Appendix D. Strength of Evidence
The strength of evidence tables in this appendix are adapted from the Agency for Healthcare Research and Quality (AHRQ) review (McDonagh et al. 2017), in which key outcomes are prioritized in terms of clinical and patient-centered outcomes. The prioritized outcomes are listed below, per intervention area. For more details, see “Strength of the Body of Evidence” and Appendix H references in the AHRQ review.
Pharmacological interventions are listed in Table D–1, and outcomes include the following:
-
Functional outcomes (e.g., social, occupational)
-
Health-related quality of life (including physical)
-
Rates of response and/or remission
-
Mortality (all-cause and/or specific)
-
Reductions in self-harm, suicide, and suicide attempts
-
Improvements in core illness symptoms, as indicated by scale score changes
-
Overall/any adverse events (rate or proportion)
-
Withdrawal due to adverse events
Psychosocial and other nonpharmacological interventions are listed in Tables D–2 to D–13, and outcomes include the following:
-
Functional outcomes (e.g., social, occupational)
-
Health-related quality of life
-
Reductions in self-harm, suicide, and suicide attempts
-
Rates of response and/or remission
-
Improvements in core illness symptoms, as indicated by scale score changes
-
Treatment discontinuation (typically reported as the number of patients lost to follow-up or leaving the study early)
-
Rates of relapse
-
Outcomes reported as adverse events related to the intervention
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence(high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Social functioning | Olanzapine, risperidone, quetiapine IR | 1 SR (2 RCTs; N = 343 and 1 observational study; N = 9,028) | Moderate | Inconsistent | Direct | Imprecise | Inconclusive | Insufficient |
| Observational evidence: moderate | Observational evidence: unknown | Observational evidence: direct | Observational evidence: precise | RCT 1: no significant differences on RFS or the SAS-SMI | ||||
| RCT 2: change on SFS greater with olanzapine (+7.75) than risperidone (–0.92, P = 0.0028) | ||||||||
| Socially active: OR 1.27 (1.05–1.54); olanzapine 84.6% vs. risperidone 82.4% | ||||||||
| Social functioning | Paliperidone LAI (monthly) vs. risperidone LAI (biweekly) | 1 SR (2 RCTs; N = 452) | Moderate | Inconsistent | Direct | Precise | No statistically significant differences in PSP scale | Low |
| Mean change from baseline: 16.8 paliperidone and 18.6 risperidone; least squares mean difference 0.5 (–2.14 to 3.12) | ||||||||
| Social functioning | Paliperidone XR vs. olanzapine | 1 meta-analysis of selected studies | High | Unknown | Direct | Precise | No significant difference in PSP scale: mean change 7.8–12.2 in paliperidone dose groups vs. 8.7 in olanzapine group | Insufficient |
| Social functioning | Risperidone LAI vs. quetiapine IR | 1 RCT; N = 666 | Moderate | Unknown | Direct | Precise | Risperidone LAI resulted in greater improvements in SOFAS at 6 months (differences in change 6.1 vs. 2.7, P = 0.02), 12 months (9.5 vs. 6.1, P = 0.009), and endpoint (6.6 vs. 1.1, P < 0.0001) | Low |
| Employment outcomes | Older SGAs (olanzapine, risperidone, quetiapine, ziprasidone) | 1 SR (2 RCTs, 3 observational studies; N = 1,379) | Low | Inconsistent | Direct | Imprecise | No significant differences in rates of employment (mean 18% in CATIE phase 1) | Low |
| Observational evidence: moderate | Observational evidence: consistent | Observational evidence: direct | Observational evidence: imprecise | |||||
| Function: employment | Haloperidol vs. risperidone | 1 SR (1 RCT; N = 100) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Proportion of patients with economic independence: RR 0.94 (0.68–1.29) | ||||||||
| Function: employment | Perphenazine vs. olanzapine | 1 SR (1 RCT; N = 597) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Proportion with paid employment: RR 1.29 (0.70–2.38) | ||||||||
| Function: employment | Perphenazine vs. quetiapine | 1 SR (1 RCT; N = 598) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Proportion with paid employment: RR 1.75 (0.90–3.43) | ||||||||
| Function: employment | Perphenazine vs. risperidone | 1 SR (1 RCT; N = 602) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Proportion with paid employment: RR 1.38 (0.74–2.57) | ||||||||
| Function: employment | Perphenazine vs. ziprasidone | 1 SR (1 RCT; N = 446) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Proportion with paid employment: RR 1.22 (0.60–2.51) | ||||||||
| Occupation and residential status | Older SGAs (olanzapine, risperidone, quetiapine, ziprasidone) | 1 SR (21 RCTs; N = 771) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| 75.5% and 75.3% had stable status, 3.8% and 3.1% had improved status (NS) | ||||||||
| Global functioning (GAF) | Olanzapine vs. risperidone | 1 SR (4 cohort studies; N = 3,211) | High | Inconsistent | Direct | Precise | No difference | Low |
| Pooled WMD 0.61 (– 1.78 to 2.99), I2 = 43% | ||||||||
| Global functioning (GAF) | Olanzapine vs. quetiapine | 1 SR (2 RCTs; N = 363) | Moderate | Consistent | Direct | Imprecise | Pooled WMD 1.14 (– 4.75 to 7.02); Q = 3.99, df = 1, P = 0.045 | Low |
| Function: general | Haloperidol vs. olanzapine | 1 SR (1 RCT; N = 208) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| GAF effect estimate: –4.00 (–13.70 to 5.70) | ||||||||
| Function: encounters with legal system | Haloperidol vs. olanzapine | 1 SR (1 RCTs; N = 31) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Encounters with legal system: RR 3.20 (0.76–13.46) | ||||||||
| Quality of life | Olanzapine vs. risperidone | 1 SR (2 RCTs; N = 492) | Moderate | Consistent | Direct | Precise | QLS change: 7 months 13.4 vs. 8.8 (P > 0.074); 12 months 0.19 vs. 0.26 (P = 0.53) | Moderate |
| Quality of life | Olanzapine vs. ziprasidone | 1 SR (2 RCTs; N = 740) | Moderate | Consistent | Direct | Precise | QLS change: 6–7 months 61.3 vs. 58.9 (P = 0.36 using mixed-effect modeling); 12 months 0.19 vs. 0.26 (P NR) | Moderate |
| Quality of life | Olanzapine vs. quetiapine IR | 1 SR (1 RCT; N = 227) | Low | Unknown | Direct | Imprecise | QLS change: 12 months 0.19 vs. 0.09 (P > 0.05) | Low |
| Quality of life | Olanzapine vs. asenapine | 1 SR (1 RCT; N = 464) | Moderate | Unknown | Direct | Imprecise | QLS change: 12 months 11.7 vs. 11.8 and 11.1 vs. 7.1 (multicountry study reported by hemisphere; P = NS) | Insufficient |
| Quality of life | Olanzapine vs. clozapine | 1 SR (1 RCT; N = 114) | Moderate | Unknown | Direct | Imprecise | SWN scale: at 26 weeks, olanzapine found noninferior to clozapine; difference 3.2 (4.2–10.5) | Insufficient |
| Quality of life | Risperidone vs. ziprasidone | 1 SR (N = 154) | Low | Unknown | Direct | Imprecise | QLS change: 12 months 0.19 vs. 0.26 (P > 0.05) | Low |
| Quality of life | Risperidone vs. quetiapine | 1 SR (1 RCT; N = 189) | Low | Unknown | Direct | Imprecise | QLS change: 12 months 0.26 vs. 0.26 (P > 0.05) | Low |
| Quality of life | Quetiapine XR vs. risperidone | 1 RCT; N = 798 | Moderate | Unknown | Direct | Imprecise | SWN short form 20% response rate at 6 months: 65% vs. 68%; adjusted difference –5.7% (–15.1 to 3.7) but not meeting noninferiority criteria | Insufficient |
