Publications by authors named "Rainer Rupprecht"

194 Publications

Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?

Mol Psychiatry 2022 Apr 20. Epub 2022 Apr 20.

Department of Neurobiology and Animal Physiology, University Regensburg, 93040, Regensburg, Germany.

Efficient treatment of stress-related disorders, such as depression, is still a major challenge. The onset of antidepressant drug action is generally quite slow, while the anxiolytic action of benzodiazepines is considerably faster. However, their long-term use is impaired by tolerance development, abuse liability and cognitive impairment. Benzodiazepines act as positive allosteric modulators of ɣ-aminobutyric acid type A (GABA) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABA receptor modulators, however, through a site different from that targeted by benzodiazepines. Recently, the administration of neurosteroids such as brexanolone or zuranolone has been shown to rapidly ameliorate symptoms in post-partum depression or major depressive disorder. An attractive alternative to the administration of exogenous neurosteroids is promoting endogenous neurosteroidogenesis via the translocator protein 18k Da (TSPO). TSPO is a transmembrane protein located primarily in mitochondria, which mediates numerous biological functions, e.g., steroidogenesis and mitochondrial bioenergetics. TSPO ligands have been used in positron emission tomography (PET) studies as putative markers of microglia activation and neuroinflammation in stress-related disorders. Moreover, TSPO ligands have been shown to modulate neuroplasticity and to elicit antidepressant and anxiolytic therapeutic effects in animals and humans. As such, TSPO may open new avenues for understanding the pathophysiology of stress-related disorders and for the development of novel treatment options.
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http://dx.doi.org/10.1038/s41380-022-01561-3DOI Listing
April 2022

A novel dual mode-of-action anti-hyperalgesic compound in rats which is neuroprotective and promotes neuroregeneration.

Eur J Pharmacol 2022 May 2;923:174935. Epub 2022 Apr 2.

Global Preclinical R&D, Grünenthal Innovation, Grünenthal GmbH, Zieglerstraße 6, D-52078, Aachen, Germany.

Chronic neuropathic pain (CNP) can result from surgery or traumatic injury, but also from peripheral neuropathies caused by diseases, viral infections, or toxic treatments. Opioids, although very effective for acute pain, do not prevent the development of CNP, and are considered as insufficient treatment. Therefore, there is high need for effective and safe non-opioid options to treat, prevent and eventually reverse CNP. A more effective approach to alleviating CNP would constitute a treatment that acts concurrently on various mechanisms involved in relieving pain symptoms and preventing or reversing chronification by enhancing both neuroprotection and neuroregeneration. We have identified and characterized GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-caboxylic acid amide), a novel drug which is able to activate both voltage-gated potassium channels of the Kv7 family and the mitochondrial translocator protein 18 kDa (TSPO). The dual mode-of-action (MoA) of GRT-X was indicated in in vitro studies and in vivo in a rat model of diabetic neuropathy. In this model, mechanical hyperalgesia was dose-dependently inhibited. After severe crush lesion of cervical spinal nerves in rats, GRT-X promoted survival, speeded up regrowth of sensory and motor neurons, and accelerated recovery of behavioral and neuronal responses to heat, cold, mechanical and electrical stimuli. These properties may reduce the likelihood of chronification of acute pain, and even potentially relieve established CNP. The absence of a conditioned place preference in rats suggests lack of abuse potential. In conclusion, GRT-X offers a promising preclinical profile with a novel dual MoA.
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http://dx.doi.org/10.1016/j.ejphar.2022.174935DOI Listing
May 2022

Differential effects of the translocator protein 18 kDa (TSPO) ligand etifoxine and the benzodiazepine alprazolam on startle response to predictable threat in a NPU-threat task after acute and short-term treatment.

Psychopharmacology (Berl) 2022 Mar 12. Epub 2022 Mar 12.

Department of Psychology, Clinical Psychology and Psychotherapy, University Regensburg, Regensburg, Germany.

Rationale: Benzodiazepines have been extensively investigated in experimental settings especially after single administration, which mostly revealed effects on unpredictable threat (U-threat) rather than predictable threat (P-threat). Given the need for pharmacological alternatives with a preferable side-effect profile and to better represent clinical conditions, research should cover also other anxiolytics and longer application times.

Objectives: The present study compared the acute and short-term effects of the translocator protein 18 kDa (TSPO) ligand etifoxine and the benzodiazepine alprazolam on P-threat and U-threat while controlling for sedation.

Methods: Sixty healthy male volunteers, aged between 18 and 55 years, were randomly assigned to receive a daily dose of either 150 mg etifoxine, 1.5 mg alprazolam, or placebo for 5 days. On days 1 and 5 of intake, they performed a NPU-threat task including neutral (N), predictable (P), and unpredictable (U) conditions, while startle responsivity and self-reports were studied. Sedative effects were assessed using a continuous performance test.

Results: Neither alprazolam nor etifoxine affected startle responsivity to U-threat on any of the testing days. While etifoxine reduced the startle response to P-threat on day 1 of treatment for transformed data, a contrary effect of alprazolam was found for raw values. No effects on self-reports and no evidence of sedation could be observed for either drug.

Conclusions: None of the anxiolytic substances had an impact on startle potentiation to U-threat even after several days of intake. The effects of the anxiolytics on startle responsivity to P-threat as well as implications for future studies are discussed.
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http://dx.doi.org/10.1007/s00213-022-06111-xDOI Listing
March 2022

Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO).

