Abstract
Background
Antidepressant discontinuation is associated with a broad range of adverse effects. Debilitating discontinuation symptoms can impede the discontinuation process and contribute to ...unnecessary long-term use of antidepressants. Antidepressant trials reveal large placebo effects, indicating a potential use of open-label placebo (OLP) treatment to facilitate the discontinuation process. We aim to determine the effect of OLP treatment in reducing antidepressant discontinuation symptoms using a series of N-of-1 trials.
Methods
A series of randomized, single-blinded N-of-1 trials will be conducted in 20 patients with fully remitted DSM-V major depressive disorder, experiencing moderate to severe discontinuation symptoms following antidepressant discontinuation. Each N-of-1 trial consists of two cycles, each comprising two-week alternating periods of OLP treatment and of no treatment in a random order, for a total of eight weeks. Our primary outcome will be self-reported discontinuation symptoms rated twice daily via the smartphone application ‘StudyU’. Secondary outcomes include expectations about discontinuation symptoms and (depressed) mood. Statistical analyses will be based on a Bayesian multi-level random effects model, reporting posterior estimates of the overall and individual treatment effects.
Discussion
Results of this trial will provide insight into the clinical application of OLP in treating antidepressant discontinuation symptoms, potentially offering a new cost-effective therapeutic tool. This trial will also determine the feasibility and applicability of a series of N-of-1 trials in a clinical discontinuation trial.
Trial registration
ClinicalTrials.gov: NCT05051995, first registered September 20, 2021.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this ...trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034.
Deceiving Oneself About Being in Control Knoblich, Günther; Kircher, Tilo T. J
Journal of experimental psychology. Human perception and performance,
08/2004, Letnik:
30, Številka:
4
Journal Article
Recenzirano
Previous research has demonstrated that compensatory movements for changes in visuomotor coupling often are not consciously detected. But what factors affect the conscious detection of such changes? ...This issue was addressed in 4 experiments. Participants carried out a drawing task in which the relative velocity between the actual movement and its visual consequences was perturbed. Unconscious compensatory movements and conscious detection rates were simultaneously recorded. There was an invariant relationship between the extent of the change and its conscious detection that was proportional to the initial drawing velocity. This suggests that conscious change detection relies on a system that integrates visual and motor information-as, for instance, suggested by the internal model theory of motor control. Figural discrepancies increased the detection rates, indicating that additional cues for the what system facilitate conscious change detection.
Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are ...under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.
Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients' pretreatment extinction learning ...performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment procedures. Therefore, we developed an extinction-training protocol highly tailored to the procedure of exposure therapy and tested it in two samples of 46 subjects in total. By using instructed fear acquisition training, including a consolidation period overnight, we wanted to ensure that the conditioned fear response was well established prior to extinction training, which is the case in patients with anxiety disorders prior to treatment. Moreover, the extinction learning process was analyzed on multiple response levels, comprising unconditioned stimulus (US) expectancy ratings, autonomic responses, defensive brain stem reflexes, and neural activation using functional magnetic resonance imaging. Using this protocol, we found robust fear conditioning and slow-speed extinction learning. We also observed within-group heterogeneity in extinction learning, albeit a stable fear response at the beginning of the extinction training. Finally, we found discordance between different response systems, suggesting that multiple processes are involved in extinction learning. The paradigm presented here might help to ameliorate the association between extinction learning performance assessed in the laboratory and therapy outcomes and thus facilitate translational science in anxiety disorders.
Sensory action consequences are highly predictable and thus engage less neural resources compared to externally generated sensory events. While this has frequently been observed to lead to attenuated ...perceptual sensitivity and suppression of activity in sensory cortices, some studies conversely reported enhanced perceptual sensitivity for action consequences. These divergent findings might be explained by the type of action feedback, i.e., discrete outcomes vs. continuous feedback. Therefore, in the present study we investigated the impact of discrete and continuous action feedback on perceptual and neural processing during action feedback monitoring.
During fMRI data acquisition, participants detected temporal delays (0–417 ms) between actively or passively generated wrist movements and visual feedback that was either continuously provided during the movement or that appeared as a discrete outcome.
Both feedback types resulted in (1) a neural suppression effect (active<passive) in a largely shared network including bilateral visual and somatosensory cortices, cerebellum and temporoparietal areas. Yet, compared to discrete outcomes, (2) processing continuous feedback led to stronger suppression in right superior temporal gyrus (STG), Heschl´s gyrus, and insula suggesting specific suppression of features linked to continuous feedback. Furthermore, (3) BOLD suppression in visual cortex for discrete outcomes was specifically related to perceptual enhancement.
Together, these findings indicate that neural representations of discrete and continuous action feedback are similarly suppressed but might depend on different predictive mechanisms, where reduced activation in visual cortex reflects facilitation specifically for discrete outcomes, and predictive processing in STG, Heschl´s gyrus, and insula is particularly relevant for continuous feedback.
