CADTH Health Technology Review

Pharmacogenomic Testing in Depression: A 2021 Update

Rapid Review

Authors: Nazia Darvesh, Jennifer Horton, Mê-Linh Lê

Key Messages

• An update to a 2020 CADTH Rapid Review was conducted to capture new literature published since 2019 examining the effectiveness of drug treatment informed by genetic testing compared to usual care for adults with depression.

• Eleven studies were identified: 1 systematic review, 1 health technology assessment, 4 randomized controlled trials reported in 5 publications, 1 non-randomized study, 1 cohort study with historical control, and 2 uncontrolled before-and-after studies.

• Similar to the conclusions of the 2020 CADTH report, the effectiveness of gene testing for treating depression was unclear. In patients with depression, some studies showed that there were improvements in the clinical effectiveness outcomes in those who received gene testing and other studies showed that there was no difference in outcomes between those who received gene testing and those who did not. No studies showed that gene testing resulted in worse outcomes compared to those who did not receive gene testing.

• In the current report, the were several limitations across studies such as poor design, inclusion of subjectively measured outcomes, small sample sizes, and a focus on hospital settings ― all of which may not be generalizable to other populations.

Context and Policy Issues

Depression, a major cause of functional disability, affects 5% of adults worldwide and is seen in more women than men.^1,2 Depression can refer to a heterogeneous group of disease processes such as a syndrome with varied symptoms and signs (e.g., major depression, minor depression); a mood state characterized by feelings of despair, sadness, anxiety, emptiness, hopelessness, or no feelings; or a mental disorder presenting as a clinical condition (e.g., bipolar disorder, major depressive disorder [MDD], substance/medication-induced depressive disorder, schizophrenia, depressive disorder).^1,2 Factors that may contribute to the development of depression include brain chemistry, stress, and genetics.³ Treatments for depression include psychotherapy, psychoeducation, pharmacotherapy (e.g., antidepressants [ADs]), or brain stimulation ― all of which can be used alone or in combination with each other.³ Many patients are prescribed medication for depression; however, this may result in patients experiencing adverse drug reactions before the correct treatment regimen for a particular patient is determined.⁴

Pharmacogenomic (PGx) testing (also referred to as pharmacogenetics) describes how the genome responds to drug treatment; PGx testing can offer patients with depression a way to individualize AD treatment based on their genome and how their physiology may react to different drugs.⁵ Testing can help select a more suitable medication type and dose for patients.⁴ However, PGx testing is not common and there are several challenges to its use including inconclusive results from trials, limited results from cost-effectiveness studies, ethical issues, availability of tests, lack of guidelines, lack of education for clinicians and patients, and delays between testing and treatment.⁵ In January 2020, CADTH published a rapid review⁶ on the clinical effectiveness, cost-effectiveness, and guidelines for PGx testing in depression. With growing interest in this topic, it is unclear whether any new evidence has been published since this report was produced.

The current report is an update to the 2020 CADTH report,⁶ with the goal of summarizing the findings from any new studies that were published since the 2020 CADTH report. The 2020 CADTH report found 1 health technology assessment (HTA), 2 systematic reviews (SRs) with meta-analyses (MAs), 1 randomized controlled trial (RCT), and 3 economic evaluations that compared PGx testing to standard care in adults with depression.⁶ The 2020 CADTH report found that there were mixed results for the clinical effectiveness of PGx testing.⁶ The objective of the current report is to summarize the evidence regarding the clinical effectiveness and safety of PGx testing guided care in adults with depression compared to standard care.

Research Question

What is the clinical effectiveness of pharmacogenomic testing for treating all severities of diagnosed depression?

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including MEDLINE, PsycInfo, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were pharmacogenomic testing and depression, as well as specific pharmacogenomic tests. No filters were applied to limit the retrieval by study type. Comments, newspaper articles, editorials, and letters were excluded. Where possible, retrieval was limited to the human population. The search was also limited to English-language documents published between January 1, 2019 and November 2, 2021.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or they were published before 2019. SRs in which all relevant studies were captured in other more recent or more comprehensive SRs were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SRs. Studies captured in the 2020 CADTH report⁶ were also excluded.

Table 1: Selection Criteria

Note: Studies that included people with an unspecified age range or where the mean age was 18 to 60 years or where the majority of the population were aged 18 to 60 years were included.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)⁷ for the SR and the HTA, and the Downs and Black checklist⁸ for RCTs and the non-randomized studies (NRSs). Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 341 citations were identified in the literature search. Following screening of titles and abstracts, 276 citations were excluded and 65 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of the potentially relevant articles, 55 publications were excluded for various reasons and 11 publications met the inclusion criteria and were included in this report. These comprised 1 SR,⁹ 1 HTA,¹⁰ 4 RCTs,^11-15 1 NRS,¹⁶ 1 cohort study with historical control,¹⁷ and 2 uncontrolled before-and-after studies.^18,19 Of the RCTs, 2 publications by Ruaño et al. reported results from the same trial:^13,14 1 study described the main results¹³ and the other summarized findings based on subgroup analyses.¹⁴ The publication by Huilei et al.¹⁶ described an intervention study; however, since randomization was not mentioned, it is assumed that the study was non-randomized for the purpose of this report. Appendix 1 presents the PRISMA²⁰ flow chart of the study selection.

