TABLE 2.
Combination of lithium and valproic acid
| References | № of patients | Certainty assessment | Effect | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Combination | Comparison treatment | Study design | Outcome/Event | Follow‐up time | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Relative (95% CI) | Absolute (95% CI) | Test (p‐value) | Certainty | |
| Valproic acid + Lithium | Valproic acid | |||||||||||||
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 69.0% |
Randomized trials | Time to intervention for any mood episode | 24 months | Seriousa | Not serious | Not serious | Not serious | None |
HR 0.57 (0.40–0.80) |
−20% (−32 to −8) |
Log‐rank (0.0014) |
⨁⨁⨁◯ MODERATE |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 45.0% |
Randomized trials | Time to intervention for depressive episode | 24 months | Seriousa | Not serious | Not serious | Seriousb | None |
HR 0.70 (0.46–1.07) |
−11% (−21 to +2) |
Log‐rank (0.11) |
⨁⨁◯◯ LOW |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 45.0% |
Randomized trials | Time to intervention for manic episode | 24 months | Seriousa | Not serious | Not serious | Not serious | None |
HR 0.51 (0.32–0.80) |
−19% (−28 to −7) |
Log‐rank (0.003) |
⨁⨁⨁◯ MODERATE |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 68.0% |
Randomized trials | Time to new drug treatment | 24 months | Seriousa | Not serious | Not serious | Not serious | None |
HR 0.57 (0.40–0.80) |
−20% (−31 to −8) |
Log‐rank (0.0014) |
⨁⨁⨁◯ MODERATE |
| The BALANCE investigators and collaborators, 2010 13 |
110 – |
110 23.0% |
Randomized trials | Time to hospital admission | 24 months | Seriousa | Not serious | Not serious | Not serious | None |
HR 0.51 (0.27–0.96) |
−11% (−16 to −1) |
Log‐rank (0.038) |
⨁⨁⨁◯ MODERATE |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 44.0% |
Randomized trials | Time to medication discontinuation | 24 months | Seriousa | Not serious | Not serious | Very seriousc | None |
HR 1.01 (0.67–1.53) |
0% (−12 to +15) |
Log‐rank (0.95) |
⨁◯◯◯ VERY LOW |
| Ahearn EP et al., 201311 | 145 | 821 | Observational studies | Suicide attempts 10,000 months on drug regimen | 6 years, mean 19.8 months | Very serious c , d | Not serious | Seriouse | Not serious | None | Valproate + Lithium: 6.3; Valproate: 7.0. | ‐ |
⨁◯◯◯ VERY LOW |
|
| Valproic acid + Lithium | Lithium | |||||||||||||
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 59.0% |
Randomized trials | Time to intervention for any mood episode | 24 months | Seriousa | Not serious | Not serious | Seriousb | None |
HR 0.80 (0.57–1.15) |
−6% (−18 to +6) |
Log‐rank (0.23) |
⨁⨁◯◯ LOW |
| Kemp DE et al., 200914 |
16 – |
15 55.0% |
Randomized trials | Time to intervention for any mood episode | 6 months | Seriousd | Not serious | Seriousf | Very serious b , c , g | None |
HR 0.72 (0.32–1.65) |
−11% (−32 to +18) |
Log‐rank (0.44) |
⨁◯◯◯ VERY LOW |
| Wingard L et al., 201912 |
217 – |
1133 87.0% |
Non‐randomized studies | Time to treatment failure | 365 days | Very serioush | Not serious | Not serious | Not serious | None |
HR 0.72 (0.62–0.85) |
−10% (−15 to −5) |
‐ |
⨁⨁◯◯ LOW |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 32.0% |
Randomized trials | Time to intervention for depressive episode | 24 months | Seriousa | Not serious | Not serious | Very serious b , c | None |
HR 1.06 (0.67–1.67) |
+2% (−9 to +15) |
Log‐rank (0.81) |
