The aim of this thesis was to gain more insight in the neural network alterations that may underl... more The aim of this thesis was to gain more insight in the neural network alterations that may underlie PTSD and trauma-focused therapy outcome. To investigate TheNeural Web of War brain scans of healthy civilians (n=26), and veterans with (n=58) and without (n=29) PTSD were assessed. Structural and functional connectivity analyses were performed. We showed alterations in connectivity related to PTSD, persistence of PTSD, acquisition method, comorbid depression, deployment and/or military training, and resilience. Furthermore, we found indicators for treatment outcome related changes that occur over the course of treatment. However, it was evident that neural networks do not simply recover after treatment, when a patient recovers from PTSD. Our results do shed light on the psychopathology of PTSD and showed that there are many individual differences that may be related to differences in neural networks, not only the presence of PTSD. Furthermore, we confirmed that PTSD patients were a h...
Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or... more Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or without PTSD. Decreasing HPA-axis reactivity to different stress cues has been reported during PTSD treatment. The cortisol awakening response (CARi) is a well-validated, standardized measure of HPA-axis reactivity which can be easily acquired in the clinical setting. Whether CARi changes over time in traumatized individuals are specific to PTSD treatment is unknown. Furthermore, a possible role for the baseline CARi in predicting symptom reduction after treatment in PTSD has not been examined before. To answer these questions, a cohort study was conducted in which the awakening cortisol was measured in both PTSD (N=41) and non-PTSD (N=25) combat-exposed male subjects. Measurements took place at inclusion and 6-8 months after inclusion for both the PTSD and the non-PTSD group. During the 6-8 months interval, PTSD patients received trauma-focused focused psychotherapy, whereas non-PTSD patients received no treatment. We found a decrease in the CARi over time in both groups, suggesting it was not specific to PTSD or the effect of treatment. Therefore, caution is warranted when attributing diminished HPA-axis reactivity over time to effects of PTSD treatment. Second, CARi prior to treatment predicted PTSD symptom reduction (CAPS score change) after treatment, and accounted for 10% of the variance, even when adjusted for changes in depressive symptoms and medication use during the study period. A putative role emerges for CARi as a predictive biomarker of symptom reduction in male individuals with combat-related PTSD.
Posttraumatic stress disorder (PTSD) is a disabling disorder associated with resting state functi... more Posttraumatic stress disorder (PTSD) is a disabling disorder associated with resting state functional connectivity alterations. However, whether specific brain regions are altered in PTSD or whether the whole brain network organization differs remains unclear. PTSD can be treated with trauma-focused therapy, although only half of the patients recover after treatment. In order to better understand PTSD psychopathology our aim was to study resting state networks in PTSD before and after treatment. Resting state functional magnetic resonance images were obtained from veterans with PTSD (n = 50) and controls (combat and civilian controls; n = 54) to explore which network topology properties (degree and clustering coefficient) of which brain regions are associated with PTSD. Then, PTSD-associated brain regions were investigated before and after treatment. PTSD patients were subdivided in persistent (n = 22) and remitted PTSD patients (n = 17), and compared with combat controls (n = 22), ...
Notorious for degrading diffusion MRI data quality are so-called susceptibility-induced off-reson... more Notorious for degrading diffusion MRI data quality are so-called susceptibility-induced off-resonance fields, which cause non-linear geometric image deformations. While acquiring additional data to correct for these distortions alleviates the adverse effects of this artifact drastically - e.g., by reversing the polarity of the phase-encoding (PE) direction - this strategy is often not an option due to scan time constraints. Especially in a clinical context, where patient comfort and safety are of paramount importance, acquisition specifications are preferred that minimize scan time, typically resulting in data obtained with only one PE direction. In this work, we investigated whether choosing a different polarity of the PE direction would affect the outcome of a specific clinical research study. To address this methodological question, fractional anisotropy (FA) estimates of FreeSurfer brain regions were obtained in civilian and combat controls, remitted posttraumatic stress disorde...
ObjectivesA comprehensive overview of the evidence for factors derived from leading psychological... more ObjectivesA comprehensive overview of the evidence for factors derived from leading psychological theories of the onset of major depressive disorder (MDD) that underpin psychological interventions is scarce . We aimed to systematically investigate the prospective evidence for factors derived from the behavioural, cognitive, diathesis–stress, psychodynamic and personality-based theories for the first onset of MDD.DesignSystematic review and meta-analysis.MethodsDatabases PubMed, PsycINFO, Cochrane and Embase and published articles were systematically searched from inception up to August 2019. Prospective, longitudinal studies that investigated theory-derived factors before the first onset of MDD, established by a clinical interview, were included. Screening, selection and data extraction of articles were conducted by two screeners. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to estimate level of confidence and risk of bias. Meta-analysis w...
