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. 2022 Sep 1;18(9):2291–2312. doi: 10.5664/jcsm.10074

Table 1.

Current nonpharmacologic and pharmacologic treatment recommendations for post–traumatic stress disorder (PTSD).

Modality Therapeutic Agent Indications Benefits Contraindications/Risks Pitfalls Sleep Effects Clinical Trials
Medications Selective serotonin reuptake inhibitors (sertraline, paroxetine) PTSD Improvement in daytime PTSD symptoms

  • 1) Black box warning for suicidal thoughts and behaviors in patients younger than 24 years old

  • 2) Risk for gastrointestinal bleeding with chronic NSAID use

  • 3) Mania in patients with comorbid bipolar disorder

  • 4) Adverse effects to fetus possible in pregnant patients

  • 5) Risk for serotonin syndrome

  • 1) Takes 4–6 weeks to reach full therapeutic effect

  • 2) May induce restless legs syndrome, periodic limb movements, and bruxism, which can disrupt sleep

  • 3) May induce REM sleep without atonia/REM behavior disorder

  • 1) Suppressed REM sleep

  • 2) Increased REM latency
Medications Serotonin norepinephrine reuptake inhibitors (venlafaxine) PTSD Improvement in daytime PTSD symptoms

  • 1) Black box warning for suicidal thoughts and behaviors in patients younger than 24 years old

  • 2) Risk for gastrointestinal bleeding with chronic NSAID use

  • 3) Mania in patients with comorbid bipolar disorder

  • 4) Adverse effects to fetus possible in pregnant patients

  • 5) Risk for serotonin syndrome

  • 1) Takes 4–6 weeks to reach full therapeutic effect

  • 2) May induce restless legs syndrome, periodic limb movements, and bruxism, which can disrupt sleep

  • 3) May induce REM sleep without atonia/REM behavior disorder

  • 1) Suppressed REM sleep

  • 2) Increased REM latency

  • 3) Sleep disruption due to noradrenergic effect
Medications Serotonin antagonist and reuptake inhibitors (trazodone, nefazodone)

  • 1) Depression

  • 2) Off-label use for insomnia

  • 1) Antidepressant effect at high doses

  • 2) Improved sleep continuity at low and high doses

  • 3) May decrease nightmares

  • 1) Hepatotoxicity (nefazodone)

  • 2) Caution in patients at high risk for falls (may cause dizziness, hypotension, or syncope)

 Mixed results on objective measures of sleep disturbance in PTSD

  • 1) Improves sleep quality

  • 2) Decreases latency

  • 3) Increases stage 3 sleep

 NCT03668041
Medications Atypical antipsychotics (quetiapine, olanzapine, risperidone) Off-label use for PTSD associated nightmares and sleep disturbances

  • 1) Reduction in PTSD sleep disturbances correlated with improvements in overall PTSD symptoms

  • 2) Rapidly effective–within 1–4 days of administration, nightmares and sleep disturbances improved

  • 1) QTc prolongation (quetiapine)

  • 2) Hyperprolactinemia (risperidone)

  • 3) Pancreatitis (olanzapine)

  • 4) Orthostatic hypotension

  • 5) Black box warning for suicidal thoughts and behaviors in patients younger than 24 years old

  • 6) Adverse effects to fetus possible in pregnant patients

  • 7) Risk for myocardial infarction

  • 1) May cause daytime sedation

  • 2) Long-term use associated with metabolic dysregulation

  • 3) Long-term use associated with extrapyramidal symptoms

  • 1) Decreased nightmares

  • 2) Decreased sleep latency
Medications α-1 Adrenergic receptor antagonist (prazosin) Off-label use for nocturnal symptoms of PTSD (ie, nightmares and hyperarousal)

  • 1) Improves sleep disturbances in PTSD patients with elevated nocturnal central sympathetic activity

  • 2) Not sedating

 Orthostatic hypotension

  • 1) Might not be effective for PTSD patients without elevated central sympathetic activity

  • 2) Slow titration required in some patients who develop orthostatic hypotension (ie, 1 mg every 4–7 days)

  • 3) Mixed evidence for PTSD-related nightmares

 May improve sleep quality in patients with elevated sympathetic activity NCT03997864
Medications α-2 Adrenergic receptor agonist (clonidine) Off-label use for nocturnal symptoms of PTSD Decreases nightmare frequency and improves PTSD-related sleep disturbances in patients who do not response to prazosin Orthostatic hypotension Suppresses REM sleep

  • 1) Decreases nightmare frequency

  • 2) Improves sleep quality

  • 3) Decreases sleep latency

  • 4) Suppresses REM sleep

 NCT04877093
Medications Benzodiazepine γ-aminobutyric-A receptor agonists

  • 1) Anxiety

  • 2) Sleep onset insomnia (triazolam and temazepam)

  • 3) Sleep maintenance insomnia (temazepam)