Nat Neurosci 2022 03 28;25(3):317-329. Epub 2022 Feb 28.

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.
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http://dx.doi.org/10.1038/s41593-022-01013-9DOI Listing
March 2022

Impact of Partial Volume Correction on [F]GE-180 PET Quantification in Subcortical Brain Regions of Patients with Corticobasal Syndrome.

Brain Sci 2022 Jan 31;12(2). Epub 2022 Jan 31.

Department of Nuclear Medicine, University Hospital, Ludwig Maximilian University of Munich, 81377 Munich, Germany.

Corticobasal syndrome (CBS) is a rare neurodegenerative condition characterized by four-repeat tau aggregation in the cortical and subcortical brain regions and accompanied by severe atrophy. The aim of this study was to evaluate partial volume effect correction (PVEC) in patients with CBS compared to a control cohort imaged with the 18-kDa translocator protein (TSPO) positron emission tomography (PET) tracer [F]GE-180. Eighteen patients with CBS and 12 age- and sex-matched healthy controls underwent [F]GE-180 PET. The cortical and subcortical regions were delineated by deep nuclei parcellation (DNP) of a 3D-T1 MRI. Region-specific subcortical volumes and standardized uptake values and ratios (SUV and SUVr) were extracted before and after region-based voxel-wise PVEC. Regional volumes were compared between patients with CBS and controls. The % group differences and effect sizes (CBS vs. controls) of uncorrected and PVE-corrected SUVr data were compared. Single-region positivity in patients with CBS was assessed by a >2 SD threshold vs. controls and compared between uncorrected and PVE-corrected data. Smaller regional volumes were detected in patients with CBS compared to controls in the right ventral striatum ( = 0.041), the left putamen ( = 0.005), the right putamen ( = 0.038) and the left pallidum ( = 0.015). After applying PVEC, the % group differences were distinctly higher, but the effect sizes of TSPO uptake were only slightly stronger due to the higher variance after PVEC. The single-region positivity of TSPO PET increased in patients with CBS after PVEC (100 vs. 83 regions). PVEC in the cortical and subcortical regions is valuable for TSPO imaging of patients with CBS, leading to the improved detection of elevated [F]GE-180 uptake, although the effect sizes in the comparison against the controls did not improve strongly.
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http://dx.doi.org/10.3390/brainsci12020204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870519PMC
January 2022

Amino Acid Uptake, Glucose Metabolism, and Neuroinflammation in John Cunningham Virus Associated Progressive Multifocal Leukoencephalopathy.

Clin Nucl Med 2022 Jun 21;47(6):543-544. Epub 2022 Feb 21.

Department of Nuclear Medicine.

Abstract: A 69-year-old woman presented with progressive dysarthria and cognitive deficits. On MRI, a T2-hyperintense, non-contrast-enhancing lesion was found in the left precentral area. 18F-FET and 18F-FDG PET scans revealed faint amino acid uptake and glucose hypometabolism of the lesion. To assess a neuroinflammatory component, TSPO PET with 18F-GE-180 was performed, where tracer uptake markedly exceeded the T2-hyperintense areas. Histology derived from a stereotactic biopsy findings confirmed John Cunningham virus-associated progressive multifocal leukoencephalopathy. This case underlines that TSPO PET comprises distinct imaging advantages over other established radioligands such as 18F-FET and 18F-FDG in progressive multifocal leukoencephalopathy.
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http://dx.doi.org/10.1097/RLU.0000000000004093DOI Listing
June 2022

Differential Spatial Distribution of TSPO or Amino Acid PET Signal and MRI Contrast Enhancement in Gliomas.

Cancers (Basel) 2021 Dec 23;14(1). Epub 2021 Dec 23.

Department of Nuclear Medicine, University Hospital, LMU Munich, 81377 Munich, Germany.

In this study, dual PET and contrast enhanced MRI were combined to investigate their correlation per voxel in patients at initial diagnosis with suspected glioblastoma. Correlation with contrast enhancement (CE) as an indicator of BBB leakage was further used to evaluate whether PET signal is likely caused by BBB disruption alone, or rather attributable to specific binding after BBB passage. PET images with [F]GE180 and the amino acid [F]FET were acquired and normalized to healthy background (tumor-to-background ratio, TBR). Contrast enhanced images were normalized voxel by voxel with the pre-contrast T1-weighted MRI to generate relative CE values (rCE). Voxel-wise analysis revealed a high PET signal even within the sub-volumes without detectable CE. No to moderate correlation of rCE with TBR voxel-values and a small overlap as well as a larger distance of the hotspots delineated in rCE and TBR-PET images were detected. In contrast, voxel-wise correlation between both PET modalities was strong for most patients and hotspots showed a moderate overlap and distance. The high PET signal in tumor sub-volumes without CE observed in voxel-wise analysis as well as the discordant hotspots emphasize the specificity of the PET signals and the relevance of combined differential information from dual PET and MRI images.
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http://dx.doi.org/10.3390/cancers14010053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750092PMC
December 2021

Rationale, Mission and Vision for a National Centre of Affective Disorders in Germany.

Pharmacopsychiatry 2022 Mar 17;55(2):65-72. Epub 2021 Dec 17.

