Research paper
Long-term use of valproic acid and the prevalence of cancers in bipolar disorder patients in a Taiwanese population: An association analysis using the National Health Insurance Research Database (NHIRD)

https://doi.org/10.1016/j.jad.2018.02.047Get rights and content

Highlights

  • Epigenetic events play a major role in the carcinogenesis of many cancers.

  • VPA associated to higher risk of genitourinary cancer in the treatment duration < 1 year in bipolar disorder.

  • A role of VPA in cancer prevention was not found in bipolar disorder patients.

Abstract

Background

Epigenetic events play a major role in the carcinogenesis of many cancers. A retrospective cohort study had been performed to evaluate the effects of exposure to the anticonvulsant agent valproic acid (VPA), a histone deacetylase inhibitor, on the risk of developing cancers.

Methods

The study was based on the 1998 through 2009 National Health Insurance Research Database (NHIRD), provided by the Taiwan National Health Research Institute. Patients with a diagnosis of bipolar disorder (ICD-9-CM codes 296.0, 296.1, 296.4–8) from 1998 to 2009 were identified. VPA and lithium were the primary index drugs. Patients treated with anticonvulsants who did not use VPA or lithium were selected as the control group. Competing risk regression analysis were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) reflecting the association between use of VPA and cancer incidence.

Results

The cancer incidence of bipolar disorder patients treated with VPA was no significant difference than treated with lithium and other anticonvulsants. In subgroup analysis, VPA associated to higher risk of genitourinary cancer in the duration < 1 year group (HR: 3.49; 95%CI: 1.04, 11.67). No significant differences in other cancers incidence in any duration of VPA treatment.

Limitations

The cancer prevalence in selected bipolar disorder patients was still low. The sample size was not enough for some types of cancer.

Conclusions

A role of VPA in cancer prevention was not found in this study. An increased subgroup risk of genitourinary cancer was observed.

Introduction

Epigenetic changes, involving either DNA methylation or changes in chromatin structure (Herman and Baylin, 2003, McCabe et al., 2009), are early carcinogenic events in many cancer sites, including the lung (Belinsky et al., 2002, Belinsky et al., 2006, Palmisano et al., 2000), prostate (Alumkal et al., 2008, Nelson et al., 2007), colon (Brandes et al., 2005, Schuebel et al., 2007), bladder (Hoffman and Cairns, 2011, Kim and Kim, 2009), and head and neck (Wong et al., 2012, Ha and Califano, 2006, Hoque et al., 2008). DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are major epigenetic mediators for which pharmacologic inhibitors are available. In animal models, inhibition of DNMTs and HDACs has been shown to prevent the development of both lung (Belinsky et al., 2003) and prostate cancers (McCabe et al., 2006). In addition, HDACs 1, 2, and 3 are not only associated with increased DNMT1 protein levels in patients with lung cancer as compared with normal controls, but are also directly responsible for stabilizing DNMT1 expression (Brodie et al., 2014). Valproic acid (VPA), which is widely used among patients with psychiatric or neurologic disorders as a mood stabilizer or antiepileptic drug, has recently been reported to act as a class 1 HDAC inhibitor (Gottlicher et al., 2001). HDAC inhibition is observed at VPA concentrations as low as 40 μg/mL (Brodie et al., 2014). Epigenetic therapies such as the DNMT inhibitor azacytidine and the HDAC inhibitor Vorinostat have proven effective against several hematologic malignancies such as myelodysplastic syndrome (Lubbert et al., 2011, Fenaux et al., 2009, Kantarjian et al., 2006) and cutaneous T-cell lymphomas (Olsen et al., 2007). A recent phase 2 study demonstrated that the combination of azacytidine with HDAC inhibitor Entinostat for the treatment of patients with lung cancer showed promising results (Juergens et al., 2011). However, to the best of our knowledge, there is no clinical evidence to date of an association between the use of HDAC inhibitors and cancer risk. Given the importance of epigenetic mechanisms in early carcinogenesis (Sharma et al., 2010) and preclinical evidence supporting the anticarcinogenic effects of VPA (Duenas-Gonzalez et al., 2008), we conducted a retrospective cohort study to evaluate the risks of various malignancies in relation to use of VPA in bipolar disorder patients.

Section snippets

Data source

We used a longitudinal health insurance database, the National Health Insurance Research Database (NHIRD), provided by the Taiwan National Health Research Institute. Taiwan launched its compulsory social insurance program, National Health Insurance (NHI), to provide health care for all the island's residents in 1995. The annual coverage rate of the NHI program has ranged from 96.1% to 99.6%, with more than 20 million Taiwanese residents enrolled since 1997.

In the Taiwan NHI system, the

Results

Data of a total of 22,865 participants who had been diagnosed with bipolar disorder during 1998–2009 were extracted from the longitudinal health insurance database; 1362 patients were excluded due to age < 18 or death caused by any cancer within 90 days after the index date. For 3528 patients, there were no records of VPA or lithium treatment; 3416 and 925 patients used VPA only and lithium only after the initial diagnosis of bipolar disorder, respectively. The sampling flow was as shown in

Discussion

It is known that HDAC inhibition, such as by VPA, can lead to reduced levels of DNMT1 expression (Du et al., 2010). Class I HDAC-mediated stabilization of DNMT1 protein expression is an early event in smoke carcinogen-induced transformation of bronchial epithelial cells (Brodie et al., 2014). This is associated with uncoupling of DNMT1 expression from the usually tight limitation to the S-phase of the cell cycle, leading to de novo methylation and epigenetic silencing of tumor suppressor genes.

Acknowledgements

None.

Ethical considerations

This research was conducted in accordance with the Helsinki Declaration. Ethical approval for this study was obtained from the Research Ethic Committee of Chang Gung Memorial Hospital, Keelung division.

Data sharing statement

All register information was provided by the Taiwan National Health Research Institute. Information about how to apply for data from Taiwan health care registers is available at http://www.nhri.org.tw.

References (33)

  • M. Gottlicher et al.

    Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells

    EMBO J.

    (2001)
  • J. Hallas et al.

    Cancer risk in long-term users of valproate: a population-based case-control study

    Cancer Epidemiol. Biomark. Prev.

    (2009)
  • J.G. Herman et al.

    Gene silencing in cancer in association with promoter hypermethylation

    N. Engl. J. Med.

    (2003)
  • A.M. Hoffman et al.

    Epigenetics of kidney cancer and bladder cancer

    Epigenomics

    (2011)
  • M.O. Hoque et al.

    Genome-wide promoter analysis uncovers portions of the cancer methylome

    Cancer Res.

    (2008)
  • R.Y. Huang et al.

    Use of lithium and cancer risk in patients with bipolar disorder: population-based cohort study

    Br. J. Psych.

    (2016)
  • Cited by (0)

    1

    These authors contributed equally to this work.

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