NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Crawford MJ, Sanatinia R, Barrett B, et al. Lamotrigine for people with borderline personality disorder: a RCT. Southampton (UK): NIHR Journals Library; 2018 Apr. (Health Technology Assessment, No. 22.17.)

Cover of Lamotrigine for people with borderline personality disorder: a RCT

Lamotrigine for people with borderline personality disorder: a RCT.

Show details

Chapter 5Discussion

Data from this randomised trial of adding lamotrigine treatment to usual care for people receiving secondary care mental health services for BPD show that the effect of this intervention was no different from that of offering an inert placebo in addition to usual care. Follow-up data collected from 195 (70.7%) out of 276 participants at 12 months showed no difference in score on the ZAN-BPD (adjusted mean difference 0.1, 95% CI –1.8 to 2.0). When differences in the primary outcome were compared over the course of the 12-month follow-up period, among the 234 participants who completed at least one follow-up assessment, no difference was observed in the adjusted ZAN-BPD score (0.0, 95% CI –1.9 to 1.9). Although costs associated with prescribing lamotrigine were small compared with those of inpatient and community care, we did not find evidence that offering patients with BPD lamotrigine was a cost-effective use of resources, given the large number of resources needed to be invested for very small changes in the ZAN-PD score outcome.

Levels of adherence to trial medication were low, with only one-third (n = 93, 33.7%) of study participants taking trial mediation throughout the 1-year follow-up period, as specified in the study protocol. Levels of adherence were higher during the first 12 weeks of the study, at which point two-thirds of participants were taking trial medication (n = 190, 68.8%). However, differences between the treatment arms in the severity of symptoms of BPD were not found at the 12-week assessment, despite medication compliance being higher during this period. In a secondary analysis using CACE methods, we found no evidence that greater adherence to medication was associated with any benefit to patients in the lamotrigine treatment arm of the trial.

In addition to there being no difference in the scores on ZAN-BPD between the treatment arms, treatment with lamotrigine was no better than placebo in terms of improvement on any other measures of mental health. Levels of depression, likelihood of self-harming or suicidal behaviour and likelihood of problem drug or alcohol use were all comparable across the groups at follow-up. Social functioning was also equivalent across groups. There were no deaths in the lamotrigine arm of the trial over the 12-month follow-up period, but three among those in the placebo arm of the trial. Quality of life, assessed using the EQ-5D-3L, was poor in both groups, a finding which is consistent with other studies in people with BPD.47

The number of AEs reported was higher in the placebo arm than in the lamotrigine treatment arm, and more participants in the placebo arm than in the lamotrigine treatment arm had at least one AE (67% vs. 56%). Serious AEs were comparable across treatment arms. A pro forma to elicit information about the known side effects of lamotrigine at each assessment showed that these were comparable across the treatment arm. Taken together, these data suggest that lamotrigine was well tolerated in participants in the active arm of the trial.

Strengths and weaknesses of the study

The LABILE trial is the first ever UK-based study of a medical treatment for people with BPD. Data were collected from participants receiving secondary care from NHS mental health services in six large mental health trusts in the north, south and centre of England. The study was designed to maximise internal validity. This included using independent remote randomisation to avoid unmasking researchers and adhering to an analysis plan that was finalised and shared with the Independent Data Monitoring and Ethics Committee and Trial Steering Group prior to the start of data analysis. Members of the research team drafted their conclusions and recommendations while still masked to treatments received by the two trial arms.

We used a validated measure of severity of BPD that is acceptable to patients and sensitive to change.37,40 All researchers were trained to use the measure, and inter-rater reliability between researchers was high.

One of the main strengths of the LABILE trial is that participants were followed up over a 12-month period. BPD is a long-term condition, but previous drug trials have not conducted double-blind assessments beyond 12 weeks.

We recruited 11% more participants than we originally planned and the study was sufficiently powered to detect a minimum clinically significant difference in the severity of symptoms of BPD. We over-recruited, as it became clear that we were not going to achieve our ambitious target of following up 85% of participants to 12 months after randomisation. The 71% rate of follow-up that we achieved was very similar to that achieved in a UK study of problem-solving therapy for people with personality disorder71 and may represent a more realistic target for studies that aim to follow up people with personality disorder in community-based studies. A planned secondary analysis using multiple imputation to account for missing data found no difference between the study arms.

In this pragmatic trial, we attempted to replicate clinical practice in the NHS. However, one area in which we were unable to do this was in the means by which participants obtained their medication. Most participants typically had medication delivered to them in person or by post, rather than collecting medication from a local pharmacy as required by this study. This meant that participants had more regular contact with staff than they would have done in normal clinical practice (once every 2 weeks during titration and once a month for the majority of participants once the recommended dose was achieved). Although levels of adherence to medication were low, we believe that the additional contact that participants had with study researchers meant that the level of adherence may have been higher in the trial than would be seen in routine clinical practice.

