ICD-10 diagnoses and medications) was assessed during the 12-months following AAP initiation. Cohorts with and without EPS were defined. Demographics, clinical characteristics, and healthcare resource use and costs over 12 months following the first EPS claim (EPS) or randomly assigned index date (Non-EPS) were assessed. Results. A total of 11,642 patients with schizophrenia were identified; 21.2% developed EPS in the 12-months following AAP initiation. EPS and Non-EPS cohorts included 2,295 (mean age 38, 61% male, CCI 0.6) and 5,607 (mean age 39, 57% male, CCI 0.7) patients, respectively. Over the 12-month post-index period, EPS cohort had significantly higher rates of all-cause (30.2% vs. 24.6%, p<0.001) and schizophrenia-related hospital-izations (22.5% vs. 12.9%, p<0.001) and schizophrenia-related emergency room visits (25.5% vs. 16.7%, p<0.001) compared to Non-EPS cohort. All-cause ($25,911 vs. $21,550, p<0.001) and schizophrenia-related healthcare costs ($12,134 vs. $6,230, p<0.001) were significantly higher in EPS vs. Non-EPS cohort. Conclusions. In the 12 months following AAP initiation, over 20% of schizophrenia patients developed EPS, which was associated with increased healthcare resource utilization and costs. Treatment options that minimize EPS may reduce the economic burden of schizophrenia. Abstract Background. The internet allows easy access for the sales of psychoactive agents that are not regulated by the Abstract Background. Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED). Materials and Methods. Patients diagnosed with MDD who had an inadequate response to ≥ 1 psychotropic medication were ran-domized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥ 1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥ 1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI. Results. Most patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41 – 2.83) and RR 2.25 (95% CI 1.39 – 3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15 – 0.99, p=0.048). No other significant dif-ferences in risk were observed at week 8. Conclusion. These data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients. Funding. Abstract Objectives. Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is hindered by significant weight gain.Acombinationofolanzapineandsamidorphan(OLZ/SAM)isindevelopmenttoprovidetheefficacyofolanzapinewhilemitigat-ingolanzapine-associatedweightgainthroughopioid-receptorblockade.Here,wesummarizeOLZ/SAMclinicaldata.

Pharmacogenomic (PGx) testing is being increasingly recognized by clinicians as an essential tool to guide medication decisions for treatment of psychiatric illnesses. Extensive implementation of PGx testing, however, varies by setting and location. In this retrospective study, we reviewed charts from 592 patients diagnosed with a psychiatric disorder at the Loyola University Medical Center, for whom PGx testing was performed. Information collected included demographics at the time of testing, psychiatric diagnosis, medical and psychiatric history and medications prior and after PGx testing. Of the 592 charts analyzed, the most common primary diagnoses were depression (52%) and anxiety (12%). Prior to PGx testing, 72% of patients were prescribed three or more medications, whereas, after testing, only 44% were prescribed three or more medications included in the test panel (p < 0.0001). The most common clinical consideration on the PGx reports was recommendation to reduce dosages (33%). After PGx testing, the proportion of patients taking incongruent medications decreased from 26% to 19% and that of patients taking congruent medications increased from 74% to 81% (p = 0.006). The results from this retrospective data analysis demonstrated a reduction in polypharmacy and an increase in recommendation-congruent medication prescribing resulting from implementation of PGx testing.

