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Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials

  • Klaus Lieb (a1), Birgit Völlm (a2), Gerta Rücker (a3), Antje Timmer (a4) and Jutta M. Stoffers (a5)...
Abstract
Background

Many patients with borderline personality disorder receive pharmacological treatment, but there is uncertainty about the usefulness of such therapies.

Aims

To evaluate the evidence of effectiveness of pharmacotherapy in treating different facets of the psychopathology of borderline personality disorder.

Method

A Cochrane Collaboration systematic review and meta-analysis of randomised comparisons of drug v. placebo, drug v. drug, or single drug v. combined drug treatment in adult patients with borderline personality disorder was conducted. Primary outcomes were overall disorder severity as well as specific core symptoms. Secondary outcomes comprised associated psychiatric pathology and drug tolerability.

Results

Twenty-seven trials were included in which first- and second-generation antipsychotics, mood stabilisers, antidepressants and omega-3 fatty acids were tested. Most beneficial effects were found for the mood stabilisers topiramate, lamotrigine and valproate semisodium, and the second-generation antipsychotics aripiprazole and olanzapine. However, the robustness of findings is low, since they are based mostly on single, small studies. Selective serotonin reuptake inhibitors so far lack high-level evidence of effectiveness.

Conclusions

The current evidence from randomised controlled trials suggests that drug treatment, especially with mood stabilisers and second-generation antipsychotics, may be effective for treating a number of core symptoms and associated psychopathology, but the evidence does not currently support effectiveness for overall severity of borderline personality disorder. Pharmacotherapy should therefore be targeted at specific symptoms.

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Copyright
Corresponding author
Dr Klaus Lieb, Department of Psychiatry and Psychotherapy, University Medical Centre Mainz, Untere Zahlbacher Str. 8, D–55131 Mainz, Germany. Email: Klaus.lieb@ukmainz.de
Footnotes
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This work was supported by grants from the German Federal Ministry of Education and Research (grant no. 01KG0609) to K.L., from the research committee of the University Medical Centre, Freiburg, to J.S. and K.L., and from the German Research Foundation (grant no. FOR 534 Schw 821/2-2) to G.R.

Declaration of interest

None.

Footnotes
References
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Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials

  • Klaus Lieb (a1), Birgit Völlm (a2), Gerta Rücker (a3), Antje Timmer (a4) and Jutta M. Stoffers (a5)...
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eLetters

Re: Cochrane guidelines for treatment of BPD

Jutta M Stoffers, researcher
02 June 2010

We share Dr. Paris’ concerns that this short report was published before the full Cochrane review (to be published in the Cochrane Library (1). In fact, we first submitted the full review to the Cochrane Collaboration, and only afterwards the short report to the BJP. The editorial procedures were overlapping, but the publication of the full review is now impending (presumably June issue 2010).

Dr. Paris raises the issue of drawing inferences from single studies in small samples. We agree that the findings have to be interpreted carefully and we have therefore discussed the quality of evidence in detail ((2), cf. p. 8f.). We also agree that the current evidence lacks robustness in terms of, e.g., the number of trials and sample sizes (e.g.,(2), p. 9: “Conclusions from the studies reported here have been drawn cautiously because of the limitations discussed above.”). The full review will contain GRADE summaries of findings tables that assess the quality ofthe sources of available evidence in-depth. Certainly one important message of our work is that more and better powered trials are urgently needed.

As concerns similarities and differences to the NICE guidelines (3), may we please refer to our previous reply at Dr. Adil’s letter (4). It would be a misunderstanding to suggest that Cochrane published “guidelines”. They do not, but instead offer an up-to-date review of validevidence.

Regards, Jutta Stoffers, Birgit Völlm, Gerta Rücker, Antje Timmer, Klaus Lieb

(1) Stoffers J, Völlm BA, Rücker G, Timmer A, Huband N & Lieb, K.Pharmacological interventions for borderline personality disorder. Cochrane Database of Systematic Reviews, in press.

(2) Lieb K, Böllm B, Rücker G, Timmer A & Stoffers JM. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry, 196, 4-12.

(2) National Institute for Health and Clinical Excellence. BorderlinePersonality Disorder: Treatment and Management. CG 78. London: National Institute for Health and Clinical Excellence, 2009. (http://www.nice.org.uk/nicemedia/pdf/CG78FullGuideline .pdf).