Additional references of potential interest are provided in Appendix 6.

Summary of Study Characteristics

Study Design

One SR⁹ published in 2021 was found and included literature published up to June 30, 2020. The studies included in this review were 6 other SRs (4 with MAs) published from 2017 to 2020 and 3 RCTs published from 2018 to 2019 that were not already included in the 6 SRs. Across the 6 SRs, population sizes ranged from 1,556 to 13,377 patients. Across the 3 RCTs, population sizes ranged from 100 to 1,541 patients.⁹

One HTA¹⁰ published in 2021 was found and included literature published up to January 24, 2020. This HTA was conducted to examine clinical effectiveness, cost-effectiveness, incremental cost per quality-adjusted life-year, and a 5-year budget impact of PGx testing compared to unguided care. The HTA included 10 primary studies with 4 post-hoc analyses published from 2012 to 2020.The mean age in the included studies ranged from 41 to 52 years for all studies (except 1 that limited age range to 51 years). The authors of the HTA¹⁰ reported that the majority of populations across included studies were female. For the current report, only the clinical effectiveness findings of this HTA¹⁰ were considered relevant. The overlap in primary studies between the SR⁹ and HTA¹⁰ in the current report is presented in Appendix 5, Table 9; there was an overlap of 3 RCTs between the 2 publications. Three RCTs overlapped between the HTA and SR; however, there was no duplication in how findings are presented in this report, as the SR reported results by individual study and the HTA reported results by specific PGx test.

Across the 4 RCTs and 4 NRSs in the current report, publication dates ranged from 2019 to 2021. Of the RCTs, 2 studies reported being single-blinded, 1 study was double-blinded, and 1 did not report blinding; 2 studies were single-centre and 2 studies were multi-centre. For the NRSs, none reported blinding and all were at single centres; 2 studies were prospective, with 1 using a historical control, and 2 were uncontrolled before-and-after studies measuring outcomes within the same study population before-and-after PGx testing was conducted.

Country of Origin

The authors of the included SR were from Qatar⁹ and those who authored the HTA¹⁰ were from Canada. Of the remaining 8 studies (where 1 was reported in 2 publications), 4 were conducted in the US,^{11,13,14,18,19} 1 in Canada,¹² 1 in Russia,¹⁵ 1 in China,¹⁶ and 1 in Germany¹⁷ (the primary author’s affiliations were both Switzerland and Germany).

Patient Population

The included SR⁹ found studies that focused on adults who were reported to have depression, uncontrolled depression, MDD, generalized anxiety disorder, or psychiatric conditions. The included HTA¹⁰ searched for studies with adults who had a primary diagnosis of major depression. In the HTA,¹⁰ all but 1 study had a mean age ranging from 41 to 52 years and studies comprised mostly female participants.

Populations in the included primary studies were adults who had a variety of conditions such as MDD, bipolar disorder, posttraumatic stress disorder (PTSD), and generalized anxiety disorder.^11-19 One study¹⁵ included patients who had comorbid affective disorder and alcohol addiction. The studies included in the current report varied in their descriptions of whether patients had already tried previous AD therapy that had been unsuccessful. Five studies reported in 6 publications took place in single hospital/health care centre setting,^13-18 1 study was in a veteran centre,¹¹ 1 study was in an urban community pharmacy,¹² and 1 study took place in an outpatient centre.¹⁹ Total study population sizes ranged from 15 to 1,459 participants. For the studies that provided age data, ages ranged from 18 to 85 years and the mean age in specific study populations ranged from 36.6 to 52.5 years. Studies did not clarify whether gender or sex was recorded or whether nonbinary identification was reported, so the results are summarized as reported by the authors of the included studies. One study included a male-only population.¹⁵ Male and female participants each represented approximately half of study populations in 4 articles;^13,14,17,19 female participants were a greater proportion in 2 studies (ranging from 72% to 75.93%)^12,18 and male participants were the greater proportion in the other 2 studies.^11,16

Interventions and Comparators

PGx-guided treatment was compared to unguided care (i.e., standard care or treatment as usual) in all included studies. Some studies referred to testing as “pharmacogenomic” and others referred to it as “pharmacogenetic.” For the purpose of this report, the term “pharmacogenomic” is used. In 2 studies,^11,15 unguided care involved placebo, whereby clinicians were given a sham report to use information as directed, or were given a report indicating that the patient’s genotype was normal. In the uncontrolled before-and-after studies, outcomes were compared before and after PGx testing at the same site;^18,19 in the cohort study, patients who had undergone PGx testing were compared to a historical control of patients who were admitted 1 year earlier and did not receive testing.¹⁷

Outcomes

Outcomes included effectiveness, safety, and medication, with follow-up ranging from 1 day to 24 weeks across studies.^9-19 Effectiveness was reported and referred to in several ways such as length of stay (LOS) in hospital, response to treatment,^9-17,19 or remission from depression.^9-11 Response and remission outcomes that were measured based on depression, anxiety, functioning, or illness severity symptoms were measured using self-reported questionnaires (3 sections: Sheehan Disability Scale;²¹ 5 items: Penn Alcohol Craving Scale;²² 7 items: General Anxiety Disorder-7 items;²³ 9 items: Patient Health Questionnaire [PHQ-9]²⁴; 14 items: Hospital Anxiety and Depression Scale,²⁵ 16-item questionnaires: Quick Inventory of Depressive Symptomatology [QIDS-SR/QIDS-C16]²⁶; 17 items: Treatment Satisfaction with Medicines Questionnaire;²⁷ 21 items: Hamilton Depression Rating Scales and Structured Interview Guide for the Hamilton rating scale [HAM-D/HAMD-17/HAM-D6/SIGH-D17]²⁸; 21 items: Beck Depression Inventory [BDI/BDI-II]²⁹), or clinician-measured questionnaires using the Clinical Global Impression [CGI] scales³⁰ (7-point scales: CGI-I [improvement], CGI-S [severity]; 16-cell matrix: CGI-E [Efficacy index]), or the Global Assessment of Functioning scale³¹ (0-to-100 scale).