| Quality of life | Aripiprazole oral vs. aripiprazole LAI (monthly) | 1 RCT; N = 724 | Moderate | Unknown | Direct | Precise | SF-36 12 months: mean changes in mental component 0.82 vs. 0.38; difference 0.44 (–1.24 to 2.12) and physical component 0.23 vs. –0.27; difference 0.50 (–1.11 to 2.11) | Low |
| Quality of life | Aripiprazole LAI vs. paliperidone palmitate LAI (monthly) | 1 RCT; N = 295 | Moderate | Unknown | Direct | Imprecise | QLS change: 28 weeks 7.47 vs. 2.80; least squares mean difference 4.67 (0.32–9.02) | Insufficient |
| Meets noninferiority criteria; does not meet minimally clinical important difference | ||||||||
| Quality of life | Risperidone LAI vs. quetiapine | 1 RCT; N = 666 | Moderate | Unknown | Direct | Precise | SF-12 physical and mental component scores and SQLS-Revision 4 scores improved from baseline in both groups but were not significantly different at endpoint, 24 months (SF-12 physical, P = 0.09; SF-12 mental and SQLS-R4, P = NR) | Low |
| Quality of life | Haloperidol vs. olanzapine | 1 SR (5 RCTs; N = 816) | Moderate | Consistent | Direct | Precise | Inconclusive | Moderate |
| Effect sizes ranged from –3.62 to 0 using different measures; CIs were not significant | ||||||||
| Quality of life | Haloperidol vs. quetiapine | 1 SR (1 RCT; N = 207) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Effect estimate 0.00 (–1.38 to 1.38) | ||||||||
| Quality of life | Haloperidol vs. risperidone | 1 SR (2 RCTs; N = 352) | Moderate | Inconsistent | Direct | Imprecise | Inconclusive | Insufficient |
| Effect estimates ranged from –0.10 to 0.10; CIs were not significant | ||||||||
| Quality of life | Haloperidol vs. ziprasidone | 1 SR (2 RCTs; N = 784) | High | Inconsistent | Direct | Imprecise | Studies favored ziprasidone in quality of life measures | Low |
| One trial found effect favoring ziprasidone based on QLS: effect estimate –12.12 (–22.06 to –2.17); there was no difference in another trial in MANSA: effect estimate –0.10 (–1.48 to 1.28) | ||||||||
| Quality of life | Perphenazine vs. aripiprazole | 1 SR (1 RCT; N = 300) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Proportion with 20% improvement: RR 4.74 (2.58–8.69) | ||||||||
| Quality of life | Perphenazine vs. olanzapine | 1 SR (1 RCT; N = 597) | Moderate | Unknown | Direct | Precise | No difference | Low |
| Effect estimate 0.00 (–0.16 to 0.16) | ||||||||
| Quality of life | Perphenazine vs. quetiapine | 1 SR (1 RCT; N = 598) | Moderate | Unknown | Direct | Precise | No difference | Low |
| Effect estimate 0.10 (–0.07 to 0.27) | ||||||||
| Quality of life | Perphenazine vs. risperidone | 1 SR (1 RCT; N = 602) | Moderate | Unknown | Direct | Precise | No difference | Low |
| Effect estimate –0.07 (–0.24 to 0.10) | ||||||||
| Quality of life | Perphenazine vs. ziprasidone | 1 SR (1 RCT; N = 446) | Moderate | Unknown | Direct | Precise | No difference | Low |
| Effect estimate -0.07 (–0.27 to 0.13) | ||||||||
| Response | Network meta-analysis of olanzapine, risperidone, quetiapine IR, aripiprazole, clozapine, ziprasidone, asenapine, paliperidone, aripiprazole LAI (monthly), carpipramine, brexpiprazole, lurasidone | 46 RCTs; N = 12,536 | Moderate | Consistent | Indirect | Precise | Two statistically significant differences between the drugs; both olanzapine (OR 1.71, 95% CI 1.11–2.68) and risperidone (OR 1.41, 95% CI 1.01–2.00) were significantly more likely to result in response than quetiapine IR | Low |
| Response | Fluphenazine vs. olanzapine | 1 SR (1 RCT; N = 60) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.74 (0.51–1.07) | Insufficient |
| Response | Fluphenazine vs. quetiapine | 1 SR (1 RCT; N = 25) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.62 (0.12–3.07) | Insufficient |
| Response | Fluphenazine vs. risperidone | 1 SR (1 RCT; N = 26) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.67 (0.13–3.35) | Insufficient |
| Response | Haloperidol vs. aripiprazole | 1 SR (5 RCTs; N = 2,185) | Moderate | Inconsistent | Direct | Precise | No difference; RR 1.01 (0.76–1.34), I2 = 83% | Low |
| Response | Haloperidol vs. asenapine | 1 SR (1 RCT; N = 335) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.82 (0.64–1.04) | Insufficient |
| Response | Haloperidol vs. clozapine | 1 SR (2 RCTs; N = 144) | Moderate | Inconsistent | Direct | Imprecise | Inconclusive; RR 0.64 (0.28–1.47), I2 = 72% | Insufficient |
| Response | Haloperidol vs. olanzapine | 1 SR (14 RCTs; N = 4,099) | Moderate | Inconsistent | Direct | Precise | Favors olanzapine; RR 0.86 (0.78–0.96), I2 = 55% | Low |
| Response | Haloperidol vs. quetiapine | 1 SR (6 RCTs; N = 1,421) | Moderate | Inconsistent | Direct | Precise | No difference; RR 0.99 (0.76–1.30), I2 = 77% | Low |
| Response | Haloperidol vs. risperidone | 1 SR (16 RCTs; N = 3,452) | Moderate | Consistent | Direct | Precise | No difference; RR 0.94 (0.87–1.02), I2 = 29% | Moderate |
| Response | Haloperidol vs. ziprasidone | 1 SR (6 RCTs; N = 1,283) | Moderate | Inconsistent | Direct | Imprecise | Inconclusive; RR 0.98 (0.74–1.30), I2 = 80% | Low |
| Response | Perphenazine vs. aripiprazole | 1 SR (1 RCT; N = 300) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.95 (0.64–1.40) | Insufficient |
| Remission | Haloperidol vs. clozapine | 1 SR (1 RCT; N = 71) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.16 (0.02–1.20) | Insufficient |
| Remission | Haloperidol vs. olanzapine | 1 SR (3 RCTs; N = 582) | Moderate | Consistent | Direct | Imprecise | Favors olanzapine; RR 0.65 (0.45–0.94), I2 = 54% | Low |
| Remission | Haloperidol vs. quetiapine | 1 SR (1 RCT; N = 207) | High | Unknown | Direct | Imprecise | Inconclusive; RR 0.72 (0.41–1.25) | Insufficient |
| Remission | Haloperidol vs. risperidone | 1 SR (2 RCTs; N = 179) | Moderate | Consistent | Direct | Imprecise | Inconclusive; RR 0.84 (0.56–1.24), I2 = 0% | Low |
| Remission | Haloperidol vs. ziprasidone | 1 SR (3 RCTs; N = 1,085) | High | Consistent | Direct | Precise | No difference; RR 0.89 (0.71–1.12), I2 = 12% | Low |
| Mortality (all-cause) | Olanzapine vs. risperidone vs. quetiapine | 1 SR (1 retrospective cohort study; N = 48,595) | Low | Unknown | Direct | Precise | No difference in all-cause mortality between risperidone and olanzapine (HR 1.09, 95% CI 0.79–1.49) or quetiapine (HR 0.75, 95% CI 0.53–1.07) | Low |
| Mortality (all-cause) | Clozapine, risperidone, olanzapine, and quetiapine vs. no treatment | 1 SR (1 retrospective cohort study; N = 6,987) | Low | Unknown | Direct | Imprecise | Clozapine and quetiapine had significantly lower risk of all-cause mortality (adjusted ORs 0.35, 95% CI 0.21–0.58 and 0.46, 95% CI 0.30–0.72), and risperidone and olanzapine were not statistically significantly different from control | Insufficient |
| Mortality (all-cause) | Asenapine vs. olanzapine | 2 RCTs; N = 2,174 (1 RCT reported 2 RCT studies) | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| RCT 1: 0.41% vs. 0.42% | ||||||||
| RCT 2: 0% vs. 0.77% | ||||||||
| RCT 3: 0.32% | ||||||||
| RR 2.49 (0.54–11.5) | ||||||||
| Mortality (all-cause) | Paliperidone palmitate LAI (monthly) vs. risperidone LAI | 2 RCTs; N = 752 | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| RCT 1: 0.79% vs. 0.27% | ||||||||
| RCT 2: 0% vs. 0.45% | ||||||||
| RR 1.26 (0.21–7.49) | ||||||||
| Mortality (all-cause) | Quetiapine vs. risperidone | 2 RCTs; N = 1,057 | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| RCT 1: 1.17% vs. 0.40% | ||||||||
| RCT 2: 0.72% vs. 0% | ||||||||
| RR 3.24 (0.72 to 14.6) | ||||||||