ObjectiveTrauma-focused psychotherapy is the first-line treatment for posttraumatic stress disord... more ObjectiveTrauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30-50% of patients do not benefit sufficiently. We investigated whether structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) data could distinguish between treatment responders and non-responders on the group and individual level.MethodsForty-four male veterans with PTSD underwent baseline scanning followed by trauma-focused psychotherapy. Voxel-wise gray matter volumes were extracted from the structural MRI data and resting-state networks (RSNs) were calculated from rs-fMRI data using independent component analysis. Data were used to detect differences between responders and non-responders on the group level using permutation testing, and the single-subject level using Gaussian process classification with cross-validation.ResultsA RSN centered on the bilateral superior frontal gyrus differed between responders and non-responder groups (PFWE <...
Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD)... more Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30–50% of patients do not benefit sufficiently. We investigated whether structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) data could distinguish between treatment responders and non-responders on the group and individual level. Forty-four male veterans with PTSD underwent baseline scanning followed by trauma-focused psychotherapy. Voxel-wise gray matter volumes were extracted from the structural MRI data and resting-state networks (RSNs) were calculated from rs-fMRI data using independent component analysis. Data were used to detect differences between responders and non-responders on the group level using permutation testing, and the single-subject level using Gaussian process classification with cross-validation. A RSN centered on the bilateral superior frontal gyrus differed between responders and non-responder groups (PFWE
Background Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress diso... more Background Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30-50% of patients do not benefit sufficiently. Here, we tested whether resting-state functional magnetic imaging (rs-fMRI) can predict treatment response for individual patients. Methods 44 male veterans with PTSD underwent baseline rs-fMRI scanning followed by trauma-focused therapy (EMDR or TF-CBT). Resting-state networks (RSN) were obtained using independent component analysis with 70 components on the basis of 28 trauma-exposed healthy controls, matched for age and gender. Dual regression was used to obtain subject-specific RSNs for the PTSD patients. All RSNs were individually included in a machine learning classification analysis using Gaussian process classifiers. Classifier performance was assessed using 10 times repeated 10-fold cross-validation. Results Patients were grouped into treatment responders (n = 24) and non-responders (n = 20), based on a 30% decrease in total clinician-administered PTSD scale for the DSM-IV (CAPS) score from pre- to post-treatment assessment. A network centered around the pre-supplementary motor area achieved an average accuracy of 81% (p < 0.001, based on a permutation test, corrected for multiple comparisons across 44 signal components), with a sensitivity of 84.5%, specificity of 77.5%, and area under receiver-operator curve (AUC) of 0.93. Conclusions Rs-fMRI recordings are capable of providing personalized predictions of treatment response in a sample of veterans with PTSD. It therefore has the potential to be useful as a biomarker of treatment response and should be validated in larger independent studies. Supported By ZonMw; AMC; Dutch Ministry of Defense
Background During the last century many biological hypotheses have been postulated to underlie th... more Background During the last century many biological hypotheses have been postulated to underlie the psychopathology of major depressive disorder (MDD). In order to gain insight in the evidence for these hypothesis from patients, a systematical search for longitudinal studies investigating biological factors before the onset of MDD was performed. Methods PubMed, PsychINFO, and Embase were used as databases. The search strategy included terms relating to (1) MDD; (2) a longitudinal design or onset/relapse/recurrence; and (3) potential biomarkers. Current leading biological models for depression were covered, including neuroimaging, neurotransmitters, neurotrophic factors, hormones and immunology. Results PRISMA guidelines were followed and 46830 articles were initially screened, indication 642 relevant articles that were screened on full text. Eventually, 90 articles fulfilled the inclusion criteria. Results were too heterogeneous or limited to perform meta-analyses for the topics: Neuroimaging (n=19), Gut (n=1), Immunology/inflammation (n=5), Neurotrophic (n=1), Neurotransmitters (n=1), Hormones (n=62), Oxidative stress (n=1). A meta analysis was performed for cortisol, which showed that higher cortisol levels predict a 44% higher chance of developing MDD (n=14, OR: 1.44 [1.12-1.84] p = 0.004), but not having a relapse or recurrent episode (n=4, OR: 1.524 [0.801 2.899] p=0.199). Conclusions Surprisingly, although a rigorous systematic search for prospective evidence for biomarkers for depression was performed, we found limited prospective studies investigating leading biological models. Only cortisol could be identified as prospective biomarker for depression onset. More prospective studies are necessary to investigate the causes (and consequences) of depression onset, relapse and recurrence. Supported By NIAS: Netherlands Institute For Advanced Study in the Humanities and Social Sciences (grant for Claudi Bocktings group)
