ARTICLE OPEN

Obesity, antioxidants and negative symptom improvement in

first-episode schizophrenia patients treated with risperidone
Zhiyong Gao1,6, Meihong Xiu2,6, Jiahong Liu1, Fengchun Wu3,4 ✉ and Xiang-Yang Zhang3,5 ✉

Negative symptoms remain a main therapeutic challenge in patients with schizophrenia (SZ). Obesity is associated with more
severe negative symptoms after the first episode of psychosis. Oxidative stress caused by an impaired antioxidant defense system is
involved in the pathophysiology of SZ. Yet, it is unclear regarding the role of obesity and antioxidants in negative symptom
improvements in SZ. Therefore, this longitudinal study was designed to assess the impact of obesity on antioxidant defenses and
negative symptom improvements in first-episode SZ patients. A total of 241 medication-naive and first-episode patients with SZ
were treated with risperidone for 3 months. Outcome measures including symptoms, body weight, and total antioxidant status
(TAS) levels were measured at baseline and the end of the third month. We found that after 12 weeks of treatment with risperidone,
the body weight increased and clinical symptoms significantly improved. Baseline body mass index (BMI) was negatively correlated
with negative symptom improvement after treatment and an increase in TAS was negatively associated with an increase in BMI
only in the high BMI group. More importantly, the TAS × BMI interaction at baseline was an independent predictor of negative
symptom improvement. Our longitudinal study indicates that the improvement in negative symptoms by risperidone was
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associated with baseline BMI and TAS levels in patients with SZ. Baseline BMI and TAS may be a predictor for negative improvement
in SZ patients after risperidone treatment.
Schizophrenia (2023)9:17 ; https://doi.org/10.1038/s41537-023-00346-z

INTRODUCTION parameters, including the homeostasis model assessment of

Schizophrenia (SZ) is a severe mental illness characterized by insulin resistance (HOMA-IR), and hemoglobin A1C (HbA1c) were
persistent or relapsing episodes of positive symptoms and associated with negative symptoms in SZ patients16,17. Even
negative symptoms1. Antipsychotics are recommended as the multiple studies showed that weight gain is related to decreased
first-line medication for treating SZ and have been reported in general psychopathology in patients with SZ treated with second-
clinical trials to be effective in improving symptoms and behaviors generation antipsychotics18,19. Some recent evidence revealed
related to SZ. Positive symptoms can be effectively treated by that weight gain is an important prognostic marker of treatment
available antipsychotics, modern therapy, and psychiatric sup- response to antipsychotics20,21, suggesting that body weight and
port2. It has been shown that about 60% of SZ patients can return weight gain are important issues in therapeutic benefits in SZ.
home after recovery from their first episode and ~50% can return On the other hand, studies have also focused on the essential
to work3,4. However, ~30% remains severely disabled by their role of oxidative stress in the pathogenesis of obesity, metabolic
condition and 10% must be hospitalized5,6. disorders, and SZ22,23. Glutathione peroxidase, catalase, and super-
The percentage of obesity in patients with SZ is significantly oxide dismutase are the main enzymatic antioxidants in the
higher than in the general population7,8. According to recent cells24,25. Vitamins A and C, tocopherol, glutathione, uric acid,
literature, 40–60% of individuals with SZ are reported to be albumin, and bilirubin are important non-enzymatic antioxi-
overweight or obese9,10. Recent meta-analyses of patients with dants26,27. These antioxidants help detoxify harmful reactive oxygen
medication-naïve and first-episode psychosis (MNFE) have species to protect from ROS-induced damage to proteins, DNA, and
revealed increased insulin resistance and impaired glucose mitochondrial membranes27. Alterations in serum or plasma levels
tolerance relative to healthy controls11, although earlier studies or activities of antioxidants have been reported in patients with
have shown that patients with first-episode psychosis were obesity or SZ28–33. Total antioxidant status is an important indicator
diagnosed with much less diabetes than chronic patients on of the additive antioxidant effect in vivo, which is measured via
antipsychotics12. Moreover, studies reported rapid weight gain ferric reducing antioxidant potential (FRAP).
(>7%), usually within 6–8 weeks after treatments with antipsycho- Atypical and typical antipsychotics have an impact on antiox-
tics13. Presumably, patients with SZ may be prone to manifest pre- idant defense system in patients with SZ34–37. Antipsychotic
diabetes, which emphasizes the need for early monitoring of medication may induce oxidative stress, which further influences
overweight/obesity in first-episode SZ. the turnover of catecholamines and suppresses the activity of
There is accumulating evidence to reveal an association antioxidant enzymes. There is clear evidence for the different
between obesity, metabolic parameters, or the changes and effects of typical and atypical antipsychotics in regulating oxidative
clinical symptoms in patients with MNFE14,15. For example, studies stress and antioxidant defense systems38–40. Risperidone is one of
have reported that body mass index (BMI) and other metabolic the most widely prescribed atypical antipsychotics used in the

