Comparison 1. VALPROATE + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + PLACEBO or ANTIPSYCHOTICS alone.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinically significant response: 1. Important change ‐ as defined by the studies	14	1049	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.16, 1.47]
2 Leaving the study early: Acceptability/tolerability of treatment	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 Acceptability of treatment: Leaving for any reason	11	951	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.47, 1.24]
2.2 Overall tolerability: Leaving due to adverse event	6	974	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.90, 1.97]
2.3 Leaving due to poor clinical effect	5	810	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.31, 0.94]
3 Clinical response: 2. Global state: 1a. mean change score CGI severity (high = poor)	1	392	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.12, 0.32]
4 Clinical response: 3. Global state: 1b. mean change score CGI improvement (high = poor)	1	393	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.26, 0.26]
5 Clinical response: 4. Mental state: 2a. mean change score PANSS total (high = poor)	13	1363	Mean Difference (IV, Random, 95% CI)	‐5.85 [‐7.80, ‐3.91]
6 Clinical response: 5. Mental state: 2b. mean endpoint score BPRS total (high = poor)	7	646	Mean Difference (IV, Random, 95% CI)	‐1.87 [‐4.46, 0.73]
7 Clinical response: 6. Mental state 2c. mean change score IMPS total (high = poor)	1	18	Mean Difference (IV, Random, 95% CI)	‐5.11 [‐26.04, 15.82]
8 Clincal response: 7. Positive symptoms: 3a. mean endpoint score PANSS positive subscale (high = poor)	9	1073	Mean Difference (IV, Random, 95% CI)	‐1.72 [‐3.01, ‐0.43]
9 Clinical response: 8. Positive symptoms: 3b. mean endpoint score PANSS positive subscale (high = poor, skewed data)			Other data	No numeric data
10 Clinical response: 9. Negative symptoms: 4a. mean endpoint score PANSS negative subscale (high = poor)	5	651	Mean Difference (IV, Random, 95% CI)	‐1.78 [‐3.13, ‐0.43]
11 Clinical response: 10. Negative symptoms: 4b. mean endpoint score PANSS negative subscale (high = poor, data skewed)			Other data	No numeric data
12 Clinical response: 11. Negative symptoms: 4c. mean endpoint score SANS subscale (skewed data)			Other data	No numeric data
13 Clinical response: 12. Negative symptoms: 4d. mean endpoint score BPRS lack of energy subscale (high = poor)	3	135	Mean Difference (IV, Random, 95% CI)	0.46 [‐0.29, 1.22]
14 Clinical response: 13. Aggression/Agitation: 5a. clinically important change ‐ Modified Overt Aggression Scale (high = poor)	1	36	Risk Ratio (M‐H, Random, 95% CI)	2.68 [1.07, 6.76]
15 Clinical response: 14. Aggression/Agitation: 5b. mean endpoint score Modified Overt Aggression Scale (high = poor)	3	186	Mean Difference (IV, Random, 95% CI)	‐2.55 [‐3.92, ‐1.19]
16 Clinical response: 15. Aggression/Agitation: 5c. mean endpoint score PANSS‐EC subscale (high = poor))	3	204	Mean Difference (IV, Random, 95% CI)	‐1.85 [‐2.63, ‐1.08]
17 Clinical response: 16. Aggression/Agitation: 5d. mean endpoint score PANSS‐EC subscale (skewed data)			Other data	No numeric data
18 Clinical response: 17. Aggression/Agitation: 5e. mean endpoint score PANSS supplementary subscale (high = poor)	1	120	Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.39, ‐0.31]
19 Clinical response: 18. Aggression/Agitation: 5f. mean endpoint score BPRS hostility subscale (high = poor)	3	135	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.34, 0.14]
20 Clinical response: 19. Depression symptoms: 6a. mild improvement at endpoint, Calgary Depression Scale (high = poor)	1	16	Risk Ratio (M‐H, Random, 95% CI)	1.4 [0.77, 2.54]
21 Clinical response: 20. Depression symptoms: 6b. mean endpoint score BPRS anxiety and depression subscale (high = poor)	3	135	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.25, 0.13]
22 Clinical response: 21.General pathology: 7a. mean change score PANSS general pathology subscale (high = poor)	8	873	Mean Difference (IV, Random, 95% CI)	‐3.05 [‐4.30, ‐1.81]
23 Use of additional medication: 1. Mean dose of antiparkinson medication (skewed data)			Other data	No numeric data
24 Use of additional medication: 2. Mean chlorprothixene dose (skewed data)			Other data	No numeric data
25 Use of additional medication: 3. Medication for sedation at least once	2	309	Risk Ratio (M‐H, Random, 95% CI)	3.65 [0.11, 122.31]
26 Adverse events: 1. Abnormal ECG	2	153	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.35, 2.18]
27 Adverse events: 2. Abnormal liver function/increase in alanine transaminase/gamma‐glutamyl transpeptidase	8	745	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.72, 2.22]
28 Adverse events: 3. Akathisia	3	186	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.36, 3.06]
29 Adverse events: 4. Anxiety	2	319	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.21, 1.24]
30 Adverse events: 5. Asthenia	1	249	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.63, 3.95]
31 Adverse events: 6. Ataxia	2	115	Risk Ratio (M‐H, Random, 95% CI)	2.42 [0.37, 15.92]
32 Adverse events: 7. At least one adverse event	5	493	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.68, 1.25]
