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Pharmacotherapy for post‑traumatic stress disorder Expert Rev. Clin. Pharmacol. 2(1), 77–86 (2009)

Christopher P Alderman†, Linda C McCarthy and Anita C Marwood Author for correspondence Repatriation General Hospital, Daw Park, South Australia 5041, Australia Tel.: +61 882 751 878 Fax: +61 883 740 225 [email protected] †

Post-traumatic stress disorder (PTSD) is a serious mental illness of considerable importance from a public health perspective. Management of PTSD may involve the use of various treatment modalities, involving both nondrug treatments and pharmacotherapy. Nondrug treatment is regarded as the first-line option for PTSD and should be routinely incorporated into management plans for patients with PTSD. However, some patients do not achieve a sufficient response to nondrug therapy or are left with disabling residual symptoms in one or more areas. Antidepressants are currently the preferred medication for PTSD, with the most substantial evidence available to support the use of the selective serotonin reuptake inhibitors. Many patients with PTSD have symptoms that are resistant to initial drug treatment, meaning that it is often necessary to explore additional pharmacotherapy options to achieve optimal symptom control: antipsychotics, anti-adrenergic drugs, anxiolytics and anticonvulsants have all been advocated as treatments for PTSD. In addition to the management of core PTSD symptoms, it is also necessary for clinicians to address important associated comorbidities, most notably, substance-use disorders and mood disturbances. Interpretation of research studies of the efficacy and safety of PTSD pharmacotherapy is often difficult owing to methodological limitations and factors such as inclusion bias. Further research in fundamental neurosciences and pharmacogenomics may help to elucidate optimal pharmacotherapy options for PTSD in the future. Keywords : adrenergic modulator • anticonvulsant • benzodiazepine • pharmacotherapy • post-traumatic stress disorder • selective serotonin-reuptake inhibitor

Post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a relatively common and serious mental illness. Patients with PTSD develop symptoms after personal exposure to trauma that involves threat of death or serious injury, after witnessing an event that involves death, injury or threat to the physical integrity of another person, or after learning about unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or someone else close to them [1] . The exposure to the traumatic events creates a personal response involving intense fear, helplessness or horror [1] . Approximately 20% of women and 8% of men who have been exposed to significant traumatic events will eventually develop symptoms of PTSD, with the lifetime prevalence for this disorder being approximately 10–14% for women and 5–6% for men [2,3] . Common forms of trauma that cause PTSD include involvement in military conflict (particularly combat or medical roles), violent crime, rape and other sexual assault, torture, natural disasters and severe injury or www.expert-reviews.com

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medical illness [1,3] . There is information to suggest that some people are more likely to develop PTSD after a traumatic event: risk factors include severe or prolonged trauma, trauma/ abuse during childhood, pre-existing history of psychiatric illness, comorbid substance abuse, poor social supports and female gender [4] . The neurobiology of PTSD is complex and is yet to be elucidated completely, but it is possible that as our understanding of the underlying physiological and neurological processes evolves, this may inform the development of new and effective treatment options. Current evidence suggests that the underlying physio­ logy of PTSD probably involves dysregulation of multiple neurochemical systems, including those regulated by noradrenaline, the hypo­ thalamic–pituitary–adrenocortical (HPA) axis, the thyroid and endogenous opioid systems [5] . PTSD is associated with the release of stress-responsive hormones, including cortisol, adrenaline, noradrenaline, vasopressin, oxytocin and endogenous opioids [5] . Research suggests that patients with PTSD develop downregulated

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adrenergic receptors in response to increased circulating noradrenaline concentrations [5] . Serotonergic systems are also important and play a role in modulating nor­adrenergic responsiveness to arousal (animal evidence suggests that underexpression of serotonergic transmission is related to reduced capacity to modulate arousal) [5] . In addition to the neuro­biological markers discussed earlier, it is also thought that certain neuroanatomical abnormalities may also be related to PTSD; these include reduced hippocampal volume and the presence of an abnormal cavum septum pellucidum [6] . Pharmacotherapy versus nondrug therapy for PTSD