Safety or harms were measured by side effects^{9-11,15,16,18} or adverse events (AEs).^9,10 Side effects were measured in some studies^15,18 using self-reported 21-item questionnaires (Antidepressant Side-Effect Checklist; ³² UKU Side-Effect Rating Scale³³). AEs such as emergency room visits and rehospitalization were reported in the included SR⁹ and 1 RCT that was reported in 2 articles.^13,14 The included HTA¹⁰ found that no studies reported on suicide.

Medication-related outcomes were reported as medication switches,^12,17,18 adding or removing medication,^12,19 dose adjustments, whether there was adherence to medication,¹² whether there was a delay in the patient receiving therapy,¹⁷ the number of medications the patient was taking,^13,14,19 compatibility with the medication,¹⁸ and how prescribers used PGx testing to influence their recommendations.^11,12

Additional details regarding the characteristics of included publications are provided in Appendix 2, Table 2 and Table 3.

Summary of Critical Appraisal

Systematic Review

The SR by Aboelbaha et al.⁹ had several strengths and some limitations. Strengths included clearly identifying the research question and eligibility criteria, following a protocol registered beforehand, using a comprehensive search strategy, conducting study selection and data extraction in duplicate, appraising the quality of studies, and providing details of included studies such as which were industry-funded. The SR⁹ only included primary studies not already included in the SRs that were part of their evidence synthesis and results for SRs and RCTs were reported separately to allow for summaries to be made by study design. In addition, since there was no funding for the SR, the authors had no financial conflicts of interest. Limitations of this review included not providing an explanation for excluding observational studies or a list of excluded studies. The authors conducted quality assessment using the Crowe Critical Appraisal Tool³⁴ for both SRs and RCTs, which may not have been appropriate enough to capture unique aspects of each study design. This assessment by the authors suggested that overall, included studies were poor- to moderate-quality because of issues in study design, inappropriate blinding, small sample sizes, and poor accounting for confounders.

Health Technology Assessment

The HTA by Ontario Health¹⁰ had several strengths and limitations. Strengths included clearly identifying the research question and eligibility criteria, following a protocol registered beforehand, using a comprehensive search strategy, appraising the quality of studies, and providing details of included studies such as which were industry-funded. In addition, authors discussed heterogeneity and the quality of the body of evidence when interpreting results (e.g., from the MAs they conducted with random effects models). Limitations of this HTA¹⁰ included having study screening and extraction performed by a single reviewer, not providing an explanation for excluding certain study designs and publications, not providing a list of all of the excluded studies (a smaller sample of 7 studies was provided out of the 104 studies that were excluded), and lacking additional details about any potential conflicts of interest or funding source. The authors’ quality assessment using the Cochrane Risk of Bias Tool, Risk of Bias Assessment Tool for Nonrandomized studies (RoBANS), and Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria suggested that, overall, included studies were of low or very low quality.

Randomized Controlled Trials

Among the 6 RCTs, there were several strengths and limitations, and these varied across studies. The 2 articles by Ruaño et al.^13,14 about the CYP-GUIDES trial reported details about the trials differently. As strengths, both studies described the objectives, main outcomes, patient characteristics, intervention, confounders, and main findings clearly. Both also reported randomization into study groups, random variability for main outcomes, and P values with exact values. One publication¹³ did not mention the blinding of participants or study personnel and the other¹⁴ indicated that both patients and physicians were blinded. Blinding would be a strength of the trial, as it would have potentially reduced biases in how physicians treated patients and how outcomes were measured and reported on. A strength of the trial mentioned in 1 of the publications¹³ is that all patients received their allocated intervention and there was no loss to follow-up. The main outcome, LOS, may also have been valid and reliable, as it could be objectively measured, and the readmission rate outcome may not have been valid because only the electronic medical record at the study site was consulted to see if patients were readmitted; if patients had been readmitted at another site, this would not be captured in the results. Further, patients were recruited from the same site, which may have increased internal validity since potential confounders may have been balanced, but may have reduced external validity, as findings may not be generalizable to other populations. In 1 publication,¹³ the trial was described to have a randomization process that resulted in adequate sample sizes for the study groups; however, a statistical analysis plan was not described in detail and it was unclear how any covariates may have biased the results. Although 1 of the publications¹⁴ conducted statistical analyses appropriately to account for confounders not adjusted for in the previous publication for the same trial,¹³ it is unclear if the sub-analyses in the more recent publication had sufficient power. Limitations in both Ruaño publications^13,14 include no data describing AEs and unknown compliance by physicians to use the PGx guidance.

