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Residential mobility during upbringing, and especially adolescence, is associated with multiple negative mental health outcomes. However, whether associations are confounded by unmeasured familial factors, including genetic liability, is unclear.
We used a population-based case–cohort study to assess whether polygenic risk scores (PRSs) for schizophrenia, bipolar disorder and major depression were associated with mobility from ages 10–14 years, and whether PRS and parental history of mental disorder together explained associations between mobility and each disorder.
Information on cases (n = 4207 schizophrenia, n = 1402 bipolar disorder, n = 18 215 major depression) and a random population sample (n = 17 582), born 1981–1997, was linked between Danish civil and psychiatric registries. Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of separate, large meta-analyses.
PRSs for schizophrenia and major depression were weakly associated with moving once (odds ratio 1.07, 95% CI 1.00–1.16; and odds ratio 1.10, 95% CI 1.04–1.17, respectively), but not twice or three or more times. Mobility was positively associated with each disorder, with more moves associated with greater risk. Adjustment for PRS produced slight reductions in the magnitude of associations. Adjustment for PRS and parental history of mental disorder together reduced estimates by 5–11%. In fully adjusted models mobility was associated with all three disorders; hazard ratios ranged from 1.33 (95% CI 1.08–1.62; one move and bipolar disorder) to 3.05 (95% CI 1.92–4.86; three or more moves and bipolar disorder).
Associations of mobility with schizophrenia, bipolar disorder and depression do not appear to be attributable to genetic liability as measured here. Potential familial confounding of mobility associations may be predominantly environmental in nature.
Genomic sequencing plays an increasing role in genetic research, also in psychiatry. This raises challenges concerning the validity and type of the informed consent and the return of incidental findings. However, no solution currently exists on the best way to obtain the informed consent and deliver findings to research subjects.
This study aims to explore the attitudes among potential stakeholders in psychiatric genomic research toward the consenting procedure and the delivery of incidental findings.
We developed a cross-sectional web-based survey among five groups of stakeholders. A total of 2637 stakeholders responded: 241 persons with a mental disorder, 671 relatives, 1623 blood donors, 74 psychiatrists, and 28 clinical geneticists.
The stakeholders wanted active involvement as 92.7% preferred a specific consent and 85.1% wanted to receive information through a dynamic consent procedure. The majority of stakeholders preferred to receive genomic information related to serious or life-threatening health conditions through direct contact (69.5%) with a health professional, i.e. face-to-face consultation or telephone consultation (82.4%). Persons with mental disorders and relatives did not differ in their attitudes from the other stakeholder groups.
The findings illustrate that the stakeholders want to be more actively involved and consider consent as a reciprocal transaction between the involved subjects and the researchers in the project. The results highlight the importance of collaboration between researchers and clinical geneticists as the latter are trained, through their education and clinical experience, to return and explain genomic data to patients, relatives, and research subjects.
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.
Attention-deficit hyperactivity disorder (ADHD) and anxiety disorders have been proposed as precursors of bipolar disorder, but their joint and relative roles in the development of bipolar disorder are unknown.
To test the prospective relationship of ADHD and anxiety with onset of bipolar disorder.
We examined the relationship between ADHD, anxiety disorders and bipolar disorder in a birth cohort of 2 409 236 individuals born in Denmark between 1955 and 1991. Individuals were followed from their sixteenth birthday or from January 1995 to their first clinical contact for bipolar disorder or until December 2012. We calculated incidence rates per 10 000 person-years and tested the effects of prior diagnoses on the risk of bipolar disorder in survival models.
Over 37 394 865 person-years follow-up, 9250 onsets of bipolar disorder occurred. The incidence rate of bipolar disorder was 2.17 (95% CI 2.12–2.19) in individuals with no prior diagnosis of ADHD or anxiety, 23.86 (95% CI 19.98–27.75) in individuals with a prior diagnosis of ADHD only, 26.05 (95% CI 24.47–27.62) in individuals with a prior diagnosis of anxiety only and 66.16 (95% CI 44.83–87.47) in those with prior diagnoses of both ADHD and anxiety. The combination of ADHD and anxiety increased the risk of bipolar disorder 30-fold (95% CI 21.66–41.40) compared with those with no prior ADHD or anxiety.
Early manifestations of both internalising and externalising psychopathology indicate liability to bipolar disorder. The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder.
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.
The identification of biomarkers for depression is of great clinical relevance as the diagnosis is currently subjective. Recent research points towards sortilin as a potential biomarker for depression, and the aim of the current study was to investigate the serum sortilin level in response to antidepressant treatment.