No discussion of pharmacotherapy for PTSD can be complete without first exploring the utility of the nondrug therapy approaches that have proven efficacy and are widely regarded as the first-line management options for this condition. A range of authoritative sources concur that the use of nondrug treatment should be regarded as the first-line approach for PTSD [7–9] . The US Department of Veterans Affairs has addressed a range of nonpharmacological management options and has summarized these in an informative fact sheet [201] . The choice of treatment to be used is determined by a range of factors, including patientspecific factors, side effects and potential negative effects, cost, duration of treatment, cultural appropriateness, the therapist’s resources and skills, the client’s resources and stressors, comorbidity of other psychiatric symptoms and forensic issues [201] . Treatment approaches that have empirical support and have demonstrated promising results include cognitive–behavioral therapy, eye-movement desensitization and reprocessing, psycho­ dynamic therapy, group therapy, marital and family therapy, social rehabilitative therapies, hypnosis and others [201] . Evidence to support the effectiveness of combining nondrug therapy with pharmacotherapy is not yet very compelling [10] , although some research has demonstrated encouraging results [11] . Even so, in the real-world environment, where PTSD is often refractory to nondrug therapy alone, the use of pharmacotherapy in combination with approaches such as cognitive–behavioral therapy and trauma-focus therapy is widely adopted [9] . Objectives of pharmacotherapy for PTSD

When designing and implementing pharmacotherapy for patients with PTSD, there are several key principles to consider. Clearly, pharmacotherapy should be directed at the core symptoms of PTSD, attempting to reduce the frequency and intensity of symptoms and the disability of these. Pharmacotherapy can be used to address recurrent and intrusive recollections of the traumatic event, such as flashbacks and recurrent dreams. Drug therapy may also assist by reducing the intense distress that some patients experience when exposed to circumstances that resemble or symbolize the event, and reduce the extent of avoidant behavior that can be maladaptive. Other primary target symptoms for pharmacotherapy include difficulties with sleep, hyper­v igilance, exaggerated startle response, irritability or outbursts of anger, and difficulty concentrating or completing tasks [1] . As PTSD is frequently associated with increased 78

rates of comorbid psychiatric and medical illnesses, it is also important that the overall treatment regimen is designed in a way that minimizes the impact of issues such as depression, substance abuse and the physical sequelae of lifestyle issues relevant to patients with PTSD. Major medical illnesses are common among people with severe PTSD: for example, in a large cohort of Vietnam veterans examined approximately 20 years after their combat experiences, there was a higher lifetime prevalence of circulatory, digestive, musculoskeletal, endocrine, nervous system, respiratory and nonsexually-transmitted infectious diseases among veterans with PTSD; an effect that persisted even after controlling for selection bias, behavioral risk factors and pre-existing medical or psychiatric issues that were documented in military records [12] . Substance abuse is also much more common in people with PTSD [13] , and with this come a range of psychiatric and medical sequelae that may require pharmacotherapy. Drug therapy should be selected and implemented in a way that is most likely to complement nonpharmacological approaches, so that maximal benefits can be gained form both interventions [9] . For example, ongoing use of heavy sedation that may have been initially appropriate during a period of severe crisis and agitation, may ultimately prove to be counterproductive if the duration of therapy is extended during the implementation of complex behavioral interventions that require intact cognition and attention. Conversely, if a patient remains very agitated because appropriate medication treatment is not in use, this may compromise the effectiveness of behavioral interventions. In designing pharmacotherapy to be used for the management of PTSD, it is important to adopt an approach that recognizes that these patients are at substantial risk for drug-related problems [14] , which can relate to adverse drug reactions, interactions between drugs and issues relating to the dosage of the medications. In view of the extensive comorbidities referred to earlier, patients with PTSD are often taking several drugs concurrently and the medication regimens involve drugs, such as the selective serotonin reuptake inhibitors (SSRIs), which have substantial potential to interact with other drugs used for the management of psychiatric and medical conditions [15] . With these factors in mind, it is critical that patients receiving pharmacotherapy for PTSD are monitored closely to ensure that treatment-related morbidity is minimized and clinical outcomes optimized. Specific drug therapy for PTSD Antidepressants

Research into the effectiveness of antidepressants for the pharmaco­therapy of PTSD appears to date back to the 1980s, with early examples including research into the possible effectiveness of the nonselective monoamine oxidase inhibitor (MAOI), phenelzine [16–19] . As the limitations of MAOI drugs in terms of drug and dietary interactions restrict the clinical usefulness of these agents, research interest soon turned to the tricyclic antidepressants (TCAs). Kosten et al. compared the TCA imipr­ amine with phenelzine and with placebo, finding that both drugs significantly reduced PTSD symptoms by week 5 (although a Expert Rev. Clin. Pharmacol. 2(1), (2009)

