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BackgroundThe deficit accumulation method considers the ageing process underlying frailty as a random accumulation of health deficits.ObjectiveAlthough Adverse Childhood Experiences (ACE) have consistently been associated with the onset of mental disorders and somatic diseases during adolescence and midlife, it remains unknown whether ACE still exert detrimental health effects in late life. Therefore, we examined cross-sectionally and prospectively the association between ACE and frailty among community-dwelling older people.DesignBased on the health-deficit accumulation method, a Frailty Index was calculated with values ≥0.25 considered as frail. ACE were measured by a validated questionnaire. The cross-sectional association was examined by logistic regression among 2,176 community dwelling participants aged 58–89 years. The prospective association was examined by Cox-regression among 1,427 non-frail participants during a 17-year follow-up. Interactions with age and sex were tested and analyses were adjusted for potential confounders.SettingThe present study was embedded in the Longitudinal Aging Study Amsterdam.ResultsACE and frailty were positively associated at baseline (OR = 1.88; 95% CI = 1.46–2.42; P = 0.05). Among non-frail participants at baseline (n = 1,427), ACE interacted with age on the prediction of frailty. Stratified analyses showed that a history of ACE only resulted in a higher hazard rate for the incidence of frailty among those aged ≥70 years (HR = 1.28; P = 0.044).ConclusionEven in the oldest-old, ACE still lead to an accelerated rate of the accumulation of health deficits and therefore contribute to the onset of frailty.

BackgroundInflammation and metabolic dysregulation are age-related physiological changes and are associated with depressive disorder. We tried to identify subgroups of depressed older patients based on their metabolic-inflammatory profile and examined the course of depression for these subgroups.MethodsThis clinical cohort study was conducted in a sample of 364 depressed older (⩾60 years) patients according to DSM-IV criteria. Severity of depressive symptoms was monitored every 6 months and a formal diagnostic interview repeated at 2-year follow-up. Latent class analyses based on baseline metabolic and inflammatory biomarkers were performed. Adjusted for confounders, we compared remission of depression at 2-year follow-up between the metabolic-inflammatory subgroups with logistic regression and the course of depression severity over 2-years by linear mixed models.ResultsWe identified a ‘healthy’ subgroup (n = 181, 49.7%) and five subgroups characterized by different profiles of metabolic-inflammatory dysregulation. Compared to the healthy subgroup, patients in the subgroup with mild ‘metabolic and inflammatory dysregulation’ (n = 137, 37.6%) had higher depressive symptom scores, a lower rate of improvement in the first year, and were less likely to be remitted after 2-years [OR 0.49 (95% CI 0.26–0.91)]. The four smaller subgroups characterized by a more specific immune-inflammatory dysregulation profile did not differ from the two main subgroups regarding the course of depression.ConclusionsNearly half of the patients with late-life depressions suffer from metabolic-inflammatory dysregulation, which is also associated with more severe depression and a worse prognosis. Future studies should examine whether these depressed older patients benefit from a metabolic-inflammatory targeted treatment.

Contains fulltext : 245998.pdf (Publisher’s version ) (Open Access) Objectives: Frailty marks an increased risk for adverse health outcomes. Since childhood trauma is associated with the onset of physical and mental health diseases during the lifespan, we examined the link between childhood trauma and multidimensional frailty. Method: A cross-sectional study embedded in a clinical cohort study (ROM-GPS) of older (>=60 years) patients (n=182) with a unipolar depressive-, anxiety- and/or somatic symptom disorder according to DSM-criteria referred to specialized geriatric mental health care. Frailty was assessed with the Tilburg Frailty Indicator (TFI), comprising a physical, psychological, and social dimension. Physical, sexual and psychological abuse and emotional neglect before the age of 16 years was measured with a structured interview. Results: Of 182 patients, 103 (56.6%) had experienced any childhood trauma and 154 (84.6%) were frail (TFI sum score >=5). Linear regression analyses, adjusted for lifestyle, psychological and physical-health factors, showed that the presence of any type of childhood trauma was not associated with the TFI sum score, however when considered separately, physical abuse was (ß=0.16, p=.037). Regarding the specific frailty dimensions, any childhood trauma was associated with social frailty (ß=0.18, p=.019), with emotional neglect as main contributor. Conclusion: These findings demonstrate a complex link between different types of childhood trauma and multidimensional frailty among older psychiatric patients. Regarding the three dimensions of frailty, social frailty seems most affected by childhood trauma. This may have been underestimated until now and should receive more attention in clinical care and future research. 7 p.

Background The frailty index (FI) is a well-recognized measurement for risk stratification in older people. Among middle-aged and older people, we examined the prospective association between the FI and mortality as well as its course over time in relation to multimorbidity and specific disease clusters. Methods A frailty index (FI) was constructed based on either 64 (baseline only) or 35 health deficits (baseline and follow-up) among people aged ≥ 40 years who participated in LifeLines, a prospective population-based cohort living in the Northern Netherlands. Among 92,640 participants, multivariable Cox proportional hazard models were fitted to study the hazard ratio (HR) of the FI at baseline, as well as for 10 chronic disease clusters for all-cause mortality over a 10-year follow-up. Among 55,426 participants, linear regression analyses were applied to study the impact of multimorbidity and of specific chronic disease clusters (independent variables) on the change of frailty over a 5-year follow-up, adjusted for demographic and lifestyle characteristics. Results The FI predicted mortality independent of multimorbidity and specific disease clusters, with the highest impact in people with either endocrine, lung, or heart diseases. Adjusted for demographic and lifestyle characteristics, all chronic disease clusters remained independently associated with an accelerated increase of frailty over time. Conclusions Frailty may be seen as a final common pathway for premature death due to chronic diseases. Our results suggest that initiating frailty prevention at middle age, when the first chronic diseases emerge, might be relevant from a public health perspective.

Highlights • Therapists were positively surprised by the online capabilities and resilience of older patients to adapt to the online treatment program. Prejudices on limited effectiveness of online psychotherapy in older adults were counteracted. • COVID-19 related social distancing measures appeared to trigger feelings of rejection in patients with borderline personality traits, while it falsely validated indoor behavior of patients with avoidant personality traits. • Patients felt being taken seriously, especially because during the online group sessions they all received detailed comments on their homework (sent by email and discussed online). • Where the non-verbal sessions initially felt relaxing and fun, patients told us that these sessions also stimulated their mutual responsiveness (in schema therapy language ‘facilitated their happy child mode’)., Background – Societal measures in context of the COVID-19 outbreak forced us to transform our schema therapy-based day-treatment for older adults with chronic affective disorders and personality problems into an online program. The objective of this paper is to present first impressions of this transformation. Methods – Using over-the-phone instructions initially, all patients were able to participate with the online therapy program. To reduce screen-time for patients, the non-verbal therapies were shortened. Four patients, aged 64-70 years, started our online program. Results – Therapists were positive about the online capabilities and resilience of patients to adapt to the new situation. Prejudices on limited effectiveness of online psychotherapy were counteracted. Sending homework by email and mail seems to facilitate therapy adherence. Non-verbal therapy could be important to stimulate the online group process. Conclusions – We were positively surprised by the online capabilities of our geriatric mental health care patients and encourage further formal effectiveness studies.

