Lamotrigine and Lithium Combination for Treatment of Rapid Cycling Bipolar Disorder: Results From Meta-Analysis

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It can seem like everyone with bipolar disorder has the rapid cycling subtype, where they could have 4 or more mood episodes per year. However, the prevalence of rapid cycling is only about 10%–30% in bipolar disorders. Even the lifetime prevalence is only 25%–40%. In part, these patients look so common because they're harder to treat. So, how should rapid cycling be treated? Specifically, does a combination of lamotrigine and lithium work better than lithium alone?

Hi! Jim Phelps here for the Psychopharmacology Institute. Before we look at that question, a few basics about rapid cycling. First, it's so consistently associated with antidepressant use that a routine treatment recommendation is taper the patient's antidepressant if they're on one. Another factor strongly associated with rapid cycling is hypothyroidism. According to one review of thyroid hormone in psychiatric disorders, one shouldn't wait for a TSH over the lab's upper limit like 4.5 mIU/L to consider thyroid augmentation. Really, anything over about 2.5 warrants that thought.

Next, you'll see some references suggesting that lithium is less effective for patients with rapid cycling. Careful, that's not a comparison with other medications; it's a comparison with its effectiveness for patients without rapid cycling. Lithium is definitely a candidate for patients with the rapid cycling subtype and particularly obvious in bipolar I, where antimanic prophylaxis is a necessary consideration. Lamotrigine is also an obvious candidate, described in one review as "the best hope for monotherapy."

So, what about the combination of lamotrigine and lithium then? A marriage of reliable antidepressant and antimanic effects and both potentially mood stabilizing? To examine this potential, Gao Zhihan and colleagues reviewed the literature and found 5 studies in which the combination was compared with a controlled therapy, most often lithium alone. Alas, there are problems with the data. These include possible publication bias, and sometimes valproate was also used either with the lithium–lamotrigine combination or with the lithium in a nominal control group. One study didn't report response rates. So, with those concerns, we have 4 studies that examine the efficacy of lithium with lamotrigine vs lithium alone, 2 studies conducted on participants with treatment-resistant rapid cycling, and 2 studies in which the patients were not regarded as treatment resistant.

So, here come the results. In the not treatment-resistant group, a lithium–lamotrigine combination was better than lithium alone, but that was in just 50 patients. In the treatment-resistant patients, the combination was not superior to the control condition, but that was in just 44 patients. In conclusion, these data are not really robust enough to clearly guide us as regards the combination of lamotrigine and lithium vs lithium alone in the treatment of rapid cycling bipolar disorder. The combination wasn't worse, so it remains an obvious option. At minimum, this article was a good reminder to check thyroid status and strongly consider tapering any antidepressant present.

For more on this, even the “taper the antidepressant” literature is tricky. It's mostly but not entirely supportive of tapering. And how fast to taper? That's a question just now being more thoroughly explored in antidepressant discontinuation generally, and it's particularly challenging in rapid cycling. You want to get the antidepressant out of there as quickly as possible, and yet these patients seem particularly vulnerable to severe withdrawal effects, including accelerating and exacerbating cycling.

So, to close, I'll share my own personal approach in antidepressant tapering in hopes of passing along something helpful here; it's a variation of the hyperbolic taper suggested by Drs. Horowitz and Taylor. In my view, the key is to make the first step successful so that you're not immediately forced to conclude, “Oh, this antidepressant is actually necessary”. Decrease by the smallest step possible, including quartering pills, and then reassess after a few days for inpatients and a few weeks for outpatients. No problem? Go down again. If you're in a hurry, you can try bigger or faster steps. But worsening? Wait until things are back to where you started, and then wait another week and then figure out how to take an even smaller step down using a liquid preparation if necessary. As you near zero, be prepared to slow down and take very small steps again to avoid withdrawal symptoms or exacerbating cycling.

Abstract

Objective: The objective of this study is to observe the effect of combination of lithium and lamotrigine in treatment of rapid-cycling bipolar disorder (RCBD).

Method: We searched MEDLINE, EMBASE, Cochrane Library in English and CBM, CNKI, WANFANG, and CSSCI in Chinese to find literature from 1 January 2000 to 31 December 2020 related to the combination of lithium carbonate and lamotrigine for treatment of RCBD.

Results: Five comparison studies with 265 subjects of 131 cases in a study group and 134 cases in a control group met the inclusion criteria and were included for the final meta-analysis. The comprehensive analysis shows that the study group had a significant lower score in mental symptoms than the control group (Z = 2.34, P = 0.02) with a random model (X 2 = 33.02, df = 7, P < 0.01). However, the differences were only shown in PANSS (Z = 5.18, P < 0.01) and BPRS (Z = 3.08, P < 0.01). There was no difference in response rate (54.9 vs. 45.7%; OR = 1.47; 95% CI: 0.79~2.73; Z = 1.21, P > 0.05,) and remission rate (47.9 vs. 45.9%; OR = 1.05; 95% CI: 0.49~2.25; Z = 0.13, P > 0.05,) found between the two groups. The response rate of lamotrigine and lithium combination was significantly higher compare to that of monotherapy of lithium in patients with no treatment resistant (82 vs. 54%; OR = 4.26; 95% CI: 1.65~10.99; Z = 3.99, P < 0.01) with the fixed effect model (X 2 = 0.89, df = 1, P > 0.05, I 2 = 0%).

Conclusion: The combination of lithium and lamotrigine resulted in better improvement of psychotic symptoms and higher response rate in patients with RCBP with no treatment resistant.

Keywords: RCBD; bipolar disorder; combination therapy; lamotrigine; lithium.

Reference

Zhihan, G., Fengli, S., Wangqiang, L., Dong, S., & Weidong, J. (2022). Lamotrigine and lithium combination for treatment of rapid cycling bipolar disorder: Results from meta-analysis. Frontiers in Psychiatry, 13, 913051.

Horowitz, M. A., & Taylor, D. (2019). Tapering of SSRI treatment to mitigate withdrawal symptoms. The Lancet Psychiatry, 6(6), 538-546.