Pharmacotherapy for posttraumatic stress disorder

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Official reprint from UpToDate www.uptodate.com 2013 UpToDate

Pharmacotherapy for posttraumatic stress disorder Author Murray B Stein, MD, MPH Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2013. | This topic last updated: Out 4, 2013. INTRODUCTION Posttraumatic stress disorder (PTSD) is a severe, often chronic and disabling disorder, which develops in some persons following exposure to a traumatic event involving actual or threatened injury to themselves or others. PTSD is characterized by intrusive thoughts, nightmares and flashbacks of past traumatic events, avoidance of reminders of trauma, hypervigilance, and sleep disturbance, all of which lead to considerable social, occupational, and interpersonal dysfunction. Effective treatments for PTSD include medications and psychotherapies. However, a substantial proportion of patients have symptoms resistant to treatment. It is often necessary to switch or combine treatments to achieve a satisfactory therapeutic response. The pharmacological treatment of PTSD is addressed in this topic. The epidemiology, pathophysiology, clinical manifestations, and diagnosis of PTSD are discussed separately, as is psychotherapy for PTSD. The epidemiology, pathophysiology, clinical manifestations, diagnosis, and treatment of acute stress disorder are also discussed separately. (See "Posttraumatic stress disorder: Epidemiology, pathophysiology, clinical manifestations, course, and diagnosis" and "Psychotherapy for posttraumatic stress disorder" and "Acute stress disorder: Epidemiology, clinical manifestations, and diagnosis" and "Treatment of acute stress disorder".) PHARMACOTHERAPY Treatment should optimally be initiated shortly after diagnosis. The diagnosis of PTSD is made after persistence of symptoms for at least four weeks following the trauma, but most patients present for treatment many months, or sometimes years, later. In theory, early treatment of PTSD may prevent chronicity, but this not been shown empirically, particularly for pharmacotherapy [1]. The therapeutic goals of pharmacologic therapy are to decrease intrusive thoughts and images, phobic avoidance, pathological hyperarousal, hypervigilance, irritability and anger, and depression. Drug therapies have generally been most effective in decreasing hyperarousal and mood (irritability, anger, depression) symptoms, and somewhat less effective for the symptoms of re-experiencing, emotional numbing, and behavioral avoidance, but individual differences in response generally outweigh treatment-specific differences. There is a great deal of variation in response to pharmacologic treatment, with few robust individual predictors of response available [2,3]. Some ancillary symptoms of PTSD, such as sleep disturbance, can be particularly difficult to treat, and are among the symptoms that result in the use of polypharmacy that is so common in the treatment of PTSD [4,5]. Selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) are first-line medications for the treatment of PTSD. In a meta-analysis of seven randomized trials, patients treated with SSRIs were more likely to experience improvement in symptoms (on the Clinician Administered PTSD Scale or CAPS) and functioning than the group receiving placebo (RR 1.59, 95% CI 1.39 to 1.82) [6]. An Institute of Medicine panel on the treatment of PTSD observed that these studies were not consistently positive and varied in quality [7]. Administration SSRIs are typically started at the low end of their therapeutic range and titrated up gradually until response is achieved. Usual starting doses, low starting doses, and therapeutic dose ranges for commonly used SSRIs are shown in a table (table 1). Although there is not clear evidence of a dose-response relationship for SSRIs in PTSD, it is common practice to push the dose to the very high end of the therapeutic range (to the extent that this is tolerated by the patient) before concluding that a therapeutic trial has failed. Duration of a therapeutic trial of an SSRI should be a minimum of six to eight weeks before concluding that the Section Editor Peter P Roy-Byrne, MD Deputy Editor Richard Hermann, MD

