TABLE 2.

Characteristics of treatments examined.

References	Intervention	N	Dose	Duration (weeks)	Tolerability	Discontinuation rate (acceptability)	Efficacy comparison (RC vs. non‐RC)
Antipsychotics
Tohen et al., 2006	Olanzapine Placebo	119 60	5–20 mg	48	8% discontinued due to AE e 0% discontinued due to AE e	32% e 13% e	NS
Baldessarini et al. 2003 a	Olanzapine Placebo	44 46	M: 15 mg —	3–4	57% of RC experienced SAE NR	38% e (RC 57% in 12 m) 62% e	Mostly NS. RC > NRC some ST; NRC > RC some LT d
Sanger et al. 2003 a	Olanzapine Placebo	19 26	5–20 mg —	3	0% discontinued due to AE 0% discontinued due to AE	21% 54%	n/a
Suppes et al. 2014	Quetiapine Placebo	36 38	300 mg —	8	88% experienced an AE e 67% experienced an AE e	38% e 31% e	NS
Cutler et al. 2011	Quetiapine Placebo	45 52	M: 604 mg —	3	3% discontinued due to AE e 8% discontinued due to AE e	28% e 28% e	NRC > RC mania interaction
Vieta et al. 2007 a	Quetiapine Placebo	42/31 35	300/600 mg —	8	15/24% discontinued due to AE 8% discontinued due to AE	36/48% 38%	NS
Thase et al. 2006	Quetiapine Placebo	44/46 53	300/600 mg —	8	8/11% discontinued due to AE e 1% discontinued due to AE e	41/47% e 35% e	NS
Muzina et al. 2008 a	Aripiprazole Placebo	14 14	M: 24 mg —	100	7% experienced an AE 0% experienced an AE	79% 100%	n/a
Suppes et al. 2008b a	Aripiprazole Placebo	52 51	M: 28 mg —	3	10% discontinued due to AE e 9% discontinued due to AE e	52% e 63% e	NS
Bobo et al. 2011	Risperidone LAI TAU	20 25	M: 27 mg Optimised	52	MC: 20% basal ganglia, 15% sedation, 10% + weight MC: 24% basal ganglia, 16% sedation, 12% + weight	20% 24%	n/a
Mood stabilisers
Kemp et al. 2012	Lamotrigine Placebo	23 26	150‐200 mg	12	4% ‐ pruritis/benign rash 4% ‐ pruritis	17% 15%	n/a
Wang et al. 2010	Lamotrigine Placebo	18 18	150‐200 mg	12	MC: 22% tremor, 11% nausea, 6% headache MC: 39% tremor, 33% headache, 11% diarrhoea	55% 55%	n/a
Suppes et al. 2008 b	Lamotrigine Lithium	34 34	M: 250 mg M: 1200 mg	16	M(SD): 4.2 ± 3.2 e M(SD): 9.2 ± 6.4 e	49% e 61% e	NS
Calabrese et al. 2000 a	Lamotrigine Placebo	90 87	M: 288 mg —	26	67% experienced an AE 68% experienced an AE	59% 74%	n/a
Goldsmith et al. 2003	Lamotrigine Placebo	66 68	50‐400 mg	32	85% experienced an AE 78% experienced an AE	40% 42%	n/a
Walden et al. 2000	Lithium Lamotrigine	7 7	M: 0.84 mmol/L M: 425 mg	52	43% weight gain, 29% slight tremor 43% dizziness, 29% headache	0% 0%	n/a
Antidepressants
Ghaemi et al. 2021	Citalopram Placebo	14 19	M: 27 mg —	52	35% experienced an AE e 37% experienced an AE e	77% e 80% e	NRC > RC mania interaction
Parker et al. 2006	Escitalopram Placebo	6 4 c	10 mg —	26	0% discontinued due to AE 0% discontinued due to AE	0% 0%	n/a
Post et al. 2006 a	Bupropion Sertraline Venlafaxine	21 12 14	M: 286 mg M: 195 mg M: 192 mg	10	0% discontinued due to an AE e 7% discontinued due to an AE e 3% discontinued due to an AE e	31% e 41% e 45% e	RC bupropion > venlafaxine mania/NRC treatment NS
Other classes
Walshaw et al. 2018	Levothyroxine T3 Placebo	13 10 9	= > index 4.5–7.5 = > serum 0.65–1.36 —	12–48	0% discontinued due to an AE 10% discontinued due to an AE 0% discontinued due to an AE	19% 0% 0%	n/a
Keck et al. 2006	Ethyl‐EPA Placebo	31 28	6 g	17	5% experienced an SAE e 5% experienced an SAE e	54% e	NR
Lenz et al. 2016	CPT Bibliotherapy	7 9	14 × 90‐min weekly 3 × 90‐min group	14 (<14 m FU)	NR	10% 23%	NR
Multiple Classes
Amsterdam et al. 2017 a	Venlafaxine Lithium	17 7	37.5‐375 mg 300‐1200 mg	12	NR	59% 22%	NS
Amsterdam et al. 2013	Fluoxetine Lithium Placebo	8 9 8	10‐40 mg 300‐1200 mg —	50	0% discontinued due to AE 0% discontinued due to AE 13% discontinued due to AE	50% 89% 88%	NS
Amsterdam et al. 2009	Venlafaxine Lithium	12 15	37.5‐ 375 mg 300‐2100 mg	12	16% discontinued due to AE	40% e	RC > NRC across arms
Suppes et al. 2005 a	Olanzapine Divalproex	76 68	M: 16 mg M: 1530 mg	47	MC: 18% + weight, 20% rhinitis, 7% edema MC: 17% + weight	85% e 84% e	NRC > RC across arms
Tohen et al. 2003	Olanzapine Placebo OFC	132 127 34	5‐20 mg ‐ 6 + 25/6 + 50/12 + 50 mg	8	9% discontinued due to AE e 5% discontinued due to AE e 2% discontinued due to AE e	52% e 62% e 36% e	NRC > RC depression interaction (not stat. tested)
Langosch et al. 2008	Quetiapine Na Valproate	21 16	M: 465 mg M: 1340 mg	52	86% experienced an AE 63% experienced an AE	63% 60%	n/a
McElroy et al. 2010	Quetiapine Paroxetine Placebo	81 24 24	300/600 mg 20 mg —	8	11% discontinued due to AE e 13% discontinued due to AE e 8% discontinued due to AE e	35% 38% 40%	NRC quetiapine > placebo/RC NS

