Table 1.
Characteristics of included studies
| Reference (ClinicalTrials.gov identifier) | Adjunctive treatment | Adjunctive treatment duration | Randomized patients | Inadequate response to (current episode) | Inadequate response definition
|
Primary efficacy measure | Setting | Source of funding | |
|---|---|---|---|---|---|---|---|---|---|
| Historical ADTa | Prospective/ongoing ADTb | ||||||||
| Berman et al, 200729 (NCT00095823) | Aripiprazole 2–20 mg | 6 weeks | 362 | 1–3 historical ADTs + 1 prospective SSRI/SNRI | <50% improved on ATRQ | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 and CGI-I score ≥3 at week 8 | MADRS total | 24 outpatient sites in the US | Bristol-Myers Squibb and Otsuka |
| Marcus et al, 200830 (NCT00095758) | Aripiprazole 2–20 mg | 6 weeks | 381 | 1–3 historical ADTs + 1 prospective SSRI/SNRI | <50% improved on ATRQ | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 and CGI-I score ≥3 at week 8 | MADRS total | 36 outpatient sites in the US | Bristol-Myers Squibb and Otsuka |
| Berman et al, 200931 (NCT00105196) | Aripiprazole 2–20 mg | 6 weeks | 349 | 1–3 historical ADTs + 1 prospective SSRI/SNRI | <50% improved on ATRQ | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 at week 8; CGI-I score ≥3 at weeks 6 and 8 | MADRS total | 36 outpatient sites in the US | Bristol-Myers Squibb and Otsuka |
| Kamijima et al, 201332 (NCT00876343) | Aripiprazole 3 mg/3–15 mg | 6 weeks | 586 | 1–3 historical ADTs + 1 prospective ADT | Not specified | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 and CGI-I score ≥3 at week 8c | MADRS total | 169 sites in Japan | Otsuka |
|
| |||||||||
| Quiroz et al, 201633 (NCT01437657) | Basimglurant MR 0.5 mg/1.5 mg | 6 weeks | 333 | 1–3 historical ADTs (1 ongoing SSRI/SNRI) | Investigator judgment | MADRS total score ≥25 and CGI-S score ≥4 at screeningd | MADRS total | 59 outpatient sites in Chile, Europe, Japan, Mexico, and the US | Hoffmann-La Roche |
|
| |||||||||
| Thase et al, 201534 (NCT01360645) | Brexpiprazole 2 mg | 6 weeks | 379 | 1–3 historical ADTs + 1 prospective SSRI/SNRI | <50% improved on ATRQ | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 at week 8; <50% reduction in MADRS total score from start of prospective treatment to weeks 2, 4, 6, and 8; CGI-I score ≥3 at weeks 2, 4, 6, and 8e | MADRS total | 59 outpatient sites in Canada, Europe, and the US | Otsuka and Lundbeck |
| Thase et al, 201535 (NCT01360632) | Brexpiprazole 1 mg/3 mg | 6 weeks | 677 | 1–3 historical ADTs + 1 prospective SSRI/SNRI | <50% improved on ATRQ | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 at week 8; <50% reduction in MADRS total score from start of prospective treatment to weeks 2, 4, 6, and 8; CGI-I score ≥3 at weeks 2, 4, 6, and 8e | MADRS total | 92 outpatient sites in Canada, Europe, Russia, and the US | Otsuka and Lundbeck |
|
| |||||||||
| Fava et al, 201636 (NCT01500200) | Buprenorphine + samidorphan 2 mg + 2 mg/8 mg + 8 mg | Stage 1: 5 weeks; stage 2: 5 weeksf | 142 | 1–2 historical ADTs (1 ongoing) | <50% improved on ATRQ | For entry into stage 2f: <50% reduction in HAM-D17 total score from start of stage 1 to week 5; HAM-D17 total score ≥14 at week 5 | HAM-D17 total | 31 sites in the US | Alkermes |
|
| |||||||||
| Durgam et al, 201637 (NCT01469377) | Cariprazine 1–2 mg/2–4.5 mg | 8 weeks | 819 | 1–2 historical ADTs (1 ongoing) | Not specified | ATHF resistance rating ≥3 with global confidence ≥3 at screeninge | MADRS total | 76 outpatient sites in Europe and the US | Forest Laboratories (Allergan) and Gedeon Richter |
|
| |||||||||
| Fava et al, 201538 (NCT01098240) | CP-601,927 2–4 mg | 6 weeks | 162 | 1–3 historical ADTs + 1 prospective SSRI | <50% improved on ATRQ | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥16 at week 8 | MADRS total | 25 outpatient sites in the US | Pfizer |
|
| |||||||||
| Vieta et al, 201439 (NCT01157078, NCT01180400) | Dexmecamylamine 2–8 mg (2 studies) | 8 weeks | 319, 295 | 0–1 historical ADTs + 1 prospective SSRI/SNRI | Not specified | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥16 and CGI-S score ≥4 at week 8 | MADRS total | 70 outpatient sites in India and the US; 80 outpatient sites in Europe | AstraZeneca and Targacept |
| Möller et al, 201540 (NCT01153347, NCT01197508) | Dexmecamylamine 0.2 mg/1 mg/2 mg/4 mg/8 mg (across 2 studies) | 8 weeks | 641, 696 | 0–1 historical ADTs + 1 prospective SSRI/SNRI | Not specified | <50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥16 and CGI-S score ≥4 at week 8 | MADRS total | 114 outpatient sites in India and the US; 132 outpatient sites in Europe, South Africa, and South America | AstraZeneca and Targacept |
