Volume 6 Issue 7 - November 21, 2008
Using the Claims Databases of National Health Insurance to Assess the Risk of Extrapyramidal Syndrome among Antipsychotics
Yea-Huei Kao Yang

Associate professor of Institute of Clinical Pharmacy, College of Medicine, National Cheng Kung University
Email: yhkao@mail.ncku.edu.tw

Clinical Pharmacology and Therapeutics 2007, 81(4):586-594

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In the treatment of schizophrenia, antipsychotic drugs (antipsychotics) are the essential interventions, which have been broadly classified into two groups. The older agents are defined as the first-generation antipsychotics (FGAs), such as chlorpromazine, haloperidol, and thioridazine, also referred to as typical or conventional antipsychotics. Newer agents are described as the second-generation antipsychotics (SGAs) or atypical, novel antipsychotics, which include clozapine, risperidone, olanzapine, quetiapine, and zotepine. The mechanism of action is believed to be through blocking the activities of dopamine in central nervous system. However, the blocking of dopamine in the cortex could lead to extrapyramidal syndrome (EPS) and movement disorders, such as acute dystonias, parkinsonism, and tremor. It has been suggested that the risk of EPS and tardive dyskinesia (TD) was associated with the degree of binding between antipsychotics and dopamine D2 receptors. A stronger affinity with D2 receptors is observed with FGAs, and leads to EPS side effects. Unlike the FGAs, the SGAs can rapidly dissociate from the D2 receptors and therefore are generally considered as a safer choice with fewer EPS. SGAs also have a high affinity for 5-HT2A receptors, which might attenuate the dopamine activity in the striatum and thus reduce the potential for EPS and TD.

Although FGAs and SGAs were hypothesized to have different risk of EPS, the available studies to compare the two generations have been limited in number and scope. Most studies that examined the relationship were based on clinical trials with selective subjects treated in highly controlled environments. To provide estimates in a “real world” scenario, we used the claims data from the National Health Insurance (NHI) in Taiwan to evaluate the EPS risk associated with FGAs, SGAs, and dosage in hospitalized patients with a diagnosis of schizophrenia.

The National Health Insurance (NHI) was implemented in Taiwan in 1995. Most health services and pharmaceuticals are covered by NHI, with various copayment rates from the patients. All the claims data are routinely compiled by the Bureau of NHI (BNHI) for reimbursement and administrative purposes. A five-year dataset from year 1999 to 2003 was obtained from BNHI to carry out this study. All hospitalizations with a diagnosis of schizophrenia (ICD-9-CM code 295) were extracted for analysis. In order to analyze the medication use, we have established a electronic interface to transform the pharmaceutical code in NHI into the hierarchical and therapeutic classification. The Anatomical Therapeutic Chemical (ATC) Classification with Defined Daily Dose (DDD) is used for the coding system, which is maintained by World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology. Drugs that are relevant to this study were identified from the dataset. These include FGAs, SGAs, antidepressants, antiepileptics and lithium (or mood stabilizers), anxiolytics, hypnotics and sedatives, and anti-Parkinson drugs (APDs).

A total of 98,320 hospitalizations from 40,561 patients with a schizophrenia diagnosis were identified. Among the hospitalizations, 59% were male patients and over 60% were between 25-44 years old. Overall, the five-year data showed that about half of the hospitalizations were prescribed with FGAs only (54.1%), about one-fourth (26.5%) used both FGAs and SGAs, while a small portion used only the SGAs (17.2%). However, the longitudinal trend during the study period indicated that the prescribing of FGAs was decreasing while both the SGAs alone and combinational use of FGAs and SGAs were increasing. Evidence from clinical trials had indicated that SGAs were more effective against negative symptoms and had a lower risk of causing EPS than FGAs. The better safety profile of SGAs could have led to the increased prescribing of these drugs to substitute the FGAs in our study duration, which in turns could have decreased EPS and the need of APDs over the years.

