Anti-Inflammatory Effects of GPR55 Agonists and Antagonists in LPS-Treated BV2 Microglial Cells.

Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer's disease, Parkinson's disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.

Modulation of neuroinflammation and oxidative stress by targeting GPR55 - new approaches in the treatment of psychiatric disorders.

Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.

Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells.

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.

Neurocognitive function as outcome and predictor for prefrontal transcranial direct current stimulation in major depressive disorder: an analysis from the DepressionDC trial.

Transcranial direct current stimulation (tDCS) of the prefrontal cortex might beneficially influence neurocognitive dysfunctions associated with major depressive disorder (MDD). However, previous studies of neurocognitive effects of tDCS have been inconclusive. In the current study, we analyzed longitudinal, neurocognitive data from 101 participants of a randomized controlled multicenter trial (DepressionDC), investigating the efficacy of bifrontal tDCS (2 mA, 30 min/d, for 6 weeks) in patients with MDD and insufficient response to selective serotonin reuptake inhibitors (SSRI). We assessed whether active tDCS compared to sham tDCS elicited beneficial effects across the domains of memory span, working memory, selective attention, sustained attention, executive process, and processing speed, assessed with a validated, digital test battery. Additionally, we explored whether baseline cognitive performance, as a proxy of fronto-parietal-network functioning, predicts the antidepressant effects of active tDCS versus sham tDCS. We found no statistically significant group differences in the change of neurocognitive performance between active and sham tDCS. Furthermore, baseline cognitive performance did not predict the clinical response to tDCS. Our findings indicate no advantage in neurocognition due to active tDCS in MDD. Additional research is required to systematically investigate the effects of tDCS protocols on neurocognitive performance in patients with MDD.

D-Cycloserine enhances the bidirectional range of NMDAR-dependent hippocampal synaptic plasticity.

The partial N-methyl-D-aspartate receptor (NMDAR) agonist D-Cycloserine (DCS) has been evaluated for the treatment of a wide variety of psychiatric disorders, including dementia, schizophrenia, depression and for the augmentation of exposure-based psychotherapy. Most if not all of the potential psychiatric applications of DCS target an enhancement or restitution of cognitive functions, learning and memory. Their molecular correlate is long-term synaptic plasticity; and many forms of synaptic plasticity depend on the activation of NMDA receptors. Here, we comprehensively examined the modulation of different forms of synaptic plasticity in the hippocampus by DCS and its mechanism. We found that DCS positively modulates NMDAR-dependent forms of long-term synaptic plasticity (long-term synaptic potentiation, LTP, and long-term synaptic depression, LTD) in hippocampal brain slices of juvenile rats without affecting basal synaptic transmission. DCS binds to the D-serine/glycine binding site of the NMDAR. Pharmacological inhibition of this site prevented the induction of LTP, whereas agonism at the D-serine/glycine binding site augmented LTP and could functionally substitute for weak LTP induction paradigms. The most probable origin of endogenous D-serine are astrocytes, and its exocytosis is regulated by astrocytic metabotropic glutamate receptors (mGluR1). Functional eradication of astrocytes, inhibition of mGluR1 receptors and G-protein signaling in astrocytes adjacent to postsynaptic neurons prevented the induction of NMDAR-dependent forms of LTP and LTD. Our results support the enhancement of a bidirectional range of NMDAR-dependent hippocampal synaptic plasticity by DCS and D-serine-mediated gliotransmission. Therefore, the D-serine/glycine-binding site in NMDAR is a major target for psychopharmacological interventions targeting plasticity-related disorders.

Ketamine in multiple treatment-resistant depressed inpatients: A naturalistic cohort study.

BACKGROUND: Ketamine has emerged as an effective treatment option for patients with treatment-resistant depression. However, there is limited evidence of the benefits of ketamine in inpatients with multiple treatment resistance (MTR), who far exceed the formal criteria for treatment resistance and suffer from extensive psychiatric comorbidities. OBJECTIVE: The aim of this naturalistic study was to provide preliminary evidence for the use of ketamine in the treatment of MTR depression in a naturalistic inpatient setting. METHODS: Seventy-seven patients (mean age 45.1 ± 13.8 years) were treated with intravenous or intranasal ketamine (1068 administrations) twice weekly for five weeks, followed by maintenance therapy if clinically indicated. Treatment effects were assessed with the BDI, and side effects were assessed by clinicians. We analyzed dose- and route of application-related changes in depression severity, response and remission rates as well as effects on suicidality and frequency of adverse events. RESULTS: Depression severity and suicidality decreased in the acute treatment phase and these changes persisted during the maintenance therapy phase. A total of 28.9 % of the patients met the criteria for response, and 15 % met the criteria for remission. The initial treatment response was highly predictive of the outcome at the end of the acute treatment phase. None of the reported side effects required medical intervention. High-dose intravenous ketamine (0.75-1 mg/kg) resulted in the most pronounced clinical effects. LIMITATIONS: This observational, retrospective, and naturalistic study may be subject to bias and did not allow control of external variables. CONCLUSIONS: We outlined a clinically feasible, high-dose ketamine treatment regimen for hospitalized patients with MTR depression.

