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, negative mood and cognitions, 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 pharmacologic 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 of acute stress disorder 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 and psychosocial interventions 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".)

APPROACH TO TREATMENT — Our approach to selecting treatment for adult posttraumatic stress disorder is described separately. (See "Approach to treating posttraumatic stress disorder in adults".)

OVERVIEW — 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.

Response to pharmacologic treatment of posttraumatic stress disorder (PTSD) varies greatly, with few robust individual predictors of response available [1,2]. 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 [3,4].

DRUG CLASSES

Serotonin reuptake inhibitors (SRIs)

Selective serotonin reuptake inhibitors — Selective serotonin reuptake inhibitors (SSRIs) are efficacious in reducing posttraumatic stress disorder (PTSD) symptoms. 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 [CAPS]) and functioning than the group receiving placebo (risk ratio 1.59, 95% CI 1.39-1.82) [5]. An Institute of Medicine panel on the treatment of PTSD observed that these studies were not consistently positive and varied in quality [6].

Serotonin-norepinephrine reuptake inhibitors — Although there are fewer studies assessing the efficacy of serotonin-norepinephrine reuptake inhibitors (SNRIs) for PTSD compared with SSRIs, two randomized trials found venlafaxine extended-release (ER) to be effective in reducing PTSD symptoms compared with placebo [7,8]. 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 with patients receiving placebo (50.9 versus 37.5 percent) [7].

Side effects of SSRIs and SNRIs are reviewed 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".)

Administration — SSRI/SNRIs 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 SRIs are shown in a table (table 1). Although there is not clear evidence of a dose-response relationship for SRIs 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 SRI should be a minimum of six to eight weeks before concluding that the medication has failed.

As examples:

●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.

●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.

Second-generation antipsychotics — Randomized clinical trials provide some evidence of efficacy for second-generation antipsychotics (SGAs) in PTSD as monotherapy or augmenting SRIs. Side effects, including weight gain and other metabolic abnormalities, make SGAs a less desirable option that SRIs. Side effects of SGAs are shown in a table (table 2) and reviewed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

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 [9-11].

As an example, a randomized clinical trial compared quetiapine monotherapy with placebo in 80 United States military veterans with chronic PTSD [9]. 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 CAPS, as well as on the re-experiencing and hyperarousal subscores compared with the placebo group.

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 mean reductions in re-experiencing and hyperarousal subscores that were clinically meaningful in some patients [12].

The trial randomly assigned 247 United States military veterans who responded inadequately to two or more trials with an SSRI or SNRI to receive adjunctive risperidone (up to 4 mg once daily) or placebo [12]. 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 with placebo, or in symptoms of anxiety, depression, or quality of life. Risperidone led to small, mean reductions in re-experiencing and hyperarousal symptoms. Participants receiving risperidone were more likely to experience weight gain, fatigue, somnolence and hypersalivation compared with patients receiving placebo.

Other, smaller trials showed mixed results [13-15]. 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 0.5 mg 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 — In our clinical experience, prazosin appears to reduce overall PTSD symptoms, nightmares, and sleep disturbance in some patients with PTSD. Prazosin use is suggested as monotherapy or particularly as an adjunct to SSRI or SNRI treatment.

Clinical trials have found mixed results for prazosin. Possible reasons for the discrepancies include methodologic differences and heterogeneity in patient populations [16]:

●A meta-analysis of six randomized clinical trials including 240 subjects (mostly military veterans or active-duty service members) with PTSD showed moderate to large effects of prazosin in reducing overall PTSD symptoms and nightmares and improving sleep quality [17].

●In a trial involving 67 active-duty United States Army personnel with PTSD returning from combat deployments from Iraq or Afghanistan, subjects were randomly assigned to treatment with prazosin versus placebo [18]. Prazosin was superior to placebo in reducing nightmares, improving overall sleep quality, and improving overall clinical symptoms. The study was stopped early because of the early benefit observed with prazosin.

●A subsequent randomized trial in 304 veterans with PTSD failed to show benefits of prazosin compared with placebo in alleviating distressing dreams or improving sleep quality [19].

Further research is needed to identify whether specific subgroups of patients with PTSD are uniquely responsive to prazosin.

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 medications 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.