Department of Psychiatry and Psychotherapy, Medical Faculty, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany.

Affective disorders are common, complex disorders representing one of the major challenges to global health in the 21st century. To mitigate the burden of disease, substantial public health efforts need to be undertaken since research on the causes and adequate treatment requires multidisciplinary approaches. These should integrate translational, and clinical research, aided by technological advancements in collecting and analysing comprehensive data. Here we present the rationale, concept, mission and vision of the recently founded National Centre of Affective Disorders (NCAD) in Germany. NCAD founding partners build on their previous successful cooperation within the German Research Network for Mental Disorders funded by the Federal Ministry of Education and Research (BMBF). They form an internationally pre-eminent network of integrative excellence, leading in science and contributing significantly to the improved care of affective disorder patients. The partners will provide complementary structures and innovative methods across the entire translational continuum from bench to clinical and real-world settings. The vision of the NCAD is to foster cross-disciplinary research from basic neuroscience to public mental health by close translational collaboration between academia, non-university research institutions, and international partners, including industry, to deliver cutting-edge research, innovative clinical services and evidence-based training to young clinicians and scientists. The mission is to accomplish research in a highly translational manner, especially with respect to clinical studies in a trans-sectoral way. This approach aims to ensure continuous improvement in the treatment and care provided to patients and an interdisciplinary environment for high-level research and education in affective disorders.
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http://dx.doi.org/10.1055/a-1697-5854DOI Listing
March 2022

Computer-Assisted Avatar-Based Treatment for Dysfunctional Beliefs in Depressive Inpatients: A Pilot Study.

Front Psychiatry 2021 15;12:608997. Epub 2021 Jul 15.

Department for Clinical Psychology, Private University of Applied Sciences Göttingen, Göttingen, Germany.

Dysfunctional cognitions are a crucial part of depression. Cognitive therapy aims to modify dysfunctional beliefs. Typically, dysfunctional beliefs are questioned, and patients are trained to think of alternative functional beliefs. We developed a computer-assisted, avatar-based adjunct for cognitive therapy that aims to reduce dysfunctional beliefs and symptom severity. Besides, it aims to promote alternative functional beliefs. In a randomized controlled trial with 34 patients diagnosed with major depression currently undergoing inpatient treatment at the university psychiatric hospital in Regensburg, Germany, participants were randomly assigned to receive either treatment as usual (TAU) or computer-assisted avatar-based treatment for dysfunctional beliefs (CAT-DB) in addition to TAU. In CAT-DB participants are faced with a virtual avatar expressing their personal dysfunctional beliefs. Participants are asked to contradict these and express alternative functional beliefs. Assessments of conviction of dysfunctional beliefs, functional beliefs and symptom severity were done shortly before the intervention (pre-treatment), right after the intervention (post-treatment) and 14 days later (follow-up). The reduction in conviction of dysfunctional beliefs and symptom severity, and the increase in conviction of alternative functional beliefs at post-treatment and follow-up were significantly greater for the group receiving CAT-DB. Our study provides an indication in favor of the effectiveness of CAT-DB for depressive patients. It is a simple tool that could support classical cognitive therapy. Further studies at different centres, with larger sample sizes and varying therapeutic contexts are required to prove the effectiveness of our intervention.
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http://dx.doi.org/10.3389/fpsyt.2021.608997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319718PMC
July 2021

Neuroinflammation and psychiatric disorders: Relevance of C1q, translocator protein (18 kDa) (TSPO), and neurosteroids.

World J Biol Psychiatry 2021 Sep 10:1-7. Epub 2021 Sep 10.

Experimental Neuropharmacology, Department of Anesthesiology, Technische Universität München, Munich, Germany.

There is increasing evidence that neuroinflammatory processes may play a role in the pathophysiology of psychiatric disorders. Recently, the complement protein C1q and the translocator protein (18 kDa) (TSPO) have attracted considerable interest in this context. C1q is a small molecule which is involved into synaptic pruning mechanisms, increases during ageing and may contribute to neurodegenerative disorders. TSPO is a transmembrane channel protein and mediates numerous biological functions such as bioenergetics and steroid synthesis. Meanwhile, there is evidence that both C1q and TSPO may be elevated in psychiatric disorders, e.g. major depression. Moreover, preclinical and first clinical studies suggest that TSPO ligands may exert antidepressant and anxiolytic properties by promoting endogenous neurosteroid synthesis. In addition, certain neurosteroids, e.g. allopregnanolone, are potent positive allosteric modulators of GABA receptors and their composition is altered in depression and anxiety disorders. Recently, neurosteroid compounds such as brexanolone or zuranolone have been reported to reduce depressive and anxiety symptoms in postpartum depression and major depressive disorder. In conclusion, compounds enhancing GABAergic neurotransmission such as neurosteroids and TSPO ligands, which also may exert anti-inflammatory properties in concert with immunomodulators such as C1q may open new avenues for the treatment of psychiatric disorders.
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http://dx.doi.org/10.1080/15622975.2021.1961503DOI Listing
September 2021

Meta-analysis of brain structural changes after electroconvulsive therapy in depression.

Brain Stimul 2021 Jul-Aug;14(4):927-937. Epub 2021 Jun 11.

