The Role of Kynurenines in Cognitive Dysfunction in Bipolar Disorder.

INTRODUCTION: Chronic low-grade inflammation is suggested to play a pathophysiological role in bipolar disorder (BD) and its related cognitive dysfunctions. Although kynurenine (KYN) pathway metabolites are key inflammatory mediators, studies investigating the association between KYN metabolism and cognition in BD are scarce. We aimed to explore the relationship between KYN metabolism and cognitive functioning across different mood states in BD. METHODS: Sixty-seven patients with BD (35 depressed and 32 [hypo] manic) and 29 healthy controls were included. Cognitive functioning was assessed at 3 time intervals (baseline, 4, and 8 months) assessing processing speed, sustained attention, verbal memory, working memory, and response inhibition. Plasma samples for quantification of 3-hydroxykynurenine, quinolinic acid, and kynurenic acid (KYNA) were concurrently provided. Linear mixed models were used for statistical analysis. RESULTS: The manic group showed deficits in all assessed cognitive domains with the exception of verbal memory at all test moments. The bipolar depression group showed deficits in the processing speed at all test moments. Throughout the whole follow-up period, KYNA was significantly lower in both patient groups than in controls. Only in the bipolar depression group, low KYNA was associated with worse global cognitive functioning (B = 0.114, p = 0.02) and slower processing speed in particular (B = 0.139, p = 0.03). CONCLUSION: Only in the bipolar depression group, lower KYNA was associated with worse cognitive functioning. Future large-scale longitudinal studies are warranted to confirm the role of KYN metabolites in cognitive impairment in patients with BD and the possible therapeutic implications of this relationship.

Post-Traumatic Stress Disorder after COVID-19 Intensive Care admission: Characteristics and Perspectives.

An increase of psychopathology such as post-traumatic stress disorder (PTSD) is described in patients affected with COVID-19 that stayed at an intensive care unit (ICU). However, data on follow-up and on impact of contextual factors are limited. In a single-center, observational study, PTSD symptomatology was prevalent among 38% of participants (n=8), persisting in clinical PTSD in 2 participants after one year. In patients with initial PTSD symptoms, scores on depression, anxiety and insomnia scales were significantly higher. A higher mental burden due to avoidance of contact and a reduced quality of life was also retained in patients with PTSD symptoms.

A mood state-specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder.

OBJECTIVES: Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause neurotoxicity. We measured inflammatory markers in patients with bipolar disorder (BD) and studied their relation to kynurenine metabolites and mood. METHODS: Patients with BD suffering from an acute mood episode were assigned to the depressive (n = 35) or (hypo)manic (n = 32) subgroup. Plasma levels of inflammatory markers [cytokines, C-reactive protein] and kynurenine metabolites [tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KYNA)] were measured on 6 time points during 8 months follow-up. Biological marker levels in patients were compared to controls (n = 35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis. RESULTS: Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor-α and KYN, KYN/TRP, 3-HK and QA (ρ > 0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3-HK, P = .0004) and a strong association between interferon-y and kynurenine pathway activation (P < .0001). KYNA was low in both patient groups versus controls throughout the whole follow-up (P = .0008). CONCLUSIONS: Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism.

Self-Reported Alcohol, Tobacco, and Cannabis Use during COVID-19 Lockdown Measures: Results from a Web-Based Survey.

BACKGROUND: The outbreak of coronavirus disease 19 (COVID-19) has led to measures of social distancing and quarantine worldwide. This stressful period may lead to psychological problems, including increases in substance use. OBJECTIVE: To investigate changes in alcohol, tobacco, and cannabis consumption before and during COVID-19 lockdown and motives for these changes in substance use. METHOD: A web-based survey was filled out by an unselected population during the social distancing measures of the COVID-19 pandemic in Belgium that assessed changes in alcohol, tobacco, and cannabis consumption in the period before and during the COVID-19 lockdown and also asked about reasons for change. RESULTS: A total of 3,632 respondents (mean age 42.1 ± 14.6 years; 70% female) filled out the survey. Overall, respondents reported consuming more alcohol (d = 0.21) and smoking more cigarettes (d = 0.13) than before the COVID-19 pandemic (both p < 0.001), while no significant changes in the consumption of cannabis were noted. The odds of consuming more alcohol during the lockdown were associated with younger age (OR = 0.981, p < 0.001), more children at home (OR = 1.220, p < 0.001), non-healthcare workers (p < 0.001), and being technically unemployed related to COVID-19 (p = 0.037). The odds of smoking more cigarettes during the lockdown were associated with younger age (OR = 0.988, p = 0.027), current living situation (p < 0.001), lower education (p = 0.015), and working situation related to COVID-19 (p = 0.018). Boredom, lack of social contacts, loss of daily structure, reward after a hard-working day, loneliness, and conviviality were the main reasons for consuming more of the various substances. CONCLUSIONS: During the lockdown, individuals consumed slightly more alcohol and smoked marginally more cigarettes compared to the period before the lockdown. Further research focussing on follow-up of individuals at risk may be useful to provide appropriate care in post-COVID times.

