Pharmacogenetics Applied to Neurological and Psychiatric Conditions

Mental health problems are among the leading causes of disease burden worldwide, encompassing a variety of nervous system disorders that challenge medicine in both diagnosis and treatment. 

To address these disorders, therapeutic approaches often include medications, but their effects can vary significantly among patients due to genetic factors. This is where pharmacogenetics stands out, offering a new possibility: personalized treatments based on each patient’s genetic profile. By understanding how genetic variants influence drug responses, the pharmacogenetic panel helps make neurological treatments more effective, reduces side effects, and improves outcomes. 

Discover how and why this approach is revolutionizing medicine in the content we’ve prepared for you. 

What is Pharmacogenetics? 

Pharmacogenetics is the field of medicine that studies how an individual’s genetic variations influence their response to medications. Combining pharmacology (the study of drugs) and genetics (the study of genes and inheritance), this field aims to develop personalized treatments that are more effective and have fewer adverse effects. 

Pharmacogenetics is particularly relevant in areas such as neurology and psychiatry, where treatments often involve a trial-and-error process. Neurological and psychiatric disorders like epilepsy, depression, schizophrenia, and bipolar disorder can be challenging to treat due to variability in patients’ responses to medications. 

Major Neurological Conditions 

Major depression (MD) is a highly prevalent neurological condition and one of the top global public health concerns. 

According to the World Health Organization (WHO), over 300 million people suffer from major depression, representing 4.4% of the global population (1). Additionally, a similar number face anxiety disorders, both incurring high healthcare costs and significantly impacting patients’ lives (2, 3). 

The complexity of depression, marked by variability in treatment response, presents a significant clinical management challenge. Responses to antidepressants vary widely among patients due to the interaction of genetic, environmental, and psychological factors. 

Although an increasing number of medications are available, psychiatry still relies on a “trial-and-error” model when selecting treatments, limiting success rates, especially for patients with mild depression (4, 5). Issues like poor treatment adherence and adverse effects further contribute to unsatisfactory outcomes. 

In some cases, depression becomes treatment-resistant, meaning it does not respond to at least two different classes of antidepressants administered at adequate doses for a sufficient period. This form of treatment-resistant depression accounts for 20% to 30% of MD cases (6), presenting an even greater challenge for professionals to find effective approaches for these patients. 

The Impact of Pharmacogenetics on the Treatment of Neurological and Psychiatric Diseases 

The application of pharmacogenetics in the treatment of neurological and psychiatric disorders has the potential to revolutionize clinical practice. For example, in neurology, pharmacogenetics can help personalize treatments for conditions such as epilepsy, multiple sclerosis, and Parkinson’s disease. Patients with epilepsy may have genetic variants that affect the metabolism of anticonvulsants, and identifying these variants allows clinicians to adjust dosages to prevent seizures and minimize side effects. 

In psychiatry, pharmacogenetic analysis is particularly useful for disorders like depression, schizophrenia, and bipolar disorder. Many patients do not respond to the first prescribed medication, and pharmacogenetics can reduce the time needed to identify the right treatment. For example, genetic variants in the genes encoding drug-metabolizing enzymes can influence the efficacy of antidepressants and antipsychotics (7). 

Advances in pharmacogenomic studies have been highly relevant across various medical disciplines, especially in psychiatry. According to international guidelines, patients with complex conditions like bipolar disorder, major depressive disorder, psychotic depression, and borderline personality disorder should undergo these studies before initiating treatment due to the frequent use of combination therapies in these conditions (8). 

The Importance of Pharmacogenetics 

Genetic variations can manifest at both pharmacokinetic and pharmacodynamic levels, ultimately resulting in distinct and personalized responses to specific treatments. 

Pharmacokinetic factors influence the plasma and tissue drug levels achieved with a given dose, determined by the processes of absorption, distribution, metabolism, and excretion. 

Pharmacodynamic factors govern the interaction between a drug and its receptor, leading to responses that may be more or less effective than expected. These factors affect receptors, enzymes, or proteins involved in signal transduction (9, 10). 

