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Die Neuropsychologie ist eine Schnittstelle zwischen Psychologie und Medizin – und kann Schnittstellenprobleme mit sich bringen. Dies wird besonders bei der psychopharmakologischen Behandlung von Patienten mit erworbenen Hirnschädigungen deutlich.

Seit den ersten erfolgreichen Ketaminbehandlungen therapieresistenter depressiver Patienten werden schnell wirksame Antidepressiva intensiv beforscht. Der zugrunde liegende Wirkmechanismus der Beeinflussung des glutamatergen Systems, vorwiegend durch eine Modulation von N‑Methyl-D-Aspartat-Rezeptoren (NMDAR), stellt einen vollkommen neuen und vielversprechenden medikamentosen Ansatz in der Behandlung affektiver Storungen dar. In diesem sehr dynamischen Feld wurde bisher lediglich Spravato® (Esketamin) zugelassen; multiple weitere Substanzen befinden sich jedoch in der Entwicklung und Erprobung. In diesem Artikel soll ein narrativer kritischer Uberblick uber die wichtigsten Substanzen, Zielstrukturen und Entwicklungsfortschritte von NMDAR-Modulatoren gegeben werden.

Background Therapeutic sleep deprivation (SD) presents a unique paradigm to study the neurobiology of major depressive disorder (MDD). However, the rapid antidepressant mechanism, which differs from today's slow first-line treatments, is not sufficiently understood. We recently integrated two prominent hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, into a synaptic plasticity model of therapeutic SD in MDD. Here, we further tested this model positing that homeostatically elevating net synaptic strength through therapeutic SD shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP)-like plasticity in patients with MDD into a more favorable window of associative plasticity. Methods We used paired associative stimulation (PAS), a transcranial magnetic stimulation protocol (TMS), to quantify cortical LTP-like plasticity after one night of therapeutic sleep deprivation in 28 patients with MDD. Results We demonstrate a significantly different inducibility of associative plasticity in clinical responders to therapeutic SD (> 50% improvement on the 6-item Hamilton-Rating-Scale for Depression, n=13) compared to non-responders (n=15), which was driven by a long-term depression (LTD)-like response in SD-non-responders. Indices of global net synaptic strength (wake EEG theta activity, intracortical inhibition and BDNF serum levels) were increased after SD in both groups, with responders showing a generally lower intracortical inhibition than non-responders. Limitations Repetitive assessments prior to and after treatment would be needed to further determine potential mechanisms. Conclusion After a night of therapeutic SD, clinical responders show a significantly higher inducibility of associative LTP-like plasticity than non-responders.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.

Synapse formation and network rewiring is key to build neural circuits during development and has been widely observed in adult brains. Maintaining neural activity with the help of synaptic plasticity is essential to enable normal brain function. The model of homeostatic structural plasticity (HSP) was proposed to reflect the homeostatic regulation of neural activity and explain structural changes seen after perturbations. However, the specific temporal profile of such plastic responses has not yet been elucidated in experiments. To address this issue, we combined computational modeling and mouse optogenetic stimulation experiments. Our model predicted that within 48 h post-stimulation, neural activity returns to baseline, while the connectivity among stimulated neurons follows a very specific transient increase and decrease. To capture such dynamics experimentally in vivo, we activated the pyramidal neurons in the anterior cingulate cortex of mice and harvested their brains at 1.5 h, 24 h, and 48 h post-stimulation. Cortical hyperactivity as demonstrated by robust c-Fos expression persisted up to 1.5 h and decayed to baseline after 24 h. However, spine density and spine head volume were increased at 24 h and decreased at 48 h. Synaptic proteins VGLUT1 and PSD-95 were also upregulated and downregulated at 24 h and 48 h, respectively, while the calmodulin-binding protein neurogranin was translocated from the soma to the dendrite. Additionally, lasting astrocyte reactivation and microglia proliferation were observed, suggesting a role of neuron-glia interaction. All this corroborates the interpretation of our experimental results in terms of homeostatic structural plasticity. Our results bring important insights of how external stimulation modulates synaptic plasticity and behaviors. Significance Statement We combined both computational modeling and mouse experiments to clarify the temporal dynamics of structural and functional homeostatic plasticity in response to external stimulation. We observed the biphasic regulation of spine density, spine head volume, and synaptic proteins at 24 h and 48 h after the optogenetic stimulation of the anterior cingulate cortex, when the neural activity was restored to the homeostatic level. The orchestrated regulation of presynaptic VGLUT1 and postsynaptic PSD-95, as well as the soma-dendrites translocation of neurogranin, suggested an elaborate molecular mechanism underlying homeostatic structural plasticity. Our experimental results thus corroborated the theoretical concept of homeostatic structural plasticity and revealed the temporal evolution of structural and functional plasticity.