Performance of the Psychotic Depression Assessment Scale as a Predictor of ECT Outcome.

OBJECTIVES: The presence of psychotic symptoms is an important predictor of responsiveness to electroconvulsive therapy (ECT). This study investigates whether a continuous severity measure, the Psychotic Depression Assessment Scale (PDAS), is a more accurate predictor. METHODS: Depression severity was assessed before and after the ECT course using the Montgomery-Asberg Depression Rating Scale (MADRS) in 31 patients with psychotic depression and 34 depressed patients without psychotic symptoms. Logistic regression models for MADRS response and remission were fitted, with either the PDAS total score or the dichotomous predictors "absence/presence of psychotic symptoms" as the independent variables. Age, episode duration, and treatment resistance were added as covariates. RESULTS: Both the asserted presence of psychotic symptoms and a higher PDAS total score reflected MADRS response (areas under the curve, 0.83 and 0.85, respectively), with MADRS remission also being predicted by the presence of psychotic symptoms and higher PDAS scores (areas under the curves, 0.86 and 0.84, respectively). Age was a contributor to these prediction models, with response and remission rates being highest in the older patients. Psychotic Depression Assessment Scale scores decreased significantly during ECT: at end point, 81.5% of the patients showed significant response and 63.9% had achieved remission. CONCLUSIONS: The PDAS indeed accurately predicts response to and remission after ECT in (psychotic) depression and most pronouncedly so in older patients but seems to have no clear advantage over simply verifying the presence of psychotic symptoms. This could be the consequence of a ceiling effect, as ECT was extremely effective in patients with psychotic depression.ClinicalTrials.gov: Identifier: NCT02562846.

Prediction of electroconvulsive therapy response and remission in major depression: meta-analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is considered to be the most effective treatment in severe major depression. The identification of reliable predictors of ECT response could contribute to a more targeted patient selection and consequently increased ECT response rates. Aims To investigate the predictive value of age, depression severity, psychotic and melancholic features for ECT response and remission in major depression. METHOD: A meta-analysis was conducted according to the PRISMA statement. A literature search identified recent studies that reported on at least one of the potential predictors. RESULTS: Of the 2193 articles screened, 34 have been included for meta-analysis. Presence of psychotic features is a predictor of ECT remission (odds ratio (OR) = 1.47, P = 0.001) and response (OR = 1.69, P < 0.001), as is older age (standardised mean difference (SMD) = 0.26 for remission and 0.35 for response (P < 0.001)). The severity of depression predicts response (SMD = 0.19, P = 0.001), but not remission. Data on melancholic symptoms were inconclusive. CONCLUSIONS: ECT is particularly effective in patients with depression with psychotic features and in elderly people with depression. More research on both biological and clinical predictors is needed to further evaluate the position of ECT in treatment protocols for major depression. Declaration of interest None.

Prediction of Electroconvulsive Therapy Response and Remission in Major Depression: Meta-analysis - CORRIGENDUM.

This notice describes a correction to the above mentioned paper.

The role of the healthcare sector in the prevention of sexual violence against sub-Saharan transmigrants in Morocco: a study of knowledge, attitudes and practices of healthcare workers.

BACKGROUND: Sub-Saharan transmigrants in Morocco are extremely vulnerable to sexual violence. From a public health perspective, the healthcare system is globally considered an important partner in the prevention of sexual violence. The aim of this study is twofold. In a first phase, we aimed to identify the current role and position of the Moroccan healthcare sector in the prevention of sexual violence against sub-Saharan transmigrants. In a second phase, we wanted these results and available guidelines to be the topic of a participatory process with local stakeholders in order to formulate recommendations for a more desirable prevention of sexual violence against sub-Saharan transmigrants by the Moroccan healthcare sector. METHODS: Knowledge, attitudes and practices of healthcare workers in Morocco concerning sexual violence against sub-Saharan transmigrants and its prevention were firstly explored in semi-structured interviews after which they were discussed in a participatory process resulting in the formulation of recommendations. RESULTS: All participants (n=24) acknowledged the need for desirable prevention of sexual violence against transmigrants. Furthermore, important barriers in tertiary prevention practices, i.e. psychosocial and judicial referral and long-term follow-up, and in secondary prevention attitudes, i.e. active identification of victims were identified. Moreover, existing services for Moroccan victims of sexual violence currently do not address the sub-Saharan population. Thus, transmigrants are bound to rely on the aid of civil society. CONCLUSIONS: This research demonstrates the low accessibility of existing Moroccan services for sub-Saharan migrants. In particular, there is an absence of prevention initiatives addressing sexual violence against the sub-Saharan transmigrant population. Although healthcare workers do wish to develop prevention initiatives, they are dealing with structural difficulties and a lack of expertise. Recommendations adapted to the context of sub-Saharan transmigrants in Morocco are suggested.

