Is elevated neutrophil count and neutrophil-to-lymphocyte ratio a cause or consequence of schizophrenia?—a scoping review

Background: Several studies have found an association between elevated neutrophil count or neutrophil-to-lymphocyte ratio (NLR) in peripheral blood from patients with schizophrenia. The etiology behind this effect is unknown, and it is unclear if changes in neutrophil count and NLR may be induced by antipsychotics or if these parameters relate to the diagnosis and symptoms of schizophrenia. The purpose of this scoping review was to map research that explores this association, and to identify gaps in the current knowledge base. Method: The work was conducted in accordance with established methodological standards for scoping reviews. Studies on neutrophil count and NLR in schizophrenia were identified through search in relevant databases, and a parallel screening procedure was performed to ensure validity and reproducibility of the search. Articles that included different comparison groups, with differences in medication status (drug-naïve or drug-free vs. medicated), current disease state (relapse vs. remission), or treatment response, were included, as well as studies evaluating the association between symptomatology and neutrophil count or NLR. Results: The available literature was limited with substantial differences in aims, methods, and outcomes. In total, 13 articles were included for the synthesis of this review. Some interesting trends were identified: Neutrophil count and NLR seem to be elevated in schizophrenia patients regardless of current or past use of antipsychotic therapy. Neutrophil count and NLR correlated significantly with positive symptoms of schizophrenia. Still, these findings should be interpreted with caution due to considerable methodological differences and weaknesses in the literature, particularly concerning the blood sampling procedure. Conclusion: By including longitudinal studies and by comparing patient groups based on medication status, disease state and response, our study provides a basis for dissecting the associations between increased neutrophil count or NLR and a diagnosis of schizophrenia. Further research should investigate and quantify the apparent strong correlation between neutrophil count or NLR and positive symptoms in schizophrenia, to evaluate its clinical potential to guide diagnostics, treatment, or as a predictor of outcome. This review also exposes important methodological weaknesses in the literature on neutrophil count and NLR measurements. Standardization of blood sampling and processing is crucial to reduce bias, and factors that are known to influence leukocyte levels need to be accounted for.publishedVersio

Lifetime Cannabis Use Is Not Associated With Negative Beliefs About Medication in Patients With First Treatment Psychosis

Objective: Cannabis use is common among patients with psychosis, and along with negative beliefs about medication, it has been found to predict poor adherence to antipsychotic drug treatment. Such lack of adherence to antipsychotic drug treatment increases the risk of poor clinical outcomes and relapse in patients with first treatment for psychosis (FTP). However, to date, it is unclear whether cannabis use may be related to negative perceptions about antipsychotic drug treatment. Methods: A cross-sectional sample of 265 FTP patients with schizophrenia spectrum disorder underwent extensive clinical assessments. Three measures of cannabis use were obtained: lifetime, current and meeting diagnostic criteria for abuse or addiction. For the primary analyses we focused on lifetime cannabis use. The Beliefs about Medication Questionnaire (BMQ) was employed to assess the patients' specific concerns and perceptions of antipsychotic medications, as well as general beliefs about pharmacotherapy. The relationship between lifetime cannabis use and BMQ scores was investigated with general linear model (GLM) analyses, controlling for age and sex. Results: Patients with lifetime use of cannabis ≥10 times were more likely to be male, younger at the age of onset of psychosis and with higher levels of alcohol use and daily tobacco smoking, as compared to the non-users (p < 0.05). Neither lifetime use of cannabis, current use nor a cannabis abuse diagnosis was associated with negative beliefs about medicines as measured by the BMQ questionnaire. Conclusion: Use of cannabis is not linked to negative perceptions about antipsychotic medicines in patients with FTP. Other reasons for poor compliance to antipsychotic drug treatment in cannabis users need to be further investigated.publishedVersio

Evaluation of the Rosa Chatbot Providing Genetic Information to patients at risk of hereditary breast and ovarian cancer: Qualitative interview study

