Pharmacogenetics of antidepressants – A step to individualized therapy

Pharmacogenetics analyzes interindividual differences that lead to variable patient responses to therapy, with the aim of indicating how individual genes and interindividual genetic variations can affect the pharmacokinetics and pharmacodynamics of drugs. It is a critical component of personalized medicine in psychopharmacology. Most studies to date indicate the great potential of pharmacogenetic studies in the individualization of antidepressant therapy. So far, the determination of the genetic profile and metabolic phenotype for CYP2C19 in patients on escitalopram and sertraline, and CYP2C19 and CYP2D6 in patients on amitriptyline, has shown clinical significance. Although less studied, pharmacodynamic variability is no less significant than pharmacokinetic variability. Serotonin transporter polymorphisms significantly influence the therapeutic response to selective serotonin reuptake inhibitors. The pharmacogenetic approach is an innovative model in understanding the heterogeneity of the therapeutic response to antidepressants. The advantage of this approach is the permanence of the genotype over time. On the other hand, there are numerous challenges and limitations to performing these analyses routinely, such as the availability of these tests and the complexity of interpreting the results. The effect of the drug is a complex phenomenon and single mutations in individual genes cannot explain all the variability of psychopharmacotherapy. Although pharmacogenetics clearly has great potential in drug development and individualization of therapy, further research is needed to fully implement this potential in clinical practice.

INTRODUCTION

Depressive disorders are among the most common diseases today, with more than 350 million patients and an annual prevalence of 4.7% globally [1],[2]. They are the most common mental disorders in the general population, with an incidence twice as high among women as among men. Depressive disorders can be accompanied by serious effects, such as high risk of suicide, comorbidities with other mental and somatic diseases, considerable impairment of the individual’s quality of life and ability to work [3]. There is a large number of drugs from the group of antidepressants in modern psychopharmacology, whose safety and efficacy has been shown in controlled, randomized clinical trials. Nevertheless, the fact remains that 30–50% of patients do not have an adequate response to the first administered drug [4]. Significant interindividual variations in response to therapy have been shown for all available antidepressants, as well as for most other psychopharmaceuticals [5]. It is clear that the “one-size-fits-all” pharmacotherapeutic approach is insufficient and that modern clinical practice, in line with the principles of evidence-based medicine, points to precision medicine and drug therapy individualization. One of the many, if not the crucial factor that influences the response to pharmacotherapy is a patient’s genetic profile. Modern methodology has enabled the sequencing of genes, including protein-coding genes that influence the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs [6]. Shedding light on the complex connection between a genetic basis and response to therapy is becoming increasingly important in developing new strategies in the treatment and prevention of diseases. In this sense, routine pharmacogenetic testing is aimed at enabling physicians to individualize dosage regimens in clinical practice and better predict therapeutic responses, both in terms of efficacy and in terms of the safety of the administered drug [6],[7].

PHARMACOGENETICS AS A CRITICAL COMPONENT OF PERSONALIZED MEDICINE

The U.S. Food and Drug Administration defines the concept of personalized medicine as an individual approach to disease prevention and treatment that takes into account interindividual differences in people’s environments, lifestyles and, increasingly, patients’ genetic profiles. In this sense, pharmacogenetics imposes itself as a crucial component of personalized medicine. The FDA has so far recommended pharmacogenetic testing for over 50 drugs in clinical practice [8]. Pharmacogenetics analyzes interindividual differences that lead to patients’ variable response to administered therapy, aiming to show how certain genes and interindividual genetic variations can affect the PK and PD of drugs. Certain genetic polymorphisms encode different proteins that determine the PK, such as enzymes for drug metabolism, or the PD, such as receptors, enzymes, intracellular messengers, and other target molecules for drug effects [6]. The better understanding of the interaction between the genome and etiopathogenesis and the disease therapy has led to the development of pharmacogenomics, which describes multiple variations and the influence of the genome, as a whole, on drug properties, as well as of pharmacoepigenetics as a new discipline that studies ways in which epigenetic mechanisms lead to variations in response to therapy [9],[10].

PHARMACOGENETICS OF ANTIDEPRESSANTS

The pharmacogenetic approach is an innovative model in understanding the heterogeneity of the therapeutic response to antidepressants. The advantage of this approach is the invariance of genotypes over time, as well as the increasing availability of reliable genetic testing [11]. In the case of antidepressants, the description predominantly covers individual genetic variations , resulting from single nucleotide polymorphisms in genes: 1) that code enzymes involved in the metabolism of these drugs (pharmacokinetic variability), and 2) that code target molecules for drug action (pharmacodynamic variability).

