There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances ...suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.
Background To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it ...from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. Methods This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime ( n = 12), or long-term ongoing ( n = 17) lithium treatment. Results Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. Conclusions Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations.
Anxiety disorders are increasingly recognised as an important determinant of outcomes in patients with bipolar disorder. However, a reliable estimate of their prevalence is still missing, because the ...published prevalence of anxiety disorders in individuals with bipolar disorder varies widely. In this study, we aimed to quantify the lifetime prevalence of anxiety disorders in individuals with bipolar disorder and compare it with rates in people without the disorder.
We searched the Web of Knowledge and Medline (through the PubMed interface) for articles published in any language from the database inception dates up until June 1, 2014, using a combination of the word "bipolar" and search terms for anxiety disorders. We included studies that reported original data about the lifetime prevalence of DSM-III and DSM-IV anxiety disorders in adults with bipolar disorder that recruited participants irrespective of comorbidities and that used a validated diagnostic interview to establish the diagnoses of bipolar disorder and at least one anxiety disorder. We excluded studies that reported only the current prevalence or if we were unable to establish whether they described current or lifetime prevalence, and those with discrepancies in the data that could not be resolved by contacting the authors. We did a random-effects meta-analysis of lifetime prevalence of DSM-III and DSM-IV anxiety disorders in adults with bipolar disorder, in which we quantified the lifetime prevalence of any anxiety disorder in people with bipolar disorder. We compared this prevalence in people with bipolar I disorder versus those with bipolar II disorder, and in people with bipolar disorder versus population controls.
Data from 40 studies, including 14 914 individuals from North America, Europe, Australia, South America, and Asia, indicate that the lifetime prevalence of anxiety disorders in individuals with bipolar disorder is 45% (95% CI 40-51). Direct comparison in five samples with a total of 1378 individuals with bipolar disorder and 56 812 population controls without bipolar disorder indicates a three-fold increase (risk ratio RR 3·22 95% CI 2·41-4·29; p<0·0001) in the prevalence of anxiety disorders in those with bipolar disorder. 13 studies that included both individuals with bipolar I disorder (n=4270) and those with bipolar II disorder (n=1939) showed no difference in the lifetime prevalence of anxiety disorders between these subtypes (RR 1·07 95% CI 0·96-1·20; p=0·223). We noted significant heterogeneity among included studies that was not accounted for by reported differences in study characteristics.
People with bipolar disorder are at increased risk of anxiety disorders compared with those without bipolar disorder; nearly one in two has an anxiety disorder in their lifetime. Anxiety disorders should therefore be assessed alongside the mood symptoms in patients with bipolar disorder.
Capital Health Research Fund.
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.
Objective
Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes ...distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories.
Methods
In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale.
Results
Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio OR = 1.68, P = 0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8.
Conclusions
We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.
Previous fMRI studies show that women with eating disorders (ED) have differential neural activation to viewing food images. However, despite clinical differences in their responses to food, ...differential neural activation to thinking about eating food, between women with anorexia nervosa (AN) and bulimia nervosa (BN) is not known.
We compare 50 women (8 with BN, 18 with AN and 24 age-matched healthy controls HC) while they view food images during functional Magnetic Resonance Imaging (fMRI).
In response to food (vs non-food) images, women with BN showed greater neural activation in the visual cortex, right dorsolateral prefrontal cortex, right insular cortex and precentral gyrus, women with AN showed greater activation in the right dorsolateral prefrontal cortex, cerebellum and right precuneus. HC women activated the cerebellum, right insular cortex, right medial temporal lobe and left caudate. Direct comparisons revealed that compared to HC, the BN group showed relative deactivation in the bilateral superior temporal gyrus/insula, and visual cortex, and compared to AN had relative deactivation in the parietal lobe and dorsal posterior cingulate cortex, but greater activation in the caudate, superior temporal gyrus, right insula and supplementary motor area.
Women with AN and BN activate top-down cognitive control in response to food images, yet women with BN have increased activation in reward and somatosensory regions, which might impinge on cognitive control over food consumption and binge eating.
