Table 2.
Summary of the studies about augmentation with SGAs in TRD.
| Reference | n | Age Mean (SD), y | Design | Augmentation Molecule | Dosage, mg/d | AD | Duration | Primary Outcome Measures | Results |
|---|---|---|---|---|---|---|---|---|---|
| RCTs | |||||||||
| Berman et al. [32] | 362 | 46.5 (±10.6) | Multicenter, double-blind | Aripiprazole | 2–20 Mean: 11.8 | Escitalopram, fluoxetine, paroxetine, sertraline, or venlafaxine | 6 weeks | MADRS | ↓ MADRS: ARI > pcb (p < 0.001) |
| Berman et al. [34] | 349 | 45.4 (±10.9) | Multicenter, double-blind | Aripiprazole | 2–20 Mean: 10.7 | ≈ | 6 weeks | MADRS | ↓ MADRS: ARI > pcb (p < 0.001) |
| Fava et al. [35] | 221 | 45.4 (±10.3) | Multicenter, double-blind Phase I: ARI 2 mg/d/pcb Phase II: ARI 5 mg/d/pcb/ARI 2 mg/d | Aripiprazole | 2 or 5 | SSRIs or SNRIs | 12 weeks | MADRS | ↓ MADRS: ARI = pcb (p = 0.06) Response rate: ARI = pcb (p = 0.18) Remission rate: ARI = pcb (p = 0.50) |
| Mischoulon et al. [36] * | ≈ | ≈ | ≈ | Aripiprazole | ≈ | ≈ | ≈ | MADRS | ↓ MADRS: ARI 5 mg/d > ARI 2 mg/d (p < 0.0001) |
| Dording et al. [37] * | ≈ | ≈ | ≈ | Aripiprazole | ≈ | ≈ | ≈ | KSQ | ↓ KSQ depressive subscale: ARI > pcb (p = 0.03) ↓ KSQ anxiety, somatic, anger-hostility subscales: ARI = pcb (p > 0.05) |
| Kamijima et al. “ADMIRE” [39] | 540 | Fixed-ARI: 39.2 (±9.1) Flexi-ARI: 38.1 (±9.6) Pcb: 38.7 (±9.2) | Multicenter, double-blind Comparison fixed-ARI/flexi-ARI/pcb | Aripiprazole | Fixed-ARI: 3 Flexi-ARI: 3–15 (mean: 9.8) | Sertraline, fluvoxamine, paroxetine, milnacipran, duloxetine | 6 weeks | MADRS | ↓ MADRS: fixed-ARI = flexi-ARI > pcb (p < 0.01) Response and remission rates: fixed-ARI = flexi-ARI > pcb (p < 0.05) |
| Ozaki et al. [40] ** | ≈ | ≈ | Subgroup analysis of ADMIRE according to: sex, age, number of AD trials, MDD diagnosis, number of depressive episodes, duration of current episode, age at first episode, time since first episode, type of SSRI/SNRI, severity at the end of AD treatment | Aripiprazole | ≈ | ≈ | ≈ | MADRS in subgroups; MADRS and HAM-D single items | No interaction effects of treatment and subgroups; ↓ core depressive symptoms (p < 0.05) |
| Lenze et al. [38] | 181 | 66 27% of the total sample > 70 | Double-blind | Aripiprazole | 2–15 Mean remitters: 7 Mean non-remitters: 10 | Venlafaxine | 12 weeks | MADRS | Remission rate: ARI > pcb (p = 0.03) |
| Marcus et al. [33] | 324 | 44.6 (±11.0) | Multicenter, double-blind | Aripiprazole | Mean: 11 | Escitalopram, fluoxetine, paroxetine, sertraline, or venlafaxine | 6 weeks | MADRS | ↓ MADRS: ARI > pcb (p = 0.001) (d = 0.35) Remission rates: ARI > pcb (p = 0.016) Response rates: ARI > pcb (p < 0.001) |
