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INTRODUCTION
Schizophrenia stands as one of the most prevalent mental disorders globally, often afflicting young adults and characterized by prolonged duration, frequent relapses, and abrupt onset 1. Individuals with schizophrenia typically exhibit disturbances in thought, consciousness, behavior, and emotion, along with inappropriate psychological and physical activities. Concurrently, they experience negative emotions encompassing fear, anger, and depression. In severe cases, some patients may even demonstrate self-destructive tendencies or resort to suicide 2. Integration into society proves challenging for schizophrenia patients due to their limited sense of affiliation and prominent negative emotional states. These significantly hamper their subjective well-being and self-esteem 3,4. While antipsychotic medications can effectively manage the condition for the majority of schizophrenia patients, approximately 30% exhibit poor or partial responses to these treatments, categorizing them as drug-resistant individuals 5. Thus, improving the efficacy of antipsychotics on mental diseases has become an attractive issue in the psychiatry department. At the same time, individualized medication can be made based on genetic evidence derived from the analysis of drug-related genes and gene polymorphisms to select the drugs and doses more precisely 6. Gene detection has been widely applied to develop antipsychotic drugs, but fewer studies report the efficacy of drugs on drug-resistant patients with schizophrenia. Consequently, we carried out this study to investigate the efficacy of drug-related-gene-guided individualized medication on drug resistant patients with schizophrenia and its effect on patients.
PATIENTS AND METHODS
Subjects
One hundred and ten individuals diagnosed with schizophrenia admitted to the Department of Psychosomatic Medicine at The First People’s Hospital of Chenzhou, Luojiajing, Chenzhou, Hunan, People’s Republic of China, during the period spanning June 2021 to February 2023, were enrolled in this study. They were subsequently categorized into the regular medication group (Group A) and the gene-guided medication group (Group B), each comprising 55 patients.
Comprehensive information about the study was provided to all patients and their families, and written informed consent was obtained. The Ethical Committee of the Hospital approved the study.
Criteria for inclusión: 1. Patients with manifestations conforming to the diagnostic criteria of schizophrenia of The Diagnostic and Statistical Manual of Mental Disorders (4th edition). 2. Patients aged between 18 and 60 years, with no response to the high dose treatment of three kinds of antipsychotics. 3. Patients with a disease course not shorter than five years.
Criteria for exclusion: 1. Patients with other diseases. 2. Patients who had received appropriate treatment prior to this study. 3. Patients with communication difficulties. 4. Patients who were uncooperative with the staff. 5. Patients with severe adverse responses to the drugs used in this study. 6. Patients with a history of drug use that might affect the result of this study.
Methods
In the current study, two distinct approaches to medication were compared: Group A received antipsychotics selected by physicians based on their expertise, whereas Group B received personalized medication determined through drug-related gene tests and the evaluation of physicians and clinical pharmacists.
Group A
The specific antipsychotic medications used in Group A included Haloperidol at doses of 2-10 mg per day, chosen for patients with positive symptoms like hallucinations and delusions based on its efficacy for these symptoms; Risperidone at 2-6 mg per day, selected for patients with both positive and negative symptoms given its broader efficacy profile; Olanzapine at 5-20 mg per day, used for patients with predominant negative symptoms like social withdrawal due to its efficacy for these symptoms; Quetiapine at 150-750 mg per day, chosen for patients with mood or sleep issues given its sedating and mood-stabilizing effects; and Aripiprazole at 10-30 mg per day, used for patients susceptible to side effects like tardive dyskinesia due to its lower risk of these effects.
Group B
In the Group B, medication was personalized based on drug-related gene tests and the collaborative analysis of physicians and clinical pharmacists. The gene tests identified genetic variations that could influence an individual’s response to specific antipsychotic medications. For example, the CYP2D6 gene was of particular interest, as it encodes an enzyme responsible for the metabolism of many antipsychotic drugs. Variations in this gene can lead to differences in how quickly medications are metabolized, potentially affecting their efficacy and side effect profiles 7,8.
Patients with the ‘poor metabolizer’ phenotype, characterized by certain SNP combinations, were prescribed lower doses or given antipsychotics not primarily metabolized by the CYP2D6 enzyme to avoid drug accumulation and subsequent side effects. In contrast, ‘rapid metabolizers’ may have required higher doses or more potent medications to achieve therapeutic drug levels.