Moreover, the terms pharmacogenetics and pharmacogenomics are often used interchangeably. Pharmacogenetics refers to the study of individual genetic variability in genes associated with drug responses, while pharmacogenomics is used to describe the process of utilizing documented genetic variation to guide drug selection and dosing (11).

Pharmacogenetic studies aim to identify genetic variants and establish genetic biomarkers capable of influencing the magnitude of pharmacological effects, side effects, and drug interactions. These studies have become a cornerstone of personalized medicine, defining treatments based on each patient’s genetic profile (9, 12). 

However, therapeutic responses are influenced by various factors, including physiological aspects like age, sex, weight, and body fat; pathophysiological conditions like renal, hepatic, or cardiovascular function; environmental factors like smoking, alcohol consumption, nutrition, and pollutants; and genetic factors that affect the absorption, distribution, metabolism, and excretion of drugs. Personalized medicine involves tailoring patient treatment based on their genetic-molecular profile (12). 

Key Genes in Psychiatric and Neurological Pharmacogenetics 

Several genes have been identified as important in psychiatric and neurological pharmacogenetics, including: 

• CYP2D6: This gene encodes a cytochrome P450 enzyme that metabolizes many psychiatric drugs, including antidepressants and antipsychotics. Variants in CYP2D6 can result in rapid or slow metabolizers, affecting drug efficacy and safety (13–16);
• CYP2C19: This gene is also involved in the metabolism of drugs such as antidepressants and anticonvulsants. Variants can influence treatment responses (17);
• HTR2A: This gene encodes a serotonin receptor targeted by many antidepressants. Variants in HTR2A can affect responses to selective serotonin reuptake inhibitors (SSRIs);
• COMT: The COMT gene encodes the enzyme catechol-O-methyltransferase, which degrades neurotransmitters like dopamine. Variants in COMT can influence responses to medications affecting dopamine levels, such as antipsychotics.

Variants in other enzymes involved in drug metabolism and transport also affect the pharmacokinetics and pharmacodynamics of drugs used in psychiatry and other medical fields. 

Benefits of Pharmacogenetic Analysis for Patients and Healthcare Professionals 

The response to psychiatric medications varies greatly among individuals, both in therapeutic effects and the risk of adverse effects. Studies indicate that 60–70% of patients with depression do not achieve full remission with antidepressants, and 30–40% fail to respond adequately (18). 

Approximately 10% of patients discontinue antidepressants due to adverse effects. Antipsychotics and mood stabilizers are also frequently associated with side effects (19–21). 

It is estimated that up to 42% of variability in antidepressant response is attributable to common genetic variants (22). Hence, the establishment of pharmacogenetic biomarkers is crucial due to their implications for drug efficacy and associated side effects. 

Adverse drug effects are responsible for approximately 7% of hospitalizations, 20% of all readmissions, and about 4% of drug withdrawals from the market (23–25). 

In this context, pharmacogenetic analysis offers numerous benefits for both patients and healthcare professionals. 

For patients, key benefits include: 

• Personalized Treatments: Tailoring treatments to individual genetic characteristics enhances drug efficacy and minimizes side effects;
• Reduced Treatment Time: By quickly identifying the most effective medications, pharmacogenetic analysis reduces the time needed to find the appropriate treatment, improving patients’ quality of life;
• Prevention of Adverse Reactions: Knowing genetic variants that influence drug metabolism helps avoid severe adverse reactions.

For healthcare professionals, benefits include: 

• Informed Decisions: Pharmacogenetic analysis provides valuable insights to guide treatment decisions, resulting in safer and more effective care;
• Treatment Efficiency: With accurate diagnoses and personalized treatments, healthcare providers can enhance care efficiency and reduce costs associated with ineffective therapies.

Understanding genetic variants involved in the expression of metabolizing enzymes enables the classification of a patient’s drug metabolism.

Discover how drug metabolism can be classified in our blog post:
What is pharmacogenetics and how it influences medication decisions 

The Future of Pharmacogenetics in Psychiatry and Neurology 

The future of pharmacogenetics in psychiatry and neurology is promising. As research progresses, pharmacogenetic analysis is expected to become a standard practice in medicine. Emerging technologies, such as next-generation sequencing (NGS), are making it easier and more affordable to identify relevant genetic variants. 

