Summary of findings for the main comparison. VALPROATE + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + PLACEBO or ANTIPSYCHOTICS alone.
| Valproate plus antipsychotics versus antipsychotics plus placebo or antipsychotics alone | ||||||
| Patient or population: people with schizophrenia Settings: inpatient/outpatient Intervention: Valproate plus antipsychotics versus antipsychotics plus placebo or antipsychotics alone | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Antipsychotics and valproate versus antipsychotics and placebo/no treatment | |||||
| Clinically significant response: important change As defined by each of the studies Follow‐up: short term | 550 per 1000 | 721 per 1000 (638 to 809) | RR 1.31 (1.16 to 1.47) | 1049 (14 studies) | ⊕⊕⊝⊝ low1 | |
| Leaving the study early: Acceptability of treatment Leaving the study early for any reason Follow‐up: short term | 364 per 1000 | 327 per 1000 (284 to 378) | RR 0.76 (0.47 to 1.24) | 951 (11 studies) | ⊕⊝⊝⊝ very low2,3,4,5 | |
| Leaving the study early: Overall tolerability Leaving the study early due adverse events Follow‐up: short term | 77 per 1000 | 102 per 1000 (69 to 150) | RR 1.33 (0.90 to 1.97) | 974 (6 studies) | ⊕⊕⊝⊝ low2,6 | |
| Clinical response: Aggression/agitation Mean Modified Overt Aggression Rating Scale. Scale from: 0‐16 Follow‐up: short term | The mean aggression in the control groups was 5.74 points | The mean aggression in the intervention groups was 2.55 lower (3.92 to 1.19 lower) | 186 (3 studies) | ⊕⊝⊝⊝ very low7,8 | ||
| Adverse events: Sedation Number of participants with sedation/somnolence/drowsiness Follow‐up: short term | 186 per 1000 | 276 per 1000 (214 to 356) | RR 1.38 (1.07 to 1.79) | 770 (8 studies) | ⊕⊕⊝⊝ low1 | |
| Adverse events: Weight gain Number of participants with weight gain Follow‐up: short term | 143 per 1000 | 169 per 1000 (109 to 260) | RR 1.17 (0.76 to 1.82) | 427 (4 studies) | ⊕⊕⊝⊝ low9,10 | |
| Quality of life: Clinically important change in quality of life ‐ as defined by individual studies | See comment | See comment | Not estimable | 0 | See comment | No study reported on the predefined outcome quality of life so it could not be presented in this summary of findings table |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
1 Risk of bias: almost all studies were open RCTs, there was no blinding. Moreover, several studies did not report rates. 2 Risk of bias: half of the studies were open RCTs without blinding. 3 Inconsistency: considerable heterogeneity based on both visual inspection, Chi2 and I2 statistics. 4 Indirectness: acceptability of treatment was measured by the number of participants leaving the study early for any reason which comprised efficacy and tolerability. Nevertheless, this is an indirect measure. 5 Imprecision: overall sample size was too small to provide a precise estimate for the small RR found. 6 Imprecision: too few events for a precise estimate and relatively broad confidence interval. 7 Risk of bias: all open RCTs, no blinding. Unclear whether ITT results were presented. 8 Inconsistency: results were significantly heterogeneous. However, all studies showed a statistically significant superiority of valproate augmentation therefore, the heterogeneity expressed a difference in the degree of the effect, but not of the direction of the effect. 9 Risk of bias: weight gain is an objective outcome. Therefore, we did not downgrade for lack of blinding. 10Imprecision: relatively few events, relatively small overall sample size for a relatively small effect size the confidence interval of which overlaps widely with zero.