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The mail objective of this study is to identificate the variations in 5 genes, of which 3 are pharmacokinetic (CYP2B6, CYP2C19, CYP2D6) and 2 pharmacodynamic (SLC6A4, HTRA2), used to optimize therapy in patients with treatment-resistant depression (TRD) using pharmacogenomic testing (PGx) and monitoring clinical evolution by using the psychometric scales HAM-D and CGI-S in the initial stage (T1) and later HAM-D at 1 month (T2), 3 months (T3), 6 months (T4) and 12 months (T5). Depressive disorder is a public health problem because this pathology has a high tendency of recurrence, is the second cause of disability worldwide and has high costs. The depressive episode causes suffering to both the person and the family and relatives. In this longitudinal prospective study, we included 128 patients from the outpatient clinic of the PsihoNeuroMag Clinic in Oradea, Romania, diagnosed with TRD. The two groups presented during the research, were compared in the pretest stage (T1) as well as in the posttest stage according to the genetic testing using the t-test for independent samples. The onset age of the patients in the pharmacogenomic testing group is younger, but significant differences were indicated in the case of gender, the environment of origin and the number of recorded relapses. CYP2B6 gene analysis indicates relevant data in TRD course change between the HAM-D testing phase (between TI and T5). When CYP2B6 is at a low level, the class of drugs was most frequently changed and neuroleptics or thymostabilizers were associated and thus improvements were obtained between the baseline and the HAM-D evaluation at 12 months.
Abstract
The mail objective of this study is to identificate the variations in 5 genes, of which 3 are pharmacokinetic (CYP2B6, CYP2C19, CYP2D6) and 2 pharmacodynamic (SLC6A4, HTRA2), used to optimize therapy in patients with treatment-resistant depression (TRD) using pharmacogenomic testing (PGx) and monitoring clinical evolution by using the psychometric scales HAM-D and CGI-S in the initial stage (T1) and later HAM-D at 1 month (T2), 3 months (T3), 6 months (T4) and 12 months (T5). Depressive disorder is a public health problem because this pathology has a high tendency of recurrence, is the second cause of disability worldwide and has high costs. The depressive episode causes suffering to both the person and the family and relatives. In this longitudinal prospective study, we included 128 patients from the outpatient clinic of the PsihoNeuroMag Clinic in Oradea, Romania, diagnosed with TRD. The two groups presented during the research, were compared in the pretest stage (T1) as well as in the posttest stage according to the genetic testing using the t-test for independent samples. The onset age of the patients in the pharmacogenomic testing group is younger, but significant differences were indicated in the case of gender, the environment of origin and the number of recorded relapses. CYP2B6 gene analysis indicates relevant data in TRD course change between the HAM-D testing phase (between TI and T5). When CYP2B6 is at a low level, the class of drugs was most frequently changed and neuroleptics or thymostabilizers were associated and thus improvements were obtained between the baseline and the HAM-D evaluation at 12 months.
Keywords: treatment-resistant depression; genes; pharmacokinetic; pharmacodynamic; pharmacogenomic testing
Introduction
Depressive disorder is a public health problem because this pathology has a high tendency of recurrence, is the second cause of disability worldwide and has high costs (Platona et al., 2024; Pantis et al., 2023; Manole et al., 2023). The depressive episode causes suffering to both the person and the family and relatives. Depending on the deficiency of cerebral neurotransmitters, the most frequent depressive symptoms due to derotonergic deficiency are anxiety, guilt, micromanic ideation, psychomotor restlessness, sleep disorders, and noradrenergic deficiency is determined by fatigue, concentration disorders and somatic disorders (Nicoara et al, 2023). Moreover, the dopaminergic imbalance is manifested by disorders of cognition and will or their association (Platona et al., 2023; Davidescu et al, 2023).