In the remaining 3 RCTs,^11,12,15 strengths were clear descriptions of objectives, patient characteristics, interventions, and main findings; randomization to study group; sufficient reporting of P values; appropriate statistical analyses with consideration for confounders; blinding; patients being recruited from similar sites suggesting high internal validity; and sufficient power to detect main effects. Specifically in 1 study,¹² there was sufficient power to detect effects after 6 months. However, there was not enough power to include all important variables in the analysis or to compare treatment recommendations across groups. Although these 3 RCTs had high internal validity, there may have been low external validity, as results may not be generalizable to other populations. In all 3 studies, reliability of the outcomes was unclear, as they may have been biased by patient or clinician judgment. Two studies^12,15 reported main outcomes sufficiently, but 1 only described tolerability in sufficient detail¹¹ and main findings for other outcomes were not clearly described with exact values. In this study,¹¹ misclassification was likely low, as physicians were provided with a sham report of PGx test results. In the Zastrozhin et al. study,¹⁵ physicians were blinded to the study assignment; however, there was no explicit mention of patients being blinded. Further, side effects were measured in the Zastrozhin et al. study.¹⁵ However, in the other 2 RCTs,^11,12 it is unclear if AEs were measured. The Papastergiou et al. study¹² had similar loss to follow-up in both study groups (15%); however, the McCarthy et al. study¹¹ had a large amount of loss to follow-up that was higher in the comparator group. In the Zastrozhin et al. study,¹⁵ loss to follow-up was not adequately described and the study may have been too short to detect outcome changes. In the McCarthy et al. study,¹¹ the authors listed several conflicts of interest and it is unclear how these affected study results.

Non-randomized Study

The study by Huilei et al.¹⁶ had strength and limitations. Strengths included clearly identifying the objective, main outcomes, patient characteristics, intervention, confounders, and main findings; measuring side effects throughout the study; providing exact P values; having patients and outcome assessors blind to the study assignment; conducting appropriate statistical tests; recruiting participants from the same site; and considering confounding in the study groups. Because patients and outcomes assessors were blinded, this may have reduced bias in how patients reported outcomes and how clinicians may have provided care or measured outcomes. Recruiting patients from the same site may have increased the internal validity, as potential confounders introduced from a more variable sample may have been controlled better. However, this may also have reduced the external validity, as results may not be applicable to other populations.

Cohort Study With Historical Control

The cohort study with historical control¹⁷ had some strengths and several limitations. Strengths included clearly describing the objectives, main outcomes, patient characteristics, interventions, and main findings, and providing exact P values for the main outcomes. Patients were recruited from the same site, which may have increased internal validity as potential confounders introduced from a more variable sample may have been controlled better. The study also provided random variability for main outcomes to indicate the distribution of the data, considered confounders to compare the study populations before and after the intervention, and reported on AEs. In addition, the study also measured outcomes such as medication changes and hospitalization stay, which may have been less influenced by bias as these would have been objectively recorded, and it indicated that the authors had no conflicts of interest.

Regarding limitations, because patients were not randomized to groups, several variables and confounders may not have been controlled and that could have biased the results. In addition, the blinding of patients or clinicians was not mentioned and was assumed not to have occurred, meaning that the knowledge of receiving the intervention may have influenced how outcomes were reported and measured. The population size of the PGx group was 49 in the intervention group and 94 in the control group, which reduced the power of the study to detect effects of the intervention. The study also did not describe how statistical analyses accounted for small sample sizes and it included outcomes measures with unclear validity and reliability, as they involved the patient or physician’s subjective judgment about depression symptoms and side effects. Further, the results may not have had external validity because the study took place at a single site and may not be applicable to other populations. The funding sources were not reported and it is unclear if there were missing patients or data, or controlling for confounders. Therefore, selection bias may have occurred to include patients in the study with longer disease history, which may have biased the results.

Uncontrolled Before-and-After Studies

The 2 uncontrolled before-after studies^18,19 had some strengths and several limitations. Strengths of both studies included clearly describing the objectives, main outcomes, patient characteristics, interventions, and main findings, and providing exact P values for the main outcomes. Both studies recruited patients from the same site, which may have increased internal validity, as potential confounders introduced from a more variable sample may have been controlled better. The Collins et al. study¹⁸ also provided random variability for main outcomes to indicate the distribution of the data, considered confounders to compare the study populations before and after the intervention, and reported on AEs. The Kierce et al. study¹⁹ also indicated that the authors had no conflicts of interest.

Regarding limitations, both studies were uncontrolled before-and-after designs, meaning that patients were not randomized to groups and several variables and confounders may not have been controlled for and could have biased the results. In addition, the blinding of patients or clinicians was not mentioned and assumed not to have occurred in these studies, meaning that the knowledge of receiving the intervention may have influenced how outcomes were reported and measured. The sample sizes of both studies were also small (ranging from 15 to 80 patients enrolled in intervention groups), which reduced the power of the studies to detect the effects of the intervention. The 2 studies also did not describe how statistical analyses accounted for small sample sizes and included outcomes measures that may not have been valid or reliable because they involved the patient’s or physician’s subjective judgment about depression symptoms and side effects. Further, the results from these studies may not have had external validity because they took place at single sites and may not be applicable to other populations. The funding source from 1 study¹⁹ was not reported and for the other study¹⁸ there may have been conflicts of interest relating to the funding of the study. In the Collins et al. study,¹⁸ loss to follow-up was greater than 30%, which may have biased the results if the reasons for dropout were related to the intervention. It is also unclear if the intervention was applied in the intervention group and if the patients were recruited over the same period of time. In the Kierce et al. study,¹⁹ it is unclear if AEs were recorded beyond the main outcome or if there were missing patients or data. Additionally, follow-up time varied and it was unclear if this was adjusted for; the short time period of the study overall may have also prevented key outcomes that occurred later from being included in the results. Finally, although the Kierce et al. study¹⁹ measured demographic characteristics, the results may have been biased by potential placebo effects and other factors such as depressive episodes and psychosocial circumstances.