The study included 56 depressed individuals of which 41 responded to treatment. Depression scores and serum levels of sortilin were measured at baseline and after 12 weeks of antidepressant treatment. Statistical analyses were performed using Stata 13.
The depression score and response to treatment were not predicted by the sortilin level. Likewise, we observed no significant change in serum sortilin levels following 12 weeks of antidepressant treatment. Furthermore, no association between the serum sortilin level and depression score was observed.
The results do not point towards sortilin as a state-dependent biomarker.
Anxiety disorders and depression are the most common mental disorders worldwide and have a striking impact on global disease burden. Although depression has consistently been found to increase mortality; the role of anxiety disorders in predicting mortality risk is unclear.
To assess mortality risk in people with anxiety disorders.
We used nationwide Danish register data to conduct a prospective cohort study with over 30 million person-years of follow-up.
In total, 1066 (2.1%) people with anxiety disorders died during an average follow-up of 9.7 years. The risk of death by natural and unnatural causes was significantly higher among individuals with anxiety disorders (natural mortality rate ratio (MRR) = 1.39, 95% CI 1.28–1.51; unnatural MRR= 2.46, 95% CI 2.20–2.73) compared with the general population. Of those who died from unnatural causes, 16.5% had comorbid diagnoses of depression (MRR = 11.72, 95% CI 10.11–13.51).
Anxiety disorders significantly increased mortality risk. Comorbidity of anxiety disorders and depression played an important part in the increased mortality.
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been reported in depression. The aim was to investigate the potential association between depression and seven genes regulating or interfering with the HPA axis, including the gene encoding angiotensin converting enzyme (ACE).
In total, 78 single nucleotide polymorphisms (SNPs) and one insertion/deletion polymorphism were genotyped. The study included 408 individuals with depression and 289 controls. In a subset of cases, the interaction between genetic variants and stressful life events (SLEs) was investigated.
After quality control, 68 genetic variants were left for analyses. Four of nine variants within ACE were nominally associated with depression and a gene-wise association was likewise observed. However, none of the SNPs located within AVP, CRH, CRHR1, CRHR2, FKBP5 or NC3C1 were associated with depression. One nominally significant interaction, most likely due to chance, was identified.
The results indicate that ACE could be a potential candidate gene for depression.
People born in densely populated areas have a higher risk of developing
schizophrenia, bipolar disorder and autism.
The purpose of this study was to investigate whether urban–rural
differences in place of birth influence a broad range of mental
Population-based cohort study of everyone born in Denmark between 1955
and 2006 (n = 2 894 640). Main outcome measures were
incidence rate ratios for five levels of urbanisation and summary
estimates contrasting birth in the capital with birth in rural areas.
For all psychiatric disorders, except intellectual disability (ICD-10
‘mental retardation’) and behavioural and emotional disorders with onset
in childhood, people born in the capital had a higher incidence than
people born in rural areas.
Birth in an urban environment is associated with an increased risk for
mental illness in general and for a broad range of specific psychiatric
disorders. Given this new evidence that urban–rural differences in
incidence are not confined to the well-studied psychotic disorders,
further work is needed to identify the underlying aetiopathogenic
In bipolar disorder, treatment with antidepressants without concomitant use of mood stabilisers (antidepressant monotherapy) is associated with development of mania and rapid cycling and is therefore not recommended. The present study aimed to investigate the psychopharmacological treatment patterns in bipolar disorder over time, with a focus on antidepressant monotherapy.
Cohort study with annual cross-sectional assessment of the use of psychotropic medications between 1995 and 2012 for all Danish residents aged 10 years or older with a diagnosis of bipolar disorder registered in the Danish Psychiatric Central Research Register. Users of a given psychotropic medication were defined as individuals having filled at least one prescription for that particular medication in the year of interest.
We identified 20 618 individuals with bipolar disorder. The proportion of patients with bipolar disorder using antidepressants, atypical antipsychotics and anticonvulsants increased over the study period, while the proportion of patients using lithium, typical antipsychotics and benzodiazepines/sedatives decreased. The proportion of patients treated with antidepressant monotherapy decreased from 20.5% in 1997 to 12.1% in 2012, and among antidepressant users, the proportion in monotherapy decreased from 47.7% to 23.9%, primarily driven by a decrease in the use of tricyclic antidepressants.
The results show an increase in the proportion of patients with bipolar disorder being treated with antidepressants in the period from 1997 to 2012. However, in accordance with international treatment guidelines, the extent of antidepressant monotherapy decreased during the same period.
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.