Objective: To study the association between vitamin D levels and frailty, its components and course in a depressed sample. Methods: Baseline and two-year follow-up data from the depressed sample of the Netherlands Study of Depression in Older persons (NESDO), a prospective observational cohort study, were analyzed. The 378 participants (aged 60-93) had a diagnosis of depression according to DSM-IV criteria. Frailty was defined according to Fried's physical phenotype. 25-OH vitamin D measurement was performed by liquid chromatography - tandem mass spectrometry. Linear and logistic regression analyses were performed, adjusted for covariates. Results: Higher vitamin D levels were cross-sectionally associated with lower prevalence of frailty (OR 0.64 [95%-CI 0.45 - 0.90], p = .010), predicted a lower incidence of frailty among non-frail depressed patients (OR 0.51 [95%-CI 0.26 - 1.00], p=.050), and, surprisingly, the persistence of frailty among frail depressed patients (OR 2.82 [95%-CI 1.23 - 6.49], p=.015). Conclusions: In a depressed population, higher vitamin D levels were associated with lower prevalence and incidence of frailty. Future studies should examine whether the favorable effect of low vitamin D levels on the course of frailty can be explained by confounding or whether unknown pathophysiological mechanisms may exert protective effects.

Background: Frailty is an important concept for risk stratification in clinical practice, but it is hardly acknowledged at all in mental healthcare settings. This paper aims to assess the impact of frailty on the course of depression and anxiety, and the impact of these affective disorders on the course of frailty.Methods: Lifelines, a prospective population-based cohort study, evaluated 167,729 people living in the northern Netherlands. Frailty was based on the deficit accumulation model, which resulted in a 60-item frailty index (FI) at baseline and a 35-item FI at baseline and 5-year follow-up. Current depressive and anxiety disorders were assessed with the Mini International Neuropsychiatric Interview according to DSM-IV criteria. Bidirectional associations between frailty and affective disorders were investigated using separate multivariable regression analyses in younger (Results: The FI was associated with the onset of a depressive disorder (younger adults: odds ratio [OR] = 1.12; 95% confidence interval [CI] 1.11–1.13; older adults: OR = 1.13; 95% CI 1.09–1.16) as well as any anxiety disorder (younger adults: OR = 1.10; 95% CI 1.09–1.10; older adults: OR = 1.07; 95% CI 1.04–1.09). The other way around, depressive disorder and anxiety disorders were associated with an accelerated increase of frailty over time (depressive disorder: younger adults: beta [β] = 0.03, p < 0.001; older adults: β = 0.04, p < 0.001; and any anxiety disorder: younger adults: β = 0.02, p < 0.001; older adults: β = 0.01, p < 0.142), although the effect of anxiety disorders was less equivocal among older adults.Conclusions: Affective disorders are reciprocally related to frailty. Results with respect to the impact of anxiety disorders on frailty suggest most impact at lower levels of frailty. Our results might imply that interventions to slow biological aging should be broadened towards younger and middle-aged people as well as non-frail older patients. To develop targeted treatment, future clinical and epidemiologic studies on the underlying pathways of this bidirectional association are needed.

Background Vitamin D deficiency is a universal risk factor for adverse health outcomes. Since depression is consistently associated with low vitamin D levels as well as several adverse health outcomes, vitamin D supplementation may be especially relevant for depressed persons. This review examines the potential benefits of vitamin D for (somatic) health outcomes in randomised controlled supplementation trials for depression. Method Systematic literature search to assess whether adverse health outcomes, such as frailty, falls, or cognitive functioning, were included in vitamin D supplementation trials for depression, and whether these outcomes were affected by supplementation. The revised Cochrane tool for assessing risk of bias in randomised trials was used. Results Thirty-one trials were included. Adverse health outcomes were considered in five studies. Two studies reported some beneficial effect on an adverse health outcome. Conclusions and implications While depressed persons are at increased risk of vitamin D deficiency, supplementation trials hardly addressed the common negative health consequences of low vitamin D levels as secondary outcome measures. Well-designed trials of the effects of vitamin D supplementation in late-life depression should explore whether adverse health outcomes can be prevented or stabilised, and whether depression benefits from this improvement.

Introduction Depressive disorder has been conceptualised as a condition of accelerated biological ageing. We operationalised a frailty index (FI) as marker for biological ageing aimed to explore the bidirectional, longitudinal association between frailty and either depressive symptoms or depressive disorder. Methods A cohort study with 6‐year follow‐up including 377 older (≥60 years) outpatients with a DSM‐IV‐defined depressive disorder and 132 never‐depressed controls. Site visits at baseline, 2 and 6‐year follow‐up were conducted and included the CIDI 2.0 to assess depressive disorder and relevant covariates. Depressive symptom severity and mortality were assessed every 6 months by mail and telephone. A 41‐item FI was operationalised and validated against the 6‐year morality rate by Cox regression (HRFI = 1.04 [95% CI: 1.02–1.06]). Results Cox regression showed that a higher FI was associated with a lower chance of remission among depressed patients (HRFI = 0.98 [95% CI: 0.97–0.99]). Nonetheless, this latter effect disappeared after adjustment for baseline depressive symptom severity. Linear mixed models showed that the FI increased over time in the whole sample (B[SE] = 0.94 (0.12), p, Key Points To disentangle the association between frailty and depression, depression should be diagnosed according to diagnostic criteria, as scores on depression rating scales are confounded by frailtyDepressive disorder is associated with accelerated ageing, as indexed by the frailty index

In the Netherlands, euthanasia or assisted suicide (EAS) in psychiatric disorders is legal in certain circumstances. Guidelines recommend a second opinion to independently check diagnosis and treatment resistance. A 68-year-old patient, diagnosed with bipolar I disorder, with a request for euthanasia because of tiredness, repeated falls and racing thoughts was seen for such a second opinion. Persisting in her wish, her reluctant family and psychiatrist became convinced of euthanasia. Our disagreement with the diagnosis of bipolar I disorder upset her, but she agreed with discontinuation of psychotropic drugs. Her mobility and tiredness improved, whereafter her request for euthanasia evolved into a death wish due to completed life. Intellectual disability and an attention deficit hyperactivity disorder could explain her struggle in life. This case report shows that extending the procedure regarding EAS with an independent psychiatric evaluation is important. For our patient, this second opinion supported her to find meaning in life.

