Lithium a continuing story in the treatment of bipolar disorder

Acta Psychiatr Scand 2005: 111 (Suppl. 426): 7 12 All rights reserved Copyright ª Blackwell Munksgaard 2005 ACTA PSYCHIATRICA SCANDINAVICA Lithium a continuing story in the treatment of bipolar disorder Carney SM, Goodwin GM. Lithium a continuing story in the treatment of bipolar disorder. Acta Psychiatr Scand 2005: 111 (Suppl. 426): 7 12. ª Blackwell Munksgaard 2005. Objective: To review the literature on the use of lithium in the treatment of bipolar disorder and highlight the evidence base supporting its efficacy and safety. Method: A selective literature review. Results: Lithium is widely believed to be effective against acute mania, acute bipolar depression and in relapse prevention to either mania or depression. In fact, the data supporting efficacy in acute treatment are less impressive than is often claimed, whereas for relapse prevention and suicide prevention no other agent has comparable depth of support. Lithium is best described as the bench mark treatment for bipolar disorder, rather than the gold standard, because only a minority of patients show major clinical benefit. There is a developing need for further trials against new alternatives and in combination studies. Conclusion: Lithium has a continuing important role in the clinical management of bipolar disorder. Its under-utilization in North America reflects opinion rather than evidence and the demonstrated anti-suicide effects should help to reignite interest in its use. S. M. Carney, G. M. Goodwin University Department of Psychiatry, Warnford Hospital, Oxford, UK Key words: lithium; bipolar disorder; evidence-based medicine; trials; mood stabilizer Guy Goodwin, University Department of Psychiatry, Warnford Hospital, Oxford OX3 7JX, UK. E-mail: guy.goodwin@psych.ox.ac.uk Introduction Lithium is the archetypal mood stabilizer. First used in psychiatry in the late 1940Õs, it rapidly became the standard treatment for relapse prevention in bipolar disorder (1). The last decade, however, has seen a dramatic reduction in its use, especially in North America. This has largely been because of concerns about its effectiveness, adherence to treatment and the risk of rebound mania following abrupt discontinuation (2 5). The promotion of newer anticonvulsants, starting with valproate, as both effective and easier to use has resulted in many clinicians discarding lithium. However, there is a substantial evidence base supporting the use of lithium both in the treatment of mania and in the prevention of relapse (6 8). Recent maintenance studies examining the relapse prevention credentials of anticonvulsants have, almost inadvertently, contributed substantial additional data in support of lithium (7). It may be premature to say so, and perhaps over optimistic, but we anticipate a renaissance of lithium s fortunes particularly in North America based on this new data. We will explain why, giving emphasis to papers that synthesize the evidence base as reviews and meta-analyses and consider directions for future research. Aims of the study The following article reviews the evidence-base that supports the use of lithium in the treatment of bipolar disorder and critically examines its credentials as a mood stabilizer. Material and methods In this paper we provide the results of a selective review of the evidence as regards the use of lithium in the treatment of bipolar disorder. The authors drew on articles known to them and performed additional searches of the literature as deemed appropriate. 7

