The psychological impact of non-responsiveness to antidepressants on patients with depression and the role of pharmacogenomics-based drug therapy

Benefits of PGx-BT

In clinical practice, it is widely recognized that patients exhibit diverse reactions to medications. This implies that while a specific drug and/or dosage may be effective for some patients, it might not be effective or may even result in adverse reactions in other patients. To explore the connection between individual genetic variations and medication response, PGx research has focused on investigating genes that influence clinical outcomes.^[27] The field of genetics has been extensively applied in precision medicine, and one of its emerging applications is in the analysis of genetic features.^[28] Genetic testing analyzes an individual’s DNA to identify specific genetic variations known as single nucleotide polymorphisms and other structural variants. These variants can influence the activity and expression of key enzymes and receptors, determining an individual’s response to therapeutic drugs like antidepressants. By detecting these genetic variants, health-care providers can gain a deeper understanding of an individual’s unique drug metabolism and response profile. It has been suggested that the response to antidepressant medications is a polygenic trait, with common genetic variants playing a significant role in determining the variability in response.^[29] Key genes often analyzed include cytochrome P450 genes (such as CYP2D6, CYP2C19, CYP2C9, and CYP1A2), which encode enzymes responsible for metabolizing medications, resulting in different levels of enzyme activity,^[30] as well as genes such as serotonin transporters (SLC6A4 and 5HTR2A) which are involved in neurotransmitter transport and receptor function.^[31,32] Consequently, these gene variants have been hypothesized to be predictive of individual variations in antidepressant drug metabolism, therapeutic responses, and the risk of drug-related toxicities.

Several studies have identified the clinical benefits of PGx-guided medication therapy management in patients with depression [Figure 1] but the applicability of these findings in real-world settings for validity is still limited.

Enhanced treatment efficacy

The use of PGx in health-care settings will enable health-care providers to tailor pharmacological treatment plans based on an individual’s genetic makeup leading to an improved effective response with reduced risk of adverse side effects and an overall reduction in medicine cost. By analyzing specific genes involved in drug metabolism, transporters, and targets, researchers can identify particular genetic variants associated with various health conditions to enable treatment. This approach increases the chances of achieving better treatment outcomes and optimizing drug selection. Studies^[11,33] provided evidence that patients with moderate-to-severe depression who had combinatorial PGx testing had substantial improvements in their depression outcomes.

Personalized dosing

The current methods of determining doses based on weight and age will be replaced by dosing based on a person’s genetics, the body’s ability to handle the medication, and the amount of time it takes for the drug to be metabolized.^[34] PGx-testing helps identify genetic markers associated with drug metabolism, enabling health-care providers to adjust medication dosages based on an individual’s genetic profile. Evidence^[35] suggests that among patients with depression, the application of PGx in predicting and monitoring drug-gene interactions reduced the prescription of medications with predicted drug-gene interactions compared with usual care. This approach ensures that patients receive optimal amounts of medication, improves efficacy, and reduces the likelihood of overdose.

Better drug selection

All antidepressants have the drawback of having a significant delay between the start of treatment and clinical improvement that can last up to several weeks or months.^[10] PGx-BT offers the opportunity to make better drug selection ensuring therapeutic response of the patients.

Avoidance of treatment resistance

PGx can identify genetic markers associated with poor treatment outcomes. The known incidence of TRD in 10– 30% of patients with depression appears as refractoriness to standard antidepressant therapy^[21] which may, in part, be due to genetic factors. To find appropriate treatments and cut down on patients’ protracted suffering, genetic testing for individuals with early TRD symptoms might be viewed as an element of the management approach.^[36]

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Figure 1:

Benefits of PGx-BT in the treatment of TRD. PGx-BT: Pharmacogenomics based therapy, TRD: Treatment-resistant depression.

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Cost-effectiveness

PGx offers the potential for significant economic benefits, both in the short term through the avoidance of potentially unsafe or ineffective medications in specific patients and the long term because patients on targeted drug treatments are more likely to experience improved health outcomes.^[37] It has the potential to lower costs associated with inappropriate or expensive treatment of depression and/or serious adverse drug reactions that may require hospitalization. In a systematic review evaluating the cost-effectiveness of pharmacogenetic and PGx screening, its application was found to be mostly cost-effective or cost-saving.^[14]

Enhanced safety profile

Genetic factors account for more than 60% of the variability in pharmacological response and side effects for various types of antidepressant drugs.^[38] Results from a systematic review^[38] suggest that drug therapy based on individuals’ genetic makeups may result in a clinically important reduction in adverse outcomes. PGx-testing helps identify genetic variants associated with a higher risk of adverse reactions. With this information, health-care providers can avoid prescribing medications that are likely to cause severe adverse effects in certain patients, thereby minimizing potential harm and improving patient safety.

Comparison of PGx-BT to traditional antidepressant therapy

PGx-BT allows for a personalized approach to antidepressant treatment by considering an individual’s genetic profile. Genetic testing helps identify specific genetic markers associated with drug metabolism and response, enabling clinicians to select medications and dosages that are more likely to be therapeutically effective for individual patients. In contrast, traditional antidepressant therapy relies on a trial-and-error process,^[39,40] where patients are often placed on multiple medications initially before finding out those that work for them. PGx-BT will lead to a decrease in the time taken for clinical effects to be observed in patients compared to the traditional approach leading to a reduction of emotional toll which arises due to the delay in the onset of the antidepressant effect. The concept of PGx provides insights into how an individual’s genetic variations may impact the metabolism and response to specific antidepressant medications.^[30] This information enables clinicians to make informed decisions about which antidepressant to prescribe and avoid medications that are likely to be less effective or cause adverse reactions. In traditional antidepressant therapy, medication selection is typically based on clinical guidelines, trial data, and the clinician’s experience, without considering an individual’s genetic factors.^[41] While PGxBT holds promise, its implementation in routine clinical practice is still evolving.^[12] Challenges such as accessibility to genetic testing, and interpretation of genetic results need to be addressed for widespread adoption while further research is needed to validate the utility and refine the applications of PGx-based drug therapy in depression treatment.