Department of Psychiatry and Psychotherapy, Clinical Division of General Psychiatry, Medical University of Vienna, Austria. Electronic address:

Background: Increases in the volume of the amygdala and hippocampus after electroconvulsive therapy (ECT) are among the most robust effects known to the brain-imaging field. Recent advances in the segmentation of substructures of these regions allow for novel insights on the relationship between brain structure and clinical outcomes of ECT.

Objective: We aimed to provide a comprehensive synthesis of evidence available on changes in brain structure after ECT, including recently published data on hippocampal subfields.

Methods: A meta-analysis of published studies was carried out using random-effects models of standardized mean change of regional brain volumes measured with longitudinal magnetic resonance imaging of depressive patients before and after a series of ECT.

Results: Data from 21 studies (543 depressed patients) were analysed, including 6 studies (118 patients) on hippocampal subfields. Meta-analyses could be carried out for seven brain regions for which data from at least three published studies was available. We observed increases in left and right hippocampi, amygdalae, cornua ammonis (CA) 1, CA 2/3, dentate gyri (DG) and subicula with standardized mean change scores ranging between 0.34 and 1.15. The model did not reveal significant volume increases in the caudate. Meta-regression indicated a negative relationship between the reported increases in the DG and relative symptom improvement (-0.27 (SE: 0.09) per 10%).

Conclusions: ECT is accompanied by significant volume increases in the bilateral hippocampus and amygdala that are not associated with treatment outcome. Among hippocampal subfields, the most robust volume increases after ECT were measured in the dentate gyrus. The indicated negative correlation of this effect with antidepressant efficacy warrants replication in data of individual patients.
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http://dx.doi.org/10.1016/j.brs.2021.05.014DOI Listing
November 2021

Impact of TSPO Receptor Polymorphism on [F]GE-180 Binding in Healthy Brain and Pseudo-Reference Regions of Neurooncological and Neurodegenerative Disorders.

Life (Basel) 2021 May 26;11(6). Epub 2021 May 26.

Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, 81377 Munich, Germany.

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [F]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [F]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [F]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer's disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age- and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [F]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions.
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http://dx.doi.org/10.3390/life11060484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229996PMC
May 2021

C1q, a small molecule with high impact on brain development: putative role for aging processes and the occurrence of Alzheimer's disease.

Eur Arch Psychiatry Clin Neurosci 2021 08;271(5):809-812

Experimental Neuropharmacology, Department of Anesthesiology, Technical University Munich, Ismaninger Strasse 22, 81675, Munich, Germany.

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http://dx.doi.org/10.1007/s00406-021-01273-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236034PMC
August 2021

Reduced microglia activity in patients with long-term immunosuppressive therapy after liver transplantation.

Eur J Nucl Med Mol Imaging 2021 12 12;49(1):234-245. Epub 2021 May 12.

Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Purpose: Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression.

Methods: PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (V) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance.

Results: In controls, V was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean V corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect.

Conclusion: Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.
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http://dx.doi.org/10.1007/s00259-021-05398-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712291PMC
December 2021

Association of Chemokine (C-C Motif) Receptor 5 and Ligand 5 with Recovery from Major Depressive Disorder and Related Neurocognitive Impairment.

Neuroimmunomodulation 2020 27;27(3):152-162. Epub 2021 Jan 27.

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany,

Introduction: Inflammatory processes play an important role in the pathophysiology of major depressive disorder (MDD), but their relevance for specific symptoms such as neurocognitive impairment is rarely investigated.

Methods: In this observational study, we investigated the changes of leukocyte chemokine (C-C motif) receptor 5 (CCR5) and ligand 5 (CCL5) mRNA levels and inflammatory cytokines in 60 MDD patients before (PRE) and after 5 weeks (W5) of antidepressive treatment in relation to therapy response and alterations in cognitive functions by means of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We hypothesized that elevated CCR5 and CCL5 levels in depressed patients would decrease upon treatment and could differ with regard to cognitive impairment associated with MDD.

Results: Both CCR5 and CCL5 levels were significantly decreased in the responder group compared to nonresponders even before treatment. The cytokine IL-6 as a marker of inflammation in depression did not show a difference before treatment in future responders versus nonresponders, but decreased significantly upon antidepressive therapy. Regarding neurocognitive impairment in MDD patients, an increased misperception of the emotion "anger" after 5 weeks of treatment proved to be associated with a more pronounced change in CCR5, and the perception of the emotion "disgust" became faster along with a stronger decrease in CCL5 over the same time. Executive functions typically impaired in MDD patients were not markedly associated with alterations in CCR5/CCL5.

Discussion: CCR5 and CCL5 are important in the targeting of immune cells by HIV. This is the first study providing valuable hints that both CCR5 and CCL5 might also serve as markers of therapy response prediction in MDD. Regarding neurocognitive impairment in depression, CCR5 and CCL5 did not reveal characteristic changes upon MDD treatment such as executive functions, which are probably delayed. However, changes of emotional perception appear to be an earlier responding feature.
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http://dx.doi.org/10.1159/000513093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006585PMC
October 2021

A direct comparison of neuronavigated and non-neuronavigated intermittent theta burst stimulation in the treatment of depression.

Brain Stimul 2021 Mar-Apr;14(2):335-343. Epub 2021 Jan 22.

Department of Psychiatry and Psychotherapy, University of Regensburg, Germany.

