Journal Pre-proof

Medication Adherence and its Correlates among Patients Affected by

Schizophrenia with an Episodic Course: A Large-Scale Multi-Center
Cross-Sectional Study in China

Dongfang Wang, Brendan Ross, Chang Xi, Yunzhi Pan, Li Zhou,

Xinhua Yang, Guowei Wu, Xuan Ouyang, Tianmei Si, Zhening Liu,
Xinran Hu

PII: S1876-2018(20)30310-5
DOI: https://doi.org/10.1016/j.ajp.2020.102198
Reference: AJP 102198

To appear in: Asian Journal of Psychiatry

Received Date: 14 January 2020

Revised Date: 21 May 2020
Accepted Date: 3 June 2020

Please cite this article as: Wang D, Ross B, Xi C, Pan Y, Zhou L, Yang X, Wu G, Ouyang X, Si
T, Liu Z, Hu X, Medication Adherence and its Correlates among Patients Affected by
Schizophrenia with an Episodic Course: A Large-Scale Multi-Center Cross-Sectional Study in
China, Asian Journal of Psychiatry (2020), doi: https://doi.org/10.1016/j.ajp.2020.102198

This is a PDF file of an article that has undergone enhancements after acceptance, such as
the addition of a cover page and metadata, and formatting for readability, but it is not yet the
definitive version of record. This version will undergo additional copyediting, typesetting and
review before it is published in its final form, but we are providing this version to give early
visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.

© 2020 Published by Elsevier.

Medication Adherence and its Correlates among Patients Affected by

Schizophrenia with an Episodic Course: A Large-Scale Multi-Center Cross-Sectional

Study in China

Dongfang Wanga,b,c d,#, Brendan Rosse,#, Chang Xia,b,c, Yunzhi Pana,b,c, Li Zhouf, Xinhua

Yangg, Guowei Wua,b,c, Xuan Ouyanga,b,c,*, Tianmei Sih, Zhening Liua,b,c，Xinran Hui

of
a Department of Psychiatry, The Second Xiangya Hospital, Central South University,

ro
Changsha, Hunan, China.

b National Clinical Research Center for Mental Disorders, National Technology

-p
Institute on Mental Disorders, Hunan Medical Center for Mental Health, Hunan Key
re
Laboratory of Psychiatry and Mental Health, Changsha, Hunan, China

c Mental Health Institute of Central South University, Changsha, Hunan, China

lP

d Centre for Studies of Psychological Applications; Guangdong Key Laboratory of

na

Mental Health and Cognitive Science; Ministry of Education Key Laboratory of brain

cognition and educational science; School of Psychology, South China Normal

ur

University, Guangzhou, Guangdong, China.

eFaculty of Medicine, McGill University, Montreal, QC, Canada

Jo

f
Department of Psychiatry, the First Affiliated Hospital of Jinan University,

Guangzhou, China

g
Department of Psychology, Institute of Education, Hunan Agricultural University,

Changsha, Hunan, China

h
Key Laboratory of Mental Health, Institute of Mental Health, Peking University Sixth

Hospital, Peking University, Beijing, China

i
Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA

#
These authors contributed equally to this work.

*Corresponding should be addressed to:

Xuan Ouyang,

of
Mental Health Institute of the Second Xiangya Hospital, Central South University,

ro
Changsha, China, 410011.

Tel. /fax: (+86)0731- 85292136

Email: ouyangxuan@csu.edu.cn
-p
re
Highlights
lP

 The MARS survey has good internal consistency in the study sample from
na

Mainland China.

 Medication adherence of patients affected by schizophrenia with an episodic

ur

course in Mainland China remains low.

 Age, steady income, and illness severity significantly affect medication

Jo

adherence.
Abstract

The Medication Adherence Rating Scale (MARS) is a fast, non-intrusive way of

measuring adherence to medication in order to improve the management of patients

with schizophrenia. The current cross-sectional study evaluated the reliability of the

Chinese (Mandarin) version of the MARS and explored clinical and demographic

correlates to medication adherence in a large sample of patients affected by

schizophrenia with an episodic course in China. 1198 patients were recruited from 37

of
different hospitals in 17 provinces/municipalities of China and evaluated with the

ro
Medication Adherence Rating Scale (MARS), Clinical Global Impression-Severity of

Illness (CGI-SI) and Sheehan Disability Scale-Chinese version (SDS-C). The MARS
-p
showed good internal consistency; Cronbach’s alpha of total MARS was 0.83. Among
re
the cohort of patients affected by schizophrenia with an episodic course, 28.5% met

the criteria of good adherence to antipsychotic medication; age, steady income, and
lP

severity of illness had significant effects on medication adherence. Medication

na

adherence of patients affected by schizophrenia in mainland China was found to be

relatively low, calling for urgent attention and intervention. Risk factors for non-
ur

adherence to medication among patients affected by schizophrenia with an episodic

course include older age, unsteady income, being in the acute period of the disease,
Jo

and severity of illness.

Keywords

Medication Adherence; MARS; Schizophrenia; China

1. Introduction

Medication adherence is defined as “the extent to which a person’s behavior

(including medication taking) corresponds with agreed recommendations from a

healthcare provider” (WHO, 2003). It can refer to various stages: initiation of

treatment, implementation of the prescribed medication regime, and discontinuation

of medical treatment (Bernard et al., 2012). Previous studies have shown that long-

of
term treatment with antipsychotics can prevent schizophrenia relapse (Barnes et al.,

ro
1997; Gray et al., 2016; Summerhayes, 2008). However, only 27% of patients with

schizophrenia met criteria for “good” adherence in one study, and in a 2015
-p
systematic review, rates of adherence ranged greatly from 47.2 to 95% (Kim et al.,
re
2006; Sendt et al., 2015). Poor medication adherence is associated with adverse

clinical outcomes, increased morbidity and mortality, substantially higher healthcare

lP

expenditures, and impaired social function (Brown and Bussell, 2011; Fernández-
na

Miranda et al., 2015; Johnson et al., 1999). Medication non-adherence is therefore a

crucial problem in treating patients suffering from schizophrenia (Kim et al., 2019;
ur

Thompson et al., 2000; Viguera et al., 1997).

