E van Duijn

Suicidality in Huntington's disease

BACKGROUNDnIn Huntingtons disease (HD) the risk of suicide is increased. Since suicidality may precede suicide, this study investigates prevalence, clinical associations and predictors of suicidality in HD.nnnMETHODSnSuicidality was investigated in 152 mutation carriers and 56 non-carriers, and was considered present if the score on the item suicidal ideation of the Problem Behaviours Assessment (PBA) was >1 point. After 2 years, 100 mutation carriers who were free of suicidality at baseline were re-assessed. Associations and predictors of suicidality were analyzed using multivariate logistic regression analysis.nnnRESULTSnEleven (20%) pre-motor and 20 (20%) motor symptomatic mutation carriers were considered suicidal compared to none of the non-carriers. Cross-sectionally, suicidal mutation carriers were more likely to use antidepressants (odds ratio=5.3), were more often apathetic (OR=2.8), more often had a depressed mood according to the PBA (OR=5.9), and were more often diagnosed with a DSM-IV depression diagnosis (OR=4.7). Independent associations were more frequent use of antidepressants (OR=4.0) and presence of a depressed mood (OR=4.2). Longitudinally, depressed mood (OR=10.6) at baseline was the only independent predictor of suicidality at follow-up.nnnLIMITATIONSnSelection bias might have occurred which could have affected the suicidality rate.nnnCONCLUSIONnIt is important to screen both pre-motor and motor symptomatic HD mutation carriers for suicidality. The presence of a depressed mood is both associated with and predictive of suicidality in HD and assessment of depressed mood can help to identify individuals with increased risk for suicide.

Psychiatric Disorders in Huntington's Disease: A 2-Year Follow-up Study

OBJECTIVEnThis study investigates the presence and course of formal psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) in 142 Huntingtons disease (HD) mutation carriers in a two-year follow-up design.nnnMETHODnOf the 142 mutation carriers, 106 (75%) participated in the second measurement of an ongoing cohort study on psychopathology in HD. Presence of psychiatric disorders was assessed using the Composite International Diagnostic Interview.nnnRESULTSnOf the 91 patients without a formal psychiatric disorder at baseline, 14 (15%) had a psychiatric disorder after 2 years, mostly a major depressive disorder (MDD) (64%). The baseline characteristics of lower education, having no children, a lower level of global daily functioning, a lifetime psychiatric diagnosis, and the use of psychotropic medication were predictive of incident psychiatric disorders after 2 years. Of the 15 patients with a psychiatric diagnosis at baseline, eight (53%) no longer had a psychiatric disorder at follow-up. All seven patients (47%) with a persistent psychiatric disorder were female and their most prevalent diagnosis was generalized anxiety disorder.nnnCONCLUSIONnThis cohort study confirms that psychiatric disorders, in particular MDD, frequently occur in patients with HD. Professionals working with HD patients should therefore be aware of the high risk of psychopathology in HD because early diagnosis and treatment of psychiatric disorders may improve the quality of life of patients and their caregivers.

Adverse childhood experiences of persons at risk for Huntington's disease or BRCA1/2 hereditary breast/ovarian cancer.

Van der Meer LB, van Duijn E, Wolterbeek R, Tibben A. Adverse childhood experiences of persons at risk for Huntingtons disease or BRCA1/2 hereditary breast/ovarian cancer.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease and its association with depressive symptoms and suicidality.

Hyperactivity of the hypothalamic‐pituitary‐adrenal (HPA) axis has been reported in Huntingtons disease (HD). In non‐HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre‐motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow‐up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre‐motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre‐motor, early and advanced disease stages, β values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre‐motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre‐motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress‐induced HPA axis hyperactivity and deserves further longitudinal study.

Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: a meta-analysis.

AIMSnSeveral authors claimed that expression of suicidal ideation is one of the most important predictors of completed suicide. However, the strength of the association between suicidal ideation and subsequent completed suicide has not been firmly established in different populations. Furthermore, the absolute suicide risk after expression of suicidal ideation is unknown. In this meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide in various populations, including both psychiatric and non-psychiatric populations.nnnMETHODSnA meta-analysis of cohort and case-control studies that assessed suicidal ideation as determinant for completed suicide in adults. Two independent reviewers screened 5726 articles for eligibility and extracted data of the 81 included studies. Pooled risk ratios were estimated in a random effects model stratified for different populations. Meta-regression analysis was used to determine suicide risk during the first year of follow-up.nnnRESULTSnThe risk for completed suicide was clearly higher in people who had expressed suicidal ideation compared with people who had not, with substantial variation between the different populations: risk ratio ranging from 2.35 (95% confidence interval (CI) 1.43-3.87) in affective disorder populations to 8.00 (95% CI 5.46-11.7) in non-psychiatric populations. In contrast, the suicide risk after expression of suicidal ideation in the first year of follow-up was higher in psychiatric patients (risk 1.40%, 95% CI 0.74-2.64) than in non-psychiatric participants (risk 0.23%, 95% CI 0.10-0.54). Past suicide attempt-adjusted risk ratios were not pooled due to large underreporting.nnnCONCLUSIONSnAssessment of suicidal ideation is of priority in psychiatric patients. Expression of suicidal ideation in psychiatric patients should prompt secondary prevention strategies to reduce their substantial increased risk of suicide.

Acute-phase proteins in relation to neuropsychiatric symptoms and use of psychotropic medication in Huntington's disease.