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medication has failed. As an example, paroxetine can be started at 20 mg/day orally. If minimal or no clinical response is seen after three to four weeks, increased doses in 10 to 20 mg/day increments can be tried, up to 60 mg/day. Side effects of SSRIs are discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Side effects' and "Sexual dysfunction associated with selective serotonin reuptake inhibitor (SSRI) antidepressants: Management".) Serotonin-norepinephrine reuptake inhibitors Although there are fewer studies assessing the efficacy of serotonin-norepinephrine reuptake inhibitors (SNRIs) than SSRIs in PTSD, two randomized trials found venlafaxine extended-release (ER) to be more effective in reducing PTSD symptoms than placebo [8,9]. As an example, 329 adults with PTSD were randomly assigned to receive venlafaxine ER or placebo for 24 weeks. Patients receiving venlafaxine ER were more likely to experience remission of PTSD symptoms compared to patients receiving placebo (50.9 versus 37.5 percent) (table 1) [8]. (See "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology, administration, and side effects".) Other antidepressants There is insufficient evidence of the effectiveness of tricyclic antidepressants (TCAs), monoamine oxidase inhibitor (MAOIs), or atypical antidepressants (eg, trazodone, mirtazapine) for PTSD. (See "Monoamine oxidase inhibitors (MAOIs) for treating depressed adults".) Atypical antipsychotics The overall evidence from clinical trials does not support the use of atypical antipsychotics to augment SSRIs or SNRIs in the treatment of PTSD in military veterans [10,11]. There are fewer, and only smaller, trials in the non-military population, which have shown mixed findings. Based on the absence of other medications that effectively treat patients with persistent PTSD symptoms following SSRI/SNRI treatment, the limited trials available on atypical antipsychotics in this population, and our clinical experience that some patients appear to benefit from these agents, we suggest adjunctive use of an atypical antipsychotic for PTSD symptoms resistant to SSRIs/SNRIs. In the largest trial to date, 247 US military veterans who responded inadequately to two or more trials with an SSRI or SNRI were randomly assigned to adjunctive risperidone (up to 4 mg once daily) or placebo [10]. Patients continued to receive other medication and psychosocial interventions for PTSD. After six months, no meaningful difference was seen in overall CAPS score (the primary outcome) compared to placebo, or in symptoms of anxiety, depression, or quality of life. Risperidone led to small, statistically significant mean reductions of uncertain clinical significance in reexperiencing and hyperarousal symptoms. Participants receiving risperidone were more likely to experience weight gain, fatigue, somnolence and hypersalivation compared to patients receiving placebo. Earlier, small trials (involving a total of 134 military veterans) had found adjunctive treatment of PTSD with risperidone or olanzapine to reduce PTSD symptoms compared to placebo [11]. The findings from the relatively large risperidone trial cannot be generalized beyond that studys focus on PTSD in an overwhelmingly male (96.6 percent) sample of military veterans [10]. There is much less data on the efficacy of the medication in civilians with PTSD, the majority of whom are female, and have experienced more varied types of trauma. Two small trials of adjunctive atypical antipsychotics for PTSD in civilian samples have shown mixed results [12-14]. An eight-week trial of 21 female patients found treatment with risperidone augmenting current antidepressant or anxiolytic treatment led to a greater reduction of PTSD symptoms compared to placebo [12]. An eight-week trial of 25 SSRI-resistant patients, mostly female, found no difference between risperidone and placebo in augmentation of sertraline in the reduction of PTSD symptoms [14]. Two small trials have found atypical antipsychotics as monotherapy to decrease PTSD symptoms in civilian samples. An eight-week trial compared olanzapine monotherapy to placebo in 28 female and male adults [15]. 2 de 6 02/12/2013 05:07

