Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). METHODS: The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. ETHICS AND DISSEMINATION: The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.

Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey.

INTRODUCTION: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. METHODS: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. RESULTS: Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). DISCUSSION: Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.

Patient characteristics, validity of clinical diagnoses and Outcomes Associated with Suicidality in Inpatients with Symptoms of Depression (OASIS-D): design, procedures and outcomes.

BACKGROUND: Suicidality, ranging from passive suicidal thoughts to suicide attempt, is common in major depressive disorder (MDD). However, relatively little is known about patient, illness and treatment characteristics in those with co-occurring MDD and suicidality, including the timing of and factors associated with the offset, continuation or reemergence of suicidality. Here, we present the background, rationale, design and hypotheses of the Patient Characteristics, Validity of Clinical Diagnoses and Outcomes Associated with Suicidality in Inpatients with Symptoms of Depression (OASIS-D) study, an investigator-initiated, observational study, funded by Janssen-Cilag GmbH. METHODS/RESULTS: OASIS-D is an eight-site, six-month, cohort study of patients aged 18-75 hospitalized with MDD. Divided into three sub-studies and patient populations (PPs), OASIS-D will (i) systematically characterize approximately 4500 consecutively hospitalized patients with any form of unipolar depressive episode (PP1), (ii) evaluate the validity of the clinical diagnosis of moderate or severe unipolar depressive episode with the Mini-International Neuropsychiatric Interview (M.I.N.I.) and present suicidality (at least passive suicidal thoughts) present ≥ 48 h after admission with the Sheehan-Suicide Tracking Scale (S-STS), assessing also predictors of the diagnostic concordance/discordance of MDD in around 500 inpatients (PP2), and (iii) characterize and prospectively follow for 6 months 315 inpatients with a research-verified moderate or severe unipolar depressive episode and at least passive suicidal thoughts ≥ 48 h after admission, evaluating treatment and illness/response patterns at baseline, hospital discharge, 3 and 6 months. Exploratory objectives will describe the association between the number of days with suicidality and utilization of outpatient and inpatient care services, and structured assessments of factors influencing the risk of self-injurious behavior without suicidal intent, and of continuous, intermittent or remitted suicidality during the 6-month observation period. CONCLUSION: Despite their frequency and clinical relevance, relatively little is known about patient and treatment characteristics of individuals with MDD and suicidality, including factors moderating and mediating the outcome of both MDD and suicidality. Results of the OASIS-D study are hoped to improve the understanding of the frequency, correlates and 6-month naturalistic treatment and outcome trajectories of different levels of suicidality in hospitalized adults with MDD and suicidality. TRIAL REGISTRATION: NCT04404309 [ClinicalTrials.gov].

Impact of COVID-19 on the treatment of depressive patients in Germany-a gap in care for the mentally ill?

Background: The COVID-19 pandemic led to a higher incidence of depression and a worsening of psychiatric conditions, while pre-existing constraints of the healthcare system and safety regulations limited psychiatric care. Aims: We investigated the impact of the pandemic on the clinical care of patients with a single episode (SE-MDD) or major depressive disorder (MDD) in Germany. Methods: Nationwide inpatient data were extracted from the German Institute for Hospital Remuneration System for 2020 and 2021 (depression data) and the Robert Koch Institute (COVID-19 incidence). Changes in inpatients were tested with linear regression models. Local cases of depression in our department compared to 2019 were explored with one-way ANOVA and Dunnett's test. Results: Across Germany, the inpatient numbers with both SE-MDD and MDD declined by more than 50% during three out of four COVID-19 waves. Higher COVID-19 incidence correlated with decreased inpatient numbers. In our department, fewer MDD inpatients were treated in 2020 (adj. p < 0.001) and 2021 (adj. p < 0.001) compared to 2019, while the number of SE-MDD inpatients remained stable. During this period fewer elective and more emergency inpatients were admitted. In parallel, MDD outpatient admissions increased in 2021 compared to 2019 (adj. p = 0.002) and 2020 (adj. p = 0.003). Conclusion: During high COVID-19 infection rates, MDD patients received less inpatient care, which might cause poor outcomes in the near future. These data highlight the necessity for improved infrastructure in the in- and outpatient domains to facilitate accessibility to adequate care.

Changes in the pattern of suicides and suicide attempt admissions in relation to the COVID-19 pandemic.

The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March-December 2019 and March-December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.

The Combination of Lithium and ACE Inhibitors: Hazardous, Critical, Possible?