Comparison with results of previous trials

In contrast to the results of the LABILE study, the two previous randomised trials of lamotrigine treatment for people with BPD both reported positive effects.28,29 Both trials were smaller, had a larger number of exclusion criteria and followed up participants for a shorter period of time. There are a number of other differences between the LABILE study and these other trials, which are summarised in Table 18.

TABLE 18

TABLE 18

Comparison of the methods, design and results of the LABILE study with two previous trials of lamotrigine for people with BPD

In their trial of 24 women with BPD recruited from advertisements in primary care clinics, Tritt et al.28 reported statistically significant reductions in four out of five scales of the State–Trait Anger Expression Inventory at 8 weeks. Reich et al.29 randomised 28 men and women with BPD who were recruited from websites and advertisements on local television and radio stations. Although a statistically significant difference was not seen in total score on the ZAN-BPD at 12 weeks, the team reported differences in two out of the four subscales of this measure (affective lability and impulsivity).29

The primary outcome of the LABILE study was assessed at 1 year, but in exploring the reasons for differences in outcomes between these trials, we have focused on data from the 12-week follow-up assessment for comparison. We believe that a number of factors may have resulted in the differences in the results between the LABILE study and the two previous randomised trials. First, we cannot rule out the possibility that apparent differences between groups in the two earlier trials result from chance. Randomisation does not guarantee that treatment arms are balanced in small-scale trials and it is possible that differences in study outcomes resulted from confounding.

The LABILE study was designed to generate evidence that can be used by secondary care mental health services. We therefore limited our exclusion criteria and recruited people who had high levels of contact with mental health services and major impairments in social functioning. This approach meant that we were able to recruit people with the type of complex and severe problems that people with BPD who use NHS secondary care mental health services generally have. A commonly used marker of severity is whether or not people have other coexisting personality problems in addition to BPD.33 It is of note that all but one of the people who took part in the LABILE trial met criteria for other personality disorders and had the types of complex personality-related problems that people in contact with NHS secondary services generally have. In contrast, the two previous trials of lamotrigine treatment for people with BPD excluded people who were misusing alcohol or other drugs, were actively suicidal or were receiving inpatient treatment. Therefore, there are important differences in the sample that we recruited compared with those in the two previous trials. For instance, 73% of participants in the trial conducted by Tritt et al.28 were employed, compared with only 22% in the LABILE trial, and none of those recruited by Tritt et al. had a recent history of deliberate self-harm, compared with two-thirds of participants in the LABILE trial. It is possible that lamotrigine treatment reduces the symptoms of BPD among people who have less complex mental health problems, higher level of social functioning and lower levels of substance misuse than those we recruited to the LABILE trial.

Previous research has shown that people with more complex and severe personality problems are less likely to adhere to treatment.17 It is possible that participants in the LABILE study were less adherent to trial medication than those in the two previous trials. Tritt et al.28 did not report data on adherence. Reich et al.29 did not provide detailed information about adherence but did note that 3 (20%) out of the 15 participants in the active arm of the trial were no longer taking medication at 12 weeks, compared with 86 (31%) of 276 participants in the LABILE trial who were no longer taking lamotrigine at 12 weeks. Although we cannot rule out the possibility that differences in levels of adherence are responsible for differences in outcomes between these trials, the results of the CACE analysis do not suggest that higher levels of adherence to lamotrigine result in greater improvements in mental health.

It is possible that other aspects of the design of previous trials contributed to their positive effects. For instance, in the LABILE trial we had a rigorous process for maintaining blinding through the use of a computerised system, managed by an independent team that allocated study participants. In contrast, Tritt et al.28 used an internal group to oversee treatment allocation. Insufficient information is provided in the paper by Reich et al.29 to establish the process they used to randomise participants.

The LABILE trial is the only one of the three studies to be publicly funded. The trial by Reich et al.29 was funded by a manufacturer of Lamictal® (a proprietary form of lamotrigine; GlaxoSmithKline UK Ltd, Brentford, UK) and the trial by Tritt et al.28 was self-funded.

Finally, we are not aware of any unpublished trials of lamotrigine for people with BPD, but we cannot rule out the possibility that publication bias helps to explain the absence of previous negative trials of this treatment approach.

