CEQUEL the sequel: bipolar disorder combination therapy
Authors: Gin S Malhi
Journal: The Lancet Psychiatry (2015)

Hollywood sequels are usually safe, predictable follow-ups to blockbuster movies that somehow hit upon a magic winning formula. Understandably, movie studios and film producers try to replicate their success by simply extending the story and using the same actors. This strategy seldom meets expectations—making the exceptions all the more remarkable—eg, the sequels to Star Wars, The Godfather, and (perhaps more controversially) Back to the Future. Published in 2010, the BALANCE study1Geddes JR Goodwin GM Rendell J et al.Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.Lancet. 2010; 375: 385-395Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar was psychiatry's Oscar equivalent of The King's Speech (Best Motion Picture, 2010). Like its cinematic counterpart, it retold a story about an element that we know, and always have known, is “King”, but that, because of a faltering voice (in lithium's case, its so-called orphan drug status), has been forced to work in silence.2Malhi G The king is dead, long live the king! The restoration of BALANCE.Bipolar Disord. 2010; 12: 681-684Crossref PubMed Scopus (11) Google Scholar The findings of the BALANCE study revitalised clinical interest in lithium and repositioned this essential element at the heart of bipolar disorder maintenance therapy.1Geddes JR Goodwin GM Rendell J et al.Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.Lancet. 2010; 375: 385-395Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar Scientifically, the landmark study tested combination therapy—a strategy that is in effect the norm in psychiatric practice, and yet for which few randomised controlled trials are done. BALANCE also studied the least investigated treatment phase of the illness—namely, prophylaxis. Though widely acknowledged as critical to functioning and overall wellbeing, prophylaxis is often considered too difficult to investigate—partly because of the length of time it takes to observe meaningful outcomes. But at least lithium has specificity of action in this phase of the illness, and is arguably most effective as maintenance therapy.3Gershon S Chengappa K Malhi G Lithium specificity in bipolar illness: a classic agent for the classic disorder.Bipolar Disord. 2009; 11: 34-44Crossref PubMed Scopus (85) Google Scholar In comparison with mania, bipolar depression is less well characterised and therefore its management is much less precise. For instance, it is mania, not the depressive phase of bipolar disorder, that defines the illness, and phenomenologically bipolar depression is indistinguishable from major depression. Hence, all the treatments for bipolar depression have been adopted, with not a single drug developed specifically for it. For example, antidepressants target major depression, antipsychotics treat schizophrenia, and anticonvulsants control epilepsy. Consequently, the effective treatment of depression in bipolar disorder remains unsatisfactory and problematic, especially because antidepressants are generally thought to be less effective in its treatment than they are for major depression and they might instead precipitate a treatment emergent affective switch or induce a mixed state.4Malhi G Diagnosis of bipolar disorder: who is in a mixed state?.Lancet. 2013; 381: 1599-1600Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar Thus, most clinical practice guidelines advise using antidepressants sparingly, and avoiding monotherapy when possible, especially in bipolar 1 disorder.5Pacchiarotti I Bond D Baldessarini R et al.The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders.Am J Psychiatry. 2013; 170: 1249-1262Crossref PubMed Scopus (494) Google Scholar Instead, conventional antidepressants should be prescribed alongside an antimanic agent (for example lithium), an antipsychotic, or an anticonvulsant. The drugs with the best evidence in this regard are quetiapine, lurasidone, olanzapine, lithium, valproate, and lamotrigine. All of these drugs can be given as monotherapy and therefore a study combining quetiapine and lamotrigine, possibly the two most common options from this menu for the treatment of bipolar depression, is both relevant and important.6Malhi GS Bassett D Boyce P et al.RANZCP clinical practice guidelines for mood disorders 2015.Aust NZ J Psychiat. 2015; 49: 1087-1206Crossref PubMed Scopus (520) Google Scholar As a sequel to BALANCE, the combination therapy study CEQUEL published in The Lancet Psychiatry does not disappoint.7Geddes JR Gardiner A Rendell J on behalf of the CEQUEL Investigators and CollaboratorsComparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial.Lancet Psychiatry. 