Table 1.
Study, Patients, and Treatment Regimens in Randomized, Controlled Trials Included in the Current Meta-analysis
| Study, Country, Funding | Total n | Blind | Duration | Inclusion Criteria | Drug | n | Mean Age(% Male) | History of Illness | Primary Outcome |
|---|---|---|---|---|---|---|---|---|---|
| Ahlfors 1981, MC, industry |
42 | OP | 18 m | Bipolar or unipolar recurrent manic-depressive illness. Pt experienced ≥3 mood episodes of sufficient severity to require treatment during the last 5 y before the enrollment. | Flup-DEC: 10, 15, or 20mg/3 wk | 25 | 50 (45.5) |
DI≥5 | Mean episode frequency: Flup- DEC=Li Mean % time ill: Flup- DEC=Li |
| Li: serum level = 0.8~1.0 mmol/L (12h after the last intake) | 17 | ||||||||
| Bobo 2011, USA, industry |
50 | OP | 12 m | Rapid cycling BDI and BDII (DSM-IV-TR, MINI- confirmed). Age=18–64. YMRS ≥8 or HAMD17 ≥8 and a history of ≥4 symptomatic relapses in the y prior to study, with ≥1 symptomatic relapse in the previous 6 m. TAU: no medication, monotherapy (MS, AP, or AD) and combination therapy (MS+AP, MS+MS, MS+AD, AP+AD, AD+AD, MS+AP+AD, or other) | RIS-LAI (27.0±10.4mg/2 wks)+TAU | 25 | 42.8±8.7 (30) | DI=26.4±7.3 | Mean any-cause relapse events: RIS-LAI+TAU =TAU, Mean time spent in an any- cause relapse event: RIS- LAI+TAU =TAU |
| TAU | 25 | 38.2±10.2 (36) | DI=22.3±9.7 | ||||||
| Chengappa 2010, USA, industry |
50 | OP | 15 m | BDI and BDII (DSM-IV-TR). Age≥18. Pt had hypomanic, manic or mixed episode (YMRS>15). TAU: CAR, LAM, Li, VAL or any combination of these agents (unchanged during the study). | RIS-LAI (25, 37.5, or 50mg/2wk)+TAU | 25 | 40±9.2 (30) | NR | Number of negative clinical events: RIS- LAI+TAU>SGA+TAU |
| SGA (ARI: 15–30mg/d, OLA: 15–25mg/d, QUE: 300–700mg/d, or ZIP: 160mg/d) +TAU | 25 | 39.4±10.9 (28) | |||||||
| Macfadden 2009, USA and India, industry |
124 | DB | 12 m | BDI and BDII (DSM-IV-TR). Age=18–70. Pt had ≥4 mood episodes (i.e. high frequency of relapses; defined as an event requiring psychiatric intervention) in the past 12 m. TAU: LAM, Li, TOP, VAL, SNRI, SSRI, TCA, anxiolytics, or any combination of these agents (unchanged during the study). | RIS-LAI [25 (67.7%), 37.5 (27.7%), or 50 (4.6%) mg/2 wk] +TAU | 65 | 40.0±11.8 (70.8) | AAD=28.3±9.4 | Time to recurrence: RIS-LAI+TAU >PBO+TAU |
| PBO+TAU | 59 | 37.6±12.0 (72.9) | AAD=24.6±8.4 | ||||||
| Quiroz 2010, MC, industry |
303 | DB | 24 m | BDI (DSM-IV-TR). Age=18–65. Acute manic or mixed episode (YMRS ≥20) or were stable (CGI-S ≤3) on APs or MDs. Pt experienced ≥2 mood episodes during the 2 y preceding enrollment. Stable pt had one episode within 4 m of enrollment. BMI=17–33. Pt who maintained response to open-label RIS-LAI for 26wk were randomly allocated to PBO-injections or to continue RIS-LAI for up to 24 m. | RIS-LAI: 12.5, 25 (77%), 37.5, or 50mg/2 wkPBO | 154149 | 39±11.8 (49)39±12.4 (54) | DI=8±8.3DI=9±9.4 | Time to recurrence: RIS-LAI >PBO |
| Vieta 2012, MC, industry |
398 | DB | 18 m | BDI (DSM-IV-TR, MINI-confirmed). Age=18–65. Acute pt (manic or mixed episode: YMRS>20 and CGI-S ≥4), or nonacute pt (between mood episodes: YMRS <12 and CGI-S ≤3), and ≥1 manic episode within 4 m of enrollment). Pt had ≥2 mood episodes in the previous y. Nonacute pt: unchanged BD medication for ≥4wk before screening. Pt who did not experience a recurrence in open-label RIS-LAI for 12wk were randomly allocated to PBO-injections or to continue RIS-LAI for up to 18 m. | RIS-LAI: 25, 37.5, or 50mg/2 wk | 132 | 35.6±11.1 (40) | NR | Time to recurrence: RIS- LAI=PBO, OLA>PBO |
| OLA: 10mg/dPBO | 131135 | 36.5±11.0 (55)36.6±11.0 (48) | |||||||
| Yatham 2007, Canada, industry |
49 | OP | 6 m | BDI and BDII (DSM-IV-TR). Age=18–65. Stable pt (CGI-S ≥3 and YMRS or MADRS ≥13): receiving one oral SGAs (OLA, QUE, RIS) in combination with a maximum of 2 of LAM, Li, or VAL and 1 AD. TAU: LAM, Li, VAL, AD or any combination of these agents (unchanged during the study). | RIS-LAI (26.1±3.6mg/2wk)+TAU | 23 | 41.8±13.1 (52) | NR | CGI-S, YMRS and MADRS: RIS- LAI+TAU=SGA+TAU |
| SGA (OLA=8±6.5mg/d, QUE=352.3±309.5mg/d, RIS=1.4±0.5mg/d)+TAU | 26 | 40.1±12.6 (46) |
Abbreviations: AAD, age at diagnosis; AD, antidepressant; AP, antipsychotic; ARI, aripiprazole; BD, bipolar disorder; BMI (kg/m2), body mass index; CAR, carbamazepine; CGI-S, Clinical Global Impressions-Severity; DB, double blind; DI (years), duration of illness; DSM-(IV)-(TR), Diagnostic and Statistical Manual of Mental Disorders, (4th Edition) (Text Revision); Flup-DEC, flupenthixol decanoate; HAMD, Hamilton Depression Rating Scale; LAI, long-acting injectable; LAM, lamotrigine; Li, lithium; m, month; MADRS, Montgomery Åsberg Depression Rating Scale; MC, multiple countries; MD, mood stabilizer; MINI, Mini International Neuropsychiatric Interview; MS, mood stabilizer; n, number of patients; NR, not reported; OLA, olanzapine; OP, open; PBO, placebo; Pt, patient; QUE, quetiapine; RIS, risperidone; SGA, second generation antipsychotic; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TAU, treatment-as-usual; TCA, tricyclic antidepressant; TOP, topiramate; VAL, valproate; wk, week; y, year; YMRS, Young Mania Rating Scale; ZIP, ziprasidone.