Predictors of adherence to exercise interventions in people with schizophrenia.

Exercise interventions are nowadays considered as effective add-on treatments in people with schizophrenia but are usually associated with high dropout rates. Therefore, the present study investigated potential predictors of adherence from a large multicenter study, encompassing two types of exercise training, conducted over a 6-month period with individuals with schizophrenia. First, we examined the role of multiple participants' characteristics, including levels of functioning, symptom severity, cognitive performance, quality of life, and physical fitness. Second, we used K-means clustering to identify clinical subgroups of participants that potentially exhibited superior adherence. Last, we explored if adherence could be predicted on the individual level using Random Forest, Logistic Regression, and Ridge Regression. We found that individuals with higher levels of functioning at baseline were more likely to adhere to the exercise interventions, while other factors such as symptom severity, cognitive performance, quality of life or physical fitness seemed to be less influential. Accordingly, the high-functioning group with low symptoms exhibited a greater likelihood of adhering to the interventions compared to the severely ill group. Despite incorporating various algorithms, it was not possible to predict adherence at the individual level. These findings add to the understanding of the factors that influence adherence to exercise interventions. They underscore the predictive importance of daily life functioning while indicating a lack of association between symptom severity and adherence. Future research should focus on developing targeted strategies to improve adherence, particularly for people with schizophrenia who suffer from impairments in daily functioning.Clinical trials registration The study of this manuscript which the manuscript is based was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112, https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1 ) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804.

Association between aerobic fitness and the functional connectome in patients with schizophrenia.

BACKGROUND: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. OBJECTIVE: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. METHODS: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. RESULTS: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. CONCLUSION: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences. TRIAL REGISTRATION: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Alterations to sphingolipid metabolism from antipsychotic administration in healthy volunteers are restored following the use of cannabidiol.

Randomized clinical trials substantiate cannabidiol (CBD) as a next-generation antipsychotic, effective in alleviating positive and negative symptoms associated with psychosis, while minimising the adverse effects seen with established treatments. Although the mechanisms remain debated, CBD is known to induce drug-responsive changes in lipid-based retrograde neurotransmitters. Lipid aberrations are also frequently observed with antipsychotics, which may contribute to their efficacy or increase the risk of undesirables, including metabolic dysfunction, obesity and dyslipidaemia. Our study investigated CBD's impact following lipid responses triggered by interaction with second-generation antipsychotics (SGA) in a randomized phase I safety study. Untargeted mass spectrometry assessed the lipidomic profiles of human sera, collected from 38 healthy volunteers. Serum samples were obtained prior to commencement of any medication (t = 0), 3 days after consecutive administration of one of the five, placebo-controlled, treatment arms designed to achieve steady-state concentrations of each SGA (amisulpride, 150 mg/day; quetiapine, 300 mg/day; olanzapine 10 mg/day; risperidone, 3 mg/day), and after six successive days of SGA treatment combined with CBD (800 mg/day). Receiver operating characteristics (ROC) refined 3712 features to a putative list of 15 lipids significantly altered (AUC > 0.7), classified into sphingolipids (53 %), glycerolipids (27 %) and glycerophospholipids (20 %). Targeted mass spectrometry confirmed reduced sphingomyelin and ceramide levels with antipsychotics, which mapped along their catabolic pathway and were restored by CBD. These sphingolipids inversely correlated with body weight after olanzapine, quetiapine, and risperidone treatment, where CBD appears to have arrested or attenuated these effects. Herein, we propose CBD may alleviate aberrant sphingolipid metabolism and that further investigation into sphingolipids as markers for monitoring side effects of SGAs and efficacy of CBD is warranted.

Effects of Exercise on Structural and Functional Brain Patterns in Schizophrenia-Data From a Multicenter Randomized-Controlled Study.

BACKGROUND AND HYPOTHESIS: Aerobic exercise interventions in people with schizophrenia have been demonstrated to improve clinical outcomes, but findings regarding the underlying neural mechanisms are limited and mainly focus on the hippocampal formation. Therefore, we conducted a global exploratory analysis of structural and functional neural adaptations after exercise and explored their clinical implications. STUDY DESIGN: In this randomized controlled trial, structural and functional MRI data were available for 91 patients with schizophrenia who performed either aerobic exercise on a bicycle ergometer or underwent a flexibility, strengthening, and balance training as control group. We analyzed clinical and neuroimaging data before and after 6 months of regular exercise. Bayesian linear mixed models and Bayesian logistic regressions were calculated to evaluate effects of exercise on multiple neural outcomes and their potential clinical relevance. STUDY RESULTS: Our results indicated that aerobic exercise in people with schizophrenia led to structural and functional adaptations mainly within the default-mode network, the cortico-striato-pallido-thalamo-cortical loop, and the cerebello-thalamo-cortical pathway. We further observed that volume increases in the right posterior cingulate gyrus as a central node of the default-mode network were linked to improvements in disorder severity. CONCLUSIONS: These exploratory findings suggest a positive impact of aerobic exercise on 3 cerebral networks that are involved in the pathophysiology of schizophrenia. CLINICAL TRIALS REGISTRATION: The underlying study of this manuscript was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112, https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Simultaneous Assessment of Serum Levels and Pharmacologic Effects of Cannabinoids on Endocannabinoids and N-Acylethanolamines by Liquid Chromatography-Tandem Mass Spectrometry.

