Pathophysiology in cortico-amygdala circuits and excessive aversion processing: the role of oligodendrocytes and myelination.

Stress-related psychiatric illnesses, such as major depressive disorder, anxiety and post-traumatic stress disorder, present with alterations in emotional processing, including excessive processing of negative/aversive stimuli and events. The bidirectional human/primate brain circuit comprising anterior cingulate cortex and amygdala is of fundamental importance in processing emotional stimuli, and in rodents the medial prefrontal cortex-amygdala circuit is to some extent analogous in structure and function. Here, we assess the comparative evidence for: (i) Anterior cingulate/medial prefrontal cortex<->amygdala bidirectional neural circuits as major contributors to aversive stimulus processing; (ii) Structural and functional changes in anterior cingulate cortex<->amygdala circuit associated with excessive aversion processing in stress-related neuropsychiatric disorders, and in medial prefrontal cortex<->amygdala circuit in rodent models of chronic stress-induced increased aversion reactivity; and (iii) Altered status of oligodendrocytes and their oligodendrocyte lineage cells and myelination in anterior cingulate/medial prefrontal cortex<->amygdala circuits in stress-related neuropsychiatric disorders and stress models. The comparative evidence from humans and rodents is that their respective anterior cingulate/medial prefrontal cortex<->amygdala circuits are integral to adaptive aversion processing. However, at the sub-regional level, the anterior cingulate/medial prefrontal cortex structure-function analogy is incomplete, and differences as well as similarities need to be taken into account. Structure-function imaging studies demonstrate that these neural circuits are altered in both human stress-related neuropsychiatric disorders and rodent models of stress-induced increased aversion processing. In both cases, the changes include altered white matter integrity, albeit the current evidence indicates that this is decreased in humans and increased in rodent models. At the cellular-molecular level, in both humans and rodents, the current evidence is that stress disorders do present with changes in oligodendrocyte lineage, oligodendrocytes and/or myelin in these neural circuits, but these changes are often discordant between and even within species. Nonetheless, by integrating the current comparative evidence, this review provides a timely insight into this field and should function to inform future studies-human, monkey and rodent-to ascertain whether or not the oligodendrocyte lineage and myelination are causally involved in the pathophysiology of stress-related neuropsychiatric disorders.

Cognition in older age bipolar disorder: An analysis of archival data across the globe.

BACKGROUND: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies. METHODS: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning. RESULTS: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning. LIMITATIONS: Cross-sectional design and loss of granularity due to harmonization. CONCLUSION: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD.

Bipolar symptoms, somatic burden and functioning in older-age bipolar disorder: A replication study from the global aging & geriatric experiments in bipolar disorder database (GAGE-BD) project.

OBJECTIVES: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset. DESIGN/METHODS: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601). RESULTS: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning. CONCLUSIONS: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning.

Daily mood and cognitive performance of women with and without bipolar disorder: role of menopausal status.

We examined the role of menopausal status in daily mood and cognitive performance among women with bipolar disorder (BD) compared to healthy comparison women. We analyzed the association of menopausal status, bipolar diagnosis, and their interaction on daily mood assessed by mobile surveys and attentional performance measured multiple times over 2 weeks. Menopausal status was associated with more daily negative affect in women with BD, but not related to attentional performance.

Prolonged Unmet Mental Health Needs of the 2017 Pohang Earthquake Survivors.

OBJECTIVE: Two years after the 2017 Pohang earthquake, some people sought follow-up mental health support. The demographic and clinical characteristics of this unique group of people were investigated to identify some insights on the predisposing factors of the longterm need for psychiatric help after a severe earthquake disaster. METHODS: De-identified data from those seeking mental health support 2 years after the 2017 Pohang earthquake were used. The descriptive statistics of demographic and clinical characteristics of the study group was identified and paired with general population data obtained from open and public governmental websites. Sex, age distribution, destruction of house, and psychiatric disorder were compared between the follow-up sample and general population. RESULTS: The proportion of women in the group seeking support was two times higher than that in the general population, and people ages between 50 and 70 years commonly sought support. The severity of home destruction was higher among people who sought and needed follow-up mental health support programs than in the general population. There was a higher proportion of people with psychiatric disorders in the group seeking support than in the general population. CONCLUSION: The need for long-term mental health support 2 years after an earthquake was higher in women than in men and those aged between 50 and 70 years, and those with a previous psychiatric history and with a higher severity of home destruction, which lead to necessitating leaving the home. Future earthquake response should include screening and psychiatric treatment referral and residential support in vulnerable people.