| Cardiovascular mortality | Olanzapine vs. risperidone vs. quetiapine | 1 SR (2 retrospective cohort studies; N = 55,582) | Low | Consistent | Direct | Precise | No significant differences between the drugs: HR 0.99 (0.37–2.67) and 0.76 (0.25–2.28), respectively | Low |
| Cardiovascular mortality | Clozapine vs. risperidone | 1 SR (2 retrospective cohort studies; N = 1,686) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| No significant differences between drugs: 4.8% vs. 2.5%; RR 1.39 (0.61–2.53) | ||||||||
| Self-harm: suicidal behavior, suicide | Clozapine vs. olanzapine in high-risk patients | 1 SR (1 RCT; N = 980) | Low | Unknown | Direct | Imprecise | Suicidal behavior: HR 0.76 (0.58–0.97) | Low |
| Self-harm: suicidal behavior, suicide | Clozapine vs. olanzapine in high-risk patients | 1 SR (1 RCT; N = 980) | Low | Unknown | Direct | Precise | Worsening on CGI-Suicide Severity: HR 0.78 (0.61–0.99) | Moderate |
| Self-harm: suicidal behavior, suicide | Clozapine vs. olanzapine in high-risk patients | 1 SR (1 RCT; N = 980) | Low | Unknown | Direct | Imprecise | Suicide deaths: no significant differences (5 clozapine, 3 olanzapine) | Low |
| Self-harm: suicidal behavior, suicide | Clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole | 1 SR (2 retrospective cohorts; N = 16,584) | Moderate | Consistent | Direct | Precise | Death by suicide lower with clozapine: OR 0.29 (0.14–0.63) compared with no treatment at 6 months and lower with clozapine (1.1%) than baseline (2.2%) or other drugs (range 2.1%–3.7%) at 1 year | Low |
| Self-harm: suicidal behavior, suicide | Clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole | 1 SR (1 prospective cohort; N = 10,204) | High | Unknown | Direct | Precise | Suicide attempts (6 months): no statistically significant difference between drugs | Insufficient |
| Self-harm: suicidal behavior, suicide | Clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole | 1 SR (1 prospective cohort; N = 20,489) | High | Unknown | Direct | Precise | Inconclusive | Insufficient |
| Suicide attempts or death by suicide: aripiprazole vs. all others combined HR 0.69 (0.42–1.14) | ||||||||
| Reduction in self-harm | Haloperidol vs. olanzapine | 1 SR (1 RCT; N = 182) | Moderate | Unknown | Indirect | Imprecise | Inconclusive | Insufficient |
| Attempted suicide: RR 3.13 (0.13–76) | ||||||||
| Completed suicide: RR 3.13 (0.13–76) | ||||||||
| Reduction in self-harm | Perphenazine vs. olanzapine | 1 SR (1 RCT; N = 597) | Moderate | Unknown | Indirect | Imprecise | Inconclusive | Insufficient |
| Attempted suicide: RR 0.64 (0.06–7.06) | ||||||||
| Completed suicide: RR 3.86 (0.40–37) | ||||||||
| Core illness symptoms | Oral SGAs (except carpipramine): meta-analysis of clozapine, amisulpride, olanzapine, risperidone, paliperidone, zotepine, haloperidol, quetiapine, aripiprazole, sertindole, ziprasidone, chlorpromazine, asenapine, lurasidone, and iloperidone | 212 RCTs; N = 43,049 | Moderate | Consistent | Indirect | Precise | Significantly better improvement with clozapine than the other drugs except olanzapine: SMDs on PANSS or BPRS –0.32 to –0.55 | Low |
| Olanzapine and risperidone superior to the other drugs, except for each other and paliperidone: SMDs –0.13 to –0.26 | ||||||||
| Paliperidone superior to lurasidone and iloperidone: SMD –0.17 | ||||||||
| All drugs superior to placebo: SMDs –0.33 to –0.88 | ||||||||
| Core illness symptoms | Treatment-resistant patients: clozapine, risperidone, olanzapine, quetiapine, ziprasidone | Network meta-analysis (40 RCTs; N = 5,172) | Moderate | Consistent | Indirect | Precise | The only significant difference was that the mean change in the PANSS was greater with olanzapine than quetiapine: SMD – 0.29 (– 0.56 to – 0.13) | Low |
| Core illness symptoms | Brexpiprazole vs. aripiprazole | 1 open label study; N = 97 | Moderate | Unknown | Indirect | Imprecise | Inconclusive | Insufficient |
| PANSS: least squares mean difference –22.9 vs. –19.4 at 6 weeks from baseline; direct comparison not reported | ||||||||
| Overall/any adverse events | Asenapine vs. olanzapine | 5 RCTs (4 publications; N = 2,189) | Moderate | Consistent | Direct | Precise | Pooled RR 1.00 (0.96–1.05), I2 = 9% | Moderate |
| Overall/any adverse events | Quetiapine vs. risperidone | 7 RCTs; N = 3,254 | Moderate | Consistent | Direct | Precise | Pooled RR 1.04 (0.97–1.12), I2 = 56% | Moderate |
| Overall/any adverse events | Clozapine vs. olanzapine | 2 RCTs; N = 182 | Moderate | Consistent | Direct | Imprecise | Pooled RR 1.15 (1.00–1.33), I2 = 0% | Low |
| Overall/any adverse events | Risperidone vs. olanzapine | 5 RCTs; N = 873 | Moderate | Inconsistent | Direct | Precise | Pooled RR 1.02 (0.81–1.29), I2 = 77% | Low |
| Overall/any adverse events | Olanzapine vs. ziprasidone | 5 RCTs; N = 1,097 (6-week to 6-month durations) | Moderate | Inconsistent | Direct | Precise | Pooled RR 1.00 (0.86–1.16), I2 = 80% | Low |
| Overall/any adverse events | Olanzapine vs. quetiapine | 3 RCTs; N = 448 | Moderate | Consistent | Direct | Imprecise | Pooled RR 0.90 (0.74–1.11), I2 = 30% | Low |
| Overall/any adverse events | Quetiapine XR vs. quetiapine IR and risperidone; risperidone vs. clozapine and aripiprazole; olanzapine vs. paliperidone; risperidone LAI vs. paliperidone and paliperidone palmitate LAI (monthly); and aripiprazole vs. aripiprazole LAI (monthly); additionally, there were 6 trials comparing asenapine and olanzapine | 1 SR (28 RCTs; N = 7,810) | Moderate | Consistent | Direct | Imprecise | No statistically significant differences were found in each comparison | Low |
| Overall/any adverse events | Oral aripiprazole vs. brexpiprazole, olanzapine, paliperidone, and risperidone LAI; ziprasidone vs. clozapine, risperidone, iloperidone, and lurasidone; risperidone vs. asenapine, carpipramine, and risperidone LAI; clozapine vs. quetiapine, quetiapine vs. risperidone LAI; olanzapine vs. olanzapine LAI and lurasidone; aripiprazole LAI (monthly) vs. paliperidone; and paliperidone palmitate LAI (monthly) vs. 3-month LAI | 1 SR (31 RCTs; N = 6,700) | Moderate | Unknown | Direct | Imprecise | No statistically significant differences were found in single studies of each comparison | Insufficient |
| Overall adverse events | Haloperidol vs. aripiprazole | 1 SR (3 RCTs; N = 1,713) | Moderate | Consistent | Direct | Precise | RR 1.11 (1.06–1.17), I2 = 0%; less with aripiprazole | Moderate |
| Overall adverse events | Haloperidol vs. risperidone | 1 SR (8 RCTs; N = 1,313) | Moderate | Consistent | Direct | Precise | RR 1.20 (1.01–1.42), I2 = 84%; less with risperidone | Moderate |
| Overall adverse events | Haloperidol vs. ziprasidone | 1 SR (6 RCTs; N = 1,448) | Moderate | Consistent | Direct | Precise | RR 1.13 (1.03–1.23), I2 = 31%; less with ziprasidone | Moderate |
| Discontinuation due to adverse events | Network meta-analysis of aripiprazole, aripiprazole LAI (monthly), asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, olanzapine LAI, paliperidone 3-month LAI, paliperidone, paliperidone LAI (monthly), quetiapine XR, quetiapine IR, risperidone, risperidone LAI, ziprasidone | 89 RCTs (N = 29,678) | Moderate | Consistent | Indirect | Precise | Risperidone LAI had statistically significantly lower risk of withdrawals due to adverse events than asenapine (OR 0.50, 95% CI 0.23–0.97), clozapine (OR 0.26, 95% CI 0.10–0.67), lurasidone (OR 0.38, 95% CI 0.17–0.79), paliperidone (OR 0.43, 95% CI 0.17–0.98), paliperidone LAI (monthly) (OR 0.51, 95% CI 0.26–0.98), quetiapine XR (OR 0.42, 95% CI 0.21–0.78), risperidone (OR 0.48, 95% CI 0.23–0.92), and ziprasidone (OR 0.39, 95% CI 0.18–0.76) | Low |
