Five-year follow-up of the iBerry Study: screening in early adolescence to identify those at risk of psychopathology in emerging adulthood.

The iBerry Study, a Dutch population-based high-risk cohort (n = 1022) examines the transition from subclinical symptoms to psychiatric disorders in adolescents. Here, we present the first follow-up measurement, approximately 3 years after baseline assessment and 5 years after the screening based on self-reported emotional and behavioral problems (SDQ-Y). We give an update on the data collection, details on the (non)response, and the results on psychopathology outcomes. The first follow-up (2019-2022) had a response rate of 79% (n = 807). Our results at baseline (mean age 15.0 years) have shown the effectiveness of using the SDQ-Y to select a cohort oversampled for the risk of psychopathology. At first follow-up (mean age 18.1 years), the previously administered SDQ-Y remains predictive for selecting adolescents at risk. At follow-up, 47% of the high-risk adolescents showed significant mental health problems based on self- and parent reports and 46% of the high-risk adolescents met the criteria for multiple DSM-5 diagnoses. Compared to low-risk adolescents, high-risk adolescents had a sevenfold higher odds of significant emotional and behavioral problems at follow-up. Comprehensive assessment on psychopathology, substance abuse, psychotic symptoms, suicidality, nonsuicidal self-injury, addiction to social media and/or video gaming, and delinquency, as well as social development, and the utilization of healthcare and social services were conducted. This wave, as well as the ones to follow, track these adolescents into their young adulthood to identify risk factors, elucidate causal mechanisms, and discern pathways leading to both common and severe mental disorders. Results from the iBerry Study will provide leads for preventive interventions.

Adolescent Nonsuicidal Self-Injury and Suicidality: A Latent Class Analysis and Associations with Clinical Characteristics in an At-Risk Cohort.

Nonsuicidal self-injury (NSSI) is frequently encountered in adolescents, but its predictive value for suicidality or other clinical characteristics is challenging due to its heterogeneous nature. This study used latent class analysis to identify subgroups of NSSI and compared these on sociodemographic characteristics, adverse outcomes and protective factors. The study included 966 high-risk adolescents, Mage 14.9 y, SD 0.9 y, 51.8% female. Four classes emerged: (1) "Low NSSI-Low suicidality", (2) "Moderate NSSI-Low suicidality", (3) "Moderate NSSI-High suicidality", and (4) "High NSSI-High suicidality". Girls predominated in the high suicidality classes. Generally, Class 4 had the poorest outcomes: more internalizing and externalizing problems, less social support from friends and families and worst self-esteem. These findings emphasize the need for interventions tailored to specific phenotypes of adolescents engaging in NSSI.

A longitudinal study of mental health in at-risk adolescents before and during the COVID-19 pandemic.

Although cross-sectional studies have shown that the COVID-19 pandemic has negatively affected the mental health of adolescents, the effect of the pandemic on adolescents with pre-pandemic symptoms is unclear. We, therefore, tested the hypothesis that adolescents had increased emotional and behavioral problems during the lockdowns imposed during the pandemic.This study included three measurements in a prospective cohort of 1022 adolescents who were oversampled based on their high risk of developing psychopathology. Before the pandemic, we assessed depressive, anxiety, stress, oppositional defiant problems, psychotic experiences and suicidality, using the Youth Self-Report; 445 and 333 of these 1,022 adolescents subsequently completed the online questionnaire in the first lockdown (in April 2020) and in the second lockdown (in January 2021), respectively. Multilevel random intercept regression models were used to determine the change in psychiatric symptoms, including an interaction term to assess whether these changes differed based on the severity of symptoms prior to the pandemic. Throughout the pandemic, the majority of the participating adolescents reported having emotional and behavioral symptoms that were within the normal range. Moreover, the mean symptom scores for all six outcomes decreased significantly among adolescents with high clinical severity prior to the pandemic.In contrast to our original hypothesis, the effects of the COVID-19 pandemic may not necessarily be detrimental, at least among a specific subgroup of adolescents with pre-existing mental health problems. Moreover, our finding that most adolescents in this at-risk sample did not report experiencing clinically relevant symptoms during the pandemic reflects their resilience during the pandemic.

A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells.

