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NIHR Signal Lamotrigine is not effective for the treatment of borderline personality disorder

Published on 17 July 2018

doi: 10.3310/signal-000617

Lamotrigine, a mood-stabilising drug, is not clinically effective for the treatment of borderline personality disorder. Over one year follow up, this NIHR-funded trial did not find a difference between lamotrigine and placebo for borderline personality disorder-related symptoms and behavioural problems, depressive symptoms, self-harm, social functioning or quality of life outcomes.

Borderline personality disorder is a severe mental health disorder characterised by rapid and distressing fluctuations in mood, impaired social functioning and increased suicidal behaviour. Since emotional instability is a key clinical feature, it was thought treatments that help to stabilise mood might help in treating the condition.  

This was a placebo-controlled, double-blind, randomised trial of lamotrigine in 276 people with borderline personality disorder, the largest trial to date. In contrast to the results of earlier smaller trials, this larger trial did not support the use of lamotrigine in the management of borderline personality disorder.

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Why was this study needed?

Borderline personality disorder (BPD) affects around 0.7% of people, and one-fifth of all patients admitted to inpatient mental health units in the UK have this condition. People with BPD experience high levels of unemployment and the rate of completed suicide is 50-times higher than in the general population.

There is little evidence for pharmacological treatments in BPD. However, mood-stabilising drugs can be useful treatments in other mental-health conditions characterised by fluctuations in mood, such as bipolar disorder. 

Previous findings from small-scale studies of mood stabilisers in BPD suggested lamotrigine may be clinically effective for BPD over the short-term. To address this uncertainty, a larger randomised placebo-controlled trial, with a longer one-year follow-up, was funded by NIHR.

What did this study do?

The LABILE trial recruited 276 participants from secondary care mental health services across England. Adult participants were included if they met the DSM-IV diagnostic criteria for BPD.  

Participants were randomised to receive lamotrigine (up to 200mg daily) or a placebo. The main outcome was the Zanarini Rating Scale for BPD at one year (ZAN-BPD), a score for describing symptoms and behavioural problems associated with BPD. In addition, depressive symptoms, deliberate self-harm and social functioning were measured.

The trial was designed carefully. To reduce the risk of bias, all patients, carers, referring psychiatrists and study investigators collecting and analysing the data were unaware of the treatment assignments. The self-reported adherence of participants to the study medication was low (only 34% took medication as per protocol).

What did it find?

  • By one year, there was no significant difference in the ZAN-BPD score. The range is from 0 to 35 with higher scores indicating worse symptoms. The average score for those on lamotrigine was 11.3 compared with 11.5 in the placebo group (adjusted mean difference 0.1, 95% confidence interval ‑1.8 to 2.0).
  • There was no significant difference between the groups for the trial’s secondary outcomes (depressive symptoms, deliberate self-harm and social functioning) at any follow-up time point.
  • The average total cost of care was £12,244 in the lamotrigine group and £8,495 in the placebo group; however, the difference in cost was not statistically significant. Differences in QALYs (calculated using health-related quality of life scores) were also not statistically significant between groups.
  • Sensitivity analyses adjusted for treatment adherence and for differences in baseline variables, considered outcomes at all follow-up visits, and used imputation of missing data (a statistical method that estimates what the likely data should have been). These analyses also supported a lack of treatment effect.

What does current guidance say on this issue?

NICE 2009 guidelines do not recommend the use of drug treatment for BPD or for the symptoms or behaviour problems associated with the disorder (for example, repeated self-harm, marked emotional instability, risk-taking behaviour and transient psychotic symptoms). Specifically, NICE do not recommend mood stabilisers, such as lamotrigine, for the treatment of BPD and rule out antipsychotic drugs for medium and long-term use in this condition.

What are the implications?

This randomised controlled trial provides strong evidence, with long-term follow up, showing lamotrigine to be clinically ineffective for the treatment of BPD.

The study responds to NICE’s call for more high-quality research in this area and supports current guidance which does not recommend the use of lamotrigine for BPD.

Citation and Funding

Crawford MJ, Sanatinia R, Barrett B, et al. Lamotrigine for people with borderline personality disorder: a RCT. Health Technol Assess. 2018;22(17):1-68.

This project was funded by the National Institute for Health Research Health Technology Assessment Programme (project number 10/103/01).

Bibliography

APA. DSM-IV and DSM-5 criteria for the personality disorders. Washington: American Psychiatric Association; 2012.