Carney and Goodwin Results Evidence-base for the treatment of mania Lithium was first claimed to be effective in bipolar disorder on the basis of uncontrolled open treatment of acute mania (9). There is now convincing randomized evidence to support the use of lithium in mania (10). One systematic review describing the results from a single randomized controlled trial (RCT) found that more patients with bipolar type 1 disorder responded after 3 4 weeks with lithium compared with placebo (8). Compared with valproate, a Cochrane review of three RCT found no difference in the proportion of people responding over 3 6 weeks (11). In the largest head-to-head randomized comparison with chlorpromazine, lithium was less effective in the most active patients (12). Nevertheless, it was slightly superior to chlorpromazine in other smaller studies, demonstrated similar efficacy to haloperidol and olanzapine but was inferior to risperidone (8, 13). The choice of first-line agent for the treatment of mania remains controversial. The US clinical guidelines have consistently advocated the use of a mood-stabilizer alone for the treatment of mania or hypomania, reserving adjunctive use of antipsychotics for the most severe presentations (14). This is clearly at odds with the near universal use of antipsychotics to treat severe mania revealed by surveys in both the USA and Europe (15). In recognition of this data and the emerging support for the use of atypical antipsychotics in mania from well conducted placebo-controlled trials, the British Association for Psychopharmacology recommended initial oral administration of an antipsychotic or valproate because of their rapid anti-manic effect (16). The UK guidelines reserve short-term lithium treatment as an option for patients who are less ill and less likely to be metabolically compromised. When employed as an anti-manic agent, lithium levels of up to 1.4 mmol/l are commonly recommended in the acute phase. Evidence-base for the treatment of bipolar depression Lithium is usually described as effective in acute bipolar depression on the basis of a number of very small trials conducted early in its adoption as a treatment for bipolar disorder (17). Furthermore, there is a very pervasive consensus view that the first step in managing bipolar depression should be to initiate or ÔoptimizeÕ treatment with a mood stabilizer, usually lithium and the second should be to combine an antidepressant with the mood stabilizer (14, 18 20). On the basis of these recommendations, one might expect the evidence for lithium s efficacy as a single treatment or when combined with another agent to be convincing. Unfortunately, scrutiny of the actual trials quickly reveals their inadequacy (21). Obviously the absence of evidence is not evidence of an absence of effect, and the effects on relapse prevention and suicide favour some action against depression (see below), but it is ironic that lithium is so confidently advocated as a treatment for acute depression on so slender an evidence base. Evidence-base for relapse prevention The most recent systematic review examining the long-term effects of lithium identified five placebocontrolled randomized trials which had included only bipolar patients (7): 770 participants were followed either until relapse or for between 11 months and 4 years. Lithium levels were maintained between 0.5 and 1.4 mmol/l. Three of the included RCTs also examined anticonvulsants (divalproex and lamotrigine): these studies were only reported or published in the last 4 years (22 24). Relapse was typically defined as requiring clinical intervention (initiation of a new treatment or admission to hospital). Taking account of statistical heterogeneity, meta-analysis found that lithium compared with placebo, reduces the risk of relapse by about one-third (risk ratio (RR) ¼ 0.65, 95% CI: 0.50, 0.84) (see Fig. 1). The average risk Fig. 1. Randomized, placebo-controlled trials assessing the effectiveness of lithium for the prevention of any relapse in bipolar disorder patients (reproduced with permission from the American Journal of Psychiatry, Copyright 2004. American Psychiatric Association). 8

Lithium in the treatment of bipolar disorder of relapse in the placebo group was 60% compared with 40% on lithium suggesting that five patients need to be treated with lithium to prevent one additional relapse within 2 years. Examining the character of the experienced relapses, suggests that lithium is more effective in the prevention of mania (RR ¼ 0.62; 95% CI: 0.40, 0.95) (7) (see Fig. 2) than depression (RR ¼ 0.85, 95% CI ¼ 0.66, 1.11)(25) (see Fig. 3). The adverse effect profile did not appear to be too burdensome with 14% (fixed effects RR ¼ 0.86; 95% CI: 0.80, 0.93) fewer participants on lithium withdrawing prematurely from the trial. Hypothyroidism, nausea, somnolence and diarrhoea occurred more commonly among those treated with lithium. Side-effects with lithium are dose related and the RCTs have aimed for levels >0.8 mmol/l, which are higher than usually achieved in clinical practice because of the trade-off between effectiveness and tolerability. One study that re-assigned patients to high or low lithium levels had an interesting outcome (3). Patients tolerating high levels who were re-assigned to lower levels tended to show an excess of relapse. By contrast there was no benefit from re-assigning patients with low prevailing lithium levels to higher doses. Accordingly, the highest well-tolerated dose should be recommended for the long term to optimize adherence to treatment. Poor adherence is a contraindication to lithium because abrupt discontinuation of treatment increases the short-term risk of relapse (26, 27). The RCTs have also allowed some comparison between lithium and the anticonvulsants: valproate, carbamazepine and lamotrogine. Valproate (usually as semi-sodium valproate) is the most commonly prescribed mood-stabilizer although there is only one RCT examining comparative effectiveness in the maintenance phase (28). For the systematic review including this RCT, relapse was the primary outcome measure. There was no statistically significant difference between the two medicines by 12 months but there was a trend in favour of divalproex (RR 0.8; 95% CI 0.5, 1.2). Secondary endpoints in the RCT suggested that divalproex may be superior to lithium in effecting longer duration of successful prophylaxis and better depressive symptom and Global Assessment Scale scores (22). The trial was an important landmark the first large maintenance study in bipolar disorder for 20 years and has informed subsequent studies as much by its failings (recruitment of non-severe patients, admission to hospital as the sole primary endpoint), as by its strengths. The side-effect profile favoured divalproex with more participants on lithium experiencing polyuria, thirst, tachycardia, akathisia and dry eyes while more participants taking divalproex felt sedated or experienced tinnitus. Similarly, no statistically significant differences were identified when the effectiveness of lithium was compared with carbamazepine in a systematic review which included the MAP study (29). Fig. 2. Randomized, placebo-controlled trials assessing the effectiveness of lithium for the prevention of manic relapse in bipolar disorder patients (reproduced with permission from the American Journal of Psychiatry, Copyright 2004. American Psychiatric Association). Fig. 3. Randomized, placebo-controlled trials assessing the effectiveness of lithium for the prevention of depressive relapse in bipolar disorder patients (reproduced with permission from the American Journal of Psychiatry, Copyright 2004. American Psychiatric Association). 9

