The association of COMT genotype with buproprion treatment response in the treatment of major depressive disorder

Abstract Background Pharmacodynamics and pharmacogenetics are being explored in pharmacological treatment response for major depressive disorder (MDD). Interactions between genotype and treatment response may be dose dependent. In this study, we examined whether MDD patients with Met/Met, Met/Val, and Val/Val COMT genotypes differed in their response to bupropion in terms of depression scores. Methods This study utilized a convenience sample of 241 adult outpatients (≥18 years) who met DSM‐5 criteria for MDD and had visits at a Midwest psychopharmacology clinic between February 2016 and January 2017. Exclusion criteria included various comorbid medical, neurological, and psychiatric conditions and current use of benzodiazepines or narcotics. Participants completed genetic testing and the 9 question patient‐rated Patient Health Questionnaire (PHQ‐9) at each clinic visit (M = 3.8 visits, SD = 1.5) and were prescribed bupropion or another antidepressant drug. All participants were adherent to pharmacotherapy treatment recommendations for >2 months following genetic testing. Results Participants were mostly Caucasian (85.9%) outpatients (154 female and 87 male) who were 44.5 years old, on average (SD = 17.9). For Val carriers, high bupropion doses resulted in significantly lower PHQ‐9 scores than no bupropion (t(868) = 5.04, p < .001) or low dose bupropion (t(868) = 3.29, p = .001). Val carriers differed significantly from Met/Met patients in response to high dose bupropion (t(868) = −2.03, p = .04), but not to low dose bupropion. Conclusion High‐dose bupropion is beneficial for MDD patients with Met/Val or Val/Val COMT genotypes, but not for patients with Met/Met genotype. Prospective studies are necessary to replicate this pharmacodynamic relationship between bupropion and COMT genotypes and explore economic and clinical outcomes.