Coid J, Yang M, Tyrer P, et al. Prevalence and correlates of personality disorder in Great Britain. Br J Psychiatry. 2006;188(5):423-31.

Hayward M, Slade M, Moran PA. Personality disorders and unmet needs among psychiatric inpatients. Psychiatric Serv. 2006;57(4):538-43.

Lieb K, Zanarini MC, Schmahl C, et al. Borderline personality disorder. Lancet. 2004;364(9432):453-61.

NICE. Borderline personality disorder: recognition and management. CG78. London: National Institute for Health and Care Excellence; 2012.

Skodol AE, Gunderson JG, McGlashan TH, et al. Functional impairment in patients with schizotypal, borderline, avoidant, or obsessive-compulsive personality disorder. Am J Psychiatry. 2002;159(2):276-83.

Why was this study needed?

Borderline personality disorder (BPD) affects around 0.7% of people, and one-fifth of all patients admitted to inpatient mental health units in the UK have this condition. People with BPD experience high levels of unemployment and the rate of completed suicide is 50-times higher than in the general population.

There is little evidence for pharmacological treatments in BPD. However, mood-stabilising drugs can be useful treatments in other mental-health conditions characterised by fluctuations in mood, such as bipolar disorder. 

Previous findings from small-scale studies of mood stabilisers in BPD suggested lamotrigine may be clinically effective for BPD over the short-term. To address this uncertainty, a larger randomised placebo-controlled trial, with a longer one-year follow-up, was funded by NIHR.

What did this study do?

The LABILE trial recruited 276 participants from secondary care mental health services across England. Adult participants were included if they met the DSM-IV diagnostic criteria for BPD.  

Participants were randomised to receive lamotrigine (up to 200mg daily) or a placebo. The main outcome was the Zanarini Rating Scale for BPD at one year (ZAN-BPD), a score for describing symptoms and behavioural problems associated with BPD. In addition, depressive symptoms, deliberate self-harm and social functioning were measured.

The trial was designed carefully. To reduce the risk of bias, all patients, carers, referring psychiatrists and study investigators collecting and analysing the data were unaware of the treatment assignments. The self-reported adherence of participants to the study medication was low (only 34% took medication as per protocol).

What did it find?

  • By one year, there was no significant difference in the ZAN-BPD score. The range is from 0 to 35 with higher scores indicating worse symptoms. The average score for those on lamotrigine was 11.3 compared with 11.5 in the placebo group (adjusted mean difference 0.1, 95% confidence interval ‑1.8 to 2.0).
  • There was no significant difference between the groups for the trial’s secondary outcomes (depressive symptoms, deliberate self-harm and social functioning) at any follow-up time point.
  • The average total cost of care was £12,244 in the lamotrigine group and £8,495 in the placebo group; however, the difference in cost was not statistically significant. Differences in QALYs (calculated using health-related quality of life scores) were also not statistically significant between groups.
  • Sensitivity analyses adjusted for treatment adherence and for differences in baseline variables, considered outcomes at all follow-up visits, and used imputation of missing data (a statistical method that estimates what the likely data should have been). These analyses also supported a lack of treatment effect.

What does current guidance say on this issue?

NICE 2009 guidelines do not recommend the use of drug treatment for BPD or for the symptoms or behaviour problems associated with the disorder (for example, repeated self-harm, marked emotional instability, risk-taking behaviour and transient psychotic symptoms). Specifically, NICE do not recommend mood stabilisers, such as lamotrigine, for the treatment of BPD and rule out antipsychotic drugs for medium and long-term use in this condition.

What are the implications?

This randomised controlled trial provides strong evidence, with long-term follow up, showing lamotrigine to be clinically ineffective for the treatment of BPD.

The study responds to NICE’s call for more high-quality research in this area and supports current guidance which does not recommend the use of lamotrigine for BPD.

Citation and Funding

Crawford MJ, Sanatinia R, Barrett B, et al. Lamotrigine for people with borderline personality disorder: a RCT. Health Technol Assess. 2018;22(17):1-68.

This project was funded by the National Institute for Health Research Health Technology Assessment Programme (project number 10/103/01).

Bibliography

APA. DSM-IV and DSM-5 criteria for the personality disorders. Washington: American Psychiatric Association; 2012.

Coid J, Yang M, Tyrer P, et al. Prevalence and correlates of personality disorder in Great Britain. Br J Psychiatry. 2006;188(5):423-31.

Hayward M, Slade M, Moran PA. Personality disorders and unmet needs among psychiatric inpatients. Psychiatric Serv. 2006;57(4):538-43.