BrainAge of patients with severe late-life depression referred for electroconvulsive therapy.

BACKGROUND: Severe depression is associated with accelerated brain aging. BrainAge gap, the difference between predicted and observed BrainAge, was investigated in patients with late-life depression (LLD). We aimed to examine BrainAge gap in LLD and its associations with clinical characteristics indexing LLD chronicity, current severity, prior to electroconvulsive therapy (ECT) and ECT outcome. METHODS: Data was analyzed from the Mood Disorders in Elderly treated with Electroconvulsive Therapy (MODECT) study. A previously established BrainAge algorithm (BrainAge R by James Cole, (https://github.com/james-cole/brainageR)) was applied to pre-ECT T1-weighted structural MRI-scans of 42 patients who underwent ECT. RESULTS: A BrainAge gap of 1.8 years (SD = 5.5) was observed, Cohen's d = 0.3. No significant associations between BrainAge gap, number of previous episodes, current episode duration, age of onset, depression severity, psychotic symptoms or ECT outcome were observed. LIMITATIONS: Limited sample size. CONCLUSIONS: Our initial findings suggest an older BrainAge than chronological age in patients with severe LLD referred for ECT, however with high degree of variability and direction of the gap. No associations were found with clinical measures. Larger samples are needed to better understand brain aging and to evaluate the usability of BrainAge gap as potential biomarker of prognosis an treatment-response in LLD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02667353.

Bipolar I and bipolar II subtypes in older age: Results from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) project.

OBJECTIVES: The distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD. METHODS: Cross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept. RESULTS: After adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p < 0.001) and current use of anti-psychotics (p = 0.003). Multivariable analyses showed that BD subtype was not related to GAF, cognitive g-score or somatic burden. CONCLUSION: BD-I and BD-II patients did not differ in terms of general functioning, cognitive impairment or somatic burden. Some clinical differences were observed between the groups, which could be the consequence of diagnostic definitions. The distinction between BD-I and BD-II is not the best way to subtype OABD patients. Future research should investigate other disease specifiers in this population.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.

Bipolar Disorder Among Older Adults: Newer Evidence to Guide Clinical Practice.

The term older-age bipolar disorder (OABD) refers to patients with bipolar disorder who are ages 50 and older. Research findings suggest important differences, including the attenuation of manic symptoms with age and the occurrence of multiple somatic comorbid conditions. Although the pharmacological treatment of OABD is fairly similar, adverse effects, somatic comorbidity, and drug-drug interactions are more common. Lithium is effective in treating OABD and may have the potential to be neuroprotective. Anticonvulsants and second-generation antipsychotics have a growing evidence supporting their use in treating OABD. Behavioral intervention can be a helpful adjunct to pharmacological treatment. Clinicians and health care systems need to be prepared to provide care and services to individuals with bipolar disorder throughout the life span. Although older adults have typically been excluded from bipolar disorder RCTs, emerging efforts organized by global advocates and harnessing teams of clinicians and scientists have the potential to advance care.

The interplay of daily affect and impulsivity measured by mobile surveys in bipolar disorder.