Objective: To investigate whether a four-week course of neuronavigated intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is superior to the non-neuronavigated F3-EEG method of positioning.

Methods: We conducted a single-center, two-arm, randomized and double-blinded study (clinicaltrials.gov NCT03953521). 37 inpatients with an at least moderate depressive episode were randomized to receive either neuronavigated or 10-20-EEG-system based F3 guided iTBS. Both groups received twenty week daily sessions of iTBS while continuing to receive standard-of-care treatment by their ward physicians. For navigated iTBS, we used magnetic resonance imaging to target the border between the anterior and middle third of the middle frontal gyrus considered to represent the left dorsolateral prefrontal cortex (lDLPFC). Differences in the treatment arms were blinded by completely mimicking the procedures of the respective other treatment group. Rating physicians were not involved in the treatment procedure. Primary outcome was defined as the change of the 21-item version of the Hamilton Depression Score (HAMD) from baseline to end of treatment at week 4. Secondary outcomes included HAMD score during the treatment, Patient Health Questionnaire-9, WHO Quality of Life-BREF and Clinical Global Impression. For primary outcome, we used a planned group comparison for the absolute change in the HAMD. For secondary outcome measures we calculated analyses of variance (ANOVAs) with the within-subjects factor time (primary: baseline vs. week 4; secondary: all visits) and the between-subjects factor group (navigated vs. F3 guided group). We also did planned contrasts between both groups for all variables and all treatment and follow-up visits with the aim not to oversee any group differences. For group contrasts we used Student T-tests for metric and chi-square tests for categorial variables. Significance threshold was set to 5% uncorrected for multiple comparisons.

Results: Enrolment of 80 patients with interim analysis was planned. Interim analysis was performed after 37 patients (intention to treat). 6 patients dropped out, leaving 31 for analysis. With respect to primary outcome criteria, absolute change in the HAMD did not differ significantly between groups. In accordance, relative change and number of responders and remitters were not significantly different. Overall number of responders was 53% and of remitters was 60%. On a descriptive level, the results favor the clinical effects of the F3 group for the absolute and relative change in the HAMD and the number of responders. Number of remitters were exactly the same for both groups. Therefore, we decided to stop the trial due to the added burden of magnetic resonance imaging and neuronavigated treatment in relation to the effect. Secondary outcomes did also not differ significantly between groups. Patients did not differ in their baseline characteristics nor with respect to intake of medication during the trial period and all had access to the same therapeutic interventions.

Conclusion: We noticed a high antidepressive effect of add-on iTBS treatment to standard inpatient treatment but failed to demonstrate a clinical superiority of neuronavigated localization. The non-navigated, F3 guided iTBS treatment used as a control group may be sophisticated enough to dilute potential added benefits, and the difference between the localization approaches is either negligible or too small to justify the additional efforts of navigation. The effects of concomitant treatment may mask effects, but our patient population reflects clinical reality in an inpatient setting. Further prospective studies are warranted to compare neuronavigated with surface-based approaches.
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http://dx.doi.org/10.1016/j.brs.2021.01.013DOI Listing
October 2021

Dissociation of endocrine responses to the Trier Social Stress Test in Virtual Reality (VR-TSST) by the benzodiazepine alprazolam and the translocator protein 18 kDa (TSPO) ligand etifoxine.

Psychoneuroendocrinology 2021 02 5;124:105100. Epub 2020 Dec 5.

Department of Medicine, Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Background: Activity of the two major stress systems, the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) axis, has already been shown to be modulated by different compounds that bind to the central benzodiazepine receptor. Less is known about ligands that modulate the peripheral benzodiazepine receptor - meanwhile known as the translocator protein 18 kDa (TSPO) - which constitute promising candidates in the search of novel anxiolytics. To close this gap, the present study compared the effects of the benzodiazepine alprazolam and the TSPO ligand etifoxine on responses of the HPA and SAM axes to the Trier Social Stress Test, a standardized paradigm to induce acute psychosocial stress in humans, performed in Virtual Reality (VR-TSST).

Methods: Sixty healthy males, aged between 18 and 55 years, were randomly assigned to receive either a daily dose of 1.5 mg alprazolam, 150 mg etifoxine, or placebo over five days. On the last day of intake, they were exposed to the VR-TSST. We assessed changes of salivary cortisol, allopregnanolone, (nor-) epinephrine in serum, TSPO expression in platelets as well as heart rate (HR), skin conductance level (SCL) and self-reports in response to the stress task. Repeated measures ANOVAs were conducted to examine treatment effects on these stress response variables during the course of VR-TSST.

Results: The response of salivary cortisol to the VR-TSST was significantly blunted in participants pre-treated with alprazolam but was not affected by etifoxine. While levels of allopregnanolone, epinephrine and norepinephrine increased in response to stress, TSPO expression decreased. None of those endocrine stress markers was affected by the active treatments, whereas TSPO expression increased after etifoxine administration over all study days. There were no effects of the two anxiolytics on HR, SCL or any self-report measurement.

Conclusion: The current study confirmed the attenuating effects of benzodiazepines on stress-induced HPA axis activity but did not reveal a comparable effect of the TSPO ligand etifoxine. The long-term consequences of a pharmacologically blunted response of the HPA axis to an acute stressor should be further elucidated. Due to the missing effects of etifoxine on stress-related parameters in our sample of healthy subjects, it might be concluded that the therapeutic effects of this TSPO ligand are restricted to stronger or pathological stress responses, respectively.
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http://dx.doi.org/10.1016/j.psyneuen.2020.105100DOI Listing
February 2021

In Vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies.

