Oxytocin vs. placebo effects on intrusive memory consolidation using a trauma film paradigm: a randomized, controlled experimental study in healthy women
Oxytocin administration during a trauma analogue has been shown to increase intrusive memories, which are a core symptom of post-traumatic stress disorder (PTSD). However, it is unknown whether oxytocin influences the acquisition or the consolidation of the trauma. The current study investigates the effect of the activation of the oxytocin system during the consolidation of an analogue trauma on the formation of intrusive memories over four consecutive days and whether this effect is influenced by individual neurobiological, genetic, or psychological factors. We conducted a randomized double-blind placebo-controlled study in 217 healthy women. They received either a single dose of intranasal oxytocin (24 IU) or placebo after exposure to a trauma film paradigm, which reliably induces intrusive memories. We used a general random forest to examine a potential heterogeneous treatment effect of oxytocin on the consolidation of intrusive memories. Furthermore, we used a poisson regression to examine whether salivary alpha amylase activity (sAA) as a marker of noradrenergic activity and cortisol response to the film, polygenic risk score (PRS) for psychiatric disorders, and psychological factors influence the number of intrusive memories. We found no significant effect of oxytocin on the formation of intrusive memories (F(2, 543.16) = 0.75, p = 0.51, ηp2 = 0.00) and identified no heterogeneous treatment effect. We replicated previous associations of the PRS for PTSD, sAA and the cortisol response on intrusive memories. We further found a positive association between high trait anxiety and intrusive memories, and a negative association between the emotion regulation strategy reappraisal and intrusive memories. Data of the present study suggest that the consolidation of intrusive memories in women is modulated by genetic, neurobiological and psychological factors, but is not influenced by oxytocin. Trial registration: NCT03875391.
Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD
Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS-) with shock. Extinction learning occurred 72â€‰h later and extinction retention was tested one week after extinction. HC 25â€‰mg, DCS 50â€‰mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS- skin conductance response (SCR) compared to placebo (bâ€‰=â€‰-0.19, CIâ€‰=â€‰-0.01 to -37, pâ€‰=â€‰0.042 and bâ€‰=â€‰-0.25, CIâ€‰=â€‰-08 to -0.43, pâ€‰=â€‰0.005, respectively). A nonsignificant trend for a lower differential CS+/CS- SCR in the DCS group, compared to placebo, (bâ€‰=â€‰-0.25, CIâ€‰=â€‰0.04 to -0.55, pâ€‰=â€‰0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.
Intranasal oxytocin administration impacts the acquisition and consolidation of trauma-associated memories: a double-blind randomized placebo-controlled experimental study in healthy women
Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD) and oxytocin has been implicated in the formation of intrusive memories. This study investigates how oxytocin influences the acquisition and consolidation of trauma-associated memories and whether these effects are influenced by individual neurobiological and genetic differences. In this randomized, double-blind, placebo-controlled study, 220 healthy women received either a single dose of intranasal 24IU oxytocin or a placebo before exposure to a trauma film paradigm that solicits intrusive memories. We used a "general random forest" machine learning approach to examine whether differences in the noradrenergic and hypothalamic-pituitary-adrenal axis activity, polygenic risk for psychiatric disorders, and genetic polymorphism of the oxytocin receptor influence the effect of oxytocin on the acquisition and consolidation of intrusive memories. Oxytocin induced significantly more intrusive memories than placebo did (t(188.33)â€‰=â€‰2.12, pâ€‰=â€‰0.035, Cohen's dâ€‰=â€‰0.30, 95% CI 0.16-0.44). As hypothesized, we found that the effect of oxytocin on intrusive memories was influenced by biological covariates, such as salivary cortisol, heart rate variability, and PTSD polygenic risk scores. The five factors that were most relevant to the oxytocin effect on intrusive memories were included in a Poisson regression, which showed that, besides oxytocin administration, higher polygenic loadings for PTSD and major depressive disorder were directly associated with a higher number of reported intrusions after exposure to the trauma film stressor. These results suggest that intranasal oxytocin amplifies the acquisition and consolidation of intrusive memories and that this effect is modulated by neurobiological and genetic factors. Trial registration: NCT03031405.
Effects of glucocorticoid and noradrenergic activity on implicit and explicit facial emotion recognition in healthy young men
The ability to recognize emotions from facial expressions is crucial for social interaction. Only few studies have examined the effect of stress hormones on facial emotion recognition, although stressful events affect social interactions on a daily basis. Those studies that examined facial emotion recognition mostly used explicit prompts to trigger consciously controlled processing. However, facial emotions are processed mainly implicitly in real life. Therefore, we investigated separate and combined effects of noradrenergic and glucocorticoid stimulation on implicit and explicit facial emotion recognition. One hundred and four healthy men (mean age = 24.1â€‰years
Immunological substrates of depressive symptoms in patients with severe obesity: An exploratory study
In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8+ effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4+ central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4+ central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders.
