Variability and efficacy in treatment effects on manic symptoms with lithium, anticonvulsants, and antipsychotics in acute bipolar mania: A systematic review and meta-analysis

Tien-Wei Hsu; Trevor Thompson; Marco Solmi; Eduard Vieta; Fu-Chi Yang; Ping-Tao Tseng; Chih-Wei Hsu; Yu-Kang Tu; Chia-Ling Yu; Chia-Kuang Tsai; Chih-Sung Liang; Andre F Carvalho

doi:10.1016/j.eclinm.2022.101690

Variability and efficacy in treatment effects on manic symptoms with lithium, anticonvulsants, and antipsychotics in acute bipolar mania: A systematic review and meta-analysis

EClinicalMedicine. 2022 Oct 6:54:101690. doi: 10.1016/j.eclinm.2022.101690. eCollection 2022 Dec.

Authors

Tien-Wei Hsu¹, Trevor Thompson², Marco Solmi^{3

4

5

6}, Eduard Vieta⁷, Fu-Chi Yang⁸, Ping-Tao Tseng^{9

10

11}, Chih-Wei Hsu¹², Yu-Kang Tu¹³, Chia-Ling Yu¹⁴, Chia-Kuang Tsai⁸, Chih-Sung Liang^{15

16}, Andre F Carvalho¹⁷

Affiliations

¹ Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
² Centre for Chronic Illness and Ageing, University of Greenwich, London, UK.
³ Department of Psychiatry, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
⁴ Department of Mental Health, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.
⁵ Clinical Epidemiology Programme, Ottawa Hospital Research Institute (OHRI), University of Ottawa, Ottawa, ON K1N 6N5, Canada.
⁶ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
⁷ Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain; Hospital Clinic, Institute of Neuroscience, Universityof Barcelona, IDIBAPS, Barcelona, Spain.
⁸ Department of Neurology, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan.
⁹ Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung City, Taiwan.
¹⁰ Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
¹¹ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
¹² Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹³ Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹⁴ Department of Pharmacy, Chang-Gung Memorial Hospital, Linkou, Taiwan.
¹⁵ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan.
¹⁶ Department of Psychiatry, National Defence Medical Centre, Taipei, Taiwan.
¹⁷ IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.

Abstract

Background: Acute mania is a psychiatric emergency requiring rapid management. However, randomised controlled trials (RCTs) have shown considerable individual differences in treatment effects on manic symptoms with antimanic drugs.

Methods: We searched the MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov to identify RCTs without language restrictions from inception to April 19, 2022. We included double-blind RCTs of oral antimanic monotherapy versus placebo in adult patients. The primary outcome was variability in improvement of manic symptoms (assessed using the coefficient of variation ratio [CVR]). The secondary outcomes were overall improvement of manic symptoms and acceptability (i.e., discontinuation for any reason). The pooled effects of outcomes were calculated by random-effects meta-analyses using restricted maximum likelihood methods. The quality of the included studies was assessed using the Cochrane Risk of Bias (ROB) Assessment Tool. This study was registered with OSF (DOI:10.17605/OSF.IO/G4JNY).

Findings: We included 39 RCTs (N=12150; mean age=39·9 years, interquartile range [IQR]=38·7-41·1; mean proportion of female=48·6%, IQR=42·3%-52·3%) and investigated 14 antimanic drugs. We found that eight antimanic drugs compared to placebo were associated with lower CVRs (95% confidence interval [CI]; I²), including risperidone (0·51; 0·37-0·70; 0%), haloperidol (0·54; 0·44-0·67; 4%), olanzapine (0·59; 0·44-0·79; 47%), ziprasidone (0·61; 0·53-0·71; 0%), lithium (0·63; 0·52-0·76; 0%), quetiapine (0·65; 0·48-0·87; 2%), aripiprazole (0·68; 0·56-0·84; 25%), and cariprazine (0·70; 0·49-0·99; 28%). There were nine antimanic drugs associated with greater efficacy than placebo, including risperidone (reported as standardised mean difference; 95% CI; I²: 0·64; 0·31-0·97; 15%), haloperidol (0·57; 0·29-0·85; 64%), cariprazine (0·51; 0·24-0·78; 0%), olanzapine (0·44; 0·30-0·58; 0%), lithium (0·42; 0·29-0·55; 0%), ziprasidone (0·42; 0·26-0·58; 0%), quetiapine (0·40; 0·13-0·67; 0%), asenapine (0·40; 0·13-0·67; 0%), and aripiprazole (0·32; 0·14-0·49; 53%). Ziprasidone (reported as risk ratio; 95% CI; I²: 0·83; 0·79-0·89; 0%) and olanzapine (0·63; 0·49-0·80; 35%) were associated with better acceptability relative to placebo. Among the 39 RCTs, none had a high ROB.

Interpretation: We demonstrated that eight antimanic drugs were associated with lower variability and better efficacy than placebo, suggesting that these antimanic drugs were associated with more homogenous and predictable improvements of manic symptoms in patients with acute mania.

Funding: The study was supported by from the Ministry of Science and Technology (MOST-110-2314-B-016-035, MOST-111-2314-B-016-054), Medical Affairs Bureau (MND-MAB-D-111102), and Tri-service General Hospital (TSGH-E-111229).

Keywords: Anticonvulsants; Antipsychotics; Bipolar mania; Meta-analysis; Mood stabilisers; Variability in improvement of manic symptoms.