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.Background: Genetic testing has become an integrated part of health care for patients with breast or ovarian cancer, and the increasing demand for genetic testing is accompanied by an increasing need for easy access to reliable genetic information for patients. Therefore, we developed a chatbot app (Rosa) that is able to perform humanlike digital conversations about genetic BRCA testing. Objective: Before implementing this new information service in daily clinical practice, we wanted to explore 2 aspects of chatbot use: the perceived utility and trust in chatbot technology among healthy patients at risk of hereditary cancer and how interaction with a chatbot regarding sensitive information about hereditary cancer influences patients. Methods: Overall, 175 healthy individuals at risk of hereditary breast and ovarian cancer were invited to test the chatbot, Rosa, before and after genetic counseling. To secure a varied sample, participants were recruited from all cancer genetic clinics in Norway, and the selection was based on age, gender, and risk of having a BRCA pathogenic variant. Among the 34.9% (61/175) of participants who consented for individual interview, a selected subgroup (16/61, 26%) shared their experience through in-depth interviews via video. The semistructured interviews covered the following topics: usability, perceived usefulness, trust in the information received via the chatbot, how Rosa influenced the user, and thoughts about future use of digital tools in health care. The transcripts were analyzed using the stepwise-deductive inductive approach. Results: The overall finding was that the chatbot was very welcomed by the participants. They appreciated the 24/7 availability wherever they were and the possibility to use it to prepare for genetic counseling and to repeat and ask questions about what had been said afterward. As Rosa was created by health care professionals, they also valued the information they received as being medically correct. Rosa was referred to as being better than Google because it provided specific and reliable answers to their questions. The findings were summed up in 3 concepts: “Anytime, anywhere”; “In addition, not instead”; and “Trustworthy and true.” All participants (16/16) denied increased worry after reading about genetic testing and hereditary breast and ovarian cancer in Rosa. Conclusions: Our results indicate that a genetic information chatbot has the potential to contribute to easy access to uniform information for patients at risk of hereditary breast and ovarian cancer, regardless of geographical location. The 24/7 availability of quality-assured information, tailored to the specific situation, had a reassuring effect on our participants. It was consistent across concepts that Rosa was a tool for preparation and repetition; however, none of the participants (0/16) supported that Rosa could replace genetic counseling if hereditary cancer was confirmed. This indicates that a chatbot can be a well-suited digital companion to genetic counseling.publishedVersio

Improvement in verbal learning over the first year of antipsychotic treatment is associated with serum HDL levels in a cohort of first episode psychosis patients

To investigate whether changes in serum lipids are associated with cognitive performance in first episode psychosis (FEP) patients during their first year of antipsychotic drug treatment. One hundred and thirty-two antipsychotic-treated FEP patients were included through the TOP study along with 83 age- and gender-matched healthy controls (HC). Information regarding cognitive performance, psychotic symptoms, lifestyle, body mass index, serum lipids [total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides] and antipsychotic treatment was obtained at baseline and after 1 year. The cognitive test battery is comprised of assessments for verbal learning, processing speed, working memory, verbal fluency, and inhibition. Mixed-effects models were used to study the relationship between changes over time in serum lipids and cognitive domains, controlling for potential confounders. There was a significant group by HDL interaction effect for verbal learning (F = 11.12, p = 0.001), where an increase in HDL levels was associated with improvement in verbal learning in FEP patients but not in HC. Practice effects, lifestyle, and psychotic symptoms did not significantly affect this relationship. Antipsychotic-treated FEP patients who increased in HDL levels during the first year of follow-up exhibited better verbal learning capacity. Further investigations are needed to clarify the underlying mechanisms.publishedVersio

Host blood-based biosignatures for subclinical TB and incipient TB: A prospective study of adult TB household contacts in Southern India

A large proportion of the global tuberculosis (TB) burden is asymptomatic and not detectable by symptom-based screening, driving the TB epidemic through continued M. tuberculosis transmission. Currently, no validated tools exist to diagnose incipient and subclinical TB. Nested within a large prospective study in household contacts of pulmonary TB cases in Southern India, we assessed 35 incipient TB and 12 subclinical TB cases, along with corresponding household active TB cases (n=11), and household controls (n=39) using high throughput methods for transcriptional and protein profiling. We split the data into training and test sets and applied a support vector machine classifier followed by a Lasso regression model to identify signatures. The Lasso regression model identified an 11-gene signature (ABLIM2, C20orf197, CTC-543D15.3, CTD-2503O16.3, HLADRB3, METRNL, RAB11B-AS1, RP4-614C10.2, RNA5SP345, RSU1P1, and UACA) that distinguished subclinical TB from incipient TB with a very good discriminatory power by AUCs in both training and test sets. Further, we identified an 8-protein signature comprising b-FGF, IFNγ, IL1RA, IL7, IL12p70, IL13, PDGF-BB, and VEGF that differentiated subclinical TB from incipient TB with good and moderate discriminatory power by AUCs in the training and test sets, respectively. The identified 11-gene signature discriminated well between the distinct stages of the TB disease spectrum, with very good discriminatory power, suggesting it could be useful for predicting TB progression in household contacts. However, the high discriminatory power could partly be due to over-fitting, and validation in other studies is warranted to confirm the potential of the immune biosignatures for identifying subclinical TB.publishedVersio