Pharmacotherapy for post‑traumatic stress disorder

greater effect was observed with phenelzine) [20] . Other research has indicated that the TCAs offer benefit as a treatment for PTSD and although these drugs have the disadvantage of toxicity in overdose (with evidence suggesting that patients with PTSD have a high risk of suicide attempt by overdose), these agents still have a place as a second-line antidepressant option in the management of PTSD [21–25] . When using TCAs for patients with PTSD it remains important to consider issues relating to the adverse-effect profile of these agents: anticholinergic effects may be particularly troublesome for those with a history of comorbid ischemic heart disease, cognitive disorders, prostatic hypertrophy and other important medical conditions. Reports of the use of the SSRIs for the management of PTSD began to emerge in the early 1990s [26–33] . In the years that followed, these agents become broadly endorsed as the first-line pharmacotherapy for PTSD [9,34,35] . Evidence has accumulated since then, to varying extents for each of the commonly prescribed SSRIs, including sertraline [32,36–41] , fluoxetine [41–44] , fluvoxamine [45] , paroxetine [46–49] and citalopram/escitalopram  [50–52] , Some studies, on the other hand, have failed to demonstrate efficacy of SSRIs for the treatment of PTSD and it is thought that PTSD related to combat trauma may be more refractory to SSRI treatment [40,53,54] . On balance, the SSRIs should be regarded as the first-line pharmacotherapy for PTSD: although the addition of other medications may be required to address specific aspects of the symptom spectrum, on the basis of current evidence, treatment with an SSRI would be regarded as the most appropriate choice in many cases. It is important to note that the SSRIs are involved in many significant drug–drug interactions and this issue must be considered and accommodated when designing a treatment regimen that includes other agents that may be used for comorbid psychiatric and medical conditions [15] . The safety and efficacy of several other antidepressant drugs as treatments for PTSD has been examined. A 6 month, randomized, controlled study demonstrated the benefit of venlafaxine for the treatment of PTSD [55] and was further supported by additional research suggesting that venlafaxine was superior to placebo and similar in efficacy and tolerability to sertraline [56] . Although initial research suggested a promising role for nefazodone, safety concerns relating to hepatotoxicity have seen this agent withdrawn from the market in many countries; thus this agent would not be considered as a routine management option for PTSD. The reversible, selective MAOI moclobemide has demonstrated some promise as a treatment for PTSD, although more robust trials are required to replicate the findings of initial research [57,58] . Bupropion does not appear to be a useful treatment option for PTSD [59] , and the only research currently to hand addressing reboxetine suggests that although this drug did produce a treatment response for patients with PTSD, there was a high drop-out rate associated with adverse events (possibly owing to the noradrenergic mechanism of the drug’s action) [60] . Perhaps the most interesting recent development in the management of PTSD with antidepressants relates to the 5HT2/3 receptor blocker, mirtazapine, which offers advantages related to www.expert-reviews.com

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a modest potential for drug interactions and a favorable effect on sleep. An early study in 1999 demonstrated some degree of benefit for PTSD [61] and subsequent research in a group of patients with PTSD replicated this finding [62] . The same group of researchers subsequently reported a follow-up study that assessed 12 out of 15 members of the original cohort in a long-term assessment (24 weeks) that demonstrated long-term efficacy and an absence of serious adverse effects related to mirtazapine [63] . Davidson et al. reported a double-blind, placebo-controlled study of mirtazapine for noncombat-related PTSD, finding a response rate of 67% for the active drug compared with 20% for the placebo [64] . In 2002, Lewis published empirical observations of the effectiveness of mirtazapine in the amelioration of nightmares and associated insomnia in a population of refugee patients with PTSD, reporting mitigation of nightmares in approximately 75% of the large cohort  [65] . Another study compared the utility of mirtazapine and sertraline for the management of combat-related PTSD, discovering that both drugs were effective and well-tolerated for the management of PTSD in Korean veterans [66] . Adverse effects with mirtazapine include sedation, constipation and weight gain. As mirtazapine has a different mechanism of action from the SSRIs and as some experts hold the view that the SSRIs may be relatively less helpful for combat-related PTSD than for noncombat-related PTSD, exploration of alternative pharmacological treatment approaches is useful [67,68] . In summary, the current state of evidence suggests that the SSRIs remain as the treatment of first choice for most patients requiring drug therapy for PTSD. Although there currently appears to be little compelling evidence to support the use of any specific SSRI, differences in pharmacokinetic profile, individual tolerability and drug interaction potential may help to guide the selection of the appropriate SSRI for an individual patient. In the event that SSRI therapy has not provided adequate benefit, or where adverse effects or drug interactions mean that SSRI treatment is unsuitable, mirtazapine or venlafaxine can be regarded as reasonable alternatives. Antipsychotics

