Circadian markers as a predictor of response in the treatment of depression-A systematic review.

Despite many available treatment options for depression, response rates remain suboptimal. To improve outcome, circadian markers may be suitable as markers of treatment response. This systematic review provides an overview of circadian markers that have been studied as predictors of response in treatment of depression. A search was performed (EMBASE, PUBMED, PSYCHINFO) for research studies or articles, randomized controlled trials and case report/series with no time boundaries on March 2, 2024 (PROSPERO: CRD42021252333). Other criteria were; an antidepressant treatment as intervention, treatment response measured by depression symptom severity and/or occurrence of a clinical diagnosis of depression and assessment of a circadian marker at baseline. 44 articles, encompassing 8,772 participants were included in the analysis. Although additional research is needed with less variation in types of markers and treatments to provide definitive recommendations, circadian markers, especially diurnal mood variation and chronotype, show potential to implement as response markers in the clinic.

Chronotype, daily affect and social contact: An ecological momentary assessment study.

Eveningness is associated with lower daily positive affect (PA). The relationship between negative affect (NA) and chronotype, however, is less consistent in the literature. Eveningness may be further characterized by increased social isolation, which could explain the associations between chronotype and PA/NA. In the present longitudinal study, we used ecological momentary assessment (EMA) to investigate the associations of chronotype with daily PA, NA, and social contact in individuals with current and remitted major depressive disorder (MDD) and healthy controls. As part of the Netherlands Study of Depression and Anxiety (NESDA), 279 participants (n = 49 depressed, n = 172 remitted, n = 58 controls) monitored daily PA, NA, and social contact (i.e., being alone vs. with others) for two weeks, five times per day. Overall, eveningness was associated with less social contact. This effect became nonsignificant, however, after accounting for sociodemographics (gender, age, education, living situation). Chronotype was not related to PA or NA. Less social contact was associated with lower PA and higher NA independent of chronotype. In conclusion, we could not replicate the finding of lower PA among evening types, but found social contact to associate with both daily PA and NA.

Chronotype changes with age; seven-year follow-up from the Netherlands study of depression and anxiety cohort.

BACKGROUND: Chronotype reflects an individual's optimal daily timing of sleep, activity, and cognitive performance. Previous, cross-sectional, studies have suggested an age effect on chronotype with later chronotypes in adolescents and earlier chronotypes in children and elderly. Additionally, later chronotypes have been associated with more depressive symptoms. Few studies have been able to study longitudinal associations between chronotype and age, while adjusting for depressive symptoms. METHODS: Chronotype was assessed twice with the Munich Chronotype Questionnaire 7 years apart in the Netherlands Study of Depression and Anxiety (T1: N = 1842, mean age (SD): 42.63 years (12.66)) and T2: N = 1829, mean age (SD) 50.67 (13.11)). The longitudinal association between change in age and change in chronotype was tested using a generalized estimated equation analysis adjusted for covariates (including level of depressive symptoms). Using age-bins of 5 years (age at T2), change in chronotype between T1 and T2 was analyzed with Linear Mixed Models. RESULTS: We found a change towards an earlier chronotype with higher age (B (95% CI): -0.011 (-0.014-0.008), p < 0.001). For the age-bins, the difference in chronotype was significant for the 25-29 years age-bin. LIMITATIONS: The sample did not include individuals younger than 19 years or older than 68 years. CONCLUSIONS: In the whole sample chronotype changed towards becoming more morning-type over a period of 7 years, but this change was only significant for those aged 25-29 years. The study was performed in a large naturalistic cohort study with a wide age-range, including patients with a diagnosis of depressive and anxiety disorder and healthy controls.

Personalized ESM monitoring and feedback to support psychological treatment for depression: a pragmatic randomized controlled trial (Therap-i).