| INTRODUC TI ON
Major depressive disorder (MDD) is a poorly understood chronic illness characterized by major alterations in mood that, even with antidepressant treatment, can result in significant suicidal ideation leading to death (Madsen et al., 2019). The clinical manifestations of MDD are typically experienced as profound sadness accompanied by numerous physiological changes, such as disturbances in sleep, appetite, sexual desire, constipation and loss of joy and pleasure with friends and co-workers (Hollon et al., 2006). The lifetime frequency of MDD is approximately 15%, and it is widely accepted that a significant cohort (at least 40%) has a genetic predilection for this disease (Lohoff, 2010). Environmental factors also play a significant role, an epigenetic factor in expressing the phenotypic manifestations of this disease (Nagy, Vaillancourt, & Turecki, 2018).
Given the complexity of genetic and environmental factors, clinicians employ a myriad of treatment interventions with varying levels of success at the individual patient level (e.g., psychotherapy, electroconvulsive therapy, and antidepressants). Pharmacotherapy is a mainstay of modern MDD treatment, but many patients do not respond to initial treatment or discontinue treatment because of adverse drug effects (Trivedi et al., 2006). Although many drugs are licensed for use in MDD, data do not consistently suggest one class or specific medication to be superior in terms of efficacy (Cipriani et al., 2018). Thus, therapeutic options frequently depend upon prescriber familiarity and comfort, patients' prior experience, cost, and other factors. Despite the discovery and commercialization of new antidepressants, very little work has focused on prospectively characterizing a personalized approach to predicting the pharmacogenetic and pharmacodynamic response to a particular therapy.
The revolution in genomic medicine holds the promise of harnessing genetic data to improve outcomes, increase the likelihood of tolerability, and decrease treatment costs. Pharmacogenetics is one form of personalized medicine involving the use of an individual's genomic profile to help predict optimal treatment outcomes.
Emerging data suggest that improved outcomes as well as decreased costs can be obtained in mental illness patients using pharmacogenetics, as it is already doing in disciplines such as oncology and cardiology (Bousman, Arandjelovic, Mancuso, Eyre, & Dunlop, 2019;Perlis, Mehta, Edwards, Tiwari, & Imbens, 2018). Genetic variation is an important factor that influences the efficacy and tolerability (therapeutic index) of pharmaceutical agents, including psychotropic drugs. In fact, many pharmaceuticals, including psychotropic drugs, have biomarker warnings or precautions in their prescribing information with respect to the effect of variants of genes on the drug's exposure. The US Food and Drug Administration (FDA, 2020) notes that "Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose." Pharmaceutical companies have also begun to state within their prescribing information packets that genotypes can influence dosage and tolerability.
Several commercial pharmacogenetic assays tailored to psychiatry patients are available. The genes for which these assays test include pharmacokinetic (PK) genes and pharmacodynamic (PD) genes. Included PK genes are most often of the CYP450 family, which encode for ubiquitous proteins responsible for the metabolism of most drugs. Two of these PK genes (cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19)), along with genes involved in hypersensitivity reactions (human leukocyte antigen, B type, allele 15:02 (HLA-B*15:02) and human leukocyte antigen, A type, allele 31:01 (HLA-A*31:01)), are currently the four genes that have amassed a level of empirical support to include them in FDA labeling (Miller, 2019).
Pharmacodynamic genes encode for proteins such as transporters, receptors, growth factors, and other targets. Although potentially actionable, they have less research support compared with the aforementioned PK genes. A PD gene incorporated into one such available pharmacogenetic assay is COMT, which encodes for catechol-o-methyl transferase, an enzyme responsible for the breakdown of dopamine in the frontal lobes. A common variant is a valine to methionine substitution (val158 → met) resulting in decreased capacity of the enzyme to degrade dopamine. Individuals with the Val/Val genotype display elevated enzyme activity and increased dopamine degradation; conversely, patients who are Met/Met homozygous have reduced enzyme activity and dopamine degradation (Sawa & Snyder, 2002). Because this gene affects synaptic dopamine levels, it is possible that individuals with the various genotypes (Val/ Val, Met/Val, Met/Met) at this locus may vary in their response and/ or tolerability to dopaminergic drugs.
Bupropion is a widely used antidepressant with a pro-dopaminergic mechanism of action. Occupancy of dopamine transporter receptors (DAT) by bupropion and its metabolites averaged 26% under conditions of steady-state oral dosing (150 mg every 12 hr of the sustained-release (SR) formulation) as determined by positron emission tomography (Learned-Coughlin et al., 2003). Norepinephrine transporter receptor occupancy has been reported to be similar to DAT occupancy (Masana, Castañé, Santana, Bortolozzi, & Artigas, 2012), possibly suggesting synergism of dopamine and norepinephrine synaptic transmission and therefore not requiring the 80%-90% occupancy required by serotonin receptor transporters. To avoid addictive features, a low level, slow onset, and long-lasting DAT occupancy is preferable for antidepressant treatment, targeting the phenotype of reduced positive affect symptoms of MDD, including sadness, anhedonia, low energy, and poor motivation (Stahl, 2013).
COMT genotyping has been useful in predicting psychostimulant responses for attention deficit disorder (Myer, Boland, & Faraone, 2018). Available genetic testing has been utilized to pharmacodynamically evaluate the association between COMT genotypes and bupropion for smoking cessation, but not for the treatment of MDD (Salloum et al., 2018). Considering the biphasic synaptic dopamine levels observed for the COMT Val/Val versus Met/Met genotypes, we hypothesized that antidepressant response to bupropion would be influenced by the COMT genotype, especially in comparing low-dose versus high-dose bupropion. This retrospective single-center study explored the outcomes of patients treated for MDD with pharmacogenomic testing before initiation of treatment. Descriptive statistics were calculated to characterize the sample for demographics, COMT genetic variants, and bupropion dosing.