Gray matter volume of rostral anterior cingulate cortex predicts rapid antidepressant response to ketamine
Ketamine was recently approved for treatment resistant depression. However, despite its therapeutic potential, about 50% of patients do not show improvement under this therapy. In this prospective two-site study, we investigated baseline brain structural predictors for rapid symptom improvement after a single subanesthetic ketamine infusion. Furthermore, given the preclinical evidence and findings from a pilot study in a clinical population that ketamine induces rapid neuroplasticity, we performed an exploratory investigation of macroscopic changes 24Â h post-treatment. T1-weighted MRI brain images from 33 depressed patients were acquired before and 24Â h after a single ketamine infusion and analyzed using voxel-based morphometry (VBM). Additionally, we performed a region of interest (ROI)-based analysis of structures that have previously been shown to play a role in the antidepressant effects of ketamine: bilateral hippocampus, nucleus accumbens, anterior cingulate cortex, and thalamus. A whole-brain regression analysis showed that greater baseline volume of the bilateral rostral anterior cingulate cortex (rACC) significantly predicts rapid symptom reduction. The right ACC showed the same association in the ROI analysis, while the other regions yielded no significant results. Exploratory follow-up analyses revealed no volumetric changes 24Â h after treatment. This is the first study reporting an association between pretreatment gray matter volume of the bilateral rACC and the rapid antidepressant effects of ketamine. Results are in line with previous investigations, which highlighted the potential of the rACC as a biomarker for response prediction to different antidepressant treatments. Ketamine-induced volumetric changes may be seen at later time points.
Noradrenergic activation induced by yohimbine decreases interoceptive accuracy in healthy individuals with childhood adversity
Acute stress affects interoception, but it remains unclear if this is due to activation of the sympatho-adreno-medullary (SAM) or hypothalamic-pituitary-adrenocortical axis. This study aimed to investigate the effect of SAM axis activation on interoceptive accuracy (IAcc). Central alpha2-adrenergic receptors represent a negative feedback mechanism of the SAM axis. Major depressive disorder and adverse childhood experiences (ACE) are associated with alterations in the biological stress systems, including central alpha2-adrenergic receptors. Here, healthy individuals with and without ACE as well as depressive patients with and without ACE (n = 114; all without antidepressant medication) were tested after yohimbine (alpha2-adrenergic antagonist) and placebo. We assessed IAcc and sensibility in a heartbeat counting task. Increases in systolic and diastolic blood pressure after yohimbine confirmed successful SAM axis activation. IAcc decreased after yohimbine only in the healthy group with ACE, but remained unchanged in all other groups (Group Ã— Drug interaction). This effect may be due to selective upregulation of alpha2-adrenergic receptors after childhood trauma, which reduces capacity for attention focus on heartbeats. The sympathetic neural pathway including alpha2-adrenergic circuitries may be essential for mediating interoceptive signal transmission. Suppressed processing of physical sensations in stressful situations may represent an adaptive response in healthy individuals who experienced ACE.
Facial emotion recognition in borderline patients is unaffected by acute psychosocial stress
Borderline Personality Disorder (BPD) is characterized by difficulties in social cognition and social interactions, which exacerbate under stress. A previous study found better facial emotion recognition (FER) in patients with personality disorders and healthy controls (HC) after stress. We recently reported that emotional empathy scores, i.e. the emotional response to another person's emotional state, were significantly lower in BPD patients than in HC after psychosocial stress. Cognitive empathy scores remained unaltered. The present study aims to further investigate the effect of psychosocial stress induced by the Trier Social Stress Test (TSST) on FER as part of social cognition in patients with BPD. We randomized 43 women with BPD and 46 female HC to either the TSST or a placebo condition. Afterwards, participants were asked in an emotion recognition test to identify emotions in faces showing anger or sadness at low and high intensity. Both groups recognized emotions better at high intensity compared with low intensity. There was no effect of stress on FER performance and we found no difference between groups. This is in line with prior research on social cognition in BPD patients demonstrating that the ability to understand another person's perspective might be unaffected by acute stress.
Using routine MRI data of depressed patients to predict individual responses to electroconvulsive therapy
Electroconvulsive therapy (ECT) is one of the most effective treatments in cases of severe and treatment resistant major depression. 60-80% of patients respond to ECT, but the procedure is demanding and robust prediction of ECT responses would be of great clinical value. Predictions based on neuroimaging data have recently come into focus, but still face methodological and practical limitations that are hampering the translation into clinical practice. In this retrospective study, we investigated the feasibility of ECT response prediction using structural magnetic resonance imaging (sMRI) data that was collected during ECT routine examinations. We applied machine learning techniques to predict individual treatment outcomes in a cohort of Nâ€¯=â€¯71 ECT patients, Nâ€¯=â€¯39 of which responded to the treatment. SMRI-based classification of ECT responders and non-responders reached an accuracy of 69% (sensitivity: 67%; specificity: 72%). Classification on additionally investigated clinical variables had no predictive power. Since dichotomisation of patients into ECT responders and non-responders is debatable due to many patients only showing a partial response, we additionally performed a post-hoc regression-based prediction analysis on continuous symptom improvements. This analysis yielded a significant relationship between true and predicted treatment outcomes and might be a promising alternative to dichotomization of patients. Based on our results, we argue that the prediction of individual ECT responses based on routine sMRI holds promise to overcome important limitations that are currently hampering the translation of such treatment biomarkers into everyday clinical practice. Finally, we discuss how the results of such predictive data analysis could best support the clinician's decision on whether a patient should be treated with ECT.
Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial
INTRODUCTION/BACKGROUND:Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity. METHODS AND ANALYSIS/UNASSIGNED:This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-Ã…sberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12. ETHICS AND DISSEMINATION/UNASSIGNED:This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut fÃ¼r Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences. TRIAL REGISTRATION NUMBERS/UNASSIGNED:NCT04301271, DRKS00021119, EudraCT 2018-002947-27.