteria and should be critically evaluated regarding its use in schizophrenia patients. Copyright (c) 2015 John Wiley & Sons, Ltd. Significant changes of schizophrenia patients during inpatient treatment were evalutaed and compared to established outcome criteria. The concept of reliable and clinically significant change methods was applied to three hundred and ninety-six patients suffering from a schizophrenia spectrum disorder. First, information on whether or not the change of the patient's condition is sufficient in order to declare that it is beyond a measurement error or random effect (=reliable change) was evaluated and in a second step it was observed if the reliable change was clinically meaningful (=clinically significant change). Different Positive and Negative Syndrome Scale for Schizophrenia (PANSS) thresholds were applied to define the clinically significant change (40, 45 and 50 points). These changes were then compared to established outcome criteria such as response and remission. Seventy-nine of the 396 patients (20%) showed a reliable improvement of symptoms, whereas 70% improved without achieving a reliable change of their condition. Of the 79 patients achieving a reliable change during treatment 8-15% concurrently showed a clinically significant change depending on the respective PANSS threshold. In contrast, 56% of the patients achieved response and 60% were in remission at discharge when applying established outcome criteria. Our results showed that a rather small number of schizophrenia patients were found to reliably change during inpatient treatment, with even less patients achieving a clinically significant change. The concept of reliable and clinically significant changes revealed to be a lot more stringent than today's established outcome criteria and should be critically evaluated regarding its use in schizophrenia patients.

Hintergrund: Das Kompetenznetz Demenzen (KND) ist ein akademischer Verbund mehrheitlich psychiatrischer Gedächtnissprechstunden und verfolgt drei Ziele: (1) Die Weiterentwicklung der Demenzdiagnostik einschließlich Neuropsychologie, Biomarker, Bildgebung und Genetik. (2) Die Durchführung von Therapiestudien bei kognitiven Störungen und Demenzen. (3) Die Verbesserung der Versorgung von Demenzerkrankten in Deutschland. Ziel der Arbeit: In diesem Beitrag werden die bisherigen Ergebnisse einzelner Teilprojekte des KND zusammengefasst sowie Ausblicke über die laufende Forschung gegeben. Methoden: Es wurden zwei multizentrische Kohorten aufgebaut. In einer ersten Kohorte wurden Menschen mit einer leichten kognitiven Störung und Menschen mit einer beginnenden Demenz klinisch, neuropsychologisch sowie hinsichtlich verschiedener Biomarker untersucht. Ein Teil dieser Kohorte wurde im Rahmen einer Beobachtungsstudie über Jahre nachverfolgt, ein weiterer Teil im Rahmen von zwei Behandlungsstudien untersucht. In der zweiten Kohorte wurden Menschen ohne Demenz klinisch, neuropsychologisch und genetisch untersucht, und es wurden psychosoziale Faktoren erhoben. In den verschiedenen Teilprojekten des KND werden Daten über Follow-up-Zeiträume bis zu zehn Jahren ausgewertet. Ergebnisse und Diskussion: Das Kompetenznetz Demenzen hat zahlreiche Publikationen zur Diagnostik und Therapie von kognitiven Störungen und Demenzen sowie zur Versorgung von Demenzerkrankten in Deutschland ermöglicht. Der Verbund hat Strukturen sowie eine Daten- und Biomaterialbank geschaffen, die auch weiterhin die Grundlage für nationale und internationale Kooperationen sind. Darüber hinaus hat das KND zur Entstigmatisierung von Demenzerkrankungen beigetragen.

Background: To assess criteria and to identify predictive factors for functional outcome. The criteria should cover all domains proposed by the Remission in Schizophrenia Working Group. Method: PANSS ratings were used to evaluate the symptomatic treatment outcome of 262 inpatients with schizophrenia spectrum disorders within a naturalistic multicenter trial. Functional remission was defined as a GAF score >61 (Global Assessment of Functioning Scale), SOFAS score >61 (Social and Occupational Functioning Scale) and a SF-36 mental health subscore >40 (Medical Outcomes Study-Short Form Health Survey). Multivariate logistic regression and CART analyses were used to determine valid clinical and sociodemographic predictors. Results: In total, 52 patients (20%) fulfilled the criteria for functional remission, 125 patients (48%) achieved symptomatic resolution and when criteria for functional remission and symptomatic resolution were combined 33 patients (13%) achieved complete remission. Younger age, employment, a shorter duration of illness, a shorter length of current episode, less suicidality, and a lower PANSS negative and global subscore at admission were predictive of functional remission. The regression model showed a predictive value of more than 80%. Conclusions: A significant association was found between functional remission and symptomatic resolution, indicating reasonable validity of the proposed definition for functional outcome. The revealed predictors for functional treatment outcome emphasize the need for psychosocial and vocational rehabilitation in schizophrenic patients. (C) 2009 Elsevier B.V. All rights reserved.

