21a
Jutta Stoffers-Winterling and Klaus Lieb
In their chapter, Links et al. gave an overview of the major findings and recent research on the topic of drug treatments for borderline personality disorder (BPD) and other personality disorders. The authors discuss the limitations of research in this area and the role of medications within the therapeutic relationship, and then give clinical recommendations.
We would like to share some thoughts about the relevance and value of current research on BPD drug treatment. Our point of view mainly comes from evidence-based medicine (EBM). In a famous article, David Sackett and colleagues defined the practice of EBM as “integrating individual clinical expertise with the best available external clinical evidence i.e., clinically relevant research” (Sackett, Rosenberg, Gray, Haynes, & Richardson, 1996, p. 71). But how relevant is research for BPD treatment in reality? What would relevant research mean in this field? And what can be done to enhance the value of future evaluation studies?
We are aware of a clear gap between current clinical practice and the corresponding evidence. For example, as Links et al. report, most people with a diagnosis of BPD are prescribed psychotropic drugs (i.e., around 80–90 percent of patients take approximately 2.7 psychotropic drugs concurrently; Bridler et al., 2015; Zanarini, Frankenburg, Reich, Harned, & Fitzmaurice, 2015). The high rate of medication use is not at all reflected by corresponding research. As the authors point out, there is only one randomized controlled trial (RCT) that investigated polypharmacy systematically (Zanarini, Frankenburg, & Parachini, 2004), and its findings do not support this practice. This is a good example of the disconnect between research and clinical practice.
Another example of the mismatch of research and clinical practice is the case of quetiapine. Although it is the single drug most often used in the field, it has only been investigated by a single placebo-controlled RCT in BPD so far (Black et al., 2014). Obviously, the lack of any high-quality supporting evidence did not keep practitioners from prescribing this medication; prescription rates of approximately 30 percent were observed at times when still not a single RCT of quetiapine was available (Bridler et al., 2015). Now that one RCT is available, replication trials are urgently needed to foster the robustness of the findings and our confidence in them; however, we are only aware of one other industry-sponsored RCT (the findings of which have never been published (NCT00254748, n.d.) and another independently funded RCT that was discontinued because the investigators had major problems in recruiting quetiapine-naïve participants (ACTRN12615000705583, n.d.). Obviously, for the case of quetiapine, clinical practice has outrun treatment evaluation research.
The field of BPD treatment research is a very busy one, but not all new RCT studies make relevant contributions. For example, olanzapine is the one drug that is clearly dominating RCT research. Overall, there are 12 RCTs involving olanzapine (Stoffers & Lieb, 2015). The findings are far from convincing as Link et al. report, with only moderate beneficial effects linked to considerable adverse effects. Still, four new olanzapine RCTs, involving another 223 participants, have become available since publication of the Cochrane review: one compares olanzapine to a first-generation antipsychotic (haloperidol; Shafti & Shahveisi, 2010), two compare it to other second-generation antipsychotics (i.e., asenapine and aripiprazole; see Bozzatello, Rocca, Uscinska, & Bellino, 2017 and Shafti & Kaviani, 2015, respectively), and another one compares olanzapine to the SSRI antidepressant sertraline (Jariani, Saaki, Nazari, & Birjandi, 2010). These trials are of limited value because they ask and investigate questions that are of minimal relevance: What can we learn from the comparison of one medication with small beneficial effects and clear adverse effects (olanzapine) to alternate medications that have never been tested in placebo-controlled trials before (asenapine, sertraline), or to drugs with available but questionable evidence of effectiveness (aripiprazole), or to a drug that no one would ever seriously regard as an alternative (haloperidol)? The findings of these studies can only suggest which medication is associated with fewer adverse effects, but this must not be mistaken as support for their overall usefulness.