The treatment protocol was adjusted within two weeks after the gene test, including maintaining, increasing, or reducing the initial drug dose or its combination with other antipsychotics or switching to other antipsychotics. The specific medications and doses used were determined based on a comprehensive analysis of the recommended drugs by the DSM4, the patient’s gene test results, and the individual’s symptomatology and treatment history.
The distribution of crucial CYP2D6 genotypes in Group B were as follows:
Poor metabolizers: 7 patients (12.7%).
Intermediate metabolizers: 18 patients (32.7%).
Normal metabolizers: 25 patients (45.5%).
Ultra-rapid metabolizers: 5 patients (9.1%).
Medications were adjusted based on this genotype data. For example, poor metabolizers were prescribed lower doses of risperidone, switched from Haloperidol to Quetiapine, or changed from Olanzapine to Aripiprazole. Ultra-rapid metabolizers were given higher doses of Haloperidol or switched from Quetiapine to Olanzapine. Table 1 shows examples of specific medication changes made.
Table 1 Medication adjustments based on CYP2D6 genotypes in Group B.
| Genotype | Patients n (%) | Initial Medication and Dose | Adjusted Medication and Dose | Rationale for Adjustment |
|---|---|---|---|---|
| Poor metabolizer | 7 (12.7%) | Haloperidol 5mg daily | Quetiapine 100mg twice daily | Haloperidol is primarily metabolized by CYP2D6 31. Due to poor metabolism, it was switched to quetiapine, which has alternate metabolic pathways to avoid drug accumulation. |
| Risperidone 3mg daily | Risperidone 1mg daily | Risperidone dosage was reduced by 50% to avoid side effects due to poor CYP2D6 metabolism 32. | ||
| Intermediate metabolizer | 18 (32.7%) | Olanzapine 10mg daily | Olanzapine 5mg daily | The dose was reduced as metabolism was expected to be slower in intermediate metabolizers. |
| Risperidone 4mg daily | Risperidone 2mg daily | |||
| Normal metabolizer | 25 (45.5%) | Haloperidol 5mg twice daily | No change | Normal metabolizer phenotype indicates haloperidol metabolism is expected to be typical. No dose adjustment was needed. |
| Quetiapine 400mg daily | Quetiapine 400mg twice daily | As a normal metabolizer, can tolerate higher doses of quetiapine. The dose was increased for improved efficacy. | ||
| Ultra-rapid metabolizer | 5 (9.1%) | Risperidone 4mg daily | Risperidone 6mg daily | More rapid CYP2D6 metabolism is expected in ultra-rapid metabolizers. The risperidone dose was increased by 50% to ensure therapeutic levels were achieved. |
| Quetiapine 400mg daily | Olanzapine 20mg daily | Switched from quetiapine to olanzapine due to concerns that quetiapine might be metabolized too rapidly in ultra-rapid metabolizers, affecting its effectiveness. |
Gene test
A customized tube obtained from Shanghai Conlight Medical Laboratory Co., Ltd was utilized to gather detached cells from the oral epithelium. This was achieved by gently swabbing the buccal region of the mouth with a cotton swab. The collected cells were then securely sealed within the tube, ensuring no contact with external materials. Two sets of samples were procured from both the left and right sides of the mouth for subsequent DNA extraction. These samples were subsequently stored at room temperature.
The genotypes and allele frequencies of three single nucleotide polymorphisms (SNPs) within the CYP2D6 gene (rs16947, rs1065852, and rs5030865) were examined. The analysis used the general sequencing kit (NovaSeq 6000 Reagent Kits) and the fluorescence in situ hybridization (FISH Tag™ DNA Multicolor Kit by Invitrogen).
Genomic analysis and protocol adjustment
Genomic analysis was conducted on patients belonging to Group B, encompassing the identification of metabolic, responsive, and toxic gene phenotypes, along with their distribution frequencies. Within two weeks after the gene testing, the treatment regimen was modified based on a comprehensive analysis that considered the recommendations provided by the DSM4 and the outcomes of the gene tests.