Abbreviations: =>, titrated to; AE, adverse event; CPT, cognitive psychoeducational therapy; ethyl‐EPA, ethyl‐eicosapentanoate; FU, follow‐up; LAI, long‐acting injectable; LT, long‐term; M, mean/median; MC, most common; n, number of patients; NR, not reported; NRC, non‐rapid cycling; NS, not significant; RC, rapid cycling; SAE, serious adverse event; ST, short‐term; T₃, triiodothyronine; TAU, treatment as usual; URI, upper respiratory infection.

^a Multiple papers per study, & in some cases multiple studies reported per article (see Supplement 2).

^b Data extracted from the whole study sample as most participants had RC and/or where no difference between RC and NRC was reported.

^c Reports data across all treatment groups.

^d Vieta et al. reported similar mania improvements in the short‐term between RC and non‐RC participants, but a higher proportion of RC patients responded in the 3–4 week blinded trial, and responded more quickly than non‐RC patients (across olanzapine and placebo arms). However, in the long‐term (1 year open label olanzapine treatment), although parity of several outcomes was reported between these subgroups, better outcomes were identified for non‐RC versus RC participants in: remission/recovery rates, time to recovery, number of episodes, rehospitalisation and suicide rates, and tolerability difficulties.

^e Describes data covering the overall study group as separate results for RC participants were not reported.