Table 2.
Investigational Glutamate-based Pharmacotherapies
| Study | Subjects | (N) - Treatment | Duration | Study Design | Treatment Response and Findings |
|---|---|---|---|---|---|
| Lamotrigine (LM) | |||||
| Hertzberg et al. (1999) [46] | xPTSD | (10) LM, 25mg/day; titrated to max of 500mg/day if tolerated. (4) Placebo |
12 weeks | Randomized 2:1, double-blind, placebo-controlled | 50% improvement in LM compared to 25% in placebo; marked improvement in reexperiencing, avoidance, numbing in LM |
| Kozaric-Kovacic & Eterovic (2013) [47] | cTRPTSD | (1) LM, 125mg/day | 12 weeks | Case Report | Reduced PTSD symptoms including aggressive behaviors, improved interpersonal relations |
| Ketamine (Ket) | |||||
| Schonenberg et al. (2005) [53] | cPTSD | (17) R-Ket* (12) S-Ket* (27) OPI *+Mdz |
Single or fractionated peritraumatically administered dose. | Retrospective analysis of acute & current PTSD 1 year posttrauma | PTSD symptoms: S-Ket > R-Ket = OPI; |
| McGhee et al. (2008) [54] | mPTSD | (119) Ket (28) No Ket |
Intraoperative dose. | Retrospective chart review | PTSD prevalence was lower in Ket group (27% vs. 46%); Ket group had more severe trauma/burns. |
| McGhee et al. (2014) [55] | mPTSD | (189) Ket (100) No Ket |
Intraoperative dose. | Retrospective analysis 30+ days posttrauma | PTSD prevalence did not differ between Ket and no Ket (24% vs. 27%); Ket group had more severe trauma/burns/surgeries. |
| Feder et al. (2014) [56] | cPTSD | (22) Ket, 0.5mg/kg. (19) Mdz, 0.045mg/kg [First-period of crossover] |
Single IV dose of each administered over 40 minutes, separated by 2 weeks. | Randomized, double-blind, crossover, active placebo controlled trial. | PTSD improvement in Ket compared to Mdz @ 24 hours with no evidence of period or crossover effects; PTSD improvement remained significant after controlling for BL & 24-hour depression; Durability of benefit was ~15 days |
| D-cycloserine (DCS) | |||||
| Attari et al. (2014) [59] | mPTSD | (38) DCS, 50mg/day. (38) Placebo. [First-period of crossover] |
11 weeks total; 4 week 1st period - 2-week washout - 4 week 2nd period. | Randomized, double-blind, placebo-controlled crossover trial. | Decreased intensity of avoidance and numbing symptoms in DCS compared to placebo. |
| Heresco- Levy et al. (2002) [60] | cPTSD | (6) DCS, 50mg/day. (5) Placebo [First-period of crossover] |
12 weeks; 2 week washout - 4 week 1st period - 2-week washout - 4 week 2nd period. | Randomized, double-blind, placebo-controlled crossover trial. | Study failed to show difference between DCS & placebo. |
| Difede et al. (2014) [61] | cPTSD | (13) DCS+VRE 100mg (12) Placebo +VRE |
12 weeks total; Dosed 1x/week 90 minutes prior to VRE session for 10 sessions. | Randomized, double-blind, placebo-controlled trial. | Greater PTSD remission for DCS+VRE compared to placebo+VRE (46% vs 8% posttreatment; 69% vs 17% at 6 months FU; secondary analysis suggest earlier & greater improvement in PTSD as well as depression, anger expression, & sleep in DCS compared to placebo. |
| Litz et al. (2012) [62] | mPTSD | (13) DCS+IE 50mg (13) Placebo + IE |
6 weeks total; Dosed 1x/week 30 minutes prior to IE sessions for 4 sessions. | Randomized, double-blind, placebo-controlled trial. | DCS showed no beneficial effect; 70% of placebo+IE showed improvement compared to 30% in DCS+IE; 3 DCS+IE patients reported significant worsening of symptoms. |
| de Kleine et al. (2012) [63] | cPTSD | (33) DCS+PE 50mg (34) Placebo+PE |
~10 weeks total; Dosed 1x/week 60 minutes prior to ~8–10 PE sessions. | Randomized, double-blind, placebo-controlled trial. | Study failed to show difference between DCS+PE and placebo+PE on primary outcome; secondary analysis suggest greater response rate in DCS+PE (64%) compared to placebo+PE (38%). |
| Rothbaum et al. (2014) [64] | mPTSD | (53) DCS+VRE 50mg (50) APZ+VRE 0.25mg (53) Placebo+VRE |
6 weeks; Dosed 1x/week 30 minutes prior to VRE session for 5 sessions. | Randomized, double-blind, active-placebo controlled trial. | Study failed to show difference between DCS+VRE and placebo+VRE on primary outcome; secondary analysis suggest DCS+VRE had lower startle during VRE sessions relative to APZ+VRE or placebo+VRE. |
Abbreviations: APZ = alprazolam; BL = baseline; cPTSD = civilian posttraumatic stress disorder; DCS = D-cycloserine; dx = diagnostic; FU = follow-up; IE = imaginal exposure (psychotherapy); Ket = ketamine; LM = lamotrigine; Mdz = midazolam; mPTSD = military posttraumatic stress disorder; OPI = opioid; PE = prolonged exposure (psychotherapy); PTSD = posttraumatic stress disorder; R-Ket = racemic ketamine; SI = seriously injured; S-Ket = (S)-ketamine; TRPTSD = treatment-resistant posttraumatic stress disorder; VRE = virtual reality exposure (psychotherapy); xPTSD = mixed military and civilian PTSD population