US Pharm. 2006;11:31-38.

Posttraumatic stress disorder (PTSD) is a severe and chronic condition, with a lifetime prevalence of 1.3% to 7.8% in the general population.1 The three main characteristics and diagnostic criteria for PTSD are symptoms of reexperiencing, numbing and avoidance, and hyperarousal.2 PTSD occurs after an individual experiences, witnesses, or is confronted with a traumatic event. Common examples of traumatic events that can lead to PTSD are war combat, motor vehicle accidents, sexual abuse, violent crimes, terrorist attacks, natural disasters, and a sudden or unexpected loss of a loved one.

Diagnosis and Symptoms
The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) classifies PTSD as an anxiety disorder. The full diagnostic criteria can be found in Table 1. If symptoms last less than three months, the condition is diagnosed as acute PTSD. If symptoms last more than three months, it is considered chronic PTSD.2 About 33% to 50% of PTSD cases will become chronic. The usual onset of symptoms is within six months of the traumatic event; otherwise, it is categorized as PTSD with delayed onset .

Reexperiencing can take on different forms. The patient can have recurrent and intrusive thoughts about the event, suffer nightmares relating to the experience, and act or feel as if the traumatic event was reoccurring. These patients also have psychological and physiological responses to reminders of the traumatic event, such as an anniversary of the event, a news story where a similar event has occurred, or a location similar to where the traumatic event took place. It is not uncommon for war veterans to become psychologically and physiologically distressed when they witness news about ongoing wars.

Persistent symptoms of increased anxiety or hyperarousal are also diagnostic criteria for PTSD. These symptoms can include difficulty with sleep, irritability, outbursts of anger, difficulty concentrating, hypervigilance, and an exaggerated startled response. Patients tend to state that they are always "jumpy" or "on edge."

Patients with PTSD also avoid any reminders of the trauma and appear numb in their mood, making great efforts to avoid thoughts, feelings, conversations, activities, places, or people that they associate with the traumatic event. They may have an inability to recall important parts of the trauma. People with PTSD may become isolated and detached from others, lose interest in activities they used to enjoy, or have a restricted affect.

Symptoms of PTSD due to combat have been described as far back as the American Civil War.3 PTSD became more prevalent after the Vietnam War, with 15% of men and 31% of women who were in combat developing it.4 In more recent wars, such as the Gulf War, there is an estimated prevalence of 5.4% to 12.1%.5

Motor vehicle accidents and sexual abuse are two causes of PTSD that are seen commonly by primary care physicians. It is estimated that 9% people involved in a motor vehicle accident will develop PTSD, making it one of the leading causes of PTSD in the United States.1

Unfortunately, PTSD often goes unrecognized in the primary care setting. One study reviewed 2,975 Israeli patients and found that only 2% of those who met the criteria for PTSD were actually diagnosed with it.6 A better understanding of the causes and symptoms of PTSD would allow these patients to be diagnosed earlier and therefore receive treatment earlier.

One of the problems of treating PTSD is that a large percentage of these patients also have a second psychiatric diagnosis. It is estimated that 79% of women and 88% of men have at least one other psychiatric diagnosis, and 49% of women and 59% of men have at least three psychiatric diagnoses. Among Vietnam War veterans, 98.9% have a second psychiatric diagnosis. These patients also have a higher risk of other mental illnesses, such as social phobia and panic attacks. Alcohol and drug abuse are also common in these patients; 52% of men and 28% of women suffer from alcohol abuse, and 35% of men and 27% of women suffer from concurrent drug abuse.7

Treatment for PTSD
Treatment of PTSD consists of pharmacotherapy to treat symptoms, as well as psychotherapy interventions, such as cognitive behavioral therapy (CBT). A combination of both pharmacologic and psychological treatment is the preferred approach. The goal of treatment is to reduce the frequency and severity of symptoms, improve social functioning, and relieve comorbid psychiatric disorders associated with PTSD, such as depression, anxiety, panic attacks, and bipolar disorder.8

Antidepressants: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line therapy for PTSD, due to treatment guideline recommendations9 and numerous double-blind placebo-controlled trials. Paroxetine and sertraline are the only two antidepressants with an FDA-approved indication for the treatment of PTSD. However, any of the SSRIs are efficacious in its treatment. All other agents discussed below are used off-label for treating the symptoms of PTSD.