Mov Disord 2021 04 27;36(4):883-894. Epub 2020 Nov 27.

Department of Neurology, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany.

Background: Neuroinflammation has received growing interest as a therapeutic target in neurodegenerative disorders, including 4-repeat tauopathies.

Objectives: The aim of this cross-sectional study was to investigate 18 kDa translocator protein positron emission tomography (PET) as a biomarker for microglial activation in the 4-repeat tauopathies corticobasal degeneration and progressive supranuclear palsy.

Methods: Specific binding of the 18 kDa translocator protein tracer F-GE-180 was determined by serial PET during pharmacological depletion of microglia in a 4-repeat tau mouse model. The 18 kDa translocator protein PET was performed in 30 patients with corticobasal syndrome (68 ± 9 years, 16 women) and 14 patients with progressive supranuclear palsy (69 ± 9 years, 8 women), and 13 control subjects (70 ± 7 years, 7 women). Group comparisons and associations with parameters of disease progression were assessed by region-based and voxel-wise analyses.

Results: Tracer binding was significantly reduced after pharmacological depletion of microglia in 4-repeat tau mice. Elevated 18 kDa translocator protein labeling was observed in the subcortical brain areas of patients with corticobasal syndrome and progressive supranuclear palsy when compared with controls and was most pronounced in the globus pallidus internus, whereas only patients with corticobasal syndrome showed additionally elevated tracer binding in motor and supplemental motor areas. The 18 kDa translocator protein labeling was not correlated with parameters of disease progression in corticobasal syndrome and progressive supranuclear palsy but allowed sensitive detection in patients with 4-repeat tauopathies by a multiregion classifier.

Conclusions: Our data indicate that F-GE-180 PET detects microglial activation in the brain of patients with 4-repeat tauopathy, fitting to predilection sites of the phenotype. The 18 kDa translocator protein PET has a potential for monitoring neuroinflammation in 4-repeat tauopathies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28395DOI Listing
April 2021

Supracategorical fear information revealed by aversively conditioning multiple categories.

Cogn Neurosci 2021 01 1;12(1):28-39. Epub 2020 Nov 1.

Department of Psychiatry and Psychotherapy, University of Regensburg , Regensburg, Germany.

Fear-generalization is a critical function for survival, in which an organism extracts information from a specific instantiation of a threat (e.g., the western diamondback rattlesnake in my front yard on Sunday) and learns to fear - and accordingly respond to - pertinent higher-order information (e.g., snakes live in my yard). Previous work investigating fear-conditioning in humans has used functional magnetic resonance imaging (fMRI) to demonstrate that activity patterns representing stimuli from an aversively-conditioned category (CS+) are more similar to each other than those of a neutral category (CS-). Here we used fMRI and aversively-conditioned categories to ask whether we would find only similarity increases the CS+ categories or also similarity increases the CS+ categories. Using representational similarity analysis, we correlated several models to activity patterns underlying different brain regions and found that, following fear-conditioning, between-category and within-category similarity increased for the CS+ categories in the insula, superior frontal gyrus (SFG), and the right temporal pole. When specifically investigating fear-, these between- and within-category effects were detected in the SFG. These results advance prior pattern-based neuroimaging work by exploring the effect of aversively-conditioning multiple categories and indicate an extended role for such regions in potentially representing supracategorical information during fear-learning.
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http://dx.doi.org/10.1080/17588928.2020.1839039DOI Listing
January 2021

Bifrontal high-frequency transcranial random noise stimulation is not effective as an add-on treatment in depression.

J Psychiatr Res 2021 01 16;132:116-122. Epub 2020 Oct 16.

Department of Psychiatry and Psychotherapy, University of Regensburg, Germany.

Background: Depressive disorders are linked to dysfunction in prefrontal cortical areas. Hence, non-invasive neurostimulation of the prefrontal cortex has demonstrated antidepressant efficacy. In the present study, we investigated the efficacy of high frequency transcranial random noise stimulation (hf-tRNS) as an add-on treatment for depression in a sham-controlled randomized trial.

Methods: Forty in-patients with depression were randomized and treated with real or sham hf-tRNS (100-650 Hz) with 0 mA offset. The electrodes were mounted over the left and right dorsolateral prefrontal cortex. The Hamilton Depression Rating Scale (primary outcome), the Major Depression Inventory, the Clinical Global Impression scale and the Global Assessment of Functioning scale were used for assessment at baseline, after 3 weeks of intervention (end of treatment), and 9 weeks after intervention. Safety parameters included cognitive functioning and reported side-effects.

Results: Comparison of real and sham treatment at the planned interim analysis showed an amelioration of symptoms in both groups for all outcomes with numeric but not statistically significant superiority of the sham arm for the primary outcome. Thus, the study was terminated prematurely after an interim analysis. There were no systematic differences with respect to safety parameters.

Limitations: The negative finding might be related to the specific stimulation parameters used in this study.