Progress in elucidating the molecular and cellular pathophysiology of neuropsychiatric disorders has been hindered by the limited availability of living human brain tissue. The emergence of induced pluripotent stem cells (iPSCs) has offered a unique alternative strategy using patient-derived functional neuronal networks. However, methods for reliably generating iPSC-derived neurons with mature electrophysiological characteristics have been difficult to develop. Here, we report a simplified differentiation protocol that yields electrophysiologically mature iPSC-derived cortical lineage neuronal networks without the need for astrocyte co-culture or specialized media. This protocol generates a consistent 60:40 ratio of neurons and astrocytes that arise from a common forebrain neural progenitor. Whole-cell patch-clamp recordings of 114 neurons derived from three independent iPSC lines confirmed their electrophysiological maturity, including resting membrane potential (-58.2±1.0 mV), capacitance (49.1±2.9 pF), action potential (AP) threshold (-50.9±0.5 mV) and AP amplitude (66.5±1.3 mV). Nearly 100% of neurons were capable of firing APs, of which 79% had sustained trains of mature APs with minimal accommodation (peak AP frequency: 11.9±0.5 Hz) and 74% exhibited spontaneous synaptic activity (amplitude, 16.03±0.82 pA; frequency, 1.09±0.17 Hz). We expect this protocol to be of broad applicability for implementing iPSC-based neuronal network models of neuropsychiatric disorders.

Need analysis for a new high acuity medical psychiatry unit: which patients are considered for admission?

BACKGROUND: The study aims were: to estimate the proportion of patients with an indication for admission to a new high acuity Medical Psychiatric Unit (MPU), to explore the reasons for MPU-admission according to different health disciplines, and to check for differences in patient characteristics. The results of this study are to be utilized in the proposed establishment of a high-acuity MPU in a University Medical Center. Such a unit currently does not exist at Erasmus MC. METHODS: Hospital in-patients were included if they received psychiatric consultation from the Psychiatric Consultative Service (PCS). As part of the study protocol, psychiatrists, other medical specialists, and nurses determined the need for admission to the proposed MPU. Patient groups were compared with respect to diagnoses, socio-demographic characteristics and patient routing. RESULTS: One hundred and fifty-one patients were included, 43% had an indication for MPU-admission, for the other patients PCS involvement was sufficient. There was agreement on suicide attempts as a reason for MPU-admission. For psychiatrists, the need for further diagnostic evaluation was a common reason for MPU admission, while other medical specialists more often emphasized the need for safety measures. Patients with an unplanned hospital admission had a higher chance of MPU eligibility (OR = 2.72, 95% CI 1.10-6.70). The main psychiatric diagnoses of MPU-eligible patients were organic disorders (including delirium), mood disorders, and disorders related to substance abuse. The most common diagnoses found were similar to those in previous research on MPU populations. CONCLUSION: Different medical disciplines have different views on the advantages of MPUs, while all see the need for such facilities. The proposed MPU should be able to accommodate patients directly from the Emergency Unit, and the MPU should provide specialized diagnostic care in an extra safe environment.

A randomized clinical trial comparing two two-phase treatment strategies for in-patients with severe depression.

OBJECTIVE: To compare the efficacy of two antidepressant treatment strategies in severely depressed in-patients, that is, imipramine vs. venlafaxine, both with subsequent lithium addition in non-responders. METHOD: In-patients (n = 88) with major depressive disorder were randomized to 7-week treatment with imipramine or venlafaxine (phase I). All non-responders (n = 44) received 4-week plasma level-targeted dose lithium addition (phase II). Efficacy was evaluated after 11 weeks of treatment. RESULTS: Analyzing phases I and II combined, non-inferiority was established and the difference in the proportion of responders (HAM-D score reduction ≥50%) by the end of phase II demonstrated the venlafaxine-lithium treatment strategy to be significantly superior to the imipramine-lithium treatment strategy (77% vs. 52%) (χ2 (1) = 6.03; P = 0.01). Regarding remission (HAM-D score ≤ 7), 15 of 44 (34%) patients in the imipramine-lithium treatment group were remitters compared to 22 of 44 (50%) patients in the venlafaxine-lithium treatment group, a non-significant difference. Patients in the venlafaxine-lithium treatment group had a non-significant larger mean HAM-D score reduction compared with patients in the imipramine-lithium treatment group (16.1 vs. 13.5 points, respectively; Cohen's d = 0.30). CONCLUSION: The venlafaxine-lithium treatment strategy can be considered a valuable alternative for the imipramine-lithium treatment strategy in the treatment of severely depressed in-patients.

A common polymorphism in the ABCB1 gene is associated with side effects of PGP-dependent antidepressants in a large naturalistic Dutch cohort.

