Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate ...medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial – a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent (‘use as directed’ or ‘use with caution’ test categories) or incongruent (‘use with increased caution and with more frequent monitoring’ test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement change in 17-item Hamilton Depression Rating Scale (HAM-D17) at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939).
The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive ...disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions.
Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD. Patients were randomized to treatment as usual (TAU) or the guided-care arm, in which clinicians had access to a combinatorial pharmacogenomic test report to inform medication selection. Patients and raters were blinded to study arm through week 8. The following outcomes were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17): symptom improvement (percent change in HDRS-17 score), response (≥ 50% decrease in HDRS-17 score), and remission (HDRS-17 score ≤ 7). In the GUIDED trial, the primary endpoint of symptom improvement did not reach significance in the intent-to-treat cohort (P = .069). Here, a post hoc analysis of patients who were taking medications subject to gene-drug interactions at baseline as predicted by combinatorial pharmacogenomic testing (N = 912) is presented.
Among participants taking medications subject to gene-drug interactions at baseline, outcomes at week 8 were significantly improved for those in the guided-care arm compared to TAU (symptom improvement: 27.1% versus 22.1%, P = .029; response: 27.0% versus 19.0%, P = .008; remission: 18.2% versus 10.7%, P = .003). When patients who switched medications were assessed, all outcomes were significantly improved in the guided-care arm compared to TAU (P = .011 for symptom improvement, P = .011 for response, P = .008 for remission).
By identifying and focusing on the patients with predicted gene-drug interactions, use of a combinatorial pharmacogenomic test significantly improved outcomes among patients with MDD who had at least 1 prior medication failure.
ClinicalTrials.gov identifier: NCT02109939.
Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder ...(MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.
This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6.
At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms.
The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms.
Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.
Medication non-adherence is a critical challenge for many patients diagnosed with mood disorders (Goodwin and Jamison, 1990). There is a need for alternative strategies that improve adherence among ...patients with mood disorders that are cost-effective, able to reach large patient populations, easy to implement, and that allow for communication with patients outside of in-person visits. Technology-based approaches to promote medication adherence are increasingly being explored to address this need. The aim of this paper is to provide a systematic review of the use of mobile technologies to improve medication adherence in patients with mood disorders.
A total of nine articles were identified as describing mobile technology targeting medication adherence in mood disorder populations.
Results showed overall satisfaction and feasibility of mobile technology, and reduction in mood symptoms; however, few examined effectiveness of mobile technology improving medication adherence through randomized control trials.
Given the limited number of studies, further research is needed to determine long term effectiveness.
Mobile technologies has the potential to improve medication adherence and can be further utilized for symptom tracking, side effects tracking, direct links to prescription refills, and provide patients with greater ownership over their treatment progress.
•Technology-based approaches to promote medication adherence are increasing in need.•Results showed satisfaction and feasibility of mobile technology.•Results showed reduction in mood symptoms.•Mobile technology can be utilized for symptom tracking.
A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could ...provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/β signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.
The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been ...identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.
•Examined fMRI brain features related to long-term lithium response in bipolar disorder.•Greater task based activation in the prefrontal cortex seen in lithium responders compared to non-responders ...for a fearful-neutral contrast.•Greater tasked based activation in limbic regions in lithium non-responders compared to responders for a fearful-neutral contrast.
Background
Genetics of Recurrent Early‐Onset Depression study (GenRED II) data were used to examine the relationship between posttraumatic stress disorder (PTSD) and attempted suicide in a population ...of 1,433 individuals with recurrent early‐onset major depressive disorder (MDD). We tested the hypothesis that PTSD resulting from assaultive trauma increases risk for attempted suicide among individuals with recurrent MDD.
Methods
Data on lifetime trauma exposures and clinical symptoms were collected using the Diagnostic Interview for Genetic Studies version 3.0 and best estimate diagnoses of MDD, PTSD, and other DSM‐IV Axis I disorders were reported with best estimated age of onset.
Results
The lifetime prevalence of suicide attempt in this sample was 28%. Lifetime PTSD was diagnosed in 205 (14.3%) participants. We used discrete time‐survival analyses to take into account timing in the PTSD‐suicide attempt relationship while adjusting for demographic variables (gender, race, age, and education level) and comorbid diagnoses prior to trauma exposure. PTSD was an independent predictor of subsequent suicide attempt (HR = 2.5, 95% CI: 1.6, 3.8; P < .0001). Neither assaultive nor nonassaultive trauma without PTSD significantly predicted subsequent suicide attempt after Bonferroni correction. The association between PTSD and subsequent suicide attempt was driven by traumatic events involving assaultive violence (HR = 1.7, 95% CI: 1.3, 2.2; P< .0001).
Conclusions
Among those with recurrent MDD, PTSD appears to be a vulnerability marker of maladaptive responses to traumatic events and an independent risk factor for attempted suicide. Additional studies examining differences between those with and without PTSD on biological measures might shed light on this potential vulnerability.
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