1
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China. 2Peking University
HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China. 3Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical
University, Guangzhou, China. 4Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China. 5CAS Key Laboratory of
Mental Health, Institute of Psychology, Beijing, China. 6These authors contributed equally: Zhiyong Gao, Meihong Xiu. ✉email: [email protected]; [email protected]

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treatment of SZ, for both acute and long-term medication41. It is a follow-up. The reduction in PANSS total score or its subscores was
benzisoxazole derivative and has a strong binding affinity for D2 calculated by the changes in the total score or subscores from
and 5-HT receptors42. Animal studies provide strong evidence for baseline to 3-month follow-up.
the regulation of risperidone in the redox system. It has antioxidant According to the obesity criteria53, our patients were classified
effects by increasing the antioxidant defenses, such as regulating into the low BMI group (BMI ≤ 24 kg/m2) and the high BMI group
glutathione levels in C6 astroglial cell model43. Administration of (BMI > 24 kg/m2). Overweight/obese participants were included in
risperidone can restore the brain glutathione levels and decrease the high BMI group and the remaining participants constituted
total antioxidant capacity in rats induced by perinatal phencycli- the low BMI group. Underweight participants also belonged to the
dine44,45. In addition, risperidone treatment significantly upregu- low BMI group. The increase in BMI was calculated by the change
lates antioxidant enzyme activities in patients with SZ46–48. in the BMI from baseline to 3-month follow-up.
Atypical antipsychotics have been reported to be linked to rapid Plasma TAS levels of all patients were measured at baseline and
weight gains and obesity in the initial period after antipsychotic follow-up. Details of the methods were described in the
medications in SZ patients49. Based on the close relationship supplementary materials.
between antipsychotic treatment, obesity, and redox regulation in
patients with SZ, the aim of this study was to investigate the effect Statistical analysis
of antioxidants and BMI on the clinical outcome of risperidone in
patients with SZ. We hypothesized that the association between For patients who discontinued the medication after 2 months, the
TAS levels and clinical symptom improvement following risperidone last observation carried forward (LOCF) was used. For patients who
treatment would be different between the low and high BMI discontinued the medication before 2 months, their clinical data
groups and that the interaction between TAS and BMI would were not included in the following analyses. Baseline demographic
predict the response to risperidone in SZ patients. Notably, to characteristics were compared between the low-BMI group and
minimize the potential effects of types and accumulative doses of high-BMI group using analysis of variance (ANOVA) and X2 tests. A
antipsychotics, physical-health comorbidity, and duration of illness, repeated-measure ANOVA was used to analyze the different
only MNFE patients with SZ were recruited in the present study. changes in PANSS total score and its subscale scores and TAS
levels between the low-BMI group and high-BMI group from
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baseline to the LOCF endpoint at the third month. Pearson’s product