Genetic basis of pharmacokinetic variability

Most studies to date analyzed the genetic variability of microsomal cytochrome P450 enzymes involved in the metabolism of antidepressants (Table 1) [12]. The results of these studies indicate that the polymorphism of genes that code these enzymes is an important factor that determines the concentration of a drug in the blood and, therefore, its efficacy and safety. Genotyping involves the identification of mutations in CYP genes by molecular diagnostic methods and PCR, and the identification of heterozygous or homozygous carriers of mutated alleles that result in a corresponding phenotype (metabolic phenotype). According to the National guide for good clinical practice for diagnosing and treating depression, one of the steps in rational procedure, in the absence of a favorable response to therapy, is genotyping and pharmacogenetic testing [3]. An illustrative example of this is pharmacogenetic testing, aimed at optimizing treatment with amitriptyline, based on which the Clinical Pharmacogenetics Implementation Consortium (CPIC) issued recommendations for the dosing of tricyclic antidepressants (TCA) depending on the patient’s genotype [13],[14]. Amitriptyline, as a typical TCA representative, is metabolized by isoenzymes CYP2C19 and CYP2D6. Studies have determined the existence of several genetic variants of these isoenzymes, which may result in high variability in the efficacy and safety of amitriptyline. In order to determine the specific phenotypic profile of amitriptyline metabolism, relative to the genes for CYP2C19 and CYP2D6, the patient genotype is tested for the most common polymorphisms CYP2C19 (*2, *3, *17) and CYP2D6 (*1XN, *2, *2XN, *3, *4, *5, *6, *9, *10, *41). Testing is optimally performed prior to starting therapy, in order to adjust the choice of drug and its dosage.

Table 1. Microsomal cytochrome P450 enzymes involved in metabolism of antidepressants

Individuals with ultra-rapid metabolism represent a special case, based on the corresponding genetic profile for CYP2C19 and the rate of drug metabolism; they account for around 30% of the European population and amitriptyline therapy is not recommended for them. The recommended therapy for persons with rapid and intermediate metabolism is provided in the Summary of Product Characteristics (SmPC), while for persons with slow metabolism (roughly 3% in the European population) it is recommended that the initial dosage be reduced by 50% (Table 2).

Table 2. Recommendations for amitriptyline therapy, subject to CYP2C19 genotype

Individuals with ultra-rapid metabolism and slow metabolism represent a special case, based on the corresponding genetic profile and metabolic phenotype for CYP2D6; they account for around 10% in the European population and amitriptyline therapy is not recommended for them. The usual dosage, in accordance with the SmPC, is recommended for persons with fast metabolism, while the reduction of the initial dosage by 25% is recommended for persons with intermediate metabolism (Table 3).

Table 3. Recommendations for amitriptyline therapy, subject to CYP2D6 genotype

Selective serotonin reuptake inhibitors (SSRI), escitalopram and sertraline, as the most commonly prescribed antidepressants, have been specifically analyzed from a pharmacogenetic aspect. Even though it is the most selective and one of the most effective SSRIs, escitalopram exhibits therapeutic failure in a certain number of patients, either due to the lack of an adequate response to therapy or due to pronounced side effects. The focus of pharmacogenetic studies is CYP2C19 genotyping in patients treated with escitalopram [15] (Table 4). A study that included more than 2,000 patients showed that persons with ultra-rapid and slow metabolism had a significantly increased risk of therapeutic failure, with these two subgroups accounting for as many as 33% of all patients on escitalopram [16]. In addition to escitalopram, sertraline is also a substrate for CYP2C19 whose polymorphisms significantly affect individual variations in its metabolism (Table 4). The meta-analysis that assessed the clinical efficacy and safety of 21 antidepressants in adult patients diagnosed with depression, sertraline proved to be one of the optimal antidepressants in terms of efficacy and safety, with significant interindividual variations in therapeutic response being recorded [17],[18]. A 2019 study with 1,200 patients confirmed the relevance of CYP2C19 genotyping in sertraline therapy. Patients with intermediate and slow metabolism had significantly elevated serum drug concentrations and a risk of developing side effects at the usual dosage, which indicated the need to reduce the dosage and increase caution in the case of such patients [19].

