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. 2021 Aug;26(8):4146-4157.
doi: 10.1038/s41380-020-00946-6. Epub 2020 Nov 11.

Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials

Taro Kishi  1 , Toshikazu Ikuta  2 , Yuki Matsuda  3 , Kenji Sakuma  4 , Makoto Okuya  4 , Kazuo Mishima  5 , Nakao Iwata  4
Affiliations

Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials

Taro Kishi et al. Mol Psychiatry. 2021 Aug.

Abstract

We searched Embase, PubMed, and CENTRAL from inception until 22 May 2020 to investigate which antipsychotics and/or mood stabilizers are better for patients with bipolar disorder in the maintenance phase. We performed two categorical network meta-analyses. The first included monotherapy studies and studies in which the two drugs used were specified (i.e., aripiprazole, aripiprazole once monthly, aripiprazole+lamotrigine, aripiprazole+valproate, asenapine, carbamazepine, lamotrigine, lamotrigine+valproate, lithium, lithium+oxcarbazepine, lithium+valproate, olanzapine, paliperidone, quetiapine, risperidone long-acting injection, valproate, and placebo). The second included studies on second-generation antipsychotic combination therapies (SGAs) (i.e., aripiprazole, lurasidone, olanzapine, quetiapine, and ziprasidone) with lithium or valproate (LIT/VAL) compared with placebo with LIT/VAL. Outcomes were recurrence/relapse rate of any mood episode (RR-any, primary), depressive episode (RR-dep) and manic/hypomanic/mixed episode (RR-mania), discontinuation, mortality, and individual adverse events. Risk ratios and 95% credible interval were calculated. Forty-one randomized controlled trials were identified (n = 9821; mean study duration, 70.5 ± 36.6 weeks; percent female, 54.1%; mean age, 40.7 years). All active treatments other than carbamazepine, lamotrigine+valproate (no data) and paliperidone outperformed the placebo for RR-any. Aripiprazole+valproate, lamotrigine, lamotrigine+valproate, lithium, olanzapine, and quetiapine outperformed placebo for RR-dep. All active treatments, other than aripiprazole+valproate, carbamazepine, lamotrigine, and lamotrigine+valproate, outperformed placebo for RR-mania. Asenapine, lithium, olanzapine, quetiapine, and valproate outperformed placebo for all-cause discontinuation. All SGAs+LIT/VALs other than olanzapine+LIT/VAL outperformed placebo+LIT/VAL for RR-any. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-dep. Aripiprazole+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-mania. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for all-cause discontinuation. Treatment efficacy, tolerability, and safety profiles differed among treatments.

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Conflict of interest statement

The authors have declared that there are no conflicts of interest relating to the subject of this study. Interests from the past three years are as follows. Dr. Kishi received speaker’s honoraria from Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen, Otsuka, Meiji, Mochida, MSD, and Tanabe-Mitsubishi (Yoshitomi); as well as research grants from the Japanese Ministry of Health, Labor and Welfare (H29-Seishin-Ippan-001, 19GC1012), Grant-in-Aid for Scientific Research (C), and Fujita Health University School of Medicine. Dr. Ikuta has no conflicts of interest with any company. Dr. Matsuda has received speaker’s honoraria from Dainippon Sumitomo, Janssen, Kyowa, Otsuka, Tanabe-Mitsubishi, and Yoshitomi. Dr. Sakuma has received speaker’s honoraria from Eisai, Kissei, Meiji, Otsuka, and Torii; and has received a Fujita Health University School of Medicine research grant, as well as a Grant-in-Aid for Young Scientists (B). Dr. Okuya has received speaker’s honoraria from Meiji. Dr. Mishima received research support from the Japanese Ministry of Health, Labor and Welfare (H29-Seishin-Ippan-001, 19GC1012) and the Japanese Ministry of Education, Culture, Sports, Science and Technology Collaborative research fund with Taisho; as well as speaker’s honoraria from Eisai, MSD, Takeda, Astellas, Pfizer, Otsuka, Mochida, Mitsubishi Tanabe, Yoshitomi, and Janssen; and research grants from Eisai, Nobelpharma, Otsuka, and Takeda. Dr. Iwata received speaker’s honoraria from Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Takeda, Meiji, and Pfizer; along with research grants from Daiichi Sankyo, Takeda, Dainippon Sumitomo Eisai, Meiji Tanabe-Mitsubishi and Otsuka.

Figures

Fig. 1
Fig. 1. Recurrence/relapse rate of any mood episode.
Drugs were compared with placebo. To visualize heterogeneity, we used prediction intervals in the forest plot. The confidence level estimated by CINeMA is shown next to 95% PI (L: low, M: moderate, VL: very low). 95% CI: 95% credible interval, 95% PI: prediction interval, CR: confidence rating, RR: risk ratio. AOM aripiprazole once monthly, ARI aripiprazole, ASE asenapine, CAR carbamazepine, LAM lamotrigine, LIT lithium, OLA olanzapine, OXC oxcarbazepine, PAL paliperidone, QUE quetiapine, RISLAI risperidone long-acting injectable, VAL valproate.
Fig. 2
Fig. 2. Recurrence/relapse rate of depressive episodes and manic/hypomanic/mixed episodes.
a Recurrence/relapse rate of depressive episodes. b Recurrence/relapse rate of manic/hypomanic/mixed episodes. Drugs were compared with placebo. To visualize heterogeneity, we used prediction intervals in the forest plot. The confidence level estimated by CINeMA is shown next to 95% PI (L: low, M: moderate, VL: very low). 95% CI: 95% credible interval, 95% PI: prediction interval, CR confidence rating, RR risk ratio. AOM aripiprazole once monthly, ARI aripiprazole, ASE asenapine, CAR carbamazepine, LAM lamotrigine, LIT lithium, OLA olanzapine, OXC oxcarbazepine, PAL paliperidone, QUE quetiapine, RISLAI risperidone long-acting injectable, VAL valproate.
Fig. 3
Fig. 3. All-cause discontinuation and discontinuation rate due to adverse events.
a All-cause discontinuation. b Discontinuation rate due to adverse events. Drugs were compared with placebo. To visualize heterogeneity, we used prediction intervals in the forest plot. The confidence level estimated by CINeMA is shown next to 95% PI (L: low, M: moderate, VL: very low). 95% CI: 95% credible interval, 95% PI: prediction interval, CR confidence rating, RR risk ratio. AOM aripiprazole once monthly, ARI aripiprazole, ASE asenapine, CAR carbamazepine, LAM lamotrigine, LIT lithium, OLA olanzapine, OXC oxcarbazepine, PAL paliperidone, QUE quetiapine, RISLAI risperidone long-acting injectable, VAL valproate.
See this image and copyright information in PMC

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