Unlocking asylum seekers' voices: protocol of a mixed-method clinical study on the use of the cultural formulation interview with asylum seekers in Belgium.

Background: Despite a high prevalence of mental disorders among asylum seekers, many barriers to mental healthcare exist. Cultural and contextual factors strongly influence the experience and expression of psychological distress, putting asylum seekers at greater risk of misdiagnosis and inappropriate treatment. The Cultural Formulation Interview (CFI) is a useful tool to map out cultural and contextual factors of mental disorders; however, to the best of our knowledge, it has not yet been investigated in asylum seekers specifically. The primary aim of this study is to evaluate the value of the CFI in the psychiatric assessment of asylum seekers. Second, we will describe the themes relevant to psychiatric distress in asylum seekers that are identified by the CFI. In addition, asylum seekers' experience of the CFI will be evaluated. Methods and analysis: This cross-sectional, mixed-method clinical study aims to recruit a group of 60-80 asylum seekers (age 15-29) with mental health symptoms. Data will be collected using structured (MINI, PCL-5, HDRS-17, WHOQoL-BREF & BSI) and semi-structured (CFI & CFI-debriefing) questionnaires to assess cultural background, contextual factors, and illness severity. Multidisciplinary case discussions will be held after the completion of interviews, following a methodological stepped approach. Combining qualitative and quantitative research techniques, this study aims to generate reliable knowledge on working with the CFI in asylum seekers. Based on the findings, recommendations for clinicians will be developed. Discussion: This study addresses the knowledge gap on using the CFI in asylum seekers. Compared to prior studies, it will provide new insights into the use of the CFI in the specific context of working with asylum seekers. Ethics and dissemination: Prior research on the CFI in asylum seekers is limited, partly because of their high vulnerability and low access to care. The study protocol has been tailored in close collaboration with several stakeholders and validated after piloting. Ethical approval has already been obtained. Together with the stakeholders, the results will be translated into guidelines and training materials. Recommendations to policymakers will also be provided.

Toward Targeted ECT: The Interdependence of Predictors of Treatment Response in Depression Further Explained.

OBJECTIVE: Several clinical variables assumed to be predictive of electroconvulsive therapy (ECT) outcome in major depressive disorder show substantial interrelations. The current study tries to disentangle this interdependence to distill the most important predictors of treatment success to help improve patient-treatment matching. METHODS: We constructed a conceptual framework of interdependence capturing age, episode duration, and treatment resistance, all variables associated with ECT outcome, and the clinical symptoms of what we coin core depression, ie, depression with psychomotor agitation, retardation, psychotic features, or a combination of the three. The model was validated in a sample of 73 patients with a major depressive episode according to DSM-5 treated twice weekly with ECT (August 2015-January 2018) using path analyses, with the size and direction of all direct and indirect paths being estimated using structural equation modeling. Reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores during treatment was the ECT outcome measure. RESULTS: The baseline presence of psychomotor agitation, retardation, and/or psychotic symptoms strongly correlated with beneficial ECT outcome (z = 0.84 [SE = 0.17]; P < .001), and the association between age and the effect of ECT appears to be mediated by their presence (z = 0.53 [SE = 0.18]; P = .004). There was no direct correlation between age and ECT response (P = .479), but there was for episode duration and ECT outcome (z = -0.38 [SE = 0.08]; P < .001). CONCLUSIONS: ECT is a very effective treatment option for severe depressive disorder, especially for patients suffering from severe depression characterized by the presence of psychomotor agitation, psychomotor retardation, psychotic symptoms, or a combination of these 3 features, with the chance of a beneficial outcome being reduced in patients with a longer episode duration. Age may heretofore have been given too much weight in ECT decision making. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02562846.

Markers of Inflammation and Monoamine Metabolism Indicate Accelerated Aging in Bipolar Disorder.