Since the first successful ketamine application in treatment-resistant depressive patients, the newly developed pharmaceutical class of rapid-acting antidepressants has been intensively investigated. The underlying mechanism of action by influencing the glutamatergic neurotransmission via a modulation of N‑methyl-D-aspartate (NMDA) receptors, represents a completely new and promising interventional strategy in the treatment of affective disorders. In this very dynamic field, Spravato® (esketamine) is so far the only approved drug; however, many other substances are currently in the development and evaluation processes. This narrative review provides a critical overview of the most important substances, target structures and developmental stages of NMDAR modulators.Seit den ersten erfolgreichen Ketaminbehandlungen therapieresistenter depressiver Patienten werden schnell wirksame Antidepressiva intensiv beforscht. Der zugrunde liegende Wirkmechanismus der Beeinflussung des glutamatergen Systems, vorwiegend durch eine Modulation von N‑Methyl-D-Aspartat-Rezeptoren (NMDAR), stellt einen vollkommen neuen und vielversprechenden medikamentösen Ansatz in der Behandlung affektiver Störungen dar. In diesem sehr dynamischen Feld wurde bisher lediglich Spravato® (Esketamin) zugelassen; multiple weitere Substanzen befinden sich jedoch in der Entwicklung und Erprobung. In diesem Artikel soll ein narrativer kritischer Überblick über die wichtigsten Substanzen, Zielstrukturen und Entwicklungsfortschritte von NMDAR-Modulatoren gegeben werden.

Major depressive disorder is one of the most prevalent forms of mental illnesses and causes tremendous individual suffering and socioeconomic burden. Despite its importance, current pharmacological treatment is limited, and novel treatment options are urgently needed. One key factor in the search for potential new drugs is evaluating their anti-depressive potency in appropriate animal models. The classical Porsolt forced swim test was used for this purpose for decades to induce and assess a depressive-like state. It consists of two short periods of forced swimming: the first to induce a depressed state and the second on the following day to evaluate the antidepressant effect of the agent given in between the two swim sessions. This model might be suitable as a screening tool for potential antidepressive agents but ignores the delayed onset of action of many antidepressants. The CDM was recently established and represented a modification of the classical test with notable differences. Mice are forced to swim for 5 consecutive days, following the idea that in humans, depression is induced by chronic rather than by acute stress. In a resting period of several days (1-3 weeks), animals develop sustained behavioral despair. The standard read-out method is the measurement of immobility time in an additional delayed swim session, but several alternative methods are proposed to get a broader view of the mood status of the animal. Multiple analysis tools can be used targeting behavioral, molecular, and electrophysiological changes. The depressed phenotype is stable for at least 4 weeks, providing a time window for rapid but also subchronic antidepressant treatment strategies. Furthermore, alterations in the development of a depressive-like state can be addressed using this approach. CDM, therefore, represents a useful tool to better understand depression and to develop novel treatment interventions.

