Invest Clin 65(2): 206 - 219, 2024 https://doi.org/10.54817/IC.v65n2a07

Corresponding author: Min Zhu. Department of Pharmacy, The Affiliated Taizhou People’s Hospital of Nanjing Medical

University, Taizhou Jiangsu, China.E-mail: zhumin2023@sina.com

The effectiveness of personalized medication

based on drug-related genes, for schizophre-

nia patients with resistance to traditional

drugs.

Shujun Zhou

, Guangqin Zhang

, Zhe Wang

, Long Wei

, Min Zhu

, Jinquan He

Department of Pharmacy，Nanjing Gaochun People’s Hospital，Nanjing, Jiangsu,

China.

Department of Pharmacy, Ezhou Central Hospital, Ezhou, Hubei, China.

Department of Pharmacy，Medical Supplies Center of PLA General Hospital，Beijing,

China.

Department of Pharmacy，The Affiliated Taizhou People’s Hospital of Nanjing Medical

University，Taizhou Jiangsu，China.

Department of Psychosomatic Medicine, Chenzhou First People’s Hospital, Chenzhou,

Hunan, China.

They contributed equally to this work.

Keywords: inflammatory cytokines; neurotrophic factors; PANSS; BPRS; social skills;

ADL; CYP2D6.

Abstract. We aimed to study the impact of personalized medication based

on drug-related genes for schizophrenia patients with resistance to traditional

drugs. One hundred and ten schizophrenia patients who sought treatment at

our medical facility between June 2021 and February 2023 were chosen and

divided at random into two groups: one group (n=55) received conventional

medication, while the other group (n=55) received personalized medication

based on their genetic profile. The study compared the levels of inflammatory

cytokines and neurotrophic factors, as well as the scores on the Positive and

Negative Symptoms Scale (PANSS), Brief Psychiatry Rating Scale (BPRS), So-

cial Skills Psychometric Instruments (SSPI), and Ability of Daily Living Scale

(ADL) between the two groups. Following the treatment, both groups exhibited

reduced levels of TNF-α and IL-1β compared to pre-treatment levels, with the

gene-guided group showing even lower levels (p<0.05). Conversely, the levels of

NGF and BDNF increased in both groups post-treatment, with the gene-guided

group demonstrating even higher levels (p<0.05). Additionally, the PANSS and

BPRS scores decreased in both groups after treatment, with the gene-guided

group showing even lower scores (p<0.05). On the other hand, both groups’

Gene-based treatment of drug-resistant patients with Schizophrenia 207

Vol. 65(2): 206 - 219, 2024

La eficacia de la medicación personalizada basada en genes

relacionados con fármacos, para pacientes con esquizofrenia

resistente a los fármacos tradicionales.

Invest Clin 2024; 65 (2): 206 – 219

Palabras clave: citoquinas inflamatorias; factores neurotróficos; PANSS; BPRS;

habilidades sociales; ADL; CYP2D6.

Resumen. Nuestro objetivo fue estudiar el impacto de la medicación persona-

lizada basada en genes relacionados con medicamentos para pacientes con esquizo-

frenia resistentes a los medicamentos tradicionales. Se seleccionaron 110 pacientes

con esquizofrenia que buscaron tratamiento en nuestra instalación médica entre

junio de 2021 y febrero de 2023, y se dividieron al azar en dos grupos: un grupo

(n=55) recibió medicación convencional, mientras que el otro grupo (n=55) re-

cibió medicación personalizada basada en su perfil genético. El estudio comparó

los niveles de citocinas inflamatorias y factores neurotróficos, así como las pun-

tuaciones en la Escala de Síntomas Positivos y Negativos (PANSS), la Escala Breve

de Evaluación Psiquiátrica (BPRS), los Instrumentos Psicométricos de Habilidades

Sociales (SSPI) y la Escala de Habilidades de Vida Diaria (ADL) entre los dos gru-

pos. Después del tratamiento, ambos grupos mostraron niveles reducidos de TNF-α

y IL-1β en comparación con los niveles previos al tratamiento, con el grupo guiado

por genes mostrando aún niveles más bajos (p<0,05). Por el contrario, los niveles

de NGF y BDNF aumentaron en ambos grupos después del tratamiento, con el gru-

po guiado por genes demostrando incluso niveles más altos (p<0,05). Además, las

puntuaciones de PANSS y BPRS disminuyeron en ambos grupos después del trata-

miento, con el grupo guiado por genes mostrando incluso puntuaciones más bajas

(p<0,05). Mientras que las puntuaciones de SSPI y ADL aumentaron en ambos

grupos después del tratamiento, con el grupo guiado por genes mostrando puntua-

ciones más altas (p<0,05). La eficacia general del tratamiento en el grupo guiado

por genes fue superior a la del grupo tratado convencionalmente (p<0,05). La me-

dicación personalizada guiada por farmacogenética tiene el potencial de mejorar la

función cognitiva, facilitar la recuperación neurológica, mejorar el funcionamiento

social y mejorar las habilidades de vida diaria de las personas con esquizofrenia, fa-

cilitando así su reintegración exitosa en la sociedad.