33 Adverse events: 8. Blood count changes	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
33.1 Eosinophilia	1	42	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.43, 4.42]
33.2 Monocytosis	1	42	Risk Ratio (M‐H, Random, 95% CI)	5.48 [0.28, 107.62]
33.3 Transient lymphocytosis	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.3 [0.37, 29.21]
33.4 Leukopenia	5	385	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.38, 3.64]
33.5 Thrombocytopenia	1	79	Risk Ratio (M‐H, Random, 95% CI)	17.42 [1.04, 291.96]
34 Adverse events: 9. Constipation	4	515	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.47, 1.85]
35 Adverse events: 10. Convulsion	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.02, 8.85]
36 Adverse events: 11. Diarrohea	3	193	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.32, 3.34]
37 Adverse events: 12. Dizziness	7	662	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.92, 2.03]
38 Adverse events: 13. Dry mouth	3	179	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.58, 2.42]
39 Adverse events: 14. Dyspepsia	1	249	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.62, 1.79]
40 Adverse events: 15. Dystonia	2	130	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.30, 3.37]
41 Adverse events: 16. Extrapyramidal adverse events (skewed data)			Other data	No numeric data
42 Adverse events: 17. Headache	4	469	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.67, 1.56]
43 Adverse events: 18. Hypersalivation	3	248	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.62, 1.70]
44 Adverse events: 19. Incontinence	1	47	Risk Ratio (M‐H, Random, 95% CI)	3.39 [0.15, 79.22]
45 Adverse events: 20. Insomnia	2	126	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.39, 1.78]
46 Adverse events: 21. Myocardial ischaemia	1	62	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.23]
47 Adverse events: 22. Nausea	9	728	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.80, 1.86]
48 Adverse events: 23. Pain	1	249	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.30, 1.25]
49 Adverse events: 24. Rash	2	190	Risk Ratio (M‐H, Random, 95% CI)	3.15 [0.33, 29.72]
50 Adverse events: 25. Rhinitis	1	249	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.09, 1.07]
51 Adverse events: 26. Rigidity/stiffness	1	33	Risk Ratio (M‐H, Random, 95% CI)	2.83 [0.12, 64.89]
52 Adverse events: 27. Sedation/somnolence/drowsiness	8	770	Risk Ratio (M‐H, Random, 95% CI)	1.38 [1.07, 1.79]
53 Adverse events: 28. Sexual dysfunction	1	33	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.01, 7.21]
54 Adverse events: 29. Suicidal or depressed	1	16	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.14]
55 Adverse events: 30. Tachycardia	3	218	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.60, 2.72]
56 Adverse events: 31.Tremor	4	199	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.46, 2.97]
57 Adverse events: 32. Unstable gait	1	19	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.02, 3.39]
58 Adverse events: 33. Vegetative adverse events	1	47	Risk Ratio (M‐H, Random, 95% CI)	1.70 [0.55, 5.27]
59 Adverse events: 34. Vomiting	2	282	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.45, 2.18]
60 Adverse events: 35. Weight gain	4	427	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.76, 1.82]
61 Adverse events: 36. Mean endpoint score TESS (high = poor)	1	60	Mean Difference (IV, Random, 95% CI)	2.06 [‐0.41, 4.53]
62 Adverse events: 37. Tardive dyskinesia ‐ mean endpoint score AIMS (high = poor)	1	79	Mean Difference (IV, Random, 95% CI)	‐3.31 [‐4.91, ‐1.71]
63 Sensitivity analysis: Primary outcome 1. Excluding open studies	3	323	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.95, 1.39]
64 Sensitivity analysis: Primary outcome 2. Fixed‐effect model	14	1049	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.21, 1.50]
65 Sensitivity analysis: Primary outcome 3. Exluding no attrition	4	517	Risk Ratio (M‐H, Random, 95% CI)	1.28 [1.03, 1.60]
66 Sensitivity analysis: Primary outcome 4. Completers	1	80	Risk Ratio (M‐H, Random, 95% CI)	3.13 [1.52, 6.44]
67 Sensitivity analysis: Primary outcome 5. Defined by PANSS reduction	12	975	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.16, 1.48]
68 Sensitivity analysis: Aggresssion/Agitation: 1. Modified Overt Aggression Scale ‐ excluding schizoaffective studies	3	186	Mean Difference (IV, Random, 95% CI)	‐2.55 [‐3.92, ‐1.19]
69 Sensitivity analysis: Aggression/Agitation: 2. PANSS‐EC subscale ‐ excluding schizoaffective studies	2	124	Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.62, ‐0.64]
70 Sensitivity analysis: Aggression/Agitation: 3. PANSS supplementary subscale ‐ excluding schizoaffective studies	1	120	Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.39, ‐0.31]
71 Sensitivity analysis: Aggression/Agitation: 4. BPRS hostility subscale ‐ excluding schizoaffective studies	3	135	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.34, 0.14]
72 Subgroup analysis: Primary outcome 6. As defined by the studies	14		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
72.1 Treatment resistant participants	2	128	Risk Ratio (M‐H, Random, 95% CI)	1.57 [1.03, 2.39]
72.2 No Treatment resistant participants	12	921	Risk Ratio (M‐H, Random, 95% CI)	1.29 [1.14, 1.46]