Background Chronic depression is characterized by persistent or recurrent depressive symptoms, defined according to DSM criteria, and is associated with lack of empathy; deficits in social perception, interaction, and communication; and social withdrawal. These symptoms are reminiscent of autism spectrum disorders, yet the co-occurrence of autistic traits and chronic depression has been rarely explored. We explored measures of autistic traits in chronically depressed adult patients in order to further define and delineate the overlap of symptoms between chronic depression and autism spectrum disorders. Method Three groups were tested: 31 patients with chronic depression, 27 patients with autism spectrum disorder, and 31 healthy controls. The Autism Spectrum Quotient (AQ) and the Empathy Quotient (EQ) were used to measure autistic traits. The severity of depression was measured by Beck’s Depression Inventory. Results The group of chronically depressed patients showed significantly elevated autistic traits according to both AQ and EQ measures. In addition, 48.4% of the patients with chronic depression showed AQ scores within the range of the broader autistic phenotype. Similar scores were found among 3.2% of the healthy controls and 100% of the patients with autism spectrum disorder. Conclusions About half of the chronically depressed patients showed elevated autistic or autism-like traits. It remained unclear whether this was due to the state of chronic depression or a kind of premorbid autistic personality trait. The findings illustrate the need for further research to clarify the possible role of autistic traits in the development of chronic depression. Furthermore, they reveal that it might be clinically useful to focus on autism-like social impairments in therapy for chronic depression.

Background Transcranial direct current stimulation (tDCS) of prefrontal cortex regions has been reported to exert antidepressant effects, though large scale multicenter trials in major depressive disorder (MDD) supporting this notion are still lacking. Application of tDCS in multicenter settings, however, requires measurement, storage and evaluation of technical parameters of tDCS sessions not only for safety reasons but also for quality control. To address this issue, we conducted an interim analysis of supervised technical data across study centers in order to monitor technical quality of tDCS in an ongoing multicenter RCT in MDD (DepressionDC trial). Methods Technical data of 818 active tDCS sessions were recorded, stored in a data cloud, and analysed without violating study blinding. Impedance, voltage and current were monitored continuously with one data point recorded every second of stimulation. Results Variability of impedance was considerable (1,42 kΩ, to 8,23 kΩ), inter-individually and even more intra-individually, but did not significantly differ between the study centre in Munich and all other sites. Conclusion Measurement, centralized data storage via data cloud and remote supervision of technical parameters of tDCS are feasible and proposed for future RCTs on therapeutic tDCS in multiple settings.

PURPOSE The aim of this study was to analyze the epidemiology of polypharmacy in hospital psychiatry. Another aim was to investigate predictors of the number of drugs taken and the associated risks of drug-drug interactions and potentially inappropriate medications in the elderly. METHODS Daily prescription data were obtained from a pharmacovigilance project sponsored by the Innovations Funds of the German Federal Joint Committee. RESULTS The study included 47 071 inpatient hospital cases from eight different study centers. The mean number of different drugs during the entire stay was 6.1 (psychotropic drugs = 2.7; others = 3.4). The mean number of drugs per day was 3.8 (psychotropic drugs = 1.6; others = 2.2). One third of cases received at least five different drugs per day on average during their hospital stay (polypharmacy). Fifty-one percent of patients received more than one psychotropic drug simultaneously. Hospital cases with polypharmacy were 18 years older (p

