False-Negative Studies May Systematically Contaminate the Literature on the Effects of Inducers in Neuropsychopharmacology. Part I: Focus on Epilepsy

I1 has pointed out that many published research findings in medicine (including highly cited clinical research, epidemiology, genomewide association studies, new technologies called omics, and brain volume measures using imaging techniques) are false. Two major biases can contribute to these false positives, namely, (1) financial and other conflicts of interest and (2) biases associated with the quest for statistical significance. The statistical and methodological literature has given less attention to the possibility that systematic false negatives contaminate the literature. This editorial is divided into 2, namely, part I, which focuses on epilepsy, and part II, which focuses on bipolar disorder and proposes that the neuropsychopharmacology literature on drug-drug interactions (DDIs) studying drug metabolic inducers is seriously contaminated not by false positives but by false-negative findings. The author is suggesting that inducer effects are systematically denied or at least undervalued and the available published literature systematically de-emphasizes their clinical relevance. Moreover, this happens both in epilepsy and bipolar disorder literature where inducers increase the metabolism of many drugs metabolized by cytochrome P450 (CYP) and/or uridine diphosphate glucuronosyltransferase (UGT) enzymes. Why is this happening? Drug-drug interactions are an annoyance for clinicians and therefore a complication for pharmaceutical company marketing. Pharmaceutical companies introducing a new drug want to sell as much of this new drug as possible and have a natural tendency to ignore or suppress interferences with reaching this goal. The promotion of a new drug that may be competing with other established drugs may be facilitated by undervaluing or understating its inductive properties and its concentration variations when coprescribed with inducers. How is this happening? Since the 1990s, the Food and Drug Administration (FDA) has progressively developed a set of regulations requiring the systematic investigation of the pharmacokinetic properties of any new drug. In this author’s view, information on drugs approved before the late 1990s is problematic, and FDA regulations are insufficient in producing clear, easy-to-use guidelines for prescribers. The current set of pharmacokinetic studies used to market a new drug usually includes determinations of its metabolic pathways through an in vitro study in hepatocytes and an in vivo radiolabel drug study in a small number of individuals to study drug elimination. Then, DDI studies using relevant inhibitors and inducers in human individuals (healthy controls or patients) are conducted. It is relatively easy to design DDI studies that undervalue inducer effects by using single doses of the inducer or drug or by using doses or treatment durations of the inducer that do not provide maximum inductive effects. Next, this editorial proposes to demonstrate to the skeptical reader that a consistent pattern of denial and undervaluation of inducer effects exists in the neuropsychopharmacology literature. This pattern may be defined as systematic because it contaminates different pharmacological categories, namely, (1) CYP3A4 drugs, (2) nonmetabolized drugs, and (3) mild inducer drugs. Moreover, it contaminates the ‘‘narrative’’ of both epilepsy (part I) and bipolar disorder (part II) pharmacological treatments, which are characterized by polypharmacy, including the use of potent inducers such as carbamazepine or the more recently introduced mild inducers. From a historical perspective, denial and undervaluation of inducer effects usually occur first in the literature on antiepileptic drugs (AEDs) (part I) and then in the literature on bipolar disorder (part II). Tiagabine is the best example of denial and undervaluation of inducer effects in a CYP3A4 drug among the AEDs. Topiramate and vigabatrin are briefly discussed as AEDs allegedly not influenced GUEST EDITORIAL