Among the 24 participants who did not achieve symptom remission by week 10, 42% (n=10) had a greater than 50% reduction in HDRS from the baseline. Among these nonremitted responders, two (20%) received a low dose, six (60%) received a medium dose, and two (20%) received a high dose. The CNSDose tool predicted that three (30%) patients would require a low dose, five (50%) patients would require a medium dose, and two (20%) patients would require a high dose. Similar to the remitter analysis, comparison of the actual and CNSDose predicted doses required for response indicated strong concordance (T b=0.87, P=0.004; κ=0.83, P=0.0001; Supplementary Fig. S1, Supplemental digital content 1, http://links.lww.com/FPC/B103). However, among the nonresponders (n=14), concordance was only moderate (T b=0.86, P=0.005; κ=0.39, P=0.006), although all nonresponders were prescribed the CNSDose predicted dose or a higher dose by week 10 (Supplementary Fig. S2, Supplemental digital content 2, http://links.lww.com/FPC/B104). Performance estimates (i.e. sensitivity, specificity, and accuracy) were not calculated within the nonremitted responder and nonresponder samples because of concerns of the reliability of such estimates, given the extremely small sample sizes 30.
Our results tentatively suggest that the CNSDose tool may have clinical utility in guiding desvenlafaxine dosing in a subset of individuals with moderate to severe depressive symptoms. We found that clinically driven (unguided by CNSDose) dosing of desvenlafaxine needed, on average, 8 weeks to find the dose required for remission. Importantly, the CNSDose predicted dose had high concordance with the actual dose required for remission, suggesting that the use of CNSDose at the commencement of desvenlafaxine treatment has the potential to shorten the time to remission, particularly among patients requiring a high dose (≥150 mg). To our knowledge, no other genetically based desvenlafaxine dosing tools have been reported in the literature. However, genetic-based dosing tools for drugs other than antidepressants such as warfarin have reported comparable concordance between actual and predicted dose (Pearson’s r=0.54–0.67) 31.
Our results, in part, also support findings from a double-blinded, randomized clinical trial that showed that the CNSDose tool improved MDD outcomes among individuals prescribed a variety of first-generation and second-generation antidepressant pharmacotherapy, although few received desvenlafaxine 22. As noted above, desvenlafaxine is not subject to phase I CYP450 metabolism 9 and the evidence supporting ABCB1 and ABCC1 as regulators of desvenlafaxine concentrations in the brain is modest. Thus, two of the genes (CYP2D6 and CYP2C19) included in the CNSDose tool are not used to predict desvenlafaxine dosing and the relevance of ABCB1 and ABCC1 is uncertain because of conflicting results in the literature. Therefore, the underlying mechanism(s) by which CNSDose confers its predictive value would presumably involve the phase II hepatic UGT1A1 gene. However, our results suggest that UGT1A1 on its own has limited ability to predict the actual dose needed to achieve remission, suggesting that the predictive value of CNSDose requires a combinatorial approach. This notion is supported by a previous work by Assurex Health (Mason, Ohio, USA), developers of the GeneSight test, that showed that a combinatorial pharmacogenetic approach had superior predictive value compared with a single-gene approach 32, albeit single genes/variants not tested to date may prove to have stronger predictive value for particular drugs in particular settings.
The current study does have some notable limitations. The exclusion of patients with current or previous exposure to antidepressants, a history of childhood trauma and comorbidities, particularly personality disorders with dysthymia and adjustment disorder with depressed mood, may limit the application of these findings to larger real-world clinical settings – settings where comorbidity is very common. This is supported by a response and remission rate that was considerably higher than that observed in most antidepressant trials. In addition to these exclusion criteria, the high response and remission rate could, in part, be attributed to the use of doses up to 150 mg above the recommended effective dose (i.e. 50 mg) 33. In addition, dose adjustments were based on clinical judgment rather than specific criteria, which may hamper the reproducibility of our findings. Our findings are also limited to Caucasians of a relatively older and more chronic population than may be seen in other settings. Furthermore, our trial used an open-label design and as such study participants were not blinded to the dosage adjustments, which may have influenced the symptom rating. Thus, generalization of our findings should be performed with caution. It should also be noted that only a small selection of the known polymorphisms in ABCB1, ABCC1, and UGT1A1 were assessed. It is likely that other polymorphisms in these genes as well as other unexamined genes are relevant to desvenlafaxine pharmacokinetics. In fact, several ABCB1 polymorphisms have been linked to antidepressant efficacy 19 and four other UGTs (UGT1A3, UGT2B4, UGT2B15, and UGT2B17) have been implicated in the metabolism of desvenlafaxine, with genetic variation in UGT1A3 and UGT2B17 linked to the mRNA expression of these genes 34. In fact, one in every 10 of our participants did not respond to desvenlafaxine despite being prescribed the CNSDose predicted dose or higher dose. This may suggest that genetic variation in the above-mentioned genes may improve dose prediction or could indicate that nonresponse was a result of nongenetic factors such as adherence or tolerability. Unfortunately, measurements of treatment adherence and tolerability as well as desvenlafaxine blood levels were not available. Although typical adverse effects reported included diaphoresis, constipation, light-headedness, and agitation, no severe adverse reactions occurred. Furthermore, the CNSDose tool, unlike other currently available tools 7, does not include genes associated with the pharmacodynamics of antidepressants, which raises the question of whether the CNSDose dosing support tool represents a significant improvement over other currently available tools. Addressing this issue was beyond the scope of the current study, but future head-to-head trials with other tools are warranted. Importantly, personal (e.g. age, sex) and environmental factors (e.g. abuse history) were not included in the CNSDose dosing tool. Given the known role that personal and environmental factors play in antidepressant response, inclusion of such factors may further improve the performance of the tool 35.
Our results serve as initial evidence for the clinical validity of CNSDose for the dosing of desvenlafaxine and, pending replication, suggest potential clinical utility. However, future pharmacogenetic-based dosing support tool development and evaluation that address the limitations of this study are warranted and are necessary before universal adoption into clinical practice.
This study was supported in part by a 2012 Pfizer Australia NSR grant (A.S.). C.B. was supported by a University of Melbourne, Ronald Phillip Griffith Fellowship. M.B. is supported by an NHMRC Senior Principal Research Fellowship (1059660).
Authors’ contribution: A.S. designed the study, K.B. performed genotyping, and C.B. analyzed the data and wrote the first draft. D.M., C.N., K.B., M.B., and A.S. revised the first draft. All authors approved the final draft of the manuscript.
A.S. owns shares in the ABC Life Pty Ltd and Baycrest Technology Pty Ltd (developer of the CNSDose tool), and is on the speakers bureau for Servier, Australia. For the remaining authors there are no conflicts of interest.
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