Introduction The aim of this study was to describe the number and type of drugs used to treat depressive disorders in inpatient psychiatry and to analyse the determinants of potential drug-drug interactions (pDDI) and potentially inappropriate medication (PIM). Methods Our study was part of a larger pharmacovigilance project funded by the German Innovation Funds. It included all inpatients with a main diagnosis in the group of depressive episodes (F32, ICD-10) or recurrent depressive disorders (F33) discharged from eight psychiatric hospitals in Germany between 1 October 2017 and 30 September 2018 or between 1 January and 31 December 2019. Results The study included 14,418 inpatient cases. The mean number of drugs per day was 3.7 (psychotropic drugs = 1.7; others = 2.0). Thirty-one percent of cases received at least five drugs simultaneously (polypharmacy). Almost one half of all cases received a combination of multiple antidepressant drugs (24.8%, 95% CI 24.1%–25.5%) or a treatment with antidepressant drugs augmented by antipsychotic drugs (21.9%, 95% CI 21.3%–22.6%). The most frequently used antidepressants were selective serotonin reuptake inhibitors, followed by serotonin and norepinephrine reuptake inhibitors and tetracyclic antidepressants. In multivariate analyses, cases with recurrent depressive disorders and cases with severe depression were more likely to receive a combination of multiple antidepressant drugs (Odds ratio recurrent depressive disorder: 1.56, 95% CI 1.41–1.70, severe depression 1.33, 95% CI 1.18–1.48). The risk of any pDDI and PIM in elderly patients increased substantially with each additional drug (Odds Ratio: pDDI 1.32, 95% CI: 1.27–1.38, PIM 1.18, 95% CI: 1.14–1.22) and severity of disease (Odds Ratio per point on CGI-Scale: pDDI 1.29, 95% CI: 1.11–1.46, PIM 1.27, 95% CI: 1.11–1.44), respectively. Conclusion This study identified potential sources and determinants of safety risks in pharmacotherapy of depressive disorders and provided additional data which were previously unavailable. Most inpatients with depressive disorders receive multiple psychotropic and non-psychotropic drugs and pDDI and PIM are relatively frequent. Patients with a high number of different drugs must be intensively monitored in the management of their individual drug-related risk-benefit profiles.

ObjectivesThe aim was to use routine data available at a patient’s admission to the hospital to predict polypharmacy and drug–drug interactions (DDI) and to evaluate the prediction performance with regard to its usefulness to support the efficient management of benefits and risks of drug prescriptions.DesignRetrospective, longitudinal study.SettingWe used data from a large multicentred pharmacovigilance project carried out in eight psychiatric hospitals in Hesse, Germany.ParticipantsInpatient episodes consecutively discharged between 1 October 2017 and 30 September 2018 (year 1) or 1 January 2019 and 31 December 2019 (year 2).Outcome measuresThe proportion of rightly classified hospital episodes.MethodsWe used gradient boosting to predict respective outcomes. We tested the performance of our final models in unseen patients from another calendar year and separated the study sites used for training from the study sites used for performance testing.ResultsA total of 53 909 episodes were included in the study. The models’ performance, as measured by the area under the receiver operating characteristic, was ‘excellent’ (0.83) and ‘acceptable’ (0.72) compared with common benchmarks for the prediction of polypharmacy and DDI, respectively. Both models were substantially better than a naive prediction based solely on basic diagnostic grouping.ConclusionThis study has shown that polypharmacy and DDI can be predicted from routine data at patient admission. These predictions could support an efficient management of benefits and risks of hospital prescriptions, for instance by including pharmaceutical supervision early after admission for patients at risk before pharmacological treatment is established.