The Medication Adherence Rating Scale (MARS) (Thompson et al., 2000) was
Jo

developed from two existing scales: the Drug Attitudes Inventory (DAI) (Hogan et al.,

1983) and the Medication Adherence Questionnaire (MAQ) (Morisky et al., 1986). The

MARS is a self-report measure of medication adherence in schizophrenia, which

consists of 10 “yes/no” items that generate total scores ranging from 0 (poor
adherence) to 10 (excellent adherence). The three-factor structure of MARS addresses

1: medication adherence behavior, 2: attitude towards taking medication, and 3:

negative side-effects and attitudes. The overall reliability and validity of MARS were

originally reported as satisfactory (Thompson et al., 2000), and the scale has been

tested across different continents and populations, including, more recently, in

Nigeria (Sowunmi and Onifade, 2020). It has been translated into multiple languages,

including German (Jaeger et al., 2012), French (Fond et al., 2017; Zemmour et al.,

of
2016), and Portuguese (Vasconcelos et al., 2016).

ro
In Hong Kong, the Cantonese version of MARS was used to study self-reported

adherence behaviors in outpatient samples of patients with schizophrenia (Hui et al.,

-p
2006). In Taiwan, the Mandarin Chinese version of MARS was used to study beliefs
re
about compliance in patients with schizophrenia (Kao and Liu, 2010). However, very

little research on the MARS has been conducted in mainland China.

lP

Compared to Hong Kong or Taiwan, the public’s health literacy of psychiatry in

na

mainland China is not as high, and a stigma against mental illness persists (Wong et al.,

2017). Patients are often reluctant to continue taking medication, leading to

ur

recurrence of illness. Currently, psychiatric resources in mainland China are

insufficient, and regional inequality remains high—for example, there are ‘blank areas’
Jo

where there are no psychiatric specialists available (Liang et al., 2018).

The current study aimed to examine medication adherence among patients

affected by schizophrenia with an episodic course and to assess the reliability of the

MARS in a large sample pulled from across mainland China. In order to address
regional discrepancies in resources, patients were recruited from each of the major

geographic regions of China. The study also combined other related measures to

explore potential factors influencing medication adherence in patients affected by

schizophrenia with an episodic course.

2. Methods

2.1. Subjects

of
This study was conducted from 2013 to 2016 at 37 first-class hospitals located in

ro
17 provinces or municipalities in China (4 provinces/municipalities in Eastern China:

Jiangsu, Zhejiang, Fujian, and Shanghai; 3 provinces in Central China: Henan, Hubei,
-p
and Hunan; 3 provinces/municipalities in Southwestern China: Sichuan, Chongqing,
re
and Yunnan; 1 province in Northwestern China: Shaanxi; 3 provinces/municipalities in

Northern China: Shanxi, Hebei, and Beijing; 2 provinces in Northeastern China:

lP

Liaoning, Heilongjiang; 1 province in Southern China: Guangdong). 240 psychiatrists

na

affiliated with specialized psychiatric hospitals or general hospitals with psychiatry

departments participated in the study. Diagnoses of schizophrenia were made by

ur

experienced psychiatrists using the Structured Clinical Interview for the Diagnostic and

Statistical Manual of Mental Disorders-IV (SCID) (APA, 1994). Patients affected by

Jo

schizophrenia with an episodic course (≥2 episodes) (WHO, 2018) were recruited by

their attending psychiatrists with whom they routinely followed up. All participants

completed a self-reported MARS questionnaire, and procedures were followed on a

script by the attending psychiatrist. For patients in an acute stage of illness or who
were non-cooperative or unable to answer the self-report survey, the treating

psychiatrist directed the same questions from the survey at the patient and the

patient’s guardian or present family member to confirm the accuracy of the answers.

This was performed to ensure the veracity of the patient’s report of medication

adherence. The acute stage of illness was determined based upon the patient’s

answers to the mental status interview and the Clinical Global Impression-Severity of

Illness (CGI-SI).

of
This study sampled 1,202 patients aged 14-81 years, and valid data were collected

ro
from 1,189 patients (7 patients with >25% data missing, 6 patients with unclear

diagnoses). Socio-demographic information, as well as the severity of illness and

-p
functional impairment, was collected by the psychiatrists.
re
2.2 Measures

Socio-demographic and clinical characteristics:

lP

Socio-demographic data included gender, age, marital status, education level,

na

employment status, and living status (living with others or alone). Clinical data

included duration of illness, number of relapses, medication use, as well as the current
ur

stage of disease evaluated by psychiatrists according to the CGI-SI.

Medication Adherence Rating Scale (MARS) –Chinese version

Jo

The Chinese (Mandarin) version of MARS was used to assess medication

adherence of patients affected by schizophrenia with an episodic course (Hui et al.,

2006; Kao and Liu, 2010).

Clinical Global Impression - Severity of Illness –Chinese version

 Clinical Global Impression is a measurement tool for comprehensive evaluation of

clinical efficacy and includes three categories: severity of illness (SI), global

improvement (GI), and efficacy index (EI) (Guy., 1976). The Chinese version is widely

used (Ren et al., 2016). In this study, only Clinical Global Impression-Severity of Illness

(CGI-SI) was employed. Psychiatrists rated the items based on an eight-point Likert

scale ranging from 0 (lack of symptoms) to 7 (severe condition) to assess illness

severity with higher scores reflecting greater severity of illness.

of
Sheehan Disability Scale- Chinese version (SDS-C)

ro
SDS-C (Leu et al., 2015) was used to measure functional impairment in three

domains (work/school activities, social functioning, and family relationships), rated on

-p
a visual analogue scale (VAS) ranging from 0-10. Cronbach’s alpha in this sample was
re
0.960.

2.3 Statistical Analyses

lP

Confirmatory factor analysis (CFA) was performed to explore the construct

na

validity of the MARS. Root mean square error of approximation (RMSEA) was set as

acceptable at or less than 0.06 (Mueller et al.), comparative fit index (CFI) and Tucker‐
ur

Lewis Index (TLI) were acceptable at greater than 0.95 (Hu and Bentler, 1998), and

factor loadings greater than 0.4 were retained and considered satisfactory (Mokkink,
Jo

2010). Pearson correlations were used to examine associations between MARS, socio-

demographic information, and clinical characteristics. Independent sample T-tests

were used to compare MARS scores between different socio-demographic and clinical

characteristics. Finally, a cut-off score of 6 on the MARS (ranging from 1 to 10) was
used to divide the sample into two groups (MARS score ≥6 identified good adherence

and MARS score <6 indicated poor adherence) (Kao and Liu, 2010). A bivariate logistic

regression model with the two groups (MARS score<6 and MARS score≥6) as the

dependent variable was used to identify factors influencing medication adherence. All

data processing and analyses were conducted on SPSS 22.0 and Mplus 7.4.