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Patients treated with olanzapine experienced greater improvement in PTSD symptoms than patients receiving placebo. Six of 14 patients in the olanzapine group experienced weight gain ranging from 13 to 22 pounds. A ten-week trial of 20 female patients found treatment with risperidone monotherapy led to a greater reduction of PTSD symptoms compared to placebo [13]. Administration As an example, start risperidone at 0.5mg orally, increase after five to seven days if the response is inadequate up to 4 mg/day. If no clinical benefit is seen after two to three weeks of treatment at the maximal tolerated dose, gradually discontinue the medication. Alpha-adrenergic receptor blockers In four clinical trials with a total of 124 patients with PTSD, prazosin has been shown to reduce nightmares and improve sleep [16-19]. As an example, 67 active-duty military personnel with PTSD were randomly assigned to receive prazosin or placebo in a 15-week trial; some patients were also taking SSRIs [19]. Patients receiving prazosin reported a greater improvement in nightmares, sleep quality, and PTSD symptoms compared to patients receiving placebo. A greater proportion of patients on prazosin were assessed as markedly or moderately improved compared to those on placebo (64 versus 27 percent). Prazosin is typically started at 1 mg at bedtime and is gradually increased to 3 to 10 mg as tolerated. Hypotensive patients or those prone to orthostatic hypotension (eg, due to being on other meds that can cause this) should be treated cautiously. Sudden discontinuation of prazosin must be avoided, as this can result in rebound hypertension; patients should be cautioned accordingly. Some experience with atypical antipsychotics and prazosin for PTSD suggests that prazosin may be preferred on the basis of its efficacy and tolerability [20]. Prazosin is often used adjunctively with SSRIs, though it may be considered as monotherapy. Benzodiazepines Benzodiazepines have been rarely studied in PTSD, yet they are frequently used to treat symptoms of anxiety and hyperarousal [4,5]. Given the high prevalence of comorbid substance abuse in patients with PTSD, benzodiazepines should be avoided in patients with a history of substance use, and all patients should be monitored for signs of abuse of the prescribed drug. Benzodiazepines can be useful to treat acute, severe symptoms of hyperarousal during an emergent situation, eg, in an emergency department. However, there is no evidence to support continued use after the acute situation has subsided. Mood stabilizers Anticonvulsant medications with mood-stabilizing properties in other psychiatric disorders have been studied for a potential effect on impulsive behavior, hyperarousal, and flashbacks in patients with PTSD, but findings have been mostly negative [2]. Few adequately powered, randomized trials have been conducted. A 12-week trial of 232 patients with PTSD found that tiagabine did not differ from placebo in reducing PTSD symptoms [21]. A 12-week trial of 38 patients with non-combat-related PTSD found no difference between topiramate and placebo on the total score on the Clinician Administered PTSD Scale [22]. A 7-week study of 40 inpatients with PTSD found no difference between topiramate and placebo added to ongoing treatment [23]. Two negative trials compared divalproex to placebo, one with 85 US military veterans with PTSD and the other with 29 civilian patients with PTSD [24,25]. Duration If effective, medication should be continued for at least six months to a year to prevent relapse or recurrence. A clinical trial randomly assigned 96 patients with PTSD who had completed 12 weeks of acute treatment with sertraline to either 28 weeks of maintenance treatment with sertraline or to placebo. Patients who continued sertraline were less likely to relapse than patients receiving placebo (5 versus 26 percent) [26]. COMPARING PHARMACOTHERAPY AND PSYCHOTHERAPY There are no placebo-controlled, randomized trials comparing SSRIs to psychotherapy for PTSD. Patients with PTSD were included in an early intervention trial comparing CBT and an SSRI to prevent development of chronic PTSD [27], but results of the study did not distinguish between patients who had experienced PTSD symptoms for more than 30 days and those who did not. (See 'Prevention' below.) COMBINING PHARMACOTHERAPY AND PSYCHOTHERAPY

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SSRI antidepressants Based on our clinical experience, we suggest combined treatment with an antidepressant (an SSRI or SNRI) and CBT that includes exposure for patients who do not respond adequately to either modality individually [28]. If no response is seen following an adequate trial with the initial modality, substitution with the second modality is a reasonable approach. Limited clinical research has not found the combination of an SSRI/SNRI and CBT to lead to greater sustained improvement than either modality alone. A systematic review identified four trials with a total of 122 patients comparing combined CBT/SSRI for PTSD to CBT alone (2 trials) and to an SSRI alone (2 trials) [28]. Three of the four trials enrolled patients who had not responded to an SSRI, while the fourth trial studied patients independent of their prior treatment status. Results of the trials did not find combined treatment to result in more improvement than monotherapy. Examples of the trials follow. (See "Psychotherapy for posttraumatic stress disorder".) In a randomized trial, 88 patients with PTSD were initially treated with sertraline for 10 weeks [29]. Those who did not achieve a full response to the medication alone were randomly assigned to continue sertraline alone or sertraline augmented with prolonged exposure for an additional five weeks. No difference in PTSD symptom reduction was seen between the two groups. In a randomized trial, 78 patients with PTSD were initially treated with eight sessions of prolonged exposure [30]. Patients experiencing a partial response were randomly assigned to continued prolonged exposure with either paroxetine CR or placebo. No difference was seen between the two groups. A more recent trial randomly assigned 37 adults with PTSD to either prolonged exposure in combination with paroxetine or prolonged exposure in combination with placebo for 10 weeks [31]. Combined treatment led to greater improvement in PTSD symptoms compared to prolonged exposure alone. No difference between groups was seen in a subset of patients who continued randomized treatment for an additional 12 weeks. D-cycloserine D-cycloserine, an NMDA (N-methyl-D-aspartic acid) partial agonist, has shown some promise for augmentation of exposure therapy for anxiety disorders [32]. The drug facilitates extinction of conditioned fear in animal models. It has shown preliminary evidence of decreasing time to a clinical response to exposure therapy for phobias, social anxiety, panic, and obsessive-compulsive disorder. Clinical trials of D-cycloserine in conjunction with exposure therapy for PTSD are underway. At present, there is no evidence to recommend the use of D-cycloserine in the treatment of PTSD. Stepped care in trauma surgery center A barrier to accessing PTSD care is that comprehensive treatment is not typically provided outside of mental health specialty settings. A randomized trial tested a stepped-care intervention for PTSD symptoms in patients hospitalized for acute physical injuries in a trauma surgery center [33]. Two hundred and seven patients with high levels of PTSD symptoms were randomly assigned to receive stepped care, consisting of care management, cognitive behavioral therapy, and medication management, or usual care. Treatment for PTSD symptoms was continued in the outpatient surgery clinic and by telephone following hospital discharge. Patients assigned to stepped care experienced reduced PTSD symptoms compared to patients receiving usual care at 6 and 12 months follow-up assessment. PREVENTION There is little evidence supporting the use of pharmacologic interventions in the aftermath of traumatic events to prevent PTSD. (See "Treatment of acute stress disorder", section on 'Other medications'.) A randomized trial that used an equipoise-stratified design had one stratum that included 46 individuals who met PTSD criteria an average of a month following exposure to a traumatic event, and accepted randomization to five months of escitalopram or placebo [27]. In this small, underpowered stratum, escitalopram was not superior to placebo. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these 4 de 6 02/12/2013 05:07