Research from the late 1980s (before the widespread introduction of antidepressant therapy for PTSD), found that low-dose neuroleptics were prescribed for 16% of a cohort of 105 veterans in one clinic [69] . More recently, Dierperink et al. have compared medications used in the treatment of PTSD at three different clinics specializing in the management of PTSD, finding that the incidence of SSRI use was between 30 and 54%  [70] . Conventional antipsychotics were not prescribed at all in two sites and the prescribing rate at the third site was 4%. By contrast, the prescribing rate for atypical antipsychotics for the three sites was 8, 2 and 4%, respectively [70] . There remains little definitive guidance regarding the real place of the antipsychotic drugs in the management of PTSD. Recent expert opinion advocates a place for these drugs in the management of PTSD, in particular pointing out that the majority of the sparse literature available to date appears to focus upon the use of the atypical agents in the context of combat-related PTSD [71] . 79

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Various recent guidelines for the management of PTSD suggest that antipsychotic drugs have a place in the management of PTSD, albeit not as a first-line treatment [72–74] . These agents are most frequently recommended for patients with symptoms refractory to simpler interventions, or where there is comorbid PTSD and psychosis. Seedat et al. have addressed issues inherent to the diagnosis of PTSD and psychosis, suggesting that there is evidence for a direct link between the two that might provide a basis for a rational role for antipsychotics in this context [75] . These authors point out that hyper-responsiveness of central dopaminergic systems may contribute to both psychosis (paranoia, delusions, hallucinations) and PTSD (hyper­ vigilance, exaggerated startle and agitation), thus the use of antipsychotic drugs appears to be supportable. In a review of the pharmacological treatment of PTSD that focuses upon the use of atypical antipsychotics, Ahearn et al. made a number of salient points [76] . They pointed out that patients affected by PTSD also frequently have other comorbid psychiatric conditions, some of which may have psychotic manifestations. Second, they noted that although the evidence base for the use of conventional antipsychotics is modest, these drugs have been in use for the management of PTSD for many years. They subsequently elaborated on the emerging evidence base for the use of various atypical antipsychotics in the management of PTSD, citing publications that provide support for the use of, or at least further exploration of the role of, olanzapine, risperidone and quetiapine. Although the review also identifies at least one reference to the use of clozapine, most clinicians would agree that this approach is difficult to justify under normal clinical circumstances in view of the particularly severe adverse-effect profile of this drug. In view of significant safety and tolerability advantages, it is understandable that attention has now turned towards the use of the atypical antipsychotics for the management of PTSD. At present, the quality of evidence available to support this approach is probably best for risperidone [77–80] , although there have also been small studies suggesting that olanzapine [81,82] and quetiapine [83,84] may also offer some benefit. Anticonvulsants

A range of different anticonvulsant agents has been examined as possible primary and adjuvant therapy for PTSD, with the rationale for exploring this approach based on the known moodstabilizing, anger/aggression-modulating and antikindling effects of these drugs. Carbamazepine [85,86] and valproate [87,88] were the first agents in this category to receive attention as possible treatments for PTSD and in more recent times, there have been studies suggesting possible roles for lamotrigine [89] and gabapentin [90] , although in both cases, more robust research is needed to validate the initial findings. The possible utility of tiagabine for PTSD was initially described in a case series [91] and was subsequently systematically evaluated by further research. Connor et al. conducted an open-label study with a follow-up double-blind discontinuation phase, observing that tiagabine produced significant benefits in a 80