The EBM community has become aware of the research–practice gap, which has been recorded across all biomedical research (Chalmers & Glasziou, 2009). Though it is clear that research should reflect and inform issues relevant to consumers (i.e., clinicians, patients, and care providers; Sackett et al., 1996), the question of why research that might transform healthcare is not being produced more successfully deserves closer examination. Chalmers and Glasziou (2009) have identified and systemized stages throughout the research process during which avoidable misallocation of resources may appear, including (1) formulating relevant research questions, (2) elaborating an appropriate research design, (3) regulating and managing research efficiently, (4) making research information accessible, and (5) reporting of research findings. In response, the REWARD alliance was established (Macleod et al., 2014), with the aim of improving the value of research by suggesting strategies to regulate, design, conduct, manage, and analyze research appropriately, as well as to facilitate the reporting and dissemination of research findings (http://rewardalliance.net).
Yet, which research questions are of value and should be prioritized? To find this out, already existing evidence must be considered before designing new projects. Both published and ongoing research is systematically synthesized in sources such as Cochrane Collaboration reviews (www.cochranelibrary.com/) or up-to-date evidence-based treatment guidelines (NHMRC, 2013; NICE, 2009). Taking into account these sources, it is possible to draw conclusions about relevant questions, including “Which encouraging pilot findings need replication?” and “Which questions or comparisons are simply redundant?”
Still too often, economic factors drive decisions about research topics, study designs, and comparators in order to bring new products to market (“seeding trials”) or to expand market shares. In contrast, public funding organizations and other non-industry sponsors facilitate setting research priorities independently from the prospects for commercial profit. We are currently aware of two such projects that are of enormous value for the field. First, there is an ongoing placebo-controlled RCT of aripiprazole (ACTRN12616001192471, n.d.). Its findings will make an important contribution to the field because, to date, there is only one small placebo-controlled RCT available reporting very large effects (Nickel et al., 2006), but its trustworthiness has been doubted (NICE, 2009). Another outstanding example of a valuable contribution is the recently published placebo-controlled RCT of lamotrigine by Crawford and colleagues (Crawford et al., 2015; Crawford et al., 2018a). Before, there were only two RCTs available, each including 27 participants who were followed up for 8 and 12 weeks (Reich, Zanarini, & Bieri, 2009; Tritt et al., 2005). This single new placebo-controlled RCT adds observations from 276 participants followed up for one year. It was sufficiently powered to detect clinically meaningful effects, but could not find any. These are robust findings in which we can have great confidence, and they have the potential to transform the prescribing habits for lamotrigine (as depicted in Table 21.2 of Links et al.’s chapter) and maybe even mood stabilizers in general (Gunderson & Choi-Kain, 2018) – if they are adequately disseminated and recognized. The chances of this are good, as the study findings and even raw data are freely available for the public (EudraCT Number 2012-003136-23, n.d.; Crawford et al., 2018b).
While updating the Cochrane Collaboration review (Stoffers-Winterling et al., 2018), we found study registrations and protocols available for almost all newly eligible RCTs, which facilitates judgment of reporting completeness and accuracy. This was not the case for the majority of trials included in the preceding Cochrane review (Stoffers et al., 2010). Without a doubt, this is the result of the “equator network” (www.equator-network.org/; Simera et al., 2010), an initiative that aims at improving transparent and accurate reporting of health research. Now, study registration is obligatory for publication of trials in high impact journals (De Angelis et al., 2004).
Finally, two initiatives should be mentioned here that come from the EBM community and aim to increase the value of research: First, the AllTrials campaign that advocates for the full publication of study results from all clinical trials (Brown, 2013), and resulted in the development of an internet-based tool for identifying unpublished results of registered trials (http://fdaaa.trialstracker.net/). Second, the James Lind Alliance (Petit-Zeman, Firkins, & Scadding, 2010; www.jla.nihr.ac.uk/) that facilitates priority setting partnerships (PSP) wherein patients, clinicians, and care providers are brought together with the aim of identifying and prioritizing questions about the effects of treatments, and formulating relevant research questions.
Despite some shortcomings outlined by Links et al., we are aware of the first results of initiatives that aim at closing the research–practice gap, including the recent study of Crawford (Crawford, et al., 2018a, 2018b). Not only is this study a fine and encouraging example of a new culture of high-quality, relevant research, it has the potential to directly improve health, which is what clinical trials are supposed to do.
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