OBJECTIVE: Frailty is a clinical phenotype that predicts negative health outcomes, including mortality, and is increasingly used for risk stratification in geriatric medicine. Similar to frailty, late-life depression is also associated with increased mortality rates. Therefore, we examined whether frailty and frailty-related biomarkers predict mortality among depressed older patients.METHODS: In our study of 378 older patients aged ≥ 60 years with a depressive disorder (DSM-IV criteria), we examined whether frailty predicts time-to-death during a 6-year follow-up using Cox proportional hazard regression analyses adjusted for confounders. Baseline data were collected from 2007 to September 2010. Frailty was defined according to the Fried Frailty Phenotype criteria (muscle weakness, slowness, exhaustion, low activity level, unintended weight loss). Similarly, we examined the predictive value of 3 inflammatory markers, vitamin D level, and leukocyte telomere length and whether these effects were independent of the frailty phenotype.RESULTS: During follow-up, 27 (26.2%) of 103 frail depressed patients died compared with 35 (12.7%) of 275 non-frail depressed patients (P CONCLUSIONS: In late-life depression, frailty identifies older patients at increased risk of adverse negative health outcomes. Therefore, among frail depressed patients, treatment models that include frailty-specific interventions might reduce mortality rates.

Objectives: A systematic review of the relationship between subclinical small vessel disease (SSVD) in the general population and apathy to examine the hypothesis that apathy has a vascular basis. Methods: We searched for studies on associations between apathy and SSVD, operationalized as white matter hyperintensities (WMH) or white matter diffusivity changes, lacunar infarcts, cerebral microbleeds, decreasing cortical thickness, and perivascular spaces, while also peripheral proxies for SSVD were considered, operationalized as ankle brachial pressure index (ABI), intima media thickness, arterial stiffness, cardio-femoral pulse wave velocity, hypertension, or cardiovascular disease. Only eligible retrospective and prospective observational studies conducted in the general population were included. Results: The 14 studies eligible for review examined the associations between apathy and hypertension (3), ABI (1), arterial stiffness (1), cardiovascular disease (2), WMH (3), white matter diffusivity (2), cerebral microbleeds (1), or cortical thickness (3). Arterial stiffness and white matter diffusivity were not related to apathy, while the associations with cortical thickness were contradictory. Cross-sectional studies in the general population did find evidence of apathy being associated with WMH, CM, cardiovascular disease, hypertension, and ABI, and cardiovascular disease was prospectively associated with apathy. The methodologies of the studies reviewed were too heterogeneous to perform meta-analyses. Conclusions: Although more prospective evidence is needed and vascular depression needs to be controlled for, cardiovascular disease, hypertension, and ABI as proxies for SSVD, and WMH and cerebral microbleeds as direct measures of SSVD have been found to be associated with apathy in the general population, supporting the hypothesis of vascular apathy.

Background: Metabolic syndrome (MetS) has been associated with both early- and late-life depression. This study investigated whether baseline MetS and its individual components are associated with the course of depression over six years among older persons with a formal depression diagnosis.Methods: Data were used from 378 older persons with a depressive disorder from the Netherlands Study of Depression in Old age (NESDO) with a 6-year follow-up. A formal depression diagnosis according to DSM-IV-TR criteria was ascertained with the Composite International Diagnostic Interview. Severity of depressive symptoms was assessed with the Inventory of Depressive Symptomatology at 6-month intervals. Metabolic syndrome (MetS) was defined according the modified National Cholesterol Education Programme - Adult Treatment Panel III criteria. Primary outcome was time to remission from depression. We applied cox regression analysis for the primary outcome and linear mixed models for secondary analyses.Results: Neither MetS nor its individual components were associated with time to remission from depression (MetS: HR = 1.03; 95% CI = 0.74 - 1.44; p = 0.85), or with depression severity (MetS: B = 0.02; SE = 0.04; p = 0.64) and course of depressive symptoms (MetS: B = -0.01; SE = 0.01; p = 0.23) over 6-years follow-up.Limitations: Attrition was relatively high (46.8%). Furthermore, we only had information on formal depression diagnosis at baseline, 2-year, and 6-year follow-up.Conclusions: We found no evidence for an effect of baseline presence of metabolic dysregulation on the course of formally diagnosed depression in older persons. Metabolic syndrome in depressed patients should be clinically monitored for other reasons than predicting chronicity or severity of depression.

Background/objectives Aging-related physiological changes like metabolic dysregulation and physical frailty are associated with depression and worsen its prognosis. Since central obesity is a key component of the metabolic syndrome and sarcopenia of physical frailty, we examined the association of sarcopenic obesity with depression cross-sectional and over time. Methods Cohort study of depressed patients and a nondepressed comparison group. Setting Primary and secondary mental health care. Participants Three hundred seventy-eight older (≥60 y) depressed patients of which 285 were followed up at 2 years and 132 nondepressed persons participating in the Netherlands Study of Depression in Older (NESDO) persons. Measurements Sarcopenic obesity was based on predefined cutoffs for both maximum handgrip strength (assessed with a dynamometer) and waist circumference (dichotomous) as well as the product term of handgrip strength by waist circumference (dimensional). Depressive disorder according to DSM-IV-TR criteria was assessed with fully structured psychiatric interview at baseline and 2-year follow-up. Results Sarcopenic obesity was more prevalent among depressed patients compared with nondepressed participants (18.9% versus 10.7%, P = 0.030). Neither the dichotomous nor dimensional operationalization of sarcopenic obesity was associated with baseline depressive disorder when adjusted for covariates. Nonetheless, among depressed patients, logistic regression showed that the interaction of handgrip strength by waist circumference was associated with remitted depression at 2-year follow-up (P = 0.044). Only among patients with a low handgrip strength, a higher waist circumference predicted nonremission. Conclusion Among depressed patients, sarcopenic obesity predicts nonremission of depression. Therefore, combined exercise and nutritional interventions might be effective for depressed patients with sarcopenic obesity.