Cognitive deficits are central attendant symptoms of major depressive disorder (MDD) with a crucial impact in patients' everyday life. Thus, it is of particular clinical importance to understand ...their pathophysiology. The aim of this study was to investigate a possible relationship between brain structure and cognitive performance in MDD patients in a well-characterized sample. N = 1007 participants (N
= 482, healthy controls (HC): N
= 525) were selected from the FOR2107 cohort for this diffusion-tensor imaging study employing tract-based spatial statistics. We conducted a principal component analysis (PCA) to reduce neuropsychological test results, and to discover underlying factors of cognitive performance in MDD patients. We tested the association between fractional anisotropy (FA) and diagnosis (MDD vs. HC) and cognitive performance factors. The PCA yielded a single general cognitive performance factor that differed significantly between MDD patients and HC (P < 0.001). We found a significant main effect of the general cognitive performance factor in FA (P
= 0.002) in a large bilateral cluster consisting of widespread frontotemporal-association fibers. In MDD patients this effect was independent of medication intake, the presence of comorbid diagnoses, the number of previous hospitalizations, and depressive symptomatology. This study provides robust evidence that white matter disturbances and cognitive performance seem to be associated. This association was independent of diagnosis, though MDD patients show more pronounced deficits and lower FA values in the global white matter fiber structure. This suggests a more general, rather than the depression-specific neurological basis for cognitive deficits.
Major depressive disorder (MDD) is a highly prevalent (8-15%), severely disabling disorder and is associated with enormous socioeconomic impact. Antidepressant medication for the treatment of MDD has ...proven effective in RCTs; however, placebo response is also substantial. Given the potential benefits of modulating the placebo response in patient care and pharmacological research, understanding the mechanisms underlying placebo response is of high clinical relevance. The placebo response is mediated by treatment expectation, i.e. an individual's belief about whether and how much they will improve as a consequence of their treatment. The mechanisms and moderators of treatment expectation effects in MDD are poorly understood. Initial brain imaging studies on placebo responses in MDD point towards the relevance of the lateral prefrontal cortex and the rostral anterior cingulate cortex (rACC). In this project, we will investigate the neural mechanisms underlying the antidepressant effects of treatment expectation associated with the fast-acting antidepressant esketamine in patients with MDD. Esketamine is an NMDA receptor antagonist inducing antidepressant effects within hours.
We will employ a fully balanced placebo design with the factors "treatment" (i.v. esketamine / placebo) and verbally induced "expectation" (high / low) combined with fMRI (resting state, emotion and reward processing paradigms) to investigate the psychological and neural mechanisms underlying the antidepressant effects of expectation, and how these interact with the pharmacological effects of esketamine.
The insights gained by this project promise fundamental implications for clinical treatment and future drug trials. Unraveling the mechanisms underlying expectation effects on antidepressant treatment may inform (1) strategies to modulate these effects and thus improve assay sensitivity in RCTs and (2) novel treatment regiments aiming to maximize the synergistic effects of expectation and pharmacological treatment in the clinical care of patients with MDD.
This trial has been prospectively registered with the EU Clinical Trials Register: EudraCT-No.: 2020-000784-23 (November 17, 2020).
Predicting the sensory consequences of our own actions contributes to efficient sensory processing and might help distinguish the consequences of self- versus externally generated actions. Previous ...research using unimodal stimuli has provided evidence for the existence of a forward model, which explains how such sensory predictions are generated and used to guide behavior. However, whether and how we predict
multisensory
action outcomes remains largely unknown. Here, we investigated this question in two behavioral experiments. In Experiment
1
, we presented unimodal (visual or auditory) and bimodal (visual and auditory) sensory feedback with various delays after a self-initiated buttonpress. Participants had to report whether they detected a delay between their buttonpress and the stimulus in the predefined task modality. In Experiment
2
, the sensory feedback and task were the same as in Experiment
1
, but in half of the trials the action was externally generated. We observed enhanced delay detection for bimodal relative to unimodal trials, with better performance in general for actively generated actions. Furthermore, in the active condition, the bimodal advantage was largest when the stimulus in the task-irrelevant modality was not delayed—that is, when it was time-contiguous with the action—as compared to when both the task-relevant and task-irrelevant modalities were delayed. This specific enhancement for trials with a nondelayed task-irrelevant modality was absent in the passive condition. These results suggest that a forward model creates predictions for multiple modalities, and consequently contributes to multisensory interactions in the context of action.
Expression of polysialic acid (polySia) in the adult brain is enriched in areas of continuous neurogenesis and plasticity such as the hippocampus. Genome-wide association studies identified variants ...of glycosylation enzyme-encoding genes, required for the generation of polySia, to be associated with the development of schizophrenia and bipolar disorder. Here, we report that serum levels of polySia are increased in patients with schizophrenia spectrum disorder compared to patients with major depressive disorders or demographically matched healthy controls. Furthermore, elevated polySia serum levels are associated with structural hippocampal gray matter decline in schizophrenia spectrum and bipolar disorder. In patients with schizophrenia spectrum disorder, polySia serum levels correlate with the number, duration of disease-related hospitalizations, early retirement and medical leave as estimators of detrimental long-term disease trajectories. Our data show that polySia serum levels are linked to structural hippocampal brain changes in schizophrenia spectrum and bipolar disorders, and suggest a contribution of polySia to the pathophysiology of these diseases.
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