Overview of Methods
Pharmacogenetics (PGx) became an increasingly valued method of investigation into the system of drug response for various diseases, including psychiatric disorders. According to Oedegaard et al. (2016), understanding the genes engaged in such a response is crucial to considerably improve the individualized treatment to target-specific genetic alterations characteristic of the particular patient or population. The proposed method implies that the examined population will be divided into two groups: one is subjected to traditional psychiatric treatment, and the other group is exposed to pharmacogenetic testing. The study will also involve the implementation of clinical and laboratory supervision. Qualified and experienced psychiatric professionals engaged in the study will generally use mood stabilizers or antipsychotic drugs. The healthcare provider will apply the findings of the genetic test to alter the treatment plan.
The proposed research study will be based on the central hypothesis that pharmacogenetic testing is a beneficial tool providing efficient treatment for patients with bipolar disorder. In addition, pharmacogenetic tests help reduce the aftermath of personal instability in genetics, which needs to be recognized as a fundamental element of the response to medical treatment and drugs. The research study will be guided by the general understanding that PGx is studying genes’ response to certain medicines in the human body. Therefore, such testing is vital to determine the most appropriate treatment interventions for a broad spectrum of mental health conditions.
The proposed scientific research will implement an observational study design. According to Bailey et al. (2019), this type of study design enables observing and recording the participants’ behavior systematically and understanding the particular characteristics of the group or their setting. It is followed by the record of the results or findings, without attempting to change the participants subjected to the examination procedure. The main advantage of using observational research design implies the systematic observation and record of the patients’ behavior. Therefore, it will be possible to learn and clarify the particular characteristics of the group under study or the target setting. Considering that the research involves two different groups, another critical approach will be the case-control observational studies to compare the groups and define the predictors of an outcome (Martínez, Papuzinski, Stojanova & Arancibia, 2019). The key advantage of the case-control studies is based on its simple approach to organizing and generating the hypothesis.
The proposed research study concerning the use of pharmacogenetics in treating bipolar disorder will be applied in clinical settings, including Crossbridge Behavioral Health, an affiliate of Baptist Medical Center South, and Cullman Regional Medical Center. With a particular focus on psychiatry, the study also focuses on private practice and community mental health, engaging a trained mental health care provider (psychiatrist and psychologist), as well as a clinical social worker.
Subjects (Population Characteristics, Inclusion and Exclusion Criteria)
The target population for the proposed research study will involve the patients diagnosed with type I or II of bipolar disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders (2013). However, the final objective is to yield results beyond the target population itself. The study will engage thirty patients with bipolar disorders divided into two groups, with fifteen individuals accordingly.
The inclusion criteria start from 18 years and older (50-60 years limit), and the patients selected for the research had to take the baseline medication for at least three months. The first-line medications for BD patients therapy include the mood stabilizers: lithium, valproate, carbamazepine, lamotrigine, and the antipsychotics: olanzapine, quetiapine, risperidone, and aripiprazole. Before the pharmacogenetic test execution and the use of findings for the research purpose, the study participants will be given in the written form written informed consent. One group of participants will be observed based on their genetic test results, while the other group of 15 people will be watched within the traditional method of treatment. The study results will demonstrate promising data concerning the effectiveness of the PGx tests tool in developing more tolerated treatment for BD.
Recruitment and Attrition
Participants’ recruitment is based on the following selection criteria: age range, non-clinical stability, medication adherence, and informed consent. First, bipolar disorder diagnosis has to be recorded at least six months before the beginning of the testing and study participation. The researcher must make sure that the patients involved in the study are 18 years and older, however, under the age of 60. Furthermore, each individual will be provided with the written informed consent before participating in the pharmacogenetic test concerning legislative purposes to ensure individuals’ protection. Before the test, this consent scoring > or equal to 3 in the index will help measure the non-clinical stability. The baseline medication consumption for the last three months before the study is also an essential requirement.
Sample Size and Power Calculations for each Outcome Measure
The unique collected sample from 30 participants will be genotyped for GWAS (genomewide association study), a useful approach in genetics research that correlates particular genetic variations with the diseases. This method implies scanning the genomes from many different individuals and identifying the genetic markers that can predict the presence of a disease. The sample size was estimated regarding the number of individuals with severe bipolar disorder in Alabama (83,000), 95% confidence level, and ~ 18% confidence interval. The sample for the proposed research will be assessed longitudinally with the aid of clinical scales, cognitive assessments, and laboratory tests. The STEP-BD (NIMH-funded Systematic Treatment Enhancement Program for Bipolar Disorder) sample will include well-documented treatment responses. STEP-BD is a long-lasting outpatient study that determines the most efficient treatments for preventing recurrent episodes in BD patients.