| Olanzapine had lower risk than clozapine (OR 0.40, 95% CI 0.21–0.79), lurasidone (OR 0.58, 95% CI 0.36–0.98), quetiapine IR (OR 0.64, 95% CI 0.45–0.93), risperidone (OR 0.74, 95% CI 0.55–0.98), and ziprasidone (OR 0.59, 95% CI 0.43–0.84) | ||||||||
| Aripiprazole had lower risk than ziprasidone (OR 0.65, 95% CI 0.44–0.95), and iloperidone had lower risk than clozapine (OR 0.35, 95% CI 0.13–0.91) | ||||||||
| Withdrawal due to adverse events | Fluphenazine vs. olanzapine | 1 SR (1 RCT; N = 60) | Moderate | Unknown | Indirect | Imprecise | Inconclusive; RR 0.74 (0.51–1.07) | Insufficient |
| Withdrawal due to adverse events | Fluphenazine vs. quetiapine | 1 SR (1 RCT; N = 25) | Moderate | Unknown | Indirect | Imprecise | Inconclusive; RR 0.19 (0.01–3.52) | Insufficient |
| Withdrawal due to adverse events | Haloperidol vs. asenapine | 1 SR (1 RCT; N = 335) | Moderate | Unknown | Indirect | Imprecise | Inconclusive; RR 1.53 (0.74–3.16) | Insufficient |
| Withdrawal due to adverse events | Haloperidol vs. aripiprazole | 1 SR (7 RCTs) plus 1 additional RCT; N = 3,232 | Moderate | Consistent | Direct | Precise | RR 1.25 (1.07–1.47), I2 = 0% | Moderate |
| Withdrawal due to adverse events | Haloperidol vs. clozapine | 1 SR (5 RCTs; N = 719) | Moderate | Consistent | Direct | Imprecise | Inconclusive; RR 1.00 (0.66–1.50), I2 = 0% | Low |
| Withdrawal due to adverse events | Haloperidol vs. olanzapine | 1 SR (21 RCTs) plus 3 RCTs; N = 5,708 | Moderate | Consistent | Direct | Precise | RR 1.89 (1.57–2.27), I2 = 0% | Moderate |
| Withdrawal due to adverse events | Haloperidol vs. quetiapine | 1 SR (8 RCTs) plus 2 RCTs; N = 1,759 | Moderate | Consistent | Direct | Imprecise | Inconclusive; RR 1.97 (0.96–4.01), I2 = 62% | Low |
| Withdrawal due to adverse events | Haloperidol vs. risperidone | 1 SR (23 RCTs) plus 2 RCTs; N = 4,581 | Moderate | Consistent | Direct | Precise | RR 1.32 (1.09–1.60), I2 = 0% | Moderate |
| Withdrawal due to adverse events | Haloperidol vs. ziprasidone | 1 SR (6 RCTs) plus 1 RCT; N = 1,597 | Moderate | Consistent | Direct | Precise | RR 1.68 (1.26–2.23), I2 = 0% | Moderate |
| Withdrawal due to adverse events | Perphenazine vs. aripiprazole | 1 SR (1 RCT; N = 300) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.53 (0.27–1.05) | Insufficient |
| Withdrawal due to adverse events | Perphenazine vs. olanzapine | 1 SR (1 RCT; N = 597) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.83 (0.58–1.19) | Insufficient |
| Withdrawal due to adverse events | Perphenazine vs. quetiapine | 1 SR (1 RCT; N = 598) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 1.05 (0.72–1.55) | Insufficient |
| Withdrawal due to adverse events | Perphenazine vs. risperidone | 1 SR (1 RCT; N = 602) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 1.54 (1.00–2.36) | Insufficient |
| Withdrawal due to adverse events | Perphenazine vs. ziprasidone | 1 SR (1 RCT; N = 446) | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 1.01 (0.65–1.58) | Insufficient |
| Abbreviations. BPRS = Brief Psychiatric Rating Scale; CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness; CGI = Clinical Global Impression; CI = confidence interval; df = degrees of freedom; GAF = Global Assessment of Functioning; HR = hazard ratio; IR = immediate release; LAI = long-acting injectable; MANSA = Manchester Short Assessment of Quality of Life; NR = normal range; NS = not significant; OR = odds ratio; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance; Q = Cochran’s Q test; QLS = Heinrichs-Carpenter Quality of Life Scale; RCT = randomized controlled trial; RFS = Role Functioning Scale; RR = relative risk; SAS-SMI = Social Adjustment Scale—Severely Mentally Ill version; SF = short form; SFS = Social Functioning Scale; SGA = second-generation antipsychotic; SMD = standard mean difference; SOFAS = Social and Occupational Functioning Assessment Scale; SQLS = Schizophrenia Quality of Life Scale; SR = systematic review; SWN = Subjective Well-being under Neuroleptic Treatment; WMD = weighted mean difference; XR = extended release. | ||||||||
Pharmacological treatment
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Function | ACT vs. usual care | 1 SR (3 RCTs) plus 1 RCT; N = 118 | Moderate | Consistent | Direct | Imprecise | No difference in social function compared with usual care | Low |
| Social function: MD 0.03 (–0.28 to 0.34) | ||||||||
| Trouble with police | ACT vs. usual care | 1 SR (4 RCTs) | Moderate | Consistent | Direct | Imprecise | No differences in arrests (2 trials; OR 1.17, 95% CI 0.60–2.29), imprisonment (4 trials; OR 1.19, 95% CI 0.70–2.01), or police contacts (2 trials; OR 0.76, 95% CI 0.32–1.79) | Low |
| Housing and independent living | ACT vs. usual care | 1 SR (3 RCTs) plus 1 RCT; N = 118 | Moderate | Consistent | Direct | Precise | Less likely to be not living independently (4 trials; OR 0.52, 95% CI 0.35–0.79) and to be homeless (4 trials; OR 0.20, 95% CI 0.09–0.47) | Moderate |
| Less likely to be homeless (4 trials; OR 0.24, 95% CI 0.12–0.48) | ||||||||
| Employment | ACT vs. usual care | 1 SR (3 RCTs) | Moderate | Consistent | Direct | Precise | Less likely to be unemployed (OR 0.46, 95% CI 0.21–0.99) | Moderate |
| Quality of life | ACT vs. usual care | 1 SR (1 RCT; N = 125) plus 1 RCT; N = 118 | Moderate | Inconsistent | Direct | Imprecise | Quality of life was slightly better with ACT (MD –0.52, 95% CI –0.99 to –0.05) in one trial, but no differences were found in the other trial | Insufficient |
| Overall symptoms | ACT vs. usual care | 1 SR (3 RCTs) plus 1 RCT; N = 118 | Moderate | Consistent | Direct | Precise | No differences were found in 4 trials (MD –0.14, 95% CI –0.36 to 0.08) | Moderate |
| Treatment maintenance (loss to follow-up) | ACT vs. usual care | 1 SR (10 RCTs) plus 1 RCT; N = 118 | Moderate | Consistent | Direct | Precise | Significantly less loss to follow-up with ACT (OR 0.51, 95% CI 0.40–0.65) on the basis of 10 trials in the SR; significantly fewer patients “out of care” in the other trial (OR 0.10, 95% CI 0.03–0.33) | Moderate |
| Abbreviations. CI = confidence interval; MD= mean difference; OR = odds ratio; RCT = randomized controlled trial; SR = systematic review. | ||||||||
Assertive community treatment (ACT)
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Function: global function, short term (≤ 6 months since CBT initiation) | CBT vs. usual care | 1 SR (3 RCTs) plus 5 RCTs; N = 701 | Moderate | Consistent | Direct | Precise | GAF (6 RCTs): MD 5.49 (1.85–9.14), I2 = 75%; excluding one outlier: 6.62 (4.68–8.56), I2 = 0% | Moderate |
| SOFAS (2 RCTs): MD 9.11 (6.31–11.91) | ||||||||
| Proportion with normal function (1 RCT): RR 2.21 (1.25–3.93) | ||||||||
| Function: global function, medium term (> 6 months to 1 year since CBT initiation) | CBT vs. usual care | 3 RCTs; N = 465 | Moderate | Inconsistent | Direct | Imprecise | Inconclusive | Insufficient |
| GAF: 1 trial with 6-month posttreatment follow-up found no difference; another trial found effect favoring CBT | ||||||||
| SOFAS, SFS: No difference between groups | ||||||||