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3, Table 4 and Table 5.

Summary of Findings

Appendix 4 presents the main study findings by outcome in Table 6, Table 7, and Table 8. Although there was an overlap of 3 RCTs between the included HTA¹⁰ and included SR,⁹ there was no duplication in how their findings were reported, as the SR reported results by study and the HTA reported results by specific PGx test. The SR included 6 SRs and 3 RCTs; 3 of the SRs were already described in the 2020 CADTH report⁶ and are not reported in the current report. The HTA¹⁰ included 8 RCTs covered in 12 publications and 2 NRSs. The results from 5 of the RCT publications and both NRSs were already included in the 2020 CADTH report and are not included in the current report.

Clinical Effectiveness of Pharmacogenomic Testing ― Effectiveness

Length of Stay in Hospital

Two studies looked at LOS in a hospital and had mixed results.^13,14,17 In the cohort study with historical control,¹⁷ there was a difference in LOS between the intervention and comparator groups and there was an association between those who underwent genotyping and a shorter LOS. The statistically significant difference remained when results were conducted within a treatment-naive subgroup and within a subgroup of patients who had previously taken ADs. For the RCT reported in 2 publications,^13,14 both publications showed no difference between the intervention and comparator groups with respect to LOS in the hospital.

Response to Treatment

Several studies reported on response to treatment using different terminology such as response, response rate, or using specific definitions based on questionnaire scores. For the current report, results are presented using the wording of the original authors and definitions are provided where available.

In the Aboelbaha et al. SR,⁹ response was considered in multiple ways such as proportion of response, improved symptoms, or a change in depression scores. One RCT included in this SR⁹ showed significant differences in response rates and depression scores (measured using HAMD-17) after 8 weeks and mixed results in another RCT. Three SRs showed improvements in response for the intervention group (PGx testing) compared to the control group.

In the included HTA,¹⁰ authors reported that response to depression treatment was defined as 50% or greater improvement in depression score from baseline in 8 studies and 4 post-hoc analyses, and that studies measured this using various tools such as the HAM-D17/SIGH-D17, QIDS-C16, HAM-D6, PHQ-9, or CGI-S, all of which measure depressive symptoms. In this HTA,¹⁰ low to very low-quality evidence showed that NeuroIDgenetix and GeneSight resulted in improvements in the response to treatment compared to treatment as usual, for Neuropharmagen the results were mixed, and there was no evidence for CNSDose. Depression results were mixed across different PGx tests compared to treatment as usual, with little to no improvement in the intervention group for GeneSight and Genecept tests, inconsistent results for Neuropharmagen, and no evidence for CNSDose or NeuroIDgenetix.¹⁰ The authors conducted an MA of 2 RCTs (1 of which was previously summarized in the 2020 CADTH report) and reported findings in 2 places in the report, with different values. The results reported in the text indicate that there was a 34% improvement in response (measured by HAMD-D17) in those who received a GeneSight PGx test compared to those who received usual care and that this was considered low-quality evidence. The results from the MA figure showed a relative risk of 1.50 (95% confidence interval, 1.14 to 1.96). It is unclear which of these are the results for the response outcomes in this study.¹⁰

The 1 included NRS¹⁶ that used the CGI-EI found that the intervention group had significantly better clinical outcomes than the comparator group. The intervention group showed better effectiveness than the comparator group at the 4-, 8-, and 12-week follow-ups but not the 2-week follow-up.¹⁶

In 1 cohort study with historical control,¹⁷ the calculated improvement rates for functioning (using the Global Assessment of Functioning) and depression (using BDI-II) were greater in the intervention group even though absolute numbers were not different between the groups.

In 1 RCT,¹² depression outcomes measured by the PHQ-9 showed improvements compared to the standard care group and in 1 uncontrolled before-and-after study,¹⁹ the PHQ-9 showed no difference in baseline and follow-up scores following guided care using PGx testing.

In 1 RCT,¹¹ within-group differences measured using CGI showed improvements over time; however, there was no difference in depressive symptoms between the intervention and the standard care groups. When these results were reexamined, results showed that when bipolar disorder patients were removed from the analysis, the intervention group had improved CGI outcomes compared to the standard care group, which was driven by PTSD patients. There were no differences in MDD patient improvement within study groups over time in either study group. When separating the study population into risk categories, moderate-risk patients in the intervention group improved better than the standard care group, while there was no difference between groups for high-risk patients. In this same RCT,¹¹ similar results were seen when depression was reported with QIDS-SR scores, which showed study population improvements over time but no difference between the intervention and standard care group. In another RCT that measured CGI,¹⁵ scores were better in the guided group compared to the unguided group at day 9 and day 16 follow-ups.

