Table 3.
Summary of the studies about lithium augmentation in TRD.
| Reference | n | Age Mean (SD), Years | Design | Dosage (mg/d)/Plasma Levels (mmol/L) | AD | Duration | Primary Outcome Measures | Results |
|---|---|---|---|---|---|---|---|---|
| RCTs | ||||||||
| Bauer et al. [60] | 27 | 47.4 (±16.9) | I: open, acute treatment phase II: RC continuation phase | Mean (SD): 980.0 (±295.6)/0.65 (±0.14) | Various ADs | 4 months | Relapse in phase II (HAM-D) | Relapse rate: Li < pcb (p = 0.02) |
| Bschor et al. [61] * | 22 | 46.4 (±15.7) | Double-blind Follow-up maintenance phase study | N.A. | Various ADs | 1 year | Recurrence (HAM-D) | Recurrence rate: Li = pcb (p = 0.49) |
| Joffe et al. | 50 | 37.4 (±11.2) | Head-to-head Double-blind Comparison Li/T3/pcb | Mean: Li: 935.3/0.68 T3: 37.5 mcg |
Desipramine, imipramine | 2 weeks | HAM-D | ↓ HAM-D: Li > pcb (p = 0.04) T3 > pcb (p = 0.02) Li = T3 (p > 0.05) |
| Kok et al. | 32 | 71.9 (±7.8) | Augmentation vs. switch Double-blind comparison VFX/NOR Not remitted patients → Open-label comparison Li augmentation/switch to PHE/switch to TCA/switch to ECT | Mean (SD): Li: 586.0 (±86.0)/0.82 (±0.15) PHE: 53.0 (±8.0) | Venlafaxine, nortriptyline | 12 weeks | MADRS | ↓ MADRS: Li (p < 0.001) TCA (p < 0.01) PHE (p > 0.05) ECT (p > 0.05) |
| Nierenberg et al. [59] | 35 | 37.2 (±8.3) | Double-blind | N.A./0.61 (range: 0.6–0.9) | Nortriptyline | 6 weeks | HAM-D, CGI | ↓ HAM-D and ↓ CGI: Li = pcb (p > 0.05) |
| Stein and Bernadt, [58] | 34 | 47.2 (±19.5) | Double-blind Experimental group: Li 250 3 weeks → 750 6 weeks Controls: pcb 3 weeks → Li 250 3 weeks → Li 750 3 weeks | Dose/mean (SD) Experimental group: 250/0.25 (±0.12) 750/0.78 (±0.35) Controls: 250/0.25 (±0.15) 750/0.65 (±0.21) | TCAs | 9 weeks | MADRS | ↓ MADRS: Li 250 = pcb (p = 0.81) Li 750 > Li 250 (p = 0.009) |
| Yoshimura et al. | 30 | Li: 39.0 (±8.0) OLA: 42.0 (±7.0) ARI: 40.0 (±10.0) | Head-to-head Comparison Li/OLA/ARI | Mean (SD): Li: 458.0 (±103.0)/N.A. OLA: 7.0 (±5.0) ARI: 9.0 (±6.0) | Paroxetine | 4 weeks | HAM-D | ↓ HAM-D: Li = OLA = ARI (p < 0.001) Response—remission rates: Li 40–20% OLA 30–10% ARI 40–20% |
| Open studies | ||||||||
| Bertschy et al. [67] | 13 | 45 | Open-label | Mean (SD): N.A./0.75 (±0.12) | Venlafaxine | 4 weeks | MADRS | ↓ MADRS: Li = pcb (p = 0.20) |
| Buspavanich et al. [70] | Tot: 167 Geriatric: 22 Non-geriatric: 145 | Tot: 48.3 (±13.9) Geriatric: 71.9 (±5.6) Non-geriatric: 44.8 (±11.0) | Prospective multicenter cohort study Comparison geriatric/non-geriatric patients | Mean (SD): 150.0 (±89.9)/0.68 (±0.2) | Various ADs | 4 weeks | HAM-D | Response rate: geriatric > non-geriatric patients (p = 0.04) |
| Dallal et al. [63] | 20 | 27–63 42.0 (±10.3) | Open-label | Range: 150–300/0.5–1.2 | Desipramine | 6 weeks | CGI | ↓ CGI (p < 0.01) |
| Dinan [65] | 11 | 37–59 | Open-label | Dose/mean (SD): 400/0.26 (±0.1) or 800/0.6 (±0.1) | Sertraline | 1 week | HAM-D | ↓ HAM-D (p < 0.01) Response not related to Li plasma levels |
| Doree et al. | 20 | QUE: 52.3 (±8.1) Li: 49.3 (±9.4) | Head-to-head Open-label Comparison QUE/Li | Mean: QUE: 430 (range: 300–700) Li: N.A./0.78 | Various ADs | 8 weeks | HAM-D MADRS | ↓ HAM-D both QUE and Li: p < 0.0001 QUE > Li (p < 0.05) ↓ MADRS: both QUE and Li: p < 0.0001 QUE > Li (p < 0.05) |
| Flint and Rifat [69] | 21 | 64–88 75.6 (±7.1) | Prospective, open-label | Mean (SD): N.A./0.67 (±0.17) | Nortriptyline, fluoxetine, phenelzine | 2 weeks | HAM-D, HAD | Response rate: 24% |
