Pharmacogenomic Testing to Increase Treatment Adherence in Bipolar Disorder

Introduction

Bipolar disorder is a serious mental disorder that is typified by drastic mood fluctuations between mania and depression. The lifetime prevalence of this disorder is about 2.4%.¹ Bipolar disorder is a longstanding disease with affective incidents that may elicit substantial personal suffering, social dysfunction and negative outcomes on the sufferers’ mental, social, and professional wellbeing. The treatment of bipolar disorder in developed countries ranges from 3308 to 13,402 US dollars yearly per patient.² Even though several efficient for the disorder exist, misdiagnoses often lead to complications such as drug-resistance, reduction in cognitive functioning, and rapid-cycling.³

Additionally, the side effects associated with some of the medications lead to high rates of non-adherence in patients. Pharmacogenetic testing entails examining how an individual’s genes predict their response to medications.² Nevertheless, despite this knowledge, high numbers of treatment non-adherence continue to be reported in patients with bipolar disorder.

The key research question that this study seeks to answer is “Will developing a treatment model, to include pharmacogenetic testing as routine clinical decision support, increase treatment adherence in patients with bipolar disorder?” This study aims to review evidence regarding the impact of including pharmacogenetic testing as routine clinical decision support on treatment adherence in bipolar disorder.

The key terms that will be used in this study are pharmacogenetic testing, adherence, and bipolar disorder. Pharmacogenetic testing refers to the application of knowledge about genetic makeup to determine the best treatment regime. Adherence denotes a commitment to treatment advice and schedule. Bipolar disorder is a mental health condition that results in sudden shifts in temperament between mania and depression.

Literature Review

Scientific evidence shows that interpersonal variations in response to medications are brought about by numerous factors, for example, diagnostic precision, hepatic and renal function, drug-drug interactions, as well as medical and mental comorbidity^.4 Furthermore, genetically influenced discrepancies in drug pharmacodynamics and pharmacokinetics can also affect how individuals respond to drugs given that genetics plays a key role in the metabolism of drugs.⁵ Therefore, pharmacogenetic tests have been suggested as the way forward in determining the most effective treatment regimen with minimal side effects. This level of evidence is mostly from primary articles (randomized controlled trials and systematic reviews and meta-analyses) and can be considered level I.

The theoretical framework that guides this study is the ACCE model of public health genomics.⁶ It was put forth by the Centers for Disease Control and Prevention (CDC). This model explores the various facets that influence the use of genetic data in disease management.

Methods

The author obtained clearance to conduct research from their institution’s Institutional Review Board (IRB). The process of obtaining IRB clearance entailed evaluating the potential risks and benefits of subjects as well as obtaining informed consent. However, since the study involved a review of the literature, these steps were not necessary.

The research design employed in the study is a systematic review, which is an evaluation of an articulated question. It uses meticulous and unambiguous methods to find, choose, analytically appraise pertinent research and collect information from previously published studies related to the research question. The key feature of a systematic review is that it applies a precise set of benchmarks to evaluate the reliability and validity of previously published research.

Articles were searched from databases such as PubMed, CINAHL, Medline, and Google Scholar. The key terms used were pharmacogenetic testing, bipolar disorder, and treatment adherence. The search was limited to articles published within the last five years. The results were filtered based on their relevance to the subject.

The inclusion criteria entailed quantitative studies, qualitative studies, secondary sources, and clinical practice guidelines or consensus statements addressing the use of pharmacogenomics in general or its application in bipolar disorder. Since bipolar disorder and depression are commonly co-occurring mood ailments, most studies that explore the treatment of mood disorders apply to bipolar disorder and depression.³ Therefore, studies that explored pharmacogenetic testing in major depressive disorder were also included in the review. Articles with explicitly defined treatment and intervention groups were included.

The exclusion criteria encompassed studies that addressed pharmacogenomic in diseases other than major depressive disorder and bipolar disorder. Experimental studies without clearly defined sample attributes were excluded. Articles involving pregnant women as subjects were also excluded from the review.

The evidence was rated into different levels using the Polit and Beck hierarchy of evidence tool, whereas the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to determine the quality of evidence. Recommendations of the study findings were made based on the Appraisal of Guidelines for Research and Evaluation II (AGREE II) Collaboration framework.

Results

A total of 12 articles were selected based on the inclusion and exclusion criteria listed above. They included 4 quantitative studies, 2 qualitative studies, 5 secondary sources, and 2 clinical practice guidelines and consensus statements. The overall observation was that pharmacogenetic testing improved the treatment outcomes in bipolar disorder. The key findings are summarized in Table 1.

Table 1: Summary of key findings.