One-Year Treatment with Olanzapine Depot in Female Rats: Metabolic Effects

Background Antipsychotic drugs can negatively affect the metabolic status of patients, with olanzapine as one of the most potent drugs. While patients are often medicated for long time periods, experiments in rats typically run for 1 to 12 weeks, showing olanzapine-related weight gain and increased plasma lipid levels, with transcriptional upregulation of lipogenic genes in liver and adipose tissue. It remains unknown whether metabolic status will deteriorate with time. Methods To examine long-term metabolic effects, we administered intramuscular long-acting injections of olanzapine (100 mg/kg BW) or control substance to female rats for up to 13 months. Results Exposure to olanzapine long-acting injections led to rapid weight gain, which was sustained throughout the experiment. At 1, 6, and 13 months, plasma lipid levels were measured in separate cohorts of rats, displaying no increase. Hepatic transcription of lipid-related genes was transiently upregulated at 1 month. Glucose and insulin tolerance tests indicated insulin resistance in olanzapine-treated rats after 12 months. Conclusion Our data show that the continuous increase in body weight in response to long-term olanzapine exposure was accompanied by surprisingly few concomitant changes in plasma lipids and lipogenic gene expression, suggesting that adaptive mechanisms are involved to reduce long-term metabolic adverse effects of this antipsychotic agent in rats.publishedVersio

Gene expression profiles in rat brain disclose CNS signature genes and regional patterns of functional specialisation

Background: The mammalian brain is divided into distinct regions with structural and neurophysiological differences. As a result, gene expression is likely to vary between regions in relation to their cellular composition and neuronal function. In order to improve our knowledge and understanding of regional patterns of gene expression in the CNS, we have generated a global map of gene expression in selected regions of the adult rat brain (frontomedial-, temporal- and occipital cortex, hippocampus, striatum and cerebellum; both right and left sides) as well as in three major non-neural tissues (spleen, liver and kidney) using the Applied Biosystems Rat Genome Survey Microarray. Results: By unsupervised hierarchical clustering, we found that the transcriptome within a region was highly conserved among individual rats and that there were no systematic differences between the two hemispheres (right versus left side). Further, we identified distinct sets of genes showing significant regional enrichment. Functional annotation of each of these gene sets clearly reflected several important physiological features of the region in question, including synaptic transmission within the cortex, neurogenesis in hippocampus and G-protein-mediated signalling in striatum. In addition, we were able to reveal potentially new regional features, such as mRNA transcription- and neurogenesis-annotated activities in cerebellum and differential use of glutamate signalling between regions. Finally, we determined a set of 'CNSsignature' genes that uncover characteristics of several common neuronal processes in the CNS, with marked overrepresentation of specific features of synaptic transmission, ion transport and cell communication, as well as numerous novel unclassified genes. Conclusion: We have generated a global map of gene expression in the rat brain and used this to determine functional processes and pathways that have a regional preference or ubiquitous distribution within the CNS, respectively. The existence of shared specialised neuronal activities in CNS is interesting in a context of potential functional redundancy, and future studies should further explore the overall characteristics of CNS-specific versus region-specific gene profiles in the brain

Association between leptin levels and severity of suicidal behaviour in schizophrenia spectrum disorders