Lieb K, Zanarini MC, Schmahl C, et al. Borderline personality disorder. Lancet. 2004;364(9432):453-61.

NICE. Borderline personality disorder: recognition and management. CG78. London: National Institute for Health and Care Excellence; 2012.

Skodol AE, Gunderson JG, McGlashan TH, et al. Functional impairment in patients with schizotypal, borderline, avoidant, or obsessive-compulsive personality disorder. Am J Psychiatry. 2002;159(2):276-83.

Lamotrigine for people with borderline personality disorder: a RCT

Published on 13 April 2018

Crawford M J, Sanatinia R, Barrett B, Cunningham G, Dale O, Ganguli P, Lawrence-Smith G, Leeson V C, Lemonsky F, Lykomitrou-Matthews G, Montgomery A, Morriss R, Munjiza J, Paton C, Skorodzien I, Singh V, Tan W, Tyrer P & Reilly J G.

Health Technology Assessment Volume 22 Issue 17 , 2018

Background No drug treatments are currently licensed for the treatment of borderline personality disorder (BPD). Despite this, people with this condition are frequently prescribed psychotropic medications and often with considerable polypharmacy. Preliminary studies have indicated that mood stabilisers may be of benefit to people with BPD. Objective To examine the clinical effectiveness and cost-effectiveness of lamotrigine for people with BPD. Design A two-arm, double-blind, placebo-controlled individually randomised trial of lamotrigine versus placebo. Participants were randomised via an independent and remote web-based service using permuted blocks and stratified by study centre, the severity of personality disorder and the extent of hypomanic symptoms. Setting Secondary care NHS mental health services in six centres in England. Participants Potential participants had to be aged ≥ 18 years, meet diagnostic criteria for BPD and provide written informed consent. We excluded people with coexisting psychosis or bipolar affective disorder, those already taking a mood stabiliser, those who spoke insufficient English to complete the baseline assessment and women who were pregnant or contemplating becoming pregnant. Interventions Up to 200 mg of lamotrigine per day or an inert placebo. Women taking combined oral contraceptives were prescribed up to 400 mg of trial medication per day. Main outcome measures Outcomes were assessed at 12, 24 and 52 weeks after randomisation. The primary outcome was the total score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. The secondary outcomes were depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment and adverse events. Higher scores on all measures indicate poorer outcomes. Results Between July 2013 and October 2015 we randomised 276 participants, of whom 195 (70.6%) were followed up 52 weeks later. At 52 weeks, 49 (36%) of those participants prescribed lamotrigine and 58 (42%) of those prescribed placebo were taking it. At 52 weeks, the mean total ZAN-BPD score was 11.3 [standard deviation (SD) 6.6] among those participants randomised to lamotrigine and 11.5 (SD 7.7) among those participants randomised to placebo (adjusted mean difference 0.1, 95% CI –1.8 to 2.0; p = 0.91). No statistically significant differences in secondary outcomes were seen at any time. Adjusted costs of direct care for those prescribed lamotrigine were similar to those prescribed placebo. Limitations Levels of adherence in this pragmatic trial were low, but greater adherence was not associated with better mental health. Conclusions The addition of lamotrigine to the usual care of people with BPD was not found to be clinically effective or provide a cost-effective use of resources. Future work Future research into the treatment of BPD should focus on improving the evidence base for the clinical effectiveness and cost-effectiveness of non-pharmacological treatments to help policy-makers make better decisions about investing in specialist treatment services. Funding Funding for this trial was provided by the Health Technology Assessment programme of the National Institute for Health Research (NIHR) and will be published in full in Health Technology Assessment; Vol. 22, No. 17. See the NIHR Journals Library website for further project information. The Imperial Biomedical Research Centre Facility, which is funded by NIHR, also provided support that has contributed to the research results reported within this paper. Part of Richard Morriss’ salary during the project was paid by NIHR Collaboration for Leadership in Applied Health Research and Care East Midlands.

Expert commentary

Borderline personality disorder (BPD) is a common mental health condition characterised by mood instability, suicidal behaviour and interpersonal difficulties. While there are no licensed drug treatments for the condition, the majority of patients are prescribed psychotropic medications. 

The lack of availability of timely and appropriate evidence-based psychological interventions should not be viewed as a reason to prescribe.

If we are to enable patients with BPD to receive the appropriate care, we must ensure that there is sufficient high-quality research to support treatment choices.

Dr Kate Saunders, Honorary Consultant Psychiatrist, University of Oxford