Rickard L. Sjoberg

Purpose: Antidepressant use, which targets intracerebral serotonin metabolism, is common among glioblastoma patients. However, its interaction with tumor metabolism and survival remains unclear. We investigated the relationships between antidepressant use, intratumoral serotonin pathway metabolites, quality-of-life, and survival. Methods: We analysed two complementary cohorts: a population-based cohort ( n = 801) and a hospital-based biobank cohort ( n = 153). In the population-based cohort, information about antidepressant use and survival were obtained from national registers. In the hospital-based cohort, intratumoral serotonin pathway metabolites were measured, and data on preoperative antidepressant use and quality-of-life were recorded. Linear and Cox regression models were used to investigate the association between antidepressant use, metabolites, quality-of-life and survival. Results: In the population-based cohort, antidepressant use was associated with poorer survival in adjusted analyses. However, use of fluoxetine or sertraline was associated with better survival compared with other selective serotonin reuptake inhibitors (HR = 0.62, 95% CI = 0.44–0.88). In the hospital-based cohort, preoperative antidepressant use was associated with lower intratumoral serotonin levels and its downstream metabolite, 5-HIAA. Higher serotonin levels were associated with better preoperative quality-of-life, especially general health. Serotonin pathway metabolites were not clearly associated with survival. Conclusions: These findings suggest that higher tumor tissue serotonin abundance was associated with better patient-reported well-being but not with survival in gliobastoma. Survival differed across SSRI exposure groups, although causal interpretation is limited by the observational design. These findings do not provide strong evidence against the continued clinical use of sertraline or fluoxetine in glioblastoma patients when indicated.

Serotonin and serotonin metabolism has for decades been understood as playing a critical role in mood disorders and has more recently also been implicated in brain tumour biology. However, in part due to the lack of direct investigation of genetic and epigenetic variation affecting serotonin pathways within human brain tissue this understanding has recently been challenged. We analysed genetic and epigenetic variation in the Monoamine oxidase A ( MAOA) and serotonin transporter ( 5HTT) genes using 232 biobanked glioma tissue samples from 216 adult patients. We further examined the association between use of antidepressants (targeting serotonergic pathways), serotonin levels and methylation. In male patients, genetic variation in the MAOA gene was significantly associated with tissue serotonin levels. Further analysis identified five single nucleotide variants (SNVs) that may contribute to this association. In contrast, 5HTT variants were not statistically associated with serotonin pathway metabolites, nor were MAOA variants in females. Increased methylation at several 5HTT CpG sites was positively correlated with serotonin levels and negatively correlated with 5-HIAA levels. In males, one CpG site in the MAOA gene was negatively associated with the 5-HIAA/serotonin ratio, suggesting reduced enzymatic degradation of serotonin due to lower MAOA activity. Patients using antidepressants had lower tissue serotonin levels. In males, genetic variation in the MAOA gene was significantly associated with tissue serotonin levels, although this association was not mediated by methylation. Our result supports the notion that the MAOA and 5HTT genes are related to serotonin metabolism and that such metabolism is related to antidepressant use.

Introduction: Pain, comprising sensory and emotional elements, is influenced by pain catastrophizing, which magnifies pain and promotes helplessness and rumination. This study explores the relationship between pain catastrophizing and outcomes following selective nerve root blockade (SNRB) in patients with lumbar radicular pain (LRP).Methods: A prospective cohort study of 103 LRP patients, confirmed by MRI, was conducted. All participants underwent SNRB at Umeå University Hospital. Outcomes were measured using PROMIS‐29 and the Pain Catastrophizing Scale (PCS) at baseline and several intervals up to 84 days post‐intervention. Patients were categorized into responder (≥30% pain reduction) and non‐responder groups and stratified into three groups based on baseline PCS scores. Changes in outcomes from baseline to 14 days post‐SNRB were analyzed in relation to PCS groups. PCS changes over time were evaluated between responders and non‐responders. Statistical analyses assessed PCS and outcome changes.Results: Baseline pain catastrophizing was not a significant predictor of pain response to SNRB. However, responders demonstrated significant reductions in pain catastrophizing following the intervention, suggesting that SNRB may influence cognitive coping mechanisms related to pain.Conclusion: SNRB reduces pain catastrophizing in LRP patients, although baseline catastrophizing does not predict pain outcomes. Addressing catastrophizing remains important but may serve better as an outcome measure rather than a predictor of treatment response.

