Treatment of sleep disturbances in posttraumatic stress disorder: a review.
Article Type: Report
Subject: Cognitive therapy (Health aspects)
Post-traumatic stress disorder (Care and treatment)
Post-traumatic stress disorder (Research)
Sleep disorders (Care and treatment)
Sleep disorders (Research)
Authors: Schoenfeld, Frank B.
DeViva, Jason C.
Manber, Rachel
Pub Date: 05/01/2012
Publication: Name: Journal of Rehabilitation Research & Development Publisher: Department of Veterans Affairs Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 Department of Veterans Affairs ISSN: 0748-7711
Issue: Date: May, 2012 Source Volume: 49 Source Issue: 5
Topic: Event Code: 310 Science & research Canadian Subject Form: Cognitive-behavioural therapy
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 301479264
Full Text: INTRODUCTION

Individuals experiencing posttraumatic stress disorder (PTSD) report insomnia (trouble initiating and maintaining sleep) and recurrent distressing dreams among their most common and distressing symptoms. These sleep disturbances have long been thought to play a central role in PTSD, and research has suggested sleep problems may predict development of PTSD after exposure to trauma. Sleep complaints at 1 month, but not at 1 week, post-trauma are a significant predictor of PTSD at 12 months posttrauma (Koren et al. [1]). Insomnia and nightmares during the first month following a traumatic event predict the development of PTSD, and the absence of these symptoms during this same period of time is a strong predictor of not developing PTSD (Harvey and Bryant [2]). These studies, based upon subjective reports, are supported by polysomnographic evidence that fragmented rapid eye movement (REM) sleep in the first month following a traumatic event is associated with the development of PTSD (Mellman et al. [3]).

"Sleep disruption is reported by 70-87% of people suffering from PTSD with a 48-60% increase in disturbed sleep compared to those who have been traumatized but do not have PTSD" (Maher et al. [4]). Nightmares were reported by 52 percent of veterans with PTSD compared with 5 percent of veterans without PTSD in a nationally representative sample of male Vietnam veterans (Neylan et al. [5]). The presence of nightmares has the strongest correlation with the diagnosis of PTSD, while problems with sleep onset are moderately correlated and difficulties maintaining sleep are weakly correlated with the diagnosis (Neylan et al. [5]). Currently, sleep disturbance is the second most common reason for referrals to mental health services following postdeployment screening of Operation Iraqi Freedom veterans. ** Untreated sleep symptoms can persist for years and intensify daytime PTSD symptoms and associated comorbid psychiatric problems (Germain et al. [6]) and, thus, may contribute to the poor clinical outcomes often observed in PTSD. Because sleep has a restorative function (Horne [7]) and affects emotional regulation (Walker [8]), poor sleep may affect the emotional processing of traumatic experiences (Maher et al. [4]). These factors emphasize the need for effective treatment interventions to minimize the impact sleep disturbance has upon people experiencing PTSD.

Studies using objective sleep measures find, compared with nondisabled control subjects, patients with PTSD have (1) greater REM density (frequency of rapid eye movements, characteristic of a dream state) (Kobayashi et al. [9]); (2) more frequent brief awakenings (less than 1 minute) across all stages of sleep, reflecting hyperarousal and possibly nonrestorative sleep (Breslau et al. [10]); (3) a greater number of shifts from REM to lighter sleep per hour of sleep (Breslau et al. [10]), possibly resulting in nonrestorative sleep; and (4) decreased stage 4 (slow wave) sleep, the most restorative sleep stage (Neylan et al. [11]). A meta-analysis of 20 polysomnographic studies showed PTSD patients had more stage 1 sleep, less slow-wave sleep, and greater REM density than with people without PTSD (Kobayashi et al. [9]). However, polysomnography-based studies yielded inconsistent results with respect to other measures of sleep, such as sleep efficiency (percent of time asleep relative to time in bed), duration of awakenings, body movement during sleep, and time to the first REM episode among individuals with PTSD (Maher et al. [4]). Nonetheless, the extant literature on objectively measured sleep suggests that individuals with PTSD have fragmented and nonrestorative sleep. The findings from objective sleep measures help inform the clinician in selecting treatment modalities that have the capacity to enhance restorative sleep and to normalize the sleep-wake pattern.

The Department of Veterans Affairs (VA) and Department of Defense (DOD) VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress [12] emphasizes the important role nightmares can play in PTSD-related insomnia. Nightmares classically associated with PTSD are characterized by a repetitive replay of the traumatic event. The more exact the replication, the more likely the nightmare will be repeated (Schreuder et al. [13]). Nightmares that replicate the traumatic event are thought to be a form of uncontrolled re-exposure and thus to contribute to the perpetuation of PTSD. Individuals with PTSD nightmares commonly awaken from the nightmare in an aroused emotional and physiological state. Holocaust survivors with significantly lower rates of dream recall when compared with nondisabled age-matched control subjects were rated as well-adjusted, while survivors with similar rates of dream recall to control subjects were less well-adjusted (Kaminer and Lavie [14]). There is an increased risk of suicide for people experiencing nightmares. A Swedish study of suicide attempters found nightmares were associated with a fivefold increase in risk for high suicidality (Sjostrom et al. [15]), and a large epidemiology study from Finland (Tanskanen et al. [16]) revealed a significantly increased risk of suicide for people reporting nightmares compared with those without nightmares. These findings suggest that nightmares play an important role in the perpetuation of PTSD symptoms and that the presence of nightmares can be an indicator of more pronounced psychological dysfunction and distress.

The high frequency of sleep disturbances associated with PTSD and their potential role in the development and course of PTSD highlight the importance of improving sleep among individuals diagnosed with PTSD. In this article, we describe some of the primary sleep disturbances associated with PTSD, with a focus on nightmares and insomnia. We then apply a general model of the development and maintenance of insomnia to PTSD-related sleep disturbance and examine evidence for the use of psychotherapy and pharmacotherapy to improve sleep among individuals diagnosed with PTSD, including those with other comorbidities.

METHODS

Primary-source literature and secondary-source reviews were identified using MEDLINE[R]/PubMed[R] and Published International Literature on Traumatic Stress (PILOTS) databases. No time constraints were used. The searches were conducted between January 2011 and April 2012. The terms PTSD, stress and stress response, sleep disorder, sleep disturbance, and insomnia were cross-referenced with specific areas of inquiry, i.e., veterans, nightmares, cognitive behavioral therapy, imagery rehearsal, polysomnography, physiology, and drug or drug class. The "Discussion" section is based on the results of the studies reviewed, the VA/DOD Clinical Practice Guideline (CPG) for PTSD, the practice guidelines of the American Academy of Sleep Medicine, and the authors' direct professional experience and scientific investigations. Clinical trial outcomes are described in terms of response rates, statistical significance, and/or effect sizes. This review gives greater weight to controlled studies than to open clinical trials. Recommendations for treatment and conclusions are based on the weight of the evidence available in the scientific literature.

DISCUSSION

Treatment of Sleep Disturbances in Posttraumatic Stress Disorder

The optimal treatment interventions for PTSD relieve symptoms in the re-experiencing, avoidant/numbing, and arousal criteria. However, sleep disturbances often persist despite relief or moderation of other symptoms. As many as one-half of positive responders to PTSD treatment continue to have residual sleep disturbance *** (Zayfert and DeViva [17]). It is therefore important to thoroughly assess and treat sleep disturbances experienced by patients with PTSD. PTSD is commonly associated with comorbid disorders such as depression; substance abuse including alcohol, nicotine, and stimulants; anxiety; pain syndrome; and traumatic brain injury (TBI). Each of these conditions can contribute to disturbed sleep and must be taken into account when considering treatment choices. Though research indicates that treatment of sleep disturbance in the presence of comorbid conditions can be effective, the contribution of all comorbid diagnoses to sleep disturbance should be factored into the treatment plan of each individual patient.