In the Papastergiou et al. RCT,12 functional disability and impairment (measured with the Sheehan Disability Scale) and anxiety (using GAD-7 questionnaire scores) assessments showed more improvements in the intervention group compared to the standard care group. However, treatment satisfaction (using the Treatment Satisfaction with Medicines Questionnaire) did not change differently across groups during the study.

In the Zastrozhin et al. RCT,15 alcohol craving (reported using the Penn Alcohol Craving Scale), depression (measured using BDI), anxiety and depression (using Hospital Anxiety and Depression Scale), and depression scores (using HAMD) were all significantly lower in the intervention group compared to the unguided group. In this same RCT, HAMD scores for depression showed reductions within study groups at multiple follow-ups and between study groups at each follow-up.¹⁵

Remission From Depression

Remission outcomes were reported in 3 studies.^9-11 In the included HTA,¹⁰ authors reported that remission from depression was defined as 5 or lower on PHQ-9, 5 or lower on QIDS-C16, 7 or lower on HAMD-D17, or 4 or lower on HAM-D6 at follow-up. Low- to very low-quality evidence showed that the NeuroIDgenetix, GeneSight, and CNSDose PGx tests resulted in improvements in remission compared to treatment with no PGx testing, while the Neuropharmagen results were mixed across studies.¹⁰ The authors conducted an MA of 2 RCTs (1 of which was previously summarized in the 2020 CADTH report) that showed an improvement in remission (measured by HAMD-D17) in those who received a GeneSight PGx test compared to those who receive usual care and this was considered low-quality evidence.¹⁰

In the SR by Aboelbaha et al.,⁹ evidence showed higher remission in the guided group compared to the standard care group in 1 RCT and 2 MAs but no significant differences in 1 primary study and no improvement in 1 MA.

In 1 RCT,¹¹ remission was defined as ending the study with a score of 1 or 2 on the CGI and, although remission was higher in the intervention group compared to the standard care group, this was not statistically significant.

Clinical Effectiveness of Pharmacogenomic Testing ― Safety and Harms

Side Effects

The included HTA¹⁰ showed inconclusive results for side effect outcomes in the included studies. The Aboelbaha et al.study⁹ found minimal evidence on safety outcomes and inconsistency in results: 1 RCT showed no differences in the mean number of side effects between study groups and another RCT showed that side effects measured using FIBSER scale (for the frequency, intensity, and burden of side effects) were significantly different between groups, showing greater improvements in the PGx group. Further, 1 SR included in the Aboelbaha et al.study⁹ showed that the intervention group had a lower risk of medication tolerability issues.

The 1 included NRS¹⁶ used the CGI-EI index and found that the intervention group had significantly fewer side effects than the comparator group at the 4-, 8-, and 12-week follow-ups but not the 2-week follow-up.

One RCT¹¹ showed that side effects were prevalent in the total study population but did not change over the course of study and there were no significant differences between those who were tested and those receiving standard care. When conducting subgroup analyses, this RCT¹¹ showed that, in the moderate-risk subgroup, side effect burden improved in the intervention group compared to standard care and the high-risk group showed higher side effect burden compared to the standard care group, which was explained by patient dropout. In another RCT,¹⁵ side effects measured using the UKU Side-Effect Rating Scale showed increases within study groups at multiple follow-ups and between study groups at each follow-up.

In 1 uncontrolled before-and-after study,¹⁸ side effects measured using the Antidepressant Side-Effect Checklist showed improvements after PGx testing and adjusted analyses showed that improvements were not correlated with medication change.

Adverse Events

In the Aboelbaha et al. study,⁹ 1 included SR showed the intervention group had lower rehospitalizations after 2 months, as well as fewer emergency room visits after 2 months. However, this was not statistically significant. The HTA¹⁰ reported that there was no evidence found for suicide.

For the RCT reported in 2 publications,^13,14 both publications showed no difference between the intervention and comparator groups with respect to the readmission rate 30 days after discharge.

Clinical Effectiveness of Pharmacogenomic Testing ― Medication

Of the included primary studies, the 2 uncontrolled before-and-after studies,^18,19 the cohort study with historical control,¹⁷ and 3 of the RCTs^11-14 reported medication-related outcomes. The included HTA¹⁰ found no studies examining medication adherence. In the cohort study with historical control,¹⁷ the number of medication switches was not different between the intervention and control groups and the subgroup analyses in treatment-naive patients showed more changes in the control group compared to the intervention group. In addition, the intervention group was given medication at a significantly delayed time point compared to the control group.¹⁷ In the Collins et al. study,¹⁸ the majority of patents had medication changes and were compatible with their treatment; the adjusted analysis showed that the medication change was not correlated to the CGI-I score. In the Papastergiou et al. study, there were more medication switches in the intervention group compared to the control group.¹²

In terms of how treatment was implemented, the Kierce et al. uncontrolled before-and-after study¹⁹ showed that, of the 15 patients who underwent PGx testing, 6 were given medication that had gene-drug interactions. In the 1 RCT conducted by Ruaño et al.,^13,14 most patients in the overall study population were given at least 2 psychotropic drug treatments: less than 100 patients were given no treatment and less than 200 patients were given 1 medication.¹⁹ The McCarthy et al. study¹¹ showed that the majority of clinicians did not change dosing based on the PGx test results but did use the test to reduce side effects. In the Papastergiou et al. study,¹² more dose adjustments and more new medication additions occurred in the PGx test group, while continuation of the medication regimen occurred more in the control group compared to the PGx test group.