Leading biological hypotheses propose that biological changes may underlie major depressive disor... more Leading biological hypotheses propose that biological changes may underlie major depressive disorder onset and relapse/recurrence. Here, we investigate if there is prospective evidence for biomarkers derived from leading theories. We focus on neuroimaging, gastrointestinal factors, immunology, neurotrophic factors, neurotransmitters, hormones, and oxidative stress. Searches were performed in Pubmed, Embase and PsychInfo for articles published up to 06/2019. References and citations of included articles were screened to identify additional articles. Inclusion criteria were having an MDD diagnosis as outcome, a biomarker as predictor, and prospective design search terms were formulated accordingly. PRISMA guidelines were applied. Meta-analyses were performed using a random effect model when three or more comparable studies were identified, using a random effect model. Our search resulted in 67,464 articles, of which 75 prospective articles were identified on: Neuroimaging (N = 24), Ga...
Psychological factors hypothesized to account for relapse of major depressive disorder (MDD) roug... more Psychological factors hypothesized to account for relapse of major depressive disorder (MDD) roughly originate from five main theories: Cognitive, diathesis-stress, behavioural, psychodynamic, and personality-based. In a meta-analysis we investigated prospective, longitudinal evidence for these leading psychological theories and their factors in relation to depressive relapse. Included studies needed to establish history of MDD and prospective depressive relapse through a clinical interview, have a longitudinal and prospective design, and measure at least one theory-derived factor before relapse. We identified 66 eligible articles out of 43,586 records published up to November 2018. Pooled odds ratios (OR) indicated a significant relationship between the cognitive, behavioural, and personality-based theories and depressive relapse (cognitive: k = 17, OR = 1.24, 95% CI = 1.10-1.40; behavioural, k = 8, OR = 1.15, 95% CI = 1.05-1.25; personality: k = 12, OR = 1.26, 95% CI = 1.02-1.54), but not for the psychodynamic theories (k = 4, OR = 1.29, 95% CI = 0.83-1.99). Pooled hazard ratios of the theories were not significant. There were no articles identified for the diathesis-stress theories. To conclude, there is a restricted number of prospective studies, and some evidence that the cognitive, behavioural, and personality-based theories indeed partially account for depressive relapse.
Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the developm... more Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = −0.84, t = −2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.
BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal... more BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.MethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115;Mage=38.9±13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.ResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail (ß=−0.13) and CA1 (ß=−0.09) after adjusting for covariates and multiple testing (adjusted p’s (q)=0.028). ...
A growing number of studies have examined alterations in white matter organization in people with... more A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,049 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,446 individuals with PTSD and 1,603 controls (2152 males/897 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fracti...
It is not clear if treatments for depression targeting repetitive negative thinking (RNT: ruminat... more It is not clear if treatments for depression targeting repetitive negative thinking (RNT: rumination, worry and content-independent perseverative thinking) have a specific effect on RNT resulting in better outcomes than treatments that do not specifically target rumination. We conducted a systematic search of PsycINFO, PubMed, Embase and the Cochrane library for randomized trials in adolescents, adults and older adults comparing CBT treatments for (previous) depression with control groups or with other treatments and reporting outcomes on RNT. Inclusion criteria were met by 36 studies with a total of 3307 participants. At post-test we found a medium-sized effect of any treatment compared to control groups on RNT (g = 0.48; 95% CI: 0.37-0.59). Rumination-focused CBT: g = 0.76, <0.01; Cognitive Control Training: g = 0.62, p < .01; CBT: g = 0.57, p < .01; Concreteness training: g = 0.53, p < .05; and Mindfulness-based Cognitive Therapy: g = 0.42, p < .05 had medium sized...