Carney and Goodwin However, a subsequent well conducted trial in patients starting maintenance treatment for the first time suggested that lithium was superior to carbamazepine (30). Two studies of lamotrigine showed no overall difference (23, 31) but see Calabrese (this issue) for a discussion of the differential effect of lithium (more effective against mania) and lamotrigine (more effective against depression). Suicide prevention An estimated 6% of individuals with affective disorders including those diagnosed with bipolar disorder commit suicide (32). Combining the results from follow-up studies conducted throughout the last century suggests that patients with bipolar disorder have a 15 times greater than expected risk of suicide (33). Furthermore, between a quarter and a half of patients with bipolar disorder attempt suicide (34). The RCT have been underpowered to assess whether mood-stabilizers including lithium are effective in preventing suicide and deliberate self harm. However, in a systematic review of all relevant trials reporting mortality and suicide, more of the lithium-treated participants survived than those in the comparison groups (35). There is also consistent evidence from nonrandomized studies that lithium not only reduces the risk of suicide attempts but also completed suicide (36). Meta-analysis of the results of 33 observational studies investigating the effectiveness of lithium suggests a 13-fold reduction among those receiving long-term treatment (37). A further retrospective cohort study with a population-based sample suggests that lithium may be more effective in reducing suicidal acts and behaviours than divalproex (38). Even adjusting for a number risk factors for suicide (age, sex, health plan, year of diagnosis, comorbid medical and psychiatric conditions, and concurrent use of other psychotropic drugs) the risk of completed suicide was 2.7 (95% CI: 1.1 6.3) times higher among those treated with divalproex compared with lithium. The possibility of Ôconfounding by indicationõ cannot be overlooked and may have resulted in the most stable patients receiving lithium and the more unwell receiving divalproex (39). There was a similar trend when lithium was compared with carbamazepine although far fewer patients were taking this mood stabilizer. The latter result is consistent with the subgroup analyses from the MAP RCT suggesting that lithium is more effective in preventing both suicide attempts and acts than carbamazepine (40). Discussion Lithium has claims to meet the most stringent criteria for a mood stabilizer (17). It is widely believed to be effective against acute mania, acute bipolar depression and in relapse prevention to either mania or depression. In fact the data for acute treatment is less impressive than is often claimed, but for relapse prevention and suicide prevention no other agent has comparably convincing data from multiple trials. Lithium is sometimes called the gold standard treatment for bipolar disorder. In fact, it would be best described as the bench mark treatment. It is the treatment against which other medicines should be measured in headto-head comparison. There is an urgent need for large simple RCT investigating the effectiveness of lithium alone and in combination compared with other agents in the prevention of not only relapse but also deliberate self-harm and suicide. Improving concordance with treatment regimes remains one of the greatest clinical challenges and future research must also evaluate strategies to improve quality of life and functioning. There are two major relapse prevention studies currently underway, Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and Bipolar Affective Disorder Lithium/Anticonvulsant Comparative Evaluation (BALANCE). The STEP-BD is a US, multicentre, longitudinal study, which provides a platform for a variety of clinical trials and other studies (41). The randomized treatment opportunities include a 2-year double-blind comparison of any mood-stabilizer and placebo compared with divalproex and lithium for patients who have become manic on either lithium or divalproex alone. Outcomes of interest include recovery, time to event, drop-out, care utilization, time in remission and functional impairment. The BALANCE is a multicentre, UK and US, randomized trial comparing lithium, divalproex and lithium and divalproex in combination (42). The pilot study and start-up phase have identified a number of pragmatic refinements to promote recruitment and follow-up including: the dropping of masking (blinding) of participants and clinicians, the introduction of postal medication delivery and fewer follow-up appointments (43). The study plans to randomize as many participants as possible before the end of 2005 and will assess whether the combination treatment arm is more effective in preventing hospital admission over a 2-year period than either monotherapy. To conclude the renewed research interest in lithium not just as Ôtreatment-as-usualÕ but also as a 10

Lithium in the treatment of bipolar disorder component of combination therapy suggests that lithium will continue to play an important role in clinical practice. We hope its much reduced role in North America will be followed by a recovery of interest, particularly because of the apparent effectiveness in preventing suicide and an improved appreciation of the need for evidence rather than opinion in shaping clinical practice. Acknowledgements This article has been supported by an unrestricted educational grant from Sanofi-Aventis. The authors would like to thank Professor John Geddes for providing data from the systematic review of long-term lithium therapy for bipolar disorder and the American Journal of Psychiatry for granting permission to reproduce the forest plots. Declaration of interest GMG is in receipt of grant support from Sanofi-Aventis for BALANCE and has advised Solvay pharmaceuticals on two occasions in the last 5 years. 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