range of symptom domains [92] . Conversely, a later double-blind, placebo-controlled study did not find that tiagabine provided significant benefit for PTSD and the clinical utility of this agent for PTSD remains unclear [93] . The most promising recent development in the use of anticonvulsant agents for PTSD symptoms is the apparent utility of topiramate. A number of reports of the clinical effects of topiramate for PTSD have emerged in the form of case series, as well as open-label studies in civilian PTSD. Other reports of topiramate in civilian PTSD have also demonstrated efficacy as a treatment for PTSD [94–96] . Tucker et al. examined topiramate for civilian PTSD in a double-blind study that found this agent to produce significant reductions in re-experiencing phenomena [97] . Another double-blind, randomized controlled study compared topiramate with placebo for veterans of the Iran–Iraq war, at a dose of up to 500 mg daily [98] . Subjects treated with topiramate reported significant reductions in intrusive memories, nightmares, flash backs, sleep problems, irritability and anger, and startle reactions compared with those receiving placebo [98] . An additional benefit of topiramate for PTSD is the possible reduction of harmful alcohol use, which has been demonstrated in other contexts [99] . Overall, recent developments relating to the use of anti­ convulsants for the management of PTSD suggest a possible role for some drugs that potentiate the effects of GABA. Agents such as topiramate or lamotrigine should be considered for patients with refractory symptoms that have not responded adequately to first-line agents. At present, no anticonvulsant agent has received marketing approval for use as a treatment for PTSD, thus further research in this area appears to be warranted. Benzodiazepines

In common with other areas where the benzodiazepines have been used, the use of these agents for the management of PTSD symptoms remains controversial. Despite the widespread use of these agents for patients with PTSD, specific evidence for their effectiveness is not available. Early research examining the effects of alprazolam did not reveal a significant benefit for PTSD symptoms [100] and a more recent study of treatment with clonazepam revealed that the effects of this drug upon sleep-related PTSD symptoms were unimpressive [101] . Gelpin et al. theorized that early treatment with high-potency benzodiazepines (alprazolam and clonazepam) for trauma survivors may prevent the subsequent development of PTSD, but the small open-label study that these researchers used to assess this approach failed to demonstrate a benefit [102] . Patients with PTSD are particularly prone to comorbid substance-use disorders and for this reason, particular caution is warranted if the benzo­diazepines are to be used [103] . Interestingly, in contrasting evidence, Kosten et al. found that among patients with PTSD and comorbid substance abuse, the use of benzodiazepines was not associated with adverse effects on health outcomes, but may actually reduce healthcare utilization [104] . Nonetheless, present consensus suggests that benzodiazepines should be avoided for patients with PTSD if possible [8,9,76,105] . Expert Rev. Clin. Pharmacol. 2(1), (2009)

Pharmacotherapy for post‑traumatic stress disorder

Although yet to be systematically evaluated for sleep disturbances associated with PTSD, alternative hypnosedatives such as zopiclone and zolpidem are used [106] , and in view of the lower potential for abuse, tolerance and dependence with these agents  [107,108] , this approach may be more useful than benzodiazepine treatment. For example, Hajak et al. have specifically examined the issue of the potential for dependence on the most popular nonbenzodiazepine hypnosedatives, zolpidem and zopiclone, in a pharmacoepidemiological study [107] . These researchers were able to locate 22 reported cases of zopiclone dependence and comment that, in view of the widespread usage of the drug (including nonprescription status in countries such as Greece and Romania), the risk for dependence and abuse is not only extremely low, but also that the risk is very much lower than for the benzodiazepines  [107] . Hajak et al. also discussed German data that suggest the approximate rate for reporting of zopiclone abuse is in the order of 4.5 cases/10,000 defined daily doses, comparing very favorably with the rate reported for benzodiazepines (106.7 cases/10,000 defined daily doses) [107] . Adrenergic modulators

There is considerable evidence to suggest that noradrenergic mechanisms play a fundamental role in the underlying neurophysiology of PTSD, in particular with respect to disturbances of arousal response and memory function [109–111] . Subsequent research has confirmed that the α-adrenoreceptor antagonist prazosin has a role in the management of PTSD, especially in connection to sleep disturbance and nightmares [112–117] . Kinzie and Leung describe some benefit from the use of clonidine in the management of PTSD among severely traumatized Cambodian refugees [118] , although the poor tolerability profile of this drug has probably contributed to a lack of subsequent investigation of this approach. The β-adrenergic blockers have also been considered as treatment options for PTSD [119,120], with the most interesting recent development in this area being studies that suggest early treatment with propranolol after severe trauma may reduce the likelihood of subsequent development of PTSD [121,122] . At this stage, although preliminary evidence for the use of noradrenergic modulation as a treatment strategy for the management of PTSD appears promising, more research addressing this approach must be undertaken before this treatment option can be advocated for use in routine clinical practice. Conclusion