The drug efflux transporter permeability glycoprotein (PGP) and cytochrome P450 (CYP) 2C19 are important for eliminating antidepressants from the brain and body. The ABCB1 gene, encoding for PGP, and CYP2C19 gene have several variants that could influence enzyme function and thereby the effect of PGP- and 2C19-dependent antidepressants. We investigated the association of antidepressant side effect and common genetic variation in 789 antidepressant users. In PGP-dependent antidepressant users, the A-allele of the rs2032588 single-nucleotide polymorphism (SNP) was associated with a lower number of side effects after adjusting for gender, age, dosage and duration of use, (B=-0.44, q=4.6 × 10(-3)). This association was different from and absent in non-PGP-dependent antidepressant users. Other SNP associations as well as an interaction analysis between the rs2032588 SNP and the CYP2C19 SNPs were not statistically significant after adjusting for covariates and multiple comparisons. The association of rs2032588 with antidepressant side effects suggests the involvement of the ABCB1 genotype in the clinical pharmacology of PGP-dependent antidepressants.

Associations between the urban environment and psychotic experiences in adolescents.

OBJECTIVE: In 2050 two-thirds of the world's population is predicted to live in cities, which asks for a better understanding of how the urban environment affects mental health. Urbanicity has repeatedly been found to be a risk factor, in particular for psychosis. Here, we explored what factors of the urban exposome underlie the association between urban characteristics and psychotic experiences (PE) in adolescents. METHODS: Participants were 815 adolescents (mean age 14.84 years, SD 0.78) from an at-risk cohort (greater Rotterdam area, the Netherlands) oversampled on their self-reported emotional and behavioral problems. We used linear regression analysis to examine the association with detailed geodata on urbanicity (surrounding address density), green space density (high and low vegetation), and mixed noise levels (road, rail, air, industry, and wind power) with PE in adolescents. Analyses were adjusted for multiple socio-economic and parental confounders. Furthermore, we explored sex-interaction effects. RESULTS: Higher surrounding address density and low greenspace density were each independently associated with more PE (B = 0.18, 95 % CI 0.02; 0.34 and B = 0.17, 95 % CI 0.01; 0.32, respectively). High mixed noise levels were only associated with more PE in boys (B = 0.23, 95 % CI 0.01; 0.46). A sex-interaction effect was found for high urbanicity (B = -0.46, 95 % CI -0.77; -0.14) and low greenspace density (B = -0.49, 95 % CI -0.73; -0.11), illustrating that these associations with PE were specific for boys. CONCLUSION: Multiple characteristics of living in an urban area are associated with more PE in adolescent boys. Our observations provide leads for prevention of mental health problems via urban designing.

[Chronotherapy for affective disorders]. / Chronotherapie bij stemmingsstoornissen.

BACKGROUND: In the literature there is increasing interest in the chronobiology of affective disorders and in the most important chronotherapies for treating these disorders. AIM: To discuss the background to and the main features of the most important therapies for affective disorders. METHOD: Using PubMed, we performed a concise review of the literature on the use of chronotherapeutics in affective disorders and we also studied the standard textbooks on the subject. RESULTS: Light therapy is the type of chronotherapy that has been studied most. Chronotherapies show interesting and promising results in open label studies, but so far there have been no randomized double-blind placebo controlled trials. CONCLUSION: Chronotherapeutics provides a neurobiological model and a series of promising, possibly effective non-pharmacological therapies, particularly for affective disorders. Light therapy deserves to be included in the multidisciplinary treatment guidelines relating to affective disorders. However, more, better and longer trials are needed in order to evaluate the various types of chronotherapies.

[Behavioural standard or coercive measure? Some considerations regarding the special issue on ROM]. / ROM: gedragsnorm of dwangmaatregel? Overwegingen bij het themanummer over routine outcome monitoring.

BACKGROUND: The cost of mental health care has possibly risen more than costs in other sectors of health care in the Netherlands. In an attempt to control the rising costs, new policies have been implemented that include the introduction of selective financial penalties for those in need of mental health care as well as the start of performance-based mental health care reimbursement. In order to achieve the latter goal, a nation-wide large-scale data collection was introduced based on clinical routine outcome monitoring (ROM) data, with a view to using these data for benchmarking. AIM: Closer inspection of the benchmarking efforts in terms of scientific validity. METHOD: Qualitative review and analysis. RESULTS: Analysis shows that the type of ROM data that is collected in the Netherlands is valid for tracking the outcomes of individual patients, but unsuitable for performance comparisons between institutions for reasons of case-mix, instrument-mix, bias and lack of sensitivity. CONCLUSION: Attempts to introduce benchmarking based on rom will probably have a negative impact on the practice of mental health care in the Netherlands. More input from mental health professionals and scientists is required in order to identify more rational and efficient ways of spending scarce resources.