IMPORTANCE: Major depressive disorder (MDD) affects approximately 10% of the population globally. Approximately 20% to 30% of patients with MDD do not sufficiently respond to standard treatment. Therefore, there is a need to develop more effective treatment strategies. OBJECTIVE: To investigate whether the efficacy of cognitive behavioral therapy (CBT) for the treatment of MDD can be enhanced by concurrent transcranial direct current stimulation (tDCS). DESIGN, SETTING, AND PARTICIPANTS: The double-blind, placebo-controlled randomized clinical trial PsychotherapyPlus was conducted at 6 university hospitals across Germany. Enrollment took place between June 2, 2016, and March 10, 2020; follow-up was completed August 27, 2020. Adults aged 20 to 65 years with a single or recurrent depressive episode were eligible. They were either not receiving medication or were receiving a stable regimen of antidepressant medication (selective serotonin reuptake inhibitor and/or mirtazapine). A total of 148 women and men underwent randomization: 53 individuals were assigned to CBT alone (group 0), 48 to CBT plus tDCS (group 1), and 47 to CBT plus sham-tDCS (group 2). INTERVENTIONS: Participants attended a 6-week group intervention comprising 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 mA for 30 minutes (anode over F3, cathode over F4). MAIN OUTCOMES AND MEASURES: The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to posttreatment in the intention-to-treat sample. Scores of 0 to 6 indicate no depression; 7 to 19, mild depression; 20 to 34, moderate depression; and 34 and higher, severe depression. RESULTS: A total of 148 patients (89 women, 59 men; mean [SD] age, 41.1 [13.7] years; MADRS score at baseline, 23.0 [6.4]) were randomized. Of these, 126 patients (mean [SD] age, 41.5 [14.0] years; MADRS score at baseline, 23.0 [6.3]) completed the study. In each of the intervention groups, intervention was able to reduce MADRS scores by a mean of 6.5 points (95% CI, 3.82-9.14 points). The Cohen d value was –0.90 (95% CI, –1.43 to –0.50), indicating a significant effect over time. However, there was no significant effect of group and no significant interaction of group × time, indicating the estimated additive effects were not statistically significant. There were no severe adverse events throughout the whole trial, and there were no significant differences of self-reported adverse effects during and after stimulation between groups 1 and 2. CONCLUSIONS AND RELEVANCE: Based on MADRS score changes, this trial did not indicate superior efficacy of tDCS-enhanced CBT compared with 2 CBT control conditions. The study confirmed that concurrent group CBT and tDCS is safe and feasible. However, additional research on mechanisms of neuromodulation to complement CBT and other behavioral interventions is needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02633449

Background: A common problem in machine learning applications is availability of data at the point of decision making. The aim of the present study was to use routine data readily available at admission to predict aspects relevant to the organization of psychiatric hospital care. A further aim was to compare the results of a machine learning approach with those obtained through a traditional method and those obtained through a naive baseline classifier.Methods: The study included consecutively discharged patients between 1st of January 2017 and 31st of December 2018 from nine psychiatric hospitals in Hesse, Germany. We compared the predictive performance achieved by stochastic gradient boosting (GBM) with multiple logistic regression and a naive baseline classifier. We tested the performance of our final models on unseen patients from another calendar year and from different hospitals. Results: The study included 45,388 inpatient episodes. The models’ performance, as measured by the area under the Receiver Operating Characteristic curve, varied strongly between the predicted outcomes, with relatively high performance in the prediction of coercive treatment (area under the curve: 0.83) and 1:1 observations (0.80) and relatively poor performance in the prediction of short length of stay (0.69) and non-response to treatment (0.65). The GBM performed slightly better than logistic regression. Both approaches were substantially better than a naive prediction based solely on basic diagnostic grouping. Conclusion: The present study has shown that administrative routine data can be used to predict aspects relevant to the organisation of psychiatric hospital care. Future research should investigate the predictive performance that is necessary to provide effective assistance in clinical practice for the benefit of both staff and patients.

Resilience to stress is critical for the development of depression. Enhanced adenosine A1 receptor (A1R) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain A1R and increases the risk of depression. To investigate the effects of A1R on mood, we utilized two transgenic mouse lines with inducible A1R overexpression in forebrain neurons. These two lines have identical levels of A1R increase in the cortex, but differ in the transgenic A1R expression in the hippocampus. Switching on the transgene promotes robust antidepressant and anxiolytic effects in both lines. The mice of the line without transgenic A1R overexpression in the hippocampus (A1Hipp-) show very strong resistance towards development of stress-induced chronic depression-like behavior. In contrast, the mice of the line in which A1R upregulation extends to the hippocampus (A1Hipp+), exhibit decreased resilience to depression as compared to A1Hipp-. Similarly, automatic analysis of reward behavior of the two lines reveals that depression resistant A1Hipp-transgenic mice exhibit high sucrose preference, while mice of the vulnerable A1Hipp + line developed stress-induced anhedonic phenotype. The A1Hipp + mice have increased Homer1a expression in hippocampus, correlating with impaired long-term potentiation in the CA1 region, mimicking the stressed mice. Furthermore, virus-mediated overexpression of Homer1a in the hippocampus decreases stress resilience. Taken together our data indicate for first time that increased expression of A1R and Homer1a in the hippocampus modulates the resilience to stress-induced depression and thus might potentially mediate the detrimental effects of chronic sleep restriction on mood.

