Bipolar disorder is a life-long mood disorder characterised by episodes of mania (or hypomania) and depression. Bipolar I disorder, characterised by the presence of periods of mania, and bipolar II disorder, characterised by the presence of hypomanic and depressed episodes without mania, are the primary forms of the disorder. While the immediate treatment of acute episodes is an important part of care in bipolar disorder, an important (and arguably main) focus of management for patients with this disorder is the prevention of the relapse to and recurrence of mood episodes.
Antipsychotic medications (and, surprisingly, antidepressants) have overtaken lithium and other “mood-stabilising” medications such as valproic acid and carbamazepine as the primary prescribed medications in the treatment of bipolar disorder. Lamotrigine, an anticonvulsant drug that is thought to exert its action by inhibiting the release of the excitatory amino acid glutamate and inhibiting voltage-sensitive sodium channels, is licensed in the United States for the maintenance treatment of bipolar I disorder and in the UK to prevent depressive episodes in bipolar disorder.
Hashimoto and colleagues (2021) performed a Cochrane Intervention Review to ask the question of whether lamotrigine is, in fact, effective and safe in the maintenance treatment of bipolar disorder, compared to the most established maintenance treatment, lithium, and compared to placebo.
This review asks: Is lamotrigine effective and safe compared to placebo and the most established bipolar disorder maintenance treatment: lithium?
Methods
The authors searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Common Mental Disorders Group’s Specialised Register (CCMDCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL) from the inception of the study of the drug for bipolar disorder until 21 May 2021. They also searched international trial registries and contacted experts in the field to complete the review.
All randomised controlled trials enrolling adults with bipolar I or II disorder (with a diagnosis based on the International Classification of Diseases 11th Revision (ICD-11) coding system or the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) (or previous versions of these diagnostic manuals)) who were treated with lamotrigine, placebo or lithium were included in the analyses. Authors independently checked the eligibility of studies and extracted data using standardised means. They extracted study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy and tolerability, and study data were then entered into RevMan web. Studies were rated for bias using Cochrane’s tool for assessing the risk of bias.
The daily dosage of lamotrigine maintenance treatment was defined to range from 100 mg to 500 mg with a treatment duration of more than 12 weeks.
Results
Of 923 records screened, 781 were excluded, leaving 142 assessed for eligibility. Ultimately, 11 studies from 8 articles were included in the qualitative and quantitative synthesis.
The 11 studies included 2,314 participants, with 1,146 randomised to lamotrigine, 869 randomised to placebo, and 299 randomised to lithium. The certainty of the evidence, however, was rated to be “very low to moderate” because the majority of the studies did not describe how treatment allocation was concealed; that is, there was a high risk of “detection bias” which represents that there may not have been adequate blinding of the outcome assess, posing a “major risk to the validity” of the finding of the systematic review.
Taking this into account, the authors still report that lamotrigine was found to be superior over placebo in:
- Reduced rate of recurrence of manic symptoms
- Suppression of depressive symptoms
- Less need for additional therapeutic agents for the recurrence of all symptoms
- Reduction in the withdrawal rate due to any cause > 6 months after the start of the intervention.
Compared to lithium, lamotrigine was found to be:
- As effective for recurrence except for manic symptoms
- With lower rates of adverse effects.
This well conducted Cochrane review suggests that lamotrigine is a good option for the maintenance treatment of bipolar disorder, but the limited and sometimes weak evidence in the review leaves us in some doubt.
Conclusions
The bottom line:
- Low-certainty evidence suggests that lamotrigine prevents the recurrence of bipolar depression at 12 months, with moderate-certainty evidence that lamotrigine’s safety profile is similar to placebo.
- In addition, lamotrigine was comparable to lithium for “bipolar disorder symptoms”, with low-certainty evidence, except for the recurrence of manic episodes and symptoms, for which lithium was superior. Adverse events were lower for lamotrigine participants than for those on lithium.
Low-certainty evidence suggests that lamotrigine prevents the recurrence of bipolar depression at 12 months, with moderate-certainty evidence that lamotrigine’s safety profile is similar to placebo and comparable to lithium for “bipolar disorder symptoms”.
Strengths and limitations
The strengths of this study are its comprehensive review of the available data for longer-term (maintenance) treatment in well-described subjects who participated in randomised controlled trials. The studies themselves follow subjects systematically for 6 months or more, allowing the comparison for true recurrence (not just relapse to the initial episode at the start of the trials), giving some confidence to the outcome differences between groups.
