Hyperglycemic adverse events following antipsychotic drug administration in spontaneous adverse event reports

Background Antipsychotics are potent dopamine antagonists used to treat schizophrenia and bipolar disorder. The aim of this study was to evaluate the relationship between antipsychotic drugs and adverse hyperglycemic events using the FDA Adverse Event Reporting System (FAERS) database. In particular, we focused on adverse hyperglycemic events associated with atypical antipsychotic use, which are major concerns. Findings We analyzed reports of adverse hyperglycemic events associated with 26 antipsychotic drugs in the FAERS database from January 2004 to March 2013. The Standardized Medical Dictionary for Regulatory Activities Queries (SMQ) preferred terms (PTs) was used to identify adverse hyperglycemic events. The number of adverse hyperglycemic reports for the top eight antipsychotic drugs, quetiapine, olanzapine, risperidone, aripiprazole, haloperidol, clozapine, prochlorperazine, and chlorpromazine was 12,471 (28.9%), 8,423 (37.9%), 5,968 (27.0%), 4,045 (23.7%), 3,445 (31.5%), 2,614 (14.3%), 1,800 (19.8%), and 1,003 (35.7%), respectively. The reporting ratio increased with co-administration of multiple antipsychotic drugs. For example, adverse hyperglycemic events represented 21.6% of reports for quetiapine monotherapy, 39.9% for two-drug polypharmacy, and 66.3% for three-drug polypharmacy. Conclusion Antipsychotic drug polypharmacy may influence signal strength, and may be associated with hyperglycemia. After considering the causality restraints of the current analysis, further robust epidemiological studies are recommended.


Findings
Background Antipsychotics are potent dopamine antagonists used to treat schizophrenia and bipolar disorder [1]. Antipsychotics are categorized as first-generation antipsychotics (typical) and second-generation antipsychotics (atypical). Several studies have reported abnormal glucose metabolism during antipsychotic drug treatment [2][3][4]. In 2002, diabetic ketoacidosis and coma were reported after olanzapine and quetiapine treatment in Japan [5]. Furthermore, the Food and Drug Administration (FDA) asked manufacturers of atypical antipsychotic (AAP) drugs to add a warning to drug labels regarding the increased risk of hyperglycemia and diabetes in 2004 [6]. Thus, hyperglycemia due to antipsychotic drug administration is a serious clinical problem.
According to clinical practice guidelines, AAPs should be used as the first and second line of treatment following the first schizophrenic episode [7][8][9][10]. However, treatment resistance and poor efficacy continue to be a significant clinical problem [2,11,12]. Since antipsychotic polypharmacy is suggested after failure of antipsychotic monotherapy [7,9,10], multiple antipsychotic drugs have been frequently prescribed [2,11,13]. A case-control study indicated that the administration of multiple antipsychotics increases the risk of diabetes mellitus when using AAPs [1]. Several studies also demonstrated the effect of antipsychotic polypharmacy on the adverse events; however, the effect of antipsychotic polypharmacy on hyperglycemia remains unclear [11][12][13][14].
The FDA Adverse Event Reporting System (FAERS) is a spontaneous reporting system for adverse events. It is the largest and best-known database worldwide, and reflects the realities of clinical practice. Therefore, the FAERS database is one of the primary tools used in pharmacovigilance. The aim of this study was to evaluate the relationship between antipsychotic drugs and adverse hyperglycemic events using the FAERS database. To our knowledge, this study is the first to evaluate the effect of antipsychotic polypharmacy on adverse hyperglycemic events using the FAERS database.

Methods
Data from the FAERS database from January 2004 to March 2013 were obtained from the FDA website. The FAERS database structure complies with the International Conference on Harmonization (ICH) E2B. We analyzed 26 antipsychotic drugs associated with hyperglycemia (Table 1). Since drug names in the FAERS database are registered arbitrarily, DrugBank, a reliable drug database, was utilized as a dictionary for the batch conversion and compilation of drug names (Table 2). We followed the FDA's recommendation to adopt the most recent case number in order to identify duplicate reports from the same patient and excluded these from analysis.
Adverse events in the FAERS database are coded according to the terminology preferred by the Medical Dictionary for Regulatory Activities (MedDRA). The Standardized MedDRA Queries (SMQ) index is widely accepted and utilized in the analysis of the FAERS database [15]. We utilized the SMQ for hyperglycemia/new onset diabetes mellitus events (SMQ code: 20000041). We selected 93 Preferred Terms (PTs), which are summarized in Table 3.
For signal detection, we calculated the reporting odds ratio (ROR), an established pharmacovigilance index, using a disproportionality analysis. The ROR is calculated as a*d/b*c ( Figure 1). The ROR is the ratio of the odds of reporting a specific adverse event versus all other adverse events for a given drug (antipsychotics), compared to the reporting odds for all other drugs present in the database. RORs were expressed as point estimates with 95% confidence intervals (CI). The detection of a signal was dependent on the signal indices exceeding a predefined threshold. Safety signals were considered significant when the ROR estimates and the lower limits of the 95% CI were greater than 2 [16]. We analyzed the effects of monotherapy, two-drug polypharmacy, and three-drug polypharmacy. Data analyses were performed using JMP 9.0 (SAS Institute Inc., Cary, NC, USA).