MATERIALS AND METHODS moment correlation was performed to investigate the association
Participants between symptom improvements and baseline BMI or changes in
BMI in the low-BMI group and high-BMI group, respectively. Linear
A total of 241 MNFE patients (128 males/113 females) diagnosed
regression analyses were performed to determine the relative
with SZ by SCID-IV, between the age of 16 and 45 years were
contribution of BMI, TAS levels, and other demographic variables to
recruited from Beijing Huilongguan Hospital and Henan Zhuma-
the variance in clinical symptom improvement after treatment.
dian psychiatric hospitals in China. Eligibility inclusion/exclusion
The data were analyzed using IBM SPSS software (version 22.0,
criteria were described in our prior studies30,50, and detailed
Chicago, IL), and statistical significance thresholds were deter-
criteria were described in the supplementary materials. In brief,
mined at P-value < 0.05.
inclusion criteria included both sexes, illness duration ≤5 years, no
previous treatment with psychotropic medicines or cumulative
use of antipsychotics ≤14 days and the clinical global impression RESULTS
(GCI) of 4 or over. The patients had a mean ± SD age of 27.6 ± 9.2 Demographic data and clinical data in patients at baseline
years, a mean BMI of 21.3 ± 3.4 kg/m2, a mean onset age of
26.1 ± 9.2 years and an average illness duration of 1.5 ± 1.3 years. At baseline, patients were classified into two groups according to
Of the 241 patients, sixty-six patients were smokers (66/241, their BMI values: the low BMI group (n = 207) and the high BMI
27.4%) and there was no difference in smoking rates between BMI group (n = 34). There was a significant difference in age between
subgroups. The average severity of the illness assessed by the the low BMI and high BMI groups (p < 0.05) (Table 1). Correlation
Positive and Negative Syndrome Scale (PANSS) was 76.0 ± 17.4. analysis showed that BMI at baseline was associated with age
The study protocol was approved by the Ethics Committees of (r = 0.25, p < 0.001), age at onset (r = 0.21, p = 0.001), and
Beijing Huilongguan Hospital, and written informed consent was negative symptoms in SZ patients (r = −0.13, p = 0.039).
obtained from each patient.
BMI and clinical symptom improvements after treatment
Study overview After treatment with risperidone for 12 weeks, weight and BMI
All recruited SZ patients received a flexible dose (4–6 mg/day) of were significantly increased compared to baseline values (weight:
oral risperidone for 3 months. The study consisted of three visits
conducted by experienced psychiatrists including a questionnaire
survey, clinical assessment scales, and blood sampling on day 1 Table 1. Demographic and clinical characteristics of patients in the
(visit 1, screening), day 1 (visit 2, baseline assessment), and at the high BMI and low BMI groups.
third month or after early discontinuation of risperidone (visit 3, Variable Patients p value
post-treatment assessment).
High BMI group Low BMI group
(n = 34) (n = 207)
Clinical evaluation and TAS measurements
The clinical symptom was assessed by six experienced clinicians Sex (M/F) 19/15 109/98 0.85
using the PANSS51. Before the PANSS rating, the raters partici- Age (ys) 30.8 ± 8.3 27.1 ± 9.3 0.03
pated in comprehensive training. After training, the inter-rater Education (ys) 10.0 ± 4.0 8.9 ± 3.9 0.15
reliability was assessed by comparing the rating of PANSS total
Onset age (ys) 28.7 ± 8.7 25.6 ± 9.2 0.07
score for the same patient assessed by six raters and was analyzed
using intraclass correlation coefficients (ICC)52. A high ICC of TAS (U/ml) 194.9 ± 64.3 227.9 ± 67.8 0.008
PANSS total score was achieved (PANSS-ICC > 0.8). The outcome BMI body mass index; ys years.
measures were respectively assessed at baseline and 3-month

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Table 2. Comparisons of clinical symptoms before and after 12 weeks of risperidone monotherapy between the low BMI group and high BMI group.

Baseline 12-week follow-up Effect

Low BMI group High BMI group Low BMI group High BMI group Time F(p) Group F(p) Interaction F(p)

Clinical symptoms
P score 22.0 ± 6.8 22.8 ± 5.3 11.9 ± 4.7 10.9 ± 3.2 298.6 (<0.001) 0.01 (0.91) 2.0 (0.16)
N score 18.9 ± 7.2 18.1 ± 6.2 14.1 ± 5.6 14.6 ± 5.6 44.1 (<0.001) 0.01 (0.91) 1.1 (0.30)
G score 35.7 ± 10.3 37.0 ± 8.9 24.9 ± 6.0 24.5 ± 6.8 149.4 (<0.001) 0.1 (0.75) 0.8 (0.36)
Total score 76.4 ± 18.7 78.0 ± 14.9 50.9 ± 13.2 49.9 ± 12.2 207.2 (<0.001) 0.02 (0.90) 0.5 (0.50)