The main aim of the present study was to replicate a previous finding in major depressive disorder (MDD) of association between reduced hippocampal volume and the long variant of the di- and triallelic serotonin transporter polymorphism in SLC6A4 on chromosome 17q11.2. Secondarily, we also hypothesised that 5-HTTLPR may be a risk factor for MDD.
Quantitative magnetic resonance imaging (MRI) of the hippocampus was studied in 23 inpatients suffering from MDD and in 33 healthy controls. Normalised volumetric MRI data of hippocampus were assessed with adjustment for total brain volume and tensor-based morphometry was used to elucidate structural brain differences. A triallelic genetic marker resulting from two SLC6A4 promoter region polymorphisms, 5-HTTLPR and rs25531, was analysed for association with MDD and quantitative traits.
Healthy controls had a smaller relative hippocampal volume (relative to brain size) but a larger total brain volume compared with patients with MDD. For patients compared with healthy controls, atrophy was found in the right temporal lobe and pons medulla. Allele and genotype frequencies were strikingly different from the previous study that we aimed to replicate, and no significant associations with the serotonin transporter polymorphism were found.
The present quantitative and morphometric MRI study was not able to replicate the previous finding of association between reduced hippocampal volume in depressed patients and the serotonin transporter polymorphism.
Objective: Causative relations between infections and psychosis, especially schizophrenia, have been speculated for more than a century, suggesting a hypothesis of association between schizophrenia and hereditary immune defects. Mannan-binding lectin (MBL) is a pattern-recognition molecule of the innate immune defence. MBL deficiency is the most common hereditary defect in the immune system and may predispose to infection and autoimmunity. Mannan-binding lectin serine protease-2 (MASP-2) is an MBL-associated serine protease mediating complement activation upon binding of MBL/MASP to microorganisms. The objective was to investigate if schizophrenia is associated with serum concentrations of MBL and MASP-2 or with genetic variants of the genes MBL2 and MASP2 encoding these proteins.
Methods: The sample consisted of 100 patients with schizophrenia and 350 controls. Concentrations of MBL and MASP-2 in serum were measured and seven single nucleotide polymorphisms known to influence these concentrations were genotyped.
Results: Significant association of disease with genetic markers was found in MBL2 but not in MASP2. Significant difference in MBL serum concentration was found between patients and controls when adjusting for MBL2 haplotypes. For concentrations of MASP-2, a significant interaction effect between a MASP2 variant and disease was found. Interestingly, MASP-2 levels also depended significantly on variants in MBL2 exon 1.
Conclusion: This study supports previous studies showing increased complement activity in patients with schizophrenia, indicates aetiological heterogeneity among patients and underlines that multilocus genotypes have to be considered when investigating effects on MBL level. It appears that inclusion of additional components from the system of complement activation is warranted.
Objective: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression.
Method: Leu7Pro was studied in a sample of depressed patients and ethnically matched controls, as well as psychiatric disease controls with schizophrenia. Possible functional consequences of Leu7Pro were explored in vitro.
Results: In contrast to previous studies, Pro7 appeared to be a risk allele for depression, being significantly more frequent in the depression sample (5.5%, n = 593; p = 0.009; odds ratio, OR: 1.46) as compared to ethnically matched controls (3.8%, n = 2912), while schizophrenia patients (4.1%, n = 503) did not differ. In vitro, the Pro7 substitution appeared to be associated with reduced levels of NPY without affecting its mRNA level.
Conclusion: The Leu7Pro variation may increase the risk of major depression, possibly by affecting the biosynthesis of NPY.
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
A few recent linkage studies have shown a possible locus for bipolar disorder on chromosome 18. Cytogenetic studies may assist in the further localisation of susceptibility loci on this chromosome.
A search was made for abnormalities of chromosome 18 in two separate large cytogenetic databases. In Denmark detection of mental illness in subjects with chromosome abnormalities was done by cross-linking the two separate register of psychiatric and chromosome disorders. In Scotland the Cytogenetic Registry of the MRC Human Genetics Unit undertakes long-term clinical follow-up of all cases with chromosome abnormalities.
Cross-linking the two Danish register's revealed a family with the rare karyotype abnormality inv(18) (p11.3;q21.1) with one inversion carrier who also suffered from bipolar disorder. In this family there were two other cases of bipolar disorder, but the karyotype of these cases could not be established. One family in Scotland showed a case of schizophrenia in a carrier of inv(18) with the same breakpoints as the Danish family.
We suggest further studies of the 18p11.3 and 18q21.1 regions in order to identify genes involved in bipolar affective disorder and schizophrenia.
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