Conflict of Interest: I must state that I am a long-time colleague of John Geddes and his group at Oxford, having been an investigator in the BALANCE trial and one of the authors of its main publication. In addition I have been a paid advisor to Sunovion, whose drug lurasidone is an approved treatment in the US for bipolar depression.

Amongst people with bipolar disorder, depression seems to be the predominant mood problem (much more than mania or hypomania) and there aren’t many effective treatments for it (Judd LL, et al, 2002).

Most of the treatments with established efficacy for bipolar depression (quetiapine, lurasidone, and olanzapine combined with fluoxetine) benefit from a typically rapid onset of action (for those who do respond to them) but are burdened by their side effects.

Lamotrigine, relatively speaking, has few intolerable side effects, but as monotherapy is of limited benefit in the short term and must be increased to a therapeutic dosage very slowly because its risk of inducing a life-threatening rash (Geddes JR, et al, 2009).

John Geddes and his colleagues at Oxford and at 27 sites across the UK sought to ask two simple, clinically relevant questions:

1. Would there be longer-term benefit from the combination of lamotrigine and quetiapine (the only monotherapy approved for bipolar depression at the start of the trial)
2. Would folic acid, an over-the-counter dietary supplement with some evidence of efficacy for unipolar depression, add additional benefit (Taylor MJ, et al, 2004)?

Methods

Adults (aged 16 or older) with bipolar I or II disorder at 27 sites across the UK who were in a depressive episode entered a run-in phase of 7-14 days during which they were begun on quetiapine with a target dose of 300 mg. Those who were able to tolerate at least 150 mg of quetiapine for at least three days with good adherence (and for whom there was uncertainty about whether lamotrigine plus quetiapine would be preferable to quetiapine monotherapy) were randomised to lamotrigine or placebo titrated to 200 mg/day (100 mg/day with concurrent valproate and 400 mg/day with concurrent combined oral contraceptives) and additionally to 500 μg/day or placebo of folic acid.

The primary outcome was improvement of depressive symptoms as measured by the Quick Inventory of Depressive Symptomatology—self report version (QIDS-SR16) at 12 weeks, with additional analyses at 22 and 52 weeks.

Patients with bipolar disorder are typically treated with multiple drugs, but trial investigators were asked to taper and discontinue any drugs used to treat mood symptoms prior to the start of the run-in phase, but subjects who for clinical reasons were not able to discontinue all their treatment were still allowed to participate, with the instruction that the doses of those medications were to remain stable during trial participation.

Notably, all the measures were self-reported by trial participants rather than by trained raters. During the trial, manic symptoms were assessed with the Altman Self Rating Mania Scale (ASRM). Quality of life was measured at baseline and at 12 weeks and 52 weeks with the EuroQol EQ-5D-3L.

Results

202 participants were randomised, 101 to lamotrigine and 101 to placebo. Of the 266 participants who entered the run-in phase of the study, 19 (7%) were unable to progress to randomisation due to adverse effects or inability to tolerate quetiapine. Three-quarters of the sample had bipolar I disorder. The modal dose of quetiapine was 300 mg, but approximately one-third of the subjects were on less than 300 mg.

At 12 weeks, participants randomised to lamotrigine had lower QIDS-SR-16 scores than those randomised to placebo (–1·73 points ([95% CI –3·57 to 0·11]; p=0·066)), but this difference was not statistically significant. Similar effects were found at 22 weeks (–1·87 points [–3·92 to 0·17]; p=0·072) and at 52 weeks (–2·69 ([95% CI –4·89 to –0·49]; p=0·017). For several secondary outcomes, lamotrigine had greater benefit than placebo, including remission (QIDS ≤5) at 12 and 52 weeks, with p-values <0.05.

Folic acid added no benefit for the 150 subjects who were randomised to it: there was no difference between folic acid or placebo at 12, 22, or 52 weeks. Quality of life improved for all groups over the trial period.

A secondary analysis examined the interaction between folic acid and lamotrigine and found that those randomised to folic acid appeared to inhibit the effects of lamotrigine compared to placebo and lamotrigine. At 12 weeks, the mean difference in QIDS-SR16 on lamotrigine compared with placebo was –4·14 ([95% CI –6·90 to –1·37]; p=0·004) with no folic acid, and 0·12 ([–2·58 to 2·82]; p=0·931) with folic acid.