2.4. Ethical Approval

The study was supported by the schizophrenia working group of the Chinese

of
Society of Psychiatry (CSP). The Second Xiangya Hospital of Central South University

ro
(with Dr. Zhening Liu overseeing the study in southern China) and the Sixth Hospital of

Peking University (with Dr. Tianmei Si overseeing the study in northern China) were
-p
responsible for this project. The study was approved by the medical ethics review
re
committees of each of the 37 hospitals that participated in this survey. Written

informed consent was obtained from each patient, and consent from legal guardians
lP

was obtained for pediatric patients (age＜16 years old).

na

3.Results
ur

3.1. Demographics and clinical characteristics

The average age for the 1,189 participants was 34.22 years (SD=12.29), with
Jo

52.3% female (n=622) and 47.7% male (n=567). Overall illness severity was moderate

(CGI-SI=4.74±2.91), with social function being moderate or above impairment (SDS-

C=17.58±7.98). The average number of relapses was greater than 2. 62.3% of patients

were in the acute period of illness, and 37.7% of patients were in remission. 89.6%
patients were receiving antipsychotic medications, and 37.7% were receiving more

than two medications (see Table 1).

3.2 Reliability and validity of MARS

In our sample, MARS demonstrated good reliability; Cronbach’s alpha of total

MARS was 0.83, Spearman-Brown coefficient was 0.72, and Kuder-Richardson

coefficient was 0.85. Findings from CFA with Maximum Likelihood (ML) estimation

indicated good fit for the three-factor model: medication adherence behavior (Factor

of
1: item 1 to item 4), attitude to taking medication (Factor 2: item 5 to item 8) and

ro
negative side-effects and attitudes to psychotropic medication (Factor 3: item 9 and

item 10) (MLχ2 =261.70, df=32, CFI = 0.95, TLI = 0.95, RMSEA = 0.07, AIC=12357.02)
-p
(see Figure 1). Cronbach’s alpha of the three factors were 0.76, 0.68, and 0.41,
re
respectively. Spearman-Brown coefficients were 0.77, 0.60, and 0.42, respectively.

Kuder-Richardson coefficients were 0.76, 0.68, and 0.41, respectively.

lP

3.3. MARS scores among subgroups with specific socio-demographic/clinical

na

characteristics

The frequency of response for each item of MARS was described in detail in Table
ur

2. 339 (28.5%) patients affected by schizophrenia with an episodic course reported

good medication adherence (MARS≥6). Table 3 related each factor as well as the total
Jo

MARS score to demographics and clinical characteristics. The average MARS total

score was 3.68 (SD=2.90). Male patients affected by schizophrenia with an episodic

course showed a better attitude towards taking medication (p<0.01). Patients with

steady income reported better medication adherence behavior, a better attitude

towards taking medication, and a higher MARS score (p<0.001). There was no

significant difference in MARS scores between subgroups with different marital status,

or between patients living alone or not. Patients in remission reported better

medication adherence behavior, better attitudes towards taking medication, better

attitudes towards psychotropic medication, less negative side-effects, and higher

MARS total score (p<0.001). However, our data indicated no significant effect of the

duration of illness on MARS score.

of
3.4. Correlation between sociodemographic/clinical characteristics and medication

ro
adherence.

Associations between medication adherence and socio-demographic/clinical

-p
characteristics in patients affected by schizophrenia with an episodic course were
re
shown in Table 4. The medication adherence behavior, attitude towards taking

medication, and MARS total score were all negatively correlated with age (r=-0.09,
lP

p<0.01). The level of education was positively correlated with medication adherence
na

behavior (r=0.07, p<0.05). The frequency of relapse was positively correlated with

fewer negative side-effects and better attitudes towards psychotropic medication

ur

(r=0.06, p<0.05). All factors of MARS and MARS total score showed significantly

negative correlations with CGI-SI, as well as disabilities of the three domains

Jo

(work/school activities, social functioning, and family relationships) of SDS-C and SDS-

C total score (p<0.001). Following further analysis, a negative correlation was also

found between education and age for the study population (r=-0.20, p<0.001).

3.5. Logistic regression analysis

 As the defined dependent variable (high score ≥6 or low score<6 MARS groups)

was dichotomous, a binary logistic regression analysis was performed to examine

potential predictive factors and relative contribution of independent variables (see

Table 5). The findings indicated older age（OR=1.04, 95%CI=1.02-1.06）, unsteady

income（OR=1.79, 95%CI=1.29-2.49）, acute period（OR=4.23, 95%CI=3.21-5.59）and

a higher CGI-SI score （OR=1.44, 95%CI=1.03-2.01）all had significantly predictive

effects on poor medication adherence.

of
4. Discussion

ro
This study of the MARS is unique for a few reasons. First, comparative reports on

MARS use in mainland China have not been published internationally; similar tests on
-p
reliability and correlation have only been reported in Hong Kong and Taiwan (Hui et
re
al., 2006; Kao and Liu, 2010). Second, in considering demographic and clinical

correlates of medication adherence in patients with schizophrenia, our MARS study

lP

broadly represents China with 17 of 27 provinces/municipalities reporting data from

na

multiple geographic regions, with the participation of hundreds of psychiatrists across

China.
ur

Furthermore, in our study, all patients were under the regular care of a psychiatrist

when they self-reported answers to the questions in the MARS survey. If a patient was
Jo

in an acute phase of illness, his/her self-reported answers were corroborated by their

guardians to confirm the reliability of information from the patient. This is in contrast

to other studies of MARS, which typically administer the survey by allowing the patient

to respond individually without clarifying or identifying acute cases (Fialko et al., 2008;
Zemmour et al., 2016). When patients respond independently, they may not answer

the survey in the same way as they would when they complete the survey in the office

of their psychiatrist, who can assess for an acute phase of their illness (Fialko et al.,

2008). For this reason, one cross-cultural MARS study in Brazil excluded acute-case

patients in their exclusion criteria (Moreira et al., 2014). This method of physician-

confirmed response can be viewed as a benefit to the study in terms of confirming the

veracity of answers. However, it can also be viewed as a drawback in terms of

of
introducing bias and the influence of providers and guardians. A discussion of the

ro
limitations of this reporting method is discussed in more detail below.