Sleep Disorders Associated with Posttraumatic Stress Disorder

Research shows that in addition to nightmares and distress about problems initiating and maintaining sleep (insomnia), patients with PTSD are more likely than the general population to have other sleep disorders. Before initiating treatment of insomnia and nightmares, it is important for providers to evaluate the possibility of other sleep disorders and refer patients to sleep specialists when indicated. We review here three sleep disorders that are common among patients with PTSD patients.

Periodic Limb Movement Disorder

Periodic limb movement disorder (PLMD) is defined as sudden repetitive episodes of leg movement occurring on average 5 or more times per hour of sleep. The leg movements are most frequent during stages 1 and 2 of non-REM sleep. This disorder was found to be more common in Vietnam veterans with PTSD than Vietnam veterans without PTSD (Mellman et al. [18]). Other investigators have also found a high incidence of PLMD in Vietnam veterans (Brown and Boudewyns [19]). The primary agents used to treat PLMD, the direct dopamine (D) agonists, have a 90 percent rate of efficacy in randomized controlled trials (RCTs) (Hening et al. [20]). However, little is known about the effects of D agonists upon patients with PTSD. Gabapentin has been given a class A recommendation for treating PLMD by the European Federation of Neurological Societies, and gabapentin enacarbil, a pro-drug of gabapentin with increased bioavailabilty, significantly reduced periodic limb movements and wake time (Winkelman et al. [21]). Bupropion has been found to be helpful in a small case series (Nofzinger et al. [22]) and may be considered as an alternative when D agonists or gabapentin are contraindicated or not well tolerated. It is important to note that medications frequently used to treat PTSD, such as selective serotonin reuptake inhibitors (SSRIs), venlafaxine (Yang et al. [23]), and tricyclic antidepressants (TCAs) (Cohrs et al. [24]), may induce or worsen PLMD.

Rapid Eye Movement Sleep Behavior Disorder

The International Classification of Sleep Disorders lists the following minimal criteria for the diagnosis of REM Sleep Behavior Disorder (RBD): the presence of REM sleep without atonia on polysomnography and at least one of the following criteria: (1) sleep-related, injurious, potentially injurious, or disruptive behaviors by history (i.e., dream enactment behavior) and/or (2) abnormal REM sleep behavior documented during polysomnographic montoring. RBD is more common in older adults, with a mean age of onset from 50 to 65 years, and can be associated with and may precede neurodegenerative disorders, such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy (Boeve et al. [25]). However, in almost 50 percent of RBD cases, no brain lesion is observed (Olson et al. [26]). Individuals with the onset of RBD at age 50 and younger have a significantly higher frequency of psychiatric diagnoses and antidepressant use compared with non-RBD control subjects (Thomas et al. [27]). Antidepressant use may contribute to the development of RBD. Monoamine oxidase inhibitors (MAOIs) and TCAs have been reported to induce RBD (Thomas et al. [27]), and a systematic polysomnographic study found selective serotonergic reuptake antidepressants and venlafaxine to increase electromyogram tonic activity in REM sleep compared with control subjects (Winkelman and James [28]). It has been proposed that individuals with PTSD have a higher prevalence of RBD (Husain et al. [29]) and that this may contribute to the acting out of dreams sometimes observed in this population (Ross et al. [30]). No RCT of drug treatment for RBD has been reported. Clonazepam was found to be effective in one study with 87 percent complete or partial responders (Olson et al. [26]). However, overall limited evidence exists of the efficacy of benzodiazepines for this disorder. **** Melatonin has "also shown efficacy alone or in combination with clonazepam" (Boeve et al. [31]).

Sleep Disordered Breathing

Obstructive sleep apnea (OSA) is a common form of sleep disordered breathing (SDB), with a prevalence of 3 to 7 percent in men and 2 to 5 percent in women (Lurie [32]). Risks for OSA include obesity, male sex, and older age (Lurie [32]). A VA study of 4,060,504 unique cases identified 118,105 cases of sleep apnea (2.9 percent of the VA sample) (Sharafkhaneh et al. [33]). PTSD was found to be comorbid in 11.9 percent of the sleep apnea patients, while the current prevalence of PTSD in the VA population as a whole is 8.4 percent. However, a large community sample of young adults did not find higher prevalence of SDB in individuals with PTSD compared with control subjects (Breslau et al. [10]). Nonetheless, a conservative approach dictates that SDB be considered during an evaluation of sleep disturbance in PTSD. There is some evidence that successful treatment of SDB can improve PTSD symptoms. A retrospective study of 15 individuals with SDB and PTSD treated with continuous positive airway pressure (CPAP) therapy revealed a 75 percent improvement in nightmares and overall PTSD symptoms (Krakow et al. [34]). A second study found that, although PTSD patients were less likely to adhere to recommendations concerning use of CPAP, patients with PTSD who did adhere to CPAP treatment reported decreased nightmares and improved sleep (El-Solh et al. [35]). A detailed case study of a patient with SDB and PTSD treated with CPAP, with polysomnography to examine sleep architecture, demonstrated normalization of sleep architecture. There was also a dramatic improvement in nightmare frequency and intensity as well as a decreased startle response (Youakim et al. [36]). Our clinical experience suggests that some veterans with OSA do not tolerate CPAP because of association with gas masks and that attention to this issue may enhance adherence.

If any of the previous sleep disorders have been diagnosed, it is recommended that providers first treat that sleep disorder and determine whether the treatment resolves the disorder and the overall sleep disturbance. If, despite this targeted treatment approach, a PTSD-related sleep disturbance (insomnia and/or nightmares) persists, it is recommended that providers proceed by adding a nonpharmacologic treatment for the specific sleep disturbance. Nonpharmacologic treatment is the first-line choice for PTSD-related sleep disturbance and is less likely to aggravate the identified sleep disorder than a pharmacologic approach. If nonpharmacologic treatment is not effective, pharmacologic treatment can be considered. Because certain pharmacologic agents used for the treatment of PTSD can aggravate PLMD and RBD, they need to be used with caution when these conditions co-occur.

Nonpharmacologic Treatments of Insomnia and Nightmares in Posttraumatic Stress Disorder

Traditionally, insomnia symptoms have been conceptualized as part of the overall syndrome of posttraumatic symptoms, and therefore, providers generally presumed that as posttraumatic symptoms improved so too would sleep. However, research indicates that although trauma-focused therapies improve sleep in some cases, sleep problems often do not remit after otherwise successful treatment of posttraumatic symptoms (Belleville et al. [37], Zayfert and DeViva [17]). The simplest explanation for this is based on a well-accepted model of the development and maintenance of insomnia by Spielman and colleagues (Spielman et al. [38]). The Spielman model hypothesizes that individuals differ in their level of predisposition toward developing insomnia (e.g., overall arousability). Precipitating factors, such as environmental stressors or medical conditions, interact with predisposing factors and produce short-term (acute) sleep disturbance. Over time, an individual's responses to disturbed sleep may serve to maintain it, even after the initial precipitants have been diminished or resolved. Examples of such maladaptive responses, referred to in the Spielman model as perpetuating factors, include spending excessive time in bed awake while "trying to sleep" or engaging in nonsleep activities while in bed. Sleep may be impaired further by the development of conditioned relationships between the bed and responses that are incompatible with sleep, such as wakefulness or elevated anxiety (Perlis et al. [39]).