Received: 01-11-2023 Accepted: 16-11-2023

SSPI and ADL scores increased post-treatment, with the gene-guided group

exhibiting higher scores (p<0.05). The overall efficacy of the treatment in the

gene-guided group was superior to that in the conventionally treated group

(p<0.05). Personalized medication guided by pharmacogenetics has the po-

tential to enhance cognitive function, facilitate neurological recovery, improve

social functioning, and enhance the daily living skills of individuals with schizo-

phrenia, thereby facilitating their successful reintegration into society.

208 Zhou et al.

Investigación Clínica 65(2): 2024

INTRODUCTION

Schizophrenia stands as one of the

most prevalent mental disorders globally, of-

ten afflicting young adults and characterized

by prolonged duration, frequent relapses,

and abrupt onset

. Individuals with schizo-

phrenia typically exhibit disturbances in

thought, consciousness, behavior, and emo-

tion, 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

Integration into society proves challenging

for schizophrenia patients due to their lim-

ited sense of affiliation and prominent nega-

tive 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, approxi-

mately 30% exhibit poor or partial responses

to these treatments, categorizing them as

drug-resistant individuals

. Thus, improving

the efficacy of antipsychotics on mental dis-

eases has become an attractive issue in the

psychiatry department. At the same time, in-

dividualized medication can be made based

on genetic evidence derived from the analy-

sis of drug-related genes and gene polymor-

phisms to select the drugs and doses more

precisely

. 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 diag-

nosed with schizophrenia admitted to the

Department of Psychosomatic Medicine at

The First People’s Hospital of Chenzhou,

Luojiajing, Chenzhou, Hunan, People’s Re-

public of China, during the period spanning

June 2021 to February 2023, were enrolled

in this study. They were subsequently cat-

egorized into the regular medication group

(Group A) and the gene-guided medication

group (Group B), each comprising 55 pa-

tients.

Comprehensive information about the

study was provided to all patients and their

families, and written informed consent was

obtained. The Ethical Committee of the Hos-

pital 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 antipsy-

chotics. 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 respons-

es 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 ap-

proaches 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 pa-

Gene-based treatment of drug-resistant patients with Schizophrenia 209

Vol. 65(2): 206 - 219, 2024

tients with positive symptoms like halluci-

nations and delusions based on its efficacy

for these symptoms; Risperidone at 2-6 mg

per day, selected for patients with both posi-

tive and negative symptoms given its broad-

er 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; Que-

tiapine 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 tar-

dive dyskinesia due to its lower risk of these

effects.

Group B

In the Group B, medication was per-

sonalized based on drug-related gene tests

and the collaborative analysis of physicians

and clinical pharmacists. The gene tests

identified genetic variations that could in-

fluence 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 me-

tabolism of many antipsychotic drugs. Varia-

tions 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 metab-

olized by the CYP2D6 enzyme to avoid drug

accumulation and subsequent side effects.

In contrast, ‘rapid metabolizers’ may have

required higher doses or more potent medi-

cations to achieve therapeutic drug levels.

The treatment protocol was adjusted

within two weeks after the gene test, includ-

ing 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 pa-

tients (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 me-

tabolizers 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. Ta-

ble 1 shows examples of specific medication

changes made.

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 sub-

sequent 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 fluo-

rescence in situ hybridization (FISH Tag™

DNA Multicolor Kit by Invitrogen).

210 Zhou et al.

Investigación Clínica 65(2): 2024

Genomic analysis and protocol adjustment

Genomic analysis was conducted on

patients belonging to Group B, encompass-

ing the identification of metabolic, respon-

sive, and toxic gene phenotypes, along with

their distribution frequencies. Within two

weeks after the gene testing, the treatment

regimen was modified based on a compre-

hensive analysis that considered the recom-

mendations provided by the DSM4 and the

outcomes of the gene tests.

These adjustments entailed the main-

tenance, augmentation, or reduction of the

initial drug dosage, either in isolation or in

combination with other antipsychotic medi-

cations. In some cases, a transition to alter-

native antipsychotic drugs was also consid-

ered. 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 suit-

able 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 centri-

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

. Due to poor metabolism, it was

switched to quetiapine, which has alternate

metabolic pathways to avoid drug accumu-

lation.

