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).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Depression prevalence was examined by race/ethnicity in a nationally representative sample. The Diagnostic Interview Schedule was administered to 8449 (response rate=96.1%) participants (aged 15-40 ...years). Prevalence of major depressive disorder was significantly higher in Whites than in African Americans and Mexican Americans; the opposite pattern was found for dysthymic disorder. Across racial/ethnic groups, poverty was a significant risk factor for major depressive disorder, but significant interactions occurred between race/ethnicity, gender, and education in relation to prevalence of dysthymic disorder.
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CEKLJ, DOBA, FSPLJ, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Greden comments on a study by Trivedi et al in which they evaluated 1,928 adult outpatients with depression who were treated with citalopram according to the well-described Sequenced Treatment ...Alternatives to Relieve Depression (STAR*D) guidelines, and they wisely added the Work Productivity and Activity Impairment scale. Workers who did not achieve symptom remission until later stages continued to manifest impairment at work. The finding that productivity improved among workers who attained wellness with early treatment is a clarion call for greater partnerships among the business and brain-science worlds in efforts to combat depression in the workforce.
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.
The burden of depression on society is sizable. Innate to this burden are underdiagnosis and under-treatment of unipolar and bipolar major depressive disorder in all parts of the health care system ...in part due to underrecognition of the physical symptoms that commonly are core components of major depressive disorder. Physical pains especially complicate the diagnosis of depression. Many patients de-emphasize psychosocial symptoms while emphasizing pains as their primary or sole complaints. There is a high correlation between the number of physical symptoms reported and the presence of depression. Additionally, patients with residual physical and emotional symptoms following treatment for depression appear to be at higher risk of relapse compared with those who have no residual symptoms. Complex genetic vulnerabilities underlie the depressive diathesis, and stress appears to be an accentuation for the gene expression that sets off episodes of depression in persons with these predispositions. If underdiagnosis interferes and acute treatment is not implemented early and effectively for initial episodes of depression and maintained after remission, individuals with genetic vulnerabilities may experience a pattern of recurrences, cycle acceleration, and increased severity. Serotonin and norepinephrine may be shared neurochemical links that tie depression and physical symptoms together. Thus, it is reasonable to hypothesize that antidepressants that incorporate both serotonin and norepinephrine reuptake inhibition might be a more efficacious treatment approach for patients with physical symptoms of depression.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Longitudinal studies of psychiatric disorders form the current basis for nosology.•The clinical course of bipolar disorder is a major feature of the phenotype.•Nearly half of the observation time in ...bipolar disorder shows symptoms of disease.•Major depression is often comorbid with other medical and psychiatric illness.•Combined treatment with medicine and therapy is most effective for depression.
Most psychiatric syndromes are chronic and lifetime in course. Kraepelin's seminal work pointed out a century ago that longitudinal/lifetime assessments were powerful aids in differentiating dementia praecox from manic-depressive disorder. Despite this, clinical research investigations in psychiatry have historically emphasized short-term and cross-sectional approaches.
This review of an array of longitudinal studies supports that they are arguably an essential component of psychiatric investigations, but that they must be coupled with other approaches. The use of standardized, validated, repeated assessments in a disease over the course of time must be incorporated with pathophysiology investigations to identify underlying mechanisms, biomarker studies, comparative effectiveness clinical trials to identify the best treatments for different causes, and translational strategies to provide the right treatments to the right patients at the right time. Strategies for incorporating longitudinal assessments into newer diagnostic proposals, such as the Research Domain Criteria (RDoC), are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Citizen soldiers (National Guard and Reserves) represent approximately 40% of the two million armed forces deployed to Afghanistan and Iraq. Twenty‐five to forty percent of them develop PTSD, ...clinical depression, sleep disturbances, or suicidal thoughts. Upon returning home, many encounter additional stresses and hurdles to obtaining care: specifically, many civilian communities lack military medical/psychiatric facilities; financial, job, home, and relationship stresses have evolved or have been exacerbated during deployment; uncertainty has increased related to future deployment; there is loss of contact with military peers; and there is reluctance to recognize and acknowledge mental health needs that interfere with treatment entry and adherence. Approximately half of those needing help are not receiving it. To address this constellation of issues, a private–public partnership was formed under the auspices of the Welcome Back Veterans Initiative. In Michigan, the Army National Guard teamed with the University of Michigan and Michigan State University to develop innovative peer‐to‐peer programs for soldiers (Buddy‐to‐Buddy) and augmented programs for military families. Goals are to improve treatment entry, adherence, clinical outcomes, and to reduce suicides. This manuscript describes training approaches, preliminary results, and explores future national dissemination.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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