Conclusions: Our study suggests that prefrontal hf-tRNS is safe but not effective as an add-on treatment of depression. The challenge for future studies employing transcranial electric stimulation remains to identify effective stimulation parameters for the treatment of depression.
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http://dx.doi.org/10.1016/j.jpsychires.2020.10.011DOI Listing
January 2021

Dual PET Imaging of an H3K27M-Mutant Glioma With 18F-GE-180 and 18F-FET PET.

Clin Nucl Med 2020 Dec;45(12):992-993

Neuropathology.

A 25-year-old man presented with headache and intracranial pressure symptoms. On MRI, an intracranial lesion was detected in the right thalamus with exophytic growth into the third ventricle and inhomogeneous contrast enhancement without necrosis. Dual amino acid (F-FET) and TSPO (F-GE-180) PET imaging showed high tumor-to-background ratios in both scans and a short time-to-peak in F-FET uptake dynamics. Biopsy revealed a diffuse midline glioma, H3K27M-mutant (WHO grade IV), a novel entity in the 2016 WHO classification with poor clinical outcome. Our case shows that the highly aggressive features of this tumor entity can be visualized in vivo by both PET modalities.
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http://dx.doi.org/10.1097/RLU.0000000000003331DOI Listing
December 2020

TSPO PET With 18F-GE-180 to Differentiate Variants of Multiple Sclerosis: Relapsing-Remitting Multiple Sclerosis, Tumefactive Demyelination, and Baló's Concentric Sclerosis.

Clin Nucl Med 2020 Oct;45(10):e447-e448

From the Departments of Neurology.

PET targeting the translocator protein (TSPO) expression is an interesting approach to detect neuroinflammation, as TSPO is upregulated in activated macrophages and microglia. Considering the variable pathophysiology of multiple sclerosis (MS) variants, we compare TSPO PET using F-GE-180 in 3 different demyelinating diseases of the central nervous system: relapsing-remitting MS, tumefactive MS, and Baló's concentric sclerosis. Visualization of neuroinflammation and its PET patterns in addition to MRI may contribute to accurate distinction and monitoring of central nervous system demyelination.
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http://dx.doi.org/10.1097/RLU.0000000000003220DOI Listing
October 2020

SARS-CoV-2 Risk Management in Clinical Psychiatry: A Few Considerations on How to Deal With an Unrivaled Threat.

Front Psychiatry 2020 11;11:550. Epub 2020 Jun 11.

Department of Psychiatry and Psychotherapy, Bezirksklinikum, University of Regensburg, Regensburg, Germany.

The pandemic spread of the corona virus SARS-CoV-2 has even-handedly shattered national and international health systems and economies almost in an instant. As numbers of infections and COVID-19-related deaths rise from day to day, fears and uncertainties on how to deal with this unknown threat are extremely present both for individuals and societies as a whole. In this manuscript, we aim to exemplarily describe the bullet points concerning (a) the internal risk management, (b) the organizational and structural changes, and (c) the communicational strategies applied in a Psychiatric University Hospital in the Southern part of Germany. The authors are well aware about the fact that almost none of these considerations may be considered as evidence-based at the moment. However, the authors trust that these reflections and experiences may be useful as an orientation for similar risk constellations in other afflicted countries due to the temporal delay of the pandemic course.
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http://dx.doi.org/10.3389/fpsyt.2020.00550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300317PMC
June 2020

Psychopharmacology- is there still room for progress in these days?

Authors:
Rainer Rupprecht

World J Biol Psychiatry 2020 04;21(4):239-240

Department of Psychiatry and Psychotherapy, University Regensburg, Germany.

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http://dx.doi.org/10.1080/15622975.2020.1757308DOI Listing
April 2020

Reliable quantification of F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio.

Eur J Nucl Med Mol Imaging 2020 11 23;47(12):2887-2900. Epub 2020 Apr 23.

Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.

Purpose: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand F-GE-180. This study tested simplified methods for quantification of F-GE-180 PET.

Methods: Dynamic F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total F-GE-180 distribution volume (V) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed.

Results: Correlation with the reference V (with individually measured input function) was very high for V with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for V with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference V, population-based V with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based V with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect.

Conclusion: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of F-GE-180 PET.
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http://dx.doi.org/10.1007/s00259-020-04810-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651670PMC
November 2020

Major Depressive Disorder is Associated with Impaired Mitochondrial Function in Skin Fibroblasts.

Cells 2020 04 4;9(4). Epub 2020 Apr 4.

Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.

Mitochondrial malfunction is supposed to be involved in the etiology and pathology of major depressive disorder (MDD). Here, we aimed to identify and characterize the molecular pathomechanisms related to mitochondrial dysfunction in adult human skin fibroblasts, which were derived from MDD patients or non-depressive control subjects. We found that MDD fibroblasts showed significantly impaired mitochondrial functioning: basal and maximal respiration, spare respiratory capacity, non-mitochondrial respiration and adenosine triphosphate (ATP)-related oxygen consumption was lower. Moreover, MDD fibroblasts harbor lower ATP levels and showed hyperpolarized mitochondrial membrane potential. To investigate cellular resilience, we challenged both groups of fibroblasts with hormonal (dexamethasone) or metabolic (galactose) stress for one week, and found that both stressors increased oxygen consumption but lowered ATP content in MDD as well as in non-depressive control fibroblasts. Interestingly, the bioenergetic differences between fibroblasts from MDD or non-depressed subjects, which were observed under non-treated conditions, could not be detected after stress. Our findings support the hypothesis that altered mitochondrial function causes a bioenergetic imbalance, which is associated with the molecular pathophysiology of MDD. The observed alterations in the oxidative phosphorylation system (OXPHOS) and other mitochondria-related properties represent a basis for further investigations of pathophysiological mechanisms and might open new ways to gain insight into antidepressant signaling pathways.
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http://dx.doi.org/10.3390/cells9040884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226727PMC
April 2020

Linking Personality Traits to Individual Differences in Affective Spaces.

