Table 6.
Summary of the studies about augmentation with non-psychopharmacological agents, other molecules and supplements in TRD.
| Reference | n | Age (Years) | Design | Augmentation Molecule | Dosage | AD | Duration | Primary Outcome Measures | Results |
|---|---|---|---|---|---|---|---|---|---|
| RCTs | |||||||||
| McAllister-Williams et al. [110] | 165 | Range: 18–65 | Double-blind | Metyrapone | 500 mg/bid | Various ADs | 3 weeks | MADRS | ↓ MADRS: MET = pcb (p = 0.74) |
| Nettis et al. [112] | 39 | MIN (n = 18): 47.0 (±10.0) pcb (n = 21): 43.7 (±10.7) | Double-blind Comparisons: MIN vs. pcb CRP+/MIN vs. CRP-/MIN vs. CRP+/pcb vs. CRP-/pcb | Minocycline | 200 mg/d | ≈ | 4 weeks | HAM-D | ↓ HAM-D: - MIN = pcb (p = 0.13) - CRP+/MIN > other subgroups (p < 0.001) |
| Mischoulon et al. | 12 | Range: 18–65 | Double-blind | Naltrexone | 1 mg/bid | Dopaminergic agents | 3 weeks | ≈ | ↓ HAM-D: LNT = pcb (p = 0.30) |
| Moreno et al. [113] | 10 | Mean (SD): 43.0 (±13.0) | Double-blind, crossover | Pindolol | 2.5 mg/tid | Desipramine, fluoxetine, bupropion | 2 weeks | ≈ | ↓ HAM-D: PIN = pcb (p = 0.72) |
| Perez et al. | 78 | Mean (SD): 47.1 (±10.1) | Double-blind | Pindolol | 2.5 mg/tid | Clomipramine, fluoxetine, fluvoxamine, paroxetine | 10 days | ≈ | ↓ HAM-D: PIN = pcb (p = 0.22) Remission rates: PIN = pcb (p > 0.05) |
| Sokolski et al. [114] | 9 | N.A. | Double-blind | Pindolol | 7.5 mg | Paroxetine | 4 weeks | ≈ | ↓ HAM-D: PIN > pcb (p = 0.001) |
| Perry et al. | 34 | Mean (SD): PIN: 49.0 (±13.0) pcb: 43.0 (±11.0) | Double-blind, hemi-crossover | Pindolol | 2.5 mg/bid | Fluoxetine, paroxetine, sertraline | 6 weeks | ≈ | ↓ HAM-D: PIN = pcb (p = 0.93) ↓ HAM-D core mood item: PIN = pcb (p = 0.50) |
| Price et al. | 8 | Mean (SD): 50.5 (±13.2) | Double-blind | Reserpine | 5 mg/bid (IM) | Desipramine | 12 days | SCRS, HAM-D | ↓ SCRS and ↓ HAM-D: RES = pcb (p > 0.05) |
| Targum et al. | 234 | Range: 21–69 Mean (SD): 47.2 (±10.78) | Multicenter, double-blind | SAME | 800 mg/d | Various ADs | 6 weeks | HAM-D, MADRS, IDS-SR30 | SAME = pcb: ↓HAM-D (p = 0.83) ↓MADRS (p = 0.42) ↓IDS-SR30 (p = 0.70) |
| Dichtel et al. | 87 women | Range: 21–70 Mean (SD): 47.0 (±14.0) | Double-blind | Testosterone | Mean (SD): 12.2 mg/d (±5.6) | SSRIs or SNRIs | 8 weeks | MADRS | ↓ MADRS: TXT = pcb (p = 0.91) |
| Siwek et al. | 21 | Range: 18–55 Mean (SD): 46.2 (±5.8) | Double-blind | Zinc | 25 mg/d | Imipramine | 12 weeks | HAM-D, MADRS, BDI, CGI | Zinc > pcb: ↓ HAM-D (p < 0.02) ↓ MADRS (p < 0.01) ↓ BDI (p < 0.02) ↓ CGI (p < 0.01) |
| Open studies | |||||||||
| Mendlewicz et al. [109] | 17 | Range: 29–62 Mean (SD): 46.1 (±9.7) | Open-label | ASA | 160 mg/d | SSRIs | 4 weeks | HAM-D | ↓ HAM-D (p < 0.0001) Response rate: 52.4% Remission rate: 43% |
| Avari et al. [111] | 13 | 73.1 (±11.2) | ≈ | Minocycline | 100 mg twice/d | Various ADs | 8 weeks | MADRS | ↓ MADRS Remission rate: 31% |
| Miller et al. | 9 women | Range: 25–59 Mean (SD): 48.1 (±12.2) | ≈ | Testosterone | 300 mcg/d (transdermal) | SSRIs or SNRIs | ≈ | ≈ | ↓ MADRS (p = 0.004) |
| Rudas et al. | 9 | Range: 21–68 | ≈ | T3/T4 | Range: 150–300 mcg/d Mean (SD): 235.0 (±58.0) mcg/d | Various ADs | ≈ | HAM-D | ↓ HAM-D (p < 0.01) |
| Hori and Kunugi | 12 | 18–64 | ≈ | Pramipexole | 0.25–3 mg/d | ≈ | 12 weeks | HAM-D, CGI | ↓ HAM-D (p < 0.0001) ↓ CGI (p = 0.003) |
| Cassano et al. | 7 | 18–74 | Prospective, open-label | Ropinirole | 0.25–1.5 mg/d | ≈ | 16 weeks | MADRS, CGI | ↓MADRS (p < 0.02) Response rate: 40% Remission rate: 40% |
| De Berardis et al. | 25 | Mean (SD): 32.0 (±5.1) | Open- label, single-blind | SAME | 800 mg/d | ≈ | 8 weeks | HAM-D | ↓ HAM-D (p < 0.001) Response rate: 62.5% Remission rate: 37.5% |
Key: ≈ = same as above; AD = antidepressant; ASA = acetylsalicylic acid; BDI = Beck Depression Inventory; bid = bis in die; CGI = Clinical Global Impression; d = day; HAM-D = Hamilton Depression Rating Scale; IDS-SR30 = Self-rated Inventory of Depressive Symptomatology; IM = intramuscular; LNT = low-dose naltrexone; MADRS = Montgomery and Asberg Depression Rating Scale; MET = metyrapone; MIN = minocycline; pcb = placebo; PIN = pindolol; RCT = randomized controlled trial; RES = reserpine; SAME = S-AdenosylMethionine; SCRS = Short Clinical Rating Scale for Depression; SD = standard deviation; SNRI = Serotonin-Norepinephrine Reuptake Inhibitor; SSRI = Selective Serotonin Reuptake Inhibitor; tid = ter in die; TXT = testosterone.