Risk factors for relapse in patients with first-episode schizophrenia: Analysis of the Health Insurance Review and Assessment Service data from 2011 to 2015

Schizophrenia has a prevalence of approximately 1%, and a considerable proportion of patients are resistant to treatment after they have progressed to the chronic stage of the disease. The quality of life of patients with chronic schizophrenia is diminished due to cognitive dysfunction, paresthesia, disordered thoughts, deterioration of emotional control, and negative symptoms [1, 2]. There is a great deal of evidence that early intervention should be conducted after the first episode of schizophrenia to ameliorate symptoms and improve the overall prognosis. The first 5 years is the most important period following the initial episode of a mental illness and is referred to as ‘the critical period’. Psychosocial and biological interventions performed during this period have been shown to positively influence the prognosis of the disease [3, 4]. Pharmacotherapy is considered to be the most important element of schizophrenia treatment, and roughly 80% of patients with first-episode schizophrenia improve within 6 months of starting medication [5, 6]. Gaebel et al. revealed that 91.5% of patients showed symptomatic remission, and 58.6% of patients remained in remission through their 1-year follow-up [7].

Once schizophrenia recurs, the psychiatric symptoms appear repeatedly, and hospitalization is recommended in many cases. The readmission rate is directly proportional to the rate of relapse, and hospitalization after treatment can thus be considered an index of relapse [8, 9]. One study reported that 41.0% of patients with schizophrenia were readmitted to a hospital within 1 year of discharge [10]. Another study indicated that 42.0% of patients with first-episode schizophrenia were readmitted to a hospital within 2 years [11]. Similarly, a Korean study also showed that 33.3–35.6% of patients with schizophrenia were re-hospitalized within 2 years [12, 13]. Collectively, the results from Lin et al., Sara et al., Kim et al. and Lee et al. studies may point to the possibility of relapse in patients with schizophrenia. Furthermore, relapse worsens a patient’s future response to treatment, lowers their quality of life, leads to social isolation, and raises social costs [14]. Relapse in younger patients with schizophrenia can have an even greater impact on their future lives, separating them from schools, workplaces, friends, and social communities [15]. Treatment with an antipsychotic drug is the most promising strategy for relapse prevention, and the risk of relapse is inversely proportional to medication adherence. Therefore, many studies have explored the correlation between relapse and treatment-related variables such as medication adherence [16‐18]. There are, however, no studies examining institutional factors such as the type of medical institution where treatment was provided. Moreover, studies on relapse are limited to a one hospital or outpatients based study in Korea. This study investigated demographic characteristics and institutional factors of patients with first-episode schizophrenia in order to identify risk factors for relapse. Data from the HIRA was used for this study to better represent the Korean patient population.

The average age of the 4567 subjects with first-episode schizophrenia was 23.12 years. Of these, 1265 (27.7%) of patients experienced a relapse during the observation period, and significant differences were found between groups according to the type of medical institution, type of medication used, medication adherence, and the severity of symptoms. Patient characteristics including gender, age, geographic location, medical benefits, type of medical institution, type of medication used, medication adherence, and the severity of symptoms are presented in Table 1.

The average follow-up period was 11.8 months with a median of 12 months. The shortest and longest follow-up periods were 1 and 24 months, respectively. During the follow-up period of 4475.1 person-years, a total of 1265 subjects were admitted to hospitals, and the calculated rate of relapse by person-years is shown in Table 2.

This study was designed to identify factors affecting relapse in patients with first-episode schizophrenia. The total number of subjects included in this study was 4567 with a total follow-up period of 4475.1 person-years. During this observation period, 1265 patients relapsed. As a result, the factors showing a statistically significant effect on relapse were age, type of medical institution, type of medication used, medication adherence, and the severity of symptoms at the time of their initial diagnosis. In general, the HR of relapse tended to vary according to the severity of symptoms.

Looking at age, the risk for relapse appeared low in patients with a delayed age of onset. Although a previous study showed that there was no correlation between the age of onset and the risk of relapse, the present study revealed that a younger age of onset was associated with a worse prognosis [18, 27]. This observation, that the risk for relapse declined significantly with a delayed age of onset, suggests that symptoms are more severe and recurrence is more frequent in patients diagnosed at a young age. Similar results were observed even when the cases were divided by severity into inpatient and outpatient treatment groups. Wood et al. also reported the same outcomes [28]. To prevent relapse in patients with first-episode schizophrenia, early screening systems would therefore be indicated.