Moving Beyond the Status Quo of Integrated Inpatient Medical and Psychiatric Care Units: The Path to Real-World Evaluation.

Integrated inpatient medical and psychiatric care units (IMPUs) are hospital wards that care for inpatients with both acute general medical and psychiatric disorders. IMPU development has stalled, and wide variation in IMPU designs may reflect the fact that IMPUs are still in an early evolutionary stage. High-quality evidence concerning the costs and effectiveness of IMPUs is sparse, because IMPUs do not lend themselves well to traditional evidence-based medicine methods. As a result, most studies of IMPUs have been only observational. Therefore, it is time for a different approach, in which goals for IMPUs are explicitly formulated and IMPU research is incorporated into evidence-based practice (EBP) instead of evidence-based medicine. EBP can be viewed as integrating best available evidence into organizational practices by using four pillars of evidence: organizational, experiential, stakeholder, and scientific. Such types of evidence require an investment in describing the field more precisely. When pragmatic reasoning, where clinical expertise and organizational needs determine IMPU designs, is replaced with EBP, researchers can more effectively perform studies that may convince health care policy makers that IMPUs represent a cost-effective way to improve patients' health and that they increase the well-being of both patients and hospital staff.

DEcrease STress through RESilience training for Students (DESTRESS) Study: Protocol for a randomized controlled trial nested in a longitudinal observational cohort study.

INTRODUCTION: Chronic stress and burnout are highly prevalent among academically trained healthcare professionals, negatively affecting their well-being and capacity to engage in their work. Resilience to stress develops early in one's career path, hence offering resilience training to university students in these professions is one approach to fostering well-being and mental health. The aim of this study is to assess whether offering mindfulness-based resilience training to university students in healthcare professions reduces their perceived chronic stress. METHODS AND ANALYSIS: The study has a hybrid design combining a longitudinal observational cohort with a nested randomized controlled trial (RCT) with sequential multiple assignment and multistage adaptive interventions while taking participants' preferences into account. All students in healthcare related programmes at the Erasmus University Rotterdam are invited to participate. Within the observational cohort, students with a score of 14 or higher on the Perceived Stress Scale (PSS) are invited to take part in the RCT (n = 706). Eligible participants are randomized to control or active intervention in a ratio of 1:6. Those randomized to the control group and non-randomized participants in the cohort receive passive web-based psychoeducation about chronic stress and burnout through referral to specific websites. Participants randomized to the intervention group receive one of 8 active mindfulness-based interventions. They select a rank order of 4 preferred interventions and are randomized across these with equal probability. Non-response to the intervention is followed by sequential randomized assignment to another intervention, for a total maximum of 3 sequential interventions. All participants receive questionnaires at baseline, before and after each 8-week intervention period, and at 1- and 2-year follow-up. The primary outcome is perceived chronic stress measured with the PSS. Secondary outcomes include mental well-being, burnout, quality of life, healthcare utilization, drug use, bodyweight, mental and physical stress-related symptoms, resilience, and study progress. ETHICS AND REGISTRATION: Approval from the Medical Ethics Review Committee was obtained under protocol number MEC-2018-1645. The trial is registered in the Netherlands National Trial Register by registration number NL7623, 22/03/2019, https://www.trialregister.nl/.

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment.

Major depressive disorder is a chronic disabling disease, often triggered and exacerbated by stressors of a social nature. Hippocampal volume reductions have been reported in depressed patients. In support of the neurogenesis theory of depression, in several stress-based animal models of depression, adult hippocampal neurogenesis was reduced and subsequently rescued by parallel antidepressant treatment. Here, we investigated whether repeated social defeat and subsequent individual housing for 3 months induces long-lasting changes in adult hippocampal neurogenesis in rats, and whether these can be normalized by late antidepressant treatment, as would match human depression. Neurogenesis was analysed by stereological quantification of the number of immature doublecortin (DCX)-immunopositive cells, in particular young (class I) and more mature (class II) DCX(+) cells, to distinguish differential effects of stress or drug treatment on these subpopulations. Using this social defeat paradigm, the total DCX(+) cell number was significantly reduced. This was most profound for older (class II) DCX(+) cells with long apical dendrites, whereas younger, class I cells remained unaffected. Treatment with the broad-acting tricyclic antidepressant imipramine, only during the last 3 weeks of the 3-month period after social defeat, completely restored the reduction in neurogenesis by increasing both class I and II DCX(+) cell populations. We conclude that despite the lack of elevated corticosterone plasma levels, neurogenesis is affected in a lasting manner by a decline in a distinct neuronal population of more mature newborn cells. Thus, the neurogenic deficit induced by this social defeat paradigm is long-lasting, but can still be normalized by late imipramine treatment.

