In the present study we measured the concentrations of cortisol, thyroid hormones, testosterone, and GABA (gamma aminobutyric acid) in am blood plasma samples of combatants with an at least 10 year... Show moreIn the present study we measured the concentrations of cortisol, thyroid hormones, testosterone, and GABA (gamma aminobutyric acid) in am blood plasma samples of combatants with an at least 10 year history of military psychological trauma (N = 74) divided in groups that either suffer from post-traumatic stress disorder (PTSD) (N = 37) or are resistant (N = 37) as well as in a control group without traumatic experience in the anamnesis, (N = 34). PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS). The results show that the am blood cortisol levels of individuals that were exposed to war zone experiences irrespective susceptibility for or resistance to PTSD were significantly higher than the values observed in the controls. Testosterone levels in PTSD patients differed neither from that observed in PTSD resistant nor control groups. In the resistant group testosterone levels were however significantly higher than in controls. The level of all thyroid hormones did not differ between the study groups. GABA level was significantly lower in the PTSD group compared with healthy controls. In the resistant group blood GABA levels were not significantly different from either PTSD patients or controls. In conclusion, the current data show that cortisol and to some extent testosterone may serve as biomarker of war zone stress per se, even if trauma was experienced at least ten years before, rather than of only PTSD or resistance to PTSD. GABA, in contrast, can be considered a potential marker of the protracted nature of PTSD. Show less
Jongs, N.; Penninx, B.; Arango, C.; Ayuso-Mateos, J.L.; Wee, N. van der; Winter-van Rossum, I.; ... ; Kas, M.J. 2022
Background: Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher)... Show moreBackground: Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher) assessments of social functioning in Schizophrenia (SZ) and Alzheimer's disease (AD) patients and evaluated if the discrepancy between the two assessments is mediated by disease-related factors such as symptom severity.Methods: We selected five items from the WHO Disability Assessment Schedule 2.0 (WHODAS) to assess social functioning in 53 AD and 61 SZ patients. Caregiver- and researcher-rated assessments of social functioning were used to calculate the discrepancies between self-rated and proxy-rated assessments. Furthermore, we used the number of communication events via smartphones to compare the questionnaire outcomes with an objective measure of social behaviour.Results: WHODAS results revealed that both AD (p < 0.001) and SZ (p < 0.004) patients significantly overestimate their social functioning relative to the assessment of their caregivers and/or researchers. This overestimation is mediated by the severity of cognitive impairments (MMSE; p = 0.019) in AD, and negative symptoms (PANSS; p = 0.028) in SZ. Subsequently, we showed that the proxy scores correlated more strongly with the smartphone communication events of the patient when compared to the patient-rated questionnaire scores (self; p = 0.076, caregiver; p < 0.001, researcher-rated; p = 0.046).Conclusion: Here we show that the observed overestimation of WHODAS social functioning scores in AD and SZ patients is partly driven by disease-related biases such as cognitive impairments and negative symptoms, respectively. Therefore, we postulate the development and implementation of objective measures of social functioning that may be less susceptible to such biases. Show less
Eshuis, L.V.; Gelderen, M.J. van; Zuiden, M. van; Nijdam, M.J.; Vermetten, E.; Olff, M.; Bakker, A. 2021
Background: Virtual reality exposure therapy (VRET) and augmented reality exposure therapy (ARET) are digitally assisted psychotherapies that potentially enhance posttraumatic stress disorder (PTSD... Show moreBackground: Virtual reality exposure therapy (VRET) and augmented reality exposure therapy (ARET) are digitally assisted psychotherapies that potentially enhance posttraumatic stress disorder (PTSD) treatment by increasing a patient's sense of presence during exposure therapy. This study aimed to systematically review current evidence regarding the efficacy of VRET and ARET as PTSD treatment. Methods: A systematic electronic database search, a systematic quality assessment and two meta-analyses were conducted in accordance with PRISMA guidelines. Results: Eleven studies on the efficacy of VRET for PTSD (n = 438) were found, but no studies on the efficacy of ARET. The majority of VRET studies were of a low quality and had heterogeneous results. Meta-analyses showed VRET outperformed waitlist control (standardized mean difference -0.64 (95% CI -1.05 to -0.22)) while no significant difference was found between VRET and active treatment conditions (standardized mean difference -0.25 (95% CI -0.77 to 0.27)). Conclusion: VRET was superior to waitlist control groups and as effective as other psychotherapies. However, the results showed considerable heterogeneity due to the low number of studies and variety of VRET methods. VRET may be an effective alternative to current treatments and shows promise for the treatment of PTSD patients that have not responded to previous treatment. Future research should focus on high quality RCTs, including information on side effects and adverse events, with sufficient numbers of participants. This study recognizes a research gap regarding the efficacy of ARET, while it may have potential for PTSD treatment. Show less
Psychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to... Show morePsychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to individual psychiatric outcomes, associations with GPF remain unclear. Using data from 440 children aged 10 years participating in the Generation R Study, we examined the associations of DNAm with both general and specific (internalizing, externalizing) factors of psychopathology. Genome-wide DNAm levels, measured in peripheral blood using the Illumina 450K array, were clustered into wider co-methylation networks ('modules') using a weighted gene co-expression network analysis. One co-methylated module associated with GPF after multiple testing correction, while none associated with the specific factors. This module comprised of 218 CpG probes, of which 198 mapped onto different genes. The CpG most strongly driving the association with GPF was annotated to FZD1, a gene that has been implicated in schizophrenia and wider neurological processes. Associations between the probes contained in the co-methylated module and GPF were supported in an independent sample of children from the Avon Longitudinal Study of Parents and Children (ALSPAC), as evidenced by significant correlations in effect sizes. These findings might contribute to improving our understanding of dynamic molecular processes underlying complex psychiatric phenotypes. Show less
Bauduin, S.E.E.C.; Giltay, E.J.; Noorden, M.S. van; Werff, S.J.A. van der; Leeuw, M. de; Hemert, A.M. van; Wee, N.J.A. van der 2021
Social withdrawal is an early and common feature of psychiatric disorders. Hypothalamic-pituitary-adrenal (HPA)-axis activation through increased salivary cortisol (sC) and sympathetic activation... Show moreSocial withdrawal is an early and common feature of psychiatric disorders. Hypothalamic-pituitary-adrenal (HPA)-axis activation through increased salivary cortisol (sC) and sympathetic activation through increased salivary alpha-amylase (sAA) may play a role. We aimed to study whether the link between increased sC and sAA on the one hand and depression on the other hand is mediated by social withdrawal. In this cross-sectional, observational study, sC and sAA measures were measured in seven saliva samples in 843 participants (231 psychiatric patients and 612 healthy controls). Social withdrawal was assessed through the Brief Symptom Inventory (BSI)-, the Short Form 36-, and the Dutch Dimensional Assessment of Personality Pathology social withdrawal subscales, and analyzed using linear regression and mediation analyses. On average, participants were 44.0 years old (SD = 12.8; 64.1% female). Basal and diurnal sAA were unrelated to any social withdrawal scale and depression. Certain sC measures were positively associated with the BSI social withdrawal subscale (i. e., area under the curve with respect to the increase, beta = 0.082, p = 0.02; evening sC value: beta = 0.110, p = 0.003; and mean sC value: beta = 0.097; p = 0.01). We found limited support for statistical mediation by social withdrawal (measured using a composite social withdrawal score) on the relationship between evening sC and depression. Thus, although we found no support for a role of basal and diurnal sAA in social withdrawal, HPAaxis activation may partly aggravate social withdrawal in depressive disorders. Show less
Gelderen, M.J. van; Nijdam, M.J.; Vries, F. de; Meijer, O.C.; Vermetten, E. 2020
Background: Hypothalamic-pituitary-adrenal axis functioning has been related to treatment outcome in posttraumatic stress disorder (PTSD). Previous studies have primarily focused on cortisol levels... Show moreBackground: Hypothalamic-pituitary-adrenal axis functioning has been related to treatment outcome in posttraumatic stress disorder (PTSD). Previous studies have primarily focused on cortisol levels before and after a course of therapy and findings have not been fully consistent. This study investigated session-related cortisol levels in veterans with treatment-resistant PTSD over the course of a novel motion-assisted virtual reality exposure therapy and aimed to determine whether cortisol levels were related to changes in PTSD symptom severity.Methods: Veterans (N = 22) received six exposure sessions during which salivary cortisol samples were collected pre-session, post-session and in the late afternoon following sessions. PTSD symptom severity was assessed by structured clinical interviews at pre- and post-treatment. Average cortisol levels were compared between responders and non-responders. Linear regression analyses were conducted with PTSD symptom change as criterion variable, average cortisol levels as predictor, and timing of sampling and baseline PTSD symptoms as covariates.Results: Responders to treatment tended to have higher average cortisol levels at pre-session (p = 0.064) and postsession (p = 0.050) compared to non-responders. Higher average pre-session and post-session cortisol levels predicted greater PTSD symptom improvement (pre: b = 1.83, p = 0.009; post: b = 3.57, p = 0.004).Conclusion: This study provides preliminary evidence for session-related cortisol as biomarker of response to exposure-based therapies for PTSD. Higher cortisol levels may have facilitated fear extinction and reconsolidation, and may indicate increased physiological stress activation necessary for appropriate treatment engagement. Further work involving comparable methodology is encouraged to establish session-related cortisol as biomarker and to determine the mechanisms through which it interacts with treatment outcome. Show less