In the analysis by type of medical institution, the relapse HR of patients treated in community hospitals compared with those treated in tertiary hospitals was 1.17, a significantly high result. The HR decreased to 0.75 in those treated in clinics. These results may involve a selection error, however, as the type of medical institution attended after the initial episode of schizophrenia depended upon the severity of symptoms. To eliminate this possibility, we examined the data after separating patients into inpatient and outpatient treatment groups. In the outpatient group, the HR of treatment in clinics compared with treatment in tertiary hospitals yielded a significantly low result, indicating that mild cases typically visit clinics. In the inpatient group, the HR of treatment in community hospitals compared with treatment in tertiary hospitals was significantly high; inpatient treatment in clinics also showed a significantly high HR. These results may suggest that treatment in community hospitals and clinics is inferior to that provided by tertiary hospitals in terms of institutional and treatment conditions. In Korea, community hospitals and clinics are regarded as primary medical institutions, thus they are very similar from a functional point of view [29]. Lee et al. reported that the quality of Korean primary medical institutions (0.3) was much poorer than that of the UK (1.9) or Canada (1.2) [30]. In addition, the results reflect that tertiary hospitals are equipped better, because they can provide a variety of medical services compared with community hospitals and clinics in Korean healthcare system [31]. To prevent relapse in patients with first-episode schizophrenia, environmental and institutional reorganization will be required. In the Korean medical system, the private medical institutions play a major role, up to 94% [32]. In the health insurance system, the daily medical cost of treatment is fixed for Medicaid patients with schizophrenia. When the price is converted to cost per day, the costs for inpatient therapy are 50,000 won (about $44.1) [33]. In this system, the hospitals and clinics use low-cost drugs in order to increase profits. Therefore, the government needs to change the health insurance system to a fee-for-service policy. However, changing to a fee-for-service (FFS) system would require fundamental rebuild of the health insurance schemes. Thus, the government will need to consider an incentive system to improve quality of care such as quality assessment system. And it is necessary to conduct further studies to suggest more viable policy implications for the reform of the schizophrenia care system. However, including patients with health insurance, the conventional drug use compared with atypical drug use in clinics and hospital was higher than in the tertiary hospital setting [34]. This result suggests that psychiatrists operating private clinic may prefer to conventional medications, which may have an impact on treatment of patients with schizophrenia. Therefore, to improve the current uneven situation, continuing education system for psychiatrist should be strengthened as well.

The relapse HR for patients treated with other drugs compared with monotherapy with an antipsychotic was significantly high at 1.81, suggesting that antipsychotic drugs are more effective [35]. To prevent relapse, antipsychotic medications should be administered from the onset of schizophrenia, regardless of the severity of symptoms. Combination therapy with more than one antipsychotic medication is becoming more common in the treatment of schizophrenia, and its efficacy is excellent [36, 37]. There was, however, no difference in the relapse HR between monotherapy and combination therapy in this study. The result was the same after adjusting for the severity of symptoms. Thus, to prevent relapse, antipsychotic medications should be administered from the onset; providers must then decide whether to use monotherapy or combination therapy.

Analyzing relapse HR according to medication adherence, the HR of the low-level adherence group (0–50%) compared with the high-level adherence group (more than 80%) was 1.59, a significantly high result. This result was the same in both the inpatient and outpatient treatment groups. These results coincide with previous studies in that the risk of relapse decreases with a higher medication adherence [38, 39].

There are several limitations in this study. First, the data did not provide information about the actual severity of patient with schizophrenia. Therefore, this study performed subgroup analysis by classifying hospital treatment and outpatient treatment in order to exclude the effect of severity. However, it could not confirm effect of severity. Second, in this study, we used indirect measures of medication adherence. Thus, we were unable to confirm whether the patients complied with the prescribed medication or not. Further research is needed to investigate these limitations.

Despite these limitations, our study has a number of strengths. Using the HIRA data, this study confirmed the risk factor for relapse in all patients with first episode schizophrenia in Korea. The results of this study showed that necessity for change of structural, institutional factors as well as medical treatments in managing patients.

This study investigated the risk factors for relapse in patients with first-episode schizophrenia using data from the HIRA in order to best represent the Korean patient population. Approximately 28% of the 4567 patients included in this study relapsed over 4475.1 person-years. After adjusting for demographic features, the factors which increased the risk of relapse include a younger age of onset, treatment in clinics and community hospitals, use of medications other than antipsychotic drugs, reduced medication adherence, and high severity of symptoms at the initial diagnosis. The results varied, however, when we stratified by the severity of symptoms. Consequently, the results of this study suggest the need for changes in the structure of care, institutional factors, and medical treatments used to manage patients with first-episode schizophrenia in Korea. It is our hope that this study can be utilized as source material for directing therapeutic interventions and improving mental health policies in the future.