Aerobic endurance training to improve cognition and enhance recovery in schizophrenia: design and methodology of a multicenter randomized controlled trial.

Even today, patients with schizophrenia often have an unfavorable outcome. Negative symptoms and cognitive deficits are common features in many patients and prevent recovery. In recent years, aerobic endurance training has emerged as a therapeutic approach with positive effects on several domains of patients' health. However, appropriately sized, multicenter randomized controlled trials that would allow better generalization of results are lacking. The exercise study presented here is a multicenter, rater-blind, two-armed, parallel-group randomized clinical trial in patients with clinically stable schizophrenia being conducted at five German tertiary hospitals. The intervention group performs aerobic endurance training on bicycle ergometers three times per week for 40-50 min/session (depending on the intervention week) for a total of 26 weeks, and the control group performs balance and tone training for the same amount of time. Participants are subsequently followed up for 26 weeks. The primary endpoint is all-cause discontinuation; secondary endpoints include psychopathology, cognition, daily functioning, cardiovascular risk factors, and explorative biological measures regarding the underlying mechanisms of exercise. A total of 180 patients will be randomized. With currently 162 randomized participants, our study is the largest trial to date to investigate endurance training in patients with schizophrenia. We hypothesize that aerobic endurance training has beneficial effects on patients' mental and physical health, leading to lower treatment discontinuation rates and improving disease outcomes. The study results will provide a basis for recommending exercise interventions as an add-on therapy in patients with schizophrenia.The study is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Neural correlates of binocular depth inversion illusion in antipsychotic-naïve first-episode schizophrenia patients.

OBJECTIVES: Binocular depth inversion illusion (BDII), a visual, 'top-down'-driven information process, is impaired in schizophrenia and particularly in its early stages. BDII is a sensitive measure of impaired visual information processing and represents a valid diagnostic tool for schizophrenia and other psychotic disorders. However, neurobiological underpinnings of aberrant BDII in first-episode schizophrenia are largely unknown at present. METHODS: In this study, 22 right-handed, first-episode, antipsychotic-naïve schizophrenia patients underwent BDII assessment and MRI scanning at 1.5 T. The surface-based analysis via new version of Freesurfer (6.0) enabled calculation of cortical thickness and surface area. BDII total and faces scores were related to the two distinct cortical measurements. RESULTS: We found a significant correlation between BDII performance and cortical thickness in the inferior frontal gyrus and middle temporal gyrus (p < 0.003, Bonferroni corr.), as well as superior parietal gyrus, postcentral gyrus, supramarginal gyrus, and precentral gyrus (p < 0.05, CWP corr.), respectively. BDII performance was significantly correlated with surface area in the superior parietal gyrus and right postcentral gyrus (p < 0.003, Bonferroni corr.). CONCLUSION: BDII performance may be linked to cortical thickness and surface area variations in regions involved in "adaptive" or "top-down" modulation and stimulus processing, i.e., frontal and parietal lobes. Our results suggest that cortical features of distinct evolutionary and genetic origin differently contribute to BDII performance in first-episode, antipsychotic-naïve schizophrenia patients.

Neurological soft signs in schizophrenia spectrum disorders are not confounded by current antipsychotic dosage.

Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD.

Moving forward: distinct sensorimotor abnormalities predict clinical outcome after 6 months in patients with schizophrenia.

Despite substantial efforts in the last decades, objective measures that can predict clinical outcome in patients with schizophrenia (SZ) after an acute psychotic episode are still lacking. Here, we introduced a comprehensive assessment of sensorimotor function to predict mid-term clinical outcome following an acute psychotic episode. This naturalistic follow-up of 43 patients with DSM-IV-TR diagnosis of SZ examined sensorimotor abnormalities (i.e. Neurological Soft Signs (NSS), parkinsonism, akathisia, catatonia and acute dyskinesia), psychopathology, cognition and psychosocial functioning using well-established instruments. A collection of statistical methods was used to examine the relationship between sensorimotor domain, psychopathology, cognition and psychosocial functioning. We also tested the clinical feasibility of this relationship when predicting clinical outcome after an acute psychotic episode. Longitudinal data were collected on 43 individuals after a follow-up period of >6 months. At follow-up, patients showed significantly reduced general symptom severity, as well as decreased levels of NSS, parkinsonism and catatonia. Further, NSS scores at baseline predicted PANSS negative scores and cognitive functioning at baseline. Finally, NSS scores at baseline predicted symptom change (reduction of PANSS positive and negative scores) at follow-up. In conclusion, our results suggest that NSS are significant predictors of poor clinical outcome in SZ at baseline and >6 months after an acute psychotic episode. These findings propose sensorimotor domain as state biomarker of SZ and support its predictive power with respect to treatment outcome.

Two Sides of the Same Coin: A Case Report of First-Episode Catatonic Syndrome in a High-Functioning Autism Patient.

