Late life depression, brain characteristics and response to ECT

Stek, M.L. [Promotor]Heuvel, O.A. van den [Promotor]Exel, E. van [Copromotor

YidC and SecY mediate membrane insertion of a type I transmembrane domain

YidC has been identified recently as an evolutionary conserved factor that is involved in the integration of inner membrane proteins (IMPs) in Escherichia coli. The discovery of YidC has inspired the reevaluation of membrane protein assembly pathways in E. coli. In this study, we have analyzed the role of YidC in membrane integration of a widely used model IMP, leader peptidase (Lep). Site-directed photocross-linking experiments demonstrate that both YidC and SecY contact nascent Lep very early during biogenesis, at only 50-amino acid nascent chain length. At this length the first transmembrane domain (TM), which acquires a type I topology, is not even fully exposed outside the ribosome. The pattern of interactions appears dependent on the position of the cross-linking probe in the nascent chain. Upon elongation, nascent Lep remains close to YidC and comes into contact with lipids as well. Our results suggest a role for YidC in both the reception and lipid partitioning of type I TMs

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness. METHODS: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R2) at the optimal p-value threshold is reported. RESULTS: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold. CONCLUSIONS: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry

White Matter Hyperintensities, Medial Temporal Lobe Atrophy, Cortical Atrophy, and Response to Electroconvulsive Therapy in Severely Depressed Elderly Patients

Objective: Electroconvulsive therapy (ECT) is a valuable treatment option in severely depressed elderly patients. Structural abnormalities in the brain, such as white matter hyperintensities, medial temporal lobe atrophy (MTA), or global cortical atrophy, may influence therapeutic response. The respective value of these factors in response prediction is unclear. Method: In a naturalistic clinical cohort of 81 elderly patients diagnosed with DSM-IV major depressive disorder, magnetic resonance imaging (MRI) was recorded and rated before ECT treatment. The study was conducted at the clinic for Geriatric Psychiatry of the VU University Medical Center/Stichting Buitenamstel Geestgronden, Amsterdam, The Netherlands, over a 5-year period (2001-2006). Severity of depressive symptoms was measured by using the Montgomery-Asberg Depression Rating Scale (MADRS). Response to ECT was defined as a decrease of at least 50 percent on the MADRS, and remission was defined as a score below 10 points on the MADRS. Results: Patients with moderate or severe MTA had a lower mean percentage decrease in MADRS scores after ECT (37.9% in those with MTA, compared to 66.2% in those without MTA, P = .008). Patients without MTA had a 3 times greater chance of remitting from their depression compared to patients with moderate or severe MTA, ie, the hazard ratio for remission was 3.22 (95% CI, 1.30 to 7.69, P = .01). In contrast, no differences in change in MADRS scores were found for white matter hyperintensities or global cortical atrophy. Conclusions: Medial temporal lobe atrophy - not white matter hyperintensities or global cortical atrophy - contributes to poor response to ECT in severely depressed elderly patients. These findings suggest that assessment of MTA in severely depressed elderly patients may be useful in the prediction of potential ECT response. © Copyright 2010 Physicians Postgraduate Press, Inc

White Matter Hyperintensities and Cognitive Impairment During Electroconvulsive Therapy in Severely Depressed Elderly Patients

Objective: Transient cognitive impairment during electroconvulsive therapy (ECT) can be a reason to discontinue ECT in depressed elderly patients. We hypothesized that both white matter hyperintensities and medial temporal lobe atrophy contribute to transient cognitive impairment during ECT. Methods: In 81 elderly patients with depression, magnetic resonance images (MRI) were recorded before ECT. We rated white matter hyperintensities (WMH) with the Age-Related White Matter Changes scale (ARWMC). Cognitive impairment during ECT was measured weekly with the Mini Mental State Examination (MMSE), 2 days after each session. Results: The mean MMSE score at baseline for all patients was 25.5 points, the lowest MMSE score during ECT was 23.3 points, and the mean MMSE score after ECT was 26.3 points. Stratification for the ECT method showed no significant difference in the lowest MMSE scores of patients with or without WMH, receiving unilateral ECT (22.5 points versus 23.9 points). There was a difference in the lowest MMSE scores in patients who switched from unilateral ECT to bilateral ECT (18.7 points in patients with WMH versus 22.0 points in patients without WMH). Conclusion: Depressed elderly patients with WMH who receive bilateral ECT are at increased risk of transient cognitive impairment. Our findings show, however, that cognitive impairment improves when ECT is continued. This implies that ECT does not have to be discontinued when patients experience transient cognitive impairment during ECT