BACKGROUND: Impulsivity is a prominent feature of bipolar disorder associated with various negative sequelae; moreover, it may be a precursor to shifts in affect or mood, but little is known about its association with affect on a day-to-day timescale. Ecological momentary assessments (a method that captures moment-to-moment ratings of psychological states by repeatedly sampling the same individual) of impulsivity and affect using mobile surveys allow for more nuanced examination of mechanisms of mood and behavior dysregulation. However, few existing studies have validated an ecological momentary assessment of impulsivity in bipolar disorder and examined its time-lagged associations with positive and negative affect. 70 participants with bipolar disorder and 102 healthy comparisons participated in an intensive longitudinal study: they underwent 14 days of ecological momentary assessment data collection annually for 1-4 years. Multiple measures of impulsivity and affect were collected using self-report, behavioral, and ecological momentary assessment modalities; these measures were compared, and levels of impulsivity were compared between bipolar disorder and healthy comparison groups. Time-lagged analyses using daily means explored the next-day predictive relationship of impulsivity on positive/negative affect, and vice versa. RESULTS: The ecological momentary measure of impulsivity was moderately correlated with the self-report but not behavioral impulsivity measure. Bipolar disorder participants evinced higher self-report, behavioral, and daily impulsivity than healthy comparison participants. Time-lagged analyses revealed a bi-directional association between high impulsivity and high next-day negative (but not positive) affect. Post hoc analyses showed that impulsivity specifically predicted next-day anger and anxiety. CONCLUSIONS: Our multimodal assessment of impulsivity allowed for an examination of the day-to-day course of impulsivity and affect, crucial steps toward understanding the mechanisms of mood symptom and episode onset in bipolar disorder.

Mobile survey engagement by older adults is high during multiple phases of the COVID-19 pandemic and is predicted by baseline and structural factors.

Digital surveys, such as mobile phone ecological momentary assessment (EMA), bear the potential to assess and target individual wellbeing in a personalized, real-time approach and allow for interaction in situations when in-person contact is not possible, such as during the coronavirus pandemic. While the use of digital technology might especially benefit research in older adults who find themselves in circumstances of reduced mobility, little is known about their barriers to adherence. We investigated baseline and structural factors that predict study withdrawal and adherence from daily smartphone EMA self-report surveys in the StayWELL Study. The StayWELL study is a longitudinal, observational study on the relationship between social restrictions during the coronavirus pandemic and mental well-being in 95 community-dwelling older aged adults (67-87 years) who were participants in a randomized clinical trial using EMA. Withdrawal was associated with less research staff changes and less likely in participants that reached the study mid-point. No baseline characteristics predicted withdrawal. Main reasons for withdrawal were communication issues, i.e. staff not being able to contact participants. We found an adherence rate of 82% and no fatigue effects. Adherence was predicted by education status, study participation duration, reaching the study midpoint and time between study start and enrollment. COVID infections or supporting people in the household was not related to adherence. To conclude, it is feasible to conduct an EMA study in older people without impacting engagement during a pandemic. Furthermore, personal characteristics and smartphone operating system (Android vs. iOS) used did not relate to engagement, allowing for a broad distribution of digital health technologies. Our study adds information on single predictive variables relevant for adherence and withdrawal from EMA smartphone surveys in older people that can inform the design of future digital EMA research to maximize engagement and reliability of study results.

Peripheral inflammation levels associated with degree of advanced brain aging in schizophrenia.

Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (n = 26; M/F: 21/5) and HC (n = 28; 20/8) (22-64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1ß, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD.

Comparing continuous and harmonized measures of depression severity in older adults with bipolar disorder: Relationship to functioning.

OBJECTIVE: Harmonizing different depression severity scales often requires creation of categorical variables that may decrease the sensitivity of the measure. Our aim was to compare the associations between categorical and continuous and harmonized measures of depression and global functioning in a large dataset of older age patients with bipolar disorder (OABD). METHOD: In the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) the 17-item Hamilton Depression scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) or the Center for Epidemiological Studies Depression scales (CES-D) was used to assess current depressive symptoms, while the Global Assessment of Functioning (GAF) assessed functional status. Data were harmonized from 8 OABD studies (n = 582). In each subsample, the relationship of depression severity as a continuous and categorical measure was compared to GAF. In the total sample, harmonized ordinal depression categories were compared to GAF. RESULTS: Effect size and variance explained by the model for the categorical measure in the total sample was higher than both the categorical and continuous measure in the CES-D subsample, higher than the categorical but lower than the continuous measure in the HAM-D subsample, and lower than both the categorical and continuous measures in the MADRS subsample. LIMITATIONS: All included studies have different inclusion and exclusion criteria, study designs, and differ in aspects of sociodemographic variables. CONCLUSIONS: Associations were only slightly larger for the continuous vs categorical measures of depression scales. Harmonizing different depression scales into ordinal categories for analyses is feasible without losing statistical power.

