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Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.
We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.
Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).
Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.
In a modified case–control association study we tested the assumption that two polymorphisms (A118G in exon 1 and IVS2+31 in intron 2) of the human μ-opioid receptor gene (OPRM1) confer susceptibility to opioid dependence.
In contrast to classical case–control studies both groups, opioid dependent cases and non-opioid dependent controls were recruited from individuals who have had access to drugs including opioids and who had been sentenced for violation of the “Dangerous Drugs Act” in Germany.
For the two allelic variants of OPRM1 under study we did not find evidence for association with opioid dependence.
Despite absence of association we think that this recruitment approach introduced here, is useful since it putatively offers a more adequate matching for case–control association studies of opioid dependent individuals.
Early identification and treatment of schizophrenia may alleviate the symptoms, delay the onset and improve the outcome of psychosis. Thus, detection of individuals at risk during the prodromal phase is an important task. Universal approaches to screen the general population or healthy subjects at risk have not proven possible to-date. However, clinical criteria for detecting ultra-high risk individuals have been developed for specialized settings, with their implementation in interventional studies. This article examines the rationale for early detection and intervention of psychosis, along with a review of some of the current studies. These target prevention using psychological and/or pharmacological intervention strategies have demonstrated promising results in high risk individuals. The German Research Network on Schizophrenia (GRNS) is conducting two multicenter early intervention studies; one with early psychological intervention in subjects who manifest early prodromal symptoms; with the second trial applying clinical management and pharmacological early intervention in subjects experiencing late prodromal symptoms (high risk subjects). Despite the promising results, many of the current studies have small sample sizes with study durations of a short period. The full benefits of early detection and intervention should be revealed once larger and longer studies are conducted.
Somatic symptoms and anxiety symptoms are often disregarded in the detection of depression in primary care. The present investigation examined to what extent somatic and anxiety symptoms recorded with the Composite International Diagnostic Interview—Primary Health Care Version (CIDI—PHC) can improve the detection of depression as compared to the General Health Questionnaire—12-item version alone. Data from the World Health Organization study on Psychological Problems in General Health Care were used. The study sample consisted of primary care attenders from 15 centres from all over the world who underwent a psychiatric examination with the CIDI—PHC. Medically unexplained somatic symptoms (back pain, feelings of heaviness/lightness in parts of the body, periods of bodily weakness, seizures/convulsions, permanent tiredness, exhaustion after a minimum of effort) and—to a smaller extent—diverse anxiety symptoms (e.g. feelings of anxiousness/nervousness, feelings of tension, difficulties relaxing) significantly contributed to the detection of depression in a logistic regression analysis. The results confirm the observation that in primary care somatic symptoms play an important role in the manifestation of depressive disorders. The items investigated herein could prove beneficial for future depression screening instruments to improve the detection of depressive disorders in primary care.
Patients with bipolar disorders experience cyclical changes in mood that present as a range of different syndromes. In classical mania, patients experience episodes of euphoria, whereas in depressive episodes they suffer from depression. In hypomania, patients experience a milder form of mania, and in mixed mania, patients may experience both manic and depressive symptoms simultaneously, or alternate between them rapidly. Because of this wide range of symptoms, bipolar disorders can appear to overlap with other mental disorders, especially personality disorders.
To examine the impact of determinants of incident dementia in three different old age groups (75–79, 80–84, 85+years) in Germany.
Multicenter prospective AgeCoDe/AgeQualiDe cohort study with baseline and nine follow-up assessments at 1.5-year intervals.
Primary care medical record registry sample.
General practitioners’ (GPs) patients aged 75+years at baseline.
Conduction of standardized interviews including neuropsychological assessment and collection of GP information at each assessment wave. We used age-stratified competing risk regression models (accounting for the competing event of mortality) to assess determinants of incident dementia and age-stratified ordinary least square regressions to quantify the impact of identified determinants on the age at dementia onset.
Among 3027 dementia-free GP patients, n = 704 (23.3%) developed dementia during the 13-year study period. Worse cognitive performance and subjective memory decline with related worries at baseline, and the APOE ε4 allele were associated independently with increased dementia risk in all three old age groups. Worse cognitive performance at baseline was also associated with younger age at dementia onset in all three age groups. Other well-known determinants were associated with dementia risk and age at dementia onset only in some or in none of the three old age groups.
This study provides further evidence for the age-specific importance of determinants of incident dementia in old age. Such specifics have to be considered more strongly particularly with regard to potential approaches of early detection and prevention of dementia.
For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).
To compare the switch between the TCA nortriptyline and the SSRI escitalopram.
Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery–Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting β-coefficients with 95% CIs.
Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, β = −0.38, 95% CI −0.51 to −0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, β = −0.34, 95% CI −0.41 to −0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions.
These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.
Declarations of interest
K.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.
Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.
To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.
The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.
In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.
This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
Subjective cognitive decline (SCD), the potentially earliest notable manifestation of preclinical Alzheimer's disease and other dementias, was consistently associated with lower quality of life in cross-sectional studies. The aim of this study was to investigate whether such an association persists longitudinally – particularly with health-related quality of life (HRQoL) in older individuals without cognitive impairment.