Trauma is often associated with nightmares and leads to high levels of general arousal and/or excessive vigilance at night, all of which can precipitate sleep problems. Trauma that occurs in the bed, bedroom, or darkness may cause a conditioned fear response in the sleep setting, which is incompatible with sleep (Zayfert and DeViva [17]). For example, the experience of nighttime combat during a military deployment or being awoken in the middle of the night during childhood by an abuser may associate the sleep setting with arousal and promote hypervigilance before and during sleep. If individuals with PTSD spend long amounts of time in bed awake, they may re-experience trauma, ruminate, or try to remain vigilant to their environment, all of which are incompatible with sleep and can result in conditioned arousal associated with the sleep environment. Posttraumatic precipitating factors may resolve with successful treatment of PTSD; however, maladaptive sleep-related perpetuating behaviors, such as going to bed very early or napping to "catch up" on lost sleep, may not resolve and may maintain insomnia. It is also possible that standard treatments for PTSD may not sufficiently reduce arousal in the bed or adequately address beliefs about the consequences of poor sleep, and these factors can continue to perpetuate sleep problems. Given the potential effects of perpetuating factors on sleep, it is a realistic possibility that individuals with PTSD who complete and respond well to treatment for PTSD symptoms may still experience poor sleep. Therefore, the next section will examine the effects of trauma-focused and sleep-focused interventions on the sleep of individuals with PTSD.

Trauma-Focused Cognitive-Behavioral Therapy for Posttraumatic Stress Disorder

The VA/DOD CPG [12] and the International Society for Traumatic Stress Studies (Foa et al. [40]) list trauma-focused cognitive-behavioral therapies (CBTs) as first-line options for the treatment of PTSD. The DOD and VA have recently begun national dissemination projects to train large numbers of clinicians in prolonged exposure (PE) therapy and cognitive processing therapy (CPT) for PTSD, and these treatments have become widely available throughout the federal system for Active Duty military and veterans. These treatments contain different combinations of direct engagement with memories of traumatic events (PE through processing after imaginal exposure and CPT through a written account) and challenging of maladaptive beliefs associated with trauma (PE through postimaginal exposure processing and CPT through systematic identification and restructuring of those beliefs). Both PE and CPT have significant empirical support for use in the treatment of PTSD (Foa et al. [40]).

Most studies of CBT for PTSD report treatment effects on overall PTSD symptom levels. A few studies have reported the effects of trauma-focused CBT on sleep, and the results are varied. These studies generally conclude that, despite an absence of interventions specifically targeting sleep, trauma-focused CBT is generally associated with improvements in sleep. Some studies have found that over half of patients completing trauma-focused CBT also experienced significant improvement in sleep (Cooper and Clum [41], Zayfert and DeViva [17]), though one other study found that only 30 percent of patients no longer reported sleep problems after treatment completion (Belleville et al. [37]). One study comparing the effects of CPT and PE on sleep found that both interventions resulted in significant improvements in sleep, though posttreatment assessment means were above an established cutoff for poor sleep quality in both conditions (Galovski et al. [42]). In a study of female rape victims with PTSD, CBT resulted in remission of PTSD symptoms, which was associated with a reduction of heart rate variability (indicator of sympathetic activity) during REM sleep (Nishith et al. [43]). Zayfert and DeViva [17] found that disturbed sleep and anger problems are the two most frequently reported residual symptoms following successful treatment of PTSD. Zayfert and DeViva also found that trauma-focused CBT was associated with a large decrease in nightmares and that of the patients who reported continued sleep problems after treatment, less than a quarter were still reporting nightmares of sufficient severity to be coded as a clinical symptom.

It is not clear why some patients' sleep problems persist after trauma-focused CBT. As noted previously, it is possible that these patients develop maladaptive patterns of thinking or behavior that interfere with sleep and perpetuate the sleep problems even after such precipitating factors as nightmares and hypervigilance have decreased (Spielman et al. [38], DeViva et al. [44]). Patients may get into a pattern of giving themselves long periods of time in bed, thus increasing the likelihood of lying in bed awake. Patients may also nap in the day to "catch up" and as a consequence decrease their sleep drive, resulting in longer sleep-onset latency at bedtime. In other words, in these cases, insomnia becomes a comorbid disorder that may require specific treatment. A second possibility is that general arousal level does not decrease despite decreases in re-experiencing and avoidance. Zayfert and DeViva [17] found that hyperarousal symptoms were more likely to be present after completion of trauma-focused CBT than avoidance or re-experiencing symptoms. Baseline arousal, and also physiological response to external stimuli, may remain high after other symptoms have decreased or remitted, and that arousal could interfere with sleep.

It is also possible that the specific circumstances of the traumatic event may have caused conditioned arousal to the bed, the bedroom, or darkness, and these conditioned relationships may not have been addressed by trauma-focused treatment. A therapist providing exposure therapy may not inquire about sleep-related avoidance behaviors such as leaving the lights on in the bedroom at night and therefore may miss sleep-related stimuli when constructing an in vivo exposure hierarchy. Similarly, a therapist providing cognitive therapy may not assess beliefs about the safety of the sleep setting. A fourth possibility is that a sustained pattern of waking in an agitated state from nightmares or chronic fear of loss of vigilance results in a fear of sleep itself that increases arousal in the sleep setting and interferes with sleep (Zayfert and DeViva [17]). Fear of the loss of vigilance may also lead to additional safety behaviors that are incompatible with sleep, such as sleeping during daylight hours when others are awake and trying to "stand guard" at night when the rest of the household is sleeping and vulnerable.

Eye Movement Desensitization and Reprocessing

Eye movement desensitization and reprocessing (EMDR) has demonstrated efficacy in the treatment of PTSD based on numerous treatment studies with medium to large effect sizes. The EMDR protocol includes saccadic eye movement tracking across the patient's visual field for a period of 20 s while the patient holds disturbing sensations and negative cognitions. EMDR incorporates validated components of other CBT modalities including exposure, cognitive restructuring, and processing of emotional responses to trauma cues. A review of dismantling studies of EMDR concluded that alternate stimuli can be substituted for the eye movement component with comparable treatment outcomes, and bilateral stimulation does not significantly influence treatment outcome (Spates and Koch [45]). Despite questions related to the role of eye movement, there is evidence supporting the efficacy of the EMDR package in the treatment of PTSD, and both the DOD and VA [12] and the International Society for Traumatic Stress Studies (Foa et al. [40]) list EMDR as a first-line option for the treatment of PTSD. There has been little focus on the effect EMDR has on sleep disturbance in PTSD. One study employing polysomnography to examine EMDR's effect on sleep in seven PTSD patients revealed significantly increased sleep efficiency and reduced wake time following sleep onset (Raboni et al. [46]).

Imagery Rehearsal for Nightmares in Posttraumatic Stress Disorder

The high prevalence of nightmares experienced by individuals with PTSD has prompted the application of imagery rehearsal (IR), initially developed to treat chronic nightmares in the general population, to individuals with PTSD (Krakow and Zadra [47]). There are numerous imagery-based protocols for reducing trauma-related nightmares, and these treatments generally include the patient choosing a repetitive distressing nightmare, changing some detail of that nightmare, and rehearsing the new version of the nightmare regularly (Gehrman and Harb [48]). IR can be administered in group or individual format.

IR has proven to be effective for the treatment of chronic nightmares in trauma survivors. Several studies have examined IR provided in a group format. In two separate studies, Krakow and colleagues (Krakow et al. [49-50]) provided three sessions of imagery rehearsal therapy (IRT), a specific IR protocol with the instruction to "change the nightmare in any way you wish" (Krakow et al. [49], p. 594). Both studies reported reduced frequency of nightmares, improved sleep quality, and decreased levels of PTSD symptoms. Forbes et al. provided six 90-minute individual sessions of IR, which was presented to participants as including their making "changes that promote mastery or control" [51] (p. 436) to their nightmares, to a sample of 12 Vietnam veterans with PTSD. This IR intervention resulted in decreases in the frequency of the target nightmare, PTSD symptom severity, and depression. Nappi et al. retrospectively examined records of veterans who completed five sessions of IR in which "therapists guided veterans in writing a highly detailed, vivid, and creative alternative ending [to the target nightmare] that did not elicit negative affect or include distressing content from the target nightmare" [52] (p. 239). The treatment, provided in group or individual format, was associated with decreases in nightmare frequency and PTSD symptoms, as well as a significant decrease on one measure of insomnia severity. Lu et al. [53] provided group IR based on the Forbes et al. [51] protocol to a sample of 17 male veterans and found no posttreatment effects on nightmares or PTSD symptoms. However, total nights with trauma-related nightmares decreased at 3- and 6-month follow-up points compared with pretreatment, and PTSD symptoms decreased at the 3-month follow-up in the intent-to-treat sample. A large RCT compared IR, based on the treatment protocol used by Forbes et al. [51], to education and relaxation alone in a sample of 124 Vietnam veterans with chronic, severe PTSD. No differences between treatment and control groups were found in the intent-to-treat analysis in nightmare frequency, sleep quality, or PTSD symptoms (Cook et al. [54]).