Zusammenfassung Einleitung Stationäre Psychotherapien können u. a. aufgrund der kurzen, aber intensiven Behandlung Nebenwirkungen auslösen. In der vorliegenden Pilotstudie wurden daher bestimmte Nebenwirkungen eines multidisziplinären, stationären CBASP-Programms (Cognitive Behavioral Analysis System of Psychotherapy) für Patienten mit therapieresistenter chronischer Depression sowie deren Zusammenhang mit dem Therapieerfolg (Response-, Remissions- und Rückfallraten) untersucht. Material & Methoden 50 Patienten mit therapieresistenter chronischer Depression nahmen an einem strukturierten 12-wöchigen, stationären CBASP-Programm teil. Nebenwirkungen wurden erfasst durch 1) eine Verschlechterung der depressiven Symptomatik im Fremdbericht bei Entlassung (Wert auf der Hamilton Depression Rating Scale, HDRS24) und 2) einem Selbstbeurteilungsfragebogen zur Erfassung von Nebenwirkungen in der stationären Psychotherapie (NESTAP), welcher von Patienten 6–12 Monate nach Entlassung ausgefüllt wurde. Ergebnisse Nach der 12-wöchigen Behandlung konnten 84% der Patienten als Responder klassifiziert werden, von denen 44% das Remissionskriterium erfüllten. 16% waren Non-Responder, wobei kein Patient gemäß HDRS eine fremdbeurteilte Verschlechterung der depressiven Symptomatik zeigte. Sechs Monate nach Entlassung erlitten 40% der Responder einen Rückfall. Im NESTAP gaben 66% der Patienten an, dass sich während der Behandlung ihre Symptomatik vorübergehend verschlechtert habe. Bei diesen Patienten zeigte sich eine geringere Remissionsrate. Über 50% berichteten von interpersonellen Konflikten mit Teammitgliedern oder anderen Patienten, wobei kein Zusammenhang mit dem Therapieerfolg nachweisbar war. Schließlich berichteten über 50% der Patienten, nach Entlassung Veränderungen in sozialen Beziehungen erlebt zu haben. Diese Patienten hatten seltener einen Rückfall. Insgesamt gaben 94% aller Patienten an, mindestens eine der in dieser Studie erhobenen Nebenwirkungen erlebt zu haben. Schlussfolgerung Diese Pilotstudie gibt trotz einiger Limitationen erste Hinweise, dass das stationäre CBASP-Programm Nebenwirkungen verursacht, wobei nur eine subjektiv wahrgenommene vorübergehende Verschlechterung den individuellen Therapieerfolg kurzfristig negativ zu beeinflussen scheint. Die Ergebnisse sprechen dafür, Nebenwirkungen im Kontext des kurz- und langfristigen Therapieerfolges zu untersuchen, um herauszufinden, wie relevant Nebenwirkungen sind.

Background Long-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both animal models and humans; however, the underlying mechanism is unclear. Methods We examined modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knockout mice. Recombinant voltage-gated calcium (Ca2+) channels in heterologous expression systems were used to determine the modulation of Ca2+ channels by SSRIs. We tested the behavioral effects of SSRIs in the chronic behavioral despair model of depression both in the presence and in the absence of SERT. Results SSRIs selectively inhibited hippocampal long-term depression. The inhibition of long-term depression by SSRIs was mediated by a direct block of voltage-activated L-type Ca2+ channels and was independent of SERT. Furthermore, SSRIs protected both wild-type and SERT knockout mice from behavioral despair induced by chronic stress. Finally, long-term depression was facilitated in animals subjected to the behavioral despair model, which was prevented by SSRI treatment. Conclusions These results showed that antidepressants protected synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca2+ channels and synaptic plasticity independent of SERT. Thus, L-type Ca2+ channels might constitute an important signaling hub for stress response and for pathophysiology and treatment of depression.