Introduction Behavioral and psychiatric symptoms of dementia (BPSD) occur frequently, representing a significant driver of the total costs of dementia in the US. Although antidepressants and atypical antipsychotics are often used in BPSD, they have limited effectiveness and significant toxicity. As a result, recent initiatives have focused on reducing polypharmacy and psychotropic prescribing in this population. Combinatorial pharmacogenomic testing has demonstrated utility in guiding prescribing for psychotropic medications in patients with depression by identifying medications unlikely to be safe or effective due to significant gene-drug interactions. Here we present data from two small, randomized, controlled trials (RCTs) designed to test the hypothesis that combinatorial pharmacogenomic testing could aid in treatment selection for BPSD. Methods The first RCT included residents being treated at the Bayleigh Chance retirement community in Maryland (inpatient RCT). The second RCT included patients from the University of Alabama at Birmingham Memory Disorders Clinic (outpatient RCT). Patients were eligible if they had a diagnosis of dementia with psychotic symptoms and/or behavioral disturbance and their condition was severe enough to trigger a consultation with a physician (inpatient RCT) or their physician was considering starting/changing a psychotropic medication (outpatient RCT). For the outpatient RCT, patients were also required to have a caregiver who spends at least 10 hours a week with them. Informed consent was obtained at the screening visit from patients’ legally authorized representatives. The inpatient RCT intended to enroll 50 patients and the outpatient RCT intended to enroll 100 patients. Both studies were stopped early due to slow enrollment. Patients were randomized 1:1 to treatment as usual (TAU) or the combinatorial pharmacogenomic-guided care arm. All patients received combinatorial pharmacogenomic testing (GeneSight, Assurex Health). Variants in multiple pharmacokinetic and pharmacodynamic genes were assessed and a weighted combinatorial algorithm categorized medications according to the level of predicted gene-drug interactions (GDI). For patients in the guided-care arm, physicians had access to the test report at the time of the baseline visit. Physicians were blinded to the test report until after the trial for patients in TAU. Assessments were performed at baseline, week 2 (AEs only, inpatient RCT only), week 4 (outpatient RCT only), week 8, and week 12. The primary outcome was the Neuropsychiatric Inventory (NPI), which assesses the presence and severity of BPSD across 12 domains. The nursing home version (NPI-NH) was used for the inpatient RCT and the NPI questionnaire (NPI-Q) was used for the outpatient RCT. A Mixed Model for Repeated Measures (MMRM) was utilized to evaluate NPI and included treatment, week, treatment-by-week interaction, baseline score, baseline score-by-week interaction as fixed effects. The presence of a condition (i.e. depression) was evaluated as a score >0 for the relevant domain on the NPI. Side effects were evaluated using the SA-EPS and MOSES scale (inpatient RCT) or the FIBSER scale (outpatient RCT). Changes in prescribing relative to a pre-test intended medication plan were evaluated in the outpatient RCT. Results A total of 12 patients were enrolled in the inpatient RCT (5 in TAU; 7 in guided-care) and 38 patients were enrolled in the outpatient RCT (19 in TAU; 19 in guided-care). At week 12, there were no significant differences in NPI or side effects between guided-care and TAU in either RCT (Table 1). However, the proportion of outpatients experiencing depression at week 12 was significantly lower in the guided-care arm versus TAU (p=0.0479). In the outpatient RCT, the proportion of patients prescribed at least one medication subject to GDI decreased from 58.8% (pre-test) to 25.0% (week 12) in the guided-care arm (Table 2). In contrast, there was an increase in the proportion of patients in TAU taking medications subject to GDI throughout the trial. A significantly higher proportion of patients in the guided-care arm had a reduction in the number of prescribed psychotropic medications by week 12 compared to TAU (Table 2). Conclusions Overall, there were no observed differences in overall neuropsychiatric symptoms or side effects among inpatients or outpatients who received pharmacogenomic-guided care compared to TAU. It should be noted that these studies were stopped early due to slow enrollment and were likely underpowered to detect any differences. However, there was a significant reduction in the proportion of outpatients with depression in the guided care arm, which is consistent with the validated use of combinatorial pharmacogenomic testing among patients with depression. There was also evidence that pharmacogenomic-guided care did inform prescribing, with reduced prescribing of medications subject to GDI and reduced psychotropic medication polypharmacy. Funding Myriad Neuroscience (Formerly Assurex Health)