The exact mechanism of change in IR is unclear. The most common explanation for its efficacy is that it promotes mastery of the content and images of the nightmare. Though instructions for IR vary widely, the general message that most protocols appear to convey is that patients should select a change to their target nightmare that decreases the negative content or changes the negative ending of the dream (Davis and Wright [55], Gehrman and Harb [48], Nappi et al. [52]), though there are protocols that specifically do not provide guidance on how to change the nightmare (Moore and Krakow [56]). "Mastery of the nightmare" is not a clearly defined construct, but appears to include two components: the recognition of an alternative ending for the nightmare that contains fewer negative connotations about the patient or the world in general, and a decrease in distress related to the nightmare. It should be noted that in one common protocol for exposure therapy for PTSD, one of the stated mechanisms of imaginal exposure (as told to the patient during presentation of treatment rationale) is promoting a sense of self-control and competence in relation to the trauma memory (Foa et al. [57]).

Another explanation for the efficacy of IR is that it facilitates exposure to the nightmare content. Research has indicated that simple systematic desensitization, without any change made to content, is helpful in reducing nightmare frequency (Cellucci and Lawrence [58]) and nightmare intensity (Miller and DiPilato [59]). In systematic desensitization protocols, the participant creates a hierarchy of distressing nightmare scenes, is taught relaxation, and then imagines the nightmares in the hierarchy (starting with the least distressing nightmare), using relaxation whenever anxiety increases. Systematic desensitization has generally been investigated in participants with nightmare disorder but not specifically with PTSD-related nightmares. One study compared desensitization to IR and found no significant differences in effects on nightmare frequency but found that systematic desensitization resulted in a significant decrease in severity of emotions present when waking up from a nightmare while IR did not (Kellner et al. [60]). Though some IR protocols specifically attempt to minimize exposure, Gehrman and Harb [48] have pointed out that rehearsing a changed nightmare script still likely entails some imaginal exposure to the original distressing nightmare content.

It is also possible that IR of trauma-related nightmares facilitates changes in beliefs and meaning associated with the traumatic event. As noted previously, some protocols focus on specific trauma-related themes that are identified in the nightmares or emphasized in trauma-focused treatments (Davis and Wright [55], Swanson et al. [61]). The imagery rescripting and rehearsal procedures used to treat nightmares share some similarities with imagery rescripting and reprocessing treatments for trauma-related intrusive memories, and imagery rescripting and reprocessing is generally viewed as an imagery-based cognitive therapy (Grunert et al. [62], Smucker and Niederee [63]).

The Standards of Practice Committee of the American Academy of Sleep Medicine gave a Level A rating to "imagery rehearsal therapy," which appeared to include protocols by Krakow and colleagues (e.g., Krakow et al. [64]) as well as Forbes et al. [51] for the treatment of nightmare disorder (Aurora et al. [65]), and noted that "IRT appears to be effective in the management of nightmares exhibited in patients with PTSD as well as idiopathic nightmares" (p. 395). In published studies, IR protocols tend to be associated with improvements in nightmare frequency and intensity as well as PTSD symptoms. However, study samples sometimes include participants with nightmares who do not meet diagnostic criteria for PTSD, and most studies include, at best, waitlist control subjects (Nappi et al. [66]). Specific protocols appear to vary widely, and posttreatment scores on measures of PTSD symptoms and sleep problems often remain at clinically significant levels.

Cognitive-Behavioral Therapy for Insomnia

Nonpharmacologic, cognitive-behavioral interventions for the treatment of late-life insomnia have been found to be equal or superior to treatment with hypnotic pharmacologic agents alone or when combined with pharmacologic agents after 8 weeks of treatment and have longer-lasting benefits for up to 24 months following discontinuation of therapy (Morin et al. [67]). Two meta-analytic studies examining the effects of nonpharmacologic treatments on a combined 3,640 subjects with insomnia in the general population demonstrated significant benefit in measures of sleep continuity and subjective quality of sleep in both the short- and long-term (mean follow-up duration 6 months) (Morin et al. [68], Murtagh and Greenwood [69]). In the 2008 practice guideline of the American Academy of Sleep Medicine (Schutte-Rodin et al. [70]), it was recommended that cognitive-behavioral therapy for insomnia (CBTI) be considered effective in the treatment of insomnia, whether that insomnia appears to be "primary" in nature (i.e., unrelated to any other medical or psychiatric condition) or whether it appears to have been initially caused by, or appears to be maintained by, another medical or psychological condition.

CBTI comprises a combination of cognitive and behavioral techniques. Stimulus control therapy aims to eliminate conditioned arousal and strengthen the association between bed and sleep. It instructs patients to (1) go to bed only when sleepy, (2) maintain a consistent wake time, (3) get out of bed when unable to sleep, (4) use the bed only for sleep and sex, and (5) avoid napping. Sleep restriction therapy aims to consolidate sleep and increase the sleep drive. It instructs patients to decrease and then gradually increase allowed time in bed. Relaxation training (progressive muscle relaxation and diaphragmatic breathing exercises) aims to decrease arousal and promote relaxation. Cognitive restructuring identifies and modifies negative attitudes and beliefs about sleep and cognitions that interfere with adherence. Sleep hygiene instructions aim to eliminate sleep-interfering habits, such as minimizing consumption of substances that interfere with sleep (e.g., caffeine, nicotine, alcohol, and large meals close to or during the sleep period) and ensuring the sleep environment is conducive to sleep (dark, quiet, comfortable, and safe). In addition to the strong evidence in support of the combination of these therapy components, there is significant empirical support for the use of stimulus control and sleep restriction as monotherapies (Morin et al. [71]). Evidence for relaxation and sleep hygiene as single components is weak, and the efficacy of cognitive therapy alone has not been tested.

Research of the efficacy of CBTI in PTSD is in its early stages. DeViva et al. [44] found modest positive results providing a version of CBTI adapted to PTSD-related sleep problems to a small clinical sample of patients who had already completed trauma-focused CBT and shown good response. However, patients in this study did not meet diagnostic criteria for PTSD when they received the CBTI, and they already had a history of good response to CBT, thus limiting generalizability to the population of all patients with PTSD.