Table 4. Recommendations for escitalopram and sertraline therapy, subject to CYP2C19 genotype

In addition to the extensively studied genetic variability of certain enzymes involved in antidepressant metabolism, other genes of importance for the PK of antidepressants have also been identified, whose polymorphisms may affect their pharmacological profile, dosage and side effects. The ABC transport protein family is an important factor in pharmacokinetic variability. One of the best studied is the P-glycoprotein, which is encoded by the ABCB1 or MDR1 gene [11]. P-glycoprotein is an integral membrane protein that affects the transport and distribution of drugs, their mutual interactions and efficacy. Preclinical studies have shown multiple increases in the concentration of certain antidepressants, such as amitriptyline, paroxetine and venlafaxine, in the absence of P-glycoproteins, which may result in drug accumulation and increased risk of side effects [20]. In addition, clinically significant interactions of nearly all ADs and their metabolites with P-glycoprotein have been shown. So far, several mutations in the MDR1/ABCB1 gene have been described, which result in altered P-glycoprotein expression and function. The influence of polymorphisms on pharmacokinetic parameters and potential possibilities of pharmacogenetic analysis of P-glycoproteins are still being investigated.

Genetic basis of pharmacodynamic variability

Although less studied, pharmacodynamic variability is no less important than pharmacokinetic variability. Polymorphisms in genes encoding target molecules for drug action can significantly affect drug efficacy and safety. Given that antidepressants have a number of sites of action in the central nervous system, including in neurotransmitter synthesis, and the transporter and receptor function, significant clinical implications of genetic variability can be expected.

An illustrative example is the polymorphism of the serotonin transporter (SERT) which has so far been the focus of pharmacogenetic testing. SERT is a protein responsible for the active transport of serotonin from the synapse to the presynaptic neuron and is the target site of action for serotonergic antidepressants. In addition to serotonin, SERT also has the ability to transport other endogenous amines, such as dopamine. Functional polymorphisms of the SERT gene have been identified in a variety of diseases, including psychiatric illnesses and depression [21], and the most studied among them is the SERTPR polymorphism, which is characterized by a variable number of repeats in the promoter region, resulting in a longer (L) and a shorter (S) variant. The L allele is characterized by increased transcription and higher biological activity of SERT proteins. It has been shown that individuals homozygous for the S allele may be more susceptible to the development of depression and suicidal behavior. These patients are thought to have a poorer appropriate therapeutic response and a poorer tolerance to SSRI antidepressants. As opposed to this, people with the L allele respond better to acute stress and the use of antidepressants [22]. Some studies, however, show contradictory results regarding the connection between SERTPR polymorphisms and the effectiveness of antidepressants [23]. Additional psychopharmacological studies are needed to determine the significance of both serotonin transporter polymorphisms and pharmacodynamic variability in general.

CONCLUSION

Pharmacogenetics is one of the foundations of personalized medicine and of individualized pharmacotherapy in psychiatry. Most of the studies carried out to date point to the great potential of pharmacogenetic studies in the individualization of therapy using antipsychotics and antidepressants. This is also confirmed by the latest FDA recommendations on pharmacogenetic testing and determination of the genetic profile and metabolic phenotype for CYP2D6 in patients on aripiprazole. In the case of anxiety and depressive disorders, pharmacogenetic testing is recommended for patients who have not shown a satisfactory therapeutic response to multiple antidepressants. To date, the determination of the genetic profile and metabolic phenotype for CYP2C19 in patients on escitalopram and sertraline, and CYP2C19 and CYP2D6 in patients on amitriptyline, respectively, has shown the greatest clinical implications. Despite the proven clinical benefit, there is still insufficient pharmacoeconomic data to support the routine use of pharmacogenetic testing in this field.

The pharmacogenetic approach is an innovative model in understanding the heterogeneity of the therapeutic response to antidepressants and psychopharmaceuticals in general. The advantage of this approach is that the individual genotype does not change, in other words, it is necessary to determine it only once at any time during treatment. On the other hand, there are many challenges and limitations to routinely performing these analyses, such as the availability of the tests and the complexity of interpreting the results. The effect of a drug is a complex phenomenon and individual mutations in individual genes cannot explain all the variability of psychopharmacotherapy. Although pharmacogenetics unequivocally has great potential in drug development and individualization of therapy, further research is needed to fully apply this potential in clinical practice.