High Probability of Gene-Drug Interactions Associated with Medication Side Effects in Adolescent Depression: Results from a Randomized Controlled Trial of Pharmacogenetic Testing.

Introduction: Combinatorial pharmacogenetic testing panels are widely available in clinical practice and often separate medications into columns/bins associated with low, medium, or high probability of gene-drug interactions. The objective of the Adolescent Management of Depression (AMOD) study was to determine the clinical utility of combinatorial pharmacogenetic testing in a double-blind, randomized, controlled effectiveness study by comparing patients who had genetic testing results at time of medication initiation to those that did not have results until week 8. The objective of this post hoc analysis was to assess and report additional outcomes with respect to significant gene-drug interactions (i.e., a medication in the high probability gene-drug interaction bin as defined by a proprietary algorithm) compared with patients taking a medication with minimal to moderate gene-drug interactions (i.e., a medication from the low or medium probability gene-drug interaction bin, respectively). Methods: Adolescents 13-18 years (N = 170) with moderate to severe major depressive disorder received pharmacogenetic testing. Symptom improvement and side effects were assessed at baseline, week 4, week 8, and 6 months. Patients were grouped into three categories based on whether the medication they were prescribed was associated with low, medium, or high risk for gene-drug interactions. Patients taking a medication from the low/medium gene-drug interaction bin were compared with patients taking a medication from the high gene-drug interaction bin. Results: Patients taking a medication from the high gene-drug interaction bin were more likely to endorse side effects compared with patients taking a medication in the low/medium gene-drug interaction bin at week 8 (p = 0.001) and 6 months (p < 0.0001). Depressive symptom severity scores did not differ significantly across the medication bins. Conclusions: This study demonstrates the utility of gene-drug interaction testing to guide medication decisions to minimize side effect burden rather than solely prioritizing the search for the most efficacious medication. (Clinical Trials Registration Identifier: NCT02286440).

A Randomized Controlled Trial of Combinatorial Pharmacogenetics Testing in Adolescent Depression.

OBJECTIVE: Numerous commercial pharmacogenetics panels are now widely available for clinical use in psychiatric practice. However, there is a paucity of literature evaluating the use of combinatorial pharmacogenetics panels to enhance outcomes in the treatment of adolescents with depression. This study sought to prospectively evaluate the clinical impact of combinatorial pharmacogenetics testing in a double-blind, randomized, controlled effectiveness study for the pharmacologic treatment of adolescents with depression. METHOD: Adolescents aged 13 to 18 years (N = 176) with moderate to severe major depressive disorder (MDD) were randomized to treatment arm guided by testing in which pharmacogenetic testing results were available at the baseline visit (GENE arm, n = 84) or a treatment-as-usual arm (TAU arm, n = 92) in which testing results were not available until an 8-week visit. Raters, participants, and families were blinded to group allocation. Symptom improvement, side effects, and satisfaction were assessed throughout the study at 4 weeks, 8 weeks, and 6 months. RESULTS: There were no differences between the GENE and TAU arms at 8 weeks or 6 months for symptom improvement, side effect burden, or satisfaction. Selective serotonin reuptake inhibitors were prescribed at higher rates in the TAU arm compared to the GENE arm (p = .024). CONCLUSION: Combinatorial pharmacogenetics-guided treatment did not demonstrate improved outcomes compared to TAU in adolescents with MDD. Future research should examine how specific medication-gene pairs may affect clinical outcomes in the treatment of adolescents with depression and how best to integrate pharmacogenetics into clinical practice. CLINICAL TRIAL REGISTRATION INFORMATION: A PK/PD Genetic Variation Treatment Algorithm Versus Treatment As Usual for Adolescent Management Of Depression; https://www.clinicaltrials.gov; NCT02286440.

Mindfulness-Based Cognitive Therapy, Acceptance and Commitment Therapy, and Positive Psychotherapy for Major Depression.