Identifying subgroups with differential response to CBASP versus Escitalopram during the first eight weeks of treatment in outpatients with persistent depressive disorder.

There exists little empirical evidence helping clinicians to select the most effective treatment for individual patients with persistent depressive disorder (PDD). This study identifies and characterizes subgroups of patients with PDD who are likely to benefit more from an acute treatment with psychotherapy than from pharmacotherapy and vice versa. Non-medicated outpatients with PDD were randomized to eight weeks of acute treatment with the Cognitive Behavioral Analysis System of Psychotherapy (CBASP; n = 29) or escitalopram plus clinical management (ESC/CM; n = 31). We combined several baseline variables to one composite moderator and identified two subgroups of patients: for 56.0%, ESC/CM was associated with a greater reduction in depression severity than CBASP, for the remaining 44.0%, it was the other way around. Patients likely to benefit more from ESC/CM were more often female, had higher rates of moderate-to-severe childhood trauma, more adverse life events and more previous suicide attempts. Patients likely to benefit more from CBASP were older, had more often an early illness onset and more previous treatments with antidepressants. Symptomatic response, remission, and reductions in symptom severity occurred more often in those patients treated with their likely more effective treatment condition. The findings suggest that the baseline phenotype of patients with PDD moderates their benefit from acute treatment with CBASP relative to ESC/CM. Once confirmed in an independent sample, these results could serve to guide the choice between primarily psychotherapeutic or pharmacological treatments for outpatients with PDD.

Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding.

Introduction: Serotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and mice. A possible link and interaction between the inflammatory effects of serotonin and metabolic derangements in SERT-deficient mice has not been investigated so far. Methods: SERT-deficient (Sert -/-) and wild type (WT) mice were fed a high-fat diet, starting at 8 weeks of age. Metabolic phenotyping (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, qPCR, histology) and assessment of adipose tissue inflammation (flow cytometry, histology, qPCR) were carried out at the end of the 19-week high-fat diet feeding period. In parallel, Sert -/- and WT mice received a control diet and were analyzed either at the time point equivalent to high-fat diet feeding or as early as 8-11 weeks of age for baseline characterization. Results: After 19 weeks of high-fat diet, Sert -/- and WT mice displayed similar whole-body and fat pad weights despite increased relative weight gain due to lower starting body weight in Sert -/-. In obese Sert -/- animals insulin resistance and liver steatosis were enhanced as compared to WT animals. Leukocyte accumulation and mRNA expression of cytokine signaling mediators were increased in epididymal adipose tissue of obese Sert -/- mice. These effects were associated with higher adipose tissue mRNA expression of the chemokine monocyte chemoattractant protein 1 and presence of monocytosis in blood with an increased proportion of pro-inflammatory Ly6C+ monocytes. By contrast, Sert -/- mice fed a control diet did not display adipose tissue inflammation. Discussion: Our observations suggest that SERT deficiency in mice is associated with inflammatory processes that manifest as increased adipose tissue inflammation upon chronic high-fat diet feeding due to enhanced leukocyte recruitment.

Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been proposed as a feasible treatment for major depressive disorder (MDD). However, meta-analytic evidence is heterogenous and data from multicentre trials are scarce. We aimed to assess the efficacy of tDCS versus sham stimulation as an additional treatment to a stable dose of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. METHODS: The DepressionDC trial was triple-blind, randomised, and sham-controlled and conducted at eight hospitals in Germany. Patients being treated at a participating hospital aged 18-65 years were eligible if they had a diagnosis of MDD, a score of at least 15 on the Hamilton Depression Rating Scale (21-item version), no response to at least one antidepressant trial in their current depressive episode, and treatment with an SSRI at a stable dose for at least 4 weeks before inclusion; the SSRI was continued at the same dose during stimulation. Patients were allocated (1:1) by fixed-blocked randomisation to receive either 30 min of 2 mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks, or sham stimulation at the same intervals. Randomisation was stratified by site and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score (ie, <31 or ≥31). Participants, raters, and operators were masked to treatment assignment. The primary outcome was change on the MADRS at week 6, analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one treatment session. The trial was registered with ClinicalTrials.gov (NCT02530164). FINDINGS: Between Jan 19, 2016, and June 15, 2020, 3601 individuals were assessed for eligibility. 160 patients were included and randomly assigned to receive either active tDCS (n=83) or sham tDCS (n=77). Six patients withdrew consent and four patients were found to have been wrongly included, so data from 150 patients were analysed (89 [59%] were female and 61 [41%] were male). No intergroup difference was found in mean improvement on the MADRS at week 6 between the active tDCS group (n=77; -8·2, SD 7·2) and the sham tDCS group (n=73; -8·0, 9·3; difference 0·3 [95% CI -2·4 to 2·9]). Significantly more participants had one or more mild adverse events in the active tDCS group (50 [60%] of 83) than in the sham tDCS group (33 [43%] of 77; p=0·028). INTERPRETATION: Active tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. FUNDING: German Federal Ministry of Education and Research.