Furthermore, the patients" symptomatology can also vary depending on how they can internalize the negative or even traumatic events in their everyday life (Marian, 2011; Marian et al, 2020; Voita-Mekeres et al., 2021; Mekeres et al, 2022; Mekeres et al, 2023). Anxiety associated with depression is encountered with an increased prevalence, which in children is included in internalizing disorders. This internalization later causes the child to have dissaptive disorders (Nicoara et al, 2023). An important role in the occurrence of depression is the environment in which the patients live, the atmosphere at work, food and vitamin deficiencies, dental conditions that appear as adverse effects of antidepressant therapy, and the lack of enough sleep to rest (Trifan et al., 2023; Voita-Mekeres et al., 2023; Marcut et al., 2024).
The somatic impact of depression was highlighted in multiple studies, which certified the negative effect of depression on the prognosis of heart diseases (Osvar et al., 2020; Taciuc et al., 2024; Tudoran et al., 2022; Beres et al., 2022), chronic respiratory diseases associated with depression can affect the quality of life (Davidescu et al, 2023; Ilisie et al, 2014; Davidescu et al, 2020), neurological damage after stroke, multiple sclerosis or Parkinson's disease or spinal lessions (Fodor et al., 2023; Lascu et al., 2023).
Moreover, patients with painful physical symptoms have more depressive symptoms, and a lower quality of life, which predisposes to the onset of depressive symptoms (Hozan etal., 2023; Vicas etal., 2020; Hozan et al., 2020; Abu-Awwad et al., 2023; Bulzan et al., 2023). More over, chronic abdominal pain, irritable bowel syndrome and Crohn's disease are predictive factors for the occurrence of depression. Mai multe studii au indicat ca depresia majoră este un factor de risc important in aparitia diabetului de tip II (Tudoran et al., 2023).
Pharmacogenetic tests represent a new method in identifying the most effective drug therapy according to the patient's genes. Genomind Professional PGx (Voiță;-Mekereş et al., 2023; Platona et al, 2024).
Objective
Our mai objective is to identificate the variations in 5 genes, of which 3 are pharmacokinetic (CYP2B6, CYP2C19, CYP2D6) and 2 pharmacodynamic (SLC6A4, HTRA2), used to optimize therapy in patients with treatment-resistant depression (TRD) using pharmacogenomic testing (PGx) and monitoring clinical evolution by using the psychometric scales HAM-D and CGI-S in the initial stage (T1) and later HAM-D at 1 month (T2), 3 months (T3), 6 months (T4) and 12 months (15).
Method
Sample
In this longitudinal prospective study, we included 128 patients from the outpatient clinic of the PhihoNeuroMag Clinic in Oradea, Romania, diagnosed with TRD. The age of the patients was between 18 and 73 years, over a period of 5 years, respectively, March 2019 - March 2024. All these patients agreed and gave a saliva sample for DNA analysis.
Inclusion criteria were: age over 18 years, Romanian language speakers, diagnosed with TRD according to the U.S. Food and Drug Administration (U.S. Food and Drug Administration, 2018.) and the European Medicines Agency (European Medicines Agency, 2018): failure to respond to two or more antidepressants despite the appropriate dose and duration and adherence to treatment.
Exclusion criteria were: patients with MDD who responded optimally to treatment, less than 2 relapses, patients non-compliant with treatment, history of drug addiction, organic mental disorders, personality disorders.
Evaluation of depressive symptoms and functionality of patientswith TRD
The Hamilton Depression Rating Scale (HAM-D-17) is a clinical tool designed and validated by Hamilton in 1960 to assess the severity of depressive symptoms and the effects of treatment, as well as the detection of relapses. The initial version consisted of 21 items, and later the reduced version of 17 items, rated on a Linkert scale from 0 to 4 points, with a total score between 0 and 52 points.
The Clinical Global Impressions (CGI) is a brief clinical assessment tool to elicit the physician's view of the patient's global functioning before and after initiation of a medication. It evaluates both, the severity (CGI-S) and the clinical progress of the patient after the initiation of therapy (CGI-D. CGI-S consists of a question whose answer is evaluated from 1 (normal) to 7 points (extremely sick) (Platona et al., 2024).
Genetic testing
PGx relates the response of a drug to the patient's specific genome, in order to better personalize the treatment. Pharmacogenomics-based research focuses both on the whole genome and centrally on genes of pharmacological importance called pharmacogenes and tries to explore the association between their variants and variable response to drugs, with implications for personalized medicine (Katara, 2019). PGx has a notable impact, both on the clinical improvement of patients with MDD, and on the reduction of the side effects of the drugs.