Discussion
Our results suggest that several antipsychotics increase adverse hyperglycemic events, and that antipsychotic polypharmacy may influence these events using the FAERS database.
In a previous cohort study, olanzapine and clozapine were associated with increased risk for type 2 diabetes [1,2,17]. Citrome et al. suggested that exposure to multiple AAPs significantly increased the risk of treatmentemergent diabetes mellitus, as compared to TAPs [1]. However, they discussed that their study design does not permit the quantification of differences between AAPs and the risk of emergent diabetes [1]. Another research group reported that AAP administration results in a small increase, as compared to TAP administration [18]. In our study, the reporting ratio of adverse hyperglycemic events in AAPs (      AAP administration and TAP administration using the reporting ratio of hyperglycemic adverse events. The lower limits of the ROR 95% CI for olanzapine, quetiapine, and haloperidol monotherapy were greater than 2 (Table 4). Baker et al. reported that olanzapine (AAP), clozapine (AAP), and risperidone (AAP) were associated with hyperglycemic adverse events, whereas aripiprazole (AAP), haloperidol (TAP), and ziprasidone (AAP) had a low association in the FAERS database. We do not have a conclusive explanation for the differences in reporting ratio between the previous report [19] and our findings. One plausible reason could be differences in the terms selected for adverse hyperglycemic events in the MedDRA database. Our study used 93 PTs, whereas Baker et al. In this study, each reporting ratio and ROR increased with increasing number of drugs administered ( Table 4). The ROR of the three-drug polypharmacy had the highest value for every antipsychotic. Therefore, antipsychoticinduced adverse hyperglycemic events may be influenced by the number of drugs administered. However, the lower limit of the clozapine ROR 95% CI was less than 2. Since the administration of clozapine is not recommended as a first-line treatment [20], physicians may be unlikely to use clozapine in diabetic patients. Therefore, the signal for adverse hyperglycemic events following clozapine might be not detected. Antipsychotic monotherapy and polypharmacy to treat schizophrenia and bipolar disorder has been compared to understand its risk-benefit profile [11,14]. In general, polypharmacy using antipsychotics is not recommended [7][8][9]. Baker et al. evaluated the adverse events signals for each AAP. However, they did not evaluate the effect of antipsychotic polypharmacy on hyperglycemia. Our results suggest that antipsychotic polypharmacy may influence adverse hyperglycemic events. Therefore, clinician should comply with guidelines [7][8][9][10] and monitor for adverse polypharmacy-induced hyperglycemic events.
The mechanism by which antipsychotics induce adverse hyperglycemic events remains unclear. AAPs are associated with clinically significant weight gain, and have raised significant concerns regarding possible association with hyperglycemia and type 2 diabetes [1,11,18,19]. Obesity or diabetes may be confounders for adverse hyperglycemic events. However, detailed information, including patient  background and diagnosis, is not included in the FAERS database. Therefore, it is difficult to define and stratify the patients investigated.
The FAERS database is subject to various biases, including the exclusion of healthy individuals, the lack of denominator, and confounding factors [21]. Because of these deficits within the spontaneous reporting, ROR do not allow for risk quantification. Rather, the RORs offer a rough indication of the signal strength [21]. Therefore, special attention has to be paid to the interpretation of results from the FAERS database. Other epidemiological studies are required to determine the true risk of adverse hyperglycemic events.
Despite the limitations inherent to spontanesous reporting, we obtained reasonable results in the context of the reported literature. The reporting ratio and ROR suggested an association between antipsychotic drugs and hyperglycemic adverse events, and the reporting ratio was increased with an increase in the number of co-administered antipsychotic drugs. Our study indicates the importance of comparing drug safety profiles using post-marketing realworld data. This information could be useful to improve schizophrenia and bipolar disorder management.   Submit your manuscript at www.biomedcentral.com/submit