Benzodiazepines — Based on the absence of clear benefit and the possibility of worsening PTSD, we suggest not using benzodiazepines to treat patients with PTSD. Benzodiazepines have not been studied in adequately powered randomized clinical trials in PTSD, yet they are frequently used to treat symptoms of anxiety and hyperarousal [3,4]. Some data suggest that benzodiazepines may impair the therapeutic effects of treatments, such as exposure therapy that rely on extinction learning [20], but further study is needed to confirm this adverse effect.

Additionally, given the high prevalence of comorbid substance use disorder in patients with PTSD, benzodiazepines should be avoided in patients with an active substance use disorder or a history of a benzodiazepine use disorder or alcohol use disorder. (See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis", section on 'Co-occurring conditions'.)

All patients prescribed benzodiazepines for PTSD should be monitored for signs of misuse or abuse. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Sedatives-hypnotics'.)

Other medications — At present research evidence is insufficient to recommend other medications for routine use in PTSD:

●Other antidepressants – There is insufficient evidence of effectiveness of antidepressants other than SSRI/SNRIs in PTSD, including tricyclic antidepressants, monoamine oxidase inhibitors, serotonin modulators (eg, trazodone), or atypical antidepressants (eg, mirtazapine) [21-23].

●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 [24].

Treatment of PTSD with beta-blockers combined with trauma memory reactivation therapy is reviewed below. (See 'Propranolol and trauma memory reactivation' below.)

●Mood stabilizers – Anticonvulsant medications with mood-stabilizing properties in other psychiatric disorders have insufficiently tested in clinical trials for their ability to reduce PTSD symptoms. Few adequately powered, randomized trials have been conducted, and findings have been mostly negative [1].

•Tiagabine – A 12-week trial of 232 patients with PTSD found that tiagabine did not differ from placebo in reducing PTSD symptoms [25].

•Topiramate – Multiple small, randomized trials have yielded mixed results [26-28]. 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 CAPS [26]. A seven-week study of 40 inpatients with PTSD found no difference between topiramate and placebo added to ongoing treatment [27].

•Divalproex – Two negative trials compared divalproex to placebo, one with 85 United States military veterans with PTSD and the other with 29 civilian patients with PTSD [29,30].

●Ketamine – Ketamine, an N-methyl-D-aspartic acid antagonist used as an anesthetic and under study in depression, has been shown to reduce PTSD symptoms in preliminary clinical trials [31,32]. In one trial, 30 patients were randomly assigned to receive either ketamine (0.5 mg/kg) or psychoactive control, midazolam (0.045 mg/kg), over two consecutive weeks [32]. The ketamine group showed greater improvement in PTSD symptom severity versus placebo group at both the week 1 measurement and the week 2 endpoint (estimated difference in CAPS-5: 8.8 at week 1; 11.9 at endpoint). In addition, significantly more participants in the ketamine group had a meaningful treatment response compared with those in the control group (67 versus 20 percent). Ketamine infusions were well-tolerated overall without serious adverse effects. (See "Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects".)

●Riluzole augmentation – In a trial of 74 veterans with combat-related PTSD, individuals refractory to SSRI or SNRI were randomly assigned to riluzole (which modulates glutamatergic function) versus placebo augmentation [33]. Riluzole improved hyperarousal symptoms as measured by PTSD Checklist-Specific subscale versus placebo but did not improve overall PTSD symptoms. Further study of riluzole and other glutamatergic modulators is warranted.

●Cannabis and synthetic cannabinoids – With the passage of legislation legalizing use of medical cannabis in many states in the United States and other countries, some researchers have questioned whether cannabis could be a useful treatment for PTSD [34-36]. A 2017 review that included a summary of open-label and observational trials of cannabis for PTSD noted that cannabis use is associated with worse treatment outcomes in some naturalistic studies and concluded that “known risks of marijuana thus currently outweigh unknown benefits for PTSD” [34].

A trial of the synthetic cannabinoid, nabilone, in 10 patients with difficult-to-treat PTSD found that it was helpful for some patients [37]; replication in a larger trial is needed before this treatment can be recommended. More broadly, a role for specific components of cannabis (eg, cannabidiol versus tetrahydrocannabinol) or other cannabinoids (synthetic and naturally occurring) in the treatment of PTSD remains to be determined with further research.

