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
1#
, Guangqin Zhang
2#
, Zhe Wang
3
, Long Wei
1
, Min Zhu
4
, Jinquan He
5
1
Department of PharmacyNanjing Gaochun People’s HospitalNanjing, Jiangsu,
China.
2
Department of Pharmacy, Ezhou Central Hospital, Ezhou, Hubei, China.
3
Department of PharmacyMedical Supplies Center of PLA General HospitalBeijing,
China.
4
Department of PharmacyThe Affiliated Taizhou People’s Hospital of Nanjing Medical
UniversityTaizhou JiangsuChina.
5
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
1
. 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
2
.
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
5
. 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
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 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
31
. 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
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 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
13
. Clinically, diagnosis or even
treatment for schizophrenia mainly depends
on the expertise of clinicians or the evalua-
tion by scales
14
. 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
15
. Continuous
progress in pharmaceutics and pharmacoge-
nomics enables the detection of drug-related
genes to guide the clinical use of psychotro-
pic drugs
16
. Gene tests before medication
can clarify the patients’ genotype, thus pro-
moting rational, precise, and individualized
medication
17
.
The essential gene examined was CY-
P2D6, which encodes a critical enzyme in-
volved 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.
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
20
. 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
21
. Elmokadem et al.
22
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
22
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
23
. 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)
c
2
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)
c
2
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
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 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.
REFERENCES
1. Yan Y, Qifeng D, Daiwei Z, Haiping Z. A
random control trial of group psychologi
-
cal crisis intervention on defensive style
and anxiety for the first-degree relatives of
patients with schizophrenia. Chinese Ment
Heal J. 2021;35(6):466-471.
2. Xiong H, Zhang H, Chen X, Cheng Y,
Huang C. Clinical characteristics and rela
-
ted factors of pneumonia in patients with
aplastic anemia. Chinese J Infect Che
-
mother. 2019;19(1):27-31. https://doi.org
/10.16718/j.1009-7708.2019.01.006
3. Green MF, Horan WP, Lee J, McCleery,
Reddy L F, Wynn JK. Social discon
-
nection in schizophrenia and the ge-
neral community. Schizophrenia bulle-
tin. 2018;44(2):242-249. https://doi.
org/10.1093/schbul/sbx082
4. Barut JK, Dietrich MS, Zanoni PA, Ridner
SH. Sense of belonging and hope in the lives
of persons with schizophrenia. Arch Psych
Nursing. 2016;30(2):178-184. https://
doi.org/10.1016/j.apnu.2015.08.009
5. Ying J, Jue L, Minghuan Z, Zuo H, Dian
-
hong S, Jia L. Comparison of efficacy and
safety between sodium valproate and mo
-
dified electroconvulsive therapy in cloza-
pine-resistant refractory schizophrenia. J
Tongji Univ Medical Sci. 2022;43(2):388-
393.
6. Xu QW, Liu X, Yao QK, Zheng ZJ. CYP co
-
rrelation study of refractory s c h i -
zophrenia drug gene detection. J Hainan
Med Coll. 2019;25(5).
7. Kane M. CYP2D6 overview: allele and
phenotype frequencies. Medical Genetics
Summaries [Internet]: National Center
for Biotechnology Information (US); 2021.
8. Pouget JG, Shams TA, Tiwari AK, Müller
DJ. Pharmacogenetics and outcome with
antipsychotic drugs. Dialogues Clin Neu
-
rosci. 2014;16(4):555-566. https://doi.
org/10.31887/DCNS.2014.16.4/jpouget
9. Zanello A, Berthoud L, Ventura J, Mer
-
lo MC. The Brief Psychiatric Rating Sca-
le (version 4.0) factorial structure and
its sensitivity in the treatment of outpa
-
tients with unipolar depression. Psychiatry
Res. 2013;210(2):626-633. https://doi.
org/10.1016/j.psychres.2013.07.001
10. Depp CA, Loughran C, Vahia I, Molinari
V. Chapter 5 - Assessing Psychosis in Acu
-
te and Chronic Mentally Ill Older Adults.
