As described in the 2004 guideline, a potential role for propranolol in preventing PTSD was suggested by a pilot study reported in 2002 by Pitman et al. (22), in which 32 emergency department patients received a 10-day course of propranolol or placebo, beginning within 6 hours of a trauma. Propranolol treatment did not change CAPS scores at 1 month but did decrease physiological response to script-driven imagery 3 months after the trauma. However, a 14-day randomized controlled trial reported in 2007 by Stein et al. (23) of propranolol compared with gabapentin compared with placebo failed to demonstrate the superiority of either medication over placebo.



Among the most promising advances in the pharmacological treatment of PTSD have been a series of placebo-controlled augmentation trials demonstrating the efficacy of the -adrenergic antagonist prazosin for the treatment of trauma-related nightmares and sleep disruption (24–26). In these trials, patients were allowed to continue maintenance medications, including SSRIs, as the primary outcome variables were related to sleep disturbance rather than daytime PTSD symptoms. However, the studies also assessed total PTSD symptoms using either the CAPS or the PTSD Checklist–Civilian Version (PCL-C).

The first study, reported in 2003 by Raskind et al. (24), was a double-blind, crossover trial in which 10 Vietnam combat veterans with PTSD received placebo or prazosin (mean dosage = 9.6 mg/night) over a 3-week dose-titration phase and a 6-week maintenance phase. Prazosin was significantly superior to placebo in reducing nightmares (CAPS "recurrent distressing dreams" item) and sleep disturbance (CAPS "difficulty sleeping" item) and in improving global clinical status (Clinical Global Impression of Change [CGIC]), with effect size z >1.0 on all measures. Change in total CAPS score and scores on all three CAPS cluster items was also significantly greater with prazosin than with placebo.

The second study, reported in 2007 by Raskind et al. (25), was a parallel-group trial in 40 veterans with chronic PTSD, most of whom experienced combat-related trauma in Vietnam. Patients received placebo or prazosin (mean dosage = 13.3 mg/night) during a 4-week dose-titration phase and an 8-week maintenance phase. Similar improvements were observed in nightmares, sleep disturbance, and CGIC scores (effect size = 0.9). A numerically greater reduction in total CAPS score was observed with prazosin, but this did not reach statistical significance.

Finally, in a double-blind, placebo-controlled crossover study of 13 civilians with trauma-related PTSD, reported in 2008 by Taylor et al. (26), prazosin was rapidly titrated to 3 mg/night during each 3-week treatment phase. Along with clinical outcomes, sleep time and sleep latency were recorded in the final 3 nights of the treatment phase. Total sleep time was 94 minutes longer with prazosin than with placebo (374 +/–86 minutes compared with 280 +/–105 minutes, p <0.01, effect size = 0.98), and total rapid eye movement (REM) sleep and mean REM duration were also longer with prazosin. Once again, reductions in trauma nightmares, total PTSD symptoms (using the PCL-C) and CGIC scores were significantly changed compared with placebo.

Further investigation may clarify an optimal dosage and titration for prazosin, which based on the above studies appears to be effective in a range of 3–15 mg/night. Clinically, a low dose could be tried and then increased if response is inadequate. Long-term efficacy has not been established.


Second-Generation (Atypical) Antipsychotic Medications

In 2006, Padala et al. (27) reported the results of a small pilot study in which 20 women ages 19–94 years with PTSD from sexual and domestic abuse were randomized during the acute phase to receive risperidone or placebo. A significant difference was observed between baseline and subsequent visit TOP-8 total scores beginning in week 6 and persisting through the 12th week of the study. This response pattern was also observed in the secondary outcome measures of CAPS, the HAM-D, and the Hamilton Anxiety Scale.

Risperidone was also studied in an 8-week randomized controlled trial reported in 2004 by Reich et al. (28) of 19 women who met DSM-III-R criteria related to childhood abuse. Significant differences in reduction from baseline total CAPS-2 score (z = –2.44, p = 0.015) and significant reductions in CAPS-2 intrusive (z = –5.71, p <0.001) and hyperarousal (z = –2.74, p = 0.006) subscores were associated with flexible dosing (0.5–8 mg/day) of risperidone. In 2008, Rothbaum et al. (29) randomized 25 adult PTSD patients whose symptoms did not remit (<70% decrease in symptoms, as measured by the CAPS) with 8 weeks of open-label sertraline to augmentation with risperidone compared with placebo for an additional 8 weeks. Patients receiving placebo and risperidone did not differ in their continued improvement in symptoms of depression or PTSD over the 8 weeks of augmentation (both groups improved), although those who received risperidone showed more improvement on the DTS sleep item on post hoc analysis.

Another second-generation (atypical) antipsychotic trial of note is a randomized, placebo-controlled augmentation study of 73 combat veterans reported in 2005 by Bartzokis et al. (30). This trial demonstrated risperidone's superiority to placebo in increasing response to SSRIs. These findings are consistent with the limited evidence from previous small randomized controlled trials of risperidone (31) and olanzapine (32).

In summary, these data are encouraging for adjunctive treatment with a second-generation antipsychotic in patients who have partially responded to an SSRI or an SNRI, including for co-occurring psychotic symptoms. As recommended in other APA practice guidelines (33), patients receiving an antipsychotic medication should be monitored for side effects including weight gain and metabolic changes.



Randomized controlled trials of anticonvulsant medications remain extremely limited in number and have shown mixed results. In a study reported in 2007 by Tucker et al. (34), 38 civilian patients with PTSD were randomized to placebo or flexibly dosed topiramate (25–400 mg/day); there were no significant differences in total CAPS scores or total Clinical Global Impression Scale scores, although patients treated with topiramate demonstrated clinically significant decreases in TOP-8 total score and CAPS reexperiencing symptoms subscale score.

In a continuation study reported in 2006 by Connor et al. (35), 29 patients with PTSD who completed an open-label trial of tiagabine and demonstrated at least minimal improvement were randomized to continued tiagabine or placebo. Benefits of treatment were maintained in the tiagabine group, and tiagabine was associated with a greater trend toward remission, but there was no statistically significant difference in remission rates, nor was there a change in rate of relapse in comparison with the placebo group.

In 2007, Davidson et al. (36) also evaluated the efficacy of tiagabine (2–4 mg/day in divided doses) in a 12-week randomized, placebo-controlled, multisite trial of 232 adult patients with PTSD. They found neither a statistically significant change from baseline CAPS score in either group nor a significant difference in any other outcome measure including CGIC, TOP-8, Davidson Trauma scale, or MADRS. Thus, while the small, open-label trial of Connor et al. (35) suggested efficacy of tiagabine, this larger randomized controlled trial failed to confirm this.

Most recently, Davis et al. (37) randomized 85 older male military veterans with PTSD to an 8-week trial of divalproex compared with placebo. No difference in outcomes was noted for either group, and no improvement was noted.

Despite the fact that anticonvulsant medications have been well tolerated in all studies and despite the promising results of some open-label studies, limited evidence of efficacy precludes any recommendations for change in practice.


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