21c
Paul S. Links, Philippe Boursiquot, and Madison Links
The two excellent commentaries have greatly enriched the discussion of the pharmacological management of patients with personality disorders (PDs) and particularly the direction that future drug trial research must take.
Stoffers-Winterling and Lieb (this volume) stressed the need for quality research that closes the gap between evidence and practice. The recently completed trial by Crawford and colleagues (2018) stands out as a reference point for trial methodology that will advance our understanding of pharmacological management of patients with PDs. They completed a multi-site randomized controlled trial comparing lamotrigine (up to 200 mg/day) versus placebo with treatment as usual in 276 patients with borderline personality disorder (BPD) and, most uniquely, completed assessments at 3-, 6-, and 12-month follow-ups. The primary outcome of the study was the improvement in BPD symptoms as measured by the total score of the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). The study also included a breadth of secondary outcomes, such as depression, self-harm, use of alcohol and other drugs, social functioning, quality of life, and cost-effectiveness of the intervention. The study, although well-conceived, suffered because only 33.7 percent of participants were compliant with medications throughout the trial. Overall, the trial demonstrated no significant differences between the lamotrigine and comparison groups in BPD symptoms at 12 months, as well as no significant differences in any of the secondary outcomes, including cost and health-related quality of life. Furthermore, an analysis of the effect of treatment adherence revealed no relationship between greater medication adherence and better outcomes. The authors concluded that there was no benefit of treating patients with BPD with lamotrigine.
Although we agree with Stoffers-Winterling and Lieb (this volume) that the Crawford et al. study represents a high-water mark for pharmacological trials done in patients with PDs, two caveats should be made regarding the results. First, almost all of the participants had “complex” PDs, which means that patients had coexisting personality problems in addition to BPD and were recruited from secondary care mental health services. Therefore, the findings may not generalize to less complex and severe patients with BPD. In keeping with the two earlier randomized controlled trials that recruited samples from primary care clinics or using community advertisements, lamotrigine may have value for less complex and severe patients with BPD. Second, the earlier randomized controlled trials suggested that lamotrigine may have a role in lessening anger, impulsivity, and affective instability (as measured by the ZAN-BPD). Unfortunately, the ZAN-BPD may not be an adequate measure to capture change in these aspects of borderline personality pathology. For example, the ZAN-BPD is a clinician-administered scale that rates the nine criteria of BPD on a severity scale from no symptoms to severe symptoms. If clinicians were to rate affective instability on patients’ single report of their mood variability or cross-sectional observations, then this rating is likely to be unreliable and invalid (Links et al., 2007). Future trials assessing affective instability should include various methods such as experience sampling methodology or laboratory assessments to capture this feature of borderline pathology.
Farhat and Potenza (this volume) discussed the need to be able to aggregate and compare across trials and the need for harmonization of outcome measures. As discussed above, although the ZAN-BPD has become an important measure to report improvement in BPD symptoms in clinical studies, the assessment of symptom improvement is insufficient to determine meaningful interventions for patients with PDs. Farhat and Potenza called for including measures that capture “clinical well-being and quality of life” and more attention to recording adverse effects. Changing functional outcomes remains one of the most challenging issues related to our current evidence-based treatment approaches for patients with PDs, as previous psychosocial intervention trials have shown an inability to improve functional outcomes despite being effective in the treatment of symptoms. For example, in their randomized controlled trial comparing Dialectical Behavior Therapy to General Psychiatric Management, McMain and colleagues (McMain, Guimond, Streiner, Cardish, & Links, 2012) found no significant improvement in the percentage of participants either working or attending school from the beginning of the trial to the end of the follow-up period (60.3 percent at the beginning of treatment versus 51.8 percent at the end of the follow-up period). Similarly, 39.7 percent of participants were receiving psychiatric disability benefits before therapy and 38.8 percent were receiving this support at the end of the follow-up period. In general, interventions for patients with PDs have not focused on rehabilitation and improving the patient’s functioning. The measurement of functional outcomes in clinical trials is also problematic. Summarizing across existing randomized controlled trials of psychotherapy interventions for BPD, we found that 14 different measures of functioning or quality of life had been employed. The need to harmonize our approach to measuring functional improvement remains a priority for future intervention research.
We fully agree with our commentators that research into pharmacological interventions for patients with PDs needs to advance by (1) using superior methodology as per Crawford et al. (2018), (2) developing a consensus on the best measures, (3) incorporating dimensional models of personality pathology, (4) accounting for patient heterogeneities, and (5) creating partnerships between patients, clinicians, and care providers in order to develop a meaningful research agenda going forward.
References
Crawford, M. J., Sanatinia, R., Barrett, B., Cunningham, G., Dale, O., Ganguli, P., … Reilly, J. G. (2018). Lamotrigine for people with borderline personality disorder: A RCT. Health Technology Assessment, 22, 1–68.
Links, P. S., Eynan, R., Heisel, M. J., Barr, A., Korzekwa, M., McMain, S., & Ball, J. S. (2007). Affective instability and suicidal ideation and behavior in patients with borderline personality disorder. Journal of Personality Disorders, 21, 72–86.
McMain, S. F., Guimond, T., Streiner, D. L., Cardish, R. J., & Links, P. S. (2012). Dialectical behavior therapy compared with general psychiatric management for borderline personality disorder: Clinical outcomes and functioning over a 2-year follow-up. American Journal of Psychiatry, 169, 650–661.