Weight gain is a common side-effect of medications used to treat major depressive disorder (MDD). We sought to estimate the frequency of weight gain for obesogenic medications prescribed for MDD and to evaluate if bupropion mitigated risk for weight gain. We analyzed a prospective cohort of patients with weight available at baseline and 12 weeks (n = 1,032) or 24 weeks (n = 871) in a post hoc analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) study of patients with MDD who failed at least one medication trial. We compared weight gain between those on versus not on medications with high risk for weight gain, including a subgroup receiving combination treatment with bupropion. A second analysis evaluated weight gain across traditional medication classes, adjusting for potential confounding variables. Those on medications identified as high risk for weight gain were significantly more likely to experience clinically significant weight gain (≥3%) at 12 weeks (29.3% vs. 16.3%, p < .001) and 24 weeks (33.5% vs. 23.5%, p = .015). No protection from clinically significant weight gain was observed among patients treated with a high-risk medication concomitantly with bupropion (N = 31, 35% and 52% with clinically significant weight gain at 12 and 24 weeks). Antipsychotic medications and tricyclic antidepressants were most often associated with clinically significant weight gain. This study helps quantify the real-world risk of weight gain for patients with MDD on medications with high risk for weight gain, especially for patients taking antipsychotics. Concurrent treatment with bupropion does not appear to mitigate the weight gain risk.

Myriad Neuroscience/Assurex Health.

Abstract:Background:The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.Methods:Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).Results:At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).Conclusions:Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.Funding Acknowledgements:Assurex Health, Inc.

Introduction Six million people in the U.S. experience depression after age 65. Major depressive disorder (MDD) in later life is associated with longer length of illness, increased number of MDD episodes, and a greater risk of comorbidities. Challenges facing clinicians when making prescription decisions for older adults include increased drug-drug interactions, lower adherence, and higher rates of adverse events. Medication trials for MDD can be difficult to navigate in older patients due to increased polypharmacy for multiple conditions. As the aging population grows, the demand for data-driven tools to optimize medication prescribing for older patients with MDD is gaining momentum. Combinatorial pharmacogenomic (PGx) testing may improve and personalize medication prescribing for older patients by identifying medications that have patient-specific adverse gene-drug interactions. Methods The GUIDED study was a blinded, randomized controlled trial which sought to evaluate the use of a combinatorial PGx test in improving outcomes for patients with MDD by guiding medication treatment decisions. Patients were randomized to either the guided-care arm where the combinatorial PGx test result was available to providers to guide treatment decisions or to the treatment as usual (TAU) arm where the test result was not available to providers until after the primary endpoint. Both patients and raters were blinded to the arm until after the completion of the primary endpoint week 8 assessment. The primary endpoint was symptom improvement on the 17-Item Hamilton Depression Rating Scale (HAM-D17). Secondary endpoints included response (50% reduction in HAM-D17 from baseline) and remission (score ≤7 on HAM-D17). In this subanalysis, we evaluated whether patients aged 65 and older had differences in outcomes based on treatment guidance from combinatorial PGx testing. Results In the GUIDED study, 206 patients were 65+ years of age at baseline with a median age of 69; 108 patients in the treatment as usual (TAU) and 98 patients in the guided-care arm (combinatorial PGx test). The mean HAM-D17 score at baseline overall was 19.8 for all patients, 20.2 in the TAU arm and 19.4 in the guided-care arm. The average number of failed medication trials was 3.5 (3.7 in TAU and 3.3 in guided-care). At week 8, there was a 26.7% decrease in HAM-D17 scores in the guided-care arm (n=86) compared to an 18.7% decrease in TAU (n=98). The difference in symptom improvement between arms did not reach statistical significance (p=0.102). Response rate was significantly higher in the guided-care arm at week 8, with 29.6% of patients experiencing response, compared to 16.1% in TAU (p=0.032). The remission rate was also significantly higher in the guided-care arm at week 8 (20.1%), compared to TAU (7.4%, p=0.014). Conclusions Patients who were 65?years or older in the GUIDED trial whose medication treatment was guided by combinatorial PGx testing achieved significantly better response and remission rates compared to TAU. The difference in symptom improvement in this population did not reach statistical significance. Overall, the data presented here support the utility of using combinatorial PGx testing to help guide antidepressant medication selection with a goal to improve outcomes of depression. This research was funded by: Myriad Genetics, Inc.