The aim of the present study was to examine the relevance of depressive symptoms during an acute schizophrenic episode for the prediction of treatment response. Two hundred inpatients who fulfilled DSM-IV criteria for schizophrenia or schizophreniform disorders were assessed at hospital admission and after 6 weeks of inpatient treatment using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Rating Scale for Depression (HAM-D). Depressive symptoms showed positive correlations with both positive and negative symptoms at admission and after 6 weeks, and decreased during 6 weeks of treatment. Pronounced depressive symptoms (HAM-D scored >= 16) were found in 28% of the sample at admission and in 9% after 6 weeks of treatment. Depressive symptoms at admission predicted a greater improvement of positive and negative symptoms over 6 weeks of treatment, but also more, rather than fewer remaining symptoms after 6 weeks. Both results, however, lost statistical significance when analyses were controlled for the influence of positive and negative symptoms at admission. Therefore, the hypothesis that depressive symptoms are predictive of a favorable treatment response was not supported by the present study. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

Objective. To evaluate depressive symptoms regarding their association with the acute outcome in first-episode schizophrenia comparing risperidone and haloperidol. Method. A total of 274 patients were analysed within a double-blind randomized controlled trial and treated with risperidone or haloperidol. The patients were grouped according to their baseline HAMD-21 total score in a "depressed" (HAMD-21 >= 16) or "non-depressed" (HAMD-21 < 16) patient subgroup. PANSS, HAMD-21, GAF, SOFAS and AIMS ratings were performed. Early response was defined as an initial 20% reduction of the PANSS total score from admission to week 2, response as an at least 50% reduction of the PANSS total score from admission to discharge and remission according to the consensus criteria. Results. A total of 124 patients were classified as depressive at baseline with 22 patients still being depressive at discharge. The depressed and non-depressed patients did not significantly differ regarding the treatment with risperidone and haloperidol (P = 0.2270). The depressive patients suffered from significantly more suicidal tendencies (P = 0.0165), had significantly less insight into their illness (P = 0.0152) and featured significantly worse functioning (P = 0.0066). Patients with depressive symptoms achieved remission significantly less often than non-depressed patients. Conclusion. The importance of a specific and adequate treatment of depressive symptoms is highlighted.

Background: Linking of the Clinical Global Impression (CGI) Scale and the Positive and Negative Syndrome Scale (PANSS) was performed within a naturalistic sample. Furthermore, these linking results were compared with those derived from randomized controlled trials to examine if the baseline severity might influence the linking results. Methods: Biweekly PANSS and CGI ratings were performed from admission to discharge in 398 schizophrenia patients treated within a naturalistic study. Equipercentile linking was performed using the statistical program, R 2.8.1. To evaluate how the naturalistic study design would influence linkage results, a so-called study sample was computed with patients of the naturalistic study fulfilling common inclusion criteria of randomized controlled trials (n = 199). Patients not fulfilling these criteria (less ill sample) and those fulfilling the criteria (study sample) were compared using confidence intervals. Results: We found a considerable difference between the linking of the CGI severity score and the PANSS total score comparing the less ill sample and the study sample. Being considered "mildly ill'' at admission in the less ill sample corresponded to a PANSS total score of 47 points and to a PANSS total score of 67 points in the study sample. Considering the linking of the CGI improvement score and PANSS changes, similar results were found for CGI improvement ratings ranging from "very much improved'' to "minimally improved.'' Conclusions: Despite considerable differences, a 50% PANSS reduction was found to correspond to a clinical rating of much improved, which seems to be a suitable definition for response in clinical drug trials.

Background: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. Methods: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer's Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. Results: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. Conclusion: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD. Copyright (C) 2009 S. Karger AG, Basel

Objective: To examine the predictive validity of early improvement in a naturalistic sample of inpatients and to identify the criterion that best defines early improvement. Methods: Two hundred and forty-seven inpatients who fulfilled ICD-10 criteria for schizophrenia were assessed with the Positive And Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the recently proposed consensus criteria, response as a reduction of at least 40% in the PANNS total score from admission to discharge. Results: Receiver operating characteristic (ROC) analyses showed that early improvement (reduction of the PANSS total score within the first 2 weeks of treatment) predicts remission (AUC = 0.659) and response (AUC = 0.737) at discharge. A 20% reduction in the PANSS total score within the first 2 weeks was the most accurate cut-off for the prediction of remission (total accuracy: 65%; sensitivity: 53%; specificity: 76%), and a 30% reduction the most accurate cut-off for the prediction of response (total accuracy: 76%; sensitivity: 47%; specificity: 90%). Conclusion: The findings of clinical drug trials that early improvement is a predictor of subsequent treatment response were replicated in a naturalistic sample. Further studies should examine whether patients without early improvement benefit from an early change of antipsychotic medication. (C) 2009 Elsevier Masson SAS. All rights reserved.

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 (200mg/d) or placebo for 6 weeks. MAIN OUTCOMES AND MEASURES Primary outcome measure was the change in MontgomeryÅsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-totreat 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 200mg/d added to antidepressant treatment as usual for 6weeks, minocyclinewaswell 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.