Only 28.5% of patients affected by schizophrenia with an episodic course met the
-p
criteria of good adherence to antipsychotic medication in this study. The overall MARS
re
total score in our study (3.68 ±2.90) is comparably lower to that of developed

countries, as MARS total score had a mean of 6.0 to 7.7 in a UK sample (Fialko et al.,
lP

2008; Jaeger et al., 2012), and 5.5 for a sample of patients with schizophrenia in France
na

(Zemmour et al., 2016). This discrepancy between MARS scores in schizophrenic

patients in Asia and the West could be an area for further investigation.
ur

Other studies have demonstrated that the Clinical Global Impression-Severity of

Illness score is negatively correlated with medication adherence, as both positive and
Jo

negative symptoms, especially cognitive impairment, disorganization, and the

presence of suspiciousness and hostility significantly contribute to poor adherence in

outpatients with schizophrenia (Kampman and Lehtinen, 2010 ; (Yang et al., 2012).

Our study confirmed these associations between medication adherence and the
severity of illness in patients affected by schizophrenia with an episodic course.

Conversely, poor compliance can affect the treatment outcome as well. Low

medication adherence can increase the risk of relapse of schizophrenia, which in turn

affects the severity of illness, leading to more severe social disability. Likewise, in our

study, medication adherence among patients affected by schizophrenia with an

episodic course was found to be negatively correlated with social disability, including

work/school activities, social functioning, and family relationships.

of
Our results also suggested that medication adherence was better in the remission

ro
period than in the acute period. While in the acute period, patients often suffer from

severe psychiatric symptoms and have poor insight and decreased awareness of self-
-p
management, leading to rejection of medication. Drug withdrawal is also a significant
re
risk factor in the development of the disease within the acute period. Our results

supported earlier findings that acute symptoms impaired medicine adherence (Hong
lP

et al., 2007), suggesting that adherence therapy is an effective method to improve

na

psychopathology in patients recovering from an acute episode of schizophrenia (David,

2010; Schulz et al., 2013).

ur

Interestingly, we found that an increased number of relapses was positively

correlated with fewer negative side-effects and better attitudes to psychotropic

Jo

medication. This runs counter to other studies in China, which have shown relapse as

a primary risk factor for poor medication adherence (Xiao, 2015). While it is difficult

to speculate the precise mediating factor in cross-sectional studies like ours, fewer

negative side-effects may have been seen in cases with more relapses, because those
patients may have been more likely to use less medication and thus less likely to

experience side effects of medication. In our sample, 51.9% of patients were under

single-drug treatment.

Unlike a previous study in Hong Kong (Hui et al., 2006), we did not find a significant

association between illness duration and medication adherence, as there was no

significant difference between the illness duration groups (≥5 years and <5 years),

which is likely attributed to the heterogeneity of patients and the sample size. We also

of
found no correlation between whether a patient was living alone or not and their

ro
medication adherence, which was consistent with previous reports (Verdoux et al.,

2010).
-p
We further explored factors influencing medication adherence and the effect of
re
demographic and clinical characteristics on medication adherence by logistic

regression. Older age, unsteady income, acute period, and more severe current
lP

symptoms could predict a high risk of poor medication adherence.

na

Older patients with schizophrenia may lack health knowledge and poor self-care,

leading to poor medication adherence. However, there have been conflicting results
ur

on the relationship between age and medication adherence. Some studies have

reported older patients showing higher rates of medication adherence, while younger
Jo

patients often forget or cease to take medication (Hui et al., 2006). One study of MARS

in France reported that age was not significantly associated with medication

adherence (Zemmour et al., 2016). Our results showed that age was negatively

correlated with MARS. This finding might be related to the low health literacy and poor
medication management ability among the elderly, both in the specific case of

schizophrenia and in more general settings (Jeste et al., 2003; Maclaughlin et al., 2005).

Another study suggested that older patients may deliberately choose not to adhere to

medication to avoid adverse effects (Stewart and Caranasos, 1989). Although older

adults are more likely to be taking multiple medications and are more susceptible to

adverse side effects, we found no correlation between age and negative side effects,

or attitudes to psychotropic medication in our study.

of
The findings related to age may also stem from education levels. Education level

ro
was found to be positively associated with medication adherence behavior in our

study, similar to a Taiwanese study that reported that patients with higher education
-p
levels (and elderly patients in their case) had better medication adherence (Kao and
re
Liu, 2010). Elderly mainland Chinese patients may lack the same level of formal

education as their Taiwanese or Hong Kong counterparts, as our study found a

lP

negative correlation between age and education among our cohort (r=-0.20, p<0.001),
na

which could lead to more inadequate health literacy and lower medication adherence.

In our study, not only did unsteady income predict a lower MARS score and poor
ur

adherence, but patients without steady income (n =513, 65.2%) were more likely to

be in the acute period than patients with steady income (n=228, 56.7%) (Chi-square =
Jo

-2.849, p of steady income= 0.004). Income instability does not necessarily confer low

economic status, however, as a patient may have family members who support them.

Therefore, while our study cannot provide evidence that a patient’s economic

condition is a strong predictor of low medication adherence, economic support in

general is seen as vital for the treatment of schizophrenia (Gurovich and Lyubov, 2002).

In this study, the majority of patients and their family members complained that they

could not afford the expense of medicines for an extended period of time. Medical

insurance can relieve some of the economic burden, but it cannot resolve the problem

since some patients with schizophrenia have to receive medication for life. Previous

studies have found that family income levels and insurance policies play essential roles

in determining psychotropic medication prescriptions for Chinese outpatients with

of
schizophrenia (Cohen et al., 2012; Xiang et al., 2007).

ro
This study had some limitations. First, the study participants were randomly

recruited in different hospitals across the country, and the difficulties in follow-up
-p
assessment resulted in the lack of a thorough test-retest reliability assessment. Other
re
research also found that insight into treatment correlated positively with medication

adherence at index interview but not at follow up, indicating that the predictive value
lP

of correlations with medication adherence can be difficult to identify (Yen et al., 2010).
na

Our study also failed to independently measure the level of insight into illness among

participants, which could have provided another useful factor for evaluating
ur

medication adherence (Kim et al., 2019).