Predictors of functional impairment in bipolar disorder: Results from 13 cohorts from seven countries by the global bipolar cohort collaborative.

OBJECTIVES: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. METHODS: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. RESULTS: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. CONCLUSIONS: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Associations Between Negative Symptoms and Effort Discounting in Patients With Schizophrenia and Major Depressive Disorder.

Deficits in goal-directed decision making and motivation are hallmark characteristics of several neuropsychiatric disorders, including schizophrenia (SZ) and major depressive disorder (MDD). Studies using effort-based decision-making tasks have shown that both patients with SZ and MDD invest less physical effort in order to obtain rewards. However, how these motivational deficits relate to clinically assessed symptom dimensions such as apathy remains controversial. Using a grip-strength-based effort discounting task we assessed effort-based decision-making behavior in healthy controls (HC) (N = 18), patients with SZ (N = 42), and MDD (N = 44). We then investigated how effort discounting relates to different symptom dimensions. There were no differences in effort discounting between HC participants and patients with SZ or MDD. In addition, we did not observe a correlation between effort discounting and negative symptoms (NS) in patients with SZ or MDD. In conclusion, the current study does not support an association between effort discounting and NS in SZ or MDD. Further studies are needed to investigate effort discounting and its relation to psychopathological dimensions across different neuropsychiatric disorders.

Common and disorder-specific upregulation of the inflammatory markers TRAIL and CCL20 in depression and schizophrenia.

Schizophrenia (SZ) and major depressive disorder (MDD) are severe mental disorders, which have been associated with alterations of the peripheral inflammatory network. However, studies for both disorders have not been fully consistent and have focused on few canonical markers with high relevance to the innate immune system, while the role of the adaptive immune system is studied less. Furthermore, it is unclear to what extent inflammatory abnormalities are diagnosis-specific or transdiagnostic. The purpose of this study was to investigate 75 peripheral inflammatory markers including the acute phase protein high-sensitivity C-reactive protein (hsCRP) in patients with MDD (n = 37), SZ (n = 42) and healthy controls (HC) (n = 17), while considering possible confounders and correcting rigorously for multiple testing in group comparisons. We identified C-C chemokine ligand 20 (CCL20) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as the inflammatory markers with significant group differences after controlling for multiple comparisons and adjusting for BMI, sex and smoking as confounders. TRAIL was elevated in both MDD and SZ compared to HC. CCL20 was specifically increased in SZ compared to MDD and HC. There were no significant group differences in hsCRP after correcting for multiple testing. Finally, we observed no significant correlations among CCL20, TRAIL and CRP. TRAIL is a transdiagnostic marker for SZ and MDD, with both markers being independent from CRP and body mass index (BMI). CCL20 may be a novel and specific biomarker of schizophrenia, but an influence of antipsychotic medication cannot be excluded. Identifying novel markers in mental disease bears the potential for future research towards novel treatment strategies by modifying inflammation-related processes.

Altered neuroaxonal integrity in schizophrenia and major depressive disorder assessed with neurofilament light chain in serum.

BACKGROUND: Schizophrenia (SZ) and major depressive disorders (MDD) have been frequently linked to anatomical brain alterations. However, the relationship between brain pathology, inflammation and clinical symptoms in these disorders is still unclear. Thus, by applying novel blood markers of neuroaxonal integrity such as neurofilament light chain (NfL), we can now address main issues in psychiatric research and potentially offer innovative diagnostic tools toward better clinical characterizations and monitoring in both SZ and MDD. METHODS: NfL levels were measured in serum of 44 patients with SZ and in 41 patients with MDD applying single molecule array technology and compared to a healthy norm population. Main inflammatory markers (C- reactive protein, interleukins IL-6 and IL-10) were measured to define patients with inflammatory phenotype. The Digit Symbol Substitution Task (DSST) and the Letter-Number-Sequencing Task were performed to estimate cognitive function in both groups. RESULTS: NfL levels in MDD group (but not in SZ group) were significantly higher than reference values of healthy norm population. A higher than expected proportion of patients with NfL levels above age-specific cut-off values was observed in both SZ and MDD groups. No correlation was observed between NfL and inflammatory markers. A negative correlation between DSST and NfL-values was observed in patients with MDD. CONCLUSIONS: Both SZ and MDD showed elevated serum levels of NfL, which were independent from inflammatory markers but associated with cognitive performance.

