Network analysis of inflammation and symptoms in recent onset schizophrenia and the influence of minocycline during a clinical trial.
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SUBMITTER: Herniman SE
PROVIDER: S-EPMC10507090 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Network analysis of inflammation and symptoms in recent onset schizophrenia and the influence of minocycline during a clinical trial.
Herniman Sarah E SE Wood Stephen J SJ Khandaker Golam G Dazzan Paola P Pariante Carmine M CM Barnes Nicholas M NM Krynicki Carl R CR Nikkheslat Naghmeh N Vincent Rachel C RC Roberts Alex A Giordano Annalisa A Watson Andrew A Suckling John J Barnes Thomas R E TRE Husain Nusrat N Jones Peter B PB Joyce Eileen E Lawrie Stephen M SM Lewis Shôn S Deakin Bill B Upthegrove Rachel R
Translational psychiatry 20230918 1
Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further ai ...[more]
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Project description:BackgroundThe antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved.MethodsIn this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I.FindingsBetween April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference -0·19, 95% CI -1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group).InterpretationMinocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy.FundingNational Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.
| S-EPMC6206257 | biostudies-literature
Project description:IntroductionDiffusion weighted MRI (dMRI) is a method sensitive to pathological changes affecting tissue microstructure. Most dMRI studies in schizophrenia, however, have focused solely on white matter. There is a possibility, however, that subtle changes in diffusivity exist in gray matter (GM). Accordingly, we investigated diffusivity in GM in patients with recent onset schizophrenia.MethodsWe enrolled 45 patients and 21 age and sex-matched healthy controls. All subjects were evaluated using the short form of the Wechsler Adult Intelligence Scale, the Positive and Negative Syndrome Scale (PANSS), and the video based social cognition scale. DMRI and T1W images were acquired on a 3 Tesla magnet, and mean Fractional Anisotropy (FA), Trace (TR) and volume were calculated for each of the 68 cortical GM Regions of Interest parcellated using FreeSurfer.ResultsThere was no significant difference of FA and GM volume between groups after Bonferroni correction. For the dMRI measures, however, patients evinced increased TR in the left bank of the superior temporal sulcus, the right inferior parietal, the right inferior temporal, and the right middle temporal gyri. In addition, higher TR in the right middle temporal gyrus and the right inferior temporal gyrus, respectively, was associated with decreased social function and higher PANSS score in patients with schizophrenia.ConclusionThis study demonstrates high sensitivity of dMRI to subtle pathology in GM in recent onset schizophrenia, as well as an association between increased diffusivity in temporal GM regions and abnormalities in social cognition and exacerbation of psychiatric symptoms.
| S-EPMC5392041 | biostudies-literature
Project description:ObjectiveClozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes.MethodsSchizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23).ResultsBrief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo.ConclusionsMinocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.
| S-EPMC4485552 | biostudies-literature
Project description:(1) Background: Our aims in this study were (i) to compare effort allocation capacity measured between patients with recent-onset schizophrenia (SCZ) and healthy controls (HCs), (ii) within the SCZ, to investigate the association of effort allocation capacity with negative symptoms (NS), and (iii) to compare this association with the type of NS scale used. (2) Methods: Thirty-one patients with SCZ and 30 HCs participated in the study. The NS was examined using an older-generation (Scale for the Assessment of Negative Symptoms, SANS), a newer-generation (Brief Negative Symptoms Scale, BNSS), and a self-rated (Self-evaluation of Negative Symptoms Scale, SNS) negative symptom scale, as well as longitudinally by using persistent NS (PNS) distinction. (3) Results: The SCZ group was less willing to expend effort in high/moderate-probability and -magnitude conditions but more in low-probability and -magnitude conditions. A general reduction in effort allocation capacity was also present. Patients with PNS were less likely to choose hard tasks than non-PNS patients. Clinician-rated scales correlated with 50% probability and moderate-reward-magnitude conditions. Correlations with the SNS were minimal. (4) Conclusions: Our findings suggest that patients with SCZ may show a general reduction in effort allocation capacity and make inefficient choices, although they are not totally reward-insensitive. The effects of NS on effort expenditure can be more pronounced when the rewarding stimulus is vague.