The data collection will be conducted with careful monitoring and accompanied by the appropriate scales. The most effective data collection method implies the observation of the participants. It will be adopted along with examining the non-verbal expression of feelings, identifying fundamental interactions between the patients involved, and defining changes in the selected group. The observation method will involve the data collection tools, such as checklists and direct observation. The proposed mixed-method research study will also employ qualitative tools for data collection, such as interviews, observation, and document analysis (Cuéllar-Barboza, McElroy, Veldic, et al., 2020). The data analysis tools for these methods involve Graph-Pad and SAS version 19. Graph-Pad is a valuable analysis tool and effective graphing solution purpose-built for scientific research. SAS is a broad-spectrum tool that can be applied in the healthcare system to enhance patient outcomes and experience through advanced analytics.
Data will be gathered on the course of the disease before randomization. It will include the “age of onset for bipolar disorder, number of prior episodes, past treatment reaction, childhood abuse, health conditions, psychoactive substance use, family history, previous lithium treatment, and prior suicide attempt history” (Salloum, McCarthy, Leckband, & Kelsoe, 2015, p. 4). The participants’ history of bipolar disorder episodes during the past two years will be obtained through a life chart method. In general, this information will be used as a covariate to adjust for a natural course in the statistical analysis.
Outcomes of Interest
The current studies demonstrate a relationship between variations in genetics and response to medications or disease predisposition for patients who have bipolar disorder (Espadaler, 2016). Nevertheless, the existing research does not entirely clarify whether pharmacogenetic testing can replace the current (more traditional) methods of clinical treatment. Such an open discussion poses critical challenges that the proposed research study aims to address. The outcomes of interest imply that the study will give sufficient data regarding pharmacogenetics and contribute to medication improvement for patients diagnosed with bipolar disorder.
The advanced medications are expected to reduce the side effects and emphasize the pivotal role of personal genetics variability in drug response. The observational study design applied for this research study will identify causal associations between two or more variables, including the implementation of the PGx testing (independent variable) and the resulting health outcomes of the population under study (dependent variable). Therefore, the main expected results are that the research findings will demonstrate promising data about the benefit of the pharmacogenetic tests measures in developing more effective and tolerated treatment in the alternative and innovative approach of bipolar disorder.
The study participants will be randomized to pharmacogenetic test guided treatment or treatment as usual (TAU), meaning the traditional treatment approach. The patients will be divided into groups accordingly. The proposed research study will implement the stratified randomization that helps obtain balance within subgroups on baseline covariates, considering certain characteristics such as gender, age, race, and disease severity. Such a randomization approach provides valid statistical tests. The subjects should take baseline measurements before randomization.
Measures to be Used
The research is based on the implementation of pharmacogenetic testing and its further application to improve the clinical treatment of bipolar disorder diagnosis. As defined by the World Health Organization (WHO, 2020), there are three main prevention levels in public health: primary, secondary, and tertiary prevention. Hence, the PGx testing in the treatment of Bipolar disorder can be referred to as a primary level of public health because its measures are aimed at improving the overall mental health of a population affected by bipolar disorder.
Pharmacogenetic testing in treating bipolar disorder is considered a mental health promotion campaign helping affected individuals access advanced treatment measures that address crucial psychiatric issues, including bipolar disorder. According to WHO (2020), such health promotion and prevention are defined as involving measures carried out to allow society to increase control over the disease and improve the overall public health outcomes. The effects of treatment regarding the selected group of participants will be assessed using the Random Effect Model and the sequel observation after the three months. Such an instrument allows the researcher to evaluate the link between the established variables.
The core data management plan includes the following steps: defining the focus of the study, designing data collection and analysis systems, timing the observations, and applying the research findings to developing the advanced treatment. The previously published data regarding cognitive dysfunction in bipolar disorder and the heritability of particular neurocognitive measures will develop the evaluation strategy for the research study and define the key study domains, such as “attention, verbal learning, and executive function” (Cuéllar-Barboza, McElroy, Veldic, et al., 2020, p. 10). The gene expression data will be applied for promoting the gene expression networks that can be compared between the particular conditions. The received data can significantly contribute to the clinician’s assessment of a molecular diagnosis of bipolar spectrum disorder patients. Once the data is collected, it will be used to optimize the medication treatment for patients with BD as means to reduce side effects and identify the personal variability in genetics as an integral part of drug response. The data will be input into the required software for data analysis through:
- Graph-Pad: involving statistics, regression, and data manipulations such as transforming, removing baselines, and normalizing.
- SAS: connecting to different data types and ensuring the availability of data required by knowledge workers while supporting multiple data processing run times.
