A randomized controlled trial comparing lithium plus valproic acid versus lithium plus carbamazepine in young patients with type 1 bipolar disorder: the LICAVAL study

Abstract

BackgroundTreatment of bipolar disorder (BD) usually requires drug combinations. Combinations of lithium plus valproic acid (Li/VPA) and lithium plus carbamazepine (Li/CBZ) are used in clinical practice but were not previously compared in a head-to-head trial.ObjectiveThe objective of this trial was to compare the efficacy and tolerability of Li/VPA versus Li/CBZ in treating type 1 BD in any phase of illness in young individuals.MethodsLICAVAL was a randomized, unicenter, open-label, parallel-group trial that was conducted from January 2009 to December 2012 in a tertiary hospital in São Paulo, Brazil. Participants were between 18 and 35 years old and were followed up for 2 years. Our primary outcome was the number of participants achieving/maintaining response and remission during the acute and maintenance phases of BD treatment, respectively. Other outcomes assessed were symptom severity and adverse events throughout the study. In the analysis of the primary outcome, we compared groups by using a two-way repeated measures analysis of variance and estimated effect sizes by using Cohen’s d.ResultsOf our 64 participants, 36 were allocated to Li/VPA and 28 to Li/CBZ. Our sample was composed predominantly of females (66.6%) and the average age was 27.8 years. A total of 27 (45.0%) participants had depression, 17 (28.3%) had mania/hypomania, and 16 (26.7%) had a mixed state. We found no between-group differences in CGI-BP (Clinical Global Impression Scale modified for use in bipolar disorder) scores (P = 0.326) or in any other outcome. Side effects differed significantly between groups only in the first week of treatment (P = 0.021), and there were more side effects in the Li/VPA group. Also, the Li/VPA group gained weight (+2.1 kg) whereas the Li/CBZ group presented slight weight loss (−0.2 kg).ConclusionOur study suggests that Li/VPA and Li/CBZ have similar efficacy and tolerability in BD but that Li/CBZ might have metabolic advantages in the long term.Trial registrationClinicalTrials.gov identifier: NCT00976794. Registered on September 9, 2009.

Polypharmacy as maintenance treatment in bipolar illness: A systematic review

“…Finally, one RCT compared valproic acid + lithium vs. carbamazepine + lithium (Table 2). The study states there were no significant differences between the time‐to‐relapse curves (no ES reported, p = 0.45) 15 …”

“…One RCT protocol for the aripiprazole + quetiapine combination has been published, but results were not available on the date of our search. 10 Two observational studies with multiple treatment groups, 11,12 4 RCT on lithium + valproic acid, [13][14][15][16] 2 RCTs on lamotrigine + lithium, 17,18 1 RCT on lamotrigine + valproic acid, 19 1 RCT on asenapine + lithium or valproic acid, 20 1 RCT on aripiprazole + lamotrigine, 21 and 1 RCT on quetiapine + lamotrigine, 22 were included.…”

“…Eight RCTs presented control groups treated with one of the drugs in the combination [14][15][16][17][19][20][21][22] ; 7 of them had also placebo treatment in the monotherapy group. 14,16,17,[19][20][21][22] Two RCT had active treatment control groups with another combination therapy.…”

Efficacy of Carbamazepine and Its Derivatives in the Treatment of Bipolar Disorder

“…Among antiepileptic mood stabilizers, CBZ and VPA are potential candidates, especially in patients with a manic polarity of episodes. Missio and colleagues conducted a randomized open trial comparing LI plus VPA versus LI plus CBZ in young BD-I patients (LICAVAL study) [ 55 ]. They found no differences between treatment arms in the primary outcome (Clinical Global Impression scale modified for use in BD (CGI-BP)) or in any secondary outcome.…”

Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters

“…Regarding safety profile, lithium plus CBZ is safer than lithium plus VPA showing less metabolic side effects: patients treated with CBZ show normal levels of high-density lipoprotein (HDL) cholesterol or blood glucose concentrations compared to patients resorting to VPA which had decreased HDL cholesterol and higher blood glucose. In addition, females on VPA treatment might have higher risk of developing metabolic syndrome compared to males [ 43 , 44 ].…”