| S-EPMC9457458 | biostudies-literature
Project description:Although cognitive dysfunction is a primary characteristic of schizophrenia, only recently have investigations begun to pinpoint when the dysfunction develops in the individual afflicted by the disorder. Research to date provides evidence for significant cognitive impairments prior to disorder onset. Less is known about the course of cognitive dysfunction from onset to the chronic phase of schizophrenia. Although longitudinal studies are optimal for assessing stability of cognitive deficits, practice effects often confound assessments, and large and representative subject samples have not been followed over long periods of time. We report results of a cross-sectional study of cognitive deficits early and late in the course of schizophrenia carried out at four different geographic locations to increase sample size and generalizability of findings. We examined a broad set of cognitive functions in 41 recent-onset schizophrenia patients and 106 chronic schizophrenia patients. The study included separate groups of 43 matched controls for the recent-onset sample and 105 matched controls for the chronic schizophrenia sample in order to evaluate the effects of cohort (i.e., age) and diagnosis (i.e., schizophrenia) on cognitive functions. All measures of cognitive function showed effects of diagnosis; however, select time-based measures of problem solving and fine motor dexterity exhibited interactions of diagnosis and cohort indicating that these deficits may progress beyond what is expected with normal aging. Also, worse recall of material in episodic memory was associated with greater length of illness. Nevertheless, findings indicate that nearly all cognitive deficits are comparably impaired across recent-onset and chronic schizophrenia.
| S-EPMC3940967 | biostudies-literature
Project description:Neuroimaging studies of childhood onset schizophrenia (COS), a rare yet severe form of schizophrenia with an onset before the age of 13 years, have shown continuity with adult onset schizophrenia. Previous research in adult patients has shown reduced sleep spindle activity, transient oscillations in the sleep electroencephalogram (EEG) generated through thalamocortical loops. The current study examines sleep spindle activity in patients with COS. Seventeen children and adolescents with COS (16 years ±6.6) underwent overnight sleep EEG recordings. Sleep spindle activity was compared between patients with COS and age and gender matched controls and correlated with clinical symptom severity. We found pronounced deficits in sleep spindle amplitude, duration, density and frequency in patients with COS (effect size = 0.61 to 1.96; dependent on metric and EEG derivation). Non-rapid eye movement (NREM) sleep EEG power and coherence in the sigma band (11-16 Hz) corresponding to spindle activity were also markedly diminished in patients with COS as compared to controls. Furthermore, the degree of deficit in power and coherence of spindles was strongly associated with clinician rated hallucinations and positive symptoms over widespread cortical regions. Our finding of diminished spindle activity and its association with hallucinations likely reflect dysfunction of the thalamocortical circuits in children and adolescents with COS. Given the relative ease of sleep EEG recordings in vulnerable populations, this study highlights the potential of such recordings to characterize brain function in schizophrenia.
| S-EPMC7704640 | biostudies-literature
Project description:BackgroundThe functional architecture of resting-state networks (RSNs) is defined by their connectivity and metastability. Disrupted RSN connectivity has been amply demonstrated in schizophrenia while the role of metastability remains poorly defined. Here, we undertake a comprehensive characterisation of RSN organization in schizophrenia and test its contribution to the clinical profile of this disorder.MethodsWe extracted RSNs representing the default mode (DMN), central executive (CEN), salience (SAL), language (LAN), sensorimotor (SMN), auditory (AN) and visual (VN) networks from resting-state functional magnetic resonance imaging data obtained from patients with schizophrenia (n = 85) and healthy individuals (n = 48). For each network, we computed its functional cohesiveness and integration and used the Kuramoto order parameter to compute metastability. We used stepwise multiple regression analyses to test these RSN features as predictors of symptom severity in patients.ResultsRSN features respectively explained 14%, 17%, 12% and 5% of the variance in positive, negative, anxious/depressive and agitation/disorganization symptoms. Lower functional integration between the DMN, CEN and SMN primarily contributed to positive symptoms. The functional properties of the SAL network were key predictors of all other symptom dimensions; specifically, lower cohesiveness of the SAL, lower integration of this network with the LAN and higher integration with the CEN respectively contributed to negative, anxious/depressive and disorganization symptoms. Increased SAL metastability was associated with negative symptoms.ConclusionsThese results confirm the primacy of the SAL network for schizophrenia and demonstrate that abnormalities in RSN connectivity and metastability are significant predictors of schizophrenia-related psychopathology.