Policy and Practice Review: A First Guideline on the Use of Pharmacogenetics in Clinical Psychiatric Practice.

Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.

Prenatal maternal psychopathology and stress and offspring HPA axis function at 6 years.

OBJECTIVE: Intrauterine exposures such as maternal psychopathology and stress are known to influence the physical and mental health of the offspring. One of the proposed pathways underlying these associations is dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity in the offspring. This study examined the relation of perinatal maternal symptoms of psychopathology and stress with offspring HPA axis activity at 6 years as measured by hair cortisol and cortisone concentrations. METHODS: The study was part of the population-based Generation R Study, a prospective population-based cohort from fetal life onwards. 2546 children and their mothers formed the study population. Perinatal maternal psychopathology and stress were assessed by questionnaires in the second and third trimester. Principal components for both psychopathology and stress were created to reduce the number of explanatory variables. Child hair samples for cortisol and cortisone measurements were collected at the age of 6. Linear regression analysis, adjusted for covariates, was used to examine associations between maternal psychopathology and stress and child hair cortisol and cortisone levels. RESULTS: The maternal psychopathology principal component was associated with higher child hair cortisone (adjusted B = 0.24, 95%CI 0.08;0.40, p-value < 0.01). Effect estimates of the individual dimensions ranged from 0.97 (95%CI 0.21;1.73, p-value = 0.01) for interpersonal sensitivity to 1.67 (95%CI 0.86;2.47, p-value < 0.01) for paranoid ideation. In addition, children exposed to intrauterine stress, as measured by the principal component, had higher hair cortisone levels (adjusted B = 0.54, 95%CI 0.21;0.88, p-value < 0.01). Exposure to maternal psychopathology and stress was not associated with offspring hair cortisol. Stratification by child sex resulted in associations between maternal symptoms of psychopathology during pregnancy and child hair cortisone levels in boys and associations between maternal symptoms of stress during pregnancy and child hair cortisone levels in girls. CONCLUSION: Our results suggest that maternal psychopathology and stress during pregnancy are associated with long-term HPA axis activity of the offspring. The association of maternal psychopathology and stress during pregnancy with offspring hair cortisone levels is a novel finding. Future studies should examine whether these psychophysiological differences between exposed and non-exposed children underlie offspring morbidity associated with maternal psychopathology and stress during pregnancy.

Inflammatory markers in late-life depression: results from a population-based study.

BACKGROUND: Previous studies have reported conflicting results concerning the association between several inflammatory markers and depression. The association between inflammation and depression may depend on the presence of specific chronic diseases or be relevant in specific sub-groups of depressed patients only. OBJECTIVE: To assess associations between inflammatory markers and depression in older people, taking account of confounding and effect-modifying factors. METHOD: Population-based study of 1285 participants of the Longitudinal Aging Study Amsterdam, aged 65 and over. Plasma concentrations of Interleukin-6 (IL-6) and C-reactive protein (CRP) were measured. Major depression (first- or recurrent episode) and sub-threshold depression were assessed. Associations were adjusted for confounding variables. Associations with inflammatory markers were further studied with regard to severity and duration of depression, and with regard to specific depressive symptoms. RESULTS: High levels of IL-6 (above 5 pg/mL) were associated with major depression (odds ratio 2.49 (1.07-5.80), both in recurrent and first episodes. No significant effect of either one of the markers on specific symptom dimensions of depression was found. Mildly elevated plasma levels of CRP (above 3.2 mg/L) were associated with higher CES-D scores, but not after correction for the confounding effect of age and chronic diseases. LIMITATIONS: The cross-sectional design limits conclusions regarding causality. CONCLUSIONS: A high plasma level of IL-6, but not CRP, is associated with an increased prevalence of major depression in older people, independent of age, chronic diseases, cognitive functioning and anti-depressants. Present results suggest new directions for clinical research into the prevention of physical consequences of depression.

The neural correlates of verbal encoding and retrieval in monozygotic twins at low or high risk for depression and anxiety.