In a pooled analysis of three paroxetine placebo-controlled trials, paroxetine was significantly better than placebo in response, remission rates, improvement in sleep disturbances, and a reduction in all three symptom clusters of PTSD.10 Two large placebo-controlled trials were conducted involving a total of 395 patients with a diagnosis of PTSD who took sertraline. In both studies, there was a statistically significant reduction in all three symptom clusters, as measured by the Cli? nician Administered PTSD Scale. The rates of response in the two trials were 53% and 60% for sertraline and 32% and 38% for placebo.11,12 In these two studies, women showed a better response to treatment than men, although this has not been a consistent finding. In addition, Vietnam combat veterans' symptoms tend to be more resistant to treatment. This may be due to the severe and repetitive nature of their trauma. It has also been suggested that veterans receiving a disability pension for PTSD may be reluctant to report improvement, in fear that their benefits would be taken away.13

It may take four to six weeks to see an initial response to treatment. Some cases may require a longer period of time, such as six to nine months, before full benefits are seen from SSRIs. In one study, patients enrolled in a double-blind, 12-week study who were taking sertraline were continued on open-label treatment for 24 more weeks. Fifty-eight percent of the patients categorized as nonresponders at the end of the initial 12-week trial became responders by the end of the 24-week open-label trial. P atients who responded to sertraline treatment in the initial 12 weeks continued to improve with an additional 30% decrease in symptoms.14

The serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine has also been shown to be beneficial in the treatment of PTSD. Davidson et al. conducted a 12-week, double-blind trial of 538 patients taking venlafaxine extended release (XR), sertraline, or placebo.15 Venlafaxine XR did have a statistical significance over placebo in reducing avoidance/numbing and hyperarousal. The improvement in reexperiencing was not significantly better in either treatment group. Remission rates were 30.2% with venlafaxine XR, 24.3% with sertraline, and 19.6% for placebo. However, in overall efficacy and tolerability, venlafaxine XR and sertraline showed similar improvement. This is the only double-blind study of venlafaxine in PTSD, but it shows promise for the SNRIs as a treatment option in PTSD.

The tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have also been used for PTSD. Amitriptyline was compared to placebo in 46 veterans over eight weeks, with modest improvement in remission rates of 36% and 28%, respectively.16 Phenelzine and imipramine were shown to be equally efficacious in overall symptom improvement in a randomized double-blind trial, with 64% and 75% of patients on phenelzine and imipramine showing improvement, respectively.17 Another trial comparing phenelzine, imipramine, and placebo demonstrated a response of 44%, 25%, and 5%, respectively.18 Although both of these drug classes appear to be effective, they are not often used due to their high incidence of side effects and patients' inability to tolerate them. In particular, MAOIs have dietary restrictions and are linked to the risk of hypertensive crisis, while TCAs have anticholinergic and cardiovascular side effects. In a retrospective analysis of veterans with PTSD and major depression, Dow and Kline19 showed that the majority of respondents were treated with SSRIs (23 of 32 patients). Imipramine was the most successful TCA in this analysis (four of 32 patients). Currently, these TCAs and MAOIs are considered as second- or third-line agents restricted for treatment-resistant cases.

Nefazodone has been compared to sertraline in a double-blind trial and shown to be comparable.20 Because of its mechanism of action, nefazodone may have a beneficial effect on sleep-related symptoms of PTSD, such as nightmares.21 However, nefazodone carries a black box warning for hepatotoxicity; therefore, caution should be used when prescribing this agent.

Other antidepressants, such as trazodone, bupropion, and mirtazapine, have limited and inconclusive data in association with PTSD. Their use is currently not recommended.

Overall, SSRIs are considered first-line agents when treating patients with PTSD. Hyperarousal and numbing/avoidance are the PTSD symptoms that respond best to treatment with SSRIs, while reduction in nightmares and reexperiencing symptoms tend to be less treatable. Common side effects with SSRIs include nausea, drowsiness, insomnia, dry mouth, sexual dysfunction, and gastrointestinal distress. If a patient does not respond to SSRI treatment, even after high doses, or cannot tolerate SSRIs, other antidepressants such as venlafaxine, TCAs, or MAOIs can be used. TCAs and MAOIs should not be considered as first-line agents due to their side-effect profile.

Atypical Antipsychotics: Atypical antipsychotics have recently begun to be used in the treatment of PTSD. They appear to be helpful in alleviating the reexperiencing cluster of symptoms. The atypical antipsychotics are not FDA approved for the treatment of PTSD, but they do appear to have a role in cases that are more severe, involve nightmares or flashbacks that have not responded to other treatment, and/or when psychotic symptoms may be present along with PTSD.

Risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole are all linked to data showing benefit in the treatment of PTSD, although none have an FDA indication for such treatment.22-28 Monnelly et al.23 treated patients with risperidone, and improvement was seen in nightmares, intrusive thoughts, irritability, and total PTSD symptoms. Olanzapine and quetiapine have also resulted in positive outcomes when used as adjunctive therapy to SSRIs. 25,26 A small amount of data suggests that the atypical antipsychotics might even be beneficial as monotherapy in treatment-resistant patients with psychotic features.29

From these studies, it appears that adjunctive therapy with a low-dose atypical antipsychotic may be effective in more resilient cases of PTSD, especially when the patient has reexperiencing or psychotic symptoms that have had partial or no response to treatment with SSRIs. If used, they are recommended as adjunctive therapy to antidepressants. However, the patient should be informed of the possible side effects associated with this class of medications, including hyperglycemia, weight gain, increased appetite, lipid abnormalities, and extrapyramidal symptoms. The association between atypical antipsychotics and metabolic syndrome is well documented in the medical literature. The Consensus Statement published by the American Diabetes Association contains information regarding these risks and appropriate monitoring for patients.30