Contains fulltext : 207225.pdf (Publisher’s version ) (Open Access) BACKGROUND: Affective disorders, encompassing depressive-, anxiety-, and somatic symptom disorders, are the most prevalent mental disorders in later life. Treatment protocols and guidelines largely rely on evidence from RCTs conducted in younger age samples and ignore comorbidity between these disorders. Moreover, studies in geriatric psychiatry are often limited to the "younger old" and rarely include the most frail. Therefore, the effectiveness of treatment in routine clinical care for older patients and impact of ageing characteristics is largely unknown. OBJECTIVE: The primary aim of the Routine Outcome Monitoring for Geriatric Psychiatry & Science (ROM-GPS) - project is to examine the impact of ageing characteristics on the effectiveness of treatment for affective disorders in specialised geriatric mental health care. METHODS: ROM-GPS is a two-stage, multicentre project. In stage one, all patients aged >/=60 years referred to participating outpatient clinics for specialised geriatric mental health care will be routinely screened with a semi-structured psychiatric interview, the Mini International Neuropsychiatric Interview and self-report symptom severity scales assessing depression, generalized anxiety, hypochondria, and alcohol use. Patients with a unipolar depressive, anxiety or somatic symptom disorder will be asked informed consent to participate in a second (research) stage to be extensively phenotyped at baseline and closely monitored during their first year of treatment with remission at one-year follow-up as the primary outcome parameter. In addition to a large test battery of potential confounders, specific attention is paid to cognitive functioning (including computerized tests with the Cogstate test battery as well as paper and pencil tests) and physical functioning (including multimorbidity, polypharmacy, and different frailty indicators). The study is designed as an ongoing project, enabling minor adaptations once a year (change of instruments). DISCUSSION: Although effectiveness studies using observational data can easily be biased, potential selection bias can be quantified and potentially corrected (e.g. by propensity scoring). Knowledge of age-related determinants of treatment effectiveness, may stimulate the development of new interventions. Moreover, studying late-life depressive, anxiety and somatic symptom disorders jointly enables data-driven studies for more optimal classification of these disorders in later life. TRIAL REGISTRATION: Dutch Trial Register: NL6704 ( www.trialregister.nl ). Retrospectively registered on 2017-12-05. 12 p.

Objective: Different biological mechanisms may underlie depression beginning in early life (early-onset) and depression beginning later in life (late-onset). Although the relation between inflammation and depression has been studied extensively, the distinct role of inflammation in early and late-onset depression in older patients has not been addressed before. In the cross-sectional part of this study, we explored differences in levels of circulating inflammatory markers and cytokine levels in lipopolysaccharide (LPS) stimulated whole blood between older subjects with a late-life onset depression (>= 60 years) and older subjects with an early-onset depression (Methods: The study was part of the Netherlands Study of Depression in Older Persons (NESDO). We included 350 patients, all aged 60 and older, with a depressive episode in the previous 6 months: 119 with a late-onset depression and 231 with an early-onset depression. Blood samples were collected and CRP, IL-6, NGAL, GDF15, and, LPS plasma levels were determined and whole blood was LPS stimulated and cytokine levels IL-1 beta, IL-6, TNF alpha, IFN gamma, IL-10, and IL-1 receptor antagonist (IL-ira) were determined.Results: After adjustment for demographics, health indicators, and medication use, increased plasma CRP levels were more strongly associated with late-onset depression than early-onset depression (OR [95% CI]: 1.43 [1.05–1.94]). In the longitudinal analyses, higher circulating IL-6 levels were associated with a significantly slower decline in IDS scores in the crude and the adjusted models (p ≤ 0.027). This relation was not different between late- and early-onset depression. Other circulating and stimulated inflammatory markers were not associated with late- and/or early-onset depression.Conclusions: This study provides preliminary evidence that low-grade inflammation is more strongly associated with late-onset than early-onset depression in older adults, suggesting a distinct inflammatory etiology for late onset depression. Cytokine production capacity did not distinguish between early- and late-onset depression.

Objectives While vitamin D is involved in frailty as well as depression, hardly any study has examined the course of vitamin D levels prospectively. The objective of this study is to examine whether a change of vitamin D in depressed older adults is associated with either depression course, course of frailty, or both. Methods The study population consisted of 232 of 378 older adults (60–93 years) with a DSM‐IV defined depressive disorder participating in the Netherlands Study of Depression in Older persons, a prospective clinical cohort study. Baseline and 2‐year follow‐up data on depressive disorder (DSM‐IV diagnosis), symptom severity (inventory of depressive symptoms), frailty phenotype (and its individual components) and vitamin D levels were obtained. Linear mixed models were used to study the association of change in vitamin D levels with depression course, course of frailty, and the combination. Results Vitamin D levels decreased from baseline to follow‐up, independent from depression course. An increase in frailty was associated with a significantly sharper decrease of vitamin D levels over time. Post hoc analyses showed that this association with frailty might be driven by an increase of exhaustion over time and counteracted by an increase in walking speed. Conclusions Our findings generate the hypothesis that vitamin D supplementation in late‐life depression may improve frailty, which may partly explain inconsistent findings of randomised controlled trials evaluating the effect of vitamin D for depression. We advocate to consider frailty (components) as an outcome in future supplementation trials in late‐life depression., Key Points Change in serum vitamin D is related to the course of frailty, and not independently to depression courseFuture vitamin D supplementation trials in depression should consider frailty (components) as an outcome

Background To examine the mortality risk of current and life-time depressive as well as anxiety disorders, whether this risk is moderated by sex or age, and whether this risk can be explained by lifestyle and/or somatic health status. Methods A cohort study (Lifelines) including 141,377 participants (18–93 years) which were followed-up regarding mortality for 8.6 years (range 3.0–13.7). Baseline depressive and anxiety disorders according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria were assessed with the Mini International Neuropsychiatric Interview and lifetime diagnoses by self-report. All-cause mortality was retrieved from Statistics Netherlands. Cox-regression was applied to calculate proportional hazard ratios, adjusted for lifestyle (physical activity, alcohol use, smoking, and body mass index) and somatic health status (multimorbidity and frailty) in different models. Results The mortality rate of depressive and anxiety disorders was conditional upon age but not on sex. Only in people below 60 years, current depressive and anxiety disorders were associated with mortality. Only depressive disorder and panic disorder independently predicted mortality when all mental disorders were included simultaneously in one overall model (hazard ratio [HR] = 2.18 [95% confidence intervals (CI): 1.56–3.05], p p = 0.020). Life-time depressive and anxiety disorders, however, were independent of each other associated with mortality. Associations hardly changed when adjusted for lifestyle characteristics but decreased substantially when adjusted for somatic health status (in particular physical frailty). Conclusions In particular, depressive disorder is associated with excess mortality in people below 60 years, independent of their lifestyle. This effect seems partly explained by multimorbidity and frailty, which suggest that chronic disease management of depression-associated somatic morbidity needs to be (further) improved.