| Function: global function, long term (> 1 year since CBT initiation) | CBT vs. usual care | 1 SR (4 RCTs) plus 4 RCTs; N = 851 | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| GAF: 1 SR found MD 4.20 (–0.63 to 9.03); another RCT found positive effect of CBT | ||||||||
| 3 RCTs found no difference in SOFAS, global function (scale not reported), and proportion of patients with normal function | ||||||||
| Function: basic living skills | CBT vs. usual care | 1 RCT; N = 76 | Moderate | Unknown | Direct | Imprecise | No difference between groups | Insufficient |
| Function: employment outcomes | CBT vs. usual care | 2 RCTs; N = 522 | Moderate | Inconsistent | Direct | Imprecise | Inconclusive | Insufficient |
| 1 RCT of vocation-focused CBT favored CBT for hours worked and WBI score; another trial found no difference in proportion of patients with occupational recovery | ||||||||
| Quality of life | CBT vs. usual care | 12- to 24-week follow-up; 2 RCTs; N = 216 | Moderate | Consistent | Direct | Imprecise | CBT led to improved quality of life 0 and 16 weeks after cessation of treatment on the basis of CHOICE, WEMWEBS, and WHOQOL-BREF scales | Low |
| Quality of life | CBT vs. usual care | 18- to 24-month follow-up; 2 RCTs; N = 489 | Moderate | Consistent | Direct | Imprecise | CBT not different from usual care on WHOQOL and EUROQOL scales | Low |
| Suicide and suicidality | CBT vs. usual care | 2 RCTs; N = 307 | Moderate | Consistent | Direct | Imprecise | Inconclusive; RR 0.68 (0.12–3.93) and RR 0.53 (0.12–2.79) | Insufficient |
| Core illness symptoms | CBT vs. usual care | 1 SR (34 RCTs; N = 2,989) | Moderate | Consistent | Direct | Precise | SMD –0.33 (0.47 to –0.19); subgroup with outcome assessment blinding SMD –0.15 (–0.27 to –0.03) | Moderate |
| Negative symptoms | CBT vs. usual care | 2 SRs (34 RCTs; N = 3,393) | Moderate | Inconsistent | Direct | Precise | SMD –0.13 (–0.25 to –0.01), I2 = 48% (in this review, a negative estimate favors CBT); SMD 0.09 (–0.03 to 0.21), I2 = 63% (in this review, a positive estimate favors CBT) | Low |
| Ability to maintain treatment | CBT vs. usual care | 13 RCTs; N = 1,847 | Moderate | Inconsistent | Direct | Precise | No difference; RR 1.03 (0.96–1.10), I2 = 64% | Low |
| Relapse | CBT vs. usual care | 6 RCTs; N = 1,090 | Moderate | Inconsistent | Direct | Imprecise | Inconclusive; RR 0.80 (0.51–1.25), I2 = 77% | Insufficient |
| Subanalysis limited to relapse defined as “hospitalization” (3 RCTs): 0.70 (0.54–0.91), I2 = 0% | ||||||||
| Harms | CBT vs. usual care | 1 RCT; N = 150 | Moderate | Inconsistent | Direct | Imprecise | None of the adverse events were related to treatment: 2 vs. 4 suicide attempts; 1 vs. 1 serious violent incident | Insufficient |
| Abbreviations. CHOICE = Choice of Outcome in CBT for psychoses; CI = confidence interval; EUROQOL = European Quality of Life scale; GAF = Global Assessment of Functioning; MD = mean difference; OR = odds ratio; RCT = randomized controlled trial; RR = relative risk; SFS = Social Functioning Scale; SMD = standard mean difference; SOFAS = Social and Occupational Functioning Assessment Scale; SR = systematic review; WBI = Work Behavior Inventory; WEMWEBS = Warwick-Edinburgh Mental Well-being Scale; WHOQOL = World Health Organization Quality of Life. | ||||||||
Cognitive-behavioral therapy (CBT)
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Function | Cognitive remediation vs. usual care | 1 SR (19 RCTs) plus 3 RCTs; N = 1,323 | Moderate | Consistent | Direct | Imprecise | In studies comparing with usual care, cognitive remediation resulted in a small positive effect on function that was not consistently statistically significant: effect size 0.16 (–0.16 to 0.49), SMD 0.56 (0.34–0.88), and SMD 0.41 (–0.10 to 0.91). | Low |
| Quality of life | Cognitive remediation vs. usual care | 1 RCT; N = 69 | Moderate | Unknown | Direct | Imprecise | Quality of life was reported in only 1 trial, with no difference between cognitive remediation and usual care | Insufficient |
| Overall symptoms | Cognitive remediation vs. usual care | 2 RCTs; N = 153 | Moderate | Consistent | Direct | Imprecise | Cognitive remediation improved total symptoms in 2 trials: SMD –0.62 (–1.01 to –0.24); 4 trials included in the Wykes review reported effect sizes ranging from 0.05 to 0.45 (CIs were not reported) | Low |
| Negative symptoms | Cognitive remediation vs. usual care | 1 SR (18 RCTs; N = 781) | Moderate | Consistent | Direct | Precise | Negative symptoms improved more in cognitive remediation groups: effect size –0.36 (–0.52 to –0.20); a negative effect size favors cognitive remediation | Moderate |
| Ability to maintain treatment | Cognitive remediation vs. usual care | 3 RCTs; N = 302 | Moderate | Consistent | Direct | Imprecise | No difference in ability to maintain treatment in 3 RCTs of cognitive remediation | Low |
| Abbreviations. CI = confidence interval; RCT = randomized controlled trial; SMD = standard mean difference; SR = systematic review. | ||||||||
Cognitive remediation
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Function: occupational (unemployed), 1 year | Family intervention vs. usual care | 1 SR (4 RCTs; N = 230) | Moderate | Consistent | Direct | Imprecise | RR 1.09 (0.92–1.29) | Low |
| Function: occupational (unemployed), 2 years | Family intervention vs. usual care | 1 SR (1 RCT; N = 51) | Moderate | Unknown | Direct | Imprecise | RR 1.33 (0.84–2.10) | Insufficient |
| Function: occupational (unemployed), 3 years | Family intervention vs. usual care | 1 SR (1 RCT; N = 99) | Moderate | Unknown | Direct | Imprecise | RR 1.19 (0.92–1.55) | Insufficient |
| Function: living situation (cannot live independently), 1 year | Family intervention vs. usual care | 1 SR (3 RCTs; N = 164) | Moderate | Consistent | Direct | Imprecise | RR 0.83 (0.66–1.03) | Low |
| Function: living situation (cannot live independently), 3 years | Family intervention vs. usual care | 1 SR (1 RCT; N = 99) | Moderate | Unknown | Direct | Imprecise | RR 0.82 (0.59–1.14) | Insufficient |
| Function: living situation (cannot live independently, months in psychiatric facility), 5 years | Family intervention vs. usual care | 1 RCT; N = 73 | Moderate | Unknown | Direct | Imprecise | 10.87 vs. 21.18 months, P = 0.04 | Insufficient |
| Social functioning | Family intervention vs. usual care | 1 RCT; N = 69 | Moderate | Unknown | Direct | Imprecise | No between-group differences | Insufficient |
| Quality of life | Family intervention vs. usual care | 1 SR (1 RCT; N = 50) plus 1 RCT not in SR; N = 55 | Moderate | Unknown | Direct | Imprecise | QLS: MD –5.05 (–15.44 to 5.34) | Insufficient |
| EUROQOL: MD –7.38 (–22.07 to 7.31) | ||||||||
| Depression | Family intervention vs. usual care | 2 RCTs; N = 124 | Moderate | Consistent | Direct | Imprecise | RCT 1, 6 months: –1.0 (–12 to 22) vs. 0 (–15 to 17) | Low |
| RCT 1, 12 months: 3.0 (–15 to 17) vs. 0 (–14 to 17) | ||||||||
| RCT 2, 12 months: 3.35 (–2.64 to 9.34) | ||||||||
| RCT 2, 24 months: –0.11 (–6.91 to 6.68) | ||||||||
| Anxiety | Family intervention vs. usual care | 1 RCT; N = 55 | Low | Unknown | Direct | Imprecise | 12 months: –0.42 (–6.97 to 6.13) | Insufficient |
| 24 months: –2.36 (–9.13 to 4.40) | ||||||||
| Suicide | Family intervention vs. usual care | 1 SR (6 RCTs; N = 314) | Moderate | Consistent | Direct | Imprecise | RR 0.85 (0.24–3.02) | Low |
| Core illness symptoms | Family intervention vs. usual care | 1 SR (2 RCTs; N = 223) | Moderate | Consistent | Direct | Imprecise | SMD – 0.46 (–0.73 to –0.20) | Low |