Background: A mild pro-inflammatory status accompanies bipolar disorder (BD). Inflammation can cause a shift in monoamine metabolism, thereby activating more cytotoxic pathways. The extent to which low-grade inflammation in BD interacts with monoamine metabolism and how this accords to aging and clinical course is unknown. Objectives: We evaluated the presence of alterations in inflammation and monoamine metabolism in BD throughout different mood states and the role of aging therein. Methods: Sixty-seven patients with BD were included during an acute mood episode, either depressive (n = 29), (hypo)manic (n = 29), or mixed (n = 9). Plasma levels of inflammatory markers [tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-y), interleukin-6 (IL-6), and C-reactive protein (CRP)] and markers of monoamine metabolism (neopterin, tryptophan, kynurenine, phenylalanine, and tyrosine) were measured repeatedly during a follow-up of 8 months. Levels in patients were compared to controls (n = 35) and correlated to HDRS-17 and YMRS scores. Spearman correlations and linear mixed model analysis were used for statistical analysis. Results: Forty-nine patients and 30 controls (age range: 22-62 years) completed the study. No significant differences in inflammatory markers were found between patients and controls overall. Tryptophan, tyrosine, and phenylalanine levels were lower in patients. In both patients and controls, markers of inflammation correlated only weakly with markers of monoamine metabolism, but correlations representative for activity of cytotoxic pathways in monoamine metabolism were more pronounced in patients. In patients, but not in controls, older age was associated with increases in inflammatory markers (IL-6, CRP, neopterin) and the kynurenine/tryptophan ratio. None of the biological markers correlated significantly with mood symptom severity. Conclusion: Our data suggest an increased susceptibility of patients with BD to develop a pro-inflammatory state and to shift monoamine metabolism toward more cytotoxic pathways. These findings are in support of the theory of neuroprogression and accelerated aging in BD. Since associations between biological markers and clinical characteristics are limited, it remains to be determined if alterations in biological markers are due to a disease effect or rather are a consequence of confounding factors.

Neurotrophic and inflammatory markers in bipolar disorder: A prospective study.

Altered neurotrophic signaling is thought to impair neuroplasticity in bipolar disorder (BD). Brain-derived neurotrophic factor (BDNF) is proposed as a neurotrophic marker in BD. However, the current evidence for its use in monitoring disease activity and illness progression is conflicting and an exploration of additional neurotrophic markers is needed. This prospective case-control study investigated mood-specific changes in potential neurotrophic markers and their association to inflammatory activity. Patients with BD were included during an acute mood episode, either depressive (n=35) or (hypo)manic (n=32). Fifty-nine patients (88%) and 29 healthy controls (97%) completed the study. Peripheral blood levels of BDNF, vascular endothelial growth factor A (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and tumor necrosis factor alpha (TNF-α) were measured at baseline and after 2 months. Biomarker levels in patients were compared to controls and correlated to HDRS-17 and YMRS total scores and the PANSS positive subscale scores. Linear mixed model analysis revealed no significant differences in neurotrophic markers between patients and controls. We found significantly increased TNF-α levels in patients and a subsequent normalization during euthymia. None of the biomarkers strongly correlated to mood symptom severity. Despite standardized methodological practices, BDNF and VEGF levels had a wide distribution range. We need a better understanding of methodological aspects influencing the analysis of neurotrophic factors to improve future research on markers for mood state monitoring and illness progression in BD.

The effect of mood-stabilizing drugs on cytokine levels in bipolar disorder: A systematic review.

OBJECTIVES: Cytokine level alterations suggest a role for the immune system in the pathophysiology of bipolar disorder (BD). Pharmacotherapy is an important confounding factor in clinical research on cytokine levels. In this systematic review we collate the evidence on blood cytokine levels in medication-free BD and the effects of single mood-stabilizing drugs on these levels. METHODS: A systematic review was conducted according to the PRISMA statement. We searched the Pubmed and Embase databases for clinical studies reporting either on cytokine levels in medication-free BD or on the effects of single mood-stabilizing drugs on cytokine levels in BD. RESULTS: Of the 564 articles screened, 17 were included. Fourteen articles report on medication-free patients with BD and indicate state-related cytokine alterations. Six articles discuss the effect of lithium. Whereas no data on short-term effects of lithium were found, ≥2 months lithium use in euthymic populations is associated with normal cytokine levels. Two studies report no effect of valproate and no studies were found on carbamazepine, lamotrigine or antipsychotics. LIMITATIONS: The available studies are characterized by a broad methodological heterogeneity and limited replication between studies. CONCLUSIONS: This systematic review suggests the presence of state-related cytokine level alterations in medication-free BD with most evidence pointing to a proinflammatory cytokine response in mania. Euthymia and long-term lithium use are associated with normal cytokine levels. To improve our understanding of the impact of mood-stabilizing drugs on cytokine levels, longitudinal studies with medication-free baseline, randomized controlled single-drug treatment protocols and close mood state monitoring are needed.