Activation of the innate immune system has been postulated in the pathogenesis of Huntingtons disease (HD). We studied serum concentrations of C-reactive protein (CRP) and low albumin as positive and negative acute-phase proteins in HD. Multivariate linear and logistic regression was used to study the association between acute-phase protein levels in relation to clinical, neuropsychiatric, cognitive, and psychotropic use characteristics in a cohort consisting of 122 HD mutation carriers and 42 controls at first biomarker measurement, and 85 HD mutation carriers and 32 controls at second biomarker measurement. Significant associations were found between acute-phase protein levels and Total Functioning Capacity (TFC) score, severity of apathy, cognitive impairment, and the use of antipsychotics. Interestingly, all significant results with neuropsychiatric symptoms disappeared after additional adjusting for antipsychotic use. High sensitivity CRP levels were highest and albumin levels were lowest in mutation carriers who continuously used antipsychotics during follow-up versus those that had never used antipsychotics (mean difference for CRP 1.4 SE mg/L; P=0.04; mean difference for albumin 3 SE g/L; P<0.001). The associations found between acute-phase proteins and TFC score, apathy, and cognitive impairment could mainly be attributed to the use of antipsychotics. This study provides evidence that HD mutation carriers who use antipsychotics are prone to develop an acute-phase response.

F23 Incidence, course and predictors of apathy in Huntington's disease: a 2-year prospective study

Background Apathy is a common neuropsychiatric symptom in patients with Huntingtons disease (HD). Aims To examine the incidence, course and predictors of apathy in subjects with HD. Methods At baseline 152 HD subjects were examined with the Apathy Scale (AS), in relation to socio-demographic, clinical, and neuropsychiatric characteristics. Two-year follow-up evaluation included 122 (80%) subjects. Incident and persistent apathy were examined using logistic regression analysis. Results At follow-up, 13 (14%) of the 88 subjects free of apathy at baseline had developed apathy. Of the 34 subjects with apathy at baseline, 14 (41%) had recovered from apathy whereas 20 (59%) had persistent apathy. In subjects without apathy at baseline, univariate predictors of incident apathy were low Mini Mental State Examination score (MMSE; p=0.01) and Total Functional Capacity (TFC; p=0.02) scores at baseline. A low baseline MMSE score remained a predictor in multivariate analysis. In subjects with apathy at baseline, univariate baseline predictors of persistent versus remitted apathy after two years were older age (p=0.006), longer disease duration (p=0.02), and lower scores on TFC (p=0.02), Symbol Digit Modalities Test (SDMT; p=0.008) and Stroop Word Test (p=0.04). A low baseline SDMT was the only predictor of persistent apathy in multivariate analysis. Conclusion Apathy in HD is most closely linked to global and executive cognitive performance, predicting incident and persistent apathy, respectively. Because apathy may be reversible it is important to examine HD patients for treatable causes of apathy.

Disease stage and plasma levels of cytokines in Huntington's disease: A 2‐year follow‐up study

It has been shown that plasma levels of cytokines are elevated in Huntington’s disease (HD) gene expansion carriers when compared with controls and are higher in advanced disease stages. To test the hypothesis that plasma cytokines may serve as a biomarker of disease progression, levels of proinflammatory and anti-inflammatory cytokines were measured in different disease stages at baseline and during a 2year follow-up.

F07 Cross-sectional and longitudinal associations between CRP and neuropsychiatric symptoms in HD

Background There is a growing body of evidence that inflammatory processes play a role in the development of neuropsychiatric symptoms in Huntingtons disease (HD). Aims To investigate the relationship between C-reactive protein (CRP) concentration in blood on the one hand and neuropsychiatric symptoms on the other hand in HD mutation carriers compared to non-mutation carriers, both cross-sectionally and longitudinally. Methods In 2003, a longitudinal cohort study was initiated in Leiden, The Netherlands, comprising 154 mutation carriers and 56 non-carriers. In 2005–2007 and 2009–2011 a first and second wave of follow-up was conducted. Blood samples for the assessment of CRP were obtained during the first and second wave of follow-up, in addition to a battery of psychometric measures, cognitive functioning tests, and a neurological examination. Multivariate regression analyses to associate neuropsychiatric symptoms with CRP and analyses of (co)variance for comparisons between different stages of HD and controls will be used. Results We will present the results regarding associations between CRP on the one hand and HD disease stage and several neuropsychiatric symptoms on the other hand, both cross-sectionally and longitudinally.

K05 Suicidality in a European huntington's disease population

Background The suicide risk in Huntingtons disease (HD) is 4–8 times higher compared to the general population, and the prevalence of suicidality (suicidal thoughts and attempts) in HD is also increased. Several previous studies reported depressed mood as an important association of suicidality in HD. Aims This study investigates clinical associations and predictors of suicidality in a large European cohort of HD mutation carriers. Methods Presence of suicidality in the preceding month was assessed in 2106 mutation carriers from 15 European countries, all participating in the European Huntington Disease Network (EHDN) REGISTRY study. Mutation carriers were considered suicidal if the total score on the item “suicidal ideation” of the Unified Huntingtons Disease Rating Scale (UHDRS) was >1point. Associations of suicidality were analysed using multivariate logistic regression analysis. Of the 1937 participants free of suicidality at baseline, 945 had one or more follow-up measurements. Cox regression analysis was used to determine predictors of suicidality. Results At baseline, 169 (8%) mutation carriers were considered suicidal. Cross-sectionally, the presence of anxiety (OR=2.1), aggression (OR=2.4), a suicide attempt in the past (OR=4.0) and a depressed mood (OR=13.7) were independently associated to suicidality. During follow-up, 45 (5.5%) mutation carriers became suicidal. The presence of a depressed mood (OR=2.0; 95% CI 1.0 to 3.8) and use of benzodiazepines (OR=2.4; 95% CI 1.2 to 4.9) at baseline were independent predictors of suicidality at follow-up. Conclusions Suicidality prevalence is increased in HD mutation carriers. Assessment of depressed mood, which is an important association and predictor of suicidality, can help to identify mutation carriers with an increased suicidality risk.