Applicability, potential and limitations of TSPO PET imaging as a clinical immunopsychiatry biomarker

PURPOSE: TSPO PET imaging may hold promise as a single-step diagnostic work-up for clinical immunopsychiatry. This review paper on the clinical applicability of TSPO PET for primary psychiatric disorders discusses if and why TSPO PET imaging might become the first clinical immunopsychiatry biomarker and the investment prerequisites and scientific advancements needed to accommodate this transition from bench to bedside. METHODS: We conducted a systematic search of the literature to identify clinical studies of TSPO PET imaging in patients with primary psychiatric disorders. We included both original case-control studies as well as longitudinal cohort studies of patients with a primary psychiatric diagnosis. RESULTS: Thirty-one original studies met our inclusion criteria. In the field of immunopsychiatry, TSPO PET has until now mostly been studied in schizophrenia and related psychotic disorders, and to a lesser extent in mood disorders and neurodevelopmental disorders. Quantitative TSPO PET appears most promising as a predictive biomarker for the transdiagnostic identification of subgroups or disease stages that could benefit from immunological treatments, or as a prognostic biomarker forecasting patients' illness course. Current scanning protocols are still too unreliable, impractical and invasive for clinical use in symptomatic psychiatric patients. CONCLUSION: TSPO PET imaging in its present form does not yet offer a sufficiently attractive cost-benefit ratio to become a clinical immunopsychiatry biomarker. Its translation to psychiatric clinical practice will depend on the prioritising of longitudinal research and the establishment of a uniform protocol rendering clinically meaningful TSPO uptake quantification at the shortest possible scan duration without arterial cannulation

Stability of chronotype over a 7-year follow-up period and its association with severity of depressive and anxiety symptoms

Background: Chronotype is an individual's preferred timing of sleep and activity, and is often referred to as a later chronotype (or evening-type) or an earlier chronotype (or morning-type). Having an evening chronotype is associated with more severe depressive and anxiety symptoms. Based on these findings it is has been suggested that chronotype is a stable construct associated with vulnerability to develop depressive or anxiety disorders. To examine this, we test the stability of chronotype over 7 years, and its longitudinal association with the change in severity of depressive and anxiety symptoms. Methods: Data of 1,417 participants with a depressive and/or anxiety disorder diagnosis and healthy controls assessed at the 2 and 9-year follow-up waves of the Netherlands Study of depression and anxiety were used. Chronotype was assessed with the Munich chronotype questionnaire. Severity of depressive and anxiety symptoms were assessed with the inventory of depressive symptomatology and Beck anxiety inventory. Results: Chronotype was found to be moderately stable (r = 0.53) and on average advanced (i.e., became earlier) with 10.8 min over 7 years (p <.001). Controlling for possible confounders, a decrease in severity of depressive symptoms was associated with an advance in chronotype (B = 0.008, p =.003). A change in severity of anxiety symptoms was not associated with a change in chronotype. Conclusion: Chronotype was found to be a stable, trait-like construct with only a minor level advance over a period of 7 years. The change in chronotype was associated with a change in severity of depressive, but not anxiety, symptoms

Dysregulation of the gut-brain axis in schizophrenia and bipolar disorder:probiotic supplementation as a supportive treatment in psychiatric disorders

Purpose of review Schizophrenia (SCZ) and bipolar disorder are severe mental disorders, both placing a significant burden on individuals' wellbeing and global health generally. The complex interaction of multiple mechanisms, underlying these disorders, still needs further elucidation. Increased activation of components of the immune system may be involved, including alterations in intestinal permeability and gut microbiome. Probiotics, defined as living microorganisms conferring health benefits to the host when administered in adequate amounts, seem to have supportive therapeutic effect in psychiatric disorders. The authors in this review provide an overview of this emerging research field and summarize both the publicated microbiome studies in SCZ and bipolar disorder and the current clinical research using probiotic supplementation in patients diagnosed with these disorders. Recent findings The current data indicate that there are differences in the microbiome in SCZ and bipolar disorder patients as compared with healthy controls. Part of these differences may be induced by medication use, others by smoking and other lifestyle factors. Correlations between microbiome quantification and symptom severity have been observed in cross-sectional studies, but unfortunately, no replicated findings so far. Probiotic supplementation was shown not only to alleviate gastrointestinal complaints but also reduce symptom severity, rehospitalization rates and cognitive improvement. Replication of improvement of cognition is needed. Summary Differences in microbiome have been shown in both SCZ and bipolar disorder in comparison to healthy controls. Evidence that probiotics can improve psychiatric functioning is still very limited

The impact of intestinal permeability and intestinal microbiome on cerebral immunological activity and myelination in bipolar disorder

Abnormal immune responses have been reported in patients with bipolar disorder (BD), mostly involving number and activity of leucocytes and the balance between pro- and anti-inflammatory cytokines in blood. What lies at the root of the immune system aberrations is still unclear. Intestinal permeability, along with alterations in the intestinal microbiota, may be a significant factor driving the immune dysregulation in BD. In a post-hoc analysis of a study investigating simvastatin augmentation for recent-onset psychotic disorder (SMRI 12T-008)5,, twenty-four patients with recent onset schizophrenia and twenty-four healthy controls were included in the analyses. We found a mean level of LBP of 9.3ng/ml (SD 5.5) in the controls, which was significantly lower than the 13.4ng/ml (SD 7.6) found in the SCZ patients (p=0.05).Although the pattern of LBP levels might be complex in this patient population, it is rational to hypothesize that probiotic treatment may be more effective in patients with higher serum LBP, corresponding to increased intestinal permeability6.In a novel randomized controlled trial we investigate - Whether intestinal permeability improving probiotics have an effect on symptom severity in patients with psychotic or bipolar disorders that have increased intestinal permeability (LBP ≥ median) - Which factors (LBP, intestinal inflammation (fecal calprotectin), intestinal microbiome, and others) can best predict individual treatment response to probiotics- We will also investigate whether treatment with probiotics have a beneficial effect on immune parameters, metabolic syndrome features, cognition, side-effects, general functioning and gastrointestinal complaintsThe probiotic formulation is specifically selected for its beneficial effect on intestinal permeability.Stool and blood samples will be analyzed to identify optimal biomarkers (serum LBP, fecal calprotectin, intestinal microbiome) for response to probiotics.Another unanswered question is how these immune abnormalities exert their effect on the brain. Strikingly few studies have investigated activity of the brain’s immune system in living BD patients. We plan to perform neuroinflammation PET scans and diffusion tensor MRI scans at baseline and after completion in a subsample (n=44) of this RCT to assess the associations between intestinal functioning and glial cell (microglia/oligodendrocyte) functioning