DURATION OF TREATMENT — 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 posttraumatic stress disorder 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) [38].

DRUG AUGMENTATION OF PSYCHOTHERAPY — Based on our clinical experience, augmentation of an evidence-based psychotherapy for posttraumatic stress disorder (PTSD) with a serotonin reuptake inhibitor (SRI) (or augmentation of an SRI with psychotherapy) can help some patients who do not respond adequately to either modality as monotherapy. Clinical trials have provided little direct support for this strategy [39,40].

SSRI/SNRI antidepressants — Clinical trials have not found the combination of a selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) and cognitive-behavioral therapy (CBT) to lead to greater 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 (two trials) and to an SSRI alone (two trials) [39]. 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. Clinical trials have not found combined treatment to be superior to SRIs or CBT as monotherapy [39-43]. As examples:

●Eighty-eight patients with PTSD who were initially treated with sertraline for 10 weeks and did not achieve a full response [41] were randomly assigned to continue to receive 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.

●Seventy-eight patients with PTSD who were initially treated with eight sessions of prolonged exposure and experienced a partial response [42] were randomly assigned to continued prolonged exposure with either controlled-release paroxetine or placebo. No difference was seen between the two groups.

●Two hundred twenty-three patients with combat-related PTSD were randomized to receive up to 13 sessions of prolonged exposure plus placebo pills, sertraline with enhanced medication management, or the combination of prolonged exposure and sertraline, with outcomes assessed by blinded raters at 24 weeks. No difference in change in PTSD symptoms or symptom severity at 24 weeks was found between sertraline plus enhanced medication management, prolonged exposure therapy plus placebo, and prolonged exposure therapy plus sertraline [43].

Dosing, side effects, and administration of SRIs are reviewed above. (See 'Serotonin reuptake inhibitors (SRIs)' above.)

Investigational treatments

Propranolol and trauma memory reactivation — Although research on the combination of propranolol and trauma memory reactivation are promising, it is too preliminary to recommend the use of this approach to treatment of PTSD. A 2018 randomized clinical trial found that trauma memory reactivation preceded by treatment with propranolol demonstrated an advantage compared with placebo-pretreatment of trauma memory reactivation in reducing PTSD symptoms [44]. Sixty-one patients were randomly assigned to receive propranolol (combination of short-acting propranolol [0.67 mg/kg] and long-acting propranolol [1.0 mg/kg]) or placebo administered one hour prior to reading of a personalized trauma script written by the patient at his/her first session; this was repeated weekly for six weeks. Patients randomized to the propranolol arm had a significantly larger reduction in PTSD symptoms (as measured by the Clinician Administered PTSD Scale) compared with those randomized to placebo.

D-cycloserine — Augmentation of exposure in PTSD with D-cycloserine, an N-methyl-D-aspartic acid partial agonist, has not shown an effect on overall PTSD symptoms [20,45]. D-cycloserine, has shown some promise for augmentation of exposure therapy for anxiety disorders [46]. The drug facilitates extinction of conditioned fear in animal models. A 2017 meta-analysis shows, on average, only a small (and not clearly of clinical relevance) augmentation effect on exposure-based therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders [47].

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 [20].

3,4 methylenedioxymethamphetamine (MDMA) — MDMA, the recreational drug also known as ecstasy, may be effective in the treatment of severe PTSD when combined with psychotherapy. From a practical standpoint, the legal status of MDMA prevents clinical use outside of clinical trials. Nevertheless, encouraging preliminary data indicate that further study into its potential role is warranted.