Background: Temporality of the association of low omega-3 polyunsaturated fatty acid (n-3 PUFA) plasma levels with depression remains questionable. To determine the underlying nature of these... Show moreBackground: Temporality of the association of low omega-3 polyunsaturated fatty acid (n-3 PUFA) plasma levels with depression remains questionable. To determine the underlying nature of these associations, this study examined the bidirectional longitudinal associations of n-3 PUFA plasma levels with (presence, onset and course of) depressive disorders and symptoms.Methods: Baseline (n = 2912, 28.6% with current depressive disorder) and 6-year follow-up data (n = 1966, 13.0% with current depressive disorder) of the Netherlands Study of Depression and Anxiety (NESDA) were used. Depression diagnoses and symptoms were based on psychiatric interviews and self-report questionnaires. N-3 PUFA levels (ratio of total fatty acids (mmol%)), were assessed using nuclear magnetic resonance.Results: Using two waves of data, n-3 PUFA levels were lower among depressed persons, as compared to healthy controls (Beta = - 0.047, SE = 0.011, p < .001). Nevertheless, baseline n-3 PUFA levels were not consistently associated with subsequent change in depressive symptoms, onset or remission of depressive disorders over 6 years. Furthermore, the difference in n-3 PUFA levels detected at baseline between depressed and non-depressed participants tended to dissipate over 6 years (depression-by-time estimate: p = .011). Finally, subjects depressed both at baseline and at 6-year follow up had consistently lower n-3 PUFA levels over the entire follow-up as compared to those who had never been depressed. Change in depressive disorders across waves was not consistently accompanied by change in n-3 PUFA levels over time.Limitations: No data on intermediate time points and EPA levels were available.Conclusions: Despite significant cross-sectional associations between n-3 PUFA plasma levels and depressive disorders and severity, this 6-year longitudinal study could not confirm an uni- or bidirectional association over time. The association between depression and n-3 PUFA plasma levels is unlikely to be causal. Show less
Diermen, L. van; Vanmarcke, S.; Walther, S.; Moens, H.; Veltman, E.; Fransen, E.; ... ; Schrijvers, D. 2019
Psychomotor symptoms are core features of melancholic depression. This study investigates whether psychomotor disturbance predicts the outcome of electroconvulsive therapy (ECT) and how the... Show morePsychomotor symptoms are core features of melancholic depression. This study investigates whether psychomotor disturbance predicts the outcome of electroconvulsive therapy (ECT) and how the treatment modulates psychomotor disturbance. In 73 adults suffering from major depressive disorder psychomotor functioning was evaluated before, during and after ECT using the observer-rated CORE measure and objective measures including accelerometry and a drawing task. Regression models were fitted to assess the predictive value of melancholic depression (CORE >= 8) and the psychomotor variables on ECT outcome, while effects on psychomotor functioning were evaluated through linear mixed models. Patients with CORE-defined melancholic depression (n = 41) had a 4.9 times greater chance of reaching response than those (n = 24) with non-melancholic depression (Chi-Square = 7.5, P = 0.006). At baseline, both higher total CORE scores (AUC = 0.76; P = 0.001) and needing more cognitive (AUC = 0.78; P = 0.001) and motor time (AUC = 0.76; P = 0.003) on the drawing task corresponded to superior ECT outcomes, as did lower daytime activity levels (AUC = 0.76) although not significantly so after Bonferroni correction for multiple testing. A greater CORE-score reduction in the first week of ECT was associated with higher ECT effectiveness. ECT reduced CORE-assessed psychomotor symptoms and improved activity levels only in those patients showing the severer baseline retardation. Although the sample was relatively small, psychomotor symptoms were clearly associated with beneficial outcome of ECT in patients with major depression, indicating that monitoring psychomotor deficits can help personalise treatment. Show less
Ai, H.; Tol, M.J. van; Marsman, J.B.C.; Veltman, D.J.; Ruhe, H.G.; Wee, N.J.A. van der; ... ; Aleman, A. 2018
Individuals suffering from depression often have difficulty trusting others. Previous research has shown a relationship between trust formation and pupil mimicry - the synchronization of pupil... Show moreIndividuals suffering from depression often have difficulty trusting others. Previous research has shown a relationship between trust formation and pupil mimicry - the synchronization of pupil sizes between individuals. The current study therefore examined whether pupil mimicry is weaker in depressed individuals and an underlying factor of their low levels of trust. Forty-two patients with major depressive disorder (MDD) and 40 healthy control subjects played trust games with virtual partners. Images of these partners' eye regions were presented to participants before they had to make a monetary investment decision. Partners' pupils either dilated, constricted, or remained static over the course of 4-s interactions. During the task, participants' pupil sizes were recorded with eye-tracking equipment to assess mimicry. The results confirm that patients with MDD were somewhat less trusting than controls and used another's pupillary cues differently when deciding to trust. Specifically, whereas healthy controls trusted partners with dilating pupils more than partners with constricting pupils, patients with MDD particularly trusted partners whose pupils changed in size less, regardless of whether partners' pupils were dilating or constricting. This difference in investment behavior was unrelated to differences in pupil mimicry, which was equally apparent in both groups and fostered trust to the same extent. Whereas lower levels of trust observed in patients with MDD could not be explained by differences in pupil mimicry, our data show that pupil dilation mimicry might help people to trust. These findings provide further evidence for the important role of pupil size and pupil mimicry in interpersonal trust formation and shed light on the pathophysiology of clinically low trust in patients with MDD. Show less
