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Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study

  • Lars Vedel Kessing (a1), Gunnar Hellmund (a2), John R. Geddes (a3), Guy M. Goodwin (a3) and Per Kragh Andersen (a2)...
Abstract
Background

Valproate is one of the most used mood stabilisers for bipolar disorder, although the evidence for the effectiveness of valproate is sparse.

Aims

To compare the effect of valproate v. lithium for treatment of bipolar disorder in clinical practice.

Method

An observational cohort study with linkage of nationwide registers of all people with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed valproate or lithium in Denmark during a period from 1995 to 2006.

Results

A total of 4268 participants were included among whom 719 received valproate and 3549 received lithium subsequent to the diagnosis of bipolar disorder. The rate of switch/add on to the opposite drug (lithium or valproate), antidepressants, antipsychotics or anticonvulsants (other than valproate) was increased for valproate compared with lithium (hazard ratio (HR) = 1.86, 95% CI 1.59–2.16). The rate of psychiatric hospital admissions was increased for valproate v. lithium (HR = 1.33, 95% CI 1.18–1.48) and regardless of the type of episode leading to a hospital admission (depressive or manic/mixed). Similarly, for participants with a depressive index episode (HR = 1.87, 95% CI 1.40–2.48), a manic index episode (HR = 1.24, 95% CI 1.01–1.51) and a mixed index episode (HR = 1.44, 95% CI 1.04–2.01), the overall rate of hospital admissions was significantly increased for valproate compared with lithium.

Conclusions

In daily clinical practice, treatment with lithium seems in general to be superior to treatment with valproate.

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Corresponding author
Lars Vedel Kessing, Psychiatric Center Copenhagen, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. Email: lars.vedel.kessing@regionh.dk
Footnotes
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Declaration of interest

L.V.K. has been a consultant for Bristol-Myers Squibb, Eli Lilly, Lundbeck, AstraZenica, Pfizer, Wyeth, Servier, Janssen-Cilag. J.R.G. has received research funding from the Medical Research Council (MRC), Economic and Social Research Council, National Institute for Health Research, and the Stanley Medical Research Institute, and has received donations of drugs supplies for trials from Sanofi-aventis and GlaxoSmithKline. He has acted as an expert witness for Dr Reddys. G.M.G. has received research grants from Baily Thomas, MRC, Sanofi-aventis, and Servier; honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Lundbeck, Sanofi-aventis, and Servier; is a shareholder in P1vital; has a paid position at University of Oxford; and has been a member of advisory boards with AstraZeneca, Bristol-Myers Squibb, Lilly, Janssen-Cilag, Lundbeck, P1Vital, Sanofi-aventis, Servier, Roche, and Wyeth. He has acted as an expert witness for Lilly and Servier.

Footnotes
References
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Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study

  • Lars Vedel Kessing (a1), Gunnar Hellmund (a2), John R. Geddes (a3), Guy M. Goodwin (a3) and Per Kragh Andersen (a2)...
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eLetters

Re: Observational BALANCE

Lars V. Kessing, Doctor
19 August 2011

We thank Hayes and Osborn for their kind interest in our paper (1). We certainly agree on the mentioned advantages and disadvantages of observational studies and on the strengths of combining findings from randomised trials with those of observational studies.

Further, we agree on the possibility of the suggested analyses with "switch to" and "add on" as two separate outcomes. We chose the combined outcome measure as using two separate outcome measures (in addition to hospitalisation as an outcome measure) would decrease the statistical power to a low level in some of the analyses and further one of the advantages of using the combined outcome measure is that the results may turn out to be more clear to guide clinical decisions on whether to use lithium or valproate in long-term treatment of bipolar disorder following a number of clinical situations (depression, mania, mixed episode or remission).

Propensity score (PS) matching (or other ways of introducing PS in the analysis (2)) is a viable alternative to the approach based on multiple Cox regression models used in our paper. However, much experience(e.g., (3)) suggests that the results thus obtained would not tend to be substantially different. The limiting factor seems to be the available amount of covariate information.