| Negative symptoms | Family intervention vs. usual care | 3 RCTs; N = 163 | Moderate | Consistent | Direct | Imprecise | SMD –0.38 (–0.69 to –0.07) | Low |
| Leaving the study early (3–6 months) | Family intervention vs. usual care | 1 SR (6 RCTs; N = 504) | Moderate | Consistent | Indirect | Imprecise | RR 0.86 (0.50–1.47) | Low |
| Leaving the study early (7–12 months) | Family intervention vs. usual care | 1 SR (9 RCTs; N = 487) plus 4 RCTs; N = 466 | Moderate | Consistent | Indirect | Imprecise | RR 0.77 (0.64–0.93) | Low |
| Leaving the study early (13–24 months) | Family intervention vs. usual care | 1 SR (6 RCTs; N = 362) | Moderate | Consistent | Indirect | Imprecise | RR 0.82 (0.57–1.16) | Low |
| Leaving the study early (25–36 months) | Family intervention vs. usual care | 1 SR (2 RCTs; N = 90) | High | Consistent | Indirect | Imprecise | RR 0.59 (0.24–1.49) | Insufficient |
| Leaving the study early after 3 years | Family intervention vs. usual care | 1 SR (1 RCT; N = 63) | Moderate | Unknown | Indirect | Imprecise | RR 1.72 (0.71–4.16) | Insufficient |
| Poor compliance with medication | Family intervention vs. usual care | 1 SR (4 RCTs; N = 174) plus 2 RCTs; N = 256 | Moderate | Consistent | Indirect | Imprecise | RR 0.78 (0.65–0.92) | Low |
| Relapse (0–6 months) | Family intervention vs. usual care | 1 SR (2 RCTs; N = 167) | Moderate | Consistent | Direct | Imprecise | RR 0.62 (0.41–0.92) | Low |
| Relapse (7–12 months) | Family intervention vs. usual care | 1 SR (16 RCTs; N = 861) plus 4 RCTs; N = 314 | Moderate | Consistent | Direct | Imprecise | RR 0.67 (0.54–0.83) | Moderate |
| Relapse (13–24 months) | Family intervention vs. usual care | 1 SR (9 RCTs; N = 517) | Moderate | Consistent | Direct | Imprecise | RR 0.75 (0.58–0.99) | Low |
| Relapse (25–36 months) | Family intervention vs. usual care | 1 SR (2 RCTs; N = 147) | Moderate | Inconsistent | Direct | Imprecise | RR 1.05 (0.80–1.39) | Low |
| Relapse (5 years) | Family intervention vs. usual care | 1 SR (1 RCT; N = 63) plus 1 RCT; N = 77 | Moderate | Consistent | Direct | Imprecise | RR 0.82 (0.72–0.94) | Low |
| Relapse (8 years) | Family intervention vs. usual care | 1 SR (1 RCT; N = 62) | Moderate | Unknown | Direct | Imprecise | RR 0.86 (0.71–1.05) | Insufficient |
| Family burden not improved or worse | Family intervention vs. usual care | 1 SR (1 RCT; N = 51) | Moderate | Unknown | Direct | Imprecise | Social functioning: | Insufficient |
| RR 2.40 (0.51–11.27) at 1 year | ||||||||
| RR 2.88 (0.64–12.97) at 2 years | ||||||||
| Subjective burden: | ||||||||
| RR 1.44 (0.60–3.46) at 1 year | ||||||||
| RR 0.58 (0.15–2.16) at 2 years | ||||||||
| Nonsuicide mortality | Family intervention vs. usual care | 1 SR (3 RCTs; N = 113) | Moderate | Consistent | Direct | Imprecise | RR 0.96 (0.17–5.33) | Insufficient |
| Abbreviations. EUROQOL = European Quality of Life scale; MD = mean difference; QLS = Heinrichs-Carpenter Quality of Life Scale; RCT = randomized controlled trial; RR = relative risk; SMD = standard mean difference; SR = systematic review. | ||||||||
Family interventions
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Function | Intensive case management vs. usual care | 1 SR (3 RCTs) plus 1 RCT; N = 77 | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| Pooled MD 0.46 (–0.34 to 1.26); one subsequent trial also found no difference using a different scale | ||||||||
| Quality of life | Intensive case management vs. usual care | 1 SR (2 RCTs) plus 1 RCT; N = 77 | Moderate | Consistent | Direct | Imprecise | Inconclusive | Insufficient |
| Pooled MD 0.09 (–0.23 to 0.42); one subsequent trial also found no difference between groups in quality of life using a different scale | ||||||||
| Overall symptoms | Intensive case management vs. usual care | 1 SR (2 RCTs) plus 1 RCT; N = 77 | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| Pooled MD 0.46 (– 3.67 to 4.60); one subsequent trial also reported no difference | ||||||||
| Loss to follow-up | Intensive case management vs. usual care | 1 SR (7 RCTs) plus 1 RCT; N = 77 | Moderate | Consistent | Direct | Precise | Less loss to follow-up with intensive case management compared with usual care: OR 0.70 (0.54–0.90) | Moderate |
| Imprisonment | Intensive case management vs. usual care | 1 SR (5 RCTs) | Moderate | Consistent | Direct | Imprecise | No significant differences in imprisonment: OR 0.90 (0.45–1.82) | Low |
| Abbreviations. CI = confidence interval; MD = mean difference; OR = odds ratio; RCT = randomized controlled trial; SR = systematic review. | ||||||||
Intensive case management
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Functioning | Illness self-management/self-management education intervention vs. usual care | 1 SR (10 RCTs; N = 409) plus 1 RCT; N = 210 | Moderate | Inconsistent | Direct | Imprecise | Inconclusive | Insufficient |
| Heterogeneous methods for measuring various types of functioning were used, with 5 finding benefit and 6 not | ||||||||
| Symptoms | Illness self-management/self-management education intervention vs. usual care | 1 SR (5 RCTs; N = 409) | Moderate | Consistent | Direct | Precise | BPRS, WMD: –4.19 (–5.84 to –2.54) | Moderate |
| Negative symptoms | Illness self-management/self-management education intervention vs. usual care | 1 SR (3 RCTs; N = 257) | Moderate | Consistent | Direct | Imprecise | PANSS negative –4.01 (–5.23 to –2.79) | Low |
| Relapse | Illness self-management/self-management education intervention vs. usual care | 1 SR (3 RCTs; N = 534) | Moderate | Consistent | Direct | Imprecise | Relapse (> 10 interventions): N = 233, OR 0.41 (0.21–0.79), P = 0.008 | Low |
| Relapse (< 10 interventions): N = 269, OR 0.67 (0.39–1.15), P = 0.014 | ||||||||
| Abbreviations. BPRS = Brief Psychiatric Rating Scale; CI = confidence interval; OR = odds ratio; PANSS = Positive and Negative Syndrome Scale; RCT = randomized controlled trial; SR = systematic review; WMD = weighted mean difference. | ||||||||
Illness management and recovery
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Global functioning (GAF/GAS) at end of intervention | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 41) | Medium | Unknown | Direct | Imprecise | Inconclusive; MD –2.64 (–12.74 to 7.46) | Insufficient |
| Global functioning (GAS) at 6 months | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 92) | Medium | Unknown | Direct | Imprecise | Inconclusive; RR 0.83 (0.50–1.38) | Insufficient |
| Global functioning (GAF/GAS) at 1 year | Psychoeducation vs. standard care | 1 SR (3 RCTs; N = 260) | Medium | Consistent | Direct | Imprecise | MD –5.23 (–8.76 to –1.71), I2 = 79% | Low |
| Global functioning (GAS) at 18 months | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 92) | Medium | Unknown | Direct | Imprecise | Inconclusive; RR 0.90 (0.58–1.39) | Insufficient |
| Global functioning (GAF/GAS) at 2 years | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 59) | Medium | Unknown | Direct | Imprecise | MD –6.70 (–13.38 to –0.02) | Insufficient |
| Global functioning (GAF/GAS) at 5 years | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 60) | Medium | Unknown | Direct | Imprecise | Inconclusive; MD –3.80 (–8.04 to 0.44) | Insufficient |
| Social functioning (SAS-II) at end of intervention | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 19) | Medium | Unknown | Direct | Imprecise | Inconclusive; MD –0.10 (–0.37 to 0.17) | Insufficient |