The patients in the AGT group, after signing the informed consent to participate in the study, had a saliva sample collected, which was later transported to the Genomind analysis center, USA. The test result was received by the attending physician in approximately 21 days.
Procedure
All patients selected in the study were diagnosed with TRD, they were applied at the initial moment (T1) the scales for depression (HAM-D). Following the medical history, it was known that these patients did not respond to antidepressant treatment and they were proposed pharmacogenomic testing (PGx). Thus, 2 groups of patients were formed: assay-guided treatment (AGT, N=63) and treatment as usual (TAU, N=65).
From the 24 genes of the Genomind Professional PGx test, we analyzed 3 pharmacokinetic (CYP2B6, CYP2C19, CYP2D6) and 2 pharmacodynamic (SLC6A4, HTRA2) variations. Patients with TRD were applied HAM-D and CGI-S at the initial moment (T1), later PGx was performed and, following its results, their treatment was optimized. Then, the HAM-D scales were applied to them at 1 month (T2), 3 months (T3), 6 months (T4) and 1 year (TS).
Participants were dichotomized into two groups, namely patients who benefited from genetic testing (AGT) and patients who did not benefit from genetic testing (TAU). In the statistical analyses, we are interested in the influence and effectiveness of genetic testing on depression measured with the HAM-D, as well as on post-genetic testing treatments.
This research has ethical approval from the PsihoNeuro Mag Clinic, Oradea, Romania (22/12.03.2019).
Data analysis
In this prospective study, we included 128 patients diagnosed with TRD, aged between 18 and 73 years. The study took place in a psychiatric clinic in the north-west of Romania, over a period of 5 years, respectively, March 2019 - March 2024.
All patients selected in the study were diagnosed with treatment-resistant depression (TRD), they were applied at the initial moment (T1) the scale for depression (HAM-D-17). Following the medical history, it was known that these patients did not respond to antidepressant treatment and they were proposed pharmacogenomic testing (PGx). Thus, 2 groups of patients were formed: assay - guided treatment (AGT, N=63) and treatment as usual (TAU, N=65).
From the 24 genes of the Genomind Professional PGx test, we analyzed 3 pharmacokinetic (CYP2B6, CYP2C19, CYP2D6) and 2 pharmacodynamic (SLC6A4, HTRA2) variations. HAM-D-17 and CGI-S were applied to patients with TRD at the initial moment (T1), later PGx was performed and, following its results, their treatment was optimized. Then, the HAM-D-17 and CGH scales were applied to them at one month (12), 3 months (T3), at 6 months (T4) and at 1 year (T5).
Statistical data were processed with SPSS version 22 in all essential stages of the study. Depending on the type of statistical analysis carried out, the variables were numerical or categorical, with averages, standard deviations or frequencies presented 1n synthetic form.
The research design is longitudinal considering that patients were surveyed in T1 -inclusion, T2 - after one month, T3 - after three months, T4 - after six months and Т5 - after 12 months. Prospective longitudinal study included participating patients who were diagnosed with TRD.
In the statistical analyses, we are interested in the influence and effectiveness of genetic testing on depression measured with the HAM-D, as well as on post-genetic testing treatments. In the case of the genetically tested group, we are looking for each gene (CYP2B6, CYP2C19, CYP2D6, SLC6A4, HTRA2) at low, intermediate, normal and high levels to see how the change in treatment and doses influences the participants HAM-D-17 scores between T1 and T5. The study being longitudinal (T1 - T5) we will use the t-test and ANOVA with repeated measurements. The results were considered significant at p<05.
Results and discussions
Baseline characteristics of study sample
Sociodemographic and clinical information for the groups of genetically tested and non-genetically tested participants are presented in Table 1. Demographically, two size-homogeneous groups were formed. The group of genetically tested participants (N=63) consisted of 25 men (39.7%) and 38 women (60.3%) who come from the urban environment (69.8%) predominantly and who have an average age of 36.14 (SD=12.77). The group of participants who were not genetically tested (N=65) consisted of 17 men (26.2%) and 48 women (73.8%) coming from the urban environment for the most part (58.5%) with a mean age of 50.15 (SD=12.15). In the case of age, we record significant differences between the two groups (t=-6.359, p<001), which indicates a greater receptivity of the genetically tested group participants to modern diagnostic techniques.