Limitations

There are several limitations to the body of evidence found. Studies varied in comparability of populations across the evidence and findings may have had low external validity. Some studies were focused on patients with a specific primary diagnosis of MDD and other studies were inclusive of various forms of depression. Some study population sizes were small (e.g., 15 participants), which may have made it difficult to draw conclusions. The majority of studies were conducted at single hospital sites in different countries. These findings may not be representative of the types of patients with depression in a more generalizable population (i.e., non-hospital contexts) or to people with depression specifically in Canada. The 1 study that was conducted in Canada¹² took place at 3 urban pharmacies in Ontario that may not be generalizable to other health care settings (e.g., primary care) or geographic settings (e.g., rural communities in Canada).

Regarding outcomes, several ways of measuring the effectiveness or response to the intervention were measured, with the majority of studies using questionnaires that relied on patients’ self-reporting or clinicians’ judgment; this may not have been reliable because the questionnaires are based on subjective responses. Different questionnaires were used across studies to measure symptoms and some studies used multiple questionnaires for the same trial, which showed conflicting findings. There were also few studies that reported on other outcomes such as side effects, AEs, or medication-related outcomes; these outcomes may be important in determining the effectiveness of PGx testing. Further, follow-up time for these outcomes ranged widely from 1 day to 24 weeks and differences between study groups were seen at some time points but not others. In the included HTA,¹⁰ no results were found for quality of life, recovery, relapse, or recurrence of depressive symptoms long term; and, of the studies found, most did not have outcomes reported after 12 weeks. In some studies, subgroup analyses were performed based on the specific PGx test, patient risk categories, or whether patients were treatment-naive or not. This variability may make it difficult to compare studies to each other as the study findings are based on different outcomes using different measures, different follow-up times, different sample sizes, and different subgroups of patients.

Conclusions and Implications for Decision- or Policy-Making

A CADTH rapid review was conducted to update a 2020 CADTH report⁶ and provide new evidence on the clinical effectiveness of guided care with PGx testing compared to standard care for adults with depression. Although trials are currently underway and new protocols have been published since the 2020 CADTH report’s⁶ literature search (see Appendix 6), the results of these studies have not been published yet. Of the literature that was found for the current report, 11 new studies were identified that included 1 SR,⁹ 1 HTA,¹⁰ 4 RCTs reported in 5 publications,^11-15 1 NRS,¹⁶ 1 cohort study with historical control,¹⁷ and 2 uncontrolled before-and-after studies.^18,19 One additional abstract for an RCT³⁵ was found in the literature search and is listed in Appendix 6. Most studies were conducted in the US and 1 RCT was conducted in Canada.¹² The populations in these studies included people aged 18 to 85 years, with various forms of depression such as MDD, BD, generalized anxiety disorder, and PTSD in study samples that ranged from 15 to 1,459 participants. Outcomes reported were LOS, response to treatment, remission from depression, side effects, AEs, and medication-related outcomes. All outcomes showed mixed results across the body of evidence.

Because PGx testing is a growing field, the current CADTH report adds to the body of evidence to ascertain what has been published since the previous report. Compared to the 2020 CADTH report,⁶ the current report only focused on updating the clinical effectiveness literature (the 2020 CADTH report included cost-effectiveness studies and guidelines). The previous report⁶ found 1 HTA, 2 SRs with MAs, and 1 RCT that showed inconclusive evidence on the clinical effectiveness of PGx testing. Specifically, the HTA included in the 2020 CADTH report found mixed results of low to very low quality for all outcomes, 1 SR with MA that showed minimal evidence of low quality, another SR with an MA that showed remission for depression for patients with moderate to severe depression who had intolerability to previous medication, and 1 RCT that showed no effect of PGx-guided care on safety or depressive symptoms.⁶ This current report found a greater number of publications; however, it also showed inconclusive evidence. In particular, LOS in hospital, response to treatment, remission from depression, side effects, and adverse event outcomes showed mixed results across study designs, with some studies reporting improvements in those patients who received PGx-guided treatment and some studies showed no difference between the PGx testing and usual care. No included studies found worse outcomes for those undergoing PGx treatment compared to standard care. There were several limitations in the included studies such as poor study design, small sample sizes, variability in measuring outcomes, subjective reporting of outcomes, and low generalizability. For the primary studies specifically, half were randomized and half were not, which may have explained why the conclusions for various outcomes differed across studies. Further, 4 of the publications included some form of blinding, with 2 trials blinding someone other than the patient.

Because of the high variability in the findings, future studies may consider the following: consensus on which tools best measure the clinical effectiveness of guided care with PGx testing, with a balance of reporting subjective and objective outcomes; the appropriate length of follow-up to allow medication changes to take place and long-term effects to be captured; all important variables that may affect results (e.g., patient risk type, patient’s medication history) and performing statistical analyses to determine whether potential effects are due to medication changes or other variables; other outcomes that are not adequately captured in current literature (e.g., long-term effects, suicide); and study conduct in settings that are more generalizable.

