Pharmacogenomic testing and antidepressant response: problems and promises

Pharmacogenomics: A road ahead for precision medicine in psychiatry

“…Figure 2: Schematic depiction of a hepatocyte illustrating current knowledge about the clozapine metabolic pathway, which highlights proteins identified in the latest PharmGKB review (Thorn et al, 2018) and those encoded by ADME genes found in GWAS approaches (Legge et al, 2017;Pardiñas et al, 2019;Smith et al, 2020). Following the analysis of the ExAC database by Ingelman-Sundberg et al (2018), boxes within each protein indicate the percentage of functional genic variation expected to be common (MAF≥1%, left box, blue) or rare (MAF<1%, right box, red).…”

“…The largest trial of this kind, GUIDED, did not show a beneficial effect of pharmacogenomic guided prescribing for its primary outcome of symptom improvement against antidepressant standardcare (Greden et al, 2019). Results on treatment response and remission outcomes were more positive, although these were secondary analyses that have been questioned on conceptual and statistical grounds (Goldberg, 2019;Smith and Nemeroff, 2020). This lack of supportive evidence, coupled with the negative results of other studies (Perlis et al, 2020;Zeier et al, 2018), underlies the lack of support from the FDA, CPIC or DPWG for all current claims of genetic markers as potential predictors of antidepressant response or indeed any other pharmacodynamic outcome (Bousman et al, 2021).…”

“…The main design chosen by clozapine pharmacogenomic studies follows this pathway (Figure 2), tracking the plasma concentrations of clozapine and norclozapine in treated individuals, and genotyping or sequencing the exonic segments of the genes coding the aforementioned enzymes and perhaps a few others. Results of these "candidate" studies have accumulated during the past two decades but have led to inconsistent findings (Li et al, 2018), potentially contributing to erroneous pharmacogenomic guidance (Rahman et al, 2017) and have been unsupported by recent GWAS in larger samples (Pardiñas et al, 2019;Smith et al, 2020).…”

“…While by terminology it is an "atypical" antipsychotic, these knowledge gaps and translational challenges are typical of many other psychiatric drugs, limiting the advance of therapeutic developments (Alavijeh et al, 2005;Kose and Cetin, 2018). Nonetheless, in the last decade, there have been significant advances in our knowledge of clozapine's metabolism and the origin of its adverse effect profile through the international application of unbiased genomewide methods to routinely collected samples with clear phenotypic definitions (Goldstein et al, 2014;Legge et al, 2017;Pardiñas et al, 2019;Smith et al, 2020). For these insights and derived findings to advance research into the pharmacogenomics of treatment response, they will have to be explored further at scale.…”

The emergence, implementation, and future growth of pharmacogenomics in psychiatry: a narrative review

“…Pooled results from these clinical trials showed patients receiving PGx-guided antidepressant treatment were 41% (95% CI 15-74%) more likely to achieve symptom remission relative to their counterparts that received treatment as usual (Brown et al, 2022). However, these encouraging trial findings have been tempered by concerns within the academic and clinical community about industry bias, the use of inappropriate comparison groups, and unsatisfactory intervention blinding (Smith & Nemeroff, 2020). Additional concerns have been raised by the FDA related to claims made by commercial PGx testing laboratories, resulting in the issuance of a warning letter to Inova Genomics Laboratory in 2019 (FDA, 2019) and two safety communications cautioning the use of PGx testing results that are not based on FDA-approved product labeling (Ellingrod, 2019).…”