Data were derived from follow-up 2–6 of the prospective Germany Study on Ageing, Cognition and Dementia in Primary Care (AgeCoDe) covering a total six-year observation period. We used linear mixed effects models to estimate the effect of SCD on HRQoL measured by the EQ-5D visual analogue scale (EQ VAS).
Of 1,387 cognitively unimpaired individuals aged 82.2 years (SD = 3.2) on average, 702 (50.6%) reported SCD and 230 (16.6%) with SCD-related concerns. Effect estimates of the linear mixed effects models revealed lower HRQoL in individuals with SCD (unadjusted: –3.7 points on the EQ VAS, 95%CI = –5.3 to –2.1; SE = 0.8; p < 0.001; adjusted: –2.9 points, 95%CI = –3.9 to –1.9; SE = 0.5; p < 0.001) than in individuals without SCD. The effect was most pronounced in SCD with related concerns (unadjusted: –5.4, 95%CI = –7.6 to –3.2; SE = 1.1; p < 0.001; adjusted: –4.3, 95%CI = –5.8 to –2.9, SE = 0.7; p < 0.001).
SCD constitutes a serious issue to older cognitively unimpaired individuals that is depicted in persisting lower levels of HRQoL beyond depressive symptoms and functional impairment. Therefore, SCD should be taken seriously in clinical practice.
Most of the previous studies attempted to disentangle the relationship between disability and depressive symptoms were limited to observation periods of only few years. Moreover, evidence is missing regarding the complex co-occurrence of disability and depressive symptoms in old age in Germany. In order to close the research gap, we aimed at disentangling the complex co-occurrence of disability and depressive symptoms in old age in Germany over a longer time frame.
Based on data from a representative survey of the German general population aged 75 years and older, the course of disability as well as depressive symptoms was observed every 1.5 years over six waves. While disability was quantified by the Lawton and Brody Instrumental Activities of Daily Living scale, the Geriatric Depression Scale was used to measure depressive symptoms. Taking into account the complex co-occurrence of depressive symptoms and disability, a panel vector autoregressive model was used. By taking the first differences, unobserved heterogeneity was taken into account.
In the total sample and in both sexes, we revealed a robust positive association between an initial change in depressive symptoms and subsequent changes in disability. No robust association between an initial change in disability and a subsequent change in depressive symptoms was detected.
Our findings highlight the importance of changes in depressive symptoms for future changes in disability in old age.
Current perspectives on attractiveness-related prosocial biases emphasize the contribution of evolutionarily shaped mating drives. Here, we extend these concepts by highlighting the pivotal role of the hypothalamic peptide oxytocin in augmenting the salience and rewarding value of social stimuli, including the partner's face, thereby fostering social bonding in general and the stability of monogamous pair bonds and offspring care in particular.
If patients are treated according to their personal preferences, depression treatment success is higher. It is not known which treatment options for late-life depression are preferred by patients aged 75 years and over and whether there are determinants of these preferences.
The data were derived from the German “Late-life depression in primary care: needs, health care utilization, and costs (AgeMooDe)” study. Patients aged 75+ years (N = 1,230) were recruited from primary care practices. Depressive symptoms were determined using the Geriatric Depression Scale (GDS-15). Support for eight treatment options was determined.
Medication, psychotherapy, talking to friends and family, and exercise were the preferred treatment options. Having a GDS score ≥ 6 significantly lowered the endorsement of some treatment options. For each treatment option, the probability of choosing the indecisive category “I do not know” was significantly increased in participants with moderate depressive symptoms.
Depressive symptoms influence the preference for certain treatment options and also increase indecision in patients. The high preference for psychotherapy suggests a much higher demand for late-life psychotherapy in the future. Healthcare systems should begin to prepare to meet this anticipated need. Future studies should include previous experience with treatment methods as a confounding variable.
The glutamate amplifies noradrenergic effects (GANE) model emphasizes the role of focal glutamate–noradrenaline interactions in creating functional hotspots for prioritized processing of salient stimuli. Here, we briefly outline current evidence that synergistic action of noradrenaline and cortisol enables emotional stimuli to gain privileged access to amygdala–hippocampus circuits, eventually resulting in the formation of indelible memories and posttraumatic stress disorder (PTSD).
This paper provides nationally representative data on how current and past mental disorders are related to functional disability and health-related quality of life (QoL).
Results are based on a nationally representative sample (DEGS1-MH; n = 4483 aged 18–79). Respondents were examined by clinical interviewers with the DSM-IV Composite International Diagnostic Interview (DIA-X/M-CIDI). Functional disability, i.e. number of disability days in the past 4 weeks, and QoL, i.e. mental (MCS) and physical (PCS) component scale of the SF-36V2, were examined in subjects with 12-month mental disorders (= active cases [AC]) and compared to (a) subjects who never met diagnostic criteria (= unaffected individuals [UAI]), and (b) those with a history of mental disorders but not meeting the diagnostic criteria in the past 12 months (= non-active cases [NAC]; partially or fully remitted).