Risperidone

3mg daily

Risperidone

1mg daily

Risperidone dosage was reduced by 50% to

avoid side effects due to poor CYP2D6 me-

tabolism

Intermediate

metabolizer

18 (32.7%) Olanzapine

10mg daily

Olanzapine

5mg daily

The dose was reduced as metabolism was

expected to be slower in intermediate me-

tabolizers.

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 hig-

her doses of quetiapine. The dose was in-

creased for improved efficacy.

Ultra rapid

metabolizer

5 (9.1%) Risperidone

4mg daily

Risperidone

6mg daily

More rapid CYP2D6 metabolism is expec-

ted in ultra-rapid metabolizers. The rispe-

ridone 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 meta-

bolizers, affecting its effectiveness.

Gene-based treatment of drug-resistant patients with Schizophrenia 211

Vol. 65(2): 206 - 219, 2024

fuged at 3000 rpm to facilitate the separa-

tion of the supernatant. This supernatant

was then carefully preserved at a tempera-

ture of -70°C.

The quantification of TNF-α, IL-1β, NGF,

BDNF, PI3K, and mTOR levels was done uti-

lizing a double sandwich enzyme-linked im-

munosorbent assay (ELISA). The procedure

encompassed the following steps: an ELISA

plate was appropriately labeled at room tem-

perature, and a standard curve was meticu-

lously prepared using the appropriate stan-

dard reagents. The patient samples and the

standard reagents were appropriately diluted

and introduced into individual wells (100 μL

per well). Subsequently, incubation was car-

ried out at 37°C within a humid environment.

Following the incubation period, the

plate underwent repeated rinsing steps, af-

ter 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 re-

spective 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 solu-

tion (100 μL per well). Subsequently, a mi-

croplate 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 fac-

tors mentioned above.

The assessment of clinical responses in

patients involved the utilization of the Posi-

tive 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, specifi-

cally 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 nega-

tive correlation with the observed clinical

response. In other words, as the scores on

these scales increase, the corresponding

clinical response tends to decrease, indicat-

ing a greater severity of symptoms.

Social skills psychometric instruments

(SSPI) and activities of daily living (ADL)

scale were used to evaluate patients’ so-

cial 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 fol-

lowing criteria: 1 point for no anomaly or

only slight functional defect; 2 points for a

definite functional defect; 3 points for se-

vere 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, re-

sponse, and failure. Remarkable response:

no psychotic symptoms, with a decrease in

PANSS scores between 50% and 74%. Re-

sponse: 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 effective-

ness 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

(±SD), and the difference between the two

groups was validated by an independent sam-

ple t-test. Enumeration data were expressed

212 Zhou et al.

Investigación Clínica 65(2): 2024

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 fa-

milial cases (Table 2).

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 statisti-

cally significant differences (p>0.05). How-

ever, 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 signifi-

cant 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 signifi-

cant differences (p>0.05). However, after

treatment, significant decreases were noted

in scores of PANSS and BPRS, and decreas-

es in Group B were more pronounced than

those in Group A (p<0.05).

Social function and daily living activities

Before treatment, we found no signifi-

cant differences when comparing the scores

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

Gene-based treatment of drug-resistant patients with Schizophrenia 213

Vol. 65(2): 206 - 219, 2024

Fig. 1. Comparison of the levels of TNF-α and IL-1β between two groups (ng/mL).

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. 2. Comparison of the levels of NGF and BDNF between two groups (ng/mL)

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).

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.

214 Zhou et al.

Investigación Clínica 65(2): 2024

of SSPI and ADL between the two groups (p

>0.05); after treatment, significant increas-

es 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).

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

. Clinically, diagnosis or even

treatment for schizophrenia mainly depends

on the expertise of clinicians or the evalua-

tion by scales

. Currently, the prevalence

of schizophrenia remains high, and an avail-

able but simple medication that can perfect

the precise treatment is an ideal strategy

for schizophrenia treatment

. Continuous

progress in pharmaceutics and pharmacoge-

nomics enables the detection of drug-related

genes to guide the clinical use of psychotro-

pic drugs

. Gene tests before medication

can clarify the patients’ genotype, thus pro-

moting rational, precise, and individualized

medication

The essential gene examined was CY-

P2D6, which encodes a critical enzyme in-

volved in metabolizing many commonly

used antipsychotics

. 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

. 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.

Fig. 4. Comparison of social function and activity of daily living between two groups (Points)

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.

Gene-based treatment of drug-resistant patients with Schizophrenia 215

Vol. 65(2): 206 - 219, 2024

The improved outcomes with gene-

guided treatment are biologically plau-

sible based on the pharmacokinetics of

antipsychotics. Variations in CYP2D6 poly-

morphisms can profoundly impact drug

exposure by causing variations in meta-

bolic capacity across different genotypes.

