Antidepressants are considered the primary class of medications for the treatment of PTSD. Given that several RCTs have repeatedly demonstrated their efficacy (Brady et al. 2000
; Connor et al. 1999
; Davidson et al. 2001
; Marshall et al. 2001a
; Neylan et al. 2001
; Tucker et al. 2001
; van der Kolk et al. 1994
), it is now well established that SSRIs are the first-line pharmacotherapy for PTSD (Ursano et al. 2004
). Further options include the dual action selective serotonin and noradrenaline reuptake inhibitors, tricyclics, monoaminoxidase inhibitors and others (nefazodone, bupropion etc.). The limited number of RCTs assessing alternative medications to be employed when patients do not tolerate or not respond to antidepressants poses a challenge to the clinicians. The authors of the present review decided not to limit the present systematic review to RCTs since open trials and case series are often the first evidence supporting innovative treatment (Albrecht et al. 2005
). Indeed, clinicians in their daily practice frequently have no controlled clinical trial-based evidence to guide them through the decision-making process and have to rely on the best available piece of evidence. Given that the majority of the studies reviewed here suffered from methodological shortcomings, there is currently no medication for the treatment of PTSD within the level A of evidence other than antidepressants. Level B of evidence was achieved by risperidone, olanzapine, lamotrigine, valproate and prazosin. Seven medications warranted level C and 13 level D ().
In four out of six RCTs with risperidone, this medication was shown to be superior to placebo in reducting overall PTSD severity (Bartzokis et al. 2005
; Monnelly et al. 2003
; Padala et al. 2006
; Reich et al. 2004
). Only Hamner et al. (2003b)
and Rothbaum et al. (2008)
failed to find significant differences. It must be noted, however, that the sample investigated by Hamner and his collaborators was composed exclusively by war veterans, a population that is characterized by high levels of refractoriness (Mohamed and Rosenheck 2008
) and that their study duration (5 weeks) was the shortest of all the five RCTs while Rothbaum and colleagues’ study was conducted with a small number of patients refractory to first-line treatment with sertraline. It is also worth mentioning that none of these six RCTs have demonstrated the efficacy of risperidone on the symptoms of the avoidance/numbing cluster.
As noted above, the two existing RCTs on olanzapine in PTSD produce conflicting results: while Stein et al. (2002)
found that olanzapine was superior to placebo as an augmentation therapy in the treatment of 19 male war veterans with refractory PTSD, Butterfield et al. (2001)
found no advantage for olanzapine in a sample of 15 civilian PTSD patients (14 women, with 4 drop-outs during the study). The inconsistency of the results could be ascribed to several factors including differences in treatment strategies (augmentation vs.
monotherapy), demographic make-up of the sample, type of trauma, level of treatment resistance, and time elapsed since the traumatic event.
It must be kept in mind that the efficacy of the antipsychotics in the treatment of refractory PTSD may not reflect any specific action on posttraumatic symptoms, but rather their effects on non-specific symptoms, such as insomnia, nightmares, and associated psychotic ideation. It is also important to note that since these trials were essentially short-term ones, the possibility of the occurrence of severe side effects such as metabolic syndrome and tardive dyskinesia should remain a major concern.
Although anticonvulsants have assumed an ever increasing role in the psychiatric armamentarium, being now used regularly to treat mood (Carvalho et al. 2007
) and anxiety disorders (Mula et al. 2007
), their real worth in the treatment of post-traumatic stress remains uncertain. Studies on the efficacy of anticonvulsants in PTSD far outnumber those of antipsychotics, but the former are clearly methodologically inferior to the latter. Only six RCTs were conducted with anticonvulsants. Most studies described a decrease in the severity PTSD symptoms after anticonvulsants were added to a pre-existing therapeutic scheme as an augmentation strategy. Herzberg et al.
(1999) reported that lamotrigine as a monotherapy was effective in reducing general symptoms, reexperiencing and avoidance/numbing, but not hyperarousal, in treatment-refractory PTSD. Steiner et al. (2007)
demonstrated that divalproex sodium, especially at doses between 500–1,500 mg/day, could ameliorate PTSD symptoms. It should be noted that this study did not compare the use of divalproate against that of placebo. However, in a placebo-controled, double-blind study, Davis et al. (2008)
found that divalproex had no discernible effects on the chronic PTSD symptoms of veterans, even in high doses. Tucker et al. (2007)
reported the effectiveness of topiramate as a monotherapy in ameliorating symptoms of reexperiencing (but not the global scores of PTSD). These findings were replicated by Lindley et al. (2007)
, who used topiramate as an augmentation strategy. Davidson et al. (2007)
failed to demonstrate the superiority of tiagabine over placebo in the treatment of 232 civilian patients with PTSD, as determined by four differents outcomes measures, even after excluding patients with history of unresponsiviness to PTSD treatment.