Highlights • The knowledge of being vulnerable and the involuntary and inescapable self-isolation are both creating anxiety and maybe other psychiatric signs and symptoms. This will be not only in the known psychiatric patients, but also in the general older population. • Psychiatric deterioration of our existing case-load could be a first manifestation of a COVID-19 infection. • In extension to this point, triage of suspected COVID-19 infections is complex in geriatric psychiatric patients, as every week a few older patients in the long-stay units get an infectious disease of all kinds. • In emergency situations as in a quick developing viral infection as with COVID-19, advance care planning is very useful in supporting clinical decision making. • As national policies restrict outpatient care programs, a rapid transformation of individual and group therapy sessions into E-health programs using telephone or video platforms is necessary., The COVID-19 pandemic has changed everyday life tremendously in a short period of time. After a brief timeline of the Dutch situation and our management strategy to adapt geriatric mental health care, we present a case-series to illustrate the specific challenges for geriatric psychiatrists.

Objective: Depression has been associated with increased mortality rates, and modifying mechanisms have not yet been elucidated. We examined whether specific subtypes or characteristics of late-life depression predict mortality. Methods: A cohort study including 378 depressed older patients according to DSM-IV criteria and 132 never depressed comparisons. The predictive value of depression subtypes and characteristics on the six-year mortality rate, as well as their interaction with somatic disease burden and antidepressant drug use, were studied by Cox proportional hazard analysis adjusted for demographic and lifestyle characteristics. Results: Depressed persons had a higher mortality risk than non-depressed comparisons (HR = 2.95 [95% CI: 1.41-6.16], p = .004), which lost significance after adjustment for age, sex, education, smoking, alcohol, physical activity, number of prescribed medications and somatic comorbidity. Regarding depression subtypes and characteristics, only minor depression was associated with a higher mortality risk when adjusted for confounders (HR = 6.59 [95% CI: 1.79-24.2], p = .005). Conclusions: Increased mortality rates of depressed older persons seem best explained by unhealthy lifestyle characteristics and multiple drug prescriptions. The high mortality rate in minor depression, independent of these factors, might point to another, yet unknown, pathway towards mortality for this depression subtype. An explanation might be that minor depression in later life reflects depressive symptoms due to underlying aging-related processes, such as inflammation-based sickness behavior, frailty, and mild cognitive impairment, which have all been associated with increased mortality.

Objective To present up-to-date information and recommendations on the management of body weight changes during the use of antiepileptic mood stabilizers in bipolar disorder to help clinicians and patients make well-informed, practical decisions.Data sources Umbrella review. Systematic reviews and meta-analyses on the prevention, treatment, and monitoring of body weight changes as a side effect of the mood stabilizers valproate, lamotrigine, topiramate, and carbamazepine were identified in Embase (2010-2015, no language restrictions).Study selection The search yielded 18 relevant publications on antiepileptic mood stabilizers and weight changes in bipolar disorder.Data extraction Relevant scientific evidence was abstracted and put into a clinical perspective by a multidisciplinary expert panel of clinicians with expertise in the treatment of bipolar disorders across all age groups and a patient representative.Results Valproate has been proven to be associated with weight gain in up to 50% of its users, and can be detected 2-3 months after initiation. Carbamazepine has been proven to have a low risk of weight gain. Lamotrigine and topiramate are associated with weight loss. Other option for this sentence = Weigth gain has been proven to be associated with valproate use in up to 50% of its users, and can be detected within 2-3 months after initiation.Conclusion Each antiepileptic mood stabilizer has specific effects on body weight and accordingly requires a discrete education, prevention, monitoring, and treatment strategy. Clinicians are recommended to adopt an active, anticipatory approach, educating patients about weight change as an important side effect in order to come to informed shared decisions about the most suitable mood stabilizer.

BackgroundDepression is associated with the metabolic syndrome (MS). We examined whether metabolic dysregulation predicted the 2-year course of clinical depression.MethodA total of 285 older persons (⩾60 years) suffering from depressive disorder according to DSM-IV-TR criteria was followed up for 2 years. Severity of depression was assessed with the Inventory of Depressive Symptomatology (IDS) at 6-month intervals. Metabolic syndrome was defined according the National Cholesterol Education Programme (NCEP-ATP III). We applied logistic regression and linear mixed models adjusted for age, sex, years of education, smoking, alcohol use, physical activity, somatic co-morbidity, cognitive functioning and drug use (antidepressants, anti-inflammatory drugs) and severity of depression at baseline.ResultsMS predicted non-remission at 2 years (odds ratioper component = 1.26, 95% confidence interval 1.00–1.58), p = 0.047), which was driven by the waist circumference and HDL cholesterol. MS was not associated with IDS sum score. Subsequent analyses on its subscales, however, identified an association with the somatic symptom subscale score over time (interaction time × somatic subscale, p = 0.005), driven by higher waist circumference and elevated fasting glucose level.ConclusionsMetabolic dysregulation predicts a poor course of late-life depression. This finding supports the concept of ‘metabolic depression’, recently proposed on population-based findings of a protracted course of depressive symptoms in the presence of metabolic dysregulation. Our findings seem to be driven by abdominal obesity (as indicated by the waist circumference) and HDL cholesterol dysregulation.

Item does not contain fulltext Oral tetrahydrocannabinol (THC) is currently studied for its possible efficacy on dementia-related neuropsychiatric symptoms (NPS), but might lead to increased risk of falling. This was a randomised, double-blind, crossover study to evaluate the effects of THC on mobility in dementia patients. Eighteen community-dwelling patients ( Mage=77 years) received 1.5 mg of oral THC twice daily and placebo, in random order, for three days, separated by a four-day washout. Balance and gait were assessed using SwayStarTM and GAITRiteTM within two hours after administration, in two consecutive intervention periods, under the following conditions: standing with eyes open (EO) and eyes closed (EC), preferred speed walking with and without a cognitive dual task. THC significantly increased sway during standing EC (roll angle 0.32[+/-0.6] degrees , p=0.05; pitch angle 1.04[+/-1.5] degrees , p=0.009; pitch velocity 1.96[+/-3.3] degrees /s, p=0.02), but not during standing EO. During preferred speed walking, THC increased stride length (4.3[+/-5.4] cm, p=0.005) and trunk sway (pitch angle 1.18[+/-1.6] degrees , p=0.005). No effects were observed during dual task walking. No differences in the number and type of adverse events were found, and no falls occurred after administration of THC. This study showed that 3 mg of THC per day has a benign adverse event profile regarding mobility and was well tolerated by community-dwelling dementia patients.

Objective: To study the effect of vitamin D levels on depression course and remission status after two years, as well as attrition and mortality, in an older cohort.Methods: This study was part of the Netherlands Study on Depression in Older persons (NESDO), a prospective cohort study. 367 depressed older persons (>= 60 years) were included. Baseline vitamin D status, reasons for loss to follow up, clinical depression diagnosis at two-year follow up, and six-monthly symptom scores were obtained. Data were analyzed by logistic regression and random coefficient models and adjusted for confounders of vitamin D status.Results: Vitamin D had no effect on the course of depression or remission, except for a trend towards lower remission rates in the severely deficient subgroup (25-(OH) vitamin D Conclusions: For the total sample we found no effect of vitamin D levels on the course of depression or remission rates. However, we did find an effect of lower vitamin D levels on mortality. This strengthens the interpretation of vitamin D deficiency being a marker for poor somatic health status. The trend towards lower remission rates in the severely deficient subgroup raises the question whether this group could benefit from supplementation. Randomized controlled trials are necessary to study this. (C) 2016 Elsevier Inc. All rights reserved.