The data analysis will be implemented with the help of SPSS, which is a software package for interactive, or batched, statistical analysis. For characterizing the patient population, the research will apply descriptive statistics and Kruskal Wallis test analysis. The Kruskal-Wallis H test is a rank-based nonparametric test that can define statistically significant disparities between groups of independent variables on a continuous or ordinal dependent variable. This will help define the relevance of medical performance differences of the PGx test group’s scale scores and the reference group (Salloum, McCarthy, Leckband & Kelsoe, 2015). Also, the Mann-Whitney U test analysis will be adapted to calculate the significance of treatment effectiveness and the aftermath differences between the reference and test samples.
The outcome measures of the sample will serve as a baseline sample for the future research and replication of results. The dissemination of the research findings will be focused on the target audience:
- commissioning organizations,
- community nursing service provider staff,
- patients and the public,
- external statutory organizations (Department of Health, NHS Information Centre, NICE, Quality Observatories),
- academic researchers.
The pharmacogenetics studies of psychiatric conditions are exposed to some methodological issues and limitations. First, there can be a lack of reproducibility between the studies conducted so far. This can be explained by the various criteria used by many studies for examining the medications response (Fortinguerra, Sorrenti, Giusti, Zusso & Buriani, 2020). Considering the diverse criteria, the research findings cannot be directly compared between the studies. However, the International Society for Psychiatric Genetics (2019) designed the recommended criteria to direct researchers in the new studies. Particular limitations derive from the complex nature of bipolar disorder.
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (DSM-5 (R)), 5th revised edition. American Psychiatric Association Publishing.
Bailey, R. L., Sahni, S., Chocano-Bedoya, P., Daly, R. M., Welch, A. A., Bischoff-Ferrari, H., & Weaver, C. M. (2019). Best practices for conducting observational research to assess the relation between nutrition and bone: an international working group summary. Advances in Nutrition, 10(3), 391–409.
Baskys, A. (2018). Application of pharmacogenetics in clinical practice: problems and solutions. Journal of Neural Transmission, 126(1), 109–113.
Cuéllar-Barboza, A.B., McElroy, S.L., Veldic, M. et al. (2020). Potential pharmacogenomic targets in bipolar disorder: considerations for current testing and the development of decision support tools to individualize treatment selection. International Journal of Bipolar Disorders, 8(23), 1–15.
Espadaler, J., Tuson, M., Lopez-Ibor, J. M., Lopez-Ibor, F., & Lopez-Ibor, M. I. (2017). Pharmacogenetic testing for the guidance of psychiatric treatment: a multicenter retrospective analysis. CNS Spectrums, 22(4), 315–324.
Fortinguerra, S., Sorrenti, V., Giusti, P., Zusso, M., & Buriani, A. (2020). Pharmacogenomic characterization in bipolar spectrum disorders. Pharmaceutics, 12(1), 13.
International Society for Psychiatric Genetics (2019). Genetic testing statement: genetic testing and psychiatric disorders: a statement from the International Society of Psychiatric Genetics.
Martínez, D., Papuzinski, C., Stojanova, J., & Arancibia, M. (2019). General concepts in biostatistics and clinical epidemiology: observational studies with case-control design. Medwave, 19(10).
Oedegaard, K. J., Alda, M., Anand, A., Andreassen, O. A., Balaraman, Y., Berrettini, W. H., Bhattacharjee6, A., Brennand, K. J., Burdick, K. E., Calabrese, J. R., Calkin, C. V., Claasen, A., Coryell, W. H., Craig, D., DeModena, A., Frye, M., Gage, F. H., Gao, Garnham, J., Gershon, E., Jakobsen, P., Leckband, S. G., McCarthy, M. J., McInnis, M. G., Maihofer, A. X., Mertens, J., Morken, G., Nievergelt, C. M., Nurnberger, J., Pham, S., Schoeyen, H., Shekhtman, T., Shilling, P. D., Szelinger, S., Tarwater, B., Yao, J., Zandi, P. P., & Kelsoe, J. R. (2016). The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample. BMC Psychiatry, 16(1).
Salloum, N.C., McCarthy, M.J., Leckband, S.G., & Kelsoe, J. R. (2015). Towards the clinical implementation of pharmacogenetics in bipolar disorder. BMC Med, 12(90), 1–15.
Weitzel, K. W., Cavallari, L. H., & Lesko, L. J. (2017). Preemptive panel-based pharmacogenetic testing: The time is now. Pharmaceutical Research, 34(8), 1551–1555.
World Health Organization (2020). EPHO5: Disease prevention, including early detection of illness. World Health Organization, WHO. Web.