| Tummala et al, 201541 (NCT01152554) | Dexmecamylamine 2–8 mg | 52 weeks | 813 (769 de novog) | 0–1 historical ADTs + 1 prospective SSRI/SNRI | Not specified | De novo patientsg: HAM-D17 total score ≥10 and CGI-S score ≥3 at week 6 of prospective treatment | Not applicable (safety) | 115 outpatient sites in the US | AstraZeneca |
|
| |||||||||
| Ball et al, 201442 (NCT00840034) | Edivoxetine 6–18 mg | 8 weeks | 227 | 1 ongoing SSRI | Not applicable | Investigator judgment at screening; <25% reduction in QIDS-SR16 score from start of adjunctive placebo phase to week 2 | MADRS total | 25 outpatient sites in the US | Eli Lilly and Company |
| Ball et al, 201643 (NCT01173601, NCT01187407, NCT01185340) | Edivoxetine 6 mg/12 mg/12–18 mg/18 mg (across 3 studies) | 8 weeks | 701, 689, 449 | 1 ongoing SSRI | Not applicable | Investigator judgment at screening and start of adjunctive placebo phase; <25% reduction in MADRS total score from start of adjunctive placebo phase to week 3; MADRS total score ≥14 at week 3 | MADRS total | Multiple outpatient sites in Australia, Europe, Japan, Russia, South Africa, and the US | Eli Lilly and Company |
|
| |||||||||
| Barbee et al, 201144 (NCT00901407) | Lamotrigine 100–400 mg | 10 weeks | 96 | ≥1 historical ADT + 1 prospective paroxetine/paroxetine CR | Not specified | HAM-D17 total score ≥15 at week 8 of prospective treatment | MADRS total | 19 sites in the US | GlaxoSmithKline |
|
| |||||||||
| Sanacora et al, 201745 (NCT01482221) | Lanicemine 50 mg/100 mg (IV regimen) | 12 weeks (primary analysis at week 6) | 302 | ≥1 historical ADT (1 ongoing) | Investigator judgment | Investigator judgment | MADRS total | 49 outpatient sites in Chile, Europe, South Africa, and the US | AstraZeneca |
|
| |||||||||
| Richards et al, 201646 (NCT01436149, NCT01436162) | Lisdexamfetamine dimesylate 20–70 mg (2 studies) | 8 weeks | 404, 426 | 0–2 historical ADTs + 1 prospective SSRI/SNRI | Not specified | <50% reduction in MADRS total score from start of prospective treatment to week 8; MADRS total score ≥18 at week 8 | MADRS total | 76 sites in Canada, Europe, Mexico and the US; 94 sites in Europe, South Africa, and the US | Shire |
|
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| Thase et al, 200747 (NCT00035321) | Olanzapine 6–18 mg (as OFC; 2 studies pooled) | 8 weeks | 605 (pooled) | 1 historical ADT + 1 prospective fluoxetine | Investigator judgment | <25% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥18 at week 8; ≤15% reduction in HAM-D17 total score from week 7 to week 8 | MADRS total | Multiple outpatient sites in Canada and the US | Eli Lilly and Company |
|
| |||||||||
| Mahmoud et al, 200748 (NCT00095134) | Risperidone 1–2 mg | 6 weeks | 274 | 1 ongoing ADT | Not applicable | CGI-S score ≥4 and CDS score ≥20 at week 4 of prospective phase | HAM-D17 total | 75 outpatient sites in the US | Ortho-McNeil-Janssen |
Notes:
a
“Historical” describes an ADT that was discontinued prior to study enrollment.
b
“Prospective” describes an ADT that was initiated during the study, whereas “ongoing” describes an ADT that was initiated prior to study enrollment and was continued during the study.
c
The manuscript states that any one of these criteria is sufficient; however, by comparison with the other aripiprazole studies, we assume this is an error.
d
In addition, where available, a patient-rated MADRS total score ≥23 at screening, with a permitted discrepancy of ≤7 points versus the clinician-rated MADRS total score.
e
Revised criteria following a protocol amendment.
f
Two-stage study design: 1) patients were randomized to placebo or active treatment; 2) placebo non-responders in stage 1 were re-randomized to placebo or active treatment.
g
Study also rolled-over a small number of patients from two acute studies (NCT01157078 and NCT01153347).
Abbreviations: ADT, antidepressant treatment; ATHF, Antidepressant Treatment History Form; ATRQ, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; CDS, Carroll Depression Scale; CGI-I/S, Clinical Global Impressions – Improvement/Severity of illness; CR, controlled release; HAM-D17, 17-item Hamilton Depression Rating Scale; IV, intravenous; MADRS, Montgomery–Åsberg Depression Rating Scale; MR, modified release; OFC, olanzapine–fluoxetine combination; QIDS-SR16, 16-item Quick Inventory of Depressive Symptomatology (Self-Report); SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.