Table 5.
Summary of the studies about augmentation with IV ketamine, esketamine nasal spray, and psychostimulant drugs in TRD.
| Reference | n | Age Mean (SD), y | Design | Augmentation Molecule | Dosage | AD | Duration | Primary Outcome Measures | Results |
|---|---|---|---|---|---|---|---|---|---|
| RCTs | |||||||||
| Daly et al. [101] * | 297 | 46.3 (±11.1) | Multicenter, double-blind TRD patients → 16 weeks ESK augmentation → R maintenance phase: comparison ESK/pcb | Esketamine | Remitters: 56 mg or 84 mg/2 weeks Responders: 56 mg or 84 mg once weekly | SSRIs or SNRIs | Median among remitters: 17.7 weeks Median among responders: 19.4 weeks | Time to relapse at MADRS | Relapse among remitters: pcb > ESK (p = 0.003) Relapse among responders: pcb > ESK (p < 0.001) |
| Fedgchin et al. [99] | 315 | 46.3 (±11.2) | Multicenter, double-blind Comparison ESK56/ESK84/pcb | Esketamine | 56 mg or 84 mg twice weekly | Escitalopram, Sertraline, Venlafaxine, Duloxetine | 4 weeks | MADRS | ↓ MADRS: ESK56 > pcb (p = 0.03) ESK84 = pcb (p = 0.09) |
| Ochs-Ross et al. [102] | 122 | 70.0 (±4.52) | Double-blind | Esketamine | 28 mg, 56 mg or 84 mg twice weekly | ≈ | ≈ | ≈ | ↓ MADRS: ESK = pcb (p = 0.06) 65–74 years old: ESK > pcb (p = 0.02) ≥ 75 years old: ESK = pcb (p = 0.93) |
| Popova et al. [100] | 197 | ESK: 44.9 (±12.6) pcb: 46.4 (±11.1) | Multicenter, double-blind | Esketamine | 56 mg or 84 mg twice weekly | ≈ | ≈ | ≈ | ↓ MADRS: ESK > pcb (p = 0.02) |
| Fava et al., 2020 [94] | 86 | KETA 0.1: 43.1 (±11.9) KETA 0.2: 45.5 (±14.6) KETA 0.5: 48.6 (±12.9) KETA 1.0: 47.4 (±10.1) | Double-blind Comparison KETA 0.1-0.2-0.5-1.0 mg/kg/pcb | IV Ketamine | 0.1-0.2-0.5-1.0 mg/kg | Various ADs | 30 days | HAM-D6 at day 1 and 3 | ↓ HAM-D6: KETA > pcb (p = 0.03) KETA 0.1-0.2-0.5-1.0 mg/kg > pcb (p = 0.04) ↓ HAM-D6 day 1: KETA 0.1–0.2 mg/kg = pcb (p-adj = 0.14 and 0.79) KETA 0.5 mg/kg > pcb (p-adj < 0.001) KETA 1.0 mg/kg > pcb (p-adj = 0.04) ↓ HAM-D6 day 3: KETA 0.1-0.2-0.5-1.0 mg/kg = pcb (p > 0.05) |
| Freeman et al. [96] ** | 99 | 18–70 Males: 47.5 (±12.5) Females: 44.8 (±12.7) |
≈ | IV Ketamine | ≈ | ≈ | ≈ | ≈ | ↓ HAM-D6: males = females (groupxgender p = 0.69) |
| Feeney et al. [98] ** | 56 | 45.7 (±12.3) | ≈ | IV Ketamine | 0.1-0.5-1.0 mg/kg | ≈ | ≈ | MADRS suicide item | ↓ MADRS suicide item at day 30: KETA > pcb (p = 0.03) |
| Ionescu et al. [95] | 26 | 45.4 (±12.4) | Double-blind | IV Ketamine | 0.5 mg/kg | Various ADs | 3 weeks | HAM-D | ↓ HAM-D: KETA = pcb (p = 0.47) |
| Salloum et al. [97] ** | 56 | KETA 0.1: 47.0 (±8.1) KETA 0.5: 45.5 (±11.9) KETA 1.0: 45.3 (±9.6) | Double-blind Comparison KETA 0.1/0.5/1.0 mg/kg | IV Ketamine | 0.1-0.5-1.0 mg/kg | Various ADs | 30 days | MADRS | At day 3: Response rate: 48% Remission rate: 34% At day 30: Remission rate: 21% |