In: Lichtenberg PA, editor. Handbook of
Assessment in Clinical Gerontology (Se
-
cond Edition). San Diego: Academic Press;
2010. p. 123-54. https://doi.org/10.1016/
B978-0-12-374961-1.10005-3
11. Edemekong PF, Bomgaars DL, Sukuma
-
ran S, Schoo C. Activities of Daily Living.
StatPearls [Internet]. Treasure Island (FL):
StatPearls Publishing; 2023 Jan. 2023 Jun
26. [PubMed ID: 29261878].
12. Yu W, Tong J, Sun X, Chen F, Zhang
J, Pei Y, Zhang T, Zhang J, Zhu B.
Analysis of medication adherence and its
influencing factors in patients with
schizophrenia in the Chinese Institutio
-
nal Environment. Int J Environ Res and
public health. 2021;18(9). https://doi.
org/10.3390/ijerph18094746
13. Yun F, Yanfang Z, Xuehao W, Jinghui T,
Mengzhuang G, Fude Y, Baopeng T, Yun
-
long T. Allostatic load and its relationship
with cognitive deficits in patients with
first-episode schizophrenia. Chinese Ment
Heal J. 2021;35(10):814-819.
14. Patel KR, Cherian J, Gohil K, Atkinson D.
Schizophrenia: overview and treatment op
-
tions. P & T: a peer-reviewed journal for for-
mulary management. 2014;39(9):638-645.
15. Zhi L, Qinfang B, Ning L, Fangbin C, Ying
C, Xiaoyan W, Falin Q, Pharmaceutical care
in 3 Patients with cchizophrenia created
with clozapine. Her Med. 2021;40(5):674-
677. https://doi.org/10.3870/j.issn.1004-
0781.2021.05.019
16. Guo-qin H, Qin-yu L, Jing Z, Ming-huan
Z, Shun-ying Y, Zheng-hui Y, Jian C. As
-
sociation study of non-coding variant
218 Zhou et al.
Investigación Clínica 65(2): 2024
of NOS1AP gene with schizophrenia.
Journal of Shanghai Jiaotong Universi
-
ty (Medical Science) 2021;41(1):29-34.
https://doi.org/10.3969/j.issn.1674-
8115.2021.01.005
17. Omelchenko MA, Atadzhykova YA, Miga
-
lina VV, Nikiforova IY, Kaleda VG. Clinical
and pathopsychological characteristics of
juvenile depression with attenuated schizo
-
phrenic spectrum symptoms. Neurosci Be-
hav Physiol 2022;52(3):330-335. https://
doi.org/10.1007/s11055-022-01244-0
18. Wannasuphoprasit Y, Andersen SE,
Arranz MJ, Catalan R, Jurgens G, Kloos
-
terboer SM.. CYP2D6 genetic variation
and antipsychotic-induced weight gain: a
systematic review and meta-analysis. Front
Psychol 2021;12:768748. https://doi.
org/10.3389/fpsyg.2021.768748
19. Dean L. Risperidone therapy and CYP2D6
genotype. In: Pratt VM, Scott SA, Pirmoha
-
med M, Esquivel B, Kattman BL, Malheiro
AJ, editors. Medical Genetics Summaries.
Bethesda (MD): National Center for Bio
-
technology Information (US); 2012. [Pub-
Med ID: 28520384].
20. Rüdesheim S, Wojtyniak JG, Selzer D,
Hanke N, Mahfoud F, Schwab M. Phy
-
siologically based pharmacokinetic mo-
deling of metoprolol enantiomers and
α-hydroxymetoprolol to describe CYP2D6
drug-gene interactions. Pharmaceutics
2020;12(12). https://doi.org/10.3390/
pharmaceutics12121200
21. Novalbos J, López-Rodríguez R, Ro
-
mán M, Gallego-Sandín S, Ochoa D,
Abad-Santos F. Effects of CYP2D6 geno
-
type on the pharmacokinetics, pharma-
codynamics, and safety of risperidone in
healthy volunteers. J Clin Psychopharma
-
col 2010;30(5):504-511. https://doi.org/
10.1097/JCP.0b013e3181ee84c7
22. Elmokadem A, Bruno CD, Housand C,
Jordie EB, Chow CR, Lesko LJ. Brexpi
-
prazole pharmacokinetics in CYP2D6 poor
metabolizers: using physiologically based
pharmacokinetic modeling to optimize
time to effective concentrations. J Clin
Pharmacol 2022;62(1):66-75. https://doi.
