Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and \u3e/=1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes

Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study

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 (\u27use as directed\u27 or \u27use with caution\u27 test categories) or incongruent (\u27use with increased caution and with more frequent monitoring\u27 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 ( \u3e /=50% decrease in HAM-D17) and remission (HAM-D17 \u3c /=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)

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic(R); weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes

Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes

Symptom severity of bipolar disorder during the menopausal transition

BACKGROUND: Little is known about the mood symptom experience of women with bipolar disorder during the menopausal transition (MT). Yet times of rapid hormonal decline, such as the postpartum, are associated with increased risk of severe mood episodes in bipolar disorder, and the MT is a time of increased risk for unipolar depression in women with or without a history of depression. METHODS: Enrollment included 56 women 40-60 years old diagnosed in the bipolar spectrum who were experiencing menopausal symptoms or were up to 5 years since their final menstrual period. Menopausal stages included early menopause, late menopause, or early postmenopause based on standardized criteria. Observational, prospective standardized mood symptom and reproductive hormone assessments were completed periodically. Concurrent menopausal symptoms as well as history of mood exacerbation during past reproductive events were assessed. RESULTS: Forty-four women were included in the main analysis. The average Montgomery-Asberg Depression Rating Scale (MADRS) score was 4.43 points higher in the late transition/early postmenopausal stage women (n = 29) compared to the early menopausal stage women (n = 15) (+/-SE 2.14; p = 0.039), corresponding to a roughly 10 % higher score (range 0-40) in the late/post stage across all study visits. Results were similar for the Young Mania Rating Scale (YMRS), where the average score was 2.54 points higher in the late/early postmenopausal stage women compared to the early menopausal stage women (+/-SE 1.15; p = 0.027), also roughly 10 % higher (range 0-26). Estradiol and follicle-stimulating hormone (FSH) absolute levels as well as between-visit change in levels were not notably associated with YMRS or MADRS during study observation. Total Greene Climacteric Symptom (menopausal symptom) score was significantly associated with MADRS but not YMRS. History of mood exacerbation premenstrually and/or postpartum was not significantly associated with YMRS or MADRS severity during the MT. CONCLUSIONS: These results support the theory that times of increased reproductive hormonal changes, such as the late MT and early postmenopause, here compared to early MT, are associated with greater mood symptom severity in bipolar spectrum women. Nonetheless, absolute or change in FSH and estradiol levels were not significantly associated with depression or mood elevation severity

Disrupted Resting-State Functional Connectivity in Medication-free Women with Postpartum Depression

Background: Women are at increased risk of developing depression in the postpartum, a time of gonadal steroid flux. Abnormalities of gonadal steroids have been identified in some depressed women at times of reproductive flux. Gonadal steroids modulate corticocortical and corticolimbic functional connectivity (FC) in healthy, non-puerperal subjects; however there are no published studies of FC in postpartum depression (PPD). Methods: Healthy comparison (HCS) (n=9) and medication-free subjects with unipolar PPD (n=8) were scanned at 3-9 weeks postpartum (using 3T Philips MRI) while ‘at rest’ with eyes open. Data analysis was carried out using SPM-8 and Data Processing Assistant for Resting-State fMRI (DPARSF) to perform seed based resting-state functional connectivity (rs-FC) analysis. Seeds were placed at bilateral anterior cingulate (ACC) and dorsolateral prefrontal cortices (DLPFC), hippocampi (HIPP) and amygdalae (AMYG). Correlation coefficients obtained from individual subject analysis were used in performing two-sample t-test to compare the two cohorts. Results: Functional connectivity maps revealed a more distributed pattern of connectivity with each seed (i.e. ACC, DLPFX, HIPP, and AMYG) for HCS than PPD. In PPD subjects as compared to HCS, there was attenuation of rs-FC between corticocortical and corticolimbic areas. Conclusions: In the early postpartum period, rs-FC patterns are disrupted in women with PPD in brain regions important for cognition, affect and the stress response. Larger studies are necessary to elucidate the role of disrupted neural connections in the pathophysiology of PPD and the potential modulatory role of gonadal steroids in women

Advancing Stage of Female Reproductive Life Associated with Bipolar Illness Exacerbation

Introduction: Perimenopause confers an increased risk of depression in the general population, yet bipolar disorder mood course remains unknown. Methods: Clinic visits in 519 premenopausal, 116 perimenopausal including 13 women transitioning from peri- to postmenopause, and 133 postmenopausal women with bipolar disorder who received naturalistic treatment in the multisite STEP-Bipolar Disorder study over 19.8 +/- 15.5 months were analyzed for mood state. Results: Advancing female reproductive stage was associated with significant decline in mood elevation; significant decline in euthymia; no significant difference in major depression; and symptomatic significant increase. Conclusions: Advancing stage of female reproductive life was associated with bipolar illness exacerbation. Women transitioning from peri- to postmenopause had significantly greater depression than other female reproductive groups

Durability of symptomatic responses obtained with adjunctive vagus nerve stimulation in treatment-resistant depression