Combined Imagery Rehearsal and Cognitive-Behavioral Therapy for Insomnia

Several studies have examined IR with some elements of CBTI included in the treatment protocol. In a randomized clinical trial of exposure, relaxation, and rescripting therapy (ERRT), which includes stimulus control, progressive muscle relaxation, and IR encouraging participants "to utilize relevant themes" (p. 127) when changing nightmares, Davis and Wright [55] reported significant improvements in nightmare frequency and severity as well as in PTSD symptom severity in a sample of trauma survivors with nightmares, 66 percent of whom met diagnostic criteria for PTSD. However, Davis and Wright [55] found no improvements in total sleep time or measures of sleep quality. Krakow et al. [50] provided combined IRT and CBTI, including stimulus control, sleep restriction, and sleep hygiene components, to a group of 62 violent crime survivors with PTSD and found improvements in sleep quality and nightmare frequency, along with decreases in PTSD symptoms. Germain et al. [72] provided a single 90minute session of instructions on IR, stimulus control, and sleep restriction along with a workbook to seven crime victims with PTSD and found that daytime PTSD symptoms, including intrusions and arousal, had significantly improved, but sleep measures had not, 6 weeks later. Swanson et al. [61] provided ten 90-minute groups to a small sample of veterans with PTSD, including five sessions of IR in which patients "rewrote the nightmare to address core themes" (p. 640) identified in other PTSD protocols such as CPT, as well as five sessions of CBTI including sleep restriction, stimulus control, sleep hygiene, cognitive restructuring, and relaxation. They found significant improvements on all measures of sleep and no changes in posttraumatic symptoms. Ulmer et al. [73] provided combined IR and CBTI in individual format to 22 veterans and found improvements in nightmare frequency, questionnaire and sleep diary measures of sleep quality, and PTSD symptoms. Long et al. [74] found that six sessions of group IR combined with a session of exposure to the original nightmare resulted in improvements from pretreatment to posttreatment in nightmare frequency, sleep quantity, and PTSD symptoms in a sample of 37 veterans with PTSD. The treatment package added a week of exposure to the original unchanged nightmare account (writing the most distressing and/or frequent nightmare and reading it several times until anxiety decreases) and an extra week of rehearsal of the rescripted account, as well as additional unspecified "cognitive-behavior skills for sleep management" (p. 533), to the ERRT protocol of Davis and Wright [55].

Treatment Considerations

Any attempt to treat PTSD-related sleep disturbance needs to be driven by a broad case conceptualization that includes trauma history and PTSD symptoms in addition to sleep symptoms, sleep habits, sleep-related cognitions, nightmares, and other comorbid primary sleep disorders, such as OSA. The clinician should do a preliminary screen for comorbid sleep disorders and refer to a sleep clinic for further assessment and treatment when indicated. The clinician also needs to identify trauma-related factors that may contribute to the patient's presentation, including history of trauma in the sleep context, safety behaviors at night (e.g., perimeter checks, sleeping with a gun near the bed), and fear of losing vigilance (e.g., sleep avoidance).

As noted previously, little research has examined the efficacy of CBTI for PTSD-related sleep difficulties. Case report series and small controlled studies have indicated that CBTI alone, IR alone, and their combination can improve sleep and reduce the severity of PTSD symptoms. Therefore, the use of CBTI should be considered with most patients with PTSD-related insomnia. Adding IR to CBTI should also be considered when the patient experiences both insomnia and nightmares. Clinicians implementing CBTI with PTSD patients need to consider and address some unique aspects of this patient group. This includes addressing high levels of nighttime arousal that are unrelated to worries about sleep, safety-related behaviors and cognitions, maladaptive nighttime vigilance behavior, and spending time awake during the night trying to figure out the meaning of dreams.

There are two situations in which it is best not to use CBTI and/or IR. The first is with patients who are undergoing or ready to engage in trauma-focused CBT for PTSD (either PE or CPT). This is because trauma-focused CBT is demanding and intensive and adding another therapy that requires behavioral changes may hinder adherence (Manber et al. [75]). Also, research reviewed here indicates that there is a reasonable chance that trauma-focused CBT will improve sleep. In addition, exposure to trauma memories and reprocessing of beliefs and attributions related to trauma are critical components of trauma-focused therapies and similar to the procedures employed in most IR protocols.

Patients who continue to report sleep disturbance after completing CBT for PTSD can then start CBTI. If there are persistent nightmares after trauma-focused CBT, IR may also be added to the treatment plan.

The second situation is the use of CBTI with PTSD-related insomnia with excessive daytime sleepiness, as is the case for PTSD patients with severe comorbid OSA. Sleep restriction therapy, a component of CBTI, is contraindicated when daytime sleepiness is severe because it poses a safety concern.

There is no published research on the best sequencing of IR and CBTI. Until this question is settled, the clinician is advised to weigh each case based on the relative contribution of nightmares to the patient's sleeplessness.

Future Directions

Though early data are promising, there have not been large RCTs to test the efficacy of CBTI for PTSD-related sleep problems (Table 1). Nonetheless, given the recommendation of the American Academy of Sleep Medicine supporting the use of CBTI for insomnia comorbid with other problems, the high prevalence of insomnia among veterans (including those with PTSD), the strong evidence for the efficacy of CBTI in primary insomnia, and the emerging evidence about its potential efficacy among PTSD patients, the DOD and VA have recently begun national dissemination projects to train large numbers of clinicians to administer CBTI. The CBTI protocol being disseminated takes into account the possibility that PTSD symptoms such as nocturnal hyperarousal and perceived need for vigilance may complicate standard application of CBTI (DeViva et al. [44]) and necessitate special adaptation of the standard CBTI protocol. The protocol is

anchored in case conceptualization (e.g., Persons [76]), taking into account factors that contribute to each patient's unique presentation (Manber et al. [75]). Special considerations for the application of CBTI for patients with PTSD-related sleep problems include, among other things, cognitive therapy techniques such as cost-benefit analysis for addressing fear of going to sleep and presleep perimeter checks, methods for addressing hyperarousal, and interventions to decrease such maladaptive behavior following nightmare arousals as staying awake trying to figure out the meaning of a nightmare (Manber et al. [75]). The CBTI protocol adapted by the VA CBTI rollout did not include training in IR, in part because of limited evidence base for its use for the treatment of nightmares in combat-related PTSD and in part because complete training in CBT for insomnia that is comorbid with medical and psychiatric disorders is intensive and left little time for inclusion of treatment modules for other sleep disorders, including nightmare disorder.

Currently, there are no guidelines regarding the sequencing of CBTI and trauma-focused therapy. For example, it is not known what type or severity of posttraumatic symptoms may interfere with the administration of CBTI or reduce its efficacy. Similarly, it is not clear what types and severity levels of sleep-interfering posttraumatic symptoms require an augmentation of CBTI with specific trauma-focused therapy. It is also not known when combining CBTI and a trauma-focused treatment may be contraindicated, though the task force that developed the VA CBTI dissemination project recommends that for patients undergoing PE therapy, CBTI should be postponed until the end of PE and administered only when residual insomnia is present.

Pharmacologic Treatments of Insomnia and Nightmares in Posttraumatic Stress Disorder

The VA/DOD CPG [12] recommends nonpharmacologic treatments as the first-line treatments for insomnia and nightmares in PTSD. However, patients are not always accepting of nonpharmacologic treatments or may not experience sufficient symptom relief with treatments like CBTI and IR. In these circumstances, pharmacologic treatment has an important role in the treatment plan. While not all patients accept medication treatment for PTSD, it is the most common form of treatment for PTSD in the VA healthcare system. A review in 2004 of 274,297 VA patients with PTSD revealed 80 percent of this population was receiving a psychotropic agent (Mohamed and Rosenheck [77]). The distribution of classes of medication prescribed was antidepressants 89 percent; anxiolytics/sedative hypnotics 64 percent; and antipsychotics 34 percent. It is suggested this substantial use of medication is "due to the targeting of specific symptoms of PTSD and comorbid disorders rather than being based on diagnosis." Despite the extensive use of medications to treat PTSD sleep-related symptoms, there are limited controlled studies to inform clinicians on how to best prescribe medication for insomnia and nightmares. It is also important to note that successful treatment of comorbid medical conditions that contribute to sleep disturbance like PLMD, RBD, OSA, chronic pain, gastresophageal reflux disease, and benign prostatic hypertrophy (BPH) can obviate the need for psychotropic medications, including sedative hypnotics. Over the past 20 years, there has been a growing body of research examining medication efficacy for the full spectrum of PTSD signs and symptoms. This review will focus on the effect pharmacologic treatment has on the sleep component of the symptom presentation.

