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Pharmacotherapy for posttraumatic stress disorder in adults
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Pharmacotherapy for posttraumatic stress disorder in adults
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Literature review current through: Sep 2017. | This topic last updated: Feb 03, 2017.

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, and diagnosis are also discussed separately. The treatment of acute stress disorder and prevention of the development of PTSD are also reviewed separately. (See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis" and "Psychotherapy for posttraumatic stress disorder in adults" and "Acute stress disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis" and "Treatment of acute stress disorder in adults".)

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 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 (with two to four weeks between dosage increases), up to 60 mg/day. As another example, sertraline can be started at 25 or 50 mg/day orally. If minimal or no clinical response is seen after three to four weeks, increased doses in 25 to 50 mg/day increments can be tried (with two to four weeks between dosage increases), up to 250 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 caused by selective serotonin reuptake inhibitors (SSRIs): 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), serotonin modulators (eg, trazodone), or atypical antidepressants (eg, mirtazapine) for PTSD.

Second-generation antipsychotics — Randomized clinical trials provide limited evidence of efficacy for second-generation antipsychotics (SGAs) in PTSD. Further, well powered trials would be optimal to support their use. We would only use SGAs in patients who experienced a minimal or partial response to an SSRI or SNRI, because of the higher side effect burden of the SGAs. However, based on the absence of other medications proven to be effective and our clinical experience that some patients appear to benefit from these agents, we suggest monotherapy with quetiapine or adjunctive treatment with quetiapine or risperidone.

Efficacy

Monotherapy — Clinical trials have found monotherapy with quetiapine and other SGAs to reduce PTSD symptoms in military and non-military patients compared with placebo; some of the trials studied small samples:

A randomized clinical trial compared quetiapine monotherapy with placebo in 80 US military veterans with chronic PTSD [10]. Quetiapine was started at 25 mg/day and increased to an average of 258 mg/day (range, 50 to 800 mg/day). After 12 weeks, patients treated with quetiapine experienced improvement in overall scores on the Clinician-Administered PTSD Scale as well as on the re-experiencing and hyperarousal subscores compared with the placebo group.

An eight-week trial compared olanzapine monotherapy to placebo in 28 female and male adults [11]. Patients treated with olanzapine experienced greater improvement in PTSD symptoms compared with 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 [12].

Augmentation — The largest randomized trial comparing SGA augmentation with placebo in the treatment of PTSD did not find differences between groups in overall PTSD symptoms, but found small but statistically significant reductions in re-experiencing and hyperarousal subscores [13]:

In a randomized clinical trial, 247 US military veterans who responded inadequately to two or more trials with an SSRI or SNRI were randomly assigned to receive adjunctive risperidone (up to 4 mg once daily) or placebo [13]. 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.

Other, smaller trials showed mixed results:

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 [14].

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 [15].

An eight-week randomized double-blind trial of 19 SSRI-resistant military veterans with combat-related PTSD found treatment with olanzapine augmenting SSRI led to a greater reduction of PTSD symptoms compared with placebo augmenting SSRI [16].

Most of the patients in these studies were treated for combat-related PTSD; it is not clear whether or not the results are generalizable to the civilian population.

Administration — Start risperidone at 0.5mg orally, increase in weekly 0.5 or 1.0 mg increments 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.  

Start quetiapine 25 mg orally, increase one week later if the response is inadequate up to 50 mg/day, and then in weekly 50 mg increments up to 400 mg/day.

Alpha-adrenergic receptor blockers — A metaanalysis and multiple clinical trials have shown that prazosin reduces nightmares and improves sleep in patients with PTSD [17-21]. 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 [20]. 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 15 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. Prazosin is often used adjunctively with SSRIs, though it may be considered as monotherapy.

Beta-adrenergic receptor blockers — Although early reports proposed a potential use for beta-adrenergic blockers such as propranolol in the early prevention or subsequent treatment of PTSD, subsequent studies have not supported this claim, and further research is needed [22].