Benzodiazepines: Benzodiazepines, although a common treatment in anxiety disorders, do not seem to be beneficial in the treatment of PTSD symptoms. It would seem that since benzodiazepines decrease arousal and promote sleep, they may be helpful in PTSD, and although case reports and retrospective chart reviews seem to support this role, double-blinded trials have failed to show their benefit. 31,32 In fact, an open-label trial found that not only are benzodiazepines ineffective for PTSD, but they also may increase the risk of PTSD and depression. Gelpin et al.33 attempted to use benzodiazepines within 18 days of a traumatic event and followed patients for six months. At the end of the study, nine of 13 benzodiazepine-treated patients had developed PTSD versus three of 13 in the control group. In addition, half of the patients in the benzodiazepine group developed depression, compared to none in the control group.

Based on the evidence available, it appears that benzodiazepines are not beneficial in the treatment of PTSD. However, there are mixed results. If a patient has a comorbid illness that may require benzodiazepines, such as panic attacks, then caution should be used.

Adrenergic-Inhibiting Agents: The adrenergic-inhibiting agents are another option in the treatment of PTSD, used best as adjunctive therapy. People with PTSD have been shown to have elevated plasma levels of nor? epinephrine (NE).34 There is also hyperactivity of NE in the brain when exposed to trauma-related stimuli.35 These two theories are the basis for the use of this class of medications. In clinical trials, the alpha-1 receptor antagonist prazosin has been shown to improve nightmares, sleep disturbances, and overall symptoms related to PTSD, when given at night.36 New data suggest that daytime treatment with prazosin may also alleviate symptoms of PTSD, particularly those related to trauma cues.37

Beta-blockers, such as propranolol, are also used in the treatment of PTSD. Unlike the other medications discussed in this article, they are used to try to prevent symptoms of PTSD. It is hypothesized that by blocking postsynaptic NE receptors with beta-blockers, there will be a reduction in hormonally enhanced memories and fear conditioning.35 Two trials showed decreased physiologic response to reminders of trauma and fewer PTSD symptoms when administered within six to 20 hours and maintained for 10 to 20 days.38,39 Although this practice is not done routinely, it could be a method of preventing or lessening the symptoms of PTSD.

Anticonvulsants: Anticonvulsants, or mood stabilizers, can be used for the treatment of bipolar disorder. Although not used frequently in the treatment of PTSD, they may have beneficial effects, particularly when patients have both PTSD and bipolar disorder. Carbamazepine, valproic acid, topiramate, and gabapentin have all been associated with positive data in open-label trials.40-43

Carbamazepine use helped improve PTSD symptoms, including intrusive thoughts, flashbacks, and insomnia in a combat veteran population, which is normally a tough population to treat. 40 Valproic acid improved hyperarousal and avoidance, but not intrusive thoughts.41 Unfortunately, frequent monitoring and high incidence of side effects limit the use of carbamazepine and valproic acid. However, if a patient has comorbid PTSD and bipolar disorder, an anticonvulsant mood stabilizer should be used. In one trial, topiramate helped reduce frequency of nightmares in PTSD patients.42 Gabapentin, when used as adjunct therapy, was found to reduce frequency of nightmares and insomnia.43 Gabapentin is generally well tolerated with mild side effects and thus might be an effective option for adjunctive therapy. It is important to note that none of these trials are double-blind placebo-controlled studies; therefore, more rigorous trials are needed to better identify the role of anticonvulsants in the treatment of PTSD. Lamotrigine is the only anticonvulsant tested in a double-blind placebo-controlled trial.44 In a 12-week trial, lamotrigine improved reexperiencing and avoidance/numbing. However, since this trial had a small sample size, its results should be interpreted carefully.

Treatment options for PTSD include antidepressants, atypical antipsychotics, adrenergic-inhibiting agents, and anticonvulsants (see Table 2). The target symptoms of pharmacologic therapy are hyperarousal, avoidance/numbing, and reexperiencing. SSRIs are considered the first-line treatment option, because these agents are generally well tolerated and have proven efficacy. Sertraline and paroxetine are the only FDA-approved pharmacologic products for the treatment of PTSD. Atypical antipsychotics can be used to reduce reexperiencing and nightmares. They are best used as adjunctive therapy to SSRIs. If patients cannot tolerate the first-line treatment options, other antidepressants, such as venlafaxine, TCAs, and MAOIs, can be used. However, TCAs and MAOIs are associated with numerous side effects. While terazosin, an adrenergic-inhibiting agent, is helpful in reducing sleep-related disorders in PTSD, the beta-blocker propranolol may be beneficial in preventing or reducing PTSD symptoms if given shortly after the trauma. Benzodiazepines should generally be avoided in this patient population unless it is necessary to treat another comorbid disease. The treatment of PTSD is not simple. It may require a long duration of pharmacologic treatment and should include nonpharmacologic treatment, such as CBT or prolonged exposure therapy.


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