To compare the risk of EPS side effects among the FGAs and SGAs, the co-prescribing of APDs was used as an indicator of presence of EPS. Clinically, when patients are suffered from EPS, physicians would prescribe APDs to alleviate the symptoms. A subset of 37,483 hospitalizations using only one of the 14 antipsychotics was extracted to estimate the prevalence of EPS of individual antipsychotics. Over the years, co-prescribing of APDs has decreased, and a 15% reduction was observed between 1999 and 2003. Longer length of stay appears to increase the co-prescribing of APDs. In terms of antipsychotics, it was found that 84.6% FGA hospitalizations had co-prescribing of APD as compared to 47.8% in the SGA group. The relative risk of APD prescribing in the FGA hospitalization was approximately 1.8 times greater than in the SGA hospitalizations. Hospitalizations that used a higher than recommended dose of antipsychotics had a greater risk of APD prescribing as compared to those used recommended or lower dose of antipsychotics. The concurrent use of psychotropic medications, including hypnotics and sedatives, anxiolytics, antidepressant, and mood stablizers, also increased the risk of APDs prescribing.

Among the SGAs, the one with the lowest APD co-prescribing rate was clozapine (30.9%) and the highest was risperidone (74.6%). Among the FGAs, the rate ranged from 66.4% in thioridazine to 96.3% in loxapine. SGAs are generally considered to have lower risk of EPS than FGAs, however, in the case of risperidone, our study did not find a lower EPS risk. Furthermore, we found that not all SGAs have the similar risk. Some SGAs have a higher EPS risk than the others. Our findings suggest that physicians should be aware of the EPS risk when prescribing FGAs and some high risk SGAs (e.g., zotepin and risperidone) to schizophrenic patients. We found that the APDs co-prescribing rate in FGA hospitalizations was almost twice of the SGAs. The 48% APD co-prescribing rate among SGAs in this study was similar to the 42 percent reported by Porcyshyn. According to a survey on the safety of psychiatric medicine in Germany, the incidence rate of involuntary movement disorders was lower in clozapine and higher in risperidone among SGAs, and lower for perazine and higher for haloperidol among FGAs. In our study, a similar pattern was found for clozapine and risperidone. The two studies seem to support the use of APD co-prescribing as an indicator for EPS.

Five antipsychotics were found to have a significant dose-response relationship with the rate of co-prescribing APD, namely, thioridazine, chlorpromazine, sulpiride, haloperidol, and rispeidone. (Table) Zotepine and risperidone had higher APD co-prescription rates (e.g., 71.8% in zotepine and 74.6% in risperidone) than the conventional antipsychotic drugs (e.g., 66.4% in thioridazine and 69.2% in chlorpromazine). Previous literature suggests that extrapyramidal adverse effects are more frequent when a higher than recommended dose of antipsychotics was used, especially in FGAs. In our study, we found that most of the PDDs of FGA prescriptions were greater than one DDD, which is an indication that they were prescribed in higher than recommended doses and could be responsible, to some degree, for the higher APD rate in FGAs than in SGAs. It is possible that the more prevailing use of higher than recommended doses in FGA prescribing also contributes to the differential EPS side effect between FGAs and SGAs. The finding is consistent with previous studies and further supports a quantitative correlation between doses used and EPS incidence rate. This dose-response relationship could be considered in clinical decision-making. Although SGAs have claimed to have a reduced EPS based on their pharmacological property, current literature does not provide a strong support to the claim.
Table. Antipsychotics dosage associated with anti-Parkinson drugs: results from simple logistic regression

Although APDs are often used with antipsychotics to prevent or treat EPS, there are still uncertainties about their appropriate prescribing. For examples, some authors recommended that APDs should not be used for more than ten days when indicated to prevent EPS; while others suggested that the medications could be used as maintenance therapy in the treatment of EPS. As such, the co-prescribing rate with antipsychotics varied significantly (range from 30 to 93 percent) in the literature. The safety of APDs has also been questioned. Previous studies, for example, have reported that the anticholinergic toxic effects of APDs can impair memory of schizophrenic patients. This memory deficit might damage the cognitive ability of patients, which in turns could negatively impact the psycho-social functioning and rehabilitation of the patients and interfere with their successful return to the community. Our study found the probability of APD co-prescribing to be as high as 80 percent; it follows that some patients might be suffered from the unwanted effects of APDs. Unfortunately, due to the limitations of the administrative database, we were unable to evaluate the adverse impacts of APDs on patients with schizophrenia.
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