2.7 ± 3.8 kg; BMI: 1.0 ± 1.3 kg/m2, all p < 0.05). Moreover, PANSS with risperidone only in the high BMI group, (2) an increase in
total score or its subscores were also significantly lower after TAS was negatively correlated with an increase in BMI after
treatment (all p < 0.01) (Table 2). Repeated-measure ANOVA treatment only in high BMI group, and (3) the TAS × BMI
showed no significant difference in the improvements in clinical interaction at baseline was an independent predictor of negative
symptoms after treatment with risperidone between high and low symptom improvement.
BMI subgroups (all p > 0.05) (Table 2). A significant difference in This study found that baseline BMI was inversely related to
the increase in weight was observed between low BMI and high negative symptom improvements only in the overweight/obesity
BMI groups (3.1 ± 3.8 vs 0.4 ± 3.0, t = −4.2, p < 0.001). MDFE patients with SZ, but not in patients with normal weight.
In addition, we found that the baseline BMI was negatively MDFE patients with higher baseline BMI showed less improve-
associated with the increase in BMI (r = −0.38, p < 0.001). Further ment in negative symptoms after risperidone treatment. Negative
subgroup analysis by baseline BMI showed that there was no symptoms of SZ refer to deficits in certain functions common to
significant association between baseline BMI and improvements in most people, such as facial expressions, emotional responses, and
positive and negative symptoms and general psychology in the joy or motivation54. It is a core component of SZ and is linked
low BMI group. Whereas in the high BMI group, a significant with poor outcomes in patients with SZ55–57. Negative symptoms
inverse association between baseline BMI and improvement in remain an unmet treatment challenge. In the CATIE study, one of
negative symptoms was observed (r = −0.44, p = 0.016). More- the largest clinical trials in SZ, negative symptoms were found to
over, in the high BMI group, an increase in BMI correlated with be common in SZ patients (40%)58. In addition, in a meta-analysis
improvements in general psychopathology (r = 0.44, p = 0.021) of placebo controlled clinical trials of atypical antipsychotic drugs
and PANSS total score (r = 0.38, p = 0.046), but not in the low BMI (n = 7450), it was reported that negative symptoms presented
group (all p > 0.05). after 6-week treatment in 1/3 of patients actively participating in
treatment59. Our findings show that for those patients who were
TAS levels and clinical symptom improvements after overweight or obese, weight gain needed to be effectively
treatment managed to obtain greater negative symptom improvements.
The burden of overweight/obesity is both a physical and a
After treatment, TAS levels were significantly increased relative to
psychological problem. An obesity intervention program for
baseline levels (215.3 ± 66.6 vs 266.4 ± 105.5, p < 0.05) (increase:
MNFE patients with SZ may improve the psychological status of
51.1, 95% confidence interval [CI]: 38.0–64.2). Repeated-measure
patients. Whereas for the patients with normal weight, fluctua-
ANOVA showed that there was no significant difference in the
tions in body weight may not be correlated with improvements in
increases in TAS levels after treatment between high and low BMI
negative symptoms.
subgroups (F = 0.5, p > 0.05).
Another finding of this study was that risperidone treatment
Correlation analyses showed that there was no significant
significantly increased BMI and TAS levels in patients with SZ. In
association between the increase in TAS levels and the
addition, BMI gain after treatment with risperidone was negatively
improvements in clinical symptoms in the low BMI and high
associated with TAS increase in overweight/obese SZ patients.
BMI groups (all p > 0.05). However, we found that in the high BMI
Namely, the more the patient gained weight, the less the increase
group, the increases in TAS levels were negatively associated with
in TAS levels, which is consistent with our expectations. In line
the increases in BMI (r = −0.46, p = 0.014), but not in the low BMI
with our findings, animal model studies have also shown that
group (p > 0.05).
antioxidative enzyme activities were reduced in obese mice
following long-term administration of antipsychotics and weight
Interaction effect of TAS levels and BMI on the clinical gain60. Many previous clinical studies have investigated the
symptom improvements after treatment association between overweight or obesity and antioxidants,
We also found significant associations between TAS levels and BMI and recent evidence supports an inverse intrinsic relationship
in patients at baseline (r = −0.18, p = 0.006) and 12-week follow- between obesity and antioxidant defense system parameters61–63.
up (r = −0.21, p = 0.004). Multiple regression analysis found that In SZ, there is also some evidence supporting that overweight/
an interaction effect of BMI and TAS levels was significantly obesity induced by antipsychotics is related to redox system
associated with negative symptoms at baseline (p < 0.05). biomarkers. Furthermore, it has been reported that the combina-
Furthermore, multiple regression analysis showed that the TAS tion of antipsychotics with antioxidants, e.g., extraction of ginkgo
levels × BMI interaction was an independent predictor for the biloba (EGb47) improved clinical symptoms in SZ patients with
improvement in the negative symptoms in the patients with an higher baseline BMI64. However, we cannot draw a conclusion on
adjusted R2 = 0.04 (β = −0.15, t = −2.1, p = 0.035), after control- the causal relationship between risperidone-induced weight gain
ling for age, gender, and education years. and TAS changes based on the current design.
We further found that the interrelationship between baseline
BMI and TAS levels was an important predictor of improvements
DISCUSSION in negative symptoms after treatment with risperidone in SZ.
We found that (1) baseline BMI was correlated with the Redox dysregulation, sequent oxidative stress, and metabolic
improvement in negative symptoms after 12 weeks of treatment abnormalities have been investigated for many years and are

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well-established in SZ65–71. Cumulative studies have shown that 9. Tardieu, S., Micallef, J., Gentile, S. & Blin, O. Weight gain profiles of new anti-
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