There were no differences between any of the groups in rates of hospitalization or start of new medications for depression. There were no differences in the rates of mania between any of the participants.

Conclusions

• Lamotrigine added a small, non-statistically difference on depression scores at 12 weeks when added to quetiapine for patients with bipolar I or II depression.
• This numerical difference persisted at 22 and at 52 weeks, and was found in other depression outcomes; the proportion of subjects requiring new treatment or hospitalisation for depression, however, did not differ between groups.
• Folic acid did not add additional benefit for the treatment of depression. In a post hoc analysis, the subgroup of subjects that received lamotrigine and placebo had improvement compared to the groups receiving both placebos or placebo and folic acid, while the subgroup of subjects that received lamotrigine and folic acid did not have this differential improvement. This raises the question of whether folic acid supplementation may have interfered with the therapeutic action of lamotrigine in this trial.

Strengths and limitations

• This a randomised trial of what appears to be a generalisable sample of subjects with bipolar disorder in a setting similar to that one would expect in clinical practice.
• Quetiapine is widely prescribed for bipolar depression, but does not work for everyone and is not always tolerated; this study attempts to answer the question of whether co-treatment with lamotrigine would add additional benefit, but also demonstrates that in clinical practice not all patients can take quetiapine at the evidence-based dose of 300 mg.
• The sample appeared to be large enough at the outset to answer the question in a clinically meaningful way, but the lack of statistical significance for the primary outcome suggests that the study may have been underpowered.

Summary

The interpretation of both the primary and secondary outcomes for this study should be taken cautiously. The authors are satisfied that lamotrigine plus quetiapine improves depression scores and remission rates at 12 and 52 weeks of treatment, yet the primary outcome measure is not statistically significant. It can be reasonably argued from a methodological perspective that the only outcome that is definitive in a clinical trial is the predetermined primary outcome – and if it is negative, the study is negative; all other outcomes are exploratory in nature.

Clinicians will probably not be satisfied with that point of view, and might want to glean something useful for their patients from a study like this, especially one in which many of the outcomes point in the direction of a finding a benefit for lamotrigine. If that is the case, there’s nothing in this study to suggest that one shouldn’t prescribe lamotrigine in such a way; in any case, lamotrigine does appear to prevent recurrence of depression, so prescribing it from the start may actually be prudent (Goodwin GM, et al, 2004).

The notion that folate may be inhibiting the antidepressants effects of lamotrigine is perhaps something to take with even more caution: it is not at all clear that this is due to anything but chance. It is an exploratory analysis undertaken post hoc, so cannot be used to say that lamotrigine is beneficial in the absence of folic acid (good luck trying that in the United States – practically everything one eats here is fortified with it!), and certainly should not be used to suggest (as the authors do in their paper) that lamotrigine not be prescribed to people who require folic acid supplementation.

Ultimately this study shows what most of the other acute studies of lamotrigine for bipolar depression have shown: that it may have some acute antidepressant effects but one probably shouldn’t rely on it for that (Geddes JR, et al, 2009; Van der Loos MLM, et al, 2009). Still, there are arguments for its use (and few against it), so go your own intrepid way.

Links

Primary paper

Geddes JR, Gardiner A, Rendell J, Voysey M, Tunbridge E, Hinds C, Yu LM, Hainsworth J, Attenburrow MJ, Simon J, Goodwin GM, Harrison PJ. (2015) Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial (PDF). CEQUEL Investigators and Collaborators. Lancet Psychiatry. 2015 Dec 10. pii: S2215-0366(15)00450-2. doi: 10.1016/S2215-0366(15)00450-2. [Epub ahead of print]

Other references

Geddes, JR, Calabrese, JR, and Goodwin, GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009; 194: 4–9

Goodwin, GM, Bowden, CL, Calabrese, JR et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004; 65: 432–441. [PubMed abstract]

Judd, LL, Akiskal, HS, Schettler, PJ et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder (PDF). Arch Gen Psychiatry. 2002; 59: 530–537.

Taylor, MJ, Carney, SM, Goodwin, GM, and Geddes, JR. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol. 2004; 18: 251–256. [PubMed abstract]

Van der Loos, MLM, Mulder, PGH, Hartong, EGTM et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009; 70: 223–231. [PubMed abstract]

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• Guian Bolisay CC BY 2.0
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