Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments ...that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor).
The hypothesis was tested in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured with a high-sensitivity method in serum samples from 241 adult men and women with major depressive disorder randomly allocated to 12-week treatment with escitalopram (N=115) or nortriptyline (N=126). The primary outcome measure was the score on the Montgomery-Åsberg Depression Rating Scale (MADRS), administered weekly.
CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: β=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome.
An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice.
Indirect evidence suggests that common genetic variation contributes to individual differences in antidepressant efficacy among individuals with major depressive disorder, but previous studies may ...have been underpowered to detect these effects.
A meta-analysis was performed on data from three genome-wide pharmacogenetic studies (the Genome-Based Therapeutic Drugs for Depression GENDEP project, the Munich Antidepressant Response Signature MARS project, and the Sequenced Treatment Alternatives to Relieve Depression STAR*D study), which included 2,256 individuals of Northern European descent with major depressive disorder, and antidepressant treatment outcomes were prospectively collected. After imputation, 1.2 million single-nucleotide polymorphisms were tested, capturing common variation for association with symptomatic improvement and remission after up to 12 weeks of antidepressant treatment.
No individual association met a genome-wide threshold for statistical significance in the primary analyses. A polygenic score derived from a meta-analysis of GENDEP and MARS participants accounted for up to approximately 1.2% of the variance in outcomes in STAR*D, suggesting a weakly concordant signal distributed over many polymorphisms. An analysis restricted to 1,354 individuals treated with citalopram (STAR*D) or escitalopram (GENDEP) identified an intergenic region on chromosome 5 associated with early improvement after 2 weeks of treatment.
Despite increased statistical power accorded by meta-analysis, the authors identified no reliable predictors of antidepressant treatment outcome, although they did identify modest, direct evidence that common genetic variation contributes to individual differences in antidepressant response.
Background Pharmacogenetic studies aiming to personalize the treatment of depression are based on the assumption that response to antidepressants is a heritable trait, but there is no compelling ...evidence to support this. Methods We estimate the contribution of common genetic variation to antidepressant response with Genome-Wide Complex Trait Analysis in a combined sample of 2799 antidepressant-treated subjects with major depressive disorder and genome-wide genotype data. Results We find that common genetic variants explain 42% (SE = .180, p = .009) of individual differences in antidepressant response. Conclusions These results suggest that response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect.
Abstract Background Reduced hippocampal volume has been consistently observed in major depressive disorder. Hippocampal volume loss is particularly evident in patients with recurrent and chronic ...depression. However, the reports in first episode depression have been mixed. Methods We performed a random effects meta-analysis to establish whether hippocampal atrophy exists from disease onset. We included magnetic resonance imaging studies of hippocampal volume in patients with first episode major depressive disorder and matched healthy controls. Results A total of 7 studies met our inclusion and exclusion criteria, representing independent observations in a total sample of 191 patients and 282 healthy controls. The cumulative analysis revealed hippocampal volume loss in patients with first episode depression relative to controls in both the left (standardised mean difference, SMD = − 0.41, 95% Confidence Interval: − 0.78;−0.03, z = − 2.14, p = 0.0321) and right (SMD = − 0.53− 0.98;−0.09, z = − 2.38, p = 0.0173) hippocampi. The average volume reduction was − 4.0% in the left and − 4.5% in the right hippocampus. Conclusions Hippocampal volume loss in first episode depression is consistent with a neurodevelopmental model of depression, advocating hippocampal structure as a potential diagnostic neurobiomarker for depression.
Abstract The outcome of treatment with antidepressants varies markedly across people with the same diagnosis. A clinically significant prediction of outcomes could spare the frustration of trial and ...error approach and improve the outcomes of major depressive disorder through individualized treatment selection. It is likely that a combination of multiple predictors is needed to achieve such prediction. We used elastic net regularized regression to optimize prediction of symptom improvement and remission during treatment with escitalopram or nortriptyline and to identify contributing predictors from a range of demographic and clinical variables in 793 adults with major depressive disorder. A combination of demographic and clinical variables, with strong contributions from symptoms of depressed mood, reduced interest, decreased activity, indecisiveness, pessimism and anxiety significantly predicted treatment outcomes, explaining 5–10% of variance in symptom improvement with escitalopram. Similar combinations of variables predicted remission with area under the curve 0.72, explaining approximately 15% of variance (pseudo R2 ) in who achieves remission, with strong contributions from body mass index, appetite, interest-activity symptom dimension and anxious-somatizing depression subtype. Escitalopram-specific outcome prediction was more accurate than generic outcome prediction, and reached effect sizes that were near or above a previously established benchmark for clinical significance. Outcome prediction on the nortriptyline arm did not significantly differ from chance. These results suggest that easily obtained demographic and clinical variables can predict therapeutic response to escitalopram with clinically meaningful accuracy, suggesting a potential for individualized prescription of this antidepressant drug.
Individuals with a mental health disorder appear to be at increased risk of medical illness.
To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the ...clinical course of the bipolar illness according to lifetime medical illness burden.
Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria.
We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset.
Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.
White matter abnormalities have been implicated in the aetiology of major depressive disorder; however, the relationship between the severity of symptoms and white matter integrity is currently ...unclear.
To investigate white matter integrity in people with major depression and healthy controls, and to assess its relationship with depressive symptom severity.
Diffusion tensor imaging data were acquired from 66 patients with recurrent major depression and a control group of 66 healthy individuals matched for age, gender and IQ score, and analysed with tract-based spatial statistics. The relationship between white matter integrity and severity of depression as measured by the Beck Depression Inventory was examined.
Depressive illness was associated with widespread regions of decreased white matter integrity, including regions in the corpus callosum, superior longitudinal fasciculus and anterior corona radiata, compared with the control group. Increasing symptom severity was negatively correlated with white matter integrity, predominantly in the corpus callosum.
Widespread alterations in white matter integrity are evident in major depressive disorder. These abnormalities are heightened with increasing severity of depressive symptoms.
The purpose of this study was to identify genetic variants underlying the considerable individual differences in response to antidepressant treatment. The authors performed a genome-wide association ...analysis of improvement of depression severity with two antidepressant drugs.
High-quality Illumina Human610-quad chip genotyping data were available for 706 unrelated participants of European ancestry treated for major depression with escitalopram (N=394) or nortriptyline (N=312) over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, a partially randomized open-label pharmacogenetic trial.
Single nucleotide polymorphisms in two intergenic regions containing copy number variants on chromosomes 1 and 10 were associated with the outcome of treatment with escitalopram or nortriptyline at suggestive levels of significance and with a high posterior likelihood of true association. Drug-specific analyses revealed a genome-wide significant association between marker rs2500535 in the uronyl 2-sulphotransferase gene and response to nortriptyline. Response to escitalopram was best predicted by a marker in the interleukin-11 (IL11) gene. A set of 72 a priori-selected candidate genes did not show pharmacogenetic associations above a chance level, but an association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11.
While limited statistical power means that a number of true associations may have been missed, these results suggest that efficacy of antidepressants may be predicted by genetic markers other than traditional candidates. Genome-wide studies, if properly replicated, may thus be important steps in the elucidation of the genetic basis of pharmacological response.
Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex ...differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.
Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect ...genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders.
Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control DeCC study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network DeNT study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression GENDEP study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry.
Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1.
This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.
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