Although a range of medications have been used for the management of PTSD, results so far have been mixed and there remains an urgent need for further research. Many patients do not achieve full symptom remission with psychological interventions and multiple trials of medication are often needed to ascertain which drug therapy best suits an individual patient. The current international climate of war, civil unrest and terrorism suggests that there will be an ongoing need to find new and effective pharmacological interventions and this will require significant investments from governments, as well as the assistance of the pharmaceutical industry. www.expert-reviews.com

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Expert commentary

A substantial proportion of the research that has been undertaken to assess pharmacological treatments for PTSD has lacked the methodological rigor that proponents of the evidence-based medicine movement would aspire to. Much of the published literature regarding PTSD pharmacotherapy is limited to case reports and descriptive reports of small, open-label studies, whereas large, well-designed and stringently conducted studies are much less common. Although this tends to undermine confidence in the findings of PTSD research, it is important to understand that conducting studies that are very strictly controlled by stringent inclusion and exclusion criteria tends to limit applicability in a real-world setting. For example, the exclusion of patients with significant comorbid substance abuse from PTSD drug treatment trials will imply that the confounding effects of alcohol and illicit substances do not need to be accommodated in the interpretation of the trial results. On the other hand, the reality is that there is a high incidence of substance use among patients with PTSD and thus an observational study of the use of a pharmacological intervention in the context of relatively uncontrolled empirical therapy may, in fact, offer practitioners information that is more practical in the clinical setting. Another problem that clinicians face in the interpretation of the results of PTSD pharmacotherapy studies is that the research currently in the published domain relates almost exclusively to drugs that were developed for other purposes (e.g., drugs for the treatment of depression, psychosis, epilepsy or other illnesses). Although this does not compromise the validity of the information per se, this phenomenon does mean that many of the drugs of clinical interest are relatively late in the patent cycle, implying that sponsor companies may not be commercially motivated to invest in underwriting PTSD research, given that the return on this investment may be compromised by competition from generic competitors. The occurrence of PTSD from different types of traumatic event may respond differently to various forms of therapy. Many researchers and clinicians share a view that combat-related PTSD may be relatively less likely to respond fully to drug therapy and that, for PTSD arising from this type of trauma, it may be necessary to employ pharmacotherapy that incorporates several different drugs with different modes of action. Moreover, the long-term duration of PTSD encountered among many war veterans may contribute to the phenomenon of treatment resistance in this setting, in that the extreme chronicity of symptoms may offer some explanation for the more modest treatment effects observed in some pharmacotherapy trials conducted for patients with combatrelated PTSD. Cultural differences may also play a role in determining the differential response to PTSD treatment; an important issue in the context of the multicultural nature of many societies and the issues surrounding the resettlement of refugees and those who have been involved in wars and other civil unrest. Five-year view

The next 5 years promises both developments and also continuing disappointments in the field of PTSD pharmacotherapy research and treatment. There will probably be further published research 81

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that adds to the body of knowledge regarding the drug treatment of PTSD, although it is difficult to imagine that much of this research will not be affected by the same types of methodological drawbacks as has been the case with previous studies. Even so, promising neurobiological targets for research are emerging, principally relating to serotonergic and noradrenergic neurotransmission, and also the inhibitory neurotransmitter GABA. Perhaps the most promising avenue for investigation in the pharmacotherapy of PTSD is that related to pharmacogenomics: as research in this area unfolds it might be possible to elucidate the influences of genetic variations upon drug therapy response. An exploration of polymorphisms affecting neuronal serotonin transporters or drug metabolism may help to explain the widely recognized interindividual variability in response to drug therapy for PTSD, possibly opening the way for a more targeted approach to drug treatment, implying that it may be possible to enhance the effectiveness of individual patient management and at the same time minimize drug toxicities. Moreover, with a more sophisticated understanding of the pharmacogenomics involved, it may be possible to design more informed approaches to combination pharmacotherapy, tailored to address the symptoms of individual patients. Given the disappointing results in relation to critical-incident debriefing for the prevention of PTSD, another area likely to become an increasing focus of clinical attention is the use of targeted pharmacotherapy in the period soon after exposure to trauma, with the aim being a reduction in the likelihood of an individual progressing to develop PTSD, or possibly aiming to reduce the severity of PTSD symptoms in cases where the condition does develop. The results of initial research with propranolol appear promising [121,122] , although one study failed to demonstrate that the early administration of this drug, or treatment with another potential candidate therapy (gabapentin) offered benefits over placebo [123] . Friedman has recently reviewed the prospect of pharmacotherapy for the prevention of PTSD, suggesting that in the future, drug treatments will be designed to address the unique pattern of psychobiological abnormalities observed in individual patients [124] . Moreover, Friedman suggests that an elucidation of the biological basis for resilience and vulnerability