Background: Catatonic phenomena such as stupor, mutism, stereotypy, echolalia, echopraxia, affective flattening, psychomotor deficits, and social withdrawal are characteristic symptoms of both schizophrenia and autism spectrum disorders (ASD), suggesting overlapping pathophysiological similarities such as altered glutamatergic and dopaminergic synaptic transmission and common genetic mutations. In daily clinical practice, ASD can be masked by manifest catatonic or psychotic symptoms and represent a diagnostic challenge, especially in patients with unknown or empty medical history. Unclear diagnosis is one of the main factors for delayed treatment. However, we are still missing diagnostic recommendations when dealing with ASD patients suffering from catatonic syndrome. Case presentation: A 31-year-old male patient without history of psychiatric disease presented with a severe catatonic syndrome and was admitted to our closed psychiatric ward. After the treatment with high-dose lorazepam and intramuscular olanzapine, catatonic symptoms largely remitted, but autistic traits persisted. Following a detailed anamnesis and a thorough neuropsychological testing, we diagnosed the patient with high-functioning autism and catatonic schizophrenia. The patient was discharged in a remitted state with long-acting injectable olanzapine. Conclusion: This case represents an example of diagnostic and therapeutic challenges of catatonic schizophrenia in high-functioning autism due to clinical and neurobiological overlaps of these conditions. We discuss clinical features together with pathophysiological concepts of both conditions. Furthermore, we tackle social and legal hurdles in Germany that naturally arise in these patients. Finally, we present diagnostic "red flags" that can be used to rationally select and conduct current recommended diagnostic assessments if there is a suspicion of ASD in patients with catatonic syndrome in order to provide them with the most appropriate treatment.

Differential contributions of brainstem structures to neurological soft signs in first- and multiple-episode schizophrenia spectrum disorders.

Neurological soft signs (NSS) are frequently found in patients with schizophrenia spectrum disorders (SSD) at any stage of the disease. Brainstem structures are crucial for motor control, integration of sensory input and coordination of automatic motor actions. It is unclear whether disease duration has an impact on NSS/brainstem volume relationships. We tested the hypothesis that volumes of brainstem structures differ between first-episode psychosis (FEP) and multiple-episodes psychosis (MEP) patients with SSD, and that alterations of these structures are associated with NSS. T1-weighted structural MRI data at 3 T were obtained from 92 right-handed SSD patients (27 FEP and 65 MEP). FreeSurfer vers. 6.0 was used for segmentation of brainstem structures including the medulla oblongata, pons, superior cerebellar pedunculus (SCP), and midbrain. Multiple regression analyses were used to describe the relationship between brainstem structures and distinct NSS subdomains. In FEP, pons volume had a significant effect on NSS total score (p = 0.001, Bonferroni corr.). Further, medulla oblongata (p = 0.001, Bonferroni corr.) and pons (p = 0.001, Bonferroni corr.) volumes had a significant effect on NSS motor coordination score. In MEP, significant associations between brainstem structures and NSS levels were not found. The present data support the notion that brainstem structures play an important role in the expression of NSS in SSD individuals with FEP, in contrast to individuals with MEP. Our study also emphasizes the need of better characterizing episode-specific brainstem correlates of NSS in SSD.

Cortical Contributions to Distinct Symptom Dimensions of Catatonia.

Catatonia is a central aspect of schizophrenia spectrum disorders (SSD) and most likely associated with abnormalities in affective, motor, and sensorimotor brain regions. However, contributions of different cortical features to the pathophysiology of catatonia in SSD are poorly understood. Here, T1-weighted structural magnetic resonance imaging data at 3 T were obtained from 56 right-handed patients with SSD. Using FreeSurfer version 6.0, we calculated cortical thickness, area, and local gyrification index (LGI). Catatonic symptoms were examined on the Northoff catatonia rating scale (NCRS). Patients with catatonia (NCRS total score ≥3; n = 25) showed reduced surface area in the parietal and medial orbitofrontal gyrus and LGI in the temporal gyrus (P < .05, corrected for cluster-wise probability [CWP]) as well as hypergyrification in rostral cingulate and medial orbitofrontal gyrus when compared with patients without catatonia (n = 22; P < .05, corrected for CWP). Following a dimensional approach, a negative association between NCRS motor and behavior scores and cortical thickness in superior frontal, insular, and precentral cortex was found (34 patients with at least 1 motor and at least 1 other affective or behavioral symptom; P < .05, corrected for CWP). Positive associations were found between NCRS motor and behavior scores and surface area and LGI in superior frontal, posterior cingulate, precentral, and pericalcarine gyrus (P < .05, corrected for CWP). The data support the notion that cortical features of distinct evolutionary and genetic origin differently contribute to catatonia in SSD. Catatonia in SSD may be essentially driven by cortex variations in frontoparietal regions including regions implicated in the coordination and goal-orientation of behavior.

Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia: Implications for Pharmacological Intervention.

The term schizophrenia describes a group of multifaceted psychiatric conditions causing significant impairment of the quality of life of affected patients. Although multiple pharmacological treatment options exist, e.g. first- or second-generation antipsychotics, these therapeutics often cause disturbing side effects, such as extrapyramidal symptoms, prolactin increase, sexual dysfunction and/or metabolic syndrome. Furthermore, cognitive impairments and negative symptoms, two factors significantly influencing the course and outcome, are not sufficiently addressed by the available antipsychotics. Since its discovery, multiple clinical and preclinical studies have linked the endocannabinoid system to schizophrenia. Both the endocannabinoid anandamide and the cannabinoid CB1 receptor are deeply linked to underlying disease processes. Based hereon, clinical trials in schizophrenia have explored cannabidiol, a primary component of Cannabis sativa, and rimonabant, a partial antagonist to the CB1 receptor. While the latter did not reveal positive results, cannabidiol significantly ameliorated psychotic symptoms, which was associated with an increase in anandamide serum levels. However, the exact mechanisms of the antipsychotic effects of cannabidiol are not fully understood, and, furthermore, only a limited number of clinical trials in humans have been concluded to date. Thus, the level of proof of safety and efficacy required to approve the therapeutic use of cannabidiol in schizophrenia is currently lacking. However, cannabidiol is a promising candidate as an effective and mechanistically different antipsychotic treatment with a favourable side-effect profile. We therefore conclude that further studies are urgently needed to clarify the antipsychotic effects and safety profile of cannabidiol, and to fully explore its potential antipsychotic mechanism.