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topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient information: Post-traumatic stress disorder (The Basics)") SUMMARY AND RECOMMENDATIONS We recommend treatment of PTSD with a trauma-focused cognitive-behavioral therapy (CBT), medication (a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI)), or a combination of both modalities (Grade 1A). (See "Psychotherapy for posttraumatic stress disorder", section on 'Cognitive and behavioral therapies'.) We suggest first-line treatment of PTSD with a trauma-focused CBT over medication ( Grade 2B). An SSRI or SNRI can be used for first-line treatment in patients who prefer medication to psychotherapy, or when CBT is not available (See 'Comparing pharmacotherapy and psychotherapy' above and "Psychotherapy for posttraumatic stress disorder", section on 'Cognitive and behavioral therapies' and 'Selective serotonin reuptake inhibitors' above and 'Serotonin-norepinephrine reuptake inhibitors' above.) As an example, paroxetine can be started at 20 mg/day orally and increased up to 60 mg/day. (See 'Selective serotonin reuptake inhibitors' above.) If effective, we recommend continuing the medication for at least six months to a year to prevent relapse or recurrence (Grade 1B). Based on the absence of other medications that effectively treat patients with persistent PTSD symptoms following SSRI/SNRI treatment, the limited trials available on atypical antipsychotics in this population, and our clinical experience that some patients appear to benefit from these agents, we suggest adjunctive use of an atypical antipsychotic for PTSD symptoms resistant to SSRIs/SNRIs (Grade 2C). (See 'Atypical antipsychotics' above.) As an example, start risperidone at 0.5mg orally, increase after five to seven days if the response is inadequate up to 4 mg/day. If no clinical benefit is seen after two to three weeks of treatment at the maximal tolerated dose, gradually discontinue the medication. We suggest trauma-focused CBT as an adjunctive treatment in patients with PTSD who have only responded partially to an SSRI or SNRI ( Grade 2C). Trauma-focused CBT can replace the SSRI/SNRI in patients who have not responded to an adequate trial of the medication. (See 'Combining pharmacotherapy and psychotherapy' above and "Psychotherapy for posttraumatic stress disorder".) We suggest treatment with prazosin for patients with PTSD who experience sleep disruption or nightmares (Grade 2B). This medication can be used alone or as an adjunct to an SSRI or SNRI. (See 'Alphaadrenergic receptor blockers' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 501 Version 14.0

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Pharmacotherapy for posttraumatic stress disorder

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GRAPHICS SSRI and SNRI oral dosage (adult) for treatment of post-traumatic stress disorder (PTSD)
Usual starting dose, mg
Paroxetine Sertraline Fluvoxamine Fluoxetine Citalopram Escitalopram Venlafaxine (extended-release) 20 50 50 20 20 10 37.5

Low starting dose, mg

5 to 10 12.5 to 25 25 5 10 10 37.5

Therapeutic dose (daily), mg

20 to 60 50 to 200 100 to 300* 20 to 60 20 to 40 20 to 30 37.5 to 300

SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin norepinephrine reuptake inhibitor. * If an immediate release preparation of fluvoxamine is used, dose shown in table should be given in two divided doses. Maximum recommended dose of citalopram is 20 mg for patients >60 years of age, with significant hepatic insufficiency, or taking interacting medications that can increase citalopram levels. See UpToDate topic: "Unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs): Pharmacology, administration and side effects", sections "Citalopram" and "Cardiac". Specific interactions of citalopram with other medications may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.

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