Aim: To perform a meta-analysis of prospective, two-arm studies examining the clinical utility of using the combinatorial pharmacogenomic test, GeneSight Psychotropic, to inform treatment decisions for patients with major depressive disorder (MDD). Patients & methods: The pooled mean effect of symptom improvement and pooled relative risk ratio (RR) of response and remission were calculated using a random effect model. Results: Overall, 1556 patients were included from four studies, with outcomes evaluated at week 8 or week 10. Patient outcomes were significantly improved for patients with MDD whose care was guided by the combinatorial pharmacogenomic test results compared with unguided care (symptom improvement Δ = 10.08%, 95% CI: 1.67-18.50; p = 0.019; response RR = 1.40, 95% CI: 1.17-1.67; p < 0.001; remission RR = 1.49, 95% CI: 1.17-1.89; p = 0.001). Conclusion: GeneSight Psychotropic guided care improves outcomes among patients with MDD.

OBJECTIVE:We compared economic outcomes when elderly patients with neuropsychiatric disorders received psychotropic medications guided by a combinatorial pharmacogenomic (PGx) test.METHODS:This is a subanalysis of a 1-year prospective assessment of medication cost for patients with neuropsychiatric disorders receiving combinatorial PGx testing. Pharmacy claims were used to compare per member per year (PMPY) medication cost for patients ≥65 and <65 years old when medications were congruent or incongruent with the PGx test. Polypharmacy was also assessed.RESULTS:Congruent prescribing was associated with savings of US$3497 PMPY (P < .001) for patients ≥65 years and US$2467 PMPY (P < .001) for patients <65, compared to incongruent prescribing. Congruent prescribing in patients ≥65 treated by primary care providers was associated with US$4113 PMPY (P = .026) in savings, while congruent prescribing by psychiatrists was associated with US$120 PMPY (P = .719). Congruent prescribing was also associated with one fewer neuropsychiatric medication for patients ≥65 (P = .070).CONCLUSION:Congruence with PGx testing was associated with medication cost savings in elderly patients.

(Reprinted with permission from Am J Geriatr Psychiatry 2020; 28:933-945).

Objective To estimate Canadian pharmacy cost savings associated with psychiatric medication prescribing that is guided by combinatorial pharmacogenomic testing in patients switching or augmenting their psychiatric medication. Methods Pharmacy claims data from a United States (US) pharmacy benefit manager were analyzed for 1662 patients who recently augmented or switched to a different antidepressant or antipsychotic medication and underwent combinatorial pharmacogenomic testing. Costs of prescription medications were translated to the Canadian healthcare system by matching drug names and doses using the Ontario Drug Benefit Formulary. One-year costs (2017 CAD) were compared between patients whose clinician prescribed antidepressants or antipsychotics that were consistent (congruent) or inconsistent (incongruent) with the combinatorial pharmacogenomic test recommendations. Results Patients whose psychiatric medication treatment was congruent with the combinatorial pharmacogenomic test report saved $1061 CAD per member per year (PMPY) on prescription medication costs relative to patients whose medications were incongruent with their test report (p<0.0001). For patients ages <65 and ≥65, prescription medication costs were $979 and $1178 CAD PMPY lower, respectively, for patients who followed the report recommendations (p=0.0004 and p=0.13). Prescription drug fills from the US pharmacy claims were concordant with the Canadian Formulary; 62% of fills matched at both the drug name and dose strength, 81% matched at drug name, and >99% matched at the therapeutic chapter. Conclusions Antidepressant and antipsychotic prescribing that was congruent with combinatorial pharmacogenomic test guidance was associated with significant cost savings on Canadian prescription medications according to the Ontario Drug Benefit Formulary.

This study assessed the efficacy and safety of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate-release tacrolimus [IR-TAC]; target minimum blood concentration [Ctrough] 4-11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR-TAC (0.1 mg/kg per day; target Ctrough 4-11 ng/mL days 0-30, then 2-5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3-5 posttransplant) and corticosteroids. One hundred thirty-eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR-TAC [n = 44]). For the primary endpoint (incidence of biopsy-proven acute rejection [BPAR] at 6 months), bleselumab + IR-TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] −8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%-46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR-TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit–risk ratio. Most treatment-emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).