Front Psychol 2020 12;11:448. Epub 2020 Mar 12.

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Different individuals respond differently to emotional stimuli in their environment. Therefore, to understand how emotions are represented mentally will ultimately require investigations into individual-level information. Here we tasked participants with freely arranging emotionally charged images on a computer screen according to their subjective emotional similarity (yielding a unique affective space for each participant) and subsequently sought external validity of the layout of the individuals' affective spaces through the five-factor personality model (Neuroticism, Extraversion, Openness to Experience, Agreeableness, Conscientiousness) assessed via the NEO Five-Factor Inventory. Applying agglomerative hierarchical clustering to the group-level affective space revealed a set of underlying affective clusters whose within-cluster dissimilarity, per individual, was then correlated with individuals' personality scores. These cluster-based analyses predominantly revealed that the dispersion of the negative cluster showed a positive relationship with Neuroticism and a negative relationship with Conscientiousness, a finding that would be predicted by prior work. Such results demonstrate the non-spurious structure of individualized emotion information revealed by data-driven analyses of a behavioral task (and validated by incorporating psychological measures of personality) and corroborate prior knowledge of the interaction between affect and personality. Future investigations can similarly combine hypothesis- and data-driven methods to extend such findings, potentially yielding new perspectives on underlying cognitive processes, disease susceptibility, or even diagnostic/prognostic markers for mental disorders involving emotion dysregulation.
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http://dx.doi.org/10.3389/fpsyg.2020.00448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082752PMC
March 2020

GDF15 promotes simultaneous astrocyte remodeling and tight junction strengthening at the blood-brain barrier.

J Neurosci Res 2020 07 13;98(7):1433-1456. Epub 2020 Mar 13.

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood-brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB.
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http://dx.doi.org/10.1002/jnr.24611DOI Listing
July 2020

The cytokine IL-17A as a marker of treatment resistance in major depressive disorder?

Eur J Neurosci 2021 01 19;53(1):172-182. Epub 2019 Dec 19.

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Major depression is a complex disease and-among others, inflammation appears to play an important role in its pathophysiology. In this study, we investigated a broad range of cytokines in depressed patients. Plasma levels of interleukin (IL)-12/ IL-23p40, IL-15, IL-16, IL-17A, IL-1α, IL-7, tumor necrosis factorβ and vascular endothelial growth factor were compared in 48 patients suffering from major depression before, after one and after six weeks of antidepressive treatment in relation to therapy response. Interestingly, the level of IL-17A turned out to rise significantly in the non-responder group compared to responder during antidepressive treatment. IL-17A is a pro-inflammatory cytokine that initiates the production of other cytokines, thereby inducing and mediating immune response. It is also involved in allergic and autoimmune-related diseases. The database investigating the role of IL-17A in major depressive disorder has grown within the last few years comparing levels of this cytokine in depressed patients versus healthy subjects. However, little is known about the expression of IL-17A during the course of antidepressive treatment. In summary, our study provides valuable evidence that this cytokine might serve as a marker of therapy resistance to antidepressants.
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http://dx.doi.org/10.1111/ejn.14636DOI Listing
January 2021

Copeptin in CCK-4-induced panic in healthy man: Sexual dimorphisms in secretion pattern and panic response, but no correlation of copeptin with panic symptoms.

Psychoneuroendocrinology 2019 12 5;110:104433. Epub 2019 Sep 5.

University Medical Center Hamburg-Eppendorf, Dept. of Psychiatry and Psychotherapy, Hamburg, Germany.

Copeptin, the C-terminal part of the hypothalamic arginine vaspopressin (AVP) precursor, closely mirrors the production of AVP and was proposed as an easily measured novel marker of the individual stress level in man. First data in male volunteers proposed copeptin as a potential endocrine surrogate marker of cholecystokinin-tetrapeptide (CCK-4)-induced panic. We tried to replicate these pilot data and to extend them to the other sex. 46 healthy human subjects (29 men, 17 women) were given an intravenous bolus of 50 μg CCK-4. Basal and stimulated plasma copeptin was measured and panic symptoms were assessed using the Acute Panic Inventory (API). Basal copeptin was significantly lower in women vs. men, while men showed a significantly higher CCK-4-induced increase of copeptin. In contrast, female subjects displayed a signifcantly higher increase of API ratings by CCK-4. No significant correlations of panic symptoms and copeptin release induced by CCK-4 could be found, neither in man, nor in women, nor in the total sample. A sexual dimorphism in copeptin secretion and in panic response was demonstrated. Prior unexpected findings of copeptin release as an objective read-out of panic could not be replicated. The role of the vasopressinergic system in panic anxiety needs further study in panic patients and in healthy man, using also other panic provocation paradigms.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104433DOI Listing
December 2019
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