Antidepressant Agents

Selective serotonin reuptake inhibitors. The SSRIs are the most commonly prescribed medication for the treatment of PTSD. Large RCTs conducted with sertraline (Brady et al. [78], Davidson et al. [79]) and paroxetine (Marshall et al. [80]) resulted in U.S. Food and Drug Administration approval for their use with PTSD. The effect size for overall symptom relief is modest, d = 0.3-0.4. The VA/DOD CPG [12] recommends sertraline and paroxetine as first-line treatments for PTSD. The effect SSRIs have upon sleep quality and nightmares is inconsistent. Overall sleep quality is reported to be improved with SSRIs, but it is important to note that individuals taking SSRIs also report insomnia as a side effect. SSRIs can increase arousals from sleep, decrease total sleep time, and suppress REM sleep (Singareddy and Balon [81]). SSRIs frequently require augmentation with another medication to help unresponsive sleep disturbances or to counteract the effect SSRIs may have in contributing to the sleep disturbance. There have been few studies with SSRIs in which measuring the effect upon sleep quality has been the primary objective. One study with fluvoxamine that had a small sample size focused on its effects on sleep in patients with PTSD (Neylan et al. [82]). Fluvoxamine improved all domains of sleep quality with a large effect on combat-related dreams. However, fluvoxamine is seldom used in PTSD treatment because of its side-effect profile relative to its efficacy.

Serotonin antagonist/reuptake inhibitors. The drugs in this class are serotonin (5-HT)-potentiating non-SSRIs. They have been shown to improve sleep disturbance in PTSD in small uncontrolled clinical trials. Nefazodone prescribed at doses of 500-600 mg per day to 10 Vietnam combat veterans with PTSD had a strong effect on nightmares (d = 1.43) and total sleep time (d = 1.95) (Neylan et al. [83]). Increased sleep maintenance and increased slow-wave sleep were also demonstrated by polysomnography in the same study. It is important to note that nefazodone has a black box warning because of the rare but potentially serious adverse effect of hepatotoxicity. Trazodone is one of the most commonly prescribed medications for the treatment of PTSD sleep disturbances. It is thought to be helpful for insomnia secondary to SSRIs because its mechanism of action counters the 5-[HT.sub.2] agonist effects of SSRIs. It is generally well tolerated at low doses (50-200 mg/night). A survey of 74 veterans with PTSD found trazodone's effect on insomnia and nightmares to be extremely helpful for sleep disruption in 88 percent and for nightmares in 72 percent of the population (Warner et al. [84]). Despite the extensive use of trazodone, there have been no RCTs to demonstrate its efficacy for insomnia related to PTSD, and research in primary insomnia (Roth et al. [85]) raises concern about impairments of short-term memory, verbal learning, and motor skills. Cyproheptadine has antihistamine as well as 5-[HT.sub.2] antagonist actions. Initial open clinical trials reported benefit for PTSD-related sleep disturbance. But a well-controlled trial found cyproheptadine was not effective for PTSD sleep disturbance and may have exacerbated sleep problems (Jacobs-Rebhun et al. [86]).

Antidepressants with mixed receptor mechanism

of action. Mirtazapine has 5-[HT.sub.2] and 5-[HT.sub.3] antagonist, arantagonist, and antihistamine mechanisms of action. This mechanism of action profile offers promise that mirtazapine can enhance sleep quality. Mirtazapine was reported to reduce the frequency and intensity of nightmares in 75 percent of a series of more than 300 refugees who experienced "catastrophic stress levels" (Lewis [87]). The one controlled clinical trial of mirtazapine treatment for PTSD reported improved PTSD symptoms and associated anxiety but did not specifically measure the effects upon the sleep of the 29 subjects in the study (Davidson et al. [88]). Mirtazapine carries a significant risk for weight gain, which in addition to other health risks can also increase the risk for new onset and exacerbation of sleep apnea (Serretti and Mandelli [89]). Venlafaxine enhances 5-HT, norepinephrine, and D activity. Venlafaxine is recommended by the VA/DOD CPG [12] as a first-line treatment for PTSD. Venlafaxine's effectiveness for the treatment of PTSD was demonstrated in a large (N = 329) multinational RCT (Davidson et al. [90]). Sleep quality measures were not reported in this study. There were significant improvements in the PTSD re-experiencing and avoidance/numbing clusters but not for hyperarousal. This would suggest venlafaxine may have been helpful for nightmares but not for improving sleep onset or maintenance. However, the Standards of Practice Committee of the American Academy of Sleep Medicine does not recommend venlafaxine for the treatment of nightmares in adults (Aurora et al. [65]) based on the findings in a pooled analysis of the Clinician-Administered PTSD Scale (CAPS) on 687 patients with PTSD treated with venlafaxine (Stein et al. [91]). There was no significant difference between venlafaxine and placebo in effect on distressing dreams and difficulty in falling and staying asleep.

Tricyclic antidepressants. Imipramine, amitriptyline, and desipramine have mixed norepinephrine and 5-HT enhancement as their mechanism of action. All have been tested for efficacy in PTSD in older, small, randomized trials (Frank et al. [92], Davidson et al. [93], Reist et al. [94]). There was modest re-experiencing and hyperarousal symptom improvement from imipramine (d = 0.25), moderate improvement for amitriptyline (d = 0.64), and no benefit from desipramine (d = 0.05). Amitriptyline and imipramine may be prescribed at low doses for sleep disturbance in PTSD, but the evidence for their efficacy is sparse and their potential toxicity, including increased risk for cardiac conduction disturbances and anticholinergic activity that can worsen symptoms of BPH by causing frequent awakening due to nocturia, makes them limited in their utility.

Monoamine oxidase inhibitors. Phenelzine is the MAOI most studied and used for the treatment of PTSD. In a comparative review, MAOIs were found to be more effective than TCAs for the treatment of PTSD (South wick et al. [95]). Phenelzine was used to treat Israeli combat veterans with PTSD. Improvement in sleep disturbance was the only symptom with a clinically impressive change (Lerer et al. [96]). The MAOIs are limited in their utility because of the dietary and drug restrictions needed to avoid the associated risk for hypertensive crisis.

Anxiolytic and Sedative Hypnotic Agents

Hypnotic drugs are recommended as a second-line approach to the management of insomnia in PTSD by the VA/DOD CPG [12].

Benzodiazepines. Benzodiazepines (BZs) bind to BZ binding sites within the y-aminobutyric acid (GABA)-A ([GABA.sub.A]) receptor resulting in GABA central nervous system inhibitory activity. Although widely prescribed for the treatment of PTSD, especially for PTSD sleep disturbance, BZs have not been found to be helpful in preventing the development of PTSD or improving intrusion, avoidance, and numbing symptoms. There have been remarkably few studies examining the efficacy of BZs for PTSD sleep disturbances. This is especially true for long-term efficacy. One small study examined the short-term effects of clonazepam on PTSD-related sleep disturbances and found no improvement (Cates et al. [97]). The VA/ DOD CPG [12] does not recommended BZs for long-term (>1 month) or short-term use for the treatment of PTSD because of lack of demonstrated efficacy, the substantial prevalence of alcohol and substance abuse in veterans with PTSD, and the risk for developing habituation and dependence. A meta-analysis of sedative hypnotic treatment for insomnia in a general population of individuals (2,417) over the age of 60 concluded that in using BZs the benefits were marginal and outweighed by the risks, which included cognitive and psychomotor impairment, daytime fatigue, falls, and motor vehicle accidents (Glass et al. [98]).