OBJECTIVEThe 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.METHODSParticipants (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 Depre​ssion 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.RESULTSAmong 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).CONCLUSIONSBy 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.TRIAL REGISTRATIONClinicalTrials.gov identifier: NCT02109939​.

Julie-Anne Tanner 1,2 Lisa C Brown 3 Kunbo Yu 3 James Li 3 Bryan M Dechairo 1Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Department of Psychiatry, Toronto, ON, Canada; 2Assurex Health Ltd., Toronto, ON, Canada; 3Assurex Health, Inc., Mason, OH, USA; 4Myriad Genetics, Inc., Salt Lake City, UT, USA Objective: To estimate Canadian pharmacy cost savings associated with psychiatric medication prescribing that is guided by combinatorial pharmacogenomic testing in patients switching or augmenting their psychiatric medication. Methods: Pharmacy claims data from a United States (US) pharmacy benefit manager were analyzed for 1662 patients who recently augmented or switched to a different antidepressant or antipsychotic medication and underwent combinatorial pharmacogenomic testing. Costs of prescription medications were translated to the Canadian healthcare system by matching drug names and doses using the Ontario Drug Benefit Formulary. One-year costs (2017 CAD) were compared between patients whose clinician prescribed antidepressants or antipsychotics that were consistent (congruent) or inconsistent (incongruent) with the combinatorial pharmacogenomic test recommendations. Results: Patients whose psychiatric medication treatment was congruent with the combinatorial pharmacogenomic test report saved $1061 CAD per member per year (PMPY) on prescription medication costs relative to patients whose medications were incongruent with their test report (p<0.0001). For patients ages <65 and ≥65, prescription medication costs were $979 and $1178 CAD PMPY lower, respectively, for patients who followed the report recommendations (p=0.0004 and p=0.13). Prescription drug fills from the US pharmacy claims were concordant with the Canadian Formulary; 62% of fills matched at both the drug name and dose strength, 81% matched at drug name, and >99% matched at the therapeutic chapter. Conclusions: Antidepressant and antipsychotic prescribing that was congruent with combinatorial pharmacogenomic test guidance was associated with significant cost savings on Canadian prescription medications according to the Ontario Drug Benefit Formulary.

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).

Background 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. Methods 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. Results 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. Conclusions 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. Trial registration Clinicaltrials.gov: NCT02109939 . Registered 10 April 2014.

AbstractBackgroundMajor depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.Methods1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.ResultsAt week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.ConclusionsCombinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.Funding Acknowledgements: This study was supported by Assurex Health, Inc.

Background: Currently, no pharmacogenetic tests for selecting an opioid-dependence pharmacotherapy have been approved by the US Food and Drug Administration. Objectives: Determine the effects of variants in 11 genes on dropout rate and dose in patients receiving methadone or buprenorphine/naloxone (ClinicalTrials.gov Identifier: NCT00315341). Methods: Variants in six pharmacokinetic genes (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4) and five pharmacodynamic genes (HTR2A, OPRM1, ADRA2A, COMT, SLC6A4) were genotyped in samples from a 24-week, randomized, open-label trial of methadone and buprenorphine/naloxone for the treatment of opioid dependence (n=764; 68.7% male). Genotypes were then used to determine the metabolism phenotype for each pharmacokinetic gene. Phenotypes or genotypes for each gene were analyzed for association with dropout rate and mean dose. Results: Genotype for 5-HTTLPR in the SLC6A4 gene was nominally associated with dropout rate when the methadone and buprenorphine/naloxone groups were combined. When the most significant variants associated with dropout rate were analyzed using pairwise analyses, SLC6A4 (5-HTTLPR) and COMT (Val158Met; rs4860) had nominally significant associations with dropout rate in methadone patients. None of the genes analyzed in the study was associated with mean dose of methadone or buprenorphine/naloxone. Conclusions: This study suggests that functional polymorphisms related to synaptic dopamine or serotonin levels may predict dropout rates during methadone treatment. Patients with the S/S genotype at 5-HTTLPR in SLC6A4 or the Val/Val genotype at Val158Met in COMT may require additional treatment to improve their chances of completing addiction treatment. Replication in other methadone patient populations will be necessary to ensure the validity of these findings.