In the case of the age of onset of the disease, we note differences (t=-5.939; p<.001) between the two groups of participants where the average age of the TAU group is higher. The analysis of recorded frequencies (y?) does not indicate significant differences in the case of gender, environment of origin and number of recorded relapses.
The CGI-S is known to ask the physician to rate the severity of the patient's illness at the time of assessment relative to the physician's previous experience with patients who have the same diagnosis. In our study, the participants of the genetically tested group have higher averages comparedto the participants of the non-genetically tested group (t=3.559; p<.001), which indicates a statistically significant severity of MDD. HAM-D-17 assessment at baseline also indicates a higher level of depression in genetically tested participants (t=5.138; p<.001) compared to those who were not tested.
We follow the graphical distribution of CYP2B6, СУР2С19, CYP2D6, SLC6A4, HTRA2 genes that can lead the specialist towards a change intreatment in people with TRD. Thus, in the graphs below, we notice thatthe class of drugs in association with neuroleptics or mood stabilizers has been changed (Figure 1 a-e).
Antidepressant treatment after genetic test:
- maintained class + dose increase;
- changed class;
- maintained class + combination of neuroleptics/thymostabilizers;
- changed class + combination of neuroleptics/thymostabilizers.
The two groups presented during the research, were compared in the pretest stage (T1) as well as in the posttest stage (after PGx optimizing antidepressant treatment) according to the genetic testing using the t-test for independent samples. The results presented in Table 2 indicate differences between the two groups in the case of the initial treatment (2.293; p<.02), but also in the posttest stage (t=5.242; p<.001) where genetically tested TRD people have higher means big.
The group results between the initial treatment stage and the PGx optimizing antidepressant treatment shows an increase in the averages in the posttest phase in people with AGT (t=-12.490; p<.001) which indicates a high rate of changes occurring in the case of treatment. TAU changes were registered with the treatment but with a lower magnitude (t=-4.750; p<.001) (see Table 3).
Comparisons in the preliminary phase of research on pharmacokinetic or pharmacodynamic gene variations have generally captured a set of changes.
The role of CYP2B6 in drug metabolism is increasingly recognized in the medical world. Its genetic polymorphisms can determine variability in the metabolism of sertraline, one of the most used antidepressants in RTD, and thus there are CYP2B6 allele variants that lead to a decrease in sertraline metabolism and the therapeutic results can vary (Yuce-Artun et al., 2016). The role of genetic polymorphisms in this phenomenon is currently being evaluated.
In-depth analysis of the data obtained in the case of the CYP2B6 gene in the posttest phase indicates a relevant data set in the change of TRD course between the test phase with HAM-D (between T1 and TS). Longitudinal comparisons with repeated measures ANOVA indicate for each CYP2B6 gene level a set of changes from T1 to TS with respect to treatment (Table 4; Figure 2 a-d). É CYP2B6 is at a low level (F=17.345; p<.001; 17=776) the drug class was changed in combination with neuroleptics or thymostabilizers. Effects on TRD are relevant between T1 and T4 (mar=16.278; p<.02) as well as between T1 and TS (Mar=22.056, p<.004).
The interim level of CYP2B6 (F=15.584; p<001; n2=510) indicates changes in HAM-D scale scores between T1 and TS similarly to the low level but without statistically relevant changes regarding treatment. Normal CYP2B6 gene level (F=45.508; p<.001; n2=717) similarly indicates changes in depression level without leading to statistically relevant drug class changes.
Genetic testing uses a variety of methods, including target variant detection, bidirectional DNA sequencing, and next-generation sequencing. Factors leading toinconsistency of CYP2C19 clinical assays between laboratories include the choice of alleles tested, selective testing of populations of different ethnic origins, and technical performance of different platforms.