Second, our sample included only patients affected by schizophrenia with an

Jo

episodic course. It would be helpful to add patients with first-episode schizophrenia

and patients without relapse to compare medication adherence in future studies,

since non-adherence to medication is the leading cause of relapse of schizophrenia.

Third, while MARS Factor 3 addresses the influence of adverse side-effects and
attitudes toward anti-psychotropic medication on medication adherence, this study

did not specifically investigate the impact of different antipsychotic treatment

regimens on medication adherence. However, one recent study (Sendt et al., 2015)

found that the route of administration and class of medication did not influence

adherence in their systematic review. Additionally, we did not collect medication-

related side effects, which could significantly influence drug adherence.

A further limitation of this study was the lack of a concurrent measurement of

of
medication adherence, such as MEMS cap monitoring, to formally assess the validity

ro
of the MARS in this patient population. Despite this limitation, as previously reported

(Thompson et al., 2000), the three factors of MARS (Factor 1: medication adherence
-p
behavior; Factor 2: attitude to taking medication; and Factor 3: negative side-effects
re
and attitudes to psychotropic medication) had statistically significant internal

correlation. The internal consistency of MARS, however, was found to be comparably

lP

weaker for two factors in our case: attitude towards taking medication (alpha=0.679)
na

and negative side-effects and attitudes towards psychotropic medication

(alpha=0.405). The Spearman-Brown coefficient was also low for the two factors. This
ur

reflects similar findings in an earlier study, which reported low value of Cronbach’s

alpha for the two factors (0.47 and 0.61 respectively) due to the fewer numbers of
Jo

questions and the poor interrelatedness of the items (Zemmour et al., 2016).

Limitations of cross-sectional studies like ours include that it can be difficult to

determine causality between medication adherence and outcome or to interpret their

associations. Cross-sectional studies are also susceptible to misclassification due to

recall bias. Our study also employed a novel method of training psychiatrists to ask

patients the MARS self-reported questions if they presented in an acute stage of illness.

Thus, a direct comparison between our results and those of other MARS studies is not

ideal. While we believe this method helps to ensure that acute patients answer in a

manner consistent with their adherence to treatment, there is not enough current

research on whether this method introduces biases in different directions. This

method might impact the variability due to raters’ biases, for example. In order to try

of
to minimize rater-related effects, all psychiatrists were trained in a formalized and

ro
standard method and used a script to confirm responses to the MARS. Confirming

answers to MARS with the patients’ guardians or family members may also introduce
-p
its own bias. However, in China, family members often play an essential role in the
re
medication adherence of a patient (Yujing et al., 2019), and thus formally seeking their

input when gathering information may be a method to consider for other studies going
lP

forward. One study of the adherence of patients with schizophrenia found that the
na

adherence rate was only 23% based on an analysis of blood levels. In contrast, 55% of

participants reported that they were perfectly adherent during the three month study
ur

period (Kim et al., 2006), which indicates that there may be value in corroborating

patient reports with guardians and family members.

Jo

5. Conclusion

In conclusion, the Medication Adherence Rating Scale (MARS) has acceptable

psychometric properties in patients affected by schizophrenia with an episodic course

in China. The stability of income, severity of illness, stage of the disease, and age of
the patient are potential influencing factors for medication adherence. One question

for further research is to examine why the elderly population in China has a relatively

lower level of medication adherence than the general patient population, compared

to Hong Kong or Taiwan, where the elderly are more likely to be adherent.

Poor medication adherence could affect the severity of the disease and damage

the social function of patients with schizophrenia, ultimately leading to multiple

relapses and worse clinical outcomes. Most importantly, medication adherence of

of
patients with schizophrenia is still deficient in mainland China and urgently needs

ro
more attention and effective interventions. Therefore, a country-wide survey of

medication compliance like this is significant and can help us understand the current
-p
medication adherence situation of patients with schizophrenia. This study and others
re
like it can have critical reference value for the evidence-based implementation of

community psychiatric services in the future.

lP
na

Contributors

Xuan Ouyang designed and coordinated the study. Dongfang Wang and Chang Xi
ur

were responsible for collecting data and statistical analyses. Dongfang Wang, Li Zhou,

Xinhua Yang, Guowei Wu, Tianmei Si, and Zhening Liu were responsible for data
Jo

analysis. Dongfang Wang, Xuan Ouyang, Xinran Hu, and Brendan Ross drafted the

paper. Dongfang Wang, Xuan Ouyang, Yunzhi Pan, Brendan Ross, and Xinran Hu

commented on the paper.

Data Statement

Due to the sensitive nature of the questions asked in this study, survey respondents were assured

raw data would remain confidential and would not be shared.

Role of funding source

This work was supported by the China Precision Medicine Initiative

(2016YFC0906300); the National Natural Science Foundation of China (81561168021,

of
81671335, 81701325, 81801353); Fogarty Center Project of NIH (D43 TW 009579); and

ro
Postgraduate Innovative Research Projects of Hunan province (CX2018B397).

Conflict of Interest
-p
re
All authors declare that they have no conflicts of interest.
lP

Declaration of Conflict of Interest

All authors declare that they have no conflicts of interest.

na

Acknowledgments
ur

The authors would like to extend our sincere gratitude to all of the patients and

doctors for their participation in this study.

Jo

References

APA, 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, 4th ed.

Washington DC.
Barnes, T.R.E., Mcphillips, M.A., Hillier, R., Puri, B.K., Joyce, E., 1997. Compliance with

maintenance medication in first-episode schizophrenia. Schizophrenia Research 24(1–2),

205-205.

Bernard, V., Sabina, D.G., Hughes, D.A., Kardas, P., Jenny, D., Todd, R., Fabienne, D.,

Emily, F., Valerie, M., Pawel, L., 2012. A new taxonomy for describing and defining

adherence to medications. British Journal of Clinical Pharmacology 73(5), 691-705.