BackgroundDepression increases the risk of subsequent vascular events in both cardiac and non-cardiac patients. Atherosclerosis, the underlying process leading to vascular events, has been associated with depression. This association, however, may be confounded by the somatic-affective symptoms being a consequence of cardiovascular disease. While taking into account the differentiation between somatic-affective and cognitive-affective symptoms of depression, we examined the association between depression and atherosclerosis in a community-based sample.MethodIn 1261 participants of the Nijmegen Biomedical Study (NBS), aged 50–70 years and free of stroke and dementia, we measured the intima–media thickness (IMT) of the carotid artery as a measure of atherosclerosis and we assessed depressive symptoms using the Beck Depression Inventory (BDI). Principal components analysis (PCA) of the BDI items yielded two factors, representing a cognitive-affective and a somatic-affective symptom cluster. While correcting for confounders, we used separate multiple regression analyses to test the BDI sum score and both depression symptom clusters.ResultsWe found a significant correlation between the BDI sum score and the IMT. Cognitive-affective, but not somatic-affective, symptoms were also associated with the IMT. When we stratified for coronary artery disease (CAD), the somatic-affective symptom cluster correlated significantly with depression in both patients with and patients without CAD.ConclusionsThe association between depressive symptoms and atherosclerosis is explained by the somatic-affective symptom cluster of depression. Subclinical vascular disease thus may inflate depressive symptom scores and may explain why treatment of depression in cardiac patients hardly affects vascular outcome.

OBJECTIVES: To examine the relationship between obesity and depressive symptoms taking into account different measures for obesity (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) and different depressive symptom clusters. DESIGN: Cross-sectional population-based survey. SETTING: Baseline data of the Nijmegen Biomedical Study. PARTICIPANTS: One thousand two hundred eighty-four persons aged 50 to 70. MEASUREMENTS: Obesity (BMI, WC, and WHR) and depressive symptoms were measured, the latter using the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, one representing a cognitive-affective symptom cluster and the other a somatic-affective symptom cluster. Multiple regression analyses corrected for confounders were conducted for each measure of obesity, with separate models testing the BDI sum score and the depression symptom clusters. RESULTS: BMI was significantly associated with BDI sum score (beta=0.12, P

In the original version of this article unfortunately two tables have been missing. By mistake they have been published as Supplementary Material. We apologize for any inconvenience caused. The original article has been corrected.

ObjectiveThe aim of the study was to describe the successful treatment of delirium with electroconvulsive therapy (ECT).MethodsThe method of the study was a case report.ResultsA 75-year-old man, with a recently diagnosed carcinoma of the parotid gland, was admitted with a fluctuating psychiatric syndrome. Delirium was diagnosed, although an acute underlying somatic cause could not be readily established. Antipsychotics and benzodiazepines were not effective. After 7 sessions of ECT, all symptoms ceased. This enabled him to receive radiotherapy for his tumor and enjoy a good quality of life for the remaining 8 months of his life.ConclusionsElectroconvulsive therapy is not only a powerful treatment for catatonia, neuroleptic malignant syndrome, and delirious mania but also for the most commonly occurring fluctuating psychiatric syndrome-delirium.

Item does not contain fulltext OBJECTIVE: Depression predicts stroke; however, meta-analyses show significant heterogeneity. We hypothesize that the risk of depression on incident stroke is conditional upon the relative contribution of vascular disease and of neuroticism in the underlying pathways to depression in a specific patient. We examined whether depression increases stroke in persons with low neuroticism and without preexisting cardiac disease. METHODS: This was a population-based cohort study with 9-year follow-up (n = 2,050; >/=55 years, 52% female). The incidence of stroke was determined by self-report data as well as data from general practitioners and death certificates. Neuroticism was measured using the Dutch Personality Questionnaire and depression using the Center for Epidemiologic Studies-Depression scale. All data were analysed by Cox proportional hazards regression. RESULTS: A total of 117 incident cases of stroke occurred during follow-up. Among persons with a history of cardiac disease (n = 401), depression predicted incident stroke independent of neuroticism level with a hazard ratio (HR) of 1.05 (95% confidence interval [CI] 1.01-1.10) (p = 0.02). In persons without cardiac disease (n = 1,649), depression and neuroticism interacted significantly in predicting incident stroke (p = 0.028). Stratified analyses showed that depression predicted incident stroke in those with low neuroticism, HR 1.05 (95% CI 1.00-1.09) (p = 0.033), but not in those with high neuroticism, HR 1.01 (95% CI 0.96-1.05) (p = 0.82). CONCLUSIONS: In persons without preexistent cardiac disease, depression is only predictive for future stroke in absence of high neuroticism. This might be explained by the hypothesis that late-life depression in context of low neuroticism is a marker of subclinical vascular disease.

Contains fulltext : 136781.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To examine the interplay between subclinical atherosclerotic disease and neuroticism in explaining variance in late-life depressive symptoms. METHODS: This study was part of the Nijmegen Biomedical Study, a population-based survey; 1,517 participants aged 50-70 years were included. Depressive symptoms were measured by the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, representing a cognitive-affective symptom cluster and a somatic-affective symptom cluster. Atherosclerotic disease was measured by the intima media thickness (IMT) of the carotid arteries and neuroticism by the revised Eysenck Personality Questionnaire. RESULTS: Multiple linear regression analyses using different measures of depressive symptoms as the dependent variable showed that neuroticism was strongly and significantly associated with the sum score of the BDI and with the two depressive symptom clusters. IMT, however, was only significantly associated with the somatic-affective symptom cluster but not with the cognitive-affective symptom cluster. Interestingly, we found a significant negative interaction between neuroticism and IMT in explaining the severity of the cognitive-affective symptom cluster but not with respect to the somatic-affective symptom cluster. CONCLUSION: The negative interaction between neuroticism and atherosclerosis indicates that neuroticism is less strongly associated with cognitive-depressive symptoms in the presence of more severe atherosclerosis. This may be explained by apathy due to cerebrovascular disease and fits with a hypothesis of vascular apathy.