| Price et al. [104] | 15 | 50.0 (±12.0) | Pcb substitution Comparison FEN/pcb | Fenfluramine (Amphetamine) | 89.0 (±26.0) mg/d | Desipramine | Mean (SD): 16.4 (±5.0) d | SCRS HAM-D |
↓ SCRS and ↓ HAM-D: FEN = pcb (p > 0.05) |
| Richards et al. [105] | Study 1: pcb = 201, LDX = 201; Study 2: pcb = 213, LDX = 211 | Study 1 LDX: 42.2 (±12.3) Study 2 LDX: 42.0 (±11.6) | Multicenter, double-blind Comparison LDX/pcb | Lisdexamfetamine dimesylate (Amphetamine) | Study 1: 46.5 (±13.7) mg/d Study 2: 43.4 (±14.3) mg/d | Various ADs | 16 weeks | MADRS | ↓ MADRS Study 1: LDX = pcb (p = 0.88) ↓ MADRS Study 2: LDX = pcb (p = 0.58) |
| Patkar et al. [106] | 50 | 48.5 | Double-blind | Metilphenidate | 34.2 (±6.3) mg/d | Various ADs | 4 weeks | HAM-D | ↓ HAM-D: MPH = pcb (p = 0.22) Response rates: MPH > pcb (p = 0.12) |
| Ravindran et al. [107] | 134 | 43.8 (±11.0) | Multicenter, double-blind | Metilphenidate | 36.4 (±9.1) mg/d | Various ADs | 5 weeks | MADRS | ↓ MADRS: MPH = pcb (p = 0.74) |
| Open studies | |||||||||
| Wajs et al. [103] *** | 150 | 52.2 (±13.7) | Multicenter, open-label | Esketamine | Flexible 14–84 mg once weekly or every-other-week | ≈ | 1 year | ≈ | Response rate: 76.5% Remission rate: 58.2% |
| Cusin et al. [93] | 12 | 48.9 | Open-label 6 infusions (2/week): infusion 1–3: 0.50 mg/kg (IV); infusion 4–6: 0.75 mg/kg (IV) | IV Ketamine | Mean (SD): infusion 1–3: 29.0 (±16.2) mg infusion 4–6: 43.5 (±24.3) mg | Various ADs | 3 weeks | HAM-D | ↓ HAM-D: p < 0.001 Response rate: 41.7% Remission rate: 16.7% |
| Schiroma et al. [92] | 14 | 54.0 | Open-label | IV Ketamine | 0.5 mg/kg | Various ADs | 12 days | MADRS | ↓ MADRS (p < 0.001) |
| Nasr et al. [108] | 78 | 44.0 | Retrospective | Modafinil | 249.0 (±122.0) mg/d | Various ADs | 9 months | CDRS | ↓ CDRS: p < 0.01 |
Key: * = analysis in the long-term of patients who achieved response in the studies by Fedgchin et al. [99] and Popova et al. [100]. ** = reanalysis on a subgroup of patients recruited by Fava et al. [94]. *** = analysis in the long-term, including, in the total sample, patients who completed the study by Ochs-Ross et al. [102]. ≈ = same as above; AD = antidepressant; CDRS = Carroll Depression Rating Scale; ESK = esketamine nasal spray; ESK56 = esketamine at 56 mg/d; ESK84 = esketamine at 84 mg/d; FEN = fenfluramine; HAM-D = Hamilton Depression Rating Scale; HAM-D6 = Hamilton Depression Rating Scale—6 items; IV = intravenous; KETA = ketamine; LDX = lisdexamfetamine dimesylate; MADRS = Montgomery and Asberg Depression Rating Scale; MPH = metilphenidate; p-adj = p value adjusted for multiple comparisons; pcb = placebo; RCT = randomized, controlled trial; SCRS = Short Clinical Rating Scale; SD = standard deviation.