Brown, M.T., Bussell, J.K., 2011. Medication adherence: WHO cares? Mayo Clinic

of
Proceedings 86(4), 268-270.

ro
Cohen, M.J., Shaykevich, S., Cawthon, C., Kripalani, S., Paasche-Orlow, M.K., Schnipper,

J.L., 2012. Predictors of medication adherence postdischarge: the impact of patient age,
-p
insurance status, and prior adherence. Journal of Hospital Medicine 7(6), 470-475.
re
David, A.S., 2010. Treatment adherence in psychoses. British Journal of Psychiatry the

Journal of Mental Science 197(6), 431-432.

lP

Fernández-Miranda, J.J., Victoria, C.G., Arantxa, S.G., 2015. Effectiveness, Good

Tolerability, and High Compliance of Doses of Risperidone Long-Acting Injectable Higher

na

Than 75 mg in People With Severe Schizophrenia: A 3-Year Follow-Up. Journal of Clinical

ur

Psychopharmacology 35(6), 630-634.

Fialko, L., Garety, P.A., Kuipers, E., Dunn, G., Bebbington, P.E., Fowler, D., Freeman, D.,
Jo

2008. A large-scale validation study of the Medication Adherence Rating Scale (MARS).

Schizophrenia Research 100(1), 53-59.

Fond, G., Boyer, L., Boucekine, M., Aden, L.A., Schurhoff, F., Tessier, A., Andrianarisoa, M.,

Berna, F., Brunel, L., Capdevielle, D., Chereau, I., Mallet, J., Denizot, H., Dorey, J.M.,
Dubertret, C., Dubreucq, J., Faget, C., Gabayet, F., Rey, R., Richieri, R., Passerieux, C.,

Schandrin, A., Urbach, M., Vidailhet, P., Llorca, P.M., Misdrahi, D., group, F.-S., 2017.

Validation study of the Medication Adherence Rating Scale. Results from the FACE-SZ

national dataset. Schizophr Res 182, 84-89.

Gray, R., Bressington, D., Ivanecka, A., Hardy, S., Jones, M., Schulz, M., Bormann, S.V.,

White, J., Anderson, K.H., Chien, W.T., 2016. Is adherence therapy an effective adjunct

treatment for patients with schizophrenia spectrum disorders? A systematic review and meta-

of
analysis. Bmc Psychiatry 16(1), 90.

ro
Gurovich, I., Lyubov, E., 2002. The economic burden of schizophrenia in Russia. European

Psychiatry 17(02), 149-149.

-p
Guy., W., 1976. ECDEU Assessment Manual for Psychopharmacology—Revised (DHEW
re
Publ No ADM 76-338). .

Hogan, T.P., Awad, A.G., Robin, E., 1983. A self-report scale predictive of drug compliance in
lP

schizophrenics: reliability and discriminative validity. Psychological Medicine 13(1), 177.

Hong, L.S., Houston, J.P., Adams, D.H., Kinon, B.J., 2007. Association of acute symptoms
na

and compliance attitude in noncompliant patients with schizophrenia. Journal of Clinical

ur

Psychopharmacology 27(4), 392-394.

Hu, L.-T., Bentler, P.M., 1998. Cutoff criteria for fit indexes in covariance structure analysis:
Jo

Conventional criteria versus new alternatives. Structural Equation Modeling A Multidisciplinary

Journal 3(4), 55-61.

Hui, C.L., Chen, E.Y., Kan, C., Yip, K., Law, C., Chiu, C.P., 2006. Anti-psychotics adherence

among out-patients with schizophrenia in Hong Kong. Keio J Med 55(1), 9-14.
Jaeger, S., Pfiffner, C., Weiser, P., Kilian, R., Becker, T., Längle, G., Eschweiler, G.W.,

Croissant, D., Schepp, W., Steinert, T., 2012. Adherence styles of schizophrenia patients

identified by a latent class analysis of the Medication Adherence Rating Scale (MARS): A six-

month follow-up study. Psychiatry Research 200(2-3), 83-88.

Jeste, S.D., Patterson, T.L., Palmer, B.W., Dolder, C.R., Goldman, S., Jeste, D.V., 2003.

Cognitive predictors of medication adherence among middle-aged and older outpatients with

schizophrenia. Schizophrenia Research 63(1), 49-58.

of
Johnson, M.J., Williams, M., ., Marshall, E.S., 1999. Adherent and nonadherent medication-

ro
taking in elderly hypertensive patients. Clinical Nursing Research 8(4), 318.

Kao, Y.C., Liu, Y.P., 2010. Compliance and schizophrenia: the predictive potential of insight
-p
into illness, symptoms, and side effects. Comprehensive Psychiatry 51(6), 557-565.
re
Kim, J., Ozzoude, M., Nakajima, S., Shah, P., Caravaggioa, F., Iwata, Y., De Luca, V., Graff-

Guerrero, A., Gerretsen, P., 2019. Insight and medication adherence in schizophrenia:
lP

Ananalysis of the CATIE trial. Neuropharmacology doi.org/10.1016.

Kim, S.W., Yoon, J.S., Choi, S.K., 2006. Survey of medication adherence in patients with
na

schizophrenia--Korean ADHES data. Human Psychopharmacology 21(8), 533.

ur

Leu, S.H., Chou, J.Y., Lee, P.C., Cheng, H.C., Shao, W.C., Hsien, W.L., Huang, C.L., Chen,

V.C., 2015. Validity and reliability of the Chinese version of the Sheehan Disability Scale
Jo

(SDS-C). Asia-Pacific Psychiatry 7(2), 215–222.

Liang, D., Mays, V.M., Wei-Chin, H., 2018. Integrated mental health services in China:

challenges and planning for the future. Health Policy & Planning 33, 107-122.

Maclaughlin, E.J., Raehl, C.L., Treadway, A.K., Sterling, T.L., Zoller, D.P., Bond, C.A., 2005.
Assessing Medication Adherence in the Elderly. Drugs Aging 22(3), 231-255.

Mokkink, L.B.T., C.B. Patrick, D.L.Alonso,J. Stratford, P.W. Knol, D.L. Bouter, L.M. de

Vet,H.C., 2010. The COSMIN checklist for assessing the methodological quality of studies on

measurement properties of health status measurement instruments: an international Delphi

study. Quality of Life Research 19(4), 539-549.