| S-EPMC6317903 | biostudies-literature
Project description:BackgroundType 1 diabetes (T1D) TrialNet is a National Institutes of Health-sponsored clinical trial network aimed at altering the disease course of T1D. The purpose of this study is to evaluate age-dependent heterogeneity in clinical, metabolic and immunologic characteristics of individuals with recent-onset T1D, to identify cohorts of interest and to aid in planning of future studies.MethodsEight hundred eighty-three individuals with recent-onset T1D involved in five TrialNet studies were categorized by age as follows: ≥18 years, 12-17 years, 8-12 years and <8 years. Data were compared with healthy age-matched subjects in the National Health and Nutrition Examination Survey.ResultsOnly 2.0% of the individuals overall were excluded from trial participation because of insufficient C-peptide values (<0.2 pmol/mL). A disproportionate number of these subjects were <8 years old. Leukopenia was present in 21.2% of individuals and lymphopenia in 11.6%; these frequencies were markedly higher than age-matched healthy National Health and Nutrition Examination Survey population. Of the cohort, 24.5% were overweight or obese. Neither high-risk human leukocyte antigen type DR3 nor DR4 was present in 31% of adults and 21% of children.ConclusionsThe ability of recent-onset T1D patients to meet key entry criteria for TrialNet studies, including C-peptide >0.2 pmol/mL, varies by age. Lower C-peptide level requirements for younger participants and other aspects of heterogeneity of recent-onset T1D patients, such as white blood cell count abnormalities and body mass index should be considered in the design of future clinical studies.
| S-EPMC4815427 | biostudies-literature
Project description:ImportanceInsufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD.ObjectiveTo determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD.Design, setting, and participantsThe study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020.InterventionsParticipants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks.Main outcomes and measuresPrimary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-to-treat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales.ResultsOf 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of treatment (1.46 [-1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically significant effect on secondary outcomes.Conclusions and relevanceIn this large randomized clinical trial with minocycline at a dose of 200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD.Trial registrationEU Clinical Trials Register Number: EudraCT 2015-001456-29.
| S-EPMC9475381 | biostudies-literature
Project description:Structural impairments in white matter tracts are well-documented in schizophrenia, though their clinical implications remain limited. Most previous studies using diffusion-weighted magnetic resonance imaging (dMRI) and tractography relied on averaged diffusion indices, potentially obscuring localized changes in white matter tracts. Tractometry enables the investigation of localized changes at specific points along white matter tracts. We used dMRI and centerline tractometry to examine along-tract white matter abnormalities in 55 patients with recent-onset schizophrenia, 69 with chronic schizophrenia, and 77 healthy controls. Fractional anisotropy (FA) and peak length were measured at individual points along tract trajectories. Group differences in diffusion indices and their associations with clinical variables, including the Positive and Negative Syndrome Scale (PANSS), were analyzed using linear mixed models and Spearman's rho. In recent-onset schizophrenia, reduced FA was observed in the genu and splenium of the corpus callosum, along with deviations in peak length across multiple white matter tracts. The peak length of association tracts showed a negative correlation with antipsychotic dose. In chronic schizophrenia, widespread reductions in FA and deviations in peak length were identified across various white matter tracts. Decreased FA in commissural tracts was negatively associated with the PANSS negative score, antipsychotic dose, and illness duration. This study identified along-tract white matter abnormalities in recent-onset and chronic schizophrenia and revealed their associations with clinical symptoms. Localized measurements along tract trajectories enhance the detection of clinically relevant abnormalities compared to traditional methods relying on averaged diffusion indices.
| S-EPMC11885433 | biostudies-literature