Lars Vedel Kessing

Per Kragh Andersen

Reference List

1. Kessing LV, Hellmund G, Geddes JR, Goodwin GM, Andersen PK. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. Br J Psychiatry 2011;199:57-63.

2. D'Agostino Jr RB. Tutorial in Biostatistics "Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group". Statistics in Medicine 1998;17:2265-81.

3. Sturmer T, Joshi M, Glynn RJ, Avorn J, Rothman KJ, Schneeweiss S.A review of the application of propensity score methods yielded increasinguse, advantages in specific settings, but not substantially different estimates compared with conventional multivariable methods. J Clin Epidemiol 2006;59:437-47.

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Conflict of interest: Lars Vedel Kessing has been a consultant for Bristol-Myers Squibb, Eli Lilly, Lundbeck, AstraZenica, Pfizer, Wyeth, Servier, Janssen-Cilag. Per Kragh Andersen reports no financial disclosure and competing interests.

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Observational BALANCE

Joseph F Hayes, Clinical Training fellow
08 June 2011

We read with interest Kessing et als timely and welcome paper(1) supporting, by way of observational cohort study, the findings of BALANCE(2). Lithium again is shown to be superior to valproate for the management of bipolar disorder. The strength in this case comes from bridging the gap between the relatively brief follow-up in randomised control trials (RCTs) and the real life situation faced by clinicians managing a lifelong illness of unpredictable course. Whilst the enriched study design in BALANCE aimed to maximise the generalisability of the findings to a clinical population, limitations inevitably remained in terms of including patients who had shown a differential previous responseto either lithium or valproate, diagnostic heterogeneity within the samplepopulation, and frequency of comorbidity compared to the general population. The limitations of observational cohort studies are multiple and well documented. One key concern is confounding by indication, but more general problems exist with group biases and masking of cause and effect relationships.

Kessing et al used “switch to” and “add on” as proxy outcomes for theefficacy of mood stabilisers. It would have been interesting, if possible,to separate the “switch to” group from the “add on” groups. The “add on” outcome probably represents a treatment failure; however “switch to” is likely to be a combination of lack of efficacy and poor tolerability. Indeed their findings suggest that the initial, very rapid increase in incidence of switch/add on is related to tolerability rather than efficacy, whereas in BALANCE this finding would have been lost by drop-outduring the run-in period. This is unlikely, however, to explain the superiority of lithium, which is clearly present in both outcome measures.

It was previously argued that observational studies would overestimate treatment effects and that they hold little value in assessing therapies, however comparative studies with RCTs, across variousbranches of medicine, have now dismissed this(3). This sort of complementary approach, reconfirming findings from RCTs over long follow-up periods is an important addition to the evidence base for treatment. This is especially true in areas where the disorder under investigation ischronic relapsing-remitting, and when the exclusion criteria of RCTs can often mean that external validity is low. If, as has been suggested, bipolar disorder is a heterogeneous condition with subtypes associated with preferential response to specific mood stabilisers(4)(which can be identified by symptoms, clinical course, and family history), then the observational study carries even more weight when compared with the RCT asit ‘allocates’ patients to treatments based on predicted response, rather than randomisation. Bias can then be minimised by propensity score matching(5), (controlling for unmeasured bias between study groups) however this method was not employed by Kessing et al.

1. Kessing LV, Hellmund G, Geddes JR, Goodwin GM, Andersen PK. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. British Journal of Psychiatry 2011: published ahead of print. doi:10.1192/bjp.bp.110.084822

2. Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, Morriss R, Alder N, Juszczak E. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010: 375: 385–395

3. Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996: 312:1215-18

4. Alda M, O’Donovan C. A much needed BALANCE. Bipolar Disorder 2010:12: 678–680.

5. Rosenbaum PR, & Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983: 70 (1): 41–55.
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Conflict of interest: None Declared

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