Benzodiazepines — Benzodiazepines have been rarely studied in PTSD, yet they are frequently used to treat symptoms of anxiety and hyperarousal [4,5]. There are some data to suggest that benzodiazepines may impair the therapeutic effects of treatments such as exposure therapy that rely on extinction learning [23], but further study is needed to confirm this adverse effect. 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.

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.

Tiagabine – A 12-week trial of 232 patients with PTSD found that tiagabine did not differ from placebo in reducing PTSD symptoms [24].

Topiramate – Multiple small randomized trials have yielded mixed results [25-27]. As examples, 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 [25]. A seven-week study of 40 inpatients with PTSD found no difference between topiramate and placebo added to ongoing treatment [26].

Divalproex – Two negative trials compared divalproex to placebo, one with 85 US military veterans with PTSD and the other with 29 civilian patients with PTSD [28,29].

Larger well-powered randomized trials of anticonvulsants for PTSD will be needed before definitive conclusions can be drawn.

Ketamine – A randomized clinical trial suggested that intravenous ketamine can reduce symptoms of PTSD [30]. The trial randomly assigned 41 patients with PTSD to receive a single intravenous infusion of either ketamine (0.5 mg/kg) or the control, midazolam (0.045 mg/kg). Assessed 24 hours after infusion, ketamine was associated with a clinically meaningful reduction in PTSD and depressive symptoms, greater than that experienced by the midazolam group. Ketamine was generally well tolerated. While the results are promising, additional trials are needed to confirm efficacy, safety, and to determine the durability of effect.

Duration — If effective, oral 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) [31].

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 [32], 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.

COMBINING PHARMACOTHERAPY AND PSYCHOTHERAPY

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 [33]. 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) [33]. 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 adults".)

In a randomized trial, 88 patients with PTSD were initially treated with sertraline for 10 weeks [34]. 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 [35]. 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 [36]. 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 [37]. 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, and panic disorder. Clinical trials of D-cycloserine in conjunction with exposure therapy for PTSD have failed to demonstrate a benefit. As an example, a clinical trial compared D-cycloserine (50 mg) augmentation with alprazolam (0.25 mg) or placebo augmentation of virtual reality exposure therapy, delivered over five sessions. No benefit of D-cycloserine was seen in the reduction of PTSD symptoms compared with placebo or alprazolam augmentation of virtual reality exposure therapy” [23].

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 [38]. 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.

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Basics topic (see "Patient education: 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 in adults", section on 'Cognitive and behavioral therapies'.)

We suggest first-line treatment of PTSD with a trauma-focused CBT rather than 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 in adults", 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).

For patients with PTSD who show minimal response to two trials of SSRIs or SNRIs, we suggest second-line treatment with quetiapine as monotherapy (Grade 2C). (See 'Second-generation antipsychotics' above.)

Start quetiapine 25 mg orally, increase one week later if the response is inadequate up to 50 mg/day, and then in weekly 50 mg increments up to 400 mg/day.

For patients with PTSD who show a partial response to an SSRI or SNRI, we suggest adjunctive treatment with quetiapine or risperidone (Grade 2C). (See 'Second-generation 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.

Patients started on quetiapine, risperidone, or other SGAs should be monitored for common side effects including weight gain, hyperglycemia, or hyperlipidemia. (See 'Second-generation antipsychotics' above.)

For patients with PTSD who achieve a partial clinical response to pharmacotherapy, we suggest trauma-focused CBT as an adjunctive treatment (Grade 2C). Trauma-focused CBT can take the place of medication in patients who have experienced no clinical response. (See 'Combining pharmacotherapy and psychotherapy' above and "Psychotherapy for posttraumatic stress disorder in adults".)

We suggest treatment of sleep disruption or nightmares in patients with PTSD with prazosin (Grade 2B). This medication can be used alone or as an adjunct to an SSRI or SNRI. (See 'Alpha-adrenergic receptor blockers' above.)

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