to the development of PTSD will inform the development of pharmaco­logical prophylaxis for PTSD [124] . The human response to stress has evolved for the preservation of the species and involves the central and peripheral nervous systems, endocrine system and immunological system [124] . The most important contributors to the stress response are the HPA system and the locus coeruleus/ norepinephrine-sympathetic (LC/NE) system, both activated by corticotropin-releasing factor (CRF), and it is thought that many other components of the stress response are also activated by CRF. It is postulated that dysregulation of HPA, LC/NE and immune mechanisms produces secondary abnormalities that persist in chronic PTSD, causing chronic neurohormonal changes and even anatomical remodeling in the brain [124] . During stress, CRF rapidly mobilizes HPA and LC/NE mechanisms but after the stress has passed, recovery of normal function is believed to be mediated through the effects of glucocorticoids, neuropeptide Y and opioids. Those most likely to develop PTSD are the people who produce the most intense HPA and/or LC/NE activation, as well as those who are unable to achieve normal recovery owing to blunted glucocorticoid, neuropeptide Y and/or opioids mobilization [124] . On this basis, Friedman canvasses possible future preventative pharmacotherapy strategies based on CRF antagonists, glucocorticoids, selective opioids agonists and other agents [124] . There is already some evidence to suggest the corticosteroids may exert a protective effect against the development of PTSD in critically ill patients and this approach warrants further systematic assessment [125–128] . Financial & competing interests disclosure

CP Alderman has performed paid consultancies for several pharmaceutical companies, including Janssen-Cilag Pty Ltd, Australia (supplier of topiramate). He has conducted a study of topiramate for the management of posttraumatic stress disorder and this research was undertaken with the financial assistance of Janssen-Cilag Pty Ltd, Australia (Grant TOPAMATPDI2001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Nondrug therapy remains the most effective and appropriate treatment for post-traumatic stress disorder (PTSD) and should be considered in all cases. • Many patients with severe PTSD remain symptomatic despite nonpharmacologic interventions and will require pharmacotherapy. • There is currently insufficient evidence to confirm that drug therapy enhances the effectiveness of nonpharmacological treatment of PTSD, but most expert guidelines advocate the use of this type of approach where indicated clinically. • The selective serotonin reuptake inhibitor antidepressants are the most widely researched and effective drug therapy for PTSD and are regarded as the first-line pharmacotherapy option. • Other antidepressants, such as venlafaxine and mirtazapine, should be considered in cases where the selective serotonin reuptake inhibitors have not been useful due to adverse effects or lack of efficacy. • Antipsychotic medications may be helpful, particularly in cases where there are severe hyperarousal symptoms or psychotic phenomena. • Benzodiazepines are not recommended for routine use as monotherapy in the management of PTSD. • Future approaches may target the neurobiology of PTSD in an attempt to reduce the likelihood of PTSD after traumatic events or to reduce the severity of the symptoms if they do appear.

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Demonstrates the effectiveness of an SSRI for the management of combatrelated PTSD.

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Study that illustrates empirical treatment practices for combat-related PTSD.

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Affiliations •

Christopher P Alderman, B Pharm, FSHP, CGP, BCPP Director of Pharmacy and Senior Clinical Pharmacist (Psychiatry), Repatriation General Hospital, Daw Park, South Australia 5041, Australia and Associate Professor, Pharmacy Practice, Quality Use of Medicines and Pharmacy Research Centre, University of South Australia, South Australia 5041, Australia Tel.: +61 882 751 878 Fax: +61 883 740 225 [email protected]

•

Linda C McCarthy, MBBS, FRANCP, Senior Specialist Psychiatrist, Director, Post-Traumatic Stress Disorder Unit, Repatriation General Hospital, Daw Park, South Australia 5041, Australia

•

Anita C Marwood, BPharm, MClin Pharm, CGP Senior Clinical Pharmacist (Psychiatry), Repatriation General Hospital, Daw Park, South Australia 5041, Australia

Expert Rev. Clin. Pharmacol. 2(1), (2009)