| MATERIAL S AND ME THODS
Four cases had erroneous data for their PHQ-9 scores and were removed. Chi-square tests of independence were used to determine whether COMT gene variant was related to treatment with bupropion or bupropion dose at time of genetic testing or for new bupropion prescriptions subsequent to genetic testing.
Multilevel models (or linear mixed-effect models) were estimated. This approach allows integration of the repeated observations for each case, while also incorporating the impact of genetic, demographic, and bupropion predictors (Snijders & Bosker, 2012).
One justification for this approach was the high intraclass correlation (42%) observed, suggesting that a high proportion of variance was due to clustering by individual. For the first model, the time sequence of observations was coded as follows: Pregenetic represented clinic visits before genetic testing was conducted; Placebo represented time period during which genetic testing had occurred, but before results were available and incorporated into the patient medical treatment (set at 4 weeks after genetic testing). For these observations, the simple effect of informing the patients that a genetic test is being conducted can be estimated; this effect was operationalized as changes to PHQ-9 scores for this time frame. In the statistical analysis, we are thus able to detect a psychological effect simply due to the genetic testing process before the changes to medical treatment, in light of the genetic test results, are implemented.
Secondly, patient demographics, COMT gene variants, and bupropion dose were tested for relation to PHQ-9 scores. Time was also included in these models such that Time 0 represented time period before genetic testing, Time 1 represented visit coinciding with genetic testing, and Times 2, 3,…, n represented subsequent clinic visits. According to the primary study hypothesis, COMT genetic variant was expected to moderate effects of bupropion dosing on PHQ-9 scores. Therefore, an interaction term was included in the model. Age and gender were also tested as covariates in all models and retained where significant. Models were specified using Restricted Maximum Likelihood and unstructured covariance and included tests of differences between all combinations of bupropion dose and COMT gene variant. At the time of genetic testing, 24.1% (n = 53) were currently taking bupropion. See Table 2  Genetic testing did have a statistically significant effect on PHQ-9

| RE SULTS
scores, however, not in the expected direction for a placebo effect.
As shown in Table 3, the predicted value of PHQ-9 was increased by 0.93 units during Placebo period.  Table 5).  Met genotype on mirtazapine and citalopram response in MDD (Arias et al., 2006;Szegedi et al., 2005). Meanwhile, a systematic review and meta-analysis of pharmacogenetics for MDD, using data from four studies and STAR-D data, COMT was unrelated to antidepressant (SSRI or non-SSRI) response or remission (Niitsu, Fabbri, Bentini, & Serretti, 2013). Finally, in a previous study of add-on therapy with substances increasing dopamine availability individually tailored according to COMT val158met genotype (Baune et al., 2008).

| D ISCUSS I ON
Although the association between COMT variant and bupropion treatment response for MDD has not been studied previously, bupropion has been examined in terms of its efficacy with different phenotypic symptoms. Most notably, a systematic review and meta-analysis identified 51 studies, divided into four categories: bupropion as a sole antidepressant, bupropion coprescribed with another antidepressant, bupropion in "other" populations (e.g., bipolar depression and elderly populations), and primary evaluation of side effects (Patel et al., 2016). Some data supported bupropion targeting specific phenotypic symptoms, but insufficient information was available to reliably inform such prescribing. Thus, it remains uncertain whether bupropion pharmacodynamically augments other drugs.
Based on the previous literature, we hypothesized that a specific variant of COMT, val158 → met, could affect response to bupropion in patients with MDD. As genomic psychiatry is still in a nascent phase, we first examined whether genetic testing, in itself, had a significant effect on patients' PHQ-9 scores. Genetic testing did have a statistically significant effect on PHQ-9 scores, however, not in the expected direction for a placebo effect-patients' scores increased significantly in the time between genetic testing and incorporation of these results into patients' medication plans. clinical assessment of depression, by a clinician blind to dosage and COMT genotype, would provide additional strength to findings.
Additionally, the patients occasionally used combination and adjunctive treatment for depression. Due to our limited sample size, these combinatorial treatments were not controlled for in this study.
Future studies with larger cohorts should control for adjunctive medications.

| CON CLUS ION
Our data suggest that a high dose of bupropion (≥200 mg daily) is beneficial for MDD patients with Val carrier COMT genotypes,

ACK N OWLED G M ENTS
We thank the following team members at Parkview Research Center for their assistance with their project: Lauren Reining, MA, and Jeanne Carroll, BA, for their assistance with data collection and poster development and presentation, and Tammy Toscos, PhD, for her direction of the research. None of those acknowledged have any conflicts of interest to report. Mirro were in charge of overall direction and planning of the project.

CO N FLI C T O F I NTE R E S T
Additionally, all authors drafted or revised this manuscript critically for important intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.