Additionally, integrating pharmacogenetics with other personalized medicine approaches, such as biomarker analysis and precision medicine, may lead to even more effective treatments. Collaboration among researchers, clinicians, and the pharmaceutical industry will be vital for the successful implementation of pharmacogenetics in clinical practice (7). 

Which Pharmacogenetic Panel for Neurological Conditions Does SYNLAB Offer? 

The Neuro PGx Pharmacogenetic Panel offered by SYNLAB evaluates variants in genes responsible for expressing key enzymes involved in the metabolism of medications commonly used to treat neurological and psychiatric conditions, such as depression, anxiety, schizophrenia, bipolar disorder, and others. 

The analysis provides relevant information on 81 medications widely used in clinical practice, based on the study of 50 genetic variants documented in scientific literature and found in 8 genes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP2B6 and ABCB1. 

To standardize and facilitate the implementation of pharmacogenetics in clinical practice, international expert consortia, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC), Pharmacogene Variation Consortium (PharmVar), American College of Medical Genetics and Genomics (ACMG), American College of Molecular Pathology (ACMP), and the Human Genome Variation Society (HGVS), among others, are dedicated to issuing and updating evidence-based clinical guidelines. These include drug-gene associations, evidence levels, standardized terminology, and clinical recommendations (26–31). 

Currently, over 35 guidelines are available on the Pharmacogenomics Knowledge Base (PharmGKB) website (32). Various platforms store comprehensive information in their databases to guide clinicians in practice, and SYNLAB adheres to all these guidelines in the development of its pharmacogenetic panels. 

Which medications are analyzed in the Neuro PGx Pharmacogenetic Panel? 

The panel analyzes 81 medications from the following classes: 

• CENTRAL ACTING ADRENERGIC AGONISTS: Clonidine, Guanfacine;
• ANTIDEPRESSANTS: NMDA RECEPTOR BLOCKERS: Ketamine, Esketamine;
• ANTIDEPRESSANTS: SEROTONIN RECEPTOR ANTAGONIST AND REUPTAKE INHIBITORS (SARI): Trazodone;
• ANTIDEPRESSANTS: SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS: Levomilnacipran, Reboxetine;
• ANTIDEPRESSANTS: MONOAMINE OXIDASE A INHIBITORS: Moclobemide;
• ANTIDEPRESSANTS: NOREPINEPHRINE AND DOPAMINE REUPTAKE INHIBITORS (NDRI): Bupropion;
• ANTIDEPRESSANTS: SELECTIVE NA AND 5HT REUPTAKE INHIBITORS: Duloxetine, Venlafaxine;
• ANTIDEPRESSANTS: SELECTIVE SEROTONIN REUPTAKE INHIBITORS: Citalopram, Escitalopram, Fluvoxamine, Paroxetine;
• ANTIDEPRESSANTS: SELECTIVE SEROTONIN REUPTAKE INHIBITORS: Sertraline;
• OTHER ANTIDEPRESSANTS: Agomelatine, Maprotiline, Mianserin, Mirtazapine, Vilazodone, Vortioxetine;
• ANTIDEPRESSANTS: TRICYCLIC ANTIDEPRESSANTS: Amitriptyline, Clomipramine, Desipramine, Dothiepin, Doxepin, Imipramine, Nortriptyline, Trimipramine;
• ANXIOLYTICS: Alprazolam, Bromazepam, Buspirone, Clobazam, Clonazepam, Chlordiazepoxide, Diazepam, Flurazepam, Ketazolam, Triazolam;
• ANTIEPILEPTICS: Phenobarbital;
• ANTIPSYCHOTICS: Amisulpride, Aripiprazole, Asenapine, Brexpiprazole, Bromperidol, Cariprazine, Clozapine, Droperidol, Fluphenazine, Flupentixol, Haloperidol, Iloperidone, Levomepromazine, Loxapine, Lurasidone, Olanzapine, Perphenazine, Pimavanserin, Pimozide, Pipotiazine, Quetiapine, Risperidone, Sertindole, Thioridazine, Trifluoperazine, Zuclopentixol;
• HYPNOTICS AND SEDATIVES: Amobarbital, Brotizolam, Eszopiclone, Hydroxyzine, Mephobarbital, Zaleplon, Zolpidem, Zopiclone;
• PARKINSON AND ALZHEIMER’S: Levodopa, Rasagiline, Selegiline;
• ADHD: AMPHETAMINES: Atomoxetine, Caffeine, Dexamfetamine, Lisdexamfetamine.