In the case of the CYP2C19 EM gene at a low level, we did not identify changes between T1 and TS of the depression measured with the HAM-D (Table 5; Figure 3.a-d) nor of the treatment. The interim level of the CYP2C19 gene indicates a large magnitude of the effect on depression and implicitly the treatment (F=35.202; p<.001; n2=.730) as can be observed in Figure 3.
The high level of CYP2C19 (F=7.872; p<.001; n2=360) indicates changes in the course of depression between T1 and TS but with a low magnitude, while the normal level of CYP2C19 (F=27.472; p<.001; n2=.544) indicates a medium effect on depression but also a direction towards maintaining the drug class in association with increasing doses (Figure 3).
CYP2D6 constitutes up to 2% of hepatic CYP content and is responsible for the metabolism of up to approximately 20% of drugs that undergo biotransformation. Compounds of clinical interest include several antidepressants, antipsychotics, beta-blockers, codeine, dextromethorphan, duloxetine, tramadol, and tamoxifen. Over time, some polymorphisms have been identified, and the frequency of these alleles differs depending on the specifics of the population examined. Clinical observations show that ultra-rapid metabolizers have multiple copies of CYP2D6.
CYP2D6 was the third gene studied for individual variation contributing to metabolism and response to psychotropic treatment. Similarly, gene variations have been pursued for therapeutic predictability as well as to reduce adverse effects.
The three levels of CYP2D6 (Table 6) indicate differences in TRD treatment after genetic testing, which in most cases led to a change in drug class (Figure 4) or an increase 1n doses. When the CYP2D6 gene 1s at a low level (F=13.665; p<001; n2=.695) the effect size indicates a substantial association and drug classes were maintained in association with other drugs or were changed (Figure 6).
The intermediate level of the CYP2D6 gene in the case of TRD (F=18.276; p<001; n°=504) indicates a moderate to medium association with the prescribed treatment where the treatment options were diversified as we can observe in Figure 4.a-c but which led towards expected results one year after the HAM-D evaluation. The normal CYP2D6 level (F=40.022; p<001; n2=580) similarly to the interim level indicates a diversity of possible treatment regimens.
HTRA2 has been shown to play an important role in cell physiology and is involved in several pathological processes as well as in neurodegenerative diseases. In the research following the genetic testing we have observed two levels, namely the normal and the variable response. In Table 7 and Figure 5 a, b, we observe that the normal level of HTRA2 (F=47.104; p<.001; n2=.506) shows a medium association with depression measured with the HAM-D but also with the genetic post-testing treatment.
The variable level of HTRA2 exerts a high magnitude of effect on depression (F=20.189; p<.001; n2=.669) and on treatment post-genetic testing leading to treatment maintenance in two of the three potential situations.
The serotonin transporter gene, SLC6A4, has demonstrated its ability to predict treatment efficacy and adverse/side effects. The SLC6A4 promoter has two main variants: long and short. The short allele leads to lower transcription rates, resulting in less active sites. People who carry the short allele may benefit from drugs outside the SSRI class. However, more data are needed before another variant can be recommended for treatment.
Medical studies have shown that alterations in serotonin transporter metabolism appear to be associated with many different phenomena, including alcoholism, clinical depression, obsessive-compulsive disorder (OCD), and social phobia. In our study we focused only on TRD, its evolution as well as the impact of SCL6A4 on treatment changes.
SLC6A4 at a LA level (F=7.443; p<001; n2=347) indicates a moderate association between the analyzed variables (Table 8; Figure 6.a-c) in our study, the situation being similar in the case of the iner level of the SLC6A4 gene (F=20.817; p<.001; n2=454). In the situation where SLC6A4 is at a high level (F=60.531; p<001; n2=812) the effect is very high, which indicates the change in the evolution of patients with TRD between T1 and TS as well as the timely change of treatment after genetic testing.
Discussions
Recent studies show that at least 30% of patients diagnosed with MDD meet the criteria for TRD, the prevalence in practice remaining unknown and due to the lack of a universal definition of TRD (McIntyre et al, 2023). In this study we used the criteria that define TRD from the European Guidelines and these consisted in a reasonable medicinal response was not obtained after treatment with at least two antidepressants from distinct pharmacological classes, in the proper therapeutic dosage and for a suitable period of time (minimum 6 weeks) (Party & Committee for Medicinal Products for Human Use, 2006).