The main limitation of the review is the quality of the evidence that comprises the data analysed in it, which is limited at times by small sample sizes and wide confidence intervals, but primarily limited by the possible bias in the trials of the concealment of randomisation assignment. The risk of detection bias was highest, found in six studies, with a high or unclear risk of bias also for selection bias and attrition bias, but not for the risk of reporting bias. In reality (and especially given the finding that lamotrigine had no greater adverse events than placebo), lamotrigine is not a drug that would be expected to have such great side effects that it would be easily apparent to the participant what their treatment assignment was. One might actually consider these data more confidently given that most of the drugs studied for use in the treatment of bipolar disorder, on the contrary, have such side effect burden that it is probably easy for participants (and investigators) to determine what the treatment assignment is, and likely over-estimating the effect for those drugs (such as quetiapine and olanzapine, for example) compared to placebo. That said, it is possible that the effect of lamotrigine compared to lithium – given that lamotrigine was the sponsor’s product – might lead to underreporting of the benefit of lithium and bias towards the better tolerated drug, lamotrigine. Given the sponsor’s “fiduciary responsibility towards its shareholders” as a publicly traded company, it’s possible that the dosing of lithium was purposefully higher than absolutely necessary in order to increase the likelihood of adverse events in that arm.
A limitation of the study, too, is that it concerns only outcomes for patients with bipolar I disorder and not for bipolar II disorder, a fairly common condition for which the treatment of and prevention of depressive episodes is an even more pressing concern.
Because these trials do not, in general, include participants who are receiving other treatments for bipolar disorder during the maintenance phase, its generalisability to practice, where patients are frequently treated with multiple medications, is not known.
This is a comprehensive review, but the high risk of bias in the included studies means we cannot be certain about the findings.
Implications for practice
This review underscores the efficacy and tolerability of lamotrigine for the maintenance treatment of bipolar disorder – especially for the prevention of depressive symptoms and episodes – but does not strongly support its use for the prevention of manic episodes. While a clinician might not be comfortable with the use of lithium because of its need for monitoring, its side effects (especially at higher doses), and its quite narrow therapeutic window, the review underscores the value of lithium in preventing mania.
How about depression? The authors clearly have a preference for lamotrigine in their discussion, primarily because of the relatively lack of adverse effects, going so far as to state that “Lithium, which has been used as standard first-line treatment, is associated with severe adverse effects and thus prone to treatment discontinuation and non-compliance.” Really? That’s not in the review. Contrary to the authors’ opining, given the need for the simultaneous prevention of depression and mania leave lithium, rather, as the preferred choice; lamotrigine, perhaps, should be left for the prevention of depression alone. And then why not the two together? Well, that might be a preferred strategy, but it’s a question not answered by this review, as the combination is not specifically studied or reviewed here. But I will go ahead anyway and suggest it: lamotrigine, given its utility for preventing depression, might be used in any patients for whom the prevention of depression is a treatment goal, but for most patients with bipolar disorder, it alone is not enough.
It is important to state the results of this systematic review, while not explicitly stated, are limited to the treatment of bipolar I disorder (those with a past history of manic episodes) and should not be extended to the treatment of patients with bipolar II disorder. In the treatment of bipolar I disorder, in spite of the presence of manic episodes as its hallmark, the course is often marked by periods of depression, so the prevention of depressive episodes should still be central to the treatment of most patients with bipolar disorder.
It is important to consider the use of lamotrigine primarily as a maintenance treatment, and as such, that clinicians adhere rigorously to the labelled titration schedule. The risk of life-threatening rash, while small, may be mitigated by slow dosage increases; it is prudent to take care when treatment is initiated or reinitiated. Because the primary benefit of the drug is in long-term treatment, rapid dose escalation is not of clinical utility.
Lamotrigine, given its utility for preventing depression, might be used in any patients for whom the prevention of depression is a treatment goal, but for most patients with bipolar disorder, it alone is not enough.
Statement of interests
Michael Ostacher is Data Safety Monitoring Board member for Janssen (Johnson & Johnson), Neurocrine and full-time employee of the United States Department of Veterans Affairs. Grant funding from Otsuka.
Links
Primary Paper
Hashimoto Y, Kotake K, Watanabe N, Fujiwara T, Sakamoto S. (2021) Lamotrigine in the maintenance treatment of bipolar disorder. Cochrane Database of Systematic Reviews 2021, Issue 9. Art. No.: CD013575. DOI: 10.1002/14651858.CD013575.pub2.
Other references
Rhee TG, Olfson M, Nierenberg AA, Wilkinson ST. 20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings. Am J Psychiatry. 2020 Aug 1;177(8):706-715. doi: 10.1176/appi.ajp.2020.19091000. Epub 2020 Apr 21. PMID: 32312111; PMCID: PMC7577523.
Perlis RH, Ostacher M, Fava M, Nierenberg AA, Sachs GS, Rosenbaum JF. Assuring that double-blind is blind. Am J Psychiatry. 2010 Mar;167(3):250-2. doi: 10.1176/appi.ajp.2009.09060820. PMID: 20194487.
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