These adjustments entailed the maintenance, augmentation, or reduction of the initial drug dosage, either in isolation or in combination with other antipsychotic medications. In some cases, a transition to alternative antipsychotic drugs was also considered. The recommended medications were categorized into primary, secondary, and tertiary options. Furthermore, medications were selected sequentially, following the gene test outcomes, and were tagged as suitable for direct use, utilization with caution, or utilization with caution accompanied by frequent monitoring.
Observation of indicators
Before and after treatment, a fasting 6 mL elbow venous blood sample was collected from each patient and subsequently centrifuged at 3000 rpm to facilitate the separation of the supernatant. This supernatant was then carefully preserved at a temperature of -70°C.
The quantification of TNF-α, IL-1β, NGF, BDNF, PI3K, and mTOR levels was done utilizing a double sandwich enzyme-linked immunosorbent assay (ELISA). The procedure encompassed the following steps: an ELISA plate was appropriately labeled at room temperature, and a standard curve was meticulously prepared using the appropriate standard reagents. The patient samples and the standard reagents were appropriately diluted and introduced into individual wells (100 μL per well). Subsequently, incubation was carried out at 37°C within a humid environment.
Following the incubation period, the plate underwent repeated rinsing steps, after which an antibody-working solution was meticulously added to each well at a dilution of 1:100 (100 μL per well). This was followed by an additional incubation at 37°C for 45 minutes. The plate was then rinsed again, and solutions of TNF-α, IL -1β, NGF, BDNF, PI3K, and mTOR were introduced to the respective wells (100 μL per well), followed by another incubation under humid conditions for 45 minutes.
The enzymatic reaction was eventually halted by introducing a termination solution (100 μL per well). Subsequently, a microplate reader obtained an optical density reading at a wavelength of 450 nm. This reading was then utilized to calculate the alterations in the concentrations of the factors mentioned above.
The assessment of clinical responses in patients involved the utilization of the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) 9,10. The PANSS comprises 30 items, each scored on a scale of 1 to 7. Similarly, the BPRS encompasses five items, specifically targeting anxiety, depression, thought disturbance, and excitability, with a pivotal score of 35 points. It should be noted that both PANSS and BPRS scores exhibit a negative correlation with the observed clinical response. In other words, as the scores on these scales increase, the corresponding clinical response tends to decrease, indicating a greater severity of symptoms.
Social skills psychometric instruments (SSPI) and activities of daily living (ADL) scale were used to evaluate patients’ social and living abilities 11,12. The SSPI scale includes ten dimensions, such as familial activity, social activity, responsibility, and planning, and scores according to the following criteria: 1 point for no anomaly or only slight functional defect; 2 points for a definite functional defect; 3 points for severe functional defect. Patients who scored not fewer than 2 points should be considered as having social dysfunction. The ADL scale includes 14 items, such as diet, medication, and housekeeping, and patients are scored as per the following criteria: 1. Patients can take care of themselves independently; 2. Patients have difficulties in taking care of themselves independently; 3. Patients need help in taking care of themselves; 4. Patients fail to take care of themselves independently.
Evaluation of clinical response
Clinical responses were classified into three grades: remarkable response, response, and failure. Remarkable response: no psychotic symptoms, with a decrease in PANSS scores between 50% and 74%. Response: no significant psychotic symptoms, with a decrease in PANSS score between 25% and 49%. Failure: no significant improvement in psychotic symptoms, with a decrease in PANSS score lower than 25%. Total effectiveness rate = Rate of remarkable response + rate of response.
Statistical methods
The SPSS 20.0 software was applied for data analysis. Measurement data were described as means ± standard deviations (X̄±SD), and the difference between the two groups was validated by an independent sample t-test. Enumeration data were expressed as ratios, and the chi-square test validated the difference. P<0.05 indicated that the difference had statistical significance.