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent mental disorder with large disease burden, high levels of relapse or persistence, and overall suboptimal outcomes of protocolized pharmacological and psychotherapeutic treatments. There is an urgent need to improve treatment effectiveness, possibly through systematic treatment personalization. In psychotherapeutic treatments this can be achieved by case conceptualization. To support this process, we developed the Therap-i module, which consists of personalized Experienced Sampling Methodology (ESM) and feedback. The Therap-i module is integrated into outpatient psychotherapeutic treatment as usual (TAU) for depression. The study aim is to investigate the efficacy of the Therap-i module in decreasing symptomatology in unresponsive or relapsing patients diagnosed with MDD. We hypothesize that the Therap-i module will contribute to TAU by i) decreasing depressive symptoms, and ii) improving general functioning, therapeutic working alliance, and illness perception. This paper provides details of the study rationale, aims, procedures, and a discussion on potential pitfalls and promises of the module. METHODS: Patients diagnosed with MDD (n = 100) will enrol in a pragmatic two-armed randomized controlled trial. Randomization is stratified according to the patient's treatment resistance level assessed with the Dutch Method for quantification of Treatment Resistance in Depression (DM-TRD). All fill-out the Inventory of Depressive Symptomatology Self Report (IDS-SR), Outcome Questionnaire (OQ-45), Illness Perception Questionnaire Mental Health (IPQ-MH), and Work Alliance Inventory Self Report (WAI-SR). In the intervention arm, through close collaboration between patient, clinician, and researcher, a personalized ESM diary is developed based on the patient's case conceptualization. During the ESM monitoring period (8 weeks, 5 assessments/day), patients receive feedback three times, which is discussed among the abovementioned three parties. Both patients and clinicians will evaluate the Therap-i module. RESULTS: Data collection is ongoing. DISCUSSION: This is the first study in which personalized ESM and feedback is integrated in outpatient psychotherapeutic TAU for depression. The labour intensive procedure and methodological pitfalls are anticipated challenges and were taken into account when designing the study. When hypotheses are confirmed, the Therap-i module may advance treatment for depression by providing insights into personalized patterns driving or perpetuating depressive complaints. TRIAL REGISTRATION: Trial NL7190 (NTR7381) , registered prospectively 03-08-2018.

Affect fluctuations examined with ecological momentary assessment in patients with current or remitted depression and anxiety disorders.

BACKGROUND: There is increasing interest in day-to-day affect fluctuations of patients with depressive and anxiety disorders. Few studies have compared repeated assessments of positive affect (PA) and negative affect (NA) across diagnostic groups, and fluctuation patterns were not uniformly defined. The aim of this study is to compare affect fluctuations in patients with a current episode of depressive or anxiety disorder, in remitted patients and in controls, using affect instability as a core concept but also describing other measures of variability and adjusting for possible confounders. METHODS: Ecological momentary assessment (EMA) data were obtained from 365 participants of the Netherlands Study of Depression and Anxiety with current (n = 95), remitted (n = 178) or no (n = 92) DSM-IV defined depression/anxiety disorder. For 2 weeks, five times per day, participants filled-out items on PA and NA. Affect instability was calculated as the root mean square of successive differences (RMSSD). Tests on group differences in RMSSD, within-person variance, and autocorrelation were performed, controlling for mean affect levels. RESULTS: Current depression/anxiety patients had the highest affect instability in both PA and NA, followed by remitters and then controls. Instability differences between groups remained significant when controlling for mean affect levels, but differences between current and remitted were no longer significant. CONCLUSIONS: Patients with a current disorder have higher instability of NA and PA than remitted patients and controls. Especially with regard to NA, this could be interpreted as patients with a current disorder being more sensitive to internal and external stressors and having suboptimal affect regulation.

Can chronotype function as predictor of a persistent course of depressive and anxiety disorder?

BACKGROUND: The role of chronotype, the individual timing of sleep/activity, has been studied in relation to depressive and anxiety disorders. A cross-sectional association between a depressive episode and evening-type has been identified. However, until now the predicting capacity of chronotype concerning persistence of psychiatric disorders remains unclear. Our aim is to examine whether a later chronotype in patients with a depressive and/or anxiety disorder can serve as a predictor of a persistent course. METHODS: A subsample of patients with a depressive and/or anxiety disorder diagnosis and chronotype data of the longitudinal Netherlands Study of Depression and Anxiety (NESDA) was used. Diagnosis of depressive and anxiety disorders (1-month DSM-IV based diagnosis) were determined at baseline (n = 505). From this group persistence was determined at 2-year (FU2) (persistent course: n = 248, non-persistent course: n = 208) and 4-year follow-up (FU4) (persistent course: n = 151, non-persistent course: n = 264). Chronotype was assessed at baseline with the Munich Chronotype Questionnaire. RESULTS: A later chronotype did not predict a persistent course of depressive and/or anxiety disorder at FU2 (OR (95% CI) = 0.99 (0.83-1.19), P = 0.92) or at FU4 (OR (95% CI) = 0.94 (0.77-1.15), P = 0.57). LIMITATIONS: Persistence was defined as having a diagnosis of depressive and/or anxiety disorder at the two-year and four-year follow-up, patients may have remitted and relapsed between assessments. CONCLUSION: Chronotype, measured as actual sleep timing, of patients with a depressive or anxiety disorder did not predict a persistent course which suggests it might be unsuitable as predictive tool in clinical settings.