2015; (published online Dec 10)http://dx.doi.org/10.1016/S2215-0366(15)00450-2Google Scholar But to facilitate success, John Geddes and colleagues have drawn on many of the original “cast” and produced the study against a backdrop of real-world practice. Here, quetiapine is often given short-term to ameliorate acute symptoms, especially those associated with anxiety, and this allows other coprescribed drugs to gain traction. For example, when used in conjunction with quetiapine in this manner, lamotrigine, which is known to be more effective longer term than acutely, is able to achieve a therapeutic level and exert its actions under the initial cover of the antipsychotic, which can then be gradually tapered and withdrawn. In CEQUEL, the investigators skillfully take advantage of the synergy between quetiapine and lamotrigine that arises from their differing, but complementary, mechanisms of action and the separate timescales over which they exert their effects. The study tests both the short-term and long-term benefits of combination therapy, and shows that lamotrigine add-on therapy to quetiapine is effective at 3 months (mean difference in QIDS-SR16 total score between the group receiving lamotrigine versus the placebo group at 12 weeks was −1·73 [95% CI −3·57 to 0·11]; p=0·066) and that the improvement is sustained for at least a year (−2·69 [−4·89 to −0·49]; p=0·017). This is the primary aim of CEQUEL, but most intriguing is exploration of the additional effect of folic acid, which the investigators cleverly include in the factorial study design. The precise role of folic acid in depression,8Papakostas GI Shelton RC Zajecka JM et al.L-Methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.Am J Psychiatry. 2012; 169: 1267-1274Crossref PubMed Scopus (200) Google Scholar and more specifically its role in bipolar depression, requires further investigation. Its involvement in methylation pathways in the one-carbon cycle, in particular the synthesis of S-adenosyl methionine from homocysteine, suggests that it facilitates antidepressant actions of medications thought to act via monoamine neurotransmitter systems.9Fava M Mischoulon D Folate in depression: efficacy, safety, differences in formulations and clinical issues.J Clin Psychiatry. 2009; 70: 12-17Crossref PubMed Scopus (103) Google Scholar In CEQUEL, lamotrigine and folic acid interact such that the latter diminishes the additive effects of lamotrigine on quetiapine at 12 weeks. The authors speculate that this is a pharmacokinetic or pharmacodynamic effect—the latter being mediated via a common enzyme or receptor site. The precise nature of the interaction is unknown, but it highlights the potential role of neutraceuticals in the treatment of mood disorders, and the need for psychiatrists to additionally consider the nutritional and metabolic health of their patients. The effects of medication withdrawal, diagnostic heterogeneity, and small sample size often confound findings from bipolar disorder trials. These are all relevant concerns for CEQUEL, which is additionally constrained by reliance on self-report measures for assessing key outcomes. However, the latter is also a potential strength and perhaps an advance, for two reasons. First, a patient rating their own symptoms reflects real-world practice, where clinicians are dependent upon what patients report. Second, with the advent of mobile technologies that can more closely and accurately monitor and capture both emotions and activity, self-report is likely to become increasingly integral to future clinical trials. The findings from CEQUEL, although interesting and clinically relevant, still need replication and corroboration from both randomised controlled trials and empirical research. Therefore let's hope there are more sequels to come, and that CEQUEL is simply the first of many such studies that aim to improve the treatment of bipolar depression. I have received research funding from AstraZeneca, Eli Lilly, Organon, Pfizer, Servier, and Wyeth; am a speaker for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and a consultant for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, and Servier. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trialAddition of lamotrigine to quetiapine treatment improved outcomes. Folic acid seems to nullify the effect of lamotrigine. CEQUEL should encourage clinicians and patients to consider lamotrigine for bipolar depression, but also to be aware that concurrent folic acid might reduce its effectiveness. Full-Text PDF Open Access