Quinolinic acid is associated with cognitive deficits in schizophrenia but not major depressive disorder.

Tryptophan and its catabolites (TRYCATs) have been suggested to link peripheral immune system activation and central neurotransmitter abnormalities with relevance to the etio-pathophysiology of schizophrenia (SZ) and major depressive disorder (MDD). The relationship to different psychopathological dimensions within these disorders however remains to be elucidated. We thus investigated potential group differences of tryptophan, kynurenine, kynurenic acid, 3-hydroxy kynurenine and quinolinic acid in the plasma of 19 healthy controls (HC), 45 patients with SZ and 43 patients with MDD and correlated plasma proteins with the "motivation and pleasure" dimension and cognition. After correcting for the covariates age, sex, body mass index, smoking and medication, patients with MDD showed lower kynurenine and 3-hydroxy kynurenine levels compared to HC. Quinolinic acid correlated negatively with composite cognitive score in patients with SZ, indicating that more severe cognitive impairments were associated with increased plasma levels of quinolinic acid. No correlations were found in patients with MDD. These results indicate that MDD and SZ are associated with dysregulation of the kynurenine pathway. Quinolinic acid might be specifically implicated in the pathophysiology of cognitive deficits in patients with SZ. Further studies are needed to determine whether TRYCATs are causally involved in the etiology of these neuropsychiatric disorders.

Chemokine MCP1 is associated with cognitive flexibility in schizophrenia: A preliminary analysis.

BACKGROUND: Peripheral levels of pro-inflammatory biomarkers have been shown to be altered in schizophrenia (SZ) and associated with cognitive impairments, but their relevance to specific cognitive domains remains unclear. METHODS: Plasma levels of cytokines, chemokines, and vascular biomarkers were quantified and compared between SZ and healthy comparison (HC) groups. Cognition was assessed using the Delis-Kaplan Executive Function System Trail Making (TM) and Color Word Interference (CWI) tests. Linear regression analyses examined differential relationships of inflammatory biomarkers with executive function between groups. RESULTS: Plasma levels of TNFα, ICAM1, and MCP1 were higher in individuals with SZ compared to HCs. Higher level of MCP1 was associated with increased CWI Inhibition Switching Errors in SZ but not HCs. CONCLUSION: Like other studies, we found evidence for increased peripheral inflammation in SZ. We also showed that SZ with particularly high MCP1 levels had poor cognitive flexibility. Interventions to reduce chemokine elevations might prove beneficial for cognitive performance.

Increased random exploration in schizophrenia is associated with inflammation.

One aspect of goal-directed behavior, which is known to be impaired in patients with schizophrenia (SZ), is balancing between exploiting a familiar choice with known reward value and exploring a lesser known, but potentially more rewarding option. Despite its relevance to several symptom domains of SZ, this has received little attention in SZ research. In addition, while there is increasing evidence that SZ is associated with chronic low-grade inflammation, few studies have investigated how this relates to specific behaviors, such as balancing exploration and exploitation. We therefore assessed behaviors underlying the exploration-exploitation trade-off using a three-armed bandit task in 45 patients with SZ and 19 healthy controls (HC). This task allowed us to dissociate goal-unrelated (random) from goal-related (directed) exploration and correlate them with psychopathological symptoms. Moreover, we assessed a broad range of inflammatory proteins in the blood and related them to bandit task behavior. We found that, compared to HC, patients with SZ showed reduced task performance. This impairment was due to a shift from exploitation to random exploration, which was associated with symptoms of disorganization. Relative to HC, patients with SZ showed a pro-inflammatory blood profile. Furthermore, high-sensitivity C-reactive protein (hsCRP) positively correlated with random exploration, but not with directed exploration or exploitation. In conclusion, we show that low-grade inflammation in patients with SZ is associated with random exploration, which can be considered a behavioral marker for disorganization. hsCRP may constitute a marker for severity of, and a potential treatment target for maladaptive exploratory behaviors.