Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Cohort Profile:Stratifying Resilience and Depression Longitudinally (STRADL): a questionnaire follow-up of Generation Scotland: Scottish Family Health Study (GS:SFHS)

Funding: STRADL is supported by the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z). The Chief Scientist Office of the Scottish Government Health Department (CZD/16/6) and the Scottish Funding Council (HR03006) provided core support for Generation Scotland. A.M.M. is supported by the Dr Mortimer and Theresa Sackler Foundation. D.J.M. is supported by an NRS Fellowship, funded by the CSO. J.S., J.M.W., K.L.E., D.J.P., I.J.D. and A.M.M. are members of the Centre for Cognitive Ageing and Cognitive Epidemiology which also supports I.J.D.; funding from the Medical Research Council and Biotechnology and Biological Sciences Research Council is gratefully acknowledged (MR/K026992/1). Acknowledgments: We would like to express gratitude to all individuals who have taken part in both GS:SFHS and STRADL, and the entire project team including academic researchers, administrative staff, research managers and statisticians. Conflict of interest: The authors declare that they have no conflicting interests.Peer reviewedPublisher PD

Using lithium as a neuroprotective agent in patients with cancer

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.<br /

Voice analysis as an objective state marker in bipolar disorder

Changes in speech have been suggested as sensitive and valid measures of depression and mania in bipolar disorder. The present study aimed at investigating (1) voice features collected during phone calls as objective markers of affective states in bipolar disorder and (2) if combining voice features with automatically generated objective smartphone data on behavioral activities (for example, number of text messages and phone calls per day) and electronic self-monitored data (mood) on illness activity would increase the accuracy as a marker of affective states. Using smartphones, voice features, automatically generated objective smartphone data on behavioral activities and electronic self-monitored data were collected from 28 outpatients with bipolar disorder in naturalistic settings on a daily basis during a period of 12 weeks. Depressive and manic symptoms were assessed using the Hamilton Depression Rating Scale 17-item and the Young Mania Rating Scale, respectively, by a researcher blinded to smartphone data. Data were analyzed using random forest algorithms. Affective states were classified using voice features extracted during everyday life phone calls. Voice features were found to be more accurate, sensitive and specific in the classification of manic or mixed states with an area under the curve (AUC)=0.89 compared with an AUC=0.78 for the classification of depressive states. Combining voice features with automatically generated objective smartphone data on behavioral activities and electronic self-monitored data increased the accuracy, sensitivity and specificity of classification of affective states slightly. Voice features collected in naturalistic settings using smartphones may be used as objective state markers in patients with bipolar disorder

Using lithium as a neuroprotective agent in patients with cancer

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.<br /

Multivariate patterns among multimodal neuroimaging and clinical, cognitive, and daily functioning characteristics in bipolar disorder

\ua9 The Author(s) 2025.Individuals with bipolar disorder (BD) show heterogeneity in clinical, cognitive, and daily functioning characteristics, which challenges accurate diagnostics and optimal treatment. A key goal is to identify brain-based biomarkers that inform patient stratification and serve as treatment targets. The objective of the present study was to apply a data-driven, multivariate approach to quantify the relationship between multimodal imaging features and behavioral phenotypes in BD. We pooled structural, task and resting-state functional magnetic resonance imaging (MRI), and clinical, cognitive, and functioning data from 167 fully or partly remitted patients with BD from three studies conducted at the same site. We performed canonical correlation analysis (CCA) to investigate multivariate relations among the 56 imaging and 23 behavioral features in patients. Data from 46 matched healthy controls were included for covariate-adjusted standardization of patients’ scores and for group comparisons. The imaging and behavioral data sets showed a strong canonical correlation (r = 0.84, p =.004). Among the behavioral variables, cognitive test scores across psychomotor speed, verbal memory, and verbal fluency were associated with the multimodal imaging variate comprising task activation within the dorsolateral prefrontal cortex and supramarginal gyrus, also when other clinical and daily functioning variables were considered. Task activation within the dorsal prefrontal and parietal cognitive control areas constitutes a potential pro-cognitive treatment target

Multivariate associations between structural brain changes and cognitive impairment in partially or fully remitted persons with bipolar disorder

Background: Cognitive impairment across cognitive domains and brain structure alterations are well documented in persons with bipolar disorder (BD) but the association between them is still unclear. Previous studies have generally applied univariate models to investigate brain-cognition correlations, which limits the discovery of complex association patterns. The aim of this study was to apply canonical correlation analysis (CCA) to identify multivariate associations between brain structure and cognitive impairment in BD. Methods: Cognitively impaired persons with BD (n = 169) in full or partial remission were included from four prior pro-cognitive intervention studies. We included healthy controls (HC, n = 40) for the calculation of covariate-adjusted brain and cognition z-scores. All participants underwent structural magnetic resonance imaging and an extensive cognitive test battery. We conducted principal component analysis on the brain data within the BD group to reduce the number of variables in the dataset. We then applied CCA to investigate multivariate associations between brain structure and cognition in the BD cohort. Results: Poorer performance across working memory, psychomotor speed, executive functions, and verbal learning and memory correlated with lower grey matter volume in frontotemporal regions, the right hippocampus, and the left caudate nucleus, and with larger frontotemporal and right posterior cingulate gyral thickness. Conclusions: The association between cognition, reduced grey matter volume and larger thickness in frontotemporal and posterior cingulate regions suggests that cognitive impairment originates from dysregulated, rather than simply reduced, neuroplasticity processes. Aberrant volume and thickness measures in these regions are potential treatment targets to promote cognition in BD

Cognitive hierarchy in mood disorders and relations to daily functioning

Cognitive impairment affects approximately 50% of patients with mood disordersduring remission, which correlates with poorer daily-life functioning. The hierarchicalorganisation of cognitive processes may mean that some cognitive deficits, e.g.,memory impairments, are secondary to impairments in suggested core processes,including executive functions, working memory, attention, and psychomotor speed. Theexact structure of a cognitive hierarchy in mood disorders is unclear. In this study, weaimed to examine relationships between cognitive domains using network graphs.Further, we aimed to explore whether impairments in the proposed ‘core cognitivedomains’ mediated patients’ verbal memory impairment and functional disability usingmediation and hierarchical regression analyses. We pooled data from patients withmood disorders and healthy controls (HC) from 10 original studies. In total, 1505participants were included in the analyses (n=900 patients; n=605 HC). We found thatcognitive domains were more intercorrelated in patients than in HC. Executivefunctions, working memory, and attention and psychomotor speed almost fullyaccounted for illness-associated verbal learning and memory impairments, indicatingpartial mediation. Of the core domains, working memory explained the largest amountof variance in memory impairments and functional disability. Our findings highlight theimportance of targeting core cognitive domains in pro-cognitive interventions