The aim of this thesis was to gain more insight in the neural network alterations that may underl... more The aim of this thesis was to gain more insight in the neural network alterations that may underlie PTSD and trauma-focused therapy outcome. To investigate TheNeural Web of War brain scans of healthy civilians (n=26), and veterans with (n=58) and without (n=29) PTSD were assessed. Structural and functional connectivity analyses were performed. We showed alterations in connectivity related to PTSD, persistence of PTSD, acquisition method, comorbid depression, deployment and/or military training, and resilience. Furthermore, we found indicators for treatment outcome related changes that occur over the course of treatment. However, it was evident that neural networks do not simply recover after treatment, when a patient recovers from PTSD. Our results do shed light on the psychopathology of PTSD and showed that there are many individual differences that may be related to differences in neural networks, not only the presence of PTSD. Furthermore, we confirmed that PTSD patients were a h...
Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or... more Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or without PTSD. Decreasing HPA-axis reactivity to different stress cues has been reported during PTSD treatment. The cortisol awakening response (CARi) is a well-validated, standardized measure of HPA-axis reactivity which can be easily acquired in the clinical setting. Whether CARi changes over time in traumatized individuals are specific to PTSD treatment is unknown. Furthermore, a possible role for the baseline CARi in predicting symptom reduction after treatment in PTSD has not been examined before. To answer these questions, a cohort study was conducted in which the awakening cortisol was measured in both PTSD (N=41) and non-PTSD (N=25) combat-exposed male subjects. Measurements took place at inclusion and 6-8 months after inclusion for both the PTSD and the non-PTSD group. During the 6-8 months interval, PTSD patients received trauma-focused focused psychotherapy, whereas non-PTSD patients received no treatment. We found a decrease in the CARi over time in both groups, suggesting it was not specific to PTSD or the effect of treatment. Therefore, caution is warranted when attributing diminished HPA-axis reactivity over time to effects of PTSD treatment. Second, CARi prior to treatment predicted PTSD symptom reduction (CAPS score change) after treatment, and accounted for 10% of the variance, even when adjusted for changes in depressive symptoms and medication use during the study period. A putative role emerges for CARi as a predictive biomarker of symptom reduction in male individuals with combat-related PTSD.
Posttraumatic stress disorder (PTSD) is a disabling disorder associated with resting state functi... more Posttraumatic stress disorder (PTSD) is a disabling disorder associated with resting state functional connectivity alterations. However, whether specific brain regions are altered in PTSD or whether the whole brain network organization differs remains unclear. PTSD can be treated with trauma-focused therapy, although only half of the patients recover after treatment. In order to better understand PTSD psychopathology our aim was to study resting state networks in PTSD before and after treatment. Resting state functional magnetic resonance images were obtained from veterans with PTSD (n = 50) and controls (combat and civilian controls; n = 54) to explore which network topology properties (degree and clustering coefficient) of which brain regions are associated with PTSD. Then, PTSD-associated brain regions were investigated before and after treatment. PTSD patients were subdivided in persistent (n = 22) and remitted PTSD patients (n = 17), and compared with combat controls (n = 22), ...
Notorious for degrading diffusion MRI data quality are so-called susceptibility-induced off-reson... more Notorious for degrading diffusion MRI data quality are so-called susceptibility-induced off-resonance fields, which cause non-linear geometric image deformations. While acquiring additional data to correct for these distortions alleviates the adverse effects of this artifact drastically - e.g., by reversing the polarity of the phase-encoding (PE) direction - this strategy is often not an option due to scan time constraints. Especially in a clinical context, where patient comfort and safety are of paramount importance, acquisition specifications are preferred that minimize scan time, typically resulting in data obtained with only one PE direction. In this work, we investigated whether choosing a different polarity of the PE direction would affect the outcome of a specific clinical research study. To address this methodological question, fractional anisotropy (FA) estimates of FreeSurfer brain regions were obtained in civilian and combat controls, remitted posttraumatic stress disorde...
ObjectivesA comprehensive overview of the evidence for factors derived from leading psychological... more ObjectivesA comprehensive overview of the evidence for factors derived from leading psychological theories of the onset of major depressive disorder (MDD) that underpin psychological interventions is scarce . We aimed to systematically investigate the prospective evidence for factors derived from the behavioural, cognitive, diathesis–stress, psychodynamic and personality-based theories for the first onset of MDD.DesignSystematic review and meta-analysis.MethodsDatabases PubMed, PsycINFO, Cochrane and Embase and published articles were systematically searched from inception up to August 2019. Prospective, longitudinal studies that investigated theory-derived factors before the first onset of MDD, established by a clinical interview, were included. Screening, selection and data extraction of articles were conducted by two screeners. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to estimate level of confidence and risk of bias. Meta-analysis w...