(3) Lieb K, Völlm B & Stoffers J. Antipsychotics and borderline personality disorder: authors’ reply. Br J Psychiatry 2010; 196: 332.
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Conflict of interest: None Declared

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Re: Cochrane guidelines for treatment of BPD

Jutta Stoffers, researcher
26 February 2010

Dear Dr. Paris,

we appreciate the issues that you have raised in your e-letter “Cochrane guidelines for treatment of BPD”.

We share your concerns that the short report (i.e. the BJP paper) waspublished before the full Cochrane review (to be published in the CochraneLibrary). In fact, we first submitted the full review to the Cochrane Collaboration, and only afterwards submitted the short report to the BJP. Unfortunately, the editorial procedures of the Cochrane Library are still in progress, but we are confident of publication there during the first half of 2010.

You raise the issue of drawing inferences from single studies in small samples. We agree that the findings have to be interpreted carefullyand have therefore discussed the quality of evidence in detail (cf. p. 8f.). We also agree that the current evidence lacks robustness in terms of, e.g., the number of trials and sample sizes (e.g., p. 9: “Conclusions from the studies reported here have been drawn cautiously because of the limitations discussed above.”). The full review will contain GRADE summaries of findings tables that assess the quality of the sources of available evidence in-depth. Certainly one important message of our work is that more and better powered trials are urgently needed.

You further mention the importance to interpret findings conservatively and refer positively to two previous publications. You seemto suggest that the difference in the conclusions drawn in our and the previous version of this Cochrane review arises from a more balanced interpretation of the evidence in the 2006 review. This is not the case. In fact, the two reviews are based on a largely different evidence base illustrating the speed of accumulating evidence. The preceding (2006) fullreview included ten RCTs, whereas we are now aware of 29. Furthermore, some drug treatments now included in our evidence had not been investigated in RCTs previously. The issue of the recent NICE guideline’s recommendations has already been discussed (cf. our response to Dr. Adil’se-letter). NICE and the Cochrane Collaboration have very different aims. NICE aims at giving specific clinical recommendations for treatment providers within the British National Health Service. NICE considers somewhat different sources of evidence and applies additional criteria to weigh the costs and benefits of treatments (“NICE has always been focused on providing guidance on the most effective way to use NHS resources” – www.nice.org.uk). Therefore, it would be a misunderstanding to suggest that Cochrane published “guidelines” (see the title of your e-letter). They do not, but instead offer an up-to-date review of valid evidence.

Regards,Klaus Lieb, Birgit Völlm, Gerta Rücker, Antje Timmer, Jutta Stoffers
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Conflict of interest: None Declared

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Cochrane guidelines for treatment of BPD

Joel Paris, McGill University
10 February 2010

I was very surprised to see the BJP publish a brief version of a Cochrane report, the full text of which is not yet available. This does not seem tobe a proper way for these important reports to be published.I was also surprised that so many of the conclusions of this paper were based on single studies in small samples. While the overall conclusions are reasonable (pharmacotherapy can reduce symptoms on BPD but does not produce remission of disorder), one sees a lack of caution in interpretingthe published data. This report is not worthy of Cochrane, famous for its conservatism. It varies greatly from a previous and more nuanced report from this source (1), and with the judicious conclusions to be found in the NICE guidelines 2).

Joel Paris, MD

References1. Binks, C.A., Fenton, M., McCarthy, L., Lee, T., Adams, C.E., & Duggan, C. (2006) Pharmacological interventions for people with borderline personality disorder. Cochrane Database of Systematic Reviews. (1):CD0056532. Kendall, T, Pilling, S, Tyrer, P, Duggan, C, Burbeck, R, Meader N, Taylor, C Borderline and antisocial personality disorders: summary of NICE guidance BMJ 2009;338:b93
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response to Dr. Adil

Jutta Stoffers, Researcher
10 February 2010

Dear Dr. Adil,

thank you very much for your positive comments about our paper. We agree that the conclusions from NICE and our review are surprisingly different, considering similar literature search periods and widely similar inclusion criteria for primary studies. However, our scope was to assess and evaluate “the mere evidence” of clinical outcomes. NICE, in contrast, aims at the formulation of instructional recommendations for the British National Health Service. Thus, the steering group may have hada broader view and considered additional criteria such as cost-effectiveness within a complex system of health care. Differences may therefore, at least in part, stem from different perspectives and scopes: the assessment of the mere evidence and the formulation of instructional guidelines.