Neuroticism's prospective association with mental disorders halves after adjustment for baseline symptoms and psychiatric history, but the adjusted association hardly decays with time: a meta-analysis on 59 longitudinal/prospective studies with 443 313 participants.

BACKGROUND: This meta-analysis seeks to quantify the prospective association between neuroticism and the common mental disorders (CMDs, including anxiety, depression, and substance abuse) as well as thought disorders (psychosis/schizophrenia) and non-specific mental distress. Data on the degree of confounding of the prospective association of neuroticism by baseline symptoms and psychiatric history, and the rate of decay of neuroticism's effect over time, can inform theories about the structure of psychopathology and role of neuroticism, in particular the vulnerability theory. METHOD: This meta-analysis included 59 longitudinal/prospective studies with 443 313 participants. RESULTS: The results showed large unadjusted prospective associations between neuroticism and symptoms/diagnosis of anxiety, depression, and non-specific mental distress (d = 0.50-0.70). Adjustment for baseline symptoms and psychiatric history reduced the associations by half (d = 0.10-0.40). Unadjusted prospective associations for substance abuse and thought disorders/symptoms were considerably weaker (d = 0.03-0.20), but were not attenuated by adjustment for baseline problems. Unadjusted prospective associations were four times larger over short (<4 year) than long (⩾4 years) follow-up intervals, suggesting a substantial decay of the association with increasing time intervals. Adjusted effects, however, were only slightly larger over short v. long time intervals. This indicates that confounding by baseline symptoms and psychiatric history masks the long-term stability of the neuroticism vulnerability effect. CONCLUSION: High neuroticism indexes a risk constellation that exists prior to the development and onset of any CMD. The adjusted prospective neuroticism effect remains robust and hardly decays with time. Our results underscore the need to focus on the mechanisms underlying this prospective association.

Early life adversities and adolescent antisocial behavior: The role of cardiac autonomic nervous system reactivity in the TRAILS study.

In the current study, the role of pre-ejection period (PEP) and respiratory sinus arrhythmia (RSA) was studied in the association between prior adversities and antisocial behavior in adolescence. PEP and RSA task reactivity and recovery to a public speaking task were assessed in adolescents from a longitudinal population-based study (N=624, Mage=16.14 years, 49.2% boys). Perinatal adversities were unrelated to antisocial behavior, but experiencing more stressful adversities between age 0 and 15 was associated with antisocial behavior at age 16 in boys with blunted PEP reactivity and smaller PEP differences from rest to recovery. Number of adversities between age 0 and 15 was associated with antisocial behavior in boys with blunted and girls with heightened RSA reactivity and larger PEP differences from rest to recovery. The association between prior adversities and antisocial behavior were small in effect size and depended upon sex and PEP and RSA reactivity and recovery.

Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study.

Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158) Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158) Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158) Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.

Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study.

Stress early in life is a known risk factor for the development of affective disorders later in life. Epigenetic mechanisms, such as DNA methylation, may have an important role in mediating that risk. Recent epigenetic research reported on the long-term relationship between traumatic stress in childhood and DNA methylation in adulthood. In this study, we examined the impact of various types of stress (perinatal stress, stressful life events (SLEs) and traumatic youth experiences) on methylation of the glucocorticoid receptor gene (NR3C1) in the blood of a population sample of 468 adolescents (50.4% female, mean age 16.1 years). Second, we determined whether stress at different ages was associated with higher NR3C1 methylation. NR3C1 methylation rates were higher after exposure to SLEs and after exposure to traumatic youth experiences. NR3C1 methylation in adolescence was not higher after exposure to perinatal stress. Experience of SLEs in adolescence was associated with a higher NR3C1 methylation, independently of childhood SLEs. We demonstrate that not only traumatic youth experiences but also (more common) SLEs are associated with higher NR3C1 methylation. In addition, our findings underline the relevance of adolescent stress for epigenetic changes in the NR3C1 gene.

Negative and positive life events are associated with small but lasting change in neuroticism.