Who is the Neuro PGx test intended for? 

The SYNLAB Neuro PGx Pharmacogenetic Panel is intended for: 

• Patients with neurological or psychiatric conditions, such as depressive, psychotic, anxiolytic, or hypnotic disorders, who wish to personalize their treatment based on their genetic profile;
• Patients undergoing pharmacological treatment who do not achieve expected outcomes, with persistent symptoms despite medication;
• Patients on polypharmacy regimens;
• Patients experiencing significant side effects from medications.

What is the methodology used for the test? 

The SYNLAB Neuro PGx Pharmacogenetic Panel utilizes the MassARRAY platform, which employs mass spectrometry to rapidly and accurately identify genetic variations, such as single nucleotide variants (SNVs), insertions, deletions, and mutations. 

The MassARRAY methodology combines DNA amplification with mass spectrometry detection. Initially, DNA is amplified via PCR. Instead of directly detecting the PCR products, the amplified fragments undergo allele-specific extension reactions. Subsequently, these fragments are ionized and analyzed by mass spectrometry, enabling the determination of the molecular weight of each genetic variant. 

Why perform the Neuro PGx panel? 

Human genome variation is a key factor in modulating individual responses to medications. Pharmacogenetics studies how genetic differences influence drug responses. 

The metabolism of a drug involves various reactions that generally modify it into a more soluble molecule for easier excretion.  

Several genes encoding enzymes involved in drug metabolism pathways contain genetic variants that alter enzyme expression, selectivity, or activity, leading to diverse drug responses. Thus, assessing the genetic profile based on these variants has become crucial for understanding drug metabolism. 

What other pharmacogenetic tests does SYNLAB offer? 

SYNLAB also provides the following pharmacogenetic tests: 

• FG Cardio Completo: Analyzes the main metabolizing enzymes and targets involved in the effectiveness and toxicity of the 52 most commonly used medications for treating cardiovascular diseases;

• FG Onco Lapatinib: Studies the presence of the alleles HLA DQA1*02:01 and DRB1*07:01 to identify an increased likelihood of severe side effects, particularly hepatotoxicity, during treatment with Lapatinib;

• Global PGx: This analysis provides relevant information about 161 drugs widely used in clinical practice, by examining 55 genetic variants present in the following genes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5, ABCB1, COMT, FACTOR II, FACTOR V, MTHFR, SLCO1B1 and VKORC1.

Discover SYNLAB, a reference in the provision of medical diagnostic services! 

Conducting precise and up-to-date tests is essential for more accurate diagnoses and better treatment planning. SYNLAB is here to support you. 

We offer diagnostic solutions with rigorous quality control to the companies, patients, and physicians we serve. Present in Brazil for over 10 years, we operate in 36 countries across three continents and are leaders in service provision in Europe. 

Contact the SYNLAB team to learn more about the available tests. 

References 

1. WHO. World Health Organization. Depression and Other Common Mental Disorders. Global Health Estimates. Geneva, Switzerland, 2017. Disponível em: https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf

2. König H, König HH, Konnopka A. The excess costs of depression: a systematic review and meta-analysis. Epidemiol Psychiatr Sci. 2019;29:e30. doi:10.1017/S2045796019000180.

3. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-1259. doi: 10.1016/S0140-6736(17)32154-2.

4. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. doi: 10.1016/S0140-6736(18)32279-7.

5. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-17.

6. Ananth J. Treatment-resistant depression. Psychother Psychosom. 1998;67(2):61-70.

7. Wielandt AM, Moreno CM, Ortiz LL. Use of pharmacogenetics as a precision tool in psychiatry: Towards a personalized medicine. Rev. Med. Clin. Condes. 2022; 33(2) 163-173.