Introduction: The primary compounds of Cannabis sativa, delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), inflict a direct influence on the endocannabinoid system-a complex lipid signaling network with a central role in neurotransmission and control of inhibitory and excitatory synapses. These phytocannabinoids often interact with endogenously produced endocannabinoids (eCBs), as well as their structurally related N-acylethanolamines (NAEs), to drive neurobiological, nociceptive, and inflammatory responses. Identifying and quantifying changes in these lipid neuromodulators can be challenging owing to their low abundance in complex matrices. Materials and Methods: This article describes a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the extraction and quantification of the eCBs anandamide and 2-arachidonoylglycerol, along with their congener NAEs oleoylethanolamine and palmitoylethanolamine, and phytocannabinoids CBD, Δ9-THC, and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol, a major metabolite of Δ9-THC. Our method was applied to explore pharmacokinetic and pharmacodynamic effects from intraperitoneal injections of Δ9-THC and CBD on circulating levels of eCBs and NAEs in rodent serum. Results: Detection limits ranged from low nanomolar to picomolar in concentration for eCBs (0.012-0.24 pmol/mL), NAEs (0.059 pmol/mL), and phytocannabinoids (0.24-0.73 pmol/mL). Our method displayed good linearity for calibration curves of all analytes (R2>0.99) as well as acceptable accuracy and precision, with quality controls not deviating >15% from their nominal value. Our LC-MS/MS method reliably identified changes to these endogenous lipid mediators that followed a causal relationship, which was dependent on both the type of phytocannabinoid administered and its pharmaceutical preparation. Conclusion: We present a rapid and reliable method for the simultaneous quantification of phytocannabinoids, eCBs, and NAEs in serum using LC-MS/MS. The accuracy and sensitivity of our assay infer it can routinely monitor endogenous levels of these lipid neuromodulators in serum and their response to external stimuli, including cannabimimetic agents.

Exercise as an add-on treatment in individuals with schizophrenia: Results from a large multicenter randomized controlled trial.

Current treatment methods do not achieve recovery for most individuals with schizophrenia, and symptoms such as negative symptoms and cognitive deficits often persist. Aerobic endurance training has been suggested as a potential add-on treatment targeting both physical and mental health. We performed a large-scale multicenter, rater-blind, parallel-group randomized controlled clinical trial in individuals with stable schizophrenia. Participants underwent a professionally supervised six-month training comprising either aerobic endurance training (AET) or flexibility, strengthening, and balance training (FSBT, control group), follow-up was another six months. The primary endpoint was all-cause discontinuation (ACD); secondary endpoints included effects on psychopathology, cognition, functioning, and cardiovascular risk. In total, 180 participants were randomized. AET was not superior to FSBT in ACD and most secondary outcomes, with dropout rates of 59.55% and 57.14% in the six-month active phase, respectively. However, both groups showed significant improvements in positive, general, and total symptoms, levels of functioning and in cognitive performance. A higher training frequency additionally promoted further memory domains. Participants with higher baseline cognitive abilities were more likely to respond to the interventions. Our results support integrating exercise into schizophrenia treatment, while future studies should aim to develop personalized training recommendations to maximize exercise-induced benefits.

Associations between aerobic fitness, negative symptoms, cognitive deficits and brain structure in schizophrenia-a cross-sectional study.

Negative symptoms and cognitive deficits are common in individuals with schizophrenia, greatly affect their outcome, and have been associated with alterations in cerebral gray and white matter volume (GMV, WMV). In the last decade, aerobic endurance training has emerged as a promising intervention to alleviate these symptoms and improved aerobic fitness has been suggested as a key moderator variable. In the present study, we investigated, whether aerobic fitness is associated with fewer cognitive deficits and negative symptoms and with GMVs and WMVs in individuals with schizophrenia in a cross-sectional design. In the largest study to date on the implications of fitness in individuals with schizophrenia, 111 participants at two centers underwent assessments of negative symptoms, cognitive functioning, and aerobic fitness and 69 underwent additional structural magnetic resonance imaging. Multilevel Bayesian partial correlations were computed to quantify relationships between the variables of interest. The main finding was a positive association of aerobic fitness with right hippocampal GMV and WMVs in parahippocampal and several cerebellar regions. We found limited evidence for an association of aerobic fitness with cognitive functioning and negative symptoms. In summary, our results strengthen the notion that aerobic fitness and hippocampal plasticity are interrelated which holds implications for the design of exercise interventions in individuals with schizophrenia.