| Hobart et al. [44] | 393 | BREX: 43.0 (±12.7) pcb: 42.7 (±12.5) | Double-blind | Brexpiprazole | 2 | SSRIs or SNRIs | 6 weeks | MADRS | ↓ MADRS: BREX > pcb (p = 0.007) |
| Hobart et al. | 443 | BREX: 43.6 (±11.5) QUE-XR: 44.6 (±11.6) pcb: 41.8 (±11.7) | Head-to-head Multicenter, double-blind Comparison BREX/QUE-XR/pcb | Brexpiprazole Quetiapine | BREX: Range: 2–3 Mean: 2.2 QUE-XR: Range: 150–300Mean: 198.5 | SSRIs or SNRIs | 6 weeks | MADRS | ↓ MADRS: BREX > pcb (p = 0.008) QUE-XR = pcb (p = 0.66) |
| Thase et al. [41] | 353 | BREX: 44.1 (±11.6) pcb: 45.2 (±11.3) | Multicenter, double-blind | Brexpiprazole | 2 | SSRIs or SNRIs | 6 weeks | MADRS | ↓ MADRS: BREX > pcb (p < 0.001) |
| Thase et al. [42] | 627 | BREX-1: 45.7 (±11.6) BREX-3: 44.5 (±11.2) pcb: 46.6 (±11.0) | Multicenter, double-blind Comparison BREX-1/BREX-3/pcb | Brexpiprazole | 1 or 3 | SSRIs or SNRIs | 6 weeks | MADRS | ↓ MADRS: BREX-3 > pcb (p = 0.008) BREX-1 = pcb (p = 0.07) |
| Earley et al. [53] | 435 | 44.2 (±11.6) | Double-blind | Cariprazine | 1.5–4.5 Mean: 2.97 | Various ADs | 8 weeks | MADRS | ↓ MADRS: CARI = pcb (p = 0.79) |
| Shelton et al. [51] | 28 | 42.0 (±11.0) | 6-week open-label fluoxetine in escalating doses; 8-week, double-blind, RCT: Comparison OLA + pcb/FLU + pcb/FLU + OLA | Olanzapine | Mean (SD) OLA + pcb: 12.5 (±5.3) Mean (SD) FLU + OLA: 13.5 (±4.1) | Fluoxetine | 8 weeks | MADRS, HAM-D | ↓ MADRS: FLU + OLA > OLA + pcb (p = 0.03) and FLU + pcb (p = 0.006) ↓ HAM-D: FLU + OLA > OLA + pcb (p = 0.03) FLU + OLA = FLU + pcb (p = 0.07) |
| Mahmoud et al. [47] | 268 | 45.9 (±10.1) | Multicenter, double-blind | Risperidone | 1–2 | Various ADs | 6 weeks | HAM-D | ↓ HAM-D: RIS > pcb (p < 0.001) Response rates: RIS > pcb (p = 0.004) Remission rates: RIS > pcb (p = 0.004) |
| Rapaport et al. [45] | Phase I: 445 Phase II: 348 Phase III: 241 | 46.3 (±12.6) | Phase I: 4–6 weeks open-label CIT monotherapy Phase II: 4–6 weeks open-label RIS augmentation Phase III: 24 weeks double-blind maintenance phase, comparison CIT + RIS/CIT + pcb |
Risperidone | Mean (SD): Phase II: 1.1 (±0.6) Phase III: 1.2 (±0.6) | Citalopram | (see Design) | Phases II: MADRS Phase III: time to relapse | ↓ MADRS (p < 0.001) Time to relapse: RIS > pcb (p = 0.05) Relapse rates: RIS < pcb (p = 0.05) |
| Alexopoulos et al. [46] *** | Phase I: 108 Phase II: 93 Phase III: 63 | 63.4 (±7.9) | ≈ | Risperidone | Mean (SD): Phase II: 0.7 (±0.3) Phase III: 0.8 (±0.3) | ≈ | ≈ | ≈ | ↓ MADRS (p < 0.001) Time to relapse: RIS > pcb (p = 0.07) |
| Open studies | |||||||||