Further research could also help shed light on how this new tool can be implemented in a way that provides clear guidelines for clinicians, helps determine the best way to manage care by setting and provider type (e.g., physicians in primary care, pharmacist in pharmacies), helps assess ethical issues regarding how patients’ biological samples and data are used, helps understand what barriers exist to accessing PGx-guided care, and helps establish best care practices during the delays between testing and medication implementation.^4,5

Guided care with PGx testing is not commonly used as part of treatment for people with depression⁵ and further research in this area could help provide more conclusive results on its clinical effectiveness.

References

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Systematic Review and Health Technology Assessment

AE = adverse event; BD = bipolar depression; GAD = generalized anxiety disorder; MA = meta-analysis; MDD = major depressive disorder; NR = not reported; NRS = non-randomized study; PGx = pharmacogenomic; RCT = randomized controlled trial; SR = systematic review; TAU = treatment as usual.

^aAssessed in a 2020 CADTH report.⁶

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Systematic Review and Meta-Analysis, and Health Technology Assessment, Using AMSTAR 2⁷

MA = meta-analysis.

Appendix 5: Overlap Between Included Systematic Reviews

Note that this appendix has not been copy-edited.

Table 9: Overlap in Relevant Primary Studies Between the Included Systematic Review and the Health Technology Assessment

Appendix 6: References of Potential Interest

Note that this appendix has not been copy-edited.

Previous CADTH Reports

Li KX, Loshak H. Pharmacogenomic testing in depression: a review of clinical effectiveness, cost-effectiveness, and guidelines. (CADTH Rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2020: https://cadth.ca/pharmacogenomic-testing-depression-review-clinical-effectiveness-cost-effectiveness-and-guidelines. Accessed 2021 Nov 10.

Review Articles

Bousman CA, Bengesser SA, Aitchison KJ, et al. Review and consensus on pharmacogenomic testing in psychiatry. Pharmacopsychiatry. 2021;54(1):5-17. PubMed

Eap CB, Grunder G, Baumann P, et al. Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants. World J Biol Psychiatry. 2021;22(8):561-628. PubMed

Zanardi R, Manfredi E, Montrasio C, Colombo C, Serretti A, Fabbri C. Pharmacogenetic-guided treatment of depression: real-world clinical applications, challenges, and perspectives. Clin Pharmacol Ther. 2021;110(3):573-581. PubMed

Zanardi R, Prestifilippo D, Fabbri C, Colombo C, Maron E, Serretti A. Precision psychiatry in clinical practice. Int J Psychiatry Clin Pract. 2021;25(1):19-27. PubMed

Arandjelovic K, Eyre HA, Lenze E, Singh AB, Berk M, Bousman C. The role of depression pharmacogenetic decision support tools in shared decision making. J Neural Transm. 2019;126(1):87-94. PubMed

Vilches S, Tuson M, Vieta E, Alvarez E, Espadaler J. Effectiveness of a pharmacogenetic tool at improving treatment efficacy in major depressive disorder: a meta-analysis of three clinical studies. Pharmaceutics. 2019;11(9):02.

Ongoing Clinical Trials

Massachusetts General Hospital. NCT03749629: Comparative Effectiveness of Pharmacogenomics for Treatment of Depression (CEPIO-D). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT03749629. Accessed 2021 Nov 11.

Weill Medical College of Cornell University. NCT03952494: Individualizing antidepressant treatment using pharmacogenomics and EHR-driven clinical decision support (MyGenes). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT03952494. Accessed 2021 Nov 11.

Assurex Health Inc. NCT02466477: Pharmacogenomic decision support with GeneSight Psychotropic to guide the treatment of major depressive disorder. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2020: https://clinicaltrials.gov/ct2/show/NCT02466477. Accessed 2021 Nov 11.

Seattle Institute for Biomedical and Clinical Research. NCT03468309: Medication optimization using pharmacogenetic testing and the G-DIG to reduce polypharmacy in a mental health population (MedOPT). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2019: https://clinicaltrials.gov/ct2/show/NCT03468309. Accessed 2021 Nov 11.

Protocols

Ginsburg GS, Cavallari LH, Chakraborty H, et al. Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network. Genet Med. 2021;23(7):1185-1191. PubMed

Oslin DW, Chapman S, Duvall SL, et al. Study design and implementation of the PRecision Medicine In MEntal health Care (PRIME Care) Trial. Contemp Clin Trials. 2021;101:106247. PubMed

Tsermpini EE, Skokou M, Ferentinos P, et al. Clinical implementation of preemptive pharmacogenomics in psychiatry: Tauhe “PREPARE” study. Psuhiatrike. 2020;31(4):341-351. PubMed

Manzor Mitrzyk B, Kadri R, Farris KB, et al. Using pharmacogenomic testing in primary care: protocol for a pilot randomized controlled study. JMIR Res Protoc. 2019;8(8):e13848. PubMed

Primary Study With Mixed Age Population

Brown L, Li J, Katel N, et al. Pharmacogenetic testing in an academic psychiatric clinic: a retrospective chart review. J Pers Med. 2021;11(9):08.

Relevant Abstract

Parikh SV, Khazanov GK, Thase ME, et al. Safety of using a combinatorial pharmacogenomic test for patients with major depressive disorder in the GUIDED trial. CNS Spectr. 2021;26(2):169-170. PubMed