ObjectiveTrauma-focused psychotherapy is the first-line treatment for posttraumatic stress disord... more ObjectiveTrauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30-50% of patients do not benefit sufficiently. We investigated whether structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) data could distinguish between treatment responders and non-responders on the group and individual level.MethodsForty-four male veterans with PTSD underwent baseline scanning followed by trauma-focused psychotherapy. Voxel-wise gray matter volumes were extracted from the structural MRI data and resting-state networks (RSNs) were calculated from rs-fMRI data using independent component analysis. Data were used to detect differences between responders and non-responders on the group level using permutation testing, and the single-subject level using Gaussian process classification with cross-validation.ResultsA RSN centered on the bilateral superior frontal gyrus differed between responders and non-responder groups (PFWE <...
Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD)... more Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30–50% of patients do not benefit sufficiently. We investigated whether structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) data could distinguish between treatment responders and non-responders on the group and individual level. Forty-four male veterans with PTSD underwent baseline scanning followed by trauma-focused psychotherapy. Voxel-wise gray matter volumes were extracted from the structural MRI data and resting-state networks (RSNs) were calculated from rs-fMRI data using independent component analysis. Data were used to detect differences between responders and non-responders on the group level using permutation testing, and the single-subject level using Gaussian process classification with cross-validation. A RSN centered on the bilateral superior frontal gyrus differed between responders and non-responder groups (PFWE
Background Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress diso... more Background Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30-50% of patients do not benefit sufficiently. Here, we tested whether resting-state functional magnetic imaging (rs-fMRI) can predict treatment response for individual patients. Methods 44 male veterans with PTSD underwent baseline rs-fMRI scanning followed by trauma-focused therapy (EMDR or TF-CBT). Resting-state networks (RSN) were obtained using independent component analysis with 70 components on the basis of 28 trauma-exposed healthy controls, matched for age and gender. Dual regression was used to obtain subject-specific RSNs for the PTSD patients. All RSNs were individually included in a machine learning classification analysis using Gaussian process classifiers. Classifier performance was assessed using 10 times repeated 10-fold cross-validation. Results Patients were grouped into treatment responders (n = 24) and non-responders (n = 20), based on a 30% decrease in total clinician-administered PTSD scale for the DSM-IV (CAPS) score from pre- to post-treatment assessment. A network centered around the pre-supplementary motor area achieved an average accuracy of 81% (p < 0.001, based on a permutation test, corrected for multiple comparisons across 44 signal components), with a sensitivity of 84.5%, specificity of 77.5%, and area under receiver-operator curve (AUC) of 0.93. Conclusions Rs-fMRI recordings are capable of providing personalized predictions of treatment response in a sample of veterans with PTSD. It therefore has the potential to be useful as a biomarker of treatment response and should be validated in larger independent studies. Supported By ZonMw; AMC; Dutch Ministry of Defense
Background During the last century many biological hypotheses have been postulated to underlie th... more Background During the last century many biological hypotheses have been postulated to underlie the psychopathology of major depressive disorder (MDD). In order to gain insight in the evidence for these hypothesis from patients, a systematical search for longitudinal studies investigating biological factors before the onset of MDD was performed. Methods PubMed, PsychINFO, and Embase were used as databases. The search strategy included terms relating to (1) MDD; (2) a longitudinal design or onset/relapse/recurrence; and (3) potential biomarkers. Current leading biological models for depression were covered, including neuroimaging, neurotransmitters, neurotrophic factors, hormones and immunology. Results PRISMA guidelines were followed and 46830 articles were initially screened, indication 642 relevant articles that were screened on full text. Eventually, 90 articles fulfilled the inclusion criteria. Results were too heterogeneous or limited to perform meta-analyses for the topics: Neuroimaging (n=19), Gut (n=1), Immunology/inflammation (n=5), Neurotrophic (n=1), Neurotransmitters (n=1), Hormones (n=62), Oxidative stress (n=1). A meta analysis was performed for cortisol, which showed that higher cortisol levels predict a 44% higher chance of developing MDD (n=14, OR: 1.44 [1.12-1.84] p = 0.004), but not having a relapse or recurrent episode (n=4, OR: 1.524 [0.801 2.899] p=0.199). Conclusions Surprisingly, although a rigorous systematic search for prospective evidence for biomarkers for depression was performed, we found limited prospective studies investigating leading biological models. Only cortisol could be identified as prospective biomarker for depression onset. More prospective studies are necessary to investigate the causes (and consequences) of depression onset, relapse and recurrence. Supported By NIAS: Netherlands Institute For Advanced Study in the Humanities and Social Sciences (grant for Claudi Bocktings group)