BACKGROUND: High neuroticism is prospectively associated with psychopathology and physical health. However, within-subject changes in neuroticism due to life experiences (LEs) or state effects of current psychopathology are largely unexplored. In this 2-year follow-up study, four hypotheses were tested: (1) positive LEs (PLEs) decrease and negative LEs (NLEs) increase neuroticism; (2) LE-driven change in neuroticism is partly long-lasting; and (3) partly independent of LE-driven changes in anxiety/depression; and (4) childhood adversity (before age 16 years) moderates the influence of NLEs/PLEs on neuroticism scores in adult life. METHOD: Data came from the Netherlands Study of Depression and Anxiety [NESDA, n = 2981, mean age 41.99 years (s.d. = 13.08), 66.6% women]. At follow-up (T2) we assessed PLEs/NLEs with the List of Threatening Experiences (LTE) over the prior 24 months and categorized them over recent and distant PLE/NLE measures (1-3 and 4-24 months prior to T2 respectively) to distinguish distant NLE/PLE-driven change in trait neuroticism (using the Dutch version of the Neuroticism-Extroversion-Openness Five Factor Inventory, NEO-FFI) from state deviations due to changes in symptoms of depression (self-rated version of the 30-item Inventory of Depressive Symptomatology, IDS-SR30) and anxiety (Beck Anxiety Inventory, BAI). RESULTS: Distant NLEs were associated with higher and distant PLEs with lower neuroticism scores. The effects of distant LEs were weak but long-lasting, especially for distant PLEs. Distant NLE-driven change in neuroticism was associated with change in symptoms of anxiety/depression whereas the effect of distant PLEs on neuroticism was independent of any such changes. Childhood adversity weakened the impact of distant NLEs but enhanced the impact of distant PLEs on neuroticism. CONCLUSIONS: Distant PLEs are associated with small but long-lasting decreases in neuroticism regardless of changes in symptom levels of anxiety/depression. Long-lasting increases in neuroticism associated with distant NLEs are mediated by anxiety/depression.

Evidence for plasticity genotypes in a gene-gene-environment interaction: the TRAILS study.

The purpose was to study how functional polymorphisms in the brain derived neurotrophic factor gene (BDNF val66met) and the serotonin transporter gene linked promotor region (5-HTTLPR) interact with childhood adversities in predicting Effortful Control. Effortful Control refers to the ability to regulate behavior in a goal-directed manner and is an interesting endophenotype for psychopathology because of its heritability and the association of low Effortful Control with both internalizing and externalizing problems. In a longitudinal population-based study Effortful Control was assessed with the parent version of the Early Adolescent Temperament Questionnaire at age 11. Pregnancy and delivery adversities and childhood events were assessed in a parent interview at age 11. Long-term difficulties until age 11 were assessed with a parent questionnaire at age 13.5. Blood or buccal cells were collected at age 16 for genotyping the rs6265 and rs25531 SNPs and the 5-HTTLPR length polymorphism. The study included 1032 complete data sets. Effortful Control was significantly predicted by the interaction between BDNF val66met, 5-HTTLPR and childhood events. The BDNF val66met val/val-5-HTTLPR l'/l' genotype was unaffected by childhood events, while having either at least one BDNF val66met met or 5-HTTLPR s' allele (l'/l'-met-carrier; l'/s'-val/val; s'/s'-val/val) made children sensitive to childhood events. Predictions of Effortful Control by pregnancy and delivery adversities and long-term difficulties were largely independent of genotype. We concluded that the l'/l'-met-carrier, l'/s'-val/val and the s'/s'-val/val genotypes showed greatest plasticity while the l'/l'-val/val genotype was unaffected by childhood events.

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: a gene x environment interaction approach.

AIMS/HYPOTHESIS: Twin and family studies have shown the importance of genetic factors influencing fasting and 2 h glucose and insulin levels. However, the genetics of the physiological response to a glucose load has not been thoroughly investigated. METHODS: We studied 580 monozygotic and 1,937 dizygotic British female twins from the Twins UK Registry. The effects of genetic and environmental factors on fasting and 2 h glucose and insulin levels were estimated using univariate genetic modelling. Bivariate model fitting was used to investigate the glucose and insulin responses to a glucose load, i.e. an OGTT. RESULTS: The genetic effect on fasting and 2 h glucose and insulin levels ranged between 40% and 56% after adjustment for age and BMI. Exposure to a glucose load resulted in the emergence of novel genetic effects on 2 h glucose independent of the fasting level, accounting for about 55% of its heritability. For 2 h insulin, the effect of the same genes that already influenced fasting insulin was amplified by about 30%. CONCLUSIONS/INTERPRETATION: Exposure to a glucose challenge uncovers new genetic variance for glucose and amplifies the effects of genes that already influence the fasting insulin level. Finding the genes acting on 2 h glucose independently of fasting glucose may offer new aetiological insight into the risk of cardiovascular events and death from all causes.

Neuroticism, recall bias and attention bias for valenced probes: a twin study.