Objective: To compare the durations of response achieved with adjunctive vagus nerve stimulation (VNS + TAU) vs treatment as usual (TAU) alone in treatment-resistant depression (TRD) over a 5-year period in the TRD registry. Materials and methods: Data from 271 participants on TAU and 328 participants on VNS + TAU were analyzed. Response was defined as \u3e /=50% decrease in baseline Montgomery-Asberg Depression Rating Scale (MADRS) score at postbaseline visit and was considered retained until the decrease was \u3c 40%. MADRS was obtained quarterly in year 1 and biannually thereafter. Time-to-events were estimated using Kaplan-Meier method and compared using log-rank test. HR was estimated using Cox proportion hazard model. Results: In the VNS + TAU arm, 62.5% (205/328) of participants had a first response over 5 years compared with 39.9% (108/271) in TAU. The time to first response was significantly shorter for VNS + TAU than for TAU (P \u3c 0.01). For responders in the first year, median time to relapse from first response was 10.1 months (Q1=4.2, Q3=31.5) for VNS + TAU vs 7.3 months (Q1=3.1, Q3=17.6) for TAU (P \u3c 0.01). HR=0.6 (95% CI: 0.4, 0.9) revealed a significantly lower chance for relapse in VNS + TAU. Probability of retaining first response for a year was 0.39 (0.27, 0.51) for TAU and 0.47 (0.38, 0.56) for VNS + TAU. Timing of the onset of the response did not impact the durability of the response. Conclusion: VNS therapy added to TAU in severe TRD leads to rapid onset and higher likelihood of response, and a greater durability of the response as compared to TAU alone

Effects of Preexisting Psychotropic Medication Use on a Cohort of Patients with Ischemic Stroke Outcome

Background: Several studies investigated the use of selective serotonin reuptake inhibitors (SSRI) after ischemic stroke to improve motor recovery. However, little is known about the effects of preexisting psychotropic medication use (PPMU), such as antidepressants, on a long-term ischemic stroke functional disability. Objective: We sought to determine the prevalence of PPMU and whether PPMU relates to the long-term clinical outcome in a cohort of patients presenting with acute ischemic strokes. Methods: We retrospectively analyzed 323 consecutive patients who presented with an acute ischemic stroke in a single institution between January 2015 and December 2017. Baseline characteristics, functional disability as measured by the modified Rankin Scale (mRS), and major adverse cardiovascular complications (MACE) within 365 days were recorded. The comparison groups included a control group of ischemic stroke patients who were not on psychotropic medications before and after the index ischemic stroke and a second group of poststroke psychotropic medication use (PoMU), which consisted of patients started on psychotropic medication during the index admission. Results: The prevalence of PPMU in the studied cohort was 21.4% (69/323). There was a greater proportion of females in the PPMU than in the comparison groups (P \u3c 0.001), while vascular risk factors were similar in all groups, except for an increased presence of posterior circulation infarcts in the PPMU (37.4% vs. 18.8%, P \u3c 0.001). Among the patients with available 1-year follow-up data (n = 246), we noted significantly greater improvement in stroke deficits, measured by National Institute of Health Stroke Scale (NIHSS) between PPMU and PoMU vs. control (3 (0-7) versus 1 (0-4), P = 0.041). The 1-year mRS was worse in PPMU and PoMU compared to the control group (2 (IQ 1-3) vs. 2 (IQ 0-3) vs. 1 (IQ 0-2), respectively, P = 0.013), but delta mRS reflecting the degree of mRS improvement showed no significant difference between any PMU and control patients (P = 0.76). There was no statistically significant difference in MACE. Conclusion: PPMU in ischemic stroke is common; it can be beneficial in ischemic stroke in the long-term clinical outcome and is not associated with increased risks of MACE

Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II

BACKGROUND: Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Electroconvulsive therapy and pharmacotherapy are each efficacious in the treatment of PD. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the acute pharmacologic treatment of PD. However, little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical importance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder. METHODS/DESIGN: The primary goal of this multicenter randomized placebo-controlled trial is to assess the risks and benefits of continuing antipsychotic medication in persons with PD once the episode of depression has responded to treatment with an antidepressant and an antipsychotic. Secondary goals are to examine age and genetic polymorphisms as predictors or moderators of treatment variability, potentially leading to more personalized treatment of PD. Individuals aged 18-85 years with unipolar psychotic depression receive up to 12 weeks of open-label treatment with sertraline and olanzapine. Participants who achieve remission of psychosis and remission/near-remission of depressive symptoms continue with 8 weeks of open-label treatment to ensure stability of remission. Participants with stability of remission are then randomized to 36 weeks of double-blind treatment with either sertraline and olanzapine or sertraline and placebo. Relapse is the primary outcome. Metabolic changes are a secondary outcome. DISCUSSION: This trial will provide clinicians with much-needed evidence to guide the continuation and maintenance treatment of one of the most disabling and lethal of psychiatric disorders. TRIAL REGISTRATION AND URL: NCT: NCT01427608