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... Show moreIntroduction: 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. Show less
Hebbrecht, K.; Skorobogatov, K.; Giltay, E.J.; Coppens, V.; Picker, L. de; Morrens, M. 2021
Objective Tryptophan catabolites (TRYCATs) are implicated in the pathophysiology of mood disorders by mediating immune-inflammation and neurodegenerative processes. We performed a meta-analysis of... Show moreObjective Tryptophan catabolites (TRYCATs) are implicated in the pathophysiology of mood disorders by mediating immune-inflammation and neurodegenerative processes. We performed a meta-analysis of TRYCAT levels in bipolar disorder (BD) patients compared to healthy controls.MethodsA systematic literature search in seven electronic databases (PubMed, Embase, Web of Science, Cochrane, Emcare, PsycINFO, Academic Search Premier) was conducted on TRYCAT levels in cerebrospinal fluid or peripheral blood according to the PRISMA statement. A minimum of three studies per TRYCAT was required for inclusion. Standardized mean differences (SMD) were computed using random effect models. Subgroup analyses were performed for BD patients in a different mood state (depressed, manic). The methodological quality of the studies was rated using the modified Newcastle-Ottawa Quality assessment Scale.ResultsTwenty-one eligible studies were identified. Peripheral levels of tryptophan (SMD = -0.44; p < 0.001), kynurenine (SMD = - 0.3; p = 0.001) and kynurenic acid (SMD = -.45; p = < 0.001) were lower in BD patients versus healthy controls. In the only three eligible studies investigating TRP in cerebrospinal fluid, tryptophan was not significantly different between BD and healthy controls. The methodological quality of the studies was moderate. Subgroup analyses revealed no significant difference in TRP and KYN values between manic and depressed BD patients, but these results were based on a limited number of studies.ConclusionThe TRYCAT pathway appears to be downregulated in BD patients. There is a need for more and high-quality studies of peripheral and central TRYCAT levels, preferably using longitudinal designs. Show less
Hebbrecht, K.; Stuivenga, M.; Birkenhäger, T.; Morrens, M.; Fried, E.I.; Sabbe, B.; Giltay, E.J. 2020
BackgroundMajor depressive disorder (MDD) shows large heterogeneity of symptoms between patients, but within patients, particular symptom clusters may show similar trajectories. While symptom... Show moreBackgroundMajor depressive disorder (MDD) shows large heterogeneity of symptoms between patients, but within patients, particular symptom clusters may show similar trajectories. While symptom clusters and networks have mostly been studied using cross-sectional designs, temporal dynamics of symptoms within patients may yield information that facilitates personalized medicine. Here, we aim to cluster depressive symptom dynamics through dynamic time warping (DTW) analysis.MethodsThe 17-item Hamilton Rating Scale for Depression (HRSD-17) was administered every 2weeks for a median of 11weeks in 255 depressed inpatients. The DTW analysis modeled the temporal dynamics of each pair of individual HRSD-17 items within each patient (i.e., 69,360 calculated "DTW distances"). Subsequently, hierarchical clustering and network models were estimated based on similarities in symptom dynamics both within each patient and at the group level.ResultsThe sample had a mean age of 51 (SD 15.4), and 64.7% were female. Clusters and networks based on symptom dynamics markedly differed across patients. At the group level, five dynamic symptom clusters emerged, which differed from a previously published cross-sectional network. Patients who showed treatment response or remission had the shortest average DTW distance, indicating denser networks with more synchronous symptom trajectories.ConclusionsSymptom dynamics over time can be clustered and visualized using DTW. DTW represents a promising new approach for studying symptom dynamics with the potential to facilitate personalized psychiatric care. Show less
Hebbrecht, K.; Giltay, E.J.; Birkenhager, T.K.; Sabbe, B.; Verwijk, E.; Obbels, J.; ... ; Diermen, L. van 2020
Objective The Montreal Cognitive Assessment (MoCA) is a sensitive and clinically practical test but its usefulness in measuring long-term cognitive effects of ECT is unclear. Using the MoCA, we... Show moreObjective The Montreal Cognitive Assessment (MoCA) is a sensitive and clinically practical test but its usefulness in measuring long-term cognitive effects of ECT is unclear. Using the MoCA, we investigated short- and long-term global cognitive change in ECT-treated patients with a Major Depressive Episode (MDE). Method We included 65 consecutive ECT-treated patients with MDE, in whom global cognitive functioning was assessed at baseline (T0); during ECT (before the third session; T1); and 1 week (T2), 3 months (T3), and 6 months (T4) after completion of the index course. Changes in MoCA (sub)scores were analyzed using linear mixed models and reliable change indices were computed to investigate individual changes in MoCA total scores. Results There was a significant effect of time on MoCA scores (F(4, 230.5) = 4.14,P = 0.003), with an improvement in global cognitive functioning from T3 compared to T1 and T2. At the individual level, 26% (n = 17) of patients showed a significantly worse cognitive functioning at T2 and 12% (n = 8) an improved cognitive functioning compared to T0. For T4, these percentages ameliorated to 8% and 18% respectively. Conclusion No persistent global cognitive impairment induced by ECT was found at the group level using the MoCA. At the individual level, however, there was clear heterogeneity in the effects of ECT on cognitive functioning. The MoCA is a suitable tool to monitor short- and long-term global cognitive functioning in ECT-treated patients with MDE but in younger patients, potential ceiling effects must be taken into account. Show less
Hebbrecht, K.; Stuivenga, M.; Birkenhager, T.; Mast, R.C. van der; Sabbe, B.; Giltay, E.J. 2020
Background:Although differences in symptom profiles and outcome between depressive patients with an underlying major depressive disorder (MDD) and bipolar depression (BD) have been reported,... Show moreBackground:Although differences in symptom profiles and outcome between depressive patients with an underlying major depressive disorder (MDD) and bipolar depression (BD) have been reported, studies with sequential short-interval assessments in a real-life inpatient setting are scarce.Objectives:To examine potential differences in symptom profile and course of depressive symptomatology in depressive inpatients with underlying MDD and BD.Methods:A cohort of 276 consecutive inpatients with MDD (n= 224) or BD (n= 52) was followed during their hospitalization using routine outcome monitoring (ROM), which included a structured diagnostic interview at baseline (Mini-International Neuropsychiatric Interview Plus [MINI-Plus]) and repeated 17-item Hamilton Depression Rating Scale every 2 weeks. MDD and BD were compared regarding their symptom profiles and time to response and remission. Furthermore, the concordance between the MINI-Plus and clinical diagnosis was analyzed.Results:Patients were on average 52 and 47 years old in the MDD and BD group, respectively, and 66 versus 64% were female. Compared to patients with BD, patients with MDD scored higher on weight loss (p= 0.02), whereas the BD group showed a higher long-term likelihood of response (hazard ratio = 1.93, 95% confidence interval 1.16-3.20,pfor interaction with time = 0.04). Although the same association was seen for remission, the interaction with time was not significant (p= 0.48). Efficiency between the MINI-Plus and clinical diagnosis of BD was high (0.90), suggesting that the MINI-Plus is an adequate ROM diagnostic tool.Conclusions:In routine clinical inpatient care, minor differences in the symptom profile and the course of depressive symptomatology may be helpful in distinguishing MDD and BD, particularly when using sequential ROM assessments. Show less