| Fontaine et al. [64] | 60 | 24–55 FLU+Li: 42.6 (±8.6) DES + Li: 41.0 (±8.8) | Open-label Comparison FLU + Li/DES + Li | Mean (SD): FLU + Li: 570.0 (±120.8)/N.A. DES + Li: 660.0 (±165.3)/N.A. | Fluoxetine, Desipramine | 6 weeks | CGI | ↓ CGI: FLU + Li = DES + Li Response rate FLU + Li: 60% Response rate DES + Li: 56.6% Rapid response (1 week): FLU + Li > DES + Li (N.S.) |
| Gervasoni et al. | 10 | N.A. | Head-to-head Observational Comparison Li-s/Li-s + T3 | Li-s: 1320/median: 0.52 (range: 0.38–1.10)T3: 37.5 mcg | Clomipramine | 2 months | MADRS | Remission rates: Li-s = 10% Li-s + T3 = 0 |
| Hoencamp et al. [66] | 22 | 43.0 (±13.0) | Open-label | Dose/mean (SD): 600/0.66 (±0.19) | Venlafaxine | 7 weeks | HAM-D MADRS CGI |
↓ HAM-D (p = 0.001) Response rate: 34.8% Remission rate: 8.7% ↓ MADRS (p = 0.005) ↓ CGI (p = 0.001) |
| Ivkovic et al. | 88 | LAM: 54.2 (±13.7) Li: 49.3 (±12.3) | Head-to-head Open-label | Mean (SD): LAM: 117.7 (±54.3) Li: 900/N.A. | Various ADs | 8 weeks | HAM-D, CGI | LAM = Li ↓ HAM-D (p = 0.83) ↓ CGI (p = 0.92) Within 2nd week: LAM > Li ↓ HAM-D (p = 0.01) ↓ CGI (p = 0.02) |
| Kok et al. [71] | 28 | Li: 73.6 (±7.3) PHE: 72.6 (±7.7) | Head-to-head Open-label, R Comparison Li augmentation/switch to PHE | Mean (SD) Li: 527.0 (±96.0)/0.71 (±0.17) PHE: 46.0 (±9.0) | TCA or venlafaxine | 6 weeks | MADRS remission | ↓ MADRS Li (p < 0.001) PHE (p = 0.85) Remission rates: Li > PHE (p = 0.04) Response rates: Li > PHE (p = 0.03) |
| Schindler and Anghelescu | 34 | Li: 50.3 (±13.6) LAM: 45.1 (±13.4) |
Head-to-head Open-label, R Comparison Li/LAM | Mean: Li: N.A./0.71 LAM: 152.9 | Various ADs | 8 weeks | HAM-D | ↓ HAM-D: Li = LAM (p = 0.11) |
| Schüle et al. | 46 | 50.78 (±12.27) | Head-to-head Open-label Comparison MIR monotherapy/Li augmentation/CAR augmentation | Mean (SD): Li: 917.0 (±144.1)/0.71 (±0.13) CAR: 370.0 (±67.5)/32.4 (±8.16) | Mirtazapine | 3 weeks | HAM-D | Response rates: MIR: 21.7% Li 53.8% CAR 20.0% Li > MIR (p = 0.05) CAR = MIR (p = 0.91) |
| Thase et al. [62] | 20 | 40.4 (±9.9) | Open-label | Responders: N.A./0.56 (±0.22) Non-responders: N.A./0.83 (±0.19) | Imipramine | 6 weeks | HAM-D | ↓ HAM-D (p < 0.001) Response rate: 65% |
| Whyte et al. | Augmentation group: 53 Switch group: 12 | Augmentation group: 76.2 (±5.7) Switch group: 78.8 (±7.2) | Augmentation vs. switch Open-label Comparison Li/NOR/BUP/switch to VFX | Max, median (range): Li: 300 (225–300)/0.5–0.7 NOR: 35 (10–50) BUP: 200 (50–400) VFX: 244 (150–300) | Paroxetine | Median (range), weeks: Li: 7 (1–22.3) NOR: 17 (0.2–28.7) BUP: 5.6 (0.3–30) VFX: 12 (8.7–12) |
HAM-D | Response rates: Li: 43% NOR: 31% BUP: 45% VFX: 41.7% |
| Zimmer et al. [68] | 13 | 74.1 (±8.2) | Open-label | Range/mean (SD): 300–450/0.65 (±0.20) | Nortriptyline | 3 weeks | HAM-D | ↓ HAM-D (p < 0.001) |
Key: * = study including subjects without relapse during the 4-months continuation phase reported by Bauer et al. [60]. AD = antidepressant; ARI = aripiprazole; BUP = bupropion; CAR = carbamazepine; CGI = Clinical Global Impression; DES = desipramine; ECT = Electro-Convulsive Therapy; FLU = fluoxetine; HAD = Hospital Anxiety and Depression; HAM-D = Hamilton Depression Rating Scale; IMAO = Monoamine Oxidase Inhibitor; LAM = lamotrigine; Li = lithium; Li 250 = lithium at 250 mg/d; Li 750 = lithium at 750 mg/d; Li-s = lithium sulfate; MADRS = Montgomery and Asberg Depression Rating Scale; MIR = mirtazapine; N.A. = not available; N.S. = not statistically significant; NOR = nortriptyline; OLA = olanzapine; pcb = placebo; PHE = phenelzine; QUE = quetiapine; R = randomized; RC = randomized controlled; RCT = randomized controlled trial; SD = standard deviation; T3: triiodothyronine; TCA = tricyclic antidepressant; VFX = venlafaxine.