Comparison 1. Lithium vs placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Efficacy ‐ response (categorical): YMRS/MRS decrease by =>50% at end of trial	6	1707	Odds Ratio (M‐H, Fixed, 95% CI)	2.13 [1.73, 2.63]
2 Efficacy ‐ response (continuous): YMRS change from baseline at end of trial	4	935	Mean Difference (IV, Random, 95% CI)	‐2.85 [‐3.14, ‐2.55]
3 Efficacy ‐ response (continuous): CGI change from baseline at end of trial	4	952	Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.35, ‐0.16]
4 Efficacy ‐ remission (categorical): YMRS < 12 at end of trial	5	1597	Odds Ratio (M‐H, Fixed, 95% CI)	2.16 [1.73, 2.69]
5 Acceptability: withdrawals	7		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 All‐cause dropouts	7	1353	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.46, 1.25]
5.2 Dropouts due to adverse events	6	1158	Odds Ratio (M‐H, Random, 95% CI)	0.92 [0.50, 1.69]
5.3 Dropouts due to lack of efficacy	6	1243	Odds Ratio (M‐H, Random, 95% CI)	0.56 [0.29, 1.08]
6 Adverse event: depression	4	1360	Odds Ratio (M‐H, Fixed, 95% CI)	0.57 [0.33, 0.98]
7 Adverse event: mania	4	1296	Odds Ratio (M‐H, Fixed, 95% CI)	0.59 [0.38, 0.93]
8 Adverse event: weight gain (categorical)	3	735	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.56, 3.92]
9 Adverse event: weight gain (continuous)	3	599	Mean Difference (IV, Random, 95% CI)	0.16 [‐0.50, 0.82]
10 Adverse event: akathisia	3	673	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.39, 1.91]
11 Adverse event: headache	6	1270	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.76, 1.48]
12 Adverse event: somnolence	7	1351	Odds Ratio (M‐H, Fixed, 95% CI)	2.28 [1.46, 3.58]
13 Adverse event: dizziness	5	873	Odds Ratio (M‐H, Fixed, 95% CI)	2.12 [1.21, 3.74]
14 Adverse event: insomnia	3	706	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.44, 1.29]
15 Adverse event: diarrhoea	6	1028	Odds Ratio (M‐H, Fixed, 95% CI)	1.51 [0.90, 2.54]
16 Adverse event: nausea	6	1220	Odds Ratio (M‐H, Fixed, 95% CI)	2.32 [1.54, 3.50]
17 Adverse event: vomiting	6	1028	Odds Ratio (M‐H, Fixed, 95% CI)	6.06 [3.21, 11.45]
18 Adverse event: dry mouth	3	682	Odds Ratio (M‐H, Fixed, 95% CI)	1.10 [0.58, 2.09]
19 Adverse event: pain	3	396	Odds Ratio (M‐H, Fixed, 95% CI)	0.23 [0.07, 0.79]
20 Adverse event: EPS	2	478	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.68, 2.19]
21 Adverse event: tremor	6	1241	Odds Ratio (M‐H, Fixed, 95% CI)	3.25 [2.10, 5.04]
22 Adverse event: constipation	5	1075	Odds Ratio (M‐H, Fixed, 95% CI)	1.28 [0.81, 2.01]
23 Adverse event: fever	2	466	Odds Ratio (M‐H, Fixed, 95% CI)	1.63 [0.75, 3.55]
24 Adverse event: rash	3	367	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.37, 2.29]
25 Efficacy ‐ response (continuous): CGI change from baseline to end of trial	2	513	Mean Difference (IV, Random, 95% CI)	‐0.46 [‐1.00, 0.07]
26 Response: YMRS decrease by ≥ 50% end of the trial	1	195	Odds Ratio (M‐H, Fixed, 95% CI)	0.23 [0.12, 0.42]
27 Response: remission YMRS < 12 at end of trial	1	195	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.11, 0.36]
28 Efficacy ‐ response (continuous): MADRS change from baseline to end of trial	2	667	Mean Difference (IV, Random, 95% CI)	‐0.55 [‐0.85, ‐0.26]
29 Efficacy ‐ response (continuous): MRS score change from baseline to end of trial	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
29.1 Manic subscale of MRS ‐ score at end of trial	2	285	Mean Difference (IV, Fixed, 95% CI)	‐1.19 [‐2.78, 0.39]
29.2 MRS 16 item scale from SAD‐C	2	285	Mean Difference (IV, Fixed, 95% CI)	‐3.67 [‐7.27, ‐0.07]
30 Efficacy ‐ (continuous): GAS score at end of trial	2	284	Mean Difference (IV, Random, 95% CI)	3.17 [‐7.02, 13.37]
31 Efficacy ‐ HAMD‐31 score at end of trial	2	285	Mean Difference (IV, Random, 95% CI)	‐1.12 [‐7.69, 5.44]
32 Efficacy ‐ BPRS score at end of trial	2	285	Mean Difference (IV, Fixed, 95% CI)	‐1.74 [‐3.70, 0.23]
33 PANSS change from baseline to end of trial	2	629	Mean Difference (IV, Random, 95% CI)	‐2.86 [‐4.33, ‐1.39]
34 CGI‐BP change from baseline to end of trial	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
34.1 Severity of illness score Overall	1	316	Mean Difference (IV, Random, 95% CI)	‐2.0 [‐2.02, ‐1.98]
34.2 Depression change from baseline at 3 weeks	1	316	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.02, 0.02]
35 Use of concomitant medications	2	479	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.52, 1.57]
36 Use of sleep medications over course of trial	1	195	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.51, 1.58]
37 Use of anticholinergic medications	2	520	Odds Ratio (M‐H, Fixed, 95% CI)	1.39 [0.73, 2.62]
38 Concomitant use of analgesics/antipyretics	1	325	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.58, 1.48]
39 Acceptability: withdrawal due to adverse events	6	1158	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.61, 1.37]