CYP2D6 is an essential drug-metabolizing

enzyme that contributes to the metabolism

of 15-25% of all clinically used drugs. Ge-

netic variations in the CYP2D6 gene can

lead to considerable phenotypical interin-

dividual differences in CYP2D6-dependent

drug metabolism

. A study by Novalbos et

al (2010), examining the relationship be-

tween the CYP2D6 genotype and the effects

of risperidone found that individuals with

different metabolizer phenotypes (ultrar-

apid metabolizers (UMs), extensive metab-

olizers (EMs), intermediate metabolizers

(IMs), and poor metabolizers (PMs)) dis-

played 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 ris-

peridone

. Elmokadem et al.

conducted

another study on aripiprazole, an antipsy-

chotic, revealing significant time-to-effect

differences between CYP2D6 EMs and PMs.

This suggests a necessity for customized

dosing strategies for PMs

and that tailor-

ing medication and dosage based on CY-

P2D6 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 lev-

els of inflammatory cytokines. For instance,

TNF-α and IL-1β are clinically common in-

flammatory cytokines that can be used to

evaluate the patients’ inflammation state

more accurately

. This study uncovered ab-

normal elevations in inflammatory cytokine

levels among individuals with schizophrenia.

With the aid of gene tests to inform indi-

vidualized 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 ef-

fectively mitigate inflammatory cytokine lev-

els and enhance drug efficacy.

Table 3

Comparison of the effectiveness rate between two groups

Group Case (n) Remarkable response Response Failure Effectiveness rate*

Group A 55 25 20 10 47 (85.45)

Group B 55 28 25 2 53 (96.36)

5.986

P 0.014

*Values are expressed as n (%).

Table 4

Comparison of the rate of adverse events between two groups.

Group Case (n) Leukopenia Constipation Insomnia Anomaly in blood

glucose/lipid

Rate of adverse

event*

Group A 55 1 1 2 1 5 (9.09)

Group B 55 0 2 0 1 3 (5.45)

0.539

P 0.462

*Values are expressed as n (%).

216 Zhou et al.

Investigación Clínica 65(2): 2024

As a nerve growth factor, NGF can regu-

late the growth and development of neurons

in the peripheral and central nervous sys-

tem, maintain neurons’ survival, promote

synaptic growth, and restore nerve func-

tion

24,25

. BDNF, as a member of the family

of neurotrophic factors, mainly distributes

in the central nervous system and the endo-

crine system, restores the survival of dam-

aged 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 schizo-

phrenia. However, with the application of

gene tests to guide individualized medica-

tion, 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’ learn-

ing and memory capacities, as well as pro-

mote 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, en-

compassing positive and negative symptom

dimensions. The SSPI scale is applicable for

gauging the social functionality of individu-

als with epilepsy-related mental disorders,

whereas the ADL scale serves to evaluate the

daily living activities of patients grappling

with mental illnesses

. 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 find-

ings imply that this approach may effectively

address mental symptoms and enhance the

social functioning and daily activities of in-

dividuals dealing with schizophrenia.

In conclusion, the utilization of person-

alized medication guided by genetic testing

has the potential to enhance the effective-

ness of drugs. This improvement can en-

hance learning and memory capabilities in

individuals with schizophrenia, facilitating

the restoration of neural function and bol-

stering social engagement and daily activi-

ties. Ultimately, this approach aids patients

in transitioning back to their daily lives. Fur-

thermore, this strategy holds the promise

of refining drug selection and dosages and

providing guidance for developing treatment

protocols. As a result, it enables the realiza-

tion of precise treatment using psychotropic

medications.

Conflict of competence

The authors declare no conflict of in-

terest.

Authors’ ORCID number

• Shujun Zhou (SZ):

0000-0002-3836-2803

• Guangqin Zhang (GZ):

0009-0007-6999-9130

• Zhe Wang (ZW):

0000-0002-8887-7979

• Long Wei (LW):

0000-0001-5962-3235

• Min Zhu (MZ):

0000-0001-7219-6944

• Jinquan He (JH):

0000-0003-0381-6884

Authors’ contribution

The present study involved a collab-

orative effort where S.Z. provided expertise

in gene-based medication, conducted data

analysis, and contributed to result inter-

pretation; GZ coordinated the study, col-

lected and organized data, and drafted the

manuscript; ZW contributed expertise in

gene-based medication, assisted in data in-

terpretation, and critically reviewed the

manuscript; LW contributed to the litera-

Gene-based treatment of drug-resistant patients with Schizophrenia 217

Vol. 65(2): 206 - 219, 2024

ture review, performed statistical analysis,

and assisted in manuscript revisions; M.Z as-

sisted in data collection and participated in

data analysis and J.H supervised the study,

contributed to data analysis and interpreta-

tion, and provided overall guidance in manu-

script preparation.

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