During the work I argued from a theoretical point of view and then from an experimental point of view that PGx connects the response of a drug with the patient's genome, in order to identify the most suitable form of treatment (Katara & Yadav, 2019).
Pharmacogenomics in recent decades deepens variable drug response with implications for personalized medicine. PGx plays an important role in the clinical improvement of TRD patients but also in reducing the side effects of the drugs (Perez et al, 2017). Thus, we aimed to identify pharmacokinetic or pharmacodynamic gene variations to optimize therapy in TRD patients using pharmacogenomic testing (PGx) and monitoring clinical evolution using HAM-D.
The role of CYP2B6 in drug metabolism is relevant although there is interindividual variability in the expression of this gene. The role of genetic polymorphisms was assessed using four levels, namely low, interim, high and normal. Low and normal levels of the CYP2B6 gene indicate an increased association between TRD and the prescribed treatment (Altar et al., 2017).
CYP2C19 is recognized as another enzyme whose genetic polymorphism can affect a range of clinically important drugs with limited therapeutic indices. Thus, in our research we showed that the interim level contributes to the metabolism of many frequently used drugs and the statistical magnitude of the effect is high.
The CYP2D6 enzyme mediates the metabolism of substrate psychotropic drugs and can inactivate an active drug or transform it into an active metabolite. If CYP2D6 activity is reduced, an active drug may accumulate toxic compounds; alternatively, a prodrug may lead to ineffective treatment. We argue experimentally that genetic testing can guide the clinician toward appropriate decisions in function of CYP2D6 levels.
Researchers have demonstrated that HTRA2 plays an important role in cell physiology with implications in pathological processes or neurodegenerative diseases. The variable response level of HTRA2 most effectively indicates the orientation of treatment customization in the case of TRD (Outhred et al, 2016).
In this segment of the research, we aimed to investigate including the variation of the serotonin transporter gene (SLC6A4). Our study may explain the association between polymorphisms in SLC6A4 and treatments prescribed in TDR especially in the situation where itis at a high level.
The antidepressant response shows great variability, in the case of TRD patients a combination of antidepressant medication and psychotherapy, esketamine, Ketamine, rTMS and ECT would be necessary (Davidescu et al., 2014).
Conclusions
The average age of genetically tested patients was 36.14, and of those not genetically tested was 50.15, thus there were significant differences between the two groups, which indicates a greater receptivity of the participants of the genetically tested group to modern techniques diagnostic.
The onset age of the patients in the AGT group 1s younger, but significant differences were indicated in the case of gender, the environment of origin and the number of recorded relapses.
The evaluation by HAM-D-17 and CGES of the participants in the baseline stage indicated a significant severity of AGT patients compared to TAU.
CYP2B6 gene analysis indicates relevant data in TRD course change between the HAM-D testing phase (between T1 and T5). When CYP2B6 is at a low level, the class of drugs was most frequently changed and neuroleptics or thymostabilizers were associated and thus improvements were obtained between the baseline and the HAM-D evaluation at 12 months.
Ethics statement
This study was carried out in accordance with the recommendations of Code of Ethics of University of Oradea. In accordance with the Declaration of Helsinki, all participants gave written informed consent for their participation in the study.
Conflicts of interest
The authors declare no conflict of interest.
Author contributions
Authors listed have made a substantial, direct and intellectual contribution to the work, and approvedit for publication.
Funding
This research received no external funding.
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Correspondence concerning this paper should be addressed to:
*Ph.D., University of Oradea, Faculty of Medicine and Pharmacy, Oradea, Romania. Address: St. Piata 1 Decembrie, No. 10, Oradea, 410087, Romania. E-mail: E-mail: voita-mekeres.fauoradea.ro
*PhD., University of Oradea, Faculty of Medicine and Pharmacy, Oradea, Romania. Address: St. Piata 1 Decembrie, No. 10, Oradea, 410087, Romania. E-mail: [email protected]
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