 Improves anxiety and insomnia associated with PTSD

  • 1) Abuse, misuse and addiction

  • 2) Dependence and withdrawal

  • 3) Anterograde amnesia

  • 4) Adverse effects to fetus during pregnancy

  • 1) Paradoxical reactions (behavioral disinhibition and aggressive behavior)

  • 2) Unclear impact on memory consolidation and cognitive functions

  • 1) Decreased sleep latency

  • 2) Improved sleep continuity

  • 3) Decreased stage 3 sleep and REM sleep

  • 4) Increased stage 2 sleep and sleep spindles
Medications Non-benzodiazepine Z-drug γ-aminobutyric-A receptor agonists (zolpidem, zopiclone, and eszopiclone) Sleep onset or sleep maintenance insomnia Improved sleep with less risk of abuse and dependence than benzodiazepines

  • 1) Prolonged use at high doses in PTSD is associated with increase of PTSD and poorer health outcomes

  • 2) Contraindicated in patients with a history of parasomnias

  • 3) Caution in patients taking other CNS depressant medications and in the setting of substance dependence (Schedule IV controlled substance)

  • 4) May cause delirium, changes in thinking or behavior, aggression, disinhibition, agitation, anxiety, and worsening of worsening of depression

  • 5) May induce complex sleep behaviors

 Mixed evidence to support use in trauma-exposed populations

  • 1) Decreased sleep latency

  • 2) Improved sleep quality

  • 3) Improved total sleep time

  • 4) Decreased wake after sleep onset
Medications Dual orexin receptor antagonists (suvorexant, lemborexant) Sleep maintenance insomnia Improved sleep with less risk of abuse and dependence than benzodiazepines. Do not suppress REM sleep.

  • 1) Contraindicated in narcolepsy patients

  • 2) Caution prescribing for depressed patients and in the setting of substance dependence (Schedule IV controlled substance)

 No evidence in trauma-exposed populations

  • 1) Improved total sleep time

  • 2) Decreased wake after sleep onset

 NCT02704754, NCT03642028, NCT02849548
Medications Synthetic cannabinoid (nabilone) Experimental use for PTSD and insomnia

  • 1) Improved overall symptom severity of PTSD and reduces the frequency of trauma-related nightmares and increases sleep length

  • 2) May assist with pain-related sleep disturbances; dual action in PTSD patients with chronic pain

  • 3) Rapidly effective

  • 4) Effects sustained to 9 weeks

  • 1) May impair physical or mental abilities, especially when performing tasks which require mental alertness

  • 2) Use with caution in patients with depression, mania, or psychosis; may unmask an underlying mental health condition

  • 3) Risk for dependency

  • 1) Limited evidence in trauma-exposed populations

  • 2) Action on sleep-wake circuit is not well understood

 May promote sleep by activation of cannabinoid type 1 receptors
Medications NMDA (N-methyl-d-aspartic acid) receptor antagonist (ketamine)

  • 1) Off-label use for severe, treatment- resistant depression

  • 2) Experimental use for PTSD and PTSD-related sleep disturbances

  • 1) Rapidly effective

  • 2) Potential dual effect in patients with history of depression and trauma exposure

  • 1) Contraindicated in patients with significant cardiac history

  • 2) Risk for dependence

  • 3) Caution in patients on medications that contribute to respiratory depression

  • 4) Risk for prolonged emergence from anesthesia, including vivid hallucinations and delirium

 Mixed evidence for use in trauma-exposed populations Beneficial effect on mood may be linked to its ability to alter sleep-wake behavior and the amplitude of circadian systems—potentially by modulating expression of circadian rhythm genes254,257 NCT04032301, NCT04889664, NCT04771767
Medication-assisted therapy β-Adrenergic receptor antagonist (propranolol) Experimental use for acute posttrauma treatment to prevent development of PTSD May prevent development of PTSD posttrauma due to administration before or after memory reactivation sessions in the context of exposure-based therapy

  • 1) Hypotension

  • 2) May cause nightmares

 Mixed evidence for use in trauma-exposed populations

  • 1) Suppressed REM sleep at higher doses

  • 2) Decreases melatonin secretion which can precipitate sleep disruptions and contribute to circadian rhythm abnormalities

 NCT03752918
Medication-assisted therapy 3,4 Methylenedioxy methamphetamine (MDMA)–assisted psychotherapy Experimental use for PTSD that targets memory consolidation and fear response which has been associated with improved self-reported sleep

  • 1) MDMA enhances the positive effects of therapy by increasing the ability of the patient to tolerate negative emotions associated with recalling traumatic events

  • 2) Decreases patient drop-out and improves treatment success

  • 1) Contraindicated in patients with significant cardiac history

  • 2) Risk for dependence

  • 3) Reports of suicidal ideation while taking MDMA

  • 4) Risk for anxiety, agitation, hyperactivity, delirium

  • 5) Risk for serotonin syndrome

  • 6) Risk for hepatotoxicity

  • 7) Risk for hyperthermia

 May increase bruxism, anxiety, and jitteriness, which could potentially cause sleep disturbance Improved self-reported sleep
Therapy Cognitive Behavioral Therapy for insomnia Sleep onset or sleep maintenance insomnia Long-term sleep improvements compared to pharmacotherapy alone and improvement of overall PTSD severity Contraindicated in patients with bipolar disorder, epilepsy, and those at high risk for falls.