Indeed, there were and still are no RCTs on Quetiapine available. We are aware of one RCT (The Verkes Borderline Study) that has not been published (yet). Thank you for the reference list. There are two more open-label trials of Quetiapine in BPD (1,2). However, this list is not necessarily exhaustive.

We agree that forest plotting would have contributed to a more immediate understanding of the evidence. However, may we refer you to the full Cochrane review which is to be published soon in the Cochrane Library. Forest plots will be provided there whenever appropriate.

Finally, we thank you for indicating this passage which is indeed liable to misunderstanding. The APA guidelines recommend low-dose antipsychotics in general(3), whereas our findings indicate that second-generation antispychotics are supported by the current RCT evidence in particular. This development of a shift towards second-generation antipsychotics has been foreshadowed by John M. Oldham in his guideline watch of 2005(4), but, to our knowledge, the original guideline recommendations have not been modified since.

(1) Bellino S, Paradiso E, Bogetto F. Efficacy and tolerability of quetiapine in the treatment of borderline personality disorder: A pilot study. J Clin Psychiatry 2006; 67(7):1042-6.

(2) Roepke S, Merkl A, Dams A, Ziegenhorn A, Anghelescu IG, Heuser I,Lammers CH. Preliminary evidence of improvement of depressive symptoms butnot impulsivity in cluster B personality disorder patients treated with quetiapine: an open label trial. Pharmacopsychiatry 2008; 41(5):176-81.

(3) American Psychiatric Association. Practice guideline fort the treatment of patients with borderline personality disorder. Am J Psychiatry 2001; 158(suppl 10): 1-52

(4) Oldham JM. Guideline watch: Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Association, 2005. Available from: http://www.psychiatryonline.com/pracGuide/pracGuideTopic_13.aspx (accessedJanuary 29th, 2010).
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Conflict of interest: None Declared

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Jawad Adil, Locum Consultant Psychiatrist
27 January 2010

I congratulate Klaus Lieb et al on the excellent systematic review ‘pharmacotherapy for borderline personality disorder - Cochrane systematicreview of randomised trials’.

It is interesting that studies till June 2008 were included in this review and in January 2009 NICE Guidelines advised ‘drug treatment shouldnot be used specifically for borderline personality disorder or for the individual symptoms or behaviour associated with the disorder'.

I am surprised that there were no RCTs available at the time of studyon usefulness of Quetiapine although some were on Aripiprazole and Olanzapine. A few open label studies have been done highlighting the usefulness of Quetiapine in reducing impulsivity and affective symptoms and it is evident in clinical practice that it does have some beneficial effects on mood instability and aggression.

It is a pity that Forest plotting could not be done which would have shown how much variation existed among studies and the degree of precisionof each study although one can understand the various difficulties faced by the authors.

Lastly I would like to seek clarification regarding somewhat conflicting statements in the paragraph ‘Implications for practice and research’; it initially states ‘nor can low-dose antipsychotics be advisedfor cognitive–perceptual symptoms as earlier recommended by the American Psychiatric Association Practice Guidelines’ but later states ‘the SGAs (aripiprazole, olanzapine) should be the first choice for treating cognitive–perceptual symptoms’.

Declaration of Interest: None

References

1. Open-label study of atypical neuroleptic, quetiapine for treatmentof borderline personality disorder: impulsivity as main target; VilleneuveE, Lemelin S, Clinique Le Faubourg St-Jean (Centre hospitalier Robert-Giffard), Québec, Québec, Canada.

2. Pharmacological interventions for people with borderline personality disorder; Claire Binks, Mark Fenton, Lucy McCarthy, Tracey Lee, Clive E Adams, Conor Duggan

3. Efficacy of quetiapine for impulsivity and affective symptoms in borderline personality disorder; Van den Eynde F, Senturk V, Naudts K, Vogels C, Bernagie K, Thas O, van Heeringen C, Audenaert K. Department of Psychiatry and Medical Psychology, Ghent University, Ghent, Belgium

4. Quetiapine in the treatment of borderline personality disorder; Hilger E, Barnas C, Kasper S, Department of General Psychiatry, Universityof Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

5. Quetiapine in patients with borderline personality disorder: an open-label trial; Adityanjee, Romine A, Brown E, Thuras P, Lee S, Schulz SC, Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55454, USA
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Conflict of interest: None Declared

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