Benzodiazepine receptor agonists. This class of drugs selectively binds to the BZ omega-1 site within the GABAA receptor to produce sedation but with minimal anticonvulsant and muscle relaxant action compared to the BZs. These drugs are considered to be preferable to the BZs by the VA/DOD CPG [12] as a second-line treatment for PTSD-related insomnia because of their shorter half-life, slower development of tolerance, lower risk for withdrawal reactions, and lower risk for dependence. The fact that hypnotic agents with a short half-life confer an increased risk for acute confusional states needs to be taken into consideration in treatment choice and management during treatment. An RCT of 788 individuals with primary insomnia treated nightly with eszopiclone, a member of this class, demonstrated sustained efficacy in a number of measures of sleep continuity, with no evidence of tolerance, withdrawal symptoms, or rebound insomnia upon completion of the study (Krystal et al. [99]). However, studies of the efficacy of this class of drugs for treating PTSD sleep disorder are limited. A case series of veterans with PTSD treated with zolpidem reported improvement in insomnia and nightmares that was sustained for more than 1 year in some cases (Dieperink and Drogemuller [100]). Controlled studies are needed to objectively demonstrate the utility of this class of drugs for PTSD sleep disturbance.

Antipsychotic Agents

The atypical antipsychotic agents are becoming more frequently used as an adjunctive treatment, especially for insomnia, in PTSD patients not responding to first-line antidepressant treatment. The VA/DOD CPG [12] does not recommend the use of atypical antipsychotics for sleep disturbance in PTSD because of the potential for adverse events relative to the benefits for this indication. The atypical antipsychotics can be considered in cases of associated psychosis, agitation, and severe unremitting PTSD symptoms.

Olanzapine. Olanzapine has 5-[HT.sub.2] and [D.sub.2] antagonism as its mechanisms of action. Olanzapine had a strong effect size (d = 1.07) in reducing overall PTSD symptoms and significantly improved sleep (p = 0.01) in a double-blind RCT of adjunctive treatment to SSRI nonresponders in a veteran population (Stein et al. [101]). Olanzapine should be used with caution because of its risk for producing weight gain and inducing new-onset diabetes mellitus.

Quetiapine. Quetiapine has 5-[HT.sub.2], [D.sub.2], and [[alpha].sub.1]-andrenergic antagonism with antihistamine properties as its mechanisms of action. This profile results in a sedating drug that is being used frequently at low doses (25-100 mg) for this purpose in the VA healthcare system. In a VA study of the off-label use of all antipsychotic medication prescriptions written during 2007, 10.6 percent of veterans with PTSD were given at least one prescription of quetiapine during the course of the year (Leslie et al. [102]). A retrospective chart review of 125 veterans treated with adjunctive quetiapine at low doses (155 [+ or -] 130 mg) found there was much or very much improved sleep in 62 percent and decreased nightmares in 25 percent with "minimal" side effects in this series (Sokolski et al. [103]). However, other studies point out that quetiapine's potential for adverse effects, even at low doses, especially a significant increase in weight gain (Williams et al. [104]) and body mass index (Cates et al. [105]), limit its usefulness for treating sleep disturbances.

Risperidone. Risperidone has 5-[HT.sub.2], [D.sub.2], and [[alpha].sub.1]-andrenergic antagonism as its mechanisms of action. Reports of risperidone's utility as an adjunctive PTSD treatment for nonresponders to other pharmacologic agents date back to 1998. In a 2008 study, 25 civilians with PTSD who did not fully respond to a course of treatment with sertraline were placed in an RCT with risperidone (Rothbaum et al. [106]). The risperidone group had significantly more improvement in sleep (p = 0.03) than the control group. The VA has subsequently completed a 6-month multisite RCT of risperidone augmentation in a SRRI treatment-resistant population of 247 veterans with combat-related PTSD (Krystal et al. [107]). The main outcome measures were the CAPS, Montgomery-Asberg Depression Rating Scale, Hamilton Anxiety Scale, Clinical Global Impression scale, and 36-Item Short Form Health Survey for Veterans. The Pittsburg Sleep Quality Index (PSQI) was also used as a measure. At the conclusion of treatment, when compared with placebo, risperidone did not reduce overall PTSD, depression, or anxiety symptoms and was associated with more frequent side effects in this population of veterans. The pretreatment PSQI scores were high (a mean of 13.6 for the placebo group and 13.9 for the risperidone group). The results from a secondary analysis determining the effect of treatment on the PSQI score have not yet been published.

Adrenergic Inhibiting Agents

Guanfacine. [[alpha].sub.2]-adrenergic receptor agonists such as guanfacine act at noradrenergic autoreceptors to inhibit the firing of noradrenergic neurons, effectively inhibiting the release of brain norepinephrine. Based on some promising open trials in treating PTSD patients with clonidine, another agent in this class, a small RCT with guanfacine was conducted to confirm the clonidine findings (Neylan et al. [108]). Guanfacine has the advantage of being longer acting than clonidine and thus is better tolerated. The study found no differences between guanfacine and placebo in all measures of PTSD symptoms, including sleep disturbance. This class of adrenergic inhibiting agents is now seldom used to treat PTSD sleep disturbances and is not recommended in the VA/DOD CPG [12].

Prazosin. In contrast to guanfacine, prazosin specifically has an [[alpha].sub.1]-receptor antagonist mechanism of action. Prazosin was initially noted in 2003 to be helpful for PTSD sleep disturbance, including nightmares, in a small controlled study of combat veterans (Raskind et al. [109]). Subsequent larger studies with a more specific focus on PTSD sleep disturbance, especially nightmares, have confirmed the earlier findings with large effect sizes for improvement in sleep quality (d = 1.0) and distressing dreams (d = 0.94) (Raskind et al. [110]). Examination of nightmare content found a shift from threatening content of actual past combat events to more "normal" dream content. The mechanism by which prazosin relieves nightmares is unknown. Dr. Raskind proposes a model explaining prazosin's effectiveness: (1) PTSD nightmares occur during light sleep and disrupted REM sleep, (2) light sleep is increased by stimulation of central nervous system [[alpha].sub.1]-receptors, and (3) prazosin's inhibitory effect on [[alpha].sub.1]-receptors decreases light sleep and normalizes REM sleep. Prazosin was tested in a population of civilians with PTSD in a RCT that also included nonpolysomnographic measurement of REM activity in the patient's home (Taylor et al. [111]). The significant improvement in sleep quality and reduction in frequency and quality of nightmares noted in the studies of combat-related PTSD were repeated in this civilian population. Also notable was an associated increase in mean REM duration and total REM sleep time. PTSD is commonly associated with TBI. The VA Cleveland Polytrauma Center conducted a carefully designed observational study with a group of 74 Operation Iraqi Freedom/Operation Enduring Freedom veterans exposed to an explosion in combat, with mild TBI characterized by residual headaches and cognitive deficits (Ruff et al. [112]). Of the group, 71 were comorbid for PTSD. Only 5 of the group reported restful sleep. Prazosin, tapered up to a treatment dose of 7 mg at bedtime, and sleep hygiene counseling were given over a 9-week period to determine whether this approach would improve sleep, headaches, and cognitive function. All members of the group completed sleep hygiene counseling, and 62 remained on prazosin for the full 9-week period. Those veterans who remained on prazosin had more restful sleep, decreased intensity and frequency of headaches, and improvement in cognition. Six months following the start of treatment, 64 veterans in the group were taking prazosin. The improvements observed at 9 weeks were maintained at 6 months. Prazosin was well tolerated. The investigators hypothesize that improvement in sleep was a significant factor in the improvement of TBI-related headache and cognition. A controlled study is needed to verify these promising findings in this challenging to treat population. Prazosin, while generally well tolerated, can cause dizziness, fainting, drowsiness, decreased energy, and headache. The mean dose in treatment studies was approximately 10 mg daily. It is best to start with a low dose (1 mg) and slowly increase the dose as tolerated until symptom relief occurs. Based on the studies conducted up to this time, prazosin is recommended by the Standards of Practice Committee of the American Academy of Sleep Medicine as the first-line pharmacologic treatment of PTSD-associated nightmares (Aurora et al. [65]). The VA/DOD CPG [12] recommends prazosin as an adjunctive treatment for cases in which severe nightmares remain unresponsive to first-line treatment (i.e., SSRIs). More investigation using objective measures is needed to understand the effect prazosin has on sleep architecture and how this correlates with the reported improvement in sleep quality and nightmare reduction. A proposal for such a study in a VA population of combat veterans with PTSD using home polysomnography and actigraphy (measurement of sleep-wake time through body movement) is currently under review.