Objective: Associations between suicidality and lipid dysregulation are documented in mental illness, but the potential role of leptin remains unclear. We examined the association between leptin and suicidal behaviour in schizophrenia, together with the influence of other clinical and biological indices. Method: We recruited a sample of 270 participants with schizophrenia spectrum diagnoses. Blood samples were analysed for leptin, while symptom severity was assessed by Positive and Negative Syndrome Scale (PANSS ) and Inventory of Depressive Symptomatology (IDS ‐C). Patients' history of suicidal behaviour was categorized into three subgroups based on IDS ‐C suicide subscale: No suicidal behaviour, mild/moderate suicidal behaviour and severe suicidal behaviour with/without attempts. Results: Mild/moderate suicidal behaviour was present in 17.4% and severe suicidal behaviour in 34.8%. Both groups were significantly associated with female gender (OR = 6.0, P = 0.004; OR = 5.9, P = 0.001), lower leptin levels (OR = 0.4, P = 0.008; OR = 0.5, P = 0.008) and more severe depression (OR = 1.2, P < 0.001; OR = 1.1, P < 0.001) respectively. Smoking (OR = 2.6, P = 0.004), younger age of onset (OR = 0.9, P = 0.003) and less use of leptin‐increasing medications (OR = 0.5, P = 0.031) were associated with severe/attempts group, while higher C‐reactive protein CRP (OR = 1.3, P = 0.008) was associated with mild/moderate group. Conclusion: Lower leptin levels were associated with higher severity of suicidal behaviour in schizophrenia.publishedVersio

Dose-dependent transcriptional effects of lithium and adverse effect burden in a psychiatric cohort

Lithium is the first-line treatment for bipolar disorder (BD), but there is a large variation in response rate and adverse effects. Although the molecular effects of lithium have been studied extensively, the specific mechanisms of action remain unclear. In particular, the molecular changes underlying lithium adverse effects are little known. Multiple linear regression analyses of lithium serum concentrations and global gene expression levels in whole blood were carried out using a large case-control sample (n = 1450). Self-reported adverse effects of lithium were assessed with the “Udvalg for Kliniske Undersøgelser” (UKU) adverse effect rating scale, and regression analysis was used to identify significant associations between lithium-related genes and six of the most common adverse effects. Serum concentrations of lithium were significantly associated with the expression levels of 52 genes (FDR < 0.01), largely replicating previous results. We found 32 up-regulated genes and 20 down-regulated genes in lithium users compared to non-users. The down-regulated gene set was enriched for several processes related to the translational machinery. Two adverse effects were significantly associated (p < 0.01) with three or more lithium-associated genes: tremor (FAM13A-AS1, FAR2, ITGAX, RWDD1, and STARD10) and xerostomia (ANKRD13A, FAR2, RPS8, and RWDD1). The adverse effect association with the largest effect was between CAMK1D expression and nausea/vomiting. These results suggest putative transcriptional mechanisms that may predict lithium adverse effects, and could thus have a large potential for informing clinical practice.publishedVersio

Differences in white blood cell proportions between schizophrenia cases and controls are influenced by medication and variations in time of day

Cases with schizophrenia (SCZ) and healthy controls show differences in white blood cell (WBC) counts and blood inflammation markers. Here, we investigate whether time of blood draw and treatment with psychiatric medications are related to differences in estimated WBC proportions between SCZ cases and controls. DNA methylation data from whole blood was used to estimate proportions of six subtypes of WBCs in SCZ patients (n = 333) and healthy controls (n = 396). We tested the association of case-control status with estimated cell-type proportions and the neutrophil-to-lymphocyte ratio (NLR) in 4 models: with/without adjusting for time of blood draw, and then compared results from blood samples drawn during a 12-h (07:00–19:00) or 7-h (07:00-14:00) period. We also investigated WBC proportions in a subgroup of medication-free patients (n = 51). Neutrophil proportions were significantly higher in SCZ cases (mean=54.1%) vs. controls (mean=51.1%; p = <0.001), and CD8+T lymphocyte proportions were lower in SCZ cases (mean=12.1%) vs. controls (mean=13.2%; p = 0.001). The effect sizes in the 12-h sample (07:00–19:00) showed a significant difference between SCZ vs. controls for neutrophils, CD4+T, CD8+T, and B-cells, which remained significant after adjusting for time of blood draw. In the samples matched for time of blood draw during 07.00–14.00, we also observed an association with neutrophils, CD4+T, CD8+T, and B-cells that was unaffected by further adjustment for time of blood draw. In the medication-free patients, we observed differences that remained significant in neutrophils (p = 0.01) and CD4+T (p = 0.01) after adjusting for time of day. The association of SCZ with NLR was significant in all models (range: p < 0.001 to p = 0.03) in both medicated and unmedicated patients. In conclusion, controlling for pharmacological treatment and circadian cycling of WBC is necessary for unbiased estimates in case-control studies. Nevertheless, the association of WBC with SCZ remains, even after adjusting for the time of day.publishedVersio