A decade of research has demonstrated the explanatory potential of interplay between genetic variants and environmental factors in the development of common mental disorders. Initial findings have ...undergone tests of replicability and specificity. Some gene–environment interactions have been confirmed, some have not replicated and yet other turned out to be more specific than initially thought. Specific and complementary roles of genetic factors have been delineated: a common functional length polymorphism in the serotonin transporter gene (5-HTTLPR) moderated the effect of childhood maltreatment on chronic depression in adulthood, but did not substantially influence the effects of adult stressful life events on the onset of new depressive episodes; in contrast, a common functional polymorphism in the brain-derived neurotrophic factor gene (BDNF) moderated the effect of stressful life events in adulthood in triggering new depressive episodes, but did not influence the effects of childhood maltreatment. Molecular mechanisms underlying gene–environment interactions are being uncovered, including DNA methylation and other epigenetic modifications. New gene–environment interactions continue to be reported, still largely from hypothesis-driven research. Statistical and biological prioritization strategies are proposed to facilitate a systematic discovery of novel gene–environment interactions in genome-wide analyses.
Anhedonia is thought to reflect deficits in reward processing that are associated with abnormal activity in mesocorticolimbic brain regions. It is expressed clinically as a deficit in the interest or ...pleasure in daily activities. More severe anhedonia in major depressive disorder (MDD) is a negative predictor of antidepressant response. It is unknown, however, whether the pathophysiology of anhedonia represents a viable avenue for identifying biological markers of antidepressant treatment response. Therefore, this study aimed to examine the relationships between reward processing and response to antidepressant treatment using clinical, behavioral, and functional neuroimaging measures. Eighty-seven participants in the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) protocol received 8 weeks of open-label escitalopram. Clinical correlates of reward processing were assessed at baseline using validated scales to measure anhedonia, and a monetary incentive delay (MID) task during functional neuroimaging was completed at baseline and after 2 weeks of treatment. Response to escitalopram was associated with significantly lower self-reported deficits in reward processing at baseline. Activity during the reward anticipation, but not the reward consumption, phase of the MID task was correlated with clinical response to escitalopram at week 8. Early (baseline to week 2) increases in frontostriatal connectivity during reward anticipation significantly correlated with reduction in depressive symptoms after 8 weeks of treatment. Escitalopram response is associated with clinical and neuroimaging correlates of reward processing. These results represent an important contribution towards identifying and integrating biological, behavioral, and clinical correlates of treatment response. ClinicalTrials.gov: NCT01655706.
Objectives
The COVID-19 pandemic has contributed to a shift from in-person to remote mental health care. While remote care methods have long existed, their widespread use is unprecedented. There is ...little research about mental health care user and provider experiences with this transition, and no published studies to date have compared satisfaction between these groups.
Methods
Canadian mental health care users (n = 332) and providers (n = 107) completed an online self-report survey from October 2020 to February 2021 hosted by the Canadian Biomarker Integration Network in Depression. Using a mixed-methods approach, participants were asked about their use of remote care, including satisfaction, barriers to use, helpful and unhelpful factors, and suggestions for improvement.
Results
Overall, 59% to 63% of health care users and 59% of health care providers were satisfied with remote care. Users reported the greatest satisfaction with the convenience of remote care, while providers were most satisfied with the speed of provision of care; all groups were least satisfied with therapeutic rapport. Health care providers were less satisfied with the user-friendliness of remote care (P < 0.001) than users, while health care users were less satisfied than providers with continuity of care (P < 0.001). The use of a video-based platform was associated with remote care satisfaction among health care users (P < 0.02), and qualitative responses support the importance of visual cues in maintaining therapeutic rapport remotely. The majority of users (55%) and providers (87%) reported a likelihood of using remote care after the pandemic.
Conclusions
Remote mental health care is generally accepted by both users and providers, and the majority would consider using remote care following the pandemic. Suggestions for improvement include greater use of video, increased attention to body language and eye contact, consistency with in-person care, as well as increased provider training and administrative support.
The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and ...glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P=0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.
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