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Antidepressants

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Selective Serotonin Reuptake Inhibitors for Non-Combat-Related PTSD

Meta-analyses and several randomized controlled trials published since 2004 generally support the superiority of SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) over placebo for non-combat-related PTSD.

In a 2006 Cochrane meta-analysis, Stein et al. (4) reviewed 35 short-term randomized controlled trials (of 14 or fewer weeks in duration) involving a total of 4,597 participants. In 17 of the trials, symptom severity was significantly reduced in the medication groups relative to placebo. Evidence of efficacy was most convincing for the SSRIs, across all symptom clusters and for co-occurring depression and disability.

In a study reported in 2007, Marshall et al. (5) evaluated the efficacy of paroxetine for treating symptoms and associated features of chronic PTSD. Fifty-two mostly minority adult patients (out of 70 initially enrolled) who were rated as not significantly improved after 1 week of placebo were randomized to receive flexibly dosed paroxetine (maximum 60 mg/day by week 7) or continued placebo. After 10 weeks, significantly more patients treated with paroxetine responded to treatment, as rated by the Clinical Global Impression–Improvement (CGI-I) scale. Patients treated with paroxetine were also observed to have significantly greater reduction in total score on the Clinician-Administered PTSD Scale (CAPS) and the Dissociative Experience Scale; self-reported interpersonal problems were also noted to be significantly decreased. During a 10-week maintenance phase, paroxetine response but not placebo response continued to improve.

In a 2006 reanalysis of two previously published trials, Stein et al. (6) examined 395 adult patients with PTSD who were randomized to double-blind treatment with flexibly dosed sertraline (50–200 mg/day) or placebo. After 12 weeks, sertraline was significantly more effective than placebo on most primary efficacy variables including Part 2 of the CAPS, irrespective of whether the patients had experienced childhood abuse or interpersonal trauma, suggesting the utility of medication treatment in individuals whose precipitating trauma is either childhood abuse in particular or interpersonal trauma in general.

In a 2005 study, Davidson et al. (7) compared the relapse rates of 57 of 62 total patients who responded to 6 months of open-label fluoxetine and who were subsequently blindly randomized to continue receiving fluoxetine (mean dosage = 42.1 mg/day) or placebo. Relapse rates were 22% for fluoxetine compared with 50% for placebo (p = 0.02); the odds ratio for relapse on placebo relative to fluoxetine was 3.50, and time to relapse on fluoxetine was longer than on placebo (p = 0.02, log rank statistic).

These newer studies augment the evidence base for SSRI efficacy previously established in samples of predominantly women with PTSD resulting from civilian trauma, including childhood and adult sexual assault, other interpersonal traumas, and motor vehicle accidents.

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SSRIs for Combat-Related PTSD

Randomized controlled trials have called into question the efficacy of SSRIs for the treatment of PTSD in combat veterans. Some of this evidence was described in the 2004 guideline, including van der Kolk et al.'s 1994 study (8) of 31 veterans with chronic PTSD randomized to fluoxetine or placebo. In this study, fluoxetine was significantly superior to placebo for symptoms of co-occurring depression as measured by the Hamilton Depression Rating Scale (HAM-D), but change in total PTSD score did not differ between placebo and fluoxetine. In a similar randomization of 88 veterans with PTSD, none of those receiving 8 weeks of fluoxetine treatment achieved an asymptomic state as measured by the CAPS at 6-month follow-up (9). Negative results were reported in a placebo-controlled, randomized controlled trial by Hertzberg et al. (10) of fluoxetine in 12 Vietnam war veterans.

More recently, Friedman et al. (11) completed a multicenter trial of sertraline in 169 combat veterans with PTSD recruited from 10 Veterans Affairs medical centers. After 1 week of placebo, the patients were randomized to receive 12 weeks of flexibly dosed sertraline (mean dosage = 156 mg/day among completers) or continued placebo. Total PTSD symptom reduction as measured by the CAPS did not significantly differ between the sertraline (–13.1, +/–3) and placebo (–15.4, +/–3.1) groups, and in both groups, combat-related PTSD was associated with poorer outcome compared with non-combat-related PTSD.

In a 2002 study, Zohar et al. (12) randomized 42 Israeli combat veterans to sertraline (mean dosage = 120 mg/day, +/–60 mg) or placebo. At 10 weeks, no significant differences were noted in total score on the CAPS-2 or on any of the three CAPS symptom cluster scores.