Author (s) and Year	Study Objectives	Key findings	Level of evidence
Heale, Khalifa, Stone, Nelson & Del Fiol (2017)	To study physicians’ pharmacogenomics information needs and behavior.	About 8 minutes was spent on searches without a detailed review of cases. Alternative options without pharmacogenomics were sought.7	IV
Rosenblat, Lee, & McIntyre (2018)	To determine the effect of gene testing on drug response and reduction of symptoms in depression treatment.	Guided treatment (pharmacogenomics) led to better treatment outcomes (p= 0.0006; n= 799).8	I
Oedegaard et al. (2016)	To use pharmacogenomics to enhance the mechanism of action of lithium different responses in patients with bipolar disorder.	No findings yet. A description of a controlled trial.9	II
Oni-Orisan et al. (2020)	To determine biases in the approximation of the relationship between variables and drug reactions using baseline measurement.	Associations between genetic variants and baseline measurement led to biases in the estimation of drug effects.10	I
Veilleux, Bouffard, & Bourque Bouliane (2020)	To identify patients’ and clinicians’ needs and penchants in pharmacogenomic testing.	Understanding the perception of patients and healthcare providers is crucial to the implementation of pharmacogenomic testing in clinical practice.11	V
Lemke et al. (2017)	To explore physicians’ views of combined pharmacogenomic testing in clinical settings.	The major factors considered by physicians include the alleged importance and usage of pharmacogenetic testing, setbacks during execution, and associated provider and patient needs.12	VI
Thiele, Clancy, Heinken, & Fleming (2017)	To evaluate recent developments in computational methods that could improve medication, diet, and microbial relationships and their influence on drug responses.	Integrating the three fields can enhance the study of individual discrepancies, thus supporting advancements in precision medicine.13	III
Fulton et al. (2018)	To prove the value of pharmacogenetic testing and clarify the interpretation and application of findings based on presenting cases.	Advanced nurse practitioners are better placed to use the findings of pharmacogenetic tests in clinical settings.14	V
Ramey, Reddy, Datla, Prakash, & Acharya (2019)	To explore the clinical value of pharmacogenetic testing.	The lack of awareness about pharmacogenetics and the lack of information about many drugs and biomarkers are the main factors that hinder its use in clinical settings.15	III
Routhieaux, Keels, & Tillery (2018)	To recount documented results of pharmacogenetic testing in cases of schizophrenia or bipolar disorder.	There was an association between genes involved in the development of the two disorders and reaction to antipsychotic medications and mood stabilizers.16	III
Tonozzi et al. (2018)	To compare pharmacogenetic test profiles and the treatment of major depressive or bipolar disorder treatment.	Pharmacogenetic testing is of immense value in psychiatric care.17	VI
Caudle et al. (2014)	To connect genetic makeup to physical attributes to augment drug therapy.	Clinicians should decode patient-specific subsets of genes occurring on homologous chromosomes into clinical traits or drug dosing clusters.18	7/7 (Yes)
Brown et al. (2019)	To clarify the construal of CYP2D6 genotype tests in clinical settings for the use of atomoxetine.	CYP2D6 genotype tests provide valuable information in the use of atomoxetine.19	5/7 (Yes)

Discussion

The current clinical guidelines recommend that the treatment of bipolar disorder uses lithium or lamotrigine monotherapy as first-line treatments. In resistance cases, mood stabilizers such as Divalproex can be used together with lithium.²⁰ Applying pharmacogenetics in the initial stages would help to determine the most appropriate treatment in the initial stages.

The study has several strengths including the use of recent research findings to address the research question. The study combines evidence from different angles of research to answer the research question. It considers findings from qualitative, quantitative research, secondary sources, and clinical practice recommendations. The weaknesses of the study encompass the shortcomings of the individual studies that were used to generate the evidence. For example, in one article, no tangible findings were reported and only the impact of pharmacogenetic testing on the action of lithium was explored.⁹ Other studies did not explore the specific use of pharmacogenetic testing in bipolar disorder.^{7,11,12, 13,14,15,16,17}

The limitations of the study include the review of a few articles with high strength of evidence. Only 3 out of the 13 studies reviewed were level I or II. Therefore, the overall strength of evidence was low.

Conclusion

The synthesis of evidence shows that pharmacogenetic testing improves treatment outcomes in mood disorders. However, it is highly underutilized in clinical settings. Nurse practitioners and other health care providers should consider integrating pharmacogenetic testing in the development of treatment regimens for patients with bipolar disorder. Implications for research are that additional testing of specific medications in large samples should be done to provide critical data on tolerability and efficiency. Personalized medicine is a great step towards personalized care that can transform treatment outcomes in bipolar disorder if used appropriately.

References

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2. Callegari, C., Isella, C., Caselli, I., Poloni, N., & Ielmini, M. (2019). Pharmacogenetic tests in reducing accesses to emergency services and days of hospitalization in bipolar disorder: A 2-year mirror analysis. J. Pers. Med., 9(2), 1-8. Web.
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