BACKGROUND: Prior research on the nature of the vulnerability of neuroticism to psychopathology suggests biases in information processing towards emotional rather than neutral information. It is unclear to what extent this relationship can be explained by genetic or environmental factors. METHOD: The genetic relationship between a neuroticism composite score and free recall of pleasant and unpleasant words and the reaction time on negative probes (dot-probe task) was investigated in 125 female twin pairs. Interaction effects were modelled to test whether the correlation between neuroticism and cognitive measures depended on the level of the neuroticism score. RESULTS: The only significant correlation was between neuroticism and the proportion of recalled unpleasant words (heritability is 30%), and was only detectable at the higher end of the neuroticism distribution. This interaction effect seems to be due to environmental effects that make people in the same family more similar (e.g. parental discipline style), rather than genetic factors. An interesting sub-finding was that faster reaction times for left versus right visual field probes in the dot-probe task suggest that cognitive processing in the right hemisphere is more sensitive to subliminal (biologically relevant) cues and that this characteristic is under substantial genetic control (49%). Individual differences in reaction times on right visual field probes were due to environmental effects only. CONCLUSIONS: There is no evidence that the predisposition of individuals to focus on negative (emotional) stimuli is a possible underlying genetic mechanism of neuroticism.

Farmacogenómica en neurooncología / Pharmacogenomics in neuro-oncology

Introducción y desarrollo. Los protocolos de quimioterapiaen el tratamiento de los tumores cerebrales, como en los deotras localizaciones, emplean moléculas tóxicas para matar célulascancerosas. Pero, al igual que sucede con todos los tratamientoscontra el cáncer, la aparición de efectos secundarios y la ausenciade respuesta son los principales problemas para su eficacia.Su predicción va a ser posible gracias a los avances tecnológicosque se apoyan en la farmacogenómica y farmacoproteómica, dandolugar a la medicina personalizada. Sin embargo, todavía sonpocos los estudios que relacionan moléculas activas para el tratamientode tumores cerebrales y la posibilidad de predecir el porcentajede respuesta y de toxicidad. Conclusiones. El desarrollo denuevas tecnologías basadas en los microarrays de alta densidadestá logrando la identificación de genes cuya presencia permitirápredecir el efecto de determinado protocolo terapéutico. Una vezidentificados, equipos de arrays de baja densidad detectarán exclusivamentelos genes que pueden intervenir en la capacidad derespuesta del paciente y la posibilidad de presentar cuadros tóxicos.Otras técnicas sofisticadas en fase más experimental, que sebasan en el estudio de proteínas (proteómica), como las MALDI(Matrix-Assisted Laser Desorption Ionization) y las SELDI (Surface-Enhanced Laser Desorption Ionization), permitirán reconocerproteínas asociadas a la predicción de respuesta y de toxicidad

Introduction and development. Chemotherapy protocols for treatment of brain tumors use toxic molecules forkilling cancer cells in a similar way that protocols for treating other cancers. Therefore, secondary effects and poor responseare the major handicaps. Technological developments based on pharmacogenomics and pharmacoproteomics will predictresponse and toxicity giving rise to a personalized medicine. However, there are only few studies that correlate chemotherapeuticalmolecules for brain tumor treatment and prediction of response and toxicity. Conclusions. The development ofnew technologies based on high-density microarrays allows the progressive identification of genes whose presence will predictthe efficacy of therapeutic protocols. Once identified, specific equipments based on low-density arrays will detect exclusivelyin an easy and fast way the presence of genes in order to predict patient’s response and avoid toxicity. Other moresophisticated techniques at present still at an experimental step based on proteomics as MALDI (Matrix-Assisted LaserDesorption Ionization) and SELDI (Surface-Enhanced Laser Desorption Ionization) will allow the identification of proteinsthat could predict response and toxicity

Role of VEGF in an experimental model of cortical micronecrosis.

Vascular endothelial growth factor (VEGF) is a major mediator in angiogenesis and vascular permeability. In central nervous system (CNS) it plays a pivotal role as: 1. inductor of endothelial cell proliferation, migration and inhibition of apoptosis, and 2. mediator of vascular permeability and subsequently of brain edema. This ubiquitous epiphenomenon is a major complication in several CNS pathologies, including head trauma and stroke. After brain injury the expression of VEGF is increased contributing to disruption of the blood brain barrier (BBB). VEGF increase the permeability of BBB via the synthesis/release of nitric oxide and subsequent activation of soluble guanylate cyclase. The immunohistochemistry shows an increase of stained astrocytes and endothelial cells around cortical micronecrosis. VEGF immunopositivity distribution shows some correspondence with the blood brain barrier breakdown following a cortical micronecrosis.