8. Ortiz L, Moreno M and Quiñones LA, Pharmacogenomics in Psychiatric Practice: Latin America Initiatives. Pharmacogenomics in Latin America: Challenges and Opportunities (Chapter 7) Editors: Luis Quiñones. Nova Science Publisher. 2017.p. 125-134.

9. Ortiz L, Tabak R. Farmacogenómica en la práctica clínica. Rev. Med. Clin Las Condes. 2012;23(5):616-621.

10. Ahmed S, Zhou Z, Zhou J, Chen SQ. Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine. Genomics Proteomics Bioinformatics. 2016;14(5):298-313.

11. Mrazek DA. Psychiatric pharmacogenomic testing in clinical practice. Dialogues Clin Neurosci. 2010;12(1):69-76.

12. Quiñones L, Roco Á, Cayún JP, Escalante P, Miranda C, Varela N, et al. Clinical applications of pharmacogenomics. Rev Med Chil. 2017;145(4):483-500.

13. Nofziger C, Turner AJ, Sangkuhl K, Whirl-Carrillo M, Agúndez JAG,Black JL, et al. PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther. 2020;107(1):154-170.

14. Varela N, Quiñones LA, Stojanova J, Garay J, Cáceres D, Cespedes S, et al. Characterization of the CYP2D6 drug metabolizing phenotypes of the Chilean mestizo population through polymorphism analyses. Pharmacol Res. 2015;101:124-9.

15. Llerena A, Naranjo ME, Rodrigues-Soares F, Penas-LLedó EM, Fariñas H, Tarazona-Santos E. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin Drug Metab Toxicol. 2014;10(11):1569-83.

16. Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes (Basel). 2020;11(11):1295.

17. Botton MR, Whirl-Carrillo M, Del Tredici AL, Sangkuhl K, Cavallari LH, Agúndez JAG, et al. PharmVar GeneFocus: CYP2C19. Clin Pharmacol Ther. 2021;109(2):352-366.

18. Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. 2010;15(5):473-500.

19. Zhang JP, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol. 2011;7(1):9-37.

20. Machado M, Iskedjian M, Ruiz I, Einarson TR. Remission, dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials. Curr Med Res Opin. 2006;22(9):1825-37.

21. Iuppa CA, Nelson LA, Elliott E, Sommi RW. Adverse drug reactions: a retrospective review of hospitalized patients at a state psychiatric hospital. Hosp Pharm. 2013;48(11):931-5.

22. Tansey KE, Guipponi M, Hu X, Domenici E, Lewis G, Malafosse A, et al. Contribution of common genetic variants to antidepressant response. Biol Psychiatry. 2013;73(7):679-82.

23. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15-9.

24. Davies EC, Green CF, Mottram DR, Rowe PH, Pirmohamed M. Emergency re-admissions to hospital due to adverse drug reactions within 1 year of the index admission. Br J Clin Pharmacol. 2010;70(5):749-55.

25. Jefferys DB, Leakey D, Lewis JA, Payne S, Rawlins MD. New active substances authorized in the United Kingdom between 1972 and 1994. Br J Clin Pharmacol. 1998;45(2):151-6.

26. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL Jr, Tran E, Berger R, et al.; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013;94(3):324-8.

27. Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, et al.; Clinical Pharmacogenetics Implementation Consortium. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther. 2014;96(5):542-8.

28. Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37-44.

29. Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, et al.; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98(2):127-34. doi:10.1002/cpt.147.

30. Caudle KE, Keeling NJ, Klein TE, Whirl-Carrillo M, Pratt VM, Hoffman JM. Standardization can accelerate the adoption of pharmacogenomics: current status and the path forward. Pharmacogenomics. 2018;19(10):847-860. doi: 10.2217/pgs-2018-0028.

31. Bank PCD, Caudle KE, Swen JJ, Gammal RS, Whirl-Carrillo M, Klein TE, et al. Comparison of the Guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group. Clin Pharmacol Ther. 2018;103(4):599-618.

32. Pharmacogenomics Knowledge Base. Disponible en: https://www.pharmgkb.org/