| Quality of life (QLS) at end of intervention | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 114) | Medium | Unknown | Direct | Imprecise | MD –8.20 (–14.78 to –1.62) | Insufficient |
| Quality of life (QLS) at 3 months | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 108) | Medium | Unknown | Direct | Imprecise | MD –9.70 (–17.22 to –2.18) | Insufficient |
| BPRS at 3 months | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 19) | Medium | Unknown | Direct | Imprecise | Inconclusive; MD –0.06 (–0.53 to 0.41) | Insufficient |
| BPRS at 1 year | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 159) | Medium | Unknown | Direct | Imprecise | MD –6.0 (–9.15 to –2.85) | Insufficient |
| Relapse with or without readmission: 9–18 months | Psychoeducation vs. standard care | 1 SR (6 RCTs; N = 720) | Medium | Consistent | Direct | Precise | RR 0.80 (0.70–0.92), I2 = 54% | Moderate |
| Relapse without readmission: total | Psychoeducation vs. standard care | 1 SR (3 RCTs; N = 385) | Medium | Consistent | Direct | Imprecise | Inconclusive; RR 1.05 (0.84–1.31), I2 = 60% | Low |
| Relapse without readmission: 1 year | Psychoeducation vs. standard care | 1 SR (2 RCTs; N = 303) | Medium | Consistent | Direct | Imprecise | Inconclusive: RR 1.16 (0.92–1.46), I2 = 0.0% | Low |
| Relapse without readmission: 18 months | Psychoeducation vs. standard care | 1 SR (1 RCT; N = 382) | Medium | Unknown | Direct | Imprecise | Inconclusive; RR 0.5 (0.23–1.11) | Insufficient |
| Harms: mortality | Psychoeducation vs. standard care | 1 SR (2 RCTs; N = 170) | Medium | Consistent | Direct | Imprecise | Inconclusive; RR 0.53 (0.07–3.95), I2 = 0.0% | Low |
| Abbreviations. BPRS = Brief Psychiatric Rating Scale; CI = confidence interval; GAF = Global Assessment of Functioning; GAS = Global Assessment Scale; MD = mean difference; QLS = Heinrichs-Carpenter Quality of Life Scale; RCT = randomized controlled trial; RR = risk ratio; SAS = Social Adjustment Scale; SR = systematic review. | ||||||||
Psychoeducation
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Function | Social skills training vs. usual care | 3 RCTs (4 publications); N = 384 | Moderate | Consistent | Direct | Imprecise | Significant improvement in scale scores during treatment for 6 months to 2 years (SMD range 0.65–1.60) | Low |
| Function | Social skills training vs. usual care | 1 RCT; N = 183 | Moderate | Unknown | Direct | Imprecise | Social function not different from control after treatment cessation (1 study; SMD 0.24, 95% CI –0.05 to 0.53) | Insufficient |
| Overall symptoms | Social skills training vs. usual care | 2 RCTs; N = 201 | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| PANSS: SMD –1.50 (–1.92 to – 1.09) and –0.81 (–1.22 to –0.40) | ||||||||
| BPRS (mixed population): SMD –0.04 (–0.33 to 0.25) | ||||||||
| Overall symptoms | Social skills training vs. usual care | 1 RCT; N = 183 | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Mixed population (55% schizophrenia), no significant effect on symptoms (BPRS): SMD –0.04 (–0.33 to 0.25) | ||||||||
| Negative symptoms | Social skills training vs. usual care | 3 RCTs (4 publications); N = 384 | Moderate | Consistent | Direct | Imprecise | Negative symptoms improved with social skills training vs. usual care on the basis of PANSS negative and SANS: SMD range –0.45 to –1.30 at 6 months to 2 years | Low |
| Negative symptoms | Social skills training vs. usual care | 1 RCT; N = 183 | Moderate | Unknown | Direct | Imprecise | Negative symptoms were better with social skills training than usual care 1 year after treatment discontinuation: SMD –0.45 (–0.74 to –0.15) | Insufficient |
| Ability to maintain treatment | Social skills training vs. usual care | 2 RCTs; N = 384 | Moderate | Consistent | Direct | Imprecise | No difference: 1 year: RR 1.10 (0.92–1.31) 2 years: RR 1.01 (0.88–1.16) | Low |
| Relapse | Social skills training vs. usual care | 1 RCT; N = 82 | Moderate | Unknown | Direct | Imprecise | Inconclusive; RR 0.50 (0.18–1.36) | Insufficient |
| Abbreviations. BPRS = Brief Psychiatric Rating Scale; CI = confidence interval; PANSS = Positive and Negative Syndrome Scale; RCT = randomized controlled trial; RR = relative risk; SANS = Scale for the Assessment of Negative Symptoms; SMD = standard mean difference. | ||||||||
Social skills training
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Functional (occupational): number in competitive employment | IPS vs. standard services | 1 trial; N = 204 | Moderate | Unknown | Direct | Imprecise | 75% vs. 27.5%, P < 0.001 | Low |
| Functional (occupational): number in competitive employment | Supported employment (primarily IPS) vs. vocational training or usual care | 1 RCT; N = 1,273 | Moderate | Consistent | Indirect for this review question | Precise | IPS vs. vocational training or usual care: 55% vs 34%, P < 0.001 | Moderate |
| Subgroup analysis of only patients with schizophrenia: 22% vs. 12%, P < 0.001 with mixed effects logistic regression | ||||||||
| Functional (occupational): number in competitive employment | All comparators | Moderate | ||||||
| Functional (occupational): days to first competitive employment | IPS vs. standard services | 1 trial; N = 204 | Moderate | Unknown | Direct | Imprecise | Days to first job: 196.63 vs. 218.84, P = 0.019 | Low |
| Functional (occupational): worked more than 20 hours per week | IPS vs. standard services | 1 trial; N = 204 | Moderate | Unknown | Direct | Imprecise | Worked > 20 hours per week: 33.8% vs. 13%, P = 0.001 | Low |
| Functional (occupational): worked more than 20 hours per week | Supported employment (primarily IPS) vs. vocational training or usual care | 1 RCT; N = 1,273 | Moderate | Consistent | Indirect for this review question | Precise | IPS vs. vocational training or usual care | Moderate |
| Working ≥ 40 hours per month: 51% vs. 39%, P < 0.001 | ||||||||
| Functional (occupational): worked more than 20 hours per week | All comparators | Moderate | ||||||
| Functional (occupational): wages earned | IPS vs. standard services | 1 trial; N = 204 | Moderate | Unknown | Direct | Imprecise | $2,078/month vs. $617.59/month, P < 0.001 | Low |
| Functional (occupational): wages earned | Supported employment (primarily IPS) vs. vocational training or usual care | 1 RCT; N = 1,273 | Moderate | Consistent | Indirect for this review question | Precise | IPS vs. vocational training or usual care | Moderate |
| $122/month vs. $99/month, P = 0.04 | ||||||||
| Functional (occupational): wages earned | All comparators | Moderate | ||||||
| Functional (occupational): weeks worked (mean) | IPS vs. standard services | 1 trial; N = 204 | Moderate | Unknown | Direct | Imprecise | Total weeks worked: 29.72 vs. 5.45, P < 0.001 | Low |
| Functional (occupational): weeks worked (mean) | Supported employment (primarily IPS) vs. vocational training | 1 SR; N = 2,265 | Moderate | Consistent | Indirect for this review question | Precise | Supported employment vs. vocational training days employed: mean difference 70.63 (43.22–98.04) | Moderate |
| Functional (occupational): weeks worked (mean) | All comparators | Moderate | ||||||
| Abbreviations. CI = confidence interval; IPS = individual placement and support; RCT = randomized controlled trial; SR = systematic review. | ||||||||
Supported employment