These findings stand in contrast to a 2006 randomized controlled trial by Martenyi and Soldatenkova (13) of 144 combat veterans of the Balkan Wars recruited at eight sites in Bosnia-Herzegovina and Croatia and randomized to fluoxetine (20–80 mg/day) or placebo for both a 12-week acute phase and 24-week relapse prevention phase. In the acute phase, fluoxetine was superior to placebo as measured by total score on the Treatment Outcome PTSD (TOP-8) scale (–9.05 compared with –5.20; p = 0.001), total score on the CAPS (–31.12 compared with –16.07; p <0.001), all CAPS subscores, and total score on the Davidson Trauma Scale (DTS). Fluoxetine was also more effective for depression as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and for anxiety symptoms as measured by the Hamilton Anxiety Scale. In the relapse prevention phase of the trial, fluoxetine was superior to placebo in sustaining improvement in TOP-8 and CAPS scores, and the risk of relapse was significantly greater in the placebo arm than in the fluoxetine arm (log rank test 2 = 4.9, df = 1, p = 0.048). The veterans of the Balkan Wars were younger than the Israeli and American combat veterans (mean age = 36), somewhat more recently traumatized (although mean duration from index trauma was 6–7 years), and had likely received less treatment for their symptoms prior to study entry. It is possible that negative results with older combat veterans (in contrast to positive results with fluoxetine among younger veterans of the Balkan Wars) may be due to the chronicity of their PTSD (and co-occurring disorders) rather than a unique resistance to SSRI treatment among individuals with combat-related PTSD.

The 2004 guideline recommends the SSRIs as a first-line medication treatment for patients with PTSD. The trials reviewed above suggest that the SSRIs may no longer be recommended with the same level of confidence for veterans with combat-related PTSD as for patients with non-combat-related PTSD. Further research is needed to answer why these populations have been shown to have differential responses to SSRI treatment.

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Other Antidepressants

Since publication of the 2004 guideline, several randomized, placebo-controlled trials of venlafaxine, one trial of mirtazapine, one trial of nefazodone, and one trial of bupropion have been reported, as well as several head-to-head comparisons of these medications with SSRIs.

In a 2006 study, Davidson et al. (14) randomly assigned 329 adult outpatients from 56 sites who had a primary diagnosis of PTSD with symptom duration of 6 months or longer and CAPS scores of 60 or greater to receive venlafaxine, extended release (37.5–300 mg/day), or placebo. At 24 weeks, mean changes in total CAPS score from baseline were –51.7 for the venlafaxine group compared with –43.9 for the placebo group (p = 0.006); improvement was significantly greater for the venlafaxine group in symptom cluster scores for reexperiencing (p = 0.008) and avoidance/numbing (p = 0.006) but not for hyperarousal. Remission rates (defined as a CAPS score of 20 or lower) were found to be 50.9% for venlafaxine and 37.5% for placebo (p = 0.01). A 12-week, multicenter double-blind trial (15) compared venlafaxine extended release (37.5–300 mg/day) to sertraline (25–200 mg/day) or placebo in adult outpatients with PTSD. Mean changes from baseline scores on the CAPS-SX17 (an abbreviated version of the CAPS) were –41.8, –39.4, and –33.9 for venlaxine, sertraline, and placebo, respectively, with only venlafaxine separating from placebo in a statistically significant manner (p <0.05).

In a 2007 study, Becker et al. (16) found no between-group differences in 30 patients with civilian- or military-related PTSD who were randomized to placebo or bupropion, sustained release, in addition to usual pharmacological care. About half of these patients were already receiving an SSRI at the time of randomization.

In a 2004 study, Davis et al. (17) randomized 41 predominantly male combat veterans with PTSD to nefazodone or placebo. After 12 weeks, they found significant improvement in percentage change of total CAPS score from baseline in those receiving nefazodone compared with those receiving placebo in a repeated analysis of variance with last observation carried forward (p = 0.04, effect size = 0.6).

Finally, in a double-blind, randomized, placebo-controlled trial of 29 patients with PTSD reported in 2003 by Davidson et al. (18), mirtazapine (up to 45 mg/day) was found to be more effective than placebo on the Global Improvement item of the Short PTSD Rating Interview (SPRINT; but not on total SPRINT score, nor on DTS total score), as well as on the Structured Interview for PTSD and anxiety subscale of the Hospital Anxiety and Depression Scale.

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Head-to-Head Comparisons of Antidepressants

As described in the 2004 guideline, no significant differences among antidepressants, including the SSRIs, were found in the few head-to-head studies then available. Since that time, studies have been published comparing nefazodone and sertraline (19), venlafaxine and sertraline (15), the SNRI reboxetine and fluvoxamine (20), and fluoxetine, moclobemide, and tianeptine (21). These studies have generally demonstrated the superiority of antidepressants to placebo but have done little to clarify the relative utility of these different antidepressants.

In total, these data build on the relatively robust evidence basis for pharmacological treatment with antidepressant medications (particularly SSRIs and SNRIs for noncombat PTSD) as compared with other classes of medications. However, the data also suggest that more effective pharmacological treatments must be identified, particularly for veterans with combat-related PTSD. It is also important to note that comparison of other pharmacotherapies with the SSRIs and SNRIs is complicated by methodological differences in the available studies. While the SSRIs and SNRIs have mostly been studied in rigorous trials compared with placebo, other agents have been studied against "treatment as usual" conditions or as augmentation agents in patients with refractory illness.

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Adrenergic Agents

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Beta-blockers

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.

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Prazosin

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.

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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.

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Anticonvulsants

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.

References

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