RESULTS
Demographic characteristics
In Group A, there were 32 males and 23 females, aged 25 to 67 years (mean ± SD: 44.5±20.1 years). Education varied: 21 had diplomas below high school, 18 had high school diplomas, and 16 had diplomas beyond high school. Illness duration ranged from 2 to 24 years (mean ± SD: 13±9 years), with onset age from 18 to 37 years (mean ± SD: 24±9 years); three patients reported familial cases. In Group B, 30 males and 25 females were aged 26 to 67 years (mean ± SD: 45.5±20.1 years). Education-wise, 25 had diplomas below high school, 16 had high school diplomas, and 14 had diplomas beyond high school. Illness duration ranged from 2 to 25 years (mean ± SD: 12±9 years), with onset age from 18 to 35 years (mean ± SD: 25±9 years); four patients reported familial cases (Table 2).
Table 2 Demographic characteristics.
| Group A | Group B | ||
|---|---|---|---|
| Participants | 55 | 55 | |
| Sex | Male | 32 | 30 |
| Female | 23 | 25 | |
| Age (Mean ± SD) | 44.5 ± 20.1 | 45.5 ± 20.1 | |
| Education Level | Lower Secondary | 21 | 25 |
| Diploma | 18 | 16 | |
| Post-High School | 16 | 14 | |
| Disease Duration (Mean ± SD) | 13 ± 9 | 12 ± 9 | |
| Age of Onset (Mean ± SD) | 24 ± 9 | 25 ± 9 | |
| Familial Positivity | 3 | 4 | |
Comparison of the inflammatory cytokines
As depicted in Fig. 1, a comparison of TNF-α and IL -1β levels between the two groups before treatment revealed no statistically significant differences (p>0.05). However, substantial reductions were observed following treatment in both TNF-α and IL -1β levels. Notably, the declines in Group B were more pronounced than Group A’s (p<0.05).
Comparison of nerve growth factors between the two groups
Before treatment, we found no significant differences in the levels of NGF and BDNF between the two groups (p>0.05); after treatment, significant increases were found in the levels of NGF and BDNF of the two groups, while the increases in Group B were more evident (p<0.05), (Fig. 2).
Comparison of the PANSS and BPRS scores between two groups
As shown in Fig. 3, comparing the scores of PANSS and BPRS between the two groups before treatment showed no significant differences (p>0.05). However, after treatment, significant decreases were noted in scores of PANSS and BPRS, and decreases in Group B were more pronounced than those in Group A (p<0.05).
Note: Group A for the regular medication group, Group B for the gene-guided medication group, 1 for before treatment, 2 for after treatment; a for p<0.05.
Fig. 3 Comparison of the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) scores between two groups (Points).
Social function and daily living activities
Before treatment, we found no significant differences when comparing the scores of SSPI and ADL between the two groups (p>0.05); after treatment, significant increases were found in the scores of SSPI and ADL of both groups, while the increases in Group B were more noticeable (p<0.05, Fig. 4).
Note: Group A for the regular medication group, Group B for the gene-guided medication group, 1 for before treatment, 2 for after treatment; a for p<0.05.
-Social skills psychometric instruments (SSPI) and activities of daily living (ADL) scores.
Fig. 4 Comparison of social function and activity of daily living between two groups (Points)
Comparison of the effectiveness rate between two groups
The total effectiveness rate in Group B was much higher than that in Group A (p< 0.05; Table 3).
Comparison of the rate of adverse events between two groups
As shown in Table 4, the rate of adverse events in patients of Group B was lower than that in Group A, although this difference had no statistical significance (p>0.05).
DISCUSSION
Schizophrenia represents a severe mental disease, and antipsychotics remain the predominant treatment for managing schizophrenia. However, about one-third of patients with schizophrenia respond poorly to these drugs 13. Clinically, diagnosis or even treatment for schizophrenia mainly depends on the expertise of clinicians or the evaluation by scales 14. Currently, the prevalence of schizophrenia remains high, and an available but simple medication that can perfect the precise treatment is an ideal strategy for schizophrenia treatment 15. Continuous progress in pharmaceutics and pharmacogenomics enables the detection of drug-related genes to guide the clinical use of psychotropic drugs 16. Gene tests before medication can clarify the patients’ genotype, thus promoting rational, precise, and individualized medication 17.