Implications for clinical practice

People with BPD experience high levels of emotional distress at times of crisis and may behave in an erratic or impulsive way that puts their health at risk. Emotional distress, suicidal behaviour or thoughts of suicide may lead people into contact with mental health services at such times. Interpersonal problems and negative experiences of previous contact with services often make it difficult for people with BPD to trust health-care professionals or feel reassured by their attempts to provide support and advice. In such circumstances, the prescription of medication can provide a clear signal to the patient that they are being taken seriously and health-care staff may also feel reassured that they are ‘doing something’ under difficult circumstances. Data from a national audit of prescribing practice suggest that one-quarter of people who are in contact with mental health services are being prescribed a mood stabiliser.72 Some patients report that prescribing medication during a crisis can help bring about short-term reductions in emotional distress. The results of the LABILE study support the clinical impression that prescribing lamotrigine can lead to improvements in mental health but suggest that this benefit is no greater than would be found if a placebo were to be prescribed.

Current NICE guidelines73 for the treatment of BPD recommend that future research should be conducted to examine the impact of mood stabilisers on people with the condition, but they conclude that there was insufficient evidence to recommend any drug treatment at the time of publication. The results of the LABILE trial provide evidence to support current NICE recommendations and emphasise the need to use alternative approaches to help people with BPD cope with crises and take steps to improve their mental health. The two best-established treatments for BPD are dialectical behaviour therapy and mentalisation-based treatment.74 More recently, evidence has begun to emerge that Systems Training for Emotional Predictability and Problem Solving (STEPPS),40 schema-focused therapy75 and day therapeutic community treatment76 can also improve the health of people with BPD. Clinicians who are working with people in secondary care mental health services should be aware of how they can help support people through mental health crises and how to access evidence-based psychological treatments when these are available.

In the LABILE trial, we took great care not to recruit women who were pregnant, wanting to become pregnant or having regular unprotected sex. Despite the assurances that potential recruits gave us, six participants subsequently became pregnant during the course of the trial. Although lamotrigine treatment has been shown to be relatively safe in pregnancy, this is not true of all mood stabilisers – notably sodium valproate.23 In January 2015, the Medicines and Healthcare products Regulatory Agency issued a warning advising clinicians to avoid prescribing sodium valproate to women of child-bearing age when possible.77 Despite this, a recent national audit showed that 11% of women with BPD who are in contact with secondary care mental health services are currently being prescribed this drug.72 The data from the LABILE study showing the high level of unplanned pregnancies among women with BPD emphasise the importance of avoiding the use of unlicensed medications, such as sodium valproate, that are potentially teratogenic.

Future research

Existing evidence-based psychological treatments for BPD are lengthy, intensive and expensive. Previous research has demonstrated that, when compared with treatment as usual, these interventions are associated with reduced levels of deliberate self-harm and contact with health-care services.74 However, studies that compare the effects of these interventions with high-quality control treatments delivered in a consistent manner show less, if any, additional benefit.78,79 Reductions in self-harm and contact with health-care services raise the possibility that specialist psychological treatment for BPD provides an effective use of available resources, but very few data on the costs and cost-effectiveness of these treatments exist. Further research is needed to examine the costs and cost-effectiveness of specialist psychological treatment for people with BPD compared with high-quality structured general psychiatric management. Such research is needed to help policy-makers make better decisions about investing in specialist treatment services, which many patients are currently unable to access in the NHS.

Even were such services to become more widely available, a substantial minority of people with BPD would be unwilling or unable to use these group-based treatments. There is a pressing need for new research to examine alternative psychological approaches to helping people with BPD cope better with emotional crises and improve their mental health. Computer-assisted self-help interventions and training and support for friends and family of people with BPD are all areas worthy of further exploration.80

An area of particular concern is how best to help people with severe BPD who are treated in inpatient mental health units. Following a number of open-label studies of clozapine treatment for people with BPD,81,82 the use of this atypical antipsychotic drug is becoming more widespread. Evidence from cohort studies suggests that this type of medication may help reduce impulsive self-harming behaviour and reduce the need for inpatient treatment.82 However, this drug is also associated with potential harms, including blood dyscrasia,82 which have the potential to be fatal if not properly monitored and treated. The large number of potential benefits and harms of clozapine for the treatment of inpatients with severe BPD provides a strong case for a placebo-controlled randomised trial of this drug. Given the high rate of drop-out in this and other Phase III trials of community-based interventions for people with BPD, consideration should be given using primary outcomes that do not require direct patient contact.

Conclusions

Based on the results of this trial, we have not shown any benefits of prescribing lamotrigine for people with BPD. These results provide further support for current NICE guidelines, which state that medication should not be used specifically for BPD and consideration should be given to referring people for specialist psychological treatment when these services are available.

Copyright © Queen’s Printer and Controller of HMSO 2018. This work was produced by Crawford et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.
Bookshelf ID: NBK493476

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (1.7M)

Other titles in this collection

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...