Pharmacogenomic Testing for Next-Step Antidepressant Selection

Abstract

Among patients with major depressive disorder (MDD), less than 40% achieve clinical remission after an initial treatment with an antidepressant. For those who do not improve after 2 or more antidepressant treatment trials (ie, treatment-resistant depression), the rates of remission are less than 20%. 1 Because each of these failed treatments translates to several months of prolonged illness, a series of multiple ineffective treatments contributes to the substantial disability and morbidity associated with MDD, as well as to an increase in the suicide risk. There is a critical need for validated biomarkers to predict treatment response and to guide the selection of the most effective next-step antidepressant treatments (ie, using another antidepressant; another treatment, such as psychotherapy or transcranial magnetic stimulation; or a combination). Promising results in this direction have been reported with clinical, 2 electroencephalographic, 3 and neuroimaging 4 variables, but none of these approaches has yet been prospectively validated or translated into clinically useful tests.Among the different biomarker strategies for next-step antidepressant selection, pharmacogenomic testing is most advanced, with several tests currently commercially available. However, the results of randomized clinical trials that have evaluated pharmacogenomic-guided antidepressant selection compared with usual treatment are underwhelming. In 2 studies 5,6 (that involved 450 patients and 100 patients with MDD, respectively), pharmacogenomic-guided treatment was more effective than usual care: at 8 weeks, more patients achieved clinical response (ie, 50% or more reduction in depression severity) with pharmacogenomic-guided treatment than usual care (49% vs 41% in one study 5 and 71.7% vs 43.6% in the other 6 ). However, in several other studies that included 316, 7 1167, 8 304, 9 71, 10 and 371 11 patients with MDD, there was no significant difference between groups in the primary outcome, with only minimal differences in secondary outcomes present in 2 of those studies. 7,8 Study design characteristics may explain the differences in the results, but an analysis of factors that may have contributed to those differences does not increase the level of confidence in the value of pharmacogenomic-guided treatment. For example, most of the studies that reported no significant benefit associated with pharmacogenomic-guided treatment had larger study samples. 8,9,11 Also, several of the studies that reported positive results in primary 5 or secondary outcomes 7 included large proportions of treatment-naive participants, whereas studies that only enrolled patients with previous antidepressant failures reported lower rates of benefit or nonsignificant results. [8][9][10][11] This is especially important because the clinical issue of next-step antidepressant treat-

Pharmacokinetic Markers of Clinical Outcomes in Severe Mental Illness: A Systematic Review

“…Over the years, several reasons have been proposed to explain this phenomenon. Among them, there are a relative lack of RCTs exploring PGx efficacy [11], a lack of knowledge on how to interpret its results by a sizeable portion of healthcare providers [11], inconsistencies in the guidance provided by different clinical practice guidelines [23], and an apparent lack of confidence in the overall value of PGx testing in clinical practice [11,81]. The results of our review seem to point to a significant heterogeneity in assessed outcomes and in the testing panels.…”

“…These factors, taken together, may increase PGx adoption in clinical practice [23]. Future efforts need to be devoted to improving the standardization for the tested algorithms and clinical practice guidelines, boosting educational programs on how to capitalize on PGx technologies in clinical care and assessing next-generation sequencing in PGx tests to address some of the lasting concerns surrounding PGx use [11,81,87,88].…”

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder

“…Most previous studies 39 , 40 , 41 , 42 of treatment for MDD guided by pharmacogenetics examined the use of combinatorial pharmacogenetic tests (ie, multigene testing). Other studies 14 , 43 , 44 , 45 found promising results regarding remission rates; however, questions have been raised about whether the studies were properly randomized and blinded. 43 In most previous studies, 39 , 40 , 41 , 42 information was not presented regarding how the pharmacogenetic test results were translated into the choice for a specific antidepressant or antidepressant dosage as well as the extent to which the prescribers adhered to the dosing advice in their treatment strategy.…”

Most patients with disorders of gut‐brain interaction receive pharmacotherapy with major or moderate drug‐gene interactions

“…47,48 In the Precision Medicine in Mental Health Care randomized clinical trial (NCT03170362), pharmacogenomic testing reduced prescription of medications associated with drug‐gene interactions but had only a small and nonpersistent effect on symptom remission 17 . Pharmacogenomics may identify variants that predict pharmacokinetic interactions as well as pharmacodynamic actions 49,50 . Future studies of patients with DGBI should compare therapy guided by pharmacogenomic testing with the standard of care to assess the extent to which pharmacogenomic testing guides prescriber patterns and patient outcomes.…”