Leading biological hypotheses propose that biological changes may underlie major depressive disor... more Leading biological hypotheses propose that biological changes may underlie major depressive disorder onset and relapse/recurrence. Here, we investigate if there is prospective evidence for biomarkers derived from leading theories. We focus on neuroimaging, gastrointestinal factors, immunology, neurotrophic factors, neurotransmitters, hormones, and oxidative stress. Searches were performed in Pubmed, Embase and PsychInfo for articles published up to 06/2019. References and citations of included articles were screened to identify additional articles. Inclusion criteria were having an MDD diagnosis as outcome, a biomarker as predictor, and prospective design search terms were formulated accordingly. PRISMA guidelines were applied. Meta-analyses were performed using a random effect model when three or more comparable studies were identified, using a random effect model. Our search resulted in 67,464 articles, of which 75 prospective articles were identified on: Neuroimaging (N = 24), Ga...
Psychological factors hypothesized to account for relapse of major depressive disorder (MDD) roug... more Psychological factors hypothesized to account for relapse of major depressive disorder (MDD) roughly originate from five main theories: Cognitive, diathesis-stress, behavioural, psychodynamic, and personality-based. In a meta-analysis we investigated prospective, longitudinal evidence for these leading psychological theories and their factors in relation to depressive relapse. Included studies needed to establish history of MDD and prospective depressive relapse through a clinical interview, have a longitudinal and prospective design, and measure at least one theory-derived factor before relapse. We identified 66 eligible articles out of 43,586 records published up to November 2018. Pooled odds ratios (OR) indicated a significant relationship between the cognitive, behavioural, and personality-based theories and depressive relapse (cognitive: k = 17, OR = 1.24, 95% CI = 1.10-1.40; behavioural, k = 8, OR = 1.15, 95% CI = 1.05-1.25; personality: k = 12, OR = 1.26, 95% CI = 1.02-1.54), but not for the psychodynamic theories (k = 4, OR = 1.29, 95% CI = 0.83-1.99). Pooled hazard ratios of the theories were not significant. There were no articles identified for the diathesis-stress theories. To conclude, there is a restricted number of prospective studies, and some evidence that the cognitive, behavioural, and personality-based theories indeed partially account for depressive relapse.
Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the developm... more Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = −0.84, t = −2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.
BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal... more BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.MethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115;Mage=38.9±13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.ResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail (ß=−0.13) and CA1 (ß=−0.09) after adjusting for covariates and multiple testing (adjusted p’s (q)=0.028). ...
A growing number of studies have examined alterations in white matter organization in people with... more A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,049 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,446 individuals with PTSD and 1,603 controls (2152 males/897 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fracti...
It is not clear if treatments for depression targeting repetitive negative thinking (RNT: ruminat... more It is not clear if treatments for depression targeting repetitive negative thinking (RNT: rumination, worry and content-independent perseverative thinking) have a specific effect on RNT resulting in better outcomes than treatments that do not specifically target rumination. We conducted a systematic search of PsycINFO, PubMed, Embase and the Cochrane library for randomized trials in adolescents, adults and older adults comparing CBT treatments for (previous) depression with control groups or with other treatments and reporting outcomes on RNT. Inclusion criteria were met by 36 studies with a total of 3307 participants. At post-test we found a medium-sized effect of any treatment compared to control groups on RNT (g = 0.48; 95% CI: 0.37-0.59). Rumination-focused CBT: g = 0.76, <0.01; Cognitive Control Training: g = 0.62, p < .01; CBT: g = 0.57, p < .01; Concreteness training: g = 0.53, p < .05; and Mindfulness-based Cognitive Therapy: g = 0.42, p < .05 had medium sized...
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Papers by Mitzy Kennis