OBJECTIVE: In the past two decades, newer psychotherapy treatments have emerged for the treatment of major depression. This review aimed to comprehensively synthesize the evidence for mindfulness-based cognitive therapy (MBCT), acceptance and commitment therapy (ACT), and positive psychotherapy (PPT) in treating a current episode of major depression. METHODS: A systematic search of the Ovid MEDLINE, Embase, PsycINFO, and Cochrane databases was conducted for randomized controlled trials of MBCT, ACT, and PPT for major depression. Standardized mean differences were calculated with Hedges' g to complete random-effects meta-analysis. Heterogeneity was assessed with the Cochran Q statistic and I2 statistic. Subgroup analysis was conducted to further investigate heterogeneity. RESULTS: A random-effects meta-analysis of 15 studies (MBCT, N=7; ACT, N=4; PPT, N=4) revealed that all three therapies showed efficacy in reducing symptoms of depression with a small favorable effect, compared with all control conditions (N=946; Hedges' g=0.34; 95% confidence interval=0.14, 0.54; p<0.001). Cochrane's Q statistic (Q=32, df=15, p=0.007) suggested significant heterogeneity (I2=53%). A mixed-effects model test for subgroup differences showed significant differences between active controls and treatment-as-usual controls (χ2=15.3, df=1, p<0.001). Overall quality of evidence and publication bias were low. CONCLUSIONS: Meta-analysis shows that MBCT and ACT may be superior to inactive or treatment-as-usual controls and that PPT may be comparable to active controls for reducing symptoms of major depression after an acute course of therapy. However, the quality of the evidence was low. High-quality studies are needed to confirm the efficacy of these interventions.

Exercise, Yoga, and Tai Chi for Treatment of Major Depressive Disorder in Outpatient Settings: A Systematic Review and Meta-Analysis.

OBJECTIVE: Exercise, yoga, and tai chi are commonly used complementary approaches for health and wellness. This review aims to synthesize the evidence for exercise, yoga, and tai chi in the outpatient treatment of major depressive disorder. STUDY SELECTION: A systematic search of the Ovid MEDLINE, EMBASE, PsycINFO, and Cochrane databases was conducted for randomized controlled trials of exercise, yoga, and tai chi for major depressive disorder. DATA EXTRACTION: Standardized mean differences were calculated and meta-analyzed using a random effects multilevel modeling framework. Heterogeneity and subgroup analysis was conducted. RESULTS: Twenty-five studies were included for final analysis (exercise: 15, yoga: 7, tai chi: 3). Overall, meta-analysis showed a moderate significant clinical effect. However, when only studies (6 studies) with the lowest risk of bias were included, the overall effect size was reduced to low to moderate efficacy. Overall quality of evidence was low. Heterogeneity and publication bias were high. CONCLUSIONS: The current meta-analysis of outpatient exercise, yoga, and tai chi for treatment of major depressive disorder suggests that adjunctive exercise and yoga may have small additive clinical effects in comparison to control for reducing depressive symptoms. The evidence for tai chi is insufficient to draw conclusions. The concerns with quality of studies, high heterogeneity, and evidence of publication bias preclude making firm conclusions.

Psychometric Properties of the Patient Health Questionnaire-9 Modified for Major Depressive Disorder in Adolescents.

OBJECTIVES: The Patient Health Questionnaire-9 Modified (PHQ-9M) is a self-report tool used to assess the presence and severity of depressive symptoms in teenagers. Despite widespread use in primary care clinics and psychiatric settings, the PHQ-9M has not been validated nor are its psychometric properties adequately understood for the adolescent population. This study sought to examine the psychometrics of the PHQ-9M in treatment-seeking, depressed adolescents at a psychiatric psychopharmacology clinic who were concurrently assessed with the Children's Depression Rating Scale Revised (CDRS-R) and Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). METHODS: Adolescents (N = 160) aged 13 through 18 years with a diagnosis of major depressive disorder, determined on the basis of a clinical interview and semi-structured interview using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version, were assessed for severity of depressive symptoms with the PHQ-9M, CDRS-R (adolescent interview only), and QIDS-A17-SR assessments at baseline, 4, and 8 weeks. Classical test theory analysis was used to evaluate the internal consistency and dimensionality of the PHQ-9M. Convergent validity was evaluated via intraclass correlations of the PHQ-9M with the CDRS-R and QIDS-A17-SR. Sensitivity to treatment response was also evaluated. RESULTS: The internal consistency (Cronbach's coefficient α) at baseline, 4, and 8 weeks was 0.879, 0.859, and 0.827 for the PHQ-9M; 0.739, 0.835, and 0.867 for CDRS-R; and 0.712, 0.777, and 0.804 for QIDS-A17-SR, respectively. The PHQ-9M had moderate convergent validity with the CDRS-R but good convergent validity with the QIDS-A17-SR. The PHQ-9M was less sensitive to changes in symptom severity than the CDRS-R and QIDS-A17-SR. CONCLUSIONS: The PHQ-9M appears to be a valid and reliable assessment tool for the severity of depressive symptoms in a psychiatric clinic setting. However, its utility as a treatment outcome measure may be limited compared with other available rating scales.