Contains fulltext : 136471.pdf (Publisher’s version ) (Open Access) A low plasma 25-OH vitamin D3 level is a universal risk factor for a wide range of diseases and has also been implicated in late-life depression. It is currently unknown whether the biologically active form of vitamin D, that is, 1,25-(OH)2 vitamin D3, is also decreased in late-life depression, or whether vitamin D levels correlate with specific depression characteristics. We determined plasma 25-OH vitamin D3, 1,25-(OH)2 vitamin D3 and parathormone levels in 355 depressed older persons and 124 non-depressed comparison subjects (age 60 years). Psychopathology was established with the Composite International Diagnostic Interview 2.1, together with potential confounders and depression characteristics (severity, symptom profile, age of onset, recurrence, chronicity and antidepressant drug use). Adjusted for confounders, depressed patients had significantly lower levels of 25-OH vitamin D33 (Cohen's d =0.28 (95% confidence interval: 0.07-0.49), P=0.033) as well as 1,25-(OH)2 vitamin D3 (Cohen's d =0.48 (95% confidence interval: 0.27-0.70), P

Item does not contain fulltext Both visceral obesity and depression are associated with impaired health and excess mortality, possibly through overlapping pathophysiological mechanisms like adipose tissue derived inflammatory markers. These results, however, are primarily based on population-based surveys, often restricted to a young population and depression severity scales instead of patients with established diagnosis of depressive disorder. We examined the relation between waist circumference and late-life depression using the baseline data of the Netherlands Study of Depression in Older people (NESDO). Psychopathology has been assessed with Composite International Diagnostic Interview version 2.1. Adjusted for age, sex, education, lifestyle (smoking, alcohol, physical activity), drug use, cognition and chronic diseases as well as adjusted for body mass index (BMI), analysis of covariance showed that depressed older patients (n=376) had a significantly lower waist circumference (WC) compared to their non-depressed comparisons (n=130): estimated marginal mean (SE)=93.9 (0.5) versus 97.8 (0.8) cm (F=15.9; df=1467; p

IntroductionDepression is associated with the metabolic syndrome (MS). Recently, the concept of ‘metabolic depression’ has been proposed based on a protracted course of depressive symptoms over time.Objective and aimsWithin the Netherlands study of depression in older persons, we examined whether metabolic dysregulation predicted the two-year course of depression.MethodsA cohort study (n = 285) of depressed persons (≥60 years) with two-year follow up. Depression was classified according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Severity of depression was assessed with sum score as well as subscale scores of the Inventory of Depressive Symptomatology (IDS) at six-month intervals. The metabolic syndrome was defined according the National Cholesterol Education Program (NCEP-ATP III). We applied logistic regression and linear mixed models adjusted for a wide range of confounders and severity of depression at baseline.ResultsThe number of MS-components predicted non-remission at two-years (OR = 1.28 [95% CI: 1.00–1.58], P = 0.047), which was driven by waist-circumference, HDL-cholesterol and triglycerides. MS was only associated with the somatic symptom subscale score of the IDS over time, but not with its sum score (interaction time × somatic subscale, P = 0.002). This effect was driven by waist circumference, elevated fasting glucose level and hypertension.ConclusionMetabolic dysregulation predicts the course of late-life depression. This effect seems to be driven by visceral obesity (as indicated by the waist circumference) and lipid dysregulations and with respect to the somatic symptoms of depression.Disclosure of interestThe authors have not supplied their declaration of competing interest.

To examine the relationship between obesity and depressive symptoms taking into account different measures for obesity (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) and different depressive symptom clusters.Cross-sectional population-based survey.Baseline data of the Nijmegen Biomedical Study.One thousand two hundred eighty-four persons aged 50 to 70.Obesity (BMI, WC, and WHR) and depressive symptoms were measured, the latter using the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, one representing a cognitive-affective symptom cluster and the other a somatic-affective symptom cluster. Multiple regression analyses corrected for confounders were conducted for each measure of obesity, with separate models testing the BDI sum score and the depression symptom clusters.BMI was significantly associated with BDI sum score (β=0.12, P.001) and the cognitive- (β=0.08, P=.008) and somatic-affective symptom clusters (β=0.10, P=.001). WC (β=0.11, P.001) and WHR (β=0.07, P=.004) were specifically associated with the somatic-affective symptom cluster.Visceral obesity, which is more indicative of vascular risk than BMI, is specifically associated with somatic-affective depressive symptom cluster, which might suggest that these symptoms are primarily due to a (subclinical) somatic condition.

Two elderly patients with dementia-related behavioral problems developed rash, edema, eosinophilia and systemic symptoms after administration of carbamazepine. Drug reaction with eosinophilia and systemic symptoms (DRESS) was diagnosed with some delay. The relevance and complexity of recognizing DRESS are shown. Symptoms occur 1 to 8 weeks after start of carbamazepine, progress slowly and are similar to those in infections and neoplastic disorders. DRESS is a severe and potentially fatal complication, occurring in 1 of every 1000 to 10,000 patients using antiepileptic drugs. Treatment consists of immediate withdrawal of the offending drug, while reexposure should be avoided. First-degree relatives need to be informed about being at increased risk. (C) 2011 Elsevier Inc. All rights reserved.

A manic episode in old age presents a diagnostic challenge to the clinician due to the different symptomatology often difficult to distinguish from delirium, dementia, agitated depression and psychosis. To complicate matters further, a first episode of mania in later life is very often based on underlying physical and cerebral pathology ('secondary mania'). Many causes of 'secondary mania', including neurological, systemic or endocrine diseases, infections, intoxications, apnoea, post-thoracic surgery and vitamin B12 deficiency have been described to date, but there have been no reports on subdural haematomas in this context. However, the elderly are more prone to subdural haematomas following head trauma than younger patients. We present two case reports of older patients with a first manic episode in later life probably caused by subdural haematomas. A first episode of mania in later life always requires thorough assessment of the patient to determine physical and cerebral pathology.