| Barbee et al. [22] | 19 | 51.2 (±8.9) | Retrospective chart review | Aripiprazole | 2.5–7.5 | Various ADs | 6 weeks | CGI | (Very) Much improved: 52.6% Mildly improved: 26.3% Unchanged: 15.8% Minimally worse: 5.3% (p < 0.001) |
| Berman et al. [26] | 987 | 45.8 (±11.3) | Open-label | Aripiprazole | 2–30 Mean:10.1 | Various ADs | 52 weeks | CGI severity | CGI-S = 1 (not at all ill) or 2 (borderline ill): 69.7% |
| Chen et al. [29] | 9 | 38.3 (±12.2) | Open-label | Aripiprazole | Mean: 4.2 | Various ADs | 4 weeks | HAM-D | Response rate: 100% Remission rate 77.8% |
| Fabrazzo et al. [27] | 35 | 38.8 (±11.5) | Open-label | Aripiprazole | 5 | SSRIs, then CLO | 24 weeks | HAM-D | ↓ HAM-D (p < 0.0001) Response rate: 91.4% Remission rate: 34.3% |
| Han et al. [23] | 38 | 28.4 (±11.3) | Retrospective MDD with mixed specifier | Aripiprazole | Mean (SD): 4.0 (±0.8) | Various ADs | 8 weeks | MADRS | ↓ MADRS (p < 0.0001) Response rate: 32% Remission rate: 21% |
| Hellerstein et al. [25] | 14 | 46.1 (±13.0) | Open-label | Aripiprazole | Mean (SD): 22.5 (±9.9) | Sertraline, fluoxetine, duloxetine, venlafaxine | 12 weeks | HAM-D | ↓ HAM-D (p < 0.001) Response rate: 50% Remission rate: 28.6% |
| Horikoshi et al. [31] | 31 | LD group: 38.8 (±12.8) HD group: 44.2 (±13.9) | Open-label, R Comparison LD-ARI/HD-ARI | Aripiprazole | LD: 3 HD: 12 | Various ADs | 6 weeks | MADRS | ↓ MADRS: LD and HD (p < 0.001) Response rate: HD > LD (p = 0.015) |
| Jon et al. [30] | 86 | 45.6 (±13.7) | Multicenter, prospective, open-label | Aripiprazole | Max: 15 Mean: 6.9 | SSRIs or SNRIs | 6 weeks | MADRS | ↓ MADRS (p < 0.001) Response rate 52.3% Remission rate 39.8% |
| Patkar et al. [24] | 10 | 44.9 (±12.2) | Prospective, open-label | Aripiprazole | 10–30 Mean: 13.2 | Various ADs | 6 weeks | HAM-D | ↓ HAM-D (p < 0.001) Response rate: 70% Remission rate: 30% |
| Yoshimura et al. [28] | 24 | 39.0 (±12.0) | Open-label | Aripiprazole | Mean (SD) PAR group: 8.73 (±3.13) Mean (SD) SER group: 9.23 (±3.11) | Paroxetine or sertraline | 4 weeks | HAM-D | ↓ HAM-D (p < 0.0001) PAR + ARI = SER + ARI (p = 0.80) |
| Fava et al. [43] | 51 | 45.6 (±12.4) | Multicenter, open-label | Brexpiprazole | 2.25 (±0.74) | SSRIs or SNRIs | 6 weeks | MADRS | ↓ MADRS (p < 0.0001) |
| Boku et al. [52] | 7 | 53.2 (±24.0) | Open-label | Olanzapine | Mean (SD): 5.0 (±1.9) | Milnacipran | 8 weeks | HAM-D, CGI | ↓ HAM-D (p < 0.01) Response rate: 100% Remission rate: 100% ↓ CGI (p < 0.01) |
| Anderson et al. [50] | 18 | 46.3 | Open-label | Quetiapine | Max 300 mg twice Mean (SD): 245.0 (±68.0) | Various ADs | 8 weeks | MADRS | ↓ MADRS (p < 0.001) Response rate: 29% Remission rate: 17% |