Background: This study aimed to explore the potential association between tumor shape, 1p/19q codeletion, EOR, and new postoperative focal deficits in patients with diffuse low-grade glioma. Methods: We analyzed data from 225 WHO grade 2 glioma surgeries performed in nine centers in Norway and Sweden. The tumor measurements were based on automatic segmentations of preoperative T2/FLAIR MRI scans by Raidionics. Contact surface area (CSA) was defined as the area between the tumor and brain parenchyma and was estimated by subtracting the surface area covered by the dura from the total surface area. The sphericity index (SI) was defined as the quotient of the tumor surface area and the surface area of a sphere with equal volume. Focal deficits were defined as any new motor, language, or visual deficits postoperatively. Results: The univariable analyses showed that a larger CSA was associated with higher age (P = .02), lower EOR (P < .0001), and more focal deficits (P = .005) but not with 1p/19q codeletion (P = .54). A higher SI was associated with higher age (P = .02) and lower EOR (P < .0001) but not with focal deficits (P = .08) or 1p/19q codeletion (P = .90). The multivariable linear regression model supported the univariable associations between EOR and CSA (P = .0003) and SI (P = .0013), respectively. Contrarily, the logistic regression model showed that focal deficits were associated with SI (P = .014) but not with CSA (P = .056) Conclusion: The tumor shape appears to be independently associated with EOR and new focal deficits but not with molecular diagnosis in patients with low-grade glioma.

Whether use of antidepressants is related to the risk of developing lower-grade (WHO grades 2-3) and higher-grade (WHO grade 4) glioma was investigated in this study. A registry-based case–control study was performed with 1283 glioma case patients and 6400 age-, sex-, and geographically matched control participants who were diagnosed in Sweden during 2009-2013. Conditional logistic regression was used to analyze whether selective serotonin reuptake inhibitors (SSRIs) or non-SSRIs were associated with the risk of developing lower- or higher-grade glioma in the study population. Our results show that use of antidepressant medication was not associated with the risk of developing glioma. We also performed a meta-analysis in which the data set from the present study was combined with results from 2 previous epidemiologic studies to answer the same questions. The meta-analysis showed a modest risk reduction of developing glioma in relation to antidepressant treatment (odds ratio = 0.90; 95% CI, 0.83-0.97) when all glioma subgroups and all forms of antidepressant medications were combined. In conclusion, it remains possible that antidepressants may have common monoaminergic mechanism(s) that reduce the risk of developing glioma.

Almost five decades ago, John Eccles used neurophysiological studies suggesting that voluntary movement is preceded by activity in the supplementary motor area (SMA) to argue that mind and brain are separate entities. Half a decade later, the finding made by Benjamin Libet that SMA activity precedes conscious decision making would put the final nail in the coffin of this dualistic theory. Today, results of neurosurgical resections of the SMA demonstrate the futility of this debate, challenging the role of the ‘Libet-study’ as an iconic symbol of the triumph of monism over dualism.

Depression and treatment with antidepressant medication is common in patients with malignant glioma. However, the extent to which antidepressants may affect the disease is not fully understood. Therefore, the purpose of the present study was to investigate possible associations between treatment with antidepressant medication and survival in glioma patients. We performed a registry-based cohort study including 1231 patients with malignant glioma (WHO grades 2, 3, and 4) having undergone surgery, and 6400 matched controls without glioma. All data were extracted from the RISK North database, which contains information from multiple national population-based registries in Sweden. Treatment with antidepressants is more common in patients with malignant glioma (27%), compared to controls (16%), P < .001. Treatment with antidepressants after surgery for glioma was significantly associated with poorer survival. These effects were observed both for selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs. In grade 4 glioma, SSRI treatment was associated with a hazard ratio (HR) of 3.32 (95% CI 2.69–4.10, P < .001), and non-SSRI treatment a HR of 3.54 (95% CI 2.52–4.99, P < .001), compared to glioma patients without antidepressants. In grade 2-3 glioma, the HR for SSRI treatment was 3.26 (95% CI 2.19–4.85, P < .001), and for non-SSRI treatment was 7.71 (95% CI 4.22–14.12, P < .001). Our results demonstrate a negative association between antidepressant medication and survival in glioma. Further research will be needed to clarify causation.

BACKGROUND: Early prognostication of long-term outcome in patients suffering from spontaneous subarachnoid hemorrhage (SAH) remains a challenge. No biomarkers are routinely used for prognostication. A previous study has indicated that the metabolite myo-inositol (MI) may be used to predict long-term outcome. OBJECTIVE: To investigate if MI measured in serum correlates with long-term clinical outcome in patients suffering from SAH. METHODS: We conducted an observational cohort study including 88 patients treated for SAH at Umeå University Hospital. Serum samples were collected in the hospital, and a gas chromatography/mass spectroscopy method was used to quantitatively measure MI. Patients were assessed after 1 year using the Glasgow Outcome Scale Extended and dichotomized to favorable or unfavorable outcome. Differences in MI levels between the 2 groups were analyzed. RESULTS: There was no difference in MI levels between the groups upon admission. Myo-inositol levels decreased over time in the entire study population. The decrease was significantly larger in the unfavorable outcome group. A receiver operating characteristics analysis yielded an area under the curve of 0.903 (CI 0.8-1.0, P < .001) for the MI value on day 7 to predict favorable outcome after 1 year. CONCLUSION: Myo-inositol measured in serum may aid prognostication of outcome in patients with SAH. The mechanism behind this remains unclear, although it can be theorized to reflect processes leading to delayed cerebral ischemia, which affects long-term outcome. This is the first study to quantitively measure MI in serum for prognostication of outcome in patients with SAH.