To the Editor: Bradycardia has recently been reported as a rare but severe adverse effect of atypical antipsychotics like risperidone,1,2 olanzapine,3 and clozapine.4 Most case reports describe bradycardia with QT interval prolongation.1–5 Until now, the mechanism of this bradyarrhythmogenic character of atypical antipsychotics has not fully been understood. Interference with K+ transport inward ventricular cells was suggested by Magyar et al.6 Quetiapine is increasingly used in the treatment of elderly patients and those with relevant comorbidity because of its apparently lower incidence of side effects. Among others, Gareri et al7 stated in their review article on adverse effects of atypical antipsychotics that no electrocardiogram (ECG) monitoring was required, because of infrequent QTc time alterations on using quetiapine. Here, however, we present a case of an elderly woman with paranoid schizophrenia treated with quetiapine who suffered from asymptomatic bradycardia without QT interval prolongation that resolved after withdrawal. Case report. Ms A, a 63-year-old woman diagnosed with paranoid schizophrenia according to DSM-IV criteria, was admitted in November 2006 to the gerontopsychiatric unit of De Gelderse Roos Mental Health Care. She had previously received several antipsychotics, both classical and atypical, and at admission was receiving quetiapine at a daily dose of 1,000 mg. Despite this high dose, the psychosis persisted, but she did not experience any physical complaints except fatigue. At physical examination, we found a slow irregular pulse rate (52 bpm) and a blood pressure of 115/77 mm Hg without orthostasis. In the following days, the bradycardia persisted with pulse rates varying from 40 to 55 bpm. The ECG showed a sinus bradycardia with normal conduction times (PQ interval = 123 ms, QT interval = 440 ms) and some ventricular extrasystoles. During exercise, the bradycardia persisted, and at laboratory examination no abnormalities were found, with findings including a plasma quetiapine concentration (160 mg/mL) within normal limits. The bradycardia and the lack of antipsychotic effect forced us to reduce the quetiapine dose. During a 6-week taper, the bradycardia persisted but completely disappeared 6 days after full cessation with the pulse rate increasing to over 60 bpm. On prescription of clozapine, the bradycardia did not return. The Holter ECG showed only a few 3- to 4-second pauses during the night. No tachycardias were registered. The echocardiography showed normal left ventricular function and normal aortic valve dimensions. Therefore, a sick-sinus syndrome or atrioventricular node dysfunction as a cause of the bradycardia—although not fully ruled out—is less likely. To our knowledge, this is the first case of quetiapine-induced bradycardia unrelated to the QT interval. According to the criteria proposed by Naranjo et al,8 it is a probable cause. Although quetiapine is assumed to be safe in elderly patients and patients with comorbidity, this report indicates that it needs to be prescribed with the same precautions as other antipsychotics. Since it is still unknown which patients are at risk for developing bradycardia, we support the advice of Stollberger et al5 of routinely monitoring the ECG when prescribing atypical antipsychotics. At least at baseline and after the introduction of the drug, both QT interval and heart rate need to be documented.

Objectives The association between depression and metabolic syndrome is becoming more obvious. Aims We examined the relationship between the number and individual components of metabolic syndrome and late-life depressive symptom clusters. Methods In 1279 individuals aged 50 through 70 participating in the Nijmegen Biomedical Study (Cross-sectional populationbased survey), we measured all metabolic syndrome components and depressive symptoms using the Beck Depression Inventory (BDI). Principal components analysis of BDI-items yielded two factors, representing a cognitive-affective and a somatic-affective symptom-cluster. Multiple regression analyses adjusted for confounders were conducted with BDI sum score and both depression symptom-clusters as dependent variables, respectively. We explored the differences in this association between men and women. Results In fully adjusted models, both presence of the metabolic syndrome as well as number of components was associated with the BDI sumscore(resp. β=0.063;p=0.022 vs. β=0.112;p Conclusions The specific association somatic-affective symptoms suggest confounding by a (subclinical) somatic condition in stead of a real association with classical depression. The identified sex-differences suggest different pathways between depression and metabolic perturbations in men only. However, as vascular disease develops at higher ages in women and findings were in the same direction but non-significant in women, future research in older women sample should confirm our findings.

BackgroundIn the eldery population anti-epileptic drugs (AED) are used in epilepsy, neuralgiform pain, psychiatric disorders and behavioral problems in dementia. The prevalence of AED- treatment in the community is 1%; among nursing home residents 10%. A complex of adverse effects, known as Drug Reaction Eosinophilia and Systemic Symptoms (DRESS), is associated with several drugs, in particular AED. The incidence of DRESS syndrome is estimated between 1 in 1000 and 1 in 10000. DRESS syndrome has a high mortality rate (around 10%), primarily due to doctor's delay in recognition.Case reportsAs AED-induced DRESS syndrome is rarely described in elderly patients, we describe two with dementia-related behavioural problems, treated with carbamazepine. Both patients developed severe rash, eosinophilia and fever after three weeks of administration. Patient 1 also developed anemia, diarrhoea and delirium; Patient 2 suffered from a severe edema of arms and face. Initially the clinical presentation of inflammatory and hypersensitivity symptoms was attributed to several diseases and/or medication other than carbamazepine. After recognition of DRESS by carbamazepine and stopping this drug, both patients fully recovered.ConclusionsRecognition of DRESS syndrome induced by AED is difficult as the condition is rare, symptoms occur 1 to 8 weeks after start of treatment; there may be slow progression and similarity with infections and neoplastic disorders exists. Withdrawal of the offending drug is the primary treatment of the DRESS syndrome and patients relatives must be informed since the incidence of the DRESS syndrome is higher amongst first- degree relatives.

Background and objective IL-21 is an immune-regulatory cytokine that can have both proinflammatory and immunosuppressive effects. The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis. Material and methods For in vitro studies, freshly isolated C57Bl6 splenocytes were stimulated with TLR2/NOD2-binding ligands in the presence or absence of IL-21. In addition, chronic Streptococcal cell wall (SCW) arthritis and antigen-induced arthritis (AIA) were induced in IL-21-receptor-deficient (IL-21R-/-) mice and wild-type (WT) controls. Results In vitro stimulation of splenocytes with TLR2/NOD2-binding SCW fragments resulted in enhanced production of IL-6 and CXCL1, but not IL-10. Interestingly, this proinflammatory response was blocked in the presence of IL-21. QPCR analysis demonstrated that IL-21 strongly induced SOCS expression, suggesting a SOCS-dependent immunosuppressive effect of IL-21 on TLR signaling. In contrast, at first sight our in vivo studies using IL-21R-deficient mice showed a proinflammatory role of IL-21 in experimental arthritis. In both SCW-induced arthritis and AIA, IL-21R-deficiency protected against severe joint inflammation and destruction. This reduced pathology in IL-21R-/- mice was accompanied by suppressed antigen-specific T cell responses, decreased serum IgG1 levels, reduced IL-17 levels in joint lavage, and lower numbers of IL-17+ IFNγ+T cells in the joint. However, during every local (re)challenge of SCW arthritis with TLR ligands, a clearly enhanced joint swelling was found in IL-21R-deficient mice. No differences were found in the expression of TLR2 and NOD2, the most important receptors for SCW. However, while the WT showed a massive upregulation of SOCS1/3 at day 4 of arthritis, IL-21R-/- mice were significantly less capable in upregulating these genes. These data suggest that impaired SOCS regulation in the absence of IL-21 signaling contributes to the increased local activation during SCW arthritis. Conclusion Despite the proinflammatory role of IL-21 in adaptive immunity, driving IL-17/IFNγ double-positive cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role in innate immunity by inhibiting TLR signaling via SOCS1/3. This dual role of IL-21 in various immune processes makes IL-21 a difficult therapeutic target in RA.