Prazosin, an adrenergic-inhibiting agent, is a promising alternative in the treatment of PTSD, particularly when trauma-related nightmares and sleep disturbances are prominent symptoms, as shown by three recent RCTs. Taylor et al. (2008)
found that prazosin not only improved the physiological patterns of sleep and produced positive qualitative changes in the character of pathological dreams, but also reduced overall PTSD severity, as measured by PCL-C. Raskind et al. (2007)
showed a significant reduction in nightmares (through the distressing dreams item of the CAPS), improvement of sleep quality (as measured by the PSQI) and decrease of the severity of PTSD symptoms (assessed through the CGI-I) in veterans medicated with prazosin, as compared to those treated with placebo. Nevertheless, no significant differences were found in CAPS total scores. Finally, Raskind et al. (2003)
reported that prazosin was effective for treating symptoms of the re-experiencing, avoidance/numbing, and hyperarousal clusters in treatment-resistant PTSD. Other adrenergic-inhibiting agents such as propranolol and clonidine were not yet evaluated by RCTs, but the few open-label studies published so far suggest that these drugs can alleviate some sleep disturbances (i.e. nightmares) and especially hyperarousal symptoms. A recent RCT showed that guanfacine (either as an augmentation strategy or as monotherapy) was ineffective in the treatment of PTSD symptoms (Neylan et al. 2006
Benzodiazepines are frequently prescribed by physicians in the aftermath of a traumatic event in an effort to prevent the development of psychological sequelae or, if PTSD eventually arises, to reduce active post-traumatic symptoms, like hypervigilance, or control associated non-specific behavioral disturbances, such as marked anxiety or agitation.
Thus far, there is no compelling scientific evidence of the effectiveness of benzodiazepines either in the prevention of PTSD or in the treatment of its core symptoms although clinical experience suggests that they may improve sleep and agitation, at least in the short term. These limited advantages must be weighted against the marked potential for addiction that characterizes this class of drugs, particularly considering that PTSD patients have higher rates of drug abuse/dependence than the general population (Kessler et al. 1995
). Recently, Westra et al. (2004)
have reported that individuals with anxiety disorders who take benzodiazepines exhibit a reduced capacity to remember material presented in cognitive-behavioral therapy and hypothesized that this memory impairment may account for the lower efficacy of this modality of psychotherapy in these patients (Westra et al., 2004
). In addition, a few studies suggest that benzodiazepines may contribute to the development and/or chronification of posttraumatic symptoms (Gelpin et al. 1996
; Mellman et al. 2002
). Following the fundamental principle of Medicine, “primum non nocere
”, future RCTs should further investigate the potentially iatrogenic effects of benzodiazepines before they can be safely recommended for the treatment of PTSD.
The scientific evidence supporting the use of opioids antagonists in PTSD is still limited: two existing open-label trials showed disappointing results (Glover 1993
; Lubin et al. 2002
Altough the use of cyproheptadine in the treatment of PTSD has a good rationale, the only open-label trial available found low efficacy and a high rate of adverse effects. Others drugs, such as dehydroepiandrosterone and propranolol, may eventually turn out to be clinically useful, but for now the few existing studies suffer from methodological limitations.
The studies reviewed here must be taken with caution for several reasons. First, many of these studies failed to specify whether the medications were employed as a monotherapy or as an augmentation strategy. This is a serious methodological problem that not only jeopardizes the comparability of the studies, but also limits their clinical usefulness. Second, the majority of the case reports and open label trials reported positive results with several medications that had not yet been otherwise rigorously evaluated in the this context. A publication bias could explain the predominance of favorable results in this literature, given that editors and authors tend to favor positive findings. Third, the majority of these studies were carried out with combat veterans, a population that is notoriously refractory to conventional treatment, making the results difficult to extrapolate to civilian samples. Fourth, the criteria for therapeutic response currently adopted are based on partial improvement rather than on full remission and may overestimate the clinical significance of even modest symptomatic improvement in PTSD. For instance, when the definition of clinical response adopted is a reduction ≥ 30% in CAPS scores, it is likely that many patients considered to be responders are continuing to suffer from clinically relevant subsyndromal PTSD, a condition that is known to be associated with substantial impairment (Marshall et al. 2001b
). Finally, the system of classification of the level of scientific evidence used in this review did not take into consideration the number of participants in the studies.