Lithium is a well established therapeutic agent in the treatment of uni- and bipolar affective disorders. Angiotensin-converting enzyme (ACE) inhibitors are the most frequently used class of drugs in the treatment of cardiovascular diseases. Combination therapy with both may be considered in clinical practice on occurrence of arterial hypertension after years of successful lithium therapy, yet an increased risk of lithium intoxication in combination with ACE inhibitors has been described and thus the combination has been warned against. We describe three cases in which enalapril, lisinopril or ramipril was combined with lithium. Either additional co-medication with hydrochlorothiazide or dehydration rather than co-medication with ACE inhibitors could be identified as necessary factors for lithium intoxication. These cases suggest that a combination of lithium with ACE inhibitors is possible when sufficient hydration is ensured and a combination with hydrochlorothiazide is avoided. Lithium concentration should be controlled on a regular level.

C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia.

A hexanucleotide repeat expansions in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. The same mutation has been described in a patient with bipolar disorder, but up to now, not in patients suffering from schizophrenia. We determined the frequency of the C9ORF72 hexanucleotide repeat expansions in a population of 298 patients with schizophrenia or schizoaffective disorder. The pathogenic repeat expansion was detected in 2 patients (0.67%). Both of them presented with auditory hallucinations and had comorbid alcohol abuse. In addition, a positive family history for psychiatric and/or neurodegenerative diseases was present. The repeat expansion in the C9ORF72 gene is a rare, but possible, cause of schizophrenic spectrum disorders. We cannot rule out however whether the number of repeats influence the phenotype.

A novel approach to probabilistic biomarker-based classification using functional near-infrared spectroscopy.

Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications.

On the longevity of resident endoneurial macrophages in the peripheral nervous system: a study of physiological macrophage turnover in bone marrow chimeric mice.

Macrophages are intimately involved in the pathogenesis of peripheral nervous system (PNS) disorders. Recently, we characterized a resident endoneurial macrophage population, which contributes rapidly to the endoneurial macrophage response in PNS diseases. Unlike microglial cells, resident macrophages undergo a physiological turnover of 50% in the sciatic nerve and 80% in dorsal root ganglia (DRG) within 12 weeks. Further information about the dynamics of this turnover is not available. This study examined the macrophage turnover in the sciatic nerve and DRGs over a longer period and addresses the question whether the turnover of resident macrophages is complete or whether there is a truly resident endoneurial macrophage population. We used chimeric mice carrying GFP(+) bone marrow and immunohistochemistry to detect hematogenous (GFP(+)) endoneurial macrophages after turnover. Non-exchanged, resident macrophages were GFP(-). Quantification of GFP(+) and GFP(-) macrophages revealed a maximal turnover of 75%, reached in DRGs after 12 weeks and in sciatic nerves after 36 weeks. GFP(-) long-term resident macrophages were further characterized after sciatic nerve injury, where they participated in the early macrophage response of Wallerian degeneration. Our results point toward a small but truly resident PNS macrophage population. These macrophages are an interesting target for further characterization and might have a distinct role in peripheral nerve disease.

Encephalopathy and myoclonus triggered by valproic acid.

In recent years, the use of valproic acid (VPA) as a mood-stabilizing agent has continuously increased. Although VPA usually is well tolerated, its use in combination with other psychotropic compounds might bear an elevated risk of adverse reactions. Here, we present the case of a 42-year-old male suffering from treatment-resistant psychotic depression, who was prescribed VPA additionally to lithium, clomipramine, flupentixol and risperidone. By doing so, he developed myoclonus, tremor and encephalopathy with sedation and marked EEG background slowing. Most notably, these side effects occurred in the presence of normal VPA and ammonia serum concentrations. On VPA discontinuation, all symptoms vanished and EEG normalized. We thus suggest that direct VPA-induced encephalopathy in the absence of ammonemia does exist, in this case probably facilitated by psychotropic polypharmacy.

Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice.

Resident microglia and hematogenous macrophages play crucial roles in the pathogenetic cascade following cerebral ischemia but may functionally differ regarding neuroprotective and cytotoxic properties. Distinction between these cells has not been possible due to a lack of discriminating cellular markers. We generated bone marrow chimeric mice by transplanting bone marrow from green fluorescent protein (GFP) transgenic mice into irradiated wild-type recipients. Transient focal cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) for 30 min. Resident microglia and infiltrating macrophages were identified by immunohistochemistry and GFP fluorescence after 1-28 days. The first blood-derived cells infiltrating the infarct area were seen on Day 1 and identified as granulocytes. Hematogenous GFP(+) macrophages were rarely observed on Day 2, reached peak numbers on Day 7, and decreased thereafter. In contrast, resident GFP(-) microglial cells rapidly became activated already on Day 1 after MCAO. Even on Days 4 and 7, most macrophage-like cells remained GFP(-), indicating their derivation from resident microglia. Hematogenous macrophages were able to acquire a ramified morphology indistinguishable from resident microglia while microglial cells could develop into a phagocytic phenotype indistinguishable from infiltrating macrophages. The vast majority of macrophages in the infarct area are derived from local microglia, revealing a remarkable predominance of local defense mechanisms over immune cells arriving from the blood. GFP bone marrow chimeric mice are a powerful tool to further differentiate the function of resident microglia and hematogenous macrophages following cerebral ischemia.