Moreira, I.C., Bandeira, M., Pollo, T.C., Oliveira, M.S.D., 2014. Cross-cultural adaptation to

Brazil of Medication Adherence Rating Scale for psychiatric patients. J Bras Psiquiatr 63(4),

of
273-280.

ro
Morisky, D.E., Green, L.W., Levine, D.M., 1986. Concurrent and predictive validity of a self-

reported measure of medication adherence. Medical Care 24(1), 67-74.

-p
Mueller, R.M., Lambert, M.J., Burlingame, G.M., Construct Validity of the Outcome
re
Questionnaire: A Confirmatory Factor Analysis. Journal of Personality Assessment 70(2),

248-262.
lP

Ren, Z., Wang, H., Feng, B., Gu, C., Ma, Y., Hong, C., Li, B., Liu, L., 2016. An exploratory

cross-sectional study on the impact of education on perception of stigma by Chinese patients

na

with schizophrenia. Bmc Health Services Research 16(1), 210.

ur

Schulz, M., Gray, R., Spiekermann, A., Abderhalden, C., Behrens, J., Driessen, M., 2013.

Adherence therapy following an acute episode of schizophrenia: A multi-centre randomised

Jo

controlled trial. Psych Pflege 19(04), 222-223.

Sendt, K.V., Tracy, D.K., Bhattacharyya, S., 2015. A systematic review of factors influencing

adherence to antipsychotic medication in schizophrenia-spectrum disorders. Psychiatry

Research 225(1-2), 14-30.

Sowunmi, O., Onifade, P., 2020. Psychometric Evaluation of Medication Adherence Rating

Scale (MARS) among Nigerian Patients with Schizophrenia Nigerian Journal of Clinical

Practice DOI: 10.4103.

Stewart, R.B., Caranasos, G.J., 1989. Medication compliance in the elderly. Medical Clinics of

North America 73(6), 1551.

Summerhayes, M., 2008. National Institute for Health and Clinical Excellence，Encyclopedia

of Cancer. Springer Berlin Heidelberg.

of
Thompson, K., ., Kulkarni, J., ., Sergejew, A.A., 2000. Reliability and validity of a new

ro
Medication Adherence Rating Scale (MARS) for the psychoses. Schizophrenia Research

42(3), 241-247.
-p
Vasconcelos, S.C., Sougey, E.B., Frazão, I.D.S., Turner, N.E., Ramos, V.P., Lima, M.D.D.C.,
re
2016. Cross-cultural adaptation of the drug-taking confidence questionnaire drug version for

use in Brazil. Bmc Medical Research Methodology 16(1), 55.

lP

Verdoux, H., ., Lengronne, J., ., Liraud, F., ., Gonzales, B., ., Assens, F., ., Abalan, F., ., Os,

J., Van, 2010. Medication adherence in psychosis: predictors and impact on outcome. A 2-
na

year follow-up of first-admitted subjects. Acta Psychiatrica Scandinavica 102(3), 203-210.

ur

Viguera, A.C., Baldessarini, R.J., Hegarty, J.D., van Kammen, D.P., Tohen, M., 1997. Clinical

risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Archives
Jo

of General Psychiatry 54(1), 49.

WHO, 2003. Adherence to long-term therapies. World Health Organization.

WHO, 2018. International classification of diseases for mortality and morbidity statistics (11th

Revision). Retrieved from https://icd.who.int/browse11/l-m/en.

Wong, D.F.K., Cheng, C.-W., Zhuang, X.Y., Ng, T.K., Pan Shu-Man., He Xuesong., Ada, P.,

2017. Comparing the mental health literacy of Chinese people in Australia, China, Hong Kong

and Taiwan: Implications for mental health promotion Psychiatry Research 256, 258-266.

Xiang, Y.T., Weng, Y.Z., Leung, C.M., Tang, W.K., Ungvari, G.S., Gerevich, J., 2007. Clinical

and social determinants of psychotropic drug prescription for schizophrenia outpatients in

China. Prog Neuropsychopharmacol Biol Psychiatry 31(3), 756-760.

Yang, J., Ko, Y.H., Paik, J.W., Lee, M.S., Han, C., Joe, S.H., Jung, I.K., Jung, H.G., Kim,

of
S.H., 2012. Symptom severity and attitudes toward medication: impacts on adherence in

ro
outpatients with schizophrenia. Schizophrenia Research 134(2-3), 226-231.

Yen, C.F., Chen, C.S., Chih-Hung, K.O., Yeh, M.L., Yang, S.J., Yen, J.Y., 2010. Relationships
-p
between insight and medication adherence in outpatients with schizophrenia and bipolar
re
disorder: prospective study. Psychiatry & Clinical Neurosciences 59(4), 403-409.

Yujing, Sun, Mingliang, Wang, Yuqiu, Zhou, Lina, Hui, Zhang, Yumei, 2019. The mediating
lP

effect of family function and medication adherence between symptoms and mental disability

among Chinese patients with schizophrenia: a cross-sectional study. Psychology Health &
na

Medicine. 24(5), 559-569.

ur

Zemmour, K., Tinland, A., Boucekine, M., Girard, V., Loubiere, S., Resseguier, N., Fond, G.,

Auquier, P., Boyer, L., French Housing First Study, G., 2016. Validation of the Medication
Jo

Adherence Rating Scale in homeless patients with schizophrenia: Results from the French

Housing First experience. Scientific reports 6, 31598.

