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Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Personality traits may predict antidepressant discontinuation and response. However, previous studies were rather small, only explored a few personality traits and did not include adverse drug effects nor the interdependency between antidepressant discontinuation patterns and response.
Methods
GENDEP included 589 patients with unipolar moderate-severe depression treated with escitalopram or nortriptyline for 12 weeks. Seven personality dimensions were measured using the self-reported 240-item Temperament and Character Inventory-Revised (TCI-R). We applied Cox proportional models to study discontinuation patterns, logistic and linear regression to investigate response and remission after 8 and 12 weeks, and mixed-effects linear models regarding time-varying treatment response and adverse drug reactions.
Results
Low harm avoidance, low cooperativeness, high self-transcendence and high novelty seeking were associated with higher risks for antidepressant discontinuation, independent of depressed mood, adverse drug reactions, drug, sex and age. Regression analyses showed that higher novelty seeking and cooperativeness scores were associated with a greater likelihood of response and remission after 8 and 12 weeks, respectively, but we found no correlations with response in the mixed-effects models. Only high harm avoidance was associated with more self-reported adverse effects.
Conclusions
This study, representing the largest investigation between several personality traits and response to two different antidepressants, suggests that correlations between personality traits and antidepressant treatment response may be confounded by differential rates of discontinuation. Future trials on personality in the treatment of depression need to consider this interdependency and study whether interventions aiming at improving compliance for some personality types may improve response to antidepressants.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
We investigated the genotype frequency of methylenetetrahydrofolate reductase (MTHFR) 1298A > C polymorphism in the group of patients with bipolar disorder type I (BDI) (n = 200) and schizophrenia (n = 200) and in the control group (n = 300). Odds ratio (OR) for patients with BD and schizophrenia in 1298CC homozygous state was 3.768 (95% CI = 1.752–8.104); P = 0.0003; (P = 0.0006 after Bonferroni correction) and 2.694; (95% CI = 1.207–6.013); P = 0.0123 (P = 0.0246 after Bonferroni correction), respectively. The stratification of patients based on gender revealed significant association of 1298CC genotype with female patients only with BDI (OR = 7.293; 95% CI = 2.017–26.363; P = 0.0005).
Our results confirm association of BD and schizophrenia with the 1p36.3 MTHFR locus and with the methyl group transfer using folate-dependent one-carbon pathway.
A polymorphism of serotonin transporter was studied in 226 patients with affective disorders (n = 132 for bipolar, n = 94 for unipolar affective disorder) and in 213 healthy subjects. Consensus diagnosis by at least two psychiatrists, according to the ICD-10 and DSM-IV criteria was made for each patient using SCID (Structured Clinical Interview for DSM-IV Axis I Disorders). A functional polymorphism in the promoter region of serotonin transporter gene, where 44 bp are either inserted (long allele) or deleted (short allele) was analysed. Genotype s/s was significantly more frequent in patients comparing to the control group (P = 0.011 for bipolar and P = 0.003 for unipolar affective disorder) - the most marked association was found in males with bipolar and unipolar illness. The allele frequencies also differ significantly between patients and controls (P = 0.003 for bipolar and P = 0.001 for unipolar affective disorder). The frequency of the low activity (short) allele was higher in patients than in controls (51.1% in bipolar, and 54.3 in unipolar vs 39.4% in controls). We suggest that the presence of allele s may increase the susceptibility to occurrence of affective disorder.
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).
Aims
To compare the switch between the TCA nortriptyline and the SSRI escitalopram.
Method
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.
Results
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.
Conclusions
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.
The aim of this study was the assessment of −308G/A tumor necrosis factor (TNF)-α gene polymorphism and intPLA2 gene polymorphism in patients with anorexia nervosa (AN) and healthy controls.
Subjects:
We studied 91 non-related patients with AN and 144 healthy women (blood donors and students). The mean age of women from study group was 18.22 years (SD ± 3.13 years) and from control group was 31.71 years (SD ± 8.22).
Methods:
Gene polymorphisms were studied with the use of polymerase chain reaction-restriction fragment length polymorphism method. TNF-α gene polymorphism consists of G/A substitution in −308 promoter region. IntPLA2 gene polymorphism is related to intron 1, in which restrictive region is found and recognized by BanI enzyme.
Results:
We did not obtain statistically significant differences in the frequency of genotypes and alleles of −308G/A TNF-α polymorphism between the study and control groups (genotypes: P = 0.106, alleles: P = 0.076). We did analogous analysis in the restrictive and bulimic subgroups. We did not observe statistically relevant differences in the frequency of genotypes (P = 0.700) and alleles (P = 0.305). We did not obtain statistically relevant difference in the frequency of genotypes and alleles of intPLA2 gene between the study group and controls (genotypes: P = 0.300, alleles: P = 0.331). We did analogous analysis in both subgroups of AN. We did not observe statistically relevant differences in the frequency of genotypes (P = 0.344) and alleles (P = 0.230).
Conclusions:
There was no statistically relevant trend for the association between TNF-α polymorphism and AN. We did not find association between studied polymorphism of intPLA2 gene and risk of AN.
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.
Aims
To evaluate a simple self-report measure and describe adverse reactions
to antidepressants in a large sample.
Method
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
nortriptyline.
Results
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.
Conclusions
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
gene.
Aims
To test the hypothesis that the 5-HTTLPR differently influences response
to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline
reuptake inhibitor).
Method
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.
Results
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.
Conclusions
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
statistical analyses.
Aims
To test the hypothesis that escitalopram and nortriptyline differ in
their effects on observed mood, cognitive and neurovegetative symptoms of
depression.
Method
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
neurovegetative symptoms.
Results
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.
Conclusions
The three symptom dimensions provided sensitive descriptors of
differential antidepressant response and enabled identification of
drug-specific effects.
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