There is an urgent, unmet clinical need for faster and more efficient antidepressant drugs with higher response rates. In animal models of depression it was shown in the last few years that inhibition of three signaling molecules (BDNF, p11 and Homerla) prevents efficacy of antidepressant therapy. These data not only show the crucial role of these factors for the treatment of depression, but may also point towards a better understanding of the molecular changes responsible for successful antidepressant therapy. Reviewing the literature concerning BNDF, p11 and Homerla we here describe a molecular network in which these molecules interact with each other finally leading to facilitation of AMPA receptor signaling and plasticity, corroborating the current idea of AMPA receptors being a promising drug target in depression.

We investigated if sleep deprivation (SD) and electroconvulsive therapy (ECT) affect striatal dopamine transporter (DAT) availability assessed by single-photon emission computed tomography (SPECT) and 123I-FP-CIT, if dopamine transporter gene (SLC6A3; DAT) variation modifies aforementioned parameters, and if SD response or SD-induced DAT changes correlate with ECT response. Sixteen patients with major depression (MDD) referred for ECT and 12 matched controls were prospectively recruited for imaging and SLC6A3 VNTR genotyping. After withdrawal from any psychiatric medication, 123I-FP-CIT-SPECT was acquired at baseline, after SD and after ECT series. Striatal DAT availability was assessed by volume-of-interest analysis of SPECT data. Eleven patients underwent combined treatment with SD and ECT (five ECT responders and six non-responders). Per-protocol analyses yielded no significant effect of SD or ECT on striatal DAT availability using repeated-measures ANOVA. However, intention-to-treat analysis indicated a significant decrease of striatal DAT availability due to SD (paired t test, p

Summary It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery., Graphical Abstract, Highlights • Several antidepressants, including SSRIs and ketamine, directly bind to TRKB • TRKB dimerization at transmembrane region forms a binding pocket for fluoxetine • Antidepressant binding to TRKB facilitates BDNF action and plasticity • Point mutation in TRKB transmembrane region blocks the effects of antidepressants, Direct binding of both typical and fast-acting antidepressants to the BDNF receptor TRKB accounts for cell biological and behavioral actions of antidepressants. This mechanism directly connects antidepressant action to neuronal plasticity and may explain the slow action of typical antidepressants.

Resilience to stress is critical for the development of depression. Enhanced adenosine A

Background: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. Methods: Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome. Results: Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H2O2) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition - reported to protect patients with depression from cardiovascular events - resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. Conclusions: Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury. Fil: Mauler, Maximilian. No especifíca; Fil: Herr, Nadine. No especifíca; Fil: Schoenichen, Claudia. No especifíca; Fil: Witsch, Thilo. No especifíca; Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Härdtner, Carmen. No especifíca; Fil: Koentges, Christoph. No especifíca; Fil: Kienle, Korbinian. Max Planck Institute Of Immunobiology And Epigenetics; Alemania Fil: Ollivier, Véronique. Inserm; Francia Fil: Schell, Maximilian. No especifíca; Fil: Dorner, Ludwig. No especifíca; Fil: Wippel, Christopher. No especifíca; Fil: Stallmann, Daniela. No especifíca; Fil: Normann, Claus. No especifíca; Fil: Bugger, Heiko. No especifíca; Fil: Walther, Paul. Universitat Ulm; Alemania Fil: Wolf, Dennis. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Ahrens, Ingo. No especifíca; Fil: Lämmermann, Tim. Max Planck Institute Of Immunobiology And Epigenetics; Alemania Fil: Ho-Tin-Noé, Benoît. Inserm; Francia Fil: Ley, Klaus. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Bode, Christoph. No especifíca; Fil: Hilgendorf, Ingo. No especifíca; Fil: Duerschmied, Daniel. No especifíca