Emotional processing and brain activation were examined during an encoding and recognition paradigm using emotionally salient words in a sample of monozygotic twin pairs at low or high risk for anxiety and depression. Discordant twin pairs were used to chart the effects of environmental risk factors and concordant twin pairs were used to chart the effects of genetic risk factors on performance and brain activation. Performance data did not support the existence of a negative response bias in subjects at high risk. At the neural level, however, increased left inferior frontal gyrus (LIFG) activation by negative words was found in high-risk subjects, most prominently during recognition. Increased LIFG activity was found in subjects at high risk through either genetic or environmental risk factors. These results suggest that fMRI activation of the LIFG in a verbal emotional memory task may be a useful vulnerability marker for anxiety and depression.

Temporal profiling of depression vulnerability in a preclinical model of sustained depression.

Major Depression is a prevalent mental disorder that is characterized by negative mood and reduced motivation, and frequently results in social withdrawal and memory-related deficits. Repeated stressors, such as adverse life events, increase the risk for development of the disorder. Consequently, individual variability in stress response greatly weighs on depression-vulnerability and -resilience. Here, we employed the social defeat-induced persistent stress (SDPS) paradigm to identify depression-prone individuals and to examine the temporal development of depression in the months following exposure to brief defeat stress. Male Wistar rats were socially defeated (5 defeat episodes) and single-housed for a prolonged period of time (~24 weeks). We assessed the emergence of a sustained depressive-like state by repeatedly evaluating social motivation (social approach avoidance) and spatial memory (object place recognition) in SDPS rats during the isolation period. Individual variability in the effects of SDPS yielded two extreme subpopulations: an SDPS-prone group that showed gradual affective and cognitive deterioration in terms of social approach and memory retention, and a SDPS-resilient group that did not develop this phenotype. Notably, in SDPS-prone individuals, the affective deficits preceded later cognitive impairments, providing a novel temporal profile of the development of pathology in this preclinical model of sustained depression.

Low-grade inflammation predicts persistence of depressive symptoms.

RATIONALE: Evidence suggests that depression is cross-sectionally and longitudinally associated with activation of inflammatory response system. A few studies, however, have investigated the longitudinal relationship between raised inflammatory biomarkers and persistence of depressive symptoms. We examined the temporal relationship between serum levels of inflammatory biomarkers and persistence of depressive symptoms among older participants. METHODS: Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms at baseline and at 5-year follow-up in 656 participants (233 men, 423 women) aged >60 years of the Rotterdam Study. Markers of inflammation interleukin (IL)-6, alpha-1-antichymotrypsin (ACT) and C-reactive protein (CRP) were assessed at baseline, and all participants taking antidepressant medications were excluded from the analysis. RESULTS: No cross-sectional association was found between IL-6, ACT and CRP with depressive symptoms at baseline. However, higher levels of IL-6 and CRP predicted depressive symptoms at 5-year follow-up. Adjustment for confounding variables had no impact on the observed associations. Similarly, a positive association was found between baseline levels of IL-6 (OR = 2.44, p = 0.030) and CRP (OR = 1.81, p = 0.052) and persistence of depressive symptoms over 5 years. CONCLUSION: Our data suggest that dysregulation of the inflammatory response system is associated with a more severe form of depression more likely to re-occur.

Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer's disease.

Pathological, genetic and epidemiological studies support the opinion that inflammatory mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recent pathological and neuroradiological (PET) data show that activation of microglia is an early pathogenic event that precedes the process of severe neuropil destruction in AD brains. In this paper we review the evidence that inflammatory mediators can play a pathogenic role in some behavioural disorders frequently encountered during the clinical course in AD patients. Motivational disturbances are the most striking of the depressive symptoms in AD and can be present in a preclinical stage of the disease. Experimental animal studies and clinical trials in humans have shown that cytokines can induce similar symptoms which were described as 'sickness behaviour' or 'depressive-like' state. Delirious states are frequently observed in more advanced stages of dementia. Delirium is generally considered the result of an imbalance in neurotransmitter systems with severe deficits of the cholinergic systems. Animal studies show that pro-inflammatory cytokines, such as interleukin-1, induce a reduced activity of the cholinergic system. In AD, the release of cytokines would exacerbate any already existing disturbances in the cholinergic neurotransmission. This could explain the susceptibility of demented patients to delirium provoked by a wide variety of trivial incidents that are accompanied by an acute phase response. The data reviewed in this paper suggest that it could be worthwhile employing a neuroimmunological approach to study at molecular level the pathogenesis of a broad spectrum of behavioural disturbances common in the clinical course of AD patients.