Outcome | Comparators | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|---|
| Global functioning | Supportive therapy vs. standard care | 1 SR (2 RCTs; N = 289) | Moderate | Consistent | Direct | Imprecise | Inconclusive | Low |
| GAF-M: n = 29; MD 1.40 (–5.09 to 7.89) | ||||||||
| GAS: n = 260; MD –2.66 (– 6.20 to 0.88) | ||||||||
| Social functioning | Supportive therapy vs. standard care | 1 SR (1 RCT; N = 260) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| SFS: MD –0.67 (–7.05 to 5.71) | ||||||||
| Quality of life | Supportive therapy vs. standard care | 1 SR (1 RCT; N = 260) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| RSES: MD –1.21 (–2.85 to 0.43) | ||||||||
| WBS: MD –2.73 (–6.04 to 0.58) | ||||||||
| GHQ: MD –2.45 (–2.41 to 7.31) | ||||||||
| Relapse | Supportive therapy vs. standard care | 1 SR (1 RCT; N = 54) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Medium-term follow-up (13–26 weeks): RR 0.12 (0.01–2.11) | ||||||||
| Long-term follow-up (> 26 weeks): RR 0.96 (0.44–2.11) | ||||||||
| Core symptoms | Supportive therapy vs. standard care | 1 SR (2 RCTs; N = 167) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| PANSS: | ||||||||
| Short term (13–26 weeks, n = 131), MD –4.42 (–10.13 to 1.29) | ||||||||
| Long term (> 26 weeks, n = 36): MD 4.70 (–6.71 to 16.11) | ||||||||
| Negative symptoms | Supportive therapy vs. standard care | 1 SR (1 RCT; N = 47) | Moderate | Unknown | Direct | Imprecise | Inconclusive | Insufficient |
| Short term: mean 10.19 vs. 10.73 | ||||||||
| Long term: mean 9.90 vs. 11.46 (no statistical analysis because of skewed data) | ||||||||
| Discontinuing treatment | Supportive therapy vs. standard care | 1 SR (4 RCTs; N = 354) | Moderate | Consistent | Direct | Imprecise | Inconclusive; RR 0.86 (0.53–1.40) | Low |
| Abbreviations. CI = confidence interval; GAF-M = Global Assessment of Functioning modified; GAS = Global Assessment Scale; GHQ = Global Health Quotient; MD = mean difference; PANSS = Positive and Negative Syndrome Scale; RCT = randomized controlled trial; RR = relative risk; RSES = Rosenberg Self-Esteem Scale; SFS = Social Functioning Scale; SR = systematic review; WBS = Well-Being Scale. | ||||||||
Supportive therapy
Outcome | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|
| Functional: global (GAS, GAF) | 1 SR, 1 RCT; N = 369 (2-year data only) plus 2 RCTs; N = 744, N = 98 | Moderate | Consistent | Direct | Precise | GAS and GAF results only | Moderate |
| Team-based CSC resulted in higher functioning scores | |||||||
| Pooled WMD: 3.88 (0.91–6.85), I2 = 64% | |||||||
| Functional: work or school | 1 SR, 1 RCT (OPUS-Scandinavia); N = 547 plus 2 RCTs; N = 744, N = 125 | Moderate | Consistent | Direct | Precise | Significantly more people (22%) are working or in school with team-based CSC | Moderate |
| Pooled RR 1.22 (1.01–1.47) | |||||||
| Functional: housing status | 1 SR, 1 RCT; N = 547 plus 1 RCT; N = 128 | Moderate | Consistent | Direct | Imprecise | No significant difference between groups | Low |
| Pooled RR 1.06 (0.86–1.30) | |||||||
| Health-related quality of life | 2 RCTs; N = 92, N = 403 | Moderate | Consistent | Direct | Precise | Team-based CSC resulted in greater quality of life ratings as endpoint | Moderate |
| Pooled effect size 0.84 (0.14–1.55), P = 0.02 | |||||||
| Cochran’s Q = 7.43 | |||||||
| P = 0.0064 (significant heterogeneity) | |||||||
| Core illness symptoms (PANSS) | 3 RCTs; N = 99, N = 403, N = 1,184 | Moderate | Inconsistent | Direct | Precise | No clinically important difference between groups in endpoint scores | Low |
| Pooled WMD of all 3 RCTs –2.53 (–5.45 to 0.39), I2 = 55% | |||||||
| Sensitivity analysis removing a study with a 5.9-point difference at baseline resulted in a very small but statistically significant difference and no heterogeneity | |||||||
| Pooled WMD of 2 RCTs –1.40 (–2.25 to –0.55); Cochran’s Q = 0.0014 (df = 1), P = 0.97 | |||||||
| Core illness symptoms (Calgary Depression Scale) | 2 RCTs; N = 99, N = 205 | Moderate | Consistent | Direct | Precise | No significant difference between groups in endpoint scores | Moderate |
| Pooled WMD –0.44 (–1.08 to 0.20); heterogeneity: Cochran’s Q = 0.528157 (df = 1), P = 0.4674 | |||||||
| Discontinuation of treatment | 2 RCTs; N = 1,239, N = 136 | Moderate | Consistent | Direct | Precise | Team-based CSC had a significantly greater rate of treatment retention compared with standard care | High |
| Pooled RR 1.27 (1.16–1.38); Cochran’s Q = 0.03 (df = 1), P = 0.86 | |||||||
| Rates of relapse | 2 RCTs; N = 1,239, N = 122 | Moderate | Consistent | Direct | Imprecise | Participants in team-based CSC were significantly less likely to relapse than those in standard care | Moderate |
| Pooled RR 0.64 (0.52–0.79), Cochran’s Q = 0.024 (df = 1), P = 0.88 | |||||||
| Abbreviations. CI = confidence interval; CSC = coordinated specialty care; df = degrees of freedom; GAF = Global Assessment of Functioning; GAS = Global Assessment Scale; PANSS = Positive and Negative Syndrome Scale; RCT = randomized controlled trial; RR = relative risk; SR = systematic review; WMD = weighted mean difference. | |||||||
Early interventions for patients with first-episode psychosis
Outcome | Number of studies and subjects | Study limitations | Consistency | Directness | Precision | Magnitude of effect: summary effect size (95% CI) | Strength of evidence (high, moderate, low, insufficient) |
|---|---|---|---|---|---|---|---|
| Function: global function (integrated models of care vs. treatment as usual: GAF; 6 months) | 1 SR (1 RCT; N = 162) | Moderate | Unknown | Direct | Imprecise | Inconclusive; MD 1.10 (–1.58 to 3.78) | Low |
| Function: global function (integrated models of care vs. treatment as usual: GAF; 18 months) | 1 SR (1 RCT; N = 176) | Moderate | Unknown | Direct | Imprecise | Inconclusive; MD 1.00 (–1.58 to 3.58) | Low |
| Function: global function (integrated models of care vs. treatment as usual: GAF; 24 months) | 1 SR (1 RCT; N = 166) | Moderate | Unknown | Direct | Imprecise | Inconclusive; MD 1.70 (–1.18 to 4.58) | Low |
| Function: global function (integrated models of care vs. treatment as usual: GAF; 30 months) | 1 SR (1 RCT; N = 164) | Moderate | Unknown | Direct | Imprecise | Inconclusive; MD –0.60 (–3.56 to 2.36) | Low |
| Function: global function (integrated models of care vs. treatment as usual: GAF; 36 months) | 1 SR (1 RCT; N = 170) | Moderate | Unknown | Direct | Imprecise | Inconclusive; MD 0.40 (–2.47 to 3.27) | Low |
| Function: global function (nonintegrated: mean RFS score; 6 months) | 1 SR (1 RCT; N = 50) | Moderate | Unknown | Direct | Imprecise | Inconclusive; MD –0.78 (–2.91 to 1.35) | Insufficient |
| Function: global function (nonintegrated: mean RFS score; 6 months) | 1 SR (1 RCT; N = 29) | Moderate | Unknown | Direct | Imprecise | MD –2.67 (–5.28 to –0.06) | Insufficient |
| Ability to maintain treatment (6 months) | 1 SR (3 RCTs; N = 134) | Moderate | Consistent | Direct | Imprecise | Inconclusive; RR 1.23 (0.73–2.06) | Insufficient |
| Ability to maintain treatment (18 months) | 1 SR (3 RCTs; N = 134) | Moderate | Consistent | Direct | Imprecise | Inconclusive; RR 1.35 (0.83–2.19) | Insufficient |
| Abbreviations. CI =confidence interval; GAF = Global Assessment of Functioning; MD = mean difference; RCT = randomized controlled trial; RFS = Role Functioning Scale; RR = relative risk; SR = systematic review. | |||||||