Origin of pathogenic macrophages and endoneurial fibroblast-like cells in an animal model of inherited neuropathy.

Macrophages have recently been shown to be critically involved in the pathogenesis of genetically determined demyelination in mice heterozygously deficient for P0 (P0(+-)). Since little is known about the origin of these cells, we created chimeric P0(+-) mice by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated P0(+-) mice. When analyzing chimeric P0(+-) mice, we could determine two populations (GFP(+) and GFP(-)) of endoneurial macrophages that became phagocytic for myelin and increased in number. We found that both GFP(-) resident macrophages and GFP(+) macrophages proliferated in peripheral nerves of P0(+-) mice but not in nerves of chimeric or nonchimeric P0(++) mice. These findings demonstrate a so far poorly recognized role of resident endoneurial macrophages in demyelinating neuropathies. Surprisingly, we also found GFP(+) cells that unequivocally showed the morphological characteristics of fibroblasts. These blood-borne fibroblast-like cells express the common hematopoetic stem cell marker CD34 and might comprise another cell type of potential importance for immune regulation in hereditary demyelinating neuropathies.

Macrophage response to peripheral nerve injury: the quantitative contribution of resident and hematogenous macrophages.

Whereas local microglial cells of the CNS rapidly respond to injury, little is known about the functional role of resident macrophages of the peripheral nervous system in nerve pathology. Using bone marrow chimeric rats, we recently identified individual resident endoneurial macrophages that rapidly became activated after nerve injury. However, the extent of local macrophage activation and its quantitative contribution to the total macrophage response is unknown. We now have created chimeric mice by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated wild-type mice, allowing easy differentiation and quantification of hematogenous and resident endoneurial macrophages. After sciatic nerve crush injury, both GFP(-) and GFP(+) resident macrophages, the latter having undergone physiological turnover from the blood before injury, rapidly underwent morphological alterations and increased in number. Proliferating GFP(-) and GFP(+) resident macrophages were abundant and peaked 3 days after injury. A major lesion-induced influx of hematogenous macrophages with a disproportionate increase of GFP(+) macrophages was not observed until Day 4. Throughout all time points examined, GFP(-) resident macrophages were strikingly frequent, reaching maximum numbers 9.5-fold above baseline. There was also a notable proportion of GFP(-) resident endoneurial macrophages phagocytosing myelin and expressing major histocompatibility complex class II. Our results demonstrate for the first time that the rapid response of resident endoneurial macrophages to nerve injury is quantitatively important and that local macrophages contribute significantly to the total endoneurial macrophage pool during Wallerian degeneration.

Lesion response of long-term and recently immigrated resident endoneurial macrophages in peripheral nerve explant cultures from bone marrow chimeric mice.

Resident macrophages of the peripheral nervous system have recently been shown to respond rapidly to Wallerian degeneration before the influx of blood-derived macrophages. Because resident endoneurial macrophages are slowly but incompletely exchanged from the blood within 3 months, they could potentially comprise a heterogenous cell population consisting of long-term resident cells and more mobile cells undergoing turnover. We used bone marrow chimeric mice created by transplanting bone marrow from green fluorescent protein-transgenic mice into irradiated wildtype recipients to selectively analyse the response of these two resident macrophage populations to Wallerian degeneration in sciatic nerve explant cultures. In such nerves, recently immigrated macrophages exhibit green fluorescence whereas long-term resident macrophages do not. Studies in cultures from wildtype controls revealed rapid morphological changes of resident macrophages towards a bloated phenotype, a proliferative response resulting in a 3.7-fold increase of macrophage numbers over 2 weeks, and phagocytosis of myelin basic protein-immunoreactive myelin debris. When chimeric mice were analysed, both populations of resident endoneurial macrophages participated in morphological transformation, proliferation and phagocytosis. Quantitative studies revealed a stronger proliferative and phagocytic response in long-term resident endoneurial macrophages compared with recently immigrated macrophages. Our results point towards subtle, but not principal, differences between the two macrophage populations, which might indicate different stages of macrophage differentiation rather than the existence of entirely distinct endoneurial macrophage populations. The results further underline the versatility of resident endoneurial macrophages following peripheral nerve injury, which is reminiscent of the lesion response of microglial cells within the brain.