  • 1) May require longer treatment course to be effective (> 12 weeks)

  • 2) Not a good treatment for patients who do not follow up regularly or have trouble implementing treatment recommendations

 Improved sleep onset latency, WASO, and sleep efficiency
Therapy Brief behavioral therapy for insomnia (BBTi) Sleep onset or sleep maintenance insomnia

  • 1) Manualized therapy designed for medical providers who did not have the time to implement CBTi and is associated with improvement of sleep efficiency both at early and late follow-up

  • 2) Rapidly effective– 4-session treatment module that focuses on stimulus control and sleep restriction

 Contraindicated in patients with bipolar disorder, epilepsy, and those at high risk for falls. No evidence for trauma-exposed populations

  • 1) Improved sleep onset latency

  • 2) Decreased wake after sleep onset

  • 3) Improved sleep efficiency
Therapy Imagery rehearsal therapy (IRT) PTSD-related nightmares

  • 1) Improvement of nightmares and nighttime hyperarousal through imagery rescripting and imaginal exposure, systematic desensitization, and progressive muscle

  • 2) Rapidly effective–within 1–4 sessions

 Contraindicated in patients with cognitive deficits, severe mental illness, and high levels of anxiety, stress, or avoidance Limited evidence for use in acute stress disorder Decreased nightmares and hyperarousal leading to improved sleep outcomes
Therapy Prolonged exposure (PE) therapy PTSD and ASD

  • 1) Cognitive therapy for PTSD that when implemented early for the treatment of ASD patients reduced the likelihood of later developing PTSD

  • 2) Rapidly effective– treatment within 12 hours of trauma exposure reduces symptom severity at 4 weeks and 12 weeks after trauma

 Contraindicated if imminent threat of suicidal or homicidal behavior, recent (past 3 months) serious self-injurious behavior, and current psychosis

  • 1) Mixed evidence for use for trauma-related sleep disturbances

  • 2) Preexisting sleep disturbances decrease the efficacy of PE to improve symptoms of PTSD

 Effects on objective measure of sleep are unknown.
Therapy Cognitive processing therapy (CPT) PTSD Cognitive intervention which assists trauma survivors to contextualize and process the highly negative affect surrounding a traumatic event in an adaptive manner Contraindicated in psychotic patients, in the presence of substance dependence, if severe dissociative reactions or panic attacks, if imminent risk of self-harm, and if the patient is in abusive relationship

  • 1) Mixed evidence for use for trauma-related sleep disturbances

  • 2) Hyperarousal may precede improvement in certain PTSD symptom domains which may worsen sleep

  • 3) Requires multiple sessions

 Effects on objective measure of sleep are unknown.
Therapy Eye movement desensitization and reprocessing (EMDR) PTSD Exposure-based psychotherapy that involves the recollection of traumatic events while focusing on external stimuli (lateral eye movements) in order to decouple the emotional saliency from the recall of traumatic events

  • 1) Contraindicated in psychotic patients

  • 2) Avoid use in patients with ocular disorders, particularly those with impaired eye movements

  • 3) Caution in patients with severe dissociative reactions, bipolar disorder, substance abuse, chronic pain or unstable medical disorders, and history of abuse

  • 1) Limited evidence supporting use for trauma-related sleep disturbances

  • 2) Requires multiple sessions

 Effects on objective measure of sleep are unknown.
Therapy Accelerated resolution therapy (ART) PTSD

  • 1) Adapted, condensed form of EMDR for PTSD with large effect sizes for the mean reduction in PCL-5 scores

  • 2) Rapidly effective–1 to 5 treatment sessions

  • 1) Contraindicated in psychotic patients

  • 2) Avoid use in patients with ocular disorders, particularly those with impaired eye movements

  • 3) Caution in patients with severe dissociative reactions, bipolar disorder, substance abuse, chronic pain or unstable medical disorders, and history of abuse

 Limited evidence supporting use for trauma-related sleep disturbances Effects on objective measure of sleep are unknown.
Technologies Transcranial magnetic stimulation (TMS) PTSD Utilizes electromagnetic currents on the skull to improve daytime PTSD symptom severity

  • 1) Increased risks for seizures

  • 2) Contraindicated for implanted metallic hardware, cochlear implants, and electrical devices

  • 3) Caution with unstable general medical disorders

 No evidence for acute stress disorder May improve sleep quality through promoting slow wave sleep and REM sleep and inhibiting a hyperarousal state in the cerebral cortex