| Sagud et al. [49] | 14 | 52.8 (±10.4) | Prospective, non-comparative, open-label | Quetiapine | Mean (SD): 315.0 (±109.0) | Various ADs | 20 weeks | HAM-D total score and insomnia/depressive mood/anxiety subscales | ↓ HAM-D total score (p < 0.001) ↓ HAM-D subscales (p < 0.001) |
| Papakostas et al. [48] | 13 | 41.9 (±10.1) | Open-label | Ziprasidone | Mean (SD): 82.1 (±48.9) | SSRIs | 6 weeks | HAM-D | Response rate: 61.5% Remission rate: 38.5% |
| Bauer et al. [54] | 557 | 18–65 | Head-to-head Open-label, R Comparison add-on QUE-XR/QUE-XR monotherapy/add-on LIT | Quetiapine | Mean (SD): add-on QUE-XR: 242.0 (±54.0) QUE-XR monotherapy: 238.0 (±60.0) add-on LIT: 882.0 (±212.0) | SSRIs or venlafaxine | 6 weeks | MADRS | ↓ MADRS: add-on QUE-XR = QUE-XR monotherapy = add-on LIT (p = 0.05) |
| Gobbi et al. | 86 | 49.9 (±13.3) | Head-to-head Naturalistic Comparison SGAs (ARI, OLA, RIS, QUE)/another AD | Aripiprazole Olanzapine Risperidone Quetiapine | Mean (SD): ARI 4.4 (±1.3) OLA 8.7 (±1.8) RIS 1.88 (±0.5) QUE 129.0 (±29.0) ADs at various dosages | SSRIs or SNRIs | 3 months | MADRS, HAM-D, QIDS, CGI | ↓ MADRS, HAM-D, QIDS, CGI scores from baseline to endpoint in both SGA and ADs groups (p < 0.001)↓ depressive symptoms MADRS and HAM-D: SGA > ADs (p < 0.05) |
| Mohamed et al. | 1137 | 54.4 (±12.2) | Head-to-head, R Comparison add-on ARI/add-on BUP/BUP switching | Aripiprazole | ARI max 10 BUP max 400 | Various ADs | 12 weeks | Remission at QIDS | Add-on ARI > BUP switching (p = 0.02) Add-on ARI = add-on BUP (p = 0.47) Add-on BUP = BUP switching (p = 0.09) |
Key: * = reanalysis on the sample recruited by Fava et al. [35]. ** = subgroup analysis of “ADMIRE” by Kamijima et al. [39]. *** = subgroup analysis on the patients over 55 of the total sample recruited by Rapaport et al. [45]. ≈ = same as above. AD = antidepressant; ARI = aripiprazole; BREX = brexpiprazole; BREX-1 = brexpiprazole 1 mg/d; BREX-3 = brexpiprazole 3 mg/d; BUP = bupropion; CARI = cariprazine; CGI = Clinical Global Impression; CIT = citalopram; CLO = clomipramine; FLU = fluoxetine; HAM-D = Hamilton Depression Rating Scale; HD = high-dose; KSQ = Kellner Symptom Questionnaire; LD = low-dose; LIT = lithium; MADRS = Montgomery and Asberg Depression Rating Scale; MDD = major depressive disorder; OLA = olanzapine; PAR = paroxetine; pcb = placebo; QUE (XR) = quetiapine (extended release); QIDS = Quick Inventory of Depressive Symptomatology; R = randomized; RCT = randomized controlled trial; RIS = risperidone; SER = sertraline; SGA = Second generation antipsychotic; SNRI = Serotonin and Norepinephrine Reuptake Inhibitor; SSRI = Selective Serotonin Reuptake Inhibitor; TCA = tricyclic antidepressants.