Animals and humans spend on average one third of their lives in sleep, but its functions remain to be specified. Distinct lines of research propose that sleep promotes local strengthening of information-bearing synapses (plasticity) and global downscaling of synaptic strength (stability) in neural networks-prerequisites for adaptive behavior in a changing environment. However, the potential orchestration of these processes, particularly in humans, needs to be further characterized. Here, we use electrophysiological, behavioral, and molecular indices to noninvasively study cortical plasticity and network stability in humans. We observe indices of local strengthening of prior induced long-term potentiation-like plasticity (paired associative stimulation induced change in motor-evoked potential) and global network stabilization (homeostatic regulation of wake EEG theta activity) after brief periods of nonrapid eye movement sleep compared with wakefulness. The interplay of local sleep slow oscillations and spindle activity, previously related to synaptic refinements during sleep, is identified as a potential mechanism. Our findings are consistent with the notion that sleep-specific brain activity patterns reduce the plasticity-stability dilemma by orchestrating local plasticity and global stability of neural assemblies in the human cortex. Future studies are needed to further decipher the neural mechanisms underlying our indirect observations.

Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide.

Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.

Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep–wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans., Sleep deprivation is believed to lead to homeostatic increases in synaptic strength and reduced inducibility of associative LTP, based mainly on findings from animal studies. Here, Kuhn et al. demonstrate similar sleep-dependent synaptic plasticity changes in humans along with altered plasma BDNF levels.

Among multiple etiological factors of depressive disorders, childhood maltreatment (CM) gains increasing attention as it confers susceptibility for depression and predisposes to chronicity. CM assumedly inhibits social-cognitive development, entailing interactional problems as observed in chronic depression (CD), especially in affective theory of mind (ToM). However, the extent of CM among CD patients varies notably as does the severity of depressive symptoms. We tested whether the extent of CM or depressive symptoms correlates with affective ToM functions in CD patients. Regional brain activation measured by functional magnetic resonance imaging during an affective ToM task was tested for correlation with CM, assessed by the Childhood Trauma Questionnaire (CTQ), and symptom severity, assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS), in 25 unmedicated CD patients (mean age 41.52, SD 11.13). Amygdala activation during affective ToM correlated positively with CTQ total scores, while (para)hippocampal response correlated negatively with MADRS scores. Our findings suggest that differential amygdala activation in affective ToM in CD is substantially modulated by previous CM and not by the pathophysiological equivalents of current depressive symptoms. This illustrates the amygdala's role in the mediation of CM effects. The negative correlation of differential (para)hippocampal activation and depressive symptom severity indicates reduced integration of interactional experiences during depressive states.

Die chronische Depression ist eine haufige und subjektiv wie gesamtwirtschaftlich sehr belastende psychische Erkrankung. Die effektive storungsspezifische Therapie dieser Storung setzt eine entsprechende Finanzierung des Ressourcenaufwandes voraus. Ermittlung einer normativen Bedarfsdefinition der Behandlungsdauer und -intensitat fur eine leitliniengerechte und empirisch nachweisbar wirksame stationare Behandlung der chronischen Depression und des daraus abgeleiteten Personalbedarfs im Vergleich mit den aktuell im Rahmen der Psychiatrie-Personalverordnung (Psych-PV) verfugbaren Ressourcen. Der entsprechend der nationalen Versorgungsgleitlinie und empirischer Befunde ableitbare Ressourcenbedarf wurde mit der Personalbemessung nach Psych-PV verglichen. Es zeigt sich fur ein normativ festgelegtes Behandlungsprogramm, selbst bei Anwendung eines 100%igen Psych-PV-Satzes, eine deutliche Unterdeckung der Finanzierung des ermittelten Ressourcenbedarfs. Die Ergebnisse zeigen deutlich, dass selbst bei Annahme einer vollstandigen Umsetzung der Psych-PV eine spezifische und wirksame stationare Therapie der chronischen Depression deutlich unterfinanziert ist. Zusatzlich besteht die Schwierigkeit der fehlenden Abbildung der chronischen Depression in der ICD-10, die eine zukunftige Differenzierung des Ressourcenbedarfs im Rahmen des PEPP-Systems verhindert.