Figure 1

Three-factor model of the Chinese language version of MARS – Factor loadings and correlations

between factors estimated by the Maximum Likelihood (ML) estimation

of
ro
-p
re
lP
na
ur
Jo
Table 1
Socio-demographic and clinical characteristics of patients affected by schizophrenia with an
episodic course in the study
Sample size
n=1189
Source of patients
Outpatient / Inpatient 649 / 540
Socio-demographic information

622（52.3）
Gender (female): n (%)
Age (years): mean (SD) 34.22 (12.29)
Marital status (single): n (%) 656 (55.2)
Education (years): mean (SD) 12.25 (3.34)

of
Steady income: n (%) 402 (33.8)
Living alone: n (%) 124 (10.4)
Clinical characteristics

ro
CGI-S: mean (SD) 4.74 (2.91)
SDS-C total score: mean (SD) 17.58 (7.98)

SDS-C “work/school activities”: mean (SD)

SDS-C “social functioning”: mean (SD)
SDS-C “family relationships”: mean (SD)
-p 5.88（2.81）

5.99 (2.73)
5.74 (2.76)
re
Illness duration (years): mean (SD) 8.04 (9.27)

≥5years: n (%) 580（48.8）

lP

Number of relapses: mean (SD) 2.04 (4.03)

Current stage of illness (acute period): n (%) 741 (62.3)
Medication situation
na

124 (10.4）
Drug withdrawal: n (%)
Single-drug treatment, n (%) 617 (51.9)
Note: CGI-S: Clinical Global Impression-Severity of illness; SDS-C: Sheehan Disability Scale- Chinese
ur

version.
Jo
 Table 2
Frequencies of responses on the MARS among patients affected by schizophrenia with an episodic
course in the study
Item Yes No
n (%) n (%)
1 Do you ever forget to take your medication? 217(18.3) 972(81.7)
2 Are you careless at times at taking medication? 471(39.6) 718(60.4)
3 When you feel better do you sometimes stop taking 281(23.6) 908(76.4)
your medication?

of
4 Sometimes if you feel worse when you take the 429(36.1) 760(63.9)
medication do you stop taking it?
5 I take my medication only when I am sick. 560(47.1) 629(52.9)

ro
6 It is unnatural for my mind and body to be controlled 498(41.9) 691(58.1)
by medication.
7 My thoughts are clearer on medication. 507(42.6) 682(57.4)
8
9
By staying on medication, I can prevent getting sick.
I feel weird, like a zombie, on medication.
-p
632(53.2)
594(50.0)
557(46.8)
595(50.0)
10 Medication makes me feel tired and sluggish. 185(15.6) 1004(84.4)
re
1
lP
na
ur
Jo
Table 3
The relationship between MARS and socio-demographic information
Medication Attitude to
Negative side-effects and MARS total
adherence taking
attitudes to psychotropic score
behavior medication
medication（2 items） （10 items）
（4 items） （4 items）

Mean (SD) 1.18(1.37) 1.85(1.42) 0.66(0.69) 3.68(2.90)

Independent-samples T test
Gender
Male 1.19(1.40) 1.96(1.44) 0.69(0.71) 3.84(2.95)
Female 1.16(1.34) 1.74(1.41) 0.62(0.67) 3.53(2.85)
t 0.35 2.64** 1.81 1.89

of
Marital status
Single 1.26(1.41) 1.93(1.42) 0.67(0.70) 3.87(2.93)
Married 1.16(1.34) 1.82(1.43) 0.65(0.69) 3.63(2.89)

ro
t 1.229 1.168 0.57 1.28
Steady income
Yes 1.39(1.40) 2.07(1.43) 0.69(0.69) 4.16(2.94)
No
t
Living alone:
1.07(1.34)
-3.75***
1.73(1.40)
-3.97***
-p0.63(0.69)
-1.47
3.43(2.86)
-4.09***
re
Yes 1.08(1.30) 1.69(1.38) 0.56(0.70) 3.33(2.76)
No 1.19(1.38) 1.87(1.42) 0.67(0.69) 3.72(2.92)
t -0.82 -1.35 -1.54 -1.41
lP

Stage of disease
Acute period 0.79(1.18) 1.39(1.29) 0.52(0.65) 2.70(2.50)
Remission period 1.81(1.43) 2.60(1.29) 0.88(0.70) 5.29(2.80)
t 12.60*** 15.73*** 8.91*** 16.07***
na

Illness duration
<5years 1.15(1.34) 1.89(1.41) 0.64(0.69) 3.67(2.80)
1.21(1.40) 1.81(1.43) 0.67(0.70) 3.68(3.01)
≥5years
ur

t -0.72 0.93 -0.92 -0.11

Pearson correlation (r)
Jo

Age -0.09** -0.09** -0.01 -0.09**

Education 0.07* 0.04 0.02 0.06
Note: MARS: Medication Adherence Rating Scale. *p < 0.05; **p < 0.01; p *** < 0.001.

31
 Table 4
The relationship between MARS and clinical characteristics
Medication Attitude to
Negative side-effects and
adherence taking MARS total score
attitudes to psychotropic
behavior medication
（10 items）
medication（2 items）
（4 items） （4 items）

Independent-samples T test
Stage of disease
Acute period 0.79(1.18) 1.39(1.29) 0.52(0.65) 2.70(2.50)

of
Remission period 1.81(1.43) 2.60(1.29) 0.88(0.70) 5.29(2.80)
t 12.60*** 15.73*** 8.91*** 16.07***
Illness duration

ro
<5years 1.15(1.34) 1.89(1.41) 0.64(0.69) 3.67(2.80)
1.21(1.40) 1.81(1.43) 0.67(0.70) 3.68(3.01)
≥5years

t
Pearson correlation (r)
MARS total score
-0.72

0.87***
0.93

0.88***
-p -0.92

0.68***
-0.11

1
re
Number of relapses -0.003 0.04 0.06* 0.03
CGI-S -0.36*** -0.42*** -0.26*** -0.43***
SDS-C “work/school activities” -0.37*** -0.46*** -0.28*** -0.46***
lP

SDS-C “social functioning” -0.37*** -0.47*** -0.28*** -0.47***

SDS-C “family relationships” -0.38*** -0.47*** -0.30*** -0.48***
SDS-C total score -0.39*** -0.48*** -0.30*** -0.49***
na

Note: MARS: Medication Adherence Rating Scale; CGI-S: Clinical Global Impression-Severity of illness; SDS-
C: Sheehan Disability Scale- Chinese version. *p < 0.05; **p < 0.01; p *** < 0.001.
ur
Jo

32
Table 5
Logistic regression of predictors of poor adherence to medication in the sample of patients affected by
schizophrenia with an episodic course in China
Wald p OR 95%CI
Age 12.22 <0.001 1.04 1.02-1.06
Unsteady income 12.18 <0.001 1.79 1.29-2.49
Acute period 103.57 <0.001 4.23 3.21-5.59
CGI-S 4.53 0.03 1.44 1.03-2.01

of
Note: MARS: Medication Adherence Rating Scale; CGI-S: Clinical Global Impression-Severity of illness.

ro
-p
re
lP
na
ur
Jo

33