⨁◯◯◯ VERY LOW |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 36.0% |
Randomized trials | Time to intervention for manic episode | 24 months | Seriousa | Not serious | Not serious | Seriousb | None |
HR 0.66 (0.41–1.07) |
−11% (−15 to +2) |
Log‐rank (0.09) |
⨁⨁◯◯ LOW |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 20.0% |
Randomized trials | Time to hospital admission | 24 months | Seriousa | Not serious | Not serious | Very serious b , c | None |
HR 0.72 (0.38–1.38) |
−5% (−12 to +7) |
Log‐rank (0.32) |
⨁◯◯◯ VERY LOW |
| Kemp DE et al., 200914 |
217 – |
1133 20.4% |
Non‐randomized studies | Time to hospital admission | 365 days | Very serioush | Not serious | Not serious | Not serious | None |
HR 1.05 (0.78–1.40) |
−1% (−41 to +69) |
‐ |
⨁⨁◯◯ LOW |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 45.0% |
Randomized trials | Time to medication discontinuation | 24 months | Seriousa | Not serious | Not serious | Very serious b , c | None |
HR 0.89 (0.60–1.34) |
−4% (−15 to +10) |
Log‐rank (0.58) |
⨁◯◯◯ VERY LOW |
| Kemp DE et al., 200914 |
217 – |
1133 20.2% |
Non‐randomized studies | Time to medication discontinuation | 365 days | Very seriouse | Not serious | Not serious | Not serious | None |
HR 0.63 (0.44–0.89) |
−7% (−11 to −2) |
‐ |
⨁⨁◯◯ LOW |
| The BALANCE investigators and collaborators, 201013 |
110 – |
110 58.0% |
Randomized trials | Time to new drug treatment | 24 months | Seriousa | Not serious | Not serious | Seriousb | None |
HR 0.80 (0.56–1.14) |
−8% (−20 to +5) |
Log‐rank (0.21) |
⨁⨁◯◯ LOW |
| Kemp DE et al., 200914 |
217 – |
1133 46.5% |
Non‐randomized studies | Time to new drug treatment | 365 days | Very serioush | Not serious | Not serious | Not serious | None |
HR 0.62 (0.49–0.79) |
−14% (−20 to −8) |
‐ |
⨁⨁◯◯ LOW |
| Solomon DA et al., 199716 | 0/5 (0.0%) | 5/7 (71.4%) | Randomized trials | Relapse frequency | 12 months | Not serious | Not serious | Seriousi | Very serious c , g | None |
RR 0.12 (0.01–1.79) |
−63% (−71 to +56) |
Chi‐squared (0.014) |
⨁◯◯◯ VERY LOW |
| Ahearn EP et al., 201311 | 145 | 436 | Observational studies | Suicide attempts 10,000 months on drug regimen | 6 years, mean 19.8 months | Very seriousc,d | Not serious | Seriousj | Not serious | None | Valproate + Lithium: 6.3; Lithium: 7.7. | ‐ |
⨁◯◯◯ VERY LOW |
|
| Valproic acid + Lithium | CBZ + Lithium | |||||||||||||
| Missio G et al., 201915 | 33 | 27 | Randomized trials | Time to relapse | 22 weeks | Very serious a , d , k | Not serious | Not serious | Seriousg | None | Time‐to‐relapse curves were not significantly different between groups | Log‐rank (0.45) |
⨁◯◯◯ VERY LOW |
|
CBZ, Carbamazepine; CI, Confidence interval; HR, Hazard Ratio; MD, Mean difference; RR, Risk ratio. Explanations:
Open‐label trial.
Low power for the outcome.
Large CI including significantly reduced and increased effect.
No measures of disease severity or comorbidities available.
Incomplete outcome reporting.
Days of prescription used as proxy of days of treatment.
Population of rapid cycling patients with recent alcohol / illicit drug abuse or dependence.
Small sample size.
Case severity assessed by length of index hospitalization and presence of psychotic symptoms. Lack of concealment for allocation.
4 patients never recovered from the index episode, but they were equally distributed between the treatment arms.
Days of prescription used as proxy of days of treatment.
No definition of relapse.