In comparison to UAI (mean: 1.9), AC reveals a 2–3 fold disability days/month (5.4, P < .001) and a substantially reduced MCS (UAI: 52.1; AC: 43.3, P < .001). NAC had a similar number of disability days as UAI, but significantly reduced MCS scores (49.9; P < .001). Disability days and QoL decrements were highest in internalizing disorders including somatoform disorders and most pronounced in comorbid cases.
By and large, findings of a previous study were confirmed and extended for this nationally representative German sample. 12-month mental disorders, particularly internalizing, including somatoform disorders, are associated with high levels of disability and increased health-related QoL decrements. Partial or complete remission of the mental disorders is associated with a normalization of the numbers of disability days.
Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.
To investigate whether higher BMI increases the risk of major depression.
Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case–control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI.
Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient −0.03, 95% CI −0.18 to 0.13, P = 0.73; GRS: coefficient −0.02, 95% CI −0.11 to 0.07, P = 0.62).
Our instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding.
Adverse drug reactions are important determinants of non-adherence to
antidepressant treatment but their assessment is complicated by overlap
with depressive symptoms and lack of reliable self-report measures.
To evaluate a simple self-report measure and describe adverse reactions
to antidepressants in a large sample.
The newly developed self-report Antidepressant Side-Effect Checklist and
the psychiatrist-rated UKU Side Effect Rating Scale were repeatedly
administered to 811 adult participants with depression in a
part-randomised multicentre open-label study comparing escitalopram and
There was good agreement between self-report and psychiatrists' ratings.
Most complaints listed as adverse reactions in people with depression
were more common when they were medication-free rather than during their
treatment with antidepressants. Dry mouth (74%), constipation (33%) and
weight gain (15%) were associated with nortriptyline treatment. Diarrhoea
(9%), insomnia (36%) and yawning (16%) were more common during treatment
with escitalopram. Problems with urination and drowsiness predicted
discontinuation of nortriptyline. Diarrhoea and decreased appetite
predicted discontinuation of escitalopram.
Adverse reactions to antidepressants can be reliably assessed by
self-report. Attention to specific adverse reactions may improve
adherence to antidepressant treatment.
There have been conflicting reports on whether the length polymorphism in
the promoter of the serotonin transporter gene (5-HTTLPR) moderates the
antidepressant effects of selective serotonin reuptake inhibitors
(SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is
modulated by gender, age and other variants in the serotonin transporter
To test the hypothesis that the 5-HTTLPR differently influences response
to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline
The 5-HTTLPR and 13 additional markers across the serotonin transporter
gene were genotyped in 795 adults with moderate-to-severe depression
treated with escitalopram or nortriptyline in the Genome Based
Therapeutic Drugs for Depression (GENDEP) project.
The 5-HTTLPR moderated the response to escitalopram, with long-allele
carriers improving more than short-allele homozygotes. A significant
three-way interaction between 5-HTTLPR, drug and gender indicated that
the effect was concentrated in males treated with escitalopram. The
single-nucleotide polymorphism rs2020933 also influenced outcome.
The effect of 5-HTTLPR on antidepressant response is SSRI specific
conditional on gender and modulated by another polymorphism at the 5' end
of the serotonin transporter gene.
Tricyclic antidepressants and serotonin reuptake inhibitors are
considered to be equally effective, but differences may have been
obscured by internally inconsistent measurement scales and inefficient
To test the hypothesis that escitalopram and nortriptyline differ in
their effects on observed mood, cognitive and neurovegetative symptoms of
In a multicentre part-randomised open-label design (the Genome Based
Therapeutic Drugs for Depression (GENDEP) study) 811 adults with moderate
to severe unipolar depression were allocated to flexible dosage
escitalopram or nortriptyline for 12 weeks. The weekly Montgomery–Åsberg
Depression Rating Scale, Hamilton Rating Scale for Depression, and Beck
Depression Inventory were scored both conventionally and in a more novel
way according to dimensions of observed mood, cognitive symptoms and
Mixed-effect linear regression showed no difference between escitalopram
and nortriptyline on the three original scales, but symptom dimensions
revealed drug-specific advantages. Observed mood and cognitive symptoms
improved more with escitalopram than with nortriptyline. Neurovegetative
symptoms improved more with nortriptyline than with escitalopram.
The three symptom dimensions provided sensitive descriptors of
differential antidepressant response and enabled identification of
People in a putatively late prodromal state not only have an enhanced
risk for psychosis but already suffer from mental and functional
To evaluate the acute effects of a combined supportive and antipsychotic
treatment on prodromal symptoms
Putatively prodromal individuals were randomly assigned to a
needs-focused intervention without (n=59) or with
amisulpride (n=65). Outcome measures at 12-weeks effects
were prodromal symptoms, global functioning and extrapyramidal
Amisulpride plus the needs-focused intervention produced superior effects
on attenuated and full-blown psychotic symptoms, basic, depressive and
negative symptoms, and global functioning. Main side-effects were
Coadministration of amisulpride yielded a marked symptomatic benefit.
Effects require confirmation by a placebo-controlled study