In a trial including 90 individuals with severe PTSD, MDMA with manualized psychotherapy was associated with improved symptoms of PTSD and reduced functional impairment greater than psychotherapy and placebo [48]. Therapy was conducted in accordance with the MDMA-assisted therapy treatment manual. The protocol called for three 90-minute preparatory sessions focused on establishing a therapeutic alliance and providing guidance on responding to memories. Individuals who were eligible to continue the protocol received three 8-hour sessions consisting of MDMA administration with MDMA-assisted psychotherapy administered by a trained therapist in accordance with the manual. At 18 weeks of treatment, the mean improvements in the Clinician-Administered PTSD scale for DSM-5 (CAPS-5), a 30-item symptom scale (120 total points) was 24 points in the treatment group and 14 in the placebo group. Additionally, there was a slightly greater decline in measures of functional impairment in the treatment group versus the placebo group. A greater percentage of individuals in the treatment group no longer met the diagnostic criteria for PTSD than individuals in the placebo group (67 versus 32 percent). MDMA was as effective in individuals with comorbidities (depression, alcohol, or substance use disorder) as in individuals without comorbidities. This effect was not modulated by type of PTSD (dissociative versus non-dissociative) or severe childhood trauma. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation.

PROCEDURES — Stellate ganglion blockade, which involves injection of local anesthetic into the stellate ganglion of the sympathetic chain in the neck, has not shown evidence of efficacy in a randomized clinical trial [49]. The trial of 42 military service members with posttraumatic stress disorder (PTSD) compared an injection blocking the stellate ganglion with sham injection. Participants were reassessed after one week, one month, and three months. Reduction of PTSD (as well as anxiety and depressive) symptoms was seen in both the actively treated and placebo groups and did not differ between them (9.6 versus 10.3 points on the clinician administered PTSD scale).

Differences in symptom reduction were also not seen in control-group patients who crossed over to receive active treatment after sham treatment. Patients who received a second active injection following nonresponse to the first showed a trend toward improvement on one of two PTSD rating scales compared with placebo, but this change was not statistically significant. No differences were seen in complication rates between active and control groups.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Trauma-related psychiatric disorders in adults".)

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 5^th to 6^th 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 10^th to 12^th 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 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 education: Post-traumatic stress disorder (The Basics)")

SUMMARY

●Our approach to selecting treatment for adult posttraumatic stress disorder (PTSD) is reviewed separately. (See "Approach to treating posttraumatic stress disorder in adults".)

●Drug therapies for PTSD have generally been most effective in decreasing hyperarousal and mood symptoms (irritability, anger, depression), 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. (See 'Overview' above.)

●Serotonin reuptake inhibitors (SRIs), including selective serotonin reuptake inhibitors and venlafaxine, a serotonin-norepinephrine reuptake inhibitor, are efficacious in reducing PTSD symptoms. If effective, the medications should be continued for at least six months to a year to prevent relapse or recurrence. Side effects of SRIs are reviewed separately. (See 'Serotonin reuptake inhibitors (SRIs)' above and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects" and "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology, administration, and side effects" and "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management".)

●Randomized clinical trials provide some evidence of efficacy for second-generation antipsychotics in PTSD as monotherapy or augmenting SRIs. Side effects, including weight gain and other metabolic abnormalities (table 2), make second-generation antipsychotics a less desirable option than SRIs. (See 'Second-generation antipsychotics' above and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

●In our clinical experience, prazosin appears to reduce overall PTSD symptoms, nightmares, and sleep disturbance in some patients with PTSD, either as monotherapy or as an adjunct to SRI treatment. Clinical trials have found mixed results on the efficacy of prazosin. (See 'Alpha-adrenergic receptor blockers' above.)

●Benzodiazepines have not been tested in adequately powered randomized clinical trials in PTSD, yet they are frequently used to treat anxiety and hyperarousal. Benzodiazepines may impair the therapeutic effects of treatments such as exposure therapy that rely on extinction learning. All patients prescribed benzodiazepines for PTSD should be monitored for signs of misuse or abuse. Benzodiazepines should be avoided in patients with an active substance use disorder or a history of a benzodiazepine use disorder or alcohol use disorder. (See 'Benzodiazepines' above.)

●Data are insufficient to support use of other agents such as anticonvulsants, D-cycloserine, ketamine, or cannabis for PTSD. Preliminary evidence suggests a potential benefit with 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy for severe PTSD, but the legal status of MDMA prevents clinical use outside trials. (See '3,4 methylenedioxymethamphetamine (MDMA)' above.)

●Based on our clinical experience, the combination of trauma-focused psychotherapy that includes exposure and an SRI can help some patients who do not respond adequately to either modality as monotherapy, even though clinical trials have provided little direct support for this strategy. (See 'Drug augmentation of psychotherapy' above.)