Reduced eye gaze during facial emotion recognition in chronic depression: Effects of intranasal oxytocin.

Chronic depression disorders (CDD) are characterized by impaired social cognitive functioning. Visual attention during social perception is altered in clinical depression and is known to be sensitive to intranasal treatment with oxytocin (OT). The present study thus investigated potential alterations in gaze preferences during a standardized facial emotion recognition (FER) task using remote eye tracking in patients with CDD and the effect of a single dose of intranasal OT (compared to placebo). In emotion recognition, CDD patients were not more impaired than healthy controls, and there was no OT effect. However, CDD patients (with placebo) demonstrated less attentional preference for the eye region during FER than healthy controls, which was not apparent in the CDD group after OT treatment. Our results suggest that despite largely preserved basic facial emotions recognition, attention in social perception may be altered in CDD, and that this bias may be sensitive to OT treatment. These findings highlight OTs potential as a means of augmenting psychotherapy.

Efficacy of Augmentation of Cognitive Behavioral Therapy With Transcranial Direct Current Stimulation for Depression: A Randomized Clinical Trial.

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.

Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation.

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.

[Ketamine and other N-methyl-D-aspartate receptor modulators in treatment of depression]. / Ketamin und andere N-Methyl-D-Aspartat-Rezeptor-Modulatoren zur Behandlung der Depression.

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 N­methyl-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.

A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.

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.

Time Course of Homeostatic Structural Plasticity in Response to Optogenetic Stimulation in Mouse Anterior Cingulate Cortex.

Plasticity is the mechanistic basis of development, aging, learning, and memory, both in healthy and pathological brains. Structural plasticity is rarely accounted for in computational network models due to a lack of insight into the underlying neuronal mechanisms and processes. Little is known about how the rewiring of networks is dynamically regulated. To inform such models, we characterized the time course of neural activity, the expression of synaptic proteins, and neural morphology employing an in vivo optogenetic mouse model. We stimulated pyramidal neurons in the anterior cingulate cortex of mice and harvested their brains at 1.5 h, 24 h, and $48\,\mathrm{h}$ after stimulation. Stimulus-induced cortical hyperactivity persisted up to 1.5 h and decayed to baseline after $24\,\mathrm{h}$ indicated by c-Fos expression. The synaptic proteins VGLUT1 and PSD-95, in contrast, were upregulated at $24\,\mathrm{h}$ and downregulated at $48\,\mathrm{h}$, respectively. Spine density and spine head volume were also increased at $24\,\mathrm{h}$ and decreased at $48\,\mathrm{h}$. This specific sequence of events reflects a continuous joint evolution of activity and connectivity that is characteristic of the model of homeostatic structural plasticity. Our computer simulations thus corroborate the observed empirical evidence from our animal experiments.

Animal Models of Depression - Chronic Despair Model (CDM).

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.

Negative Effects of a Multimodal Inpatient CBASP Program: Rate of Occurrence and Their Impact on Treatment Outcome in Chronic and Treatment-Resistant Depression.

Background: A growing number of studies indicate that the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) is effective in treating chronic depression. However, there is no systematic research into possible negative effects. Therefore, the objectives of the study were to investigate the rate of occurrence of negative effects of an inpatient CBASP program and their impact on treatment response. Methods: Patients with chronic depression and treatment resistance who completed the 12-week multimodal inpatient CBASP treatment program in an open trial (N = 52) retrospectively completed the Inventory for the Assessment of Negative Effects of Psychotherapy (INEP) during follow-up data collection. Severity of depressive symptoms was assessed self- and observer-rated at admission, discharge, and 6 months follow-up. Rates of occurrence of negative effects were calculated and binary logistic regression analyses were conducted to determine the relationship to treatment outcome. Results: The results indicate that 92.3% of patients reported having experienced at least one negative effect and 45.2% indicated dependence on their therapist. Stigmatization and financial concerns as well as intrapersonal changes were reported by about one-third. Only dependence on the therapist negatively impacted treatment outcome in both outcome measures. Conclusions: While almost all patients reported at least one negative effect of a multimodal inpatient CBASP treatment program, most of the reported negative effects appear to be benign. However, dependence on the therapist seems to have a negative impact on treatment outcome. If these results can be replicated in future large-scale, randomized controlled prospective studies, CBASP therapists should be aware of possible dependence and consciously address it during treatment.

Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders.

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.