org/10.1002/jcph.1946
23. Zhu F JM, Ma Q. Correlation of serum
inflammatory factors with clinical symp
-
toms and cognitive functions in schizo-
phrenia. J Xi’an Jiaotong Univ Medical
Sci 2021;42(2):301-305. https://doi.org/
10.7652/jdyxb202102023
24. Ding X-W, Li R, Geetha T, Tao Y-X, Babu
JR. Nerve growth factor in metabolic com
-
plications and Alzheimer’s disease: Physio-
logy and therapeutic potential. Biochim
Biophys Acta - (BBA) Molecular Basis of
Disease. 2020;1866(10):165858. https://
doi.org/10.1016/j.bbadis.2020.165858
25. Aloe L, Rocco ML, Bianchi P, Manni L.
Nerve growth factor: from the early dis
-
coveries to the potential clinical use. J
Translat Med. 2012;10(1):239. https://doi.
org/10.1186/1479-5876-10-239
26. Gao L, Zhang Y, Sterling K, Song W. Brain-
derived neurotrophic factor in Alzheimer’s
disease and its pharmaceutical poten
-
tial. Translational Neurodegeneration.
2022;11(1):4. https://doi.org/10.1186/
s40035-022-00279-0
27. Li Y, Li F, Qin D, Chen H, Wang J, Wang
J. The role of brain derived neurotrophic
factor in central nervous system. Front
Aging Neurosc. 2022;14:986443. https://
doi.org/10.3389/fnagi.2022.986443
28. Fuentes-Claramonte P, Ramiro N, To
-
rres L, Argila-Plaza I, Salgado-Pineda
P, Soler-Vidal J. Negative schizophre
-
nic symptoms as prefrontal cortex dys-
function: Examination using a task
measuring goal neglect. NeuroImage: Cli
-
nical. 2022;35:103119. https://doi.org/
10.1016/j.nicl.2022.103119
29. Yali W, Xiaoping Z To study the efficacy
and safety of phenobarbital and phenyto
-
in combined with valproate sodium in the
treatment of epileptic mental disorders.
Cardiovasc Dis J Integr Tradit Chinese
West Med. 2020;8(34):5-9.
30. Fleischhacker W, Galderisi S, Laszlo
-
vszky I, Szatmári B, Barabássy Á, Acsai
K, Szalai E, Harsányi J, Earley W, Patel
M, Németh G. The efficacy of cariprazi
-
ne in negative symptoms of schizophre-
nia: Post hoc analyses of PANSS individual
items and PANSS-derived factors. Euro
-
Gene-based treatment of drug-resistant patients with Schizophrenia 219
Vol. 65(2): 206 - 219, 2024
pean Psychiatry.2019;58:1-9. https://doi.
org/10.1016/j.eurpsy.2019.01.015
31. Šimić I, Potočnjak I, Kraljičković I,
Stanić Benić M, Čegec I, Juričić Nahal
D. CYP2D6 *6/*6 genotype and drug in
-
teractions as cause of haloperidol-induced
extrapyramidal symptoms. Pharmacoge
-
nomics. 2016;17(13):1385-0389. https://
doi.org/10.2217/pgs-2016-0069
32. Cui Y, Yan H, Su Y, Wang L, Lu T, Zhang D.
CYP2D6 genotype-based dose recommen
-
dations for risperidone in Asian people.
Front Pharmacol 2020;11:936. https://doi.
org/10.3389/fphar.2020.00936