The essential gene examined was CYP2D6, which encodes a critical enzyme involved in metabolizing many commonly used antipsychotics 18. Patients received drug changes according to their CYP2D6 genotype to maximize efficacy and reduce adverse effects, as shown in Table 1. Poor metabolizers, possessing alleles leading to nonfunctional CYP2D6, were switched from Haloperidol and risperidone to alternative antipsychotics not extensively metabolized by this enzyme, like quetiapine 19. This avoids drug accumulation and toxicity in these patients from impaired metabolism. In contrast, doses were increased for normal or ultra-rapid metabolizers to achieve adequate plasma concentrations.
The improved outcomes with gene- guided treatment are biologically plausible based on the pharmacokinetics of antipsychotics. Variations in CYP2D6 polymorphisms can profoundly impact drug exposure by causing variations in metabolic capacity across different genotypes. CYP2D6 is an essential drug-metabolizing enzyme that contributes to the metabolism of 15-25% of all clinically used drugs. Genetic variations in the CYP2D6 gene can lead to considerable phenotypical interindividual differences in CYP2D6-dependent drug metabolism 20. A study by Novalbos et al (2010), examining the relationship between the CYP2D6 genotype and the effects of risperidone found that individuals with different metabolizer phenotypes (ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs)) displayed distinct pharmacokinetic patterns. PMs and IMs exhibited higher levels and longer half-life of risperidone, while UMs and EMs had higher levels of 9-hydroxy risperidone 21. Elmokadem et al. 22 conducted another study on aripiprazole, an antipsychotic, revealing significant time-to-effect differences between CYP2D6 EMs and PMs. This suggests a necessity for customized dosing strategies for PMs 22 and that tailoring medication and dosage based on CYP2D6 activity can optimize plasma levels, potentially reducing side effects in PMs and improving efficacy in rapid metabolizers
According to a current clinical study, schizophrenia is somehow related to the levels of inflammatory cytokines. For instance, TNF-α and IL -1β are clinically common inflammatory cytokines that can be used to evaluate the patients’ inflammation state more accurately 23. This study uncovered abnormal elevations in inflammatory cytokine levels among individuals with schizophrenia. With the aid of gene tests to inform individualized medication, the levels of TNF-α and IL -1β were reduced in patients. These results imply a direct association between inflammatory cytokines and schizophrenia, indicating that tailored medication can effectively mitigate inflammatory cytokine levels and enhance drug efficacy.
As a nerve growth factor, NGF can regulate the growth and development of neurons in the peripheral and central nervous system, maintain neurons’ survival, promote synaptic growth, and restore nerve function24,25. BDNF, as a member of the family of neurotrophic factors, mainly distributes in the central nervous system and the endocrine system, restores the survival of damaged neurons and improves the functions in memory and learning 26,27. In the present study, a decline in levels of NGF and BDNF was observed following the onset of schizophrenia. However, with the application of gene tests to guide individualized medication, it was observed that the levels of NGF and BDNF could be elevated in patients with schizophrenia. This finding indicates that personalized medication has the potential to facilitate the restoration of patients’ learning and memory capacities, as well as promote the recovery of nerve function.
Since physicians may not provide the optimal choice in the efficacy and safety of antipsychotics according to their expertise or evaluation results, precise individualized medication is necessary for improving social function and activities of daily living 28,29. The PANSS scale is a clinically established tool for assessing mental functioning, encompassing positive and negative symptom dimensions. The SSPI scale is applicable for gauging the social functionality of individuals with epilepsy-related mental disorders, whereas the ADL scale serves to evaluate the daily living activities of patients grappling with mental illnesses 30. In the present study, we discovered that personalized medication, guided by genetic tests, has the potential to decrease PANSS scores while simultaneously elevating SSPI and ADL scores. These findings imply that this approach may effectively address mental symptoms and enhance the social functioning and daily activities of individuals dealing with schizophrenia.
In conclusion, the utilization of personalized medication guided by genetic testing has the potential to enhance the effectiveness of drugs. This improvement can enhance learning and memory capabilities in individuals with schizophrenia, facilitating the restoration of neural function and bolstering social engagement and daily activities. Ultimately, this approach aids patients in transitioning back to their daily lives. Furthermore, this strategy holds the promise of refining drug selection and dosages and providing guidance for developing treatment protocols. As a result, it enables the realization of precise treatment using psychotropic medications.