Treatment Considerations

Pharmacologic treatment should be guided by the principal of using the least complex approach to achieve the broadest relief of signs and symptoms. The SSRIs (sertraline and paroxetine) and the selective norepinephrine reuptake inhibitor, venlafaxine, are recommended as a first-line pharmacologic treatment for PTSD by the VA/ DOD CPG [12] based on large RCTs. Many patients experience a global improvement in PTSD symptoms, including sleep disturbance. Only in cases in which these first-line medications are not well tolerated or do not significantly relieve PTSD symptoms, including sleep disturbances, should other medications be considered. There is evidence that mirtazapine and nefazodone are helpful for PTSD-related sleep disturbances and can be considered as single-agent alternatives to the SSRIs or venlafaxine. However, mirtazapine can cause significant weight gain that may cause or exacerbate sleep apnea, and nefazodone needs to be used with caution because of the rare but serious risk of liver damage. Trazodone is infrequently used as a single agent to relieve global PTSD symptoms because of the sedation and postural hypotension it produces at full antidepressant doses. The TCAs and MAOIs are seldom used as single-agent alternatives for the treatment of PTSD because of their side-effect profiles. In circumstances in which sleep disturbance continues despite otherwise successful CBT or antidepressant treatment, adjunctive medications should be considered. There is evidence from clinical observation and polysomnography that trazodone at low doses (up to 200 mg at bedtime) is helpful in improving sleep quality. It can be prescribed long-term without the risk of developing tolerance to its effects. Prazosin is an [alpha]-1 inhibiting agent, has the strongest evidence of any medication for the relief of nightmares, and is recommended by the VA/DOD CPG [12] as an adjunctive agent for this purpose. Prazosin can also be used alone to treat nightmares and insomnia. Other adrenergic inhibiting agents, such as guanfacine, have not proven to be helpful for this indication. The antipsychotic quetiapine is commonly used to treat sleep disturbance, but it and other antipsychotic agents are not recommended by the VA/DOD CPG [12] because of their poor risk to benefit ratio for this indication. Finally, BZs are not recommended for the short- or long-term treatment of sleep disturbance in PTSD by the VA/DOD CPG [12] because of a lack of proven efficacy and the risks for habituation and dependence. The BZ receptor agonists such as zolpidem and eszopiclone are a safer alternative to the BZs with regard to habituation and dependence. At this time, given the limited evidence for their efficacy in PTSD-related sleep disturbance, it is prudent to prescribe them for short-term use (days to weeks) on a schedule of 3-5 days a week (Table 2).

CONCLUSIONS

Nightmares and insomnia are common, persistent, and significant problems in individuals with PTSD. Commonly occurring comorbid conditions such as depression, substance abuse, anxiety, TBI, other sleep disorders, and chronic pain can further contribute to sleep disturbance. A comprehensive assessment of the contributing factors to the sleep disturbance is needed so that the clinician can optimize treatment and decide when referral for additional consultation and treatment may be indicated. In order to arrive at an accurate diagnosis and optimize treatment, the assessment should also include a detailed review of the nature of the presenting sleep problem, including sleep habits, associated daytime symptoms, and thought patterns that may contribute to the problem or to adherence with treatment recommendations.

CBT for PTSD does not always successfully relieve insomnia or nightmares. CBTs designed to specifically treat insomnia and nightmares, such as CBTI and IRT, offer promise for a more robust improvement in PTSD sleep disturbances. CBT has been demonstrated to be at least as or more effective and with more sustained benefit than medication treatment for sleep disturbance and is considered the first-line treatment for PTSD-related sleep disturbances by the VA/DOD CPG [12]. The VA rollout of CBTI is focused on training mental health providers in the VA to provide CBTI and therefore will make CBTI more accessible to veterans. By providing an individual with skills to master symptoms that have been very distressing, CBTI can also help address demoralization that is commonly experienced by traumatized individuals. Anecdotal reports suggest that successful treatment of insomnia with CBTI may help prepare veterans to engage in trauma-focused therapy, though this possibility has not been tested.

Despite the fact that nonpharmacologic treatments are considered the first-line treatments for PTSD-related sleep disturbances, medication treatments have an important place in the management of insomnia and nightmares in PTSD. Medication can be used as the sole treatment or as an adjunct to CBTI or IRT. There is a need for RCTs comparing the relative efficacy of pharmacotherapy combined with CBTI and/or IRT as well as RCTs to compare the relative sequencing of pharmacological and nonpharmacological treatments for improving sleep in patients with PTSD. Medication treatment studies designed to assess the overall response of PTSD symptoms infrequently assess the effects of treatment on insomnia and nightmares. Antidepressant agents are recommended as the initial choice for treating the full range of PTSD symptoms. The anxiolytic and sedative hypnotic agents would appear to be a logical choice for treating sleep disturbances that do not respond to antidepressant treatment. However, the BZs, while commonly prescribed for PTSD sleep disturbance, are judged not to have long-term benefit and carry the risk for potential harm from habituation and dependence. Antipsychotic agents such as quetiapine are also commonly prescribed for treating sleep disturbances, but their adverse effects significantly reduce their utility, and they are not recommended by the VA/DOD CPG [12] for this indication. Prazosin is one of the few medications in this review that has been studied specifically to determine its effect on PTSD-related sleep disturbances. The VA/DOD CPG [12] recommends prazosin as an adjunctive treatment for PTSD nightmares unresponsive to CBT and/or antidepressant treatment.

Sleep disturbance in PTSD has been an ongoing challenge for clinicians treating traumatized individuals. Progress has been made in identifying treatments that provide relief from the suffering associated with insomnia and nightmares. CBT and some pharmacologic treatments offer relief. However, even when using best practices, insomnia and nightmares may not fully resolve in all patients, suggesting the need to develop treatments that are even more specific to the unique features of PTSD sleep disturbances.

at a Glance

Poor sleep is a common problem for people who have posttraumatic stress disorder (PTSD). Treatments have been developed to treat nightmares and problems in getting a full night's sleep. Clinicians across the United States are being trained to give these treatments. These treatments help people with PTSD learn special skills to help improve their sleep and make their nightmares less frequent and frightening. Medication can also help if the skills training does not give all the relief that is needed. This article reviews the progress that has been made to help people with sleep problems from PTSD.

Abbreviations: 5-HT = 5-hydroxytryptamine (serotonin); BPH = benign prostatic hypertrophy; BZ = benzodiazepine; CAPS = Clinician-Administered PTSD Scale; CBT = cognitive-behavioral therapy; CBTI = cognitive-behavioral therapy for insomnia; CPG = Clinical Practice Guideline; CPAP = continuous positive airway pressure; CPT = cognitive processing therapy; D = dopamine; DOD = Department of Defense; EMDR = eye movement desensitization and reprocessing; ERRT = exposure, relaxation, and rescripting therapy; GABA = y-aminobutyric acid; IR = imagery rehearsal; IRT = IR therapy; MAOI = monoamine oxidase inhibitor; OSA = obstructive sleep apnea; PE = prolonged exposure; PLMD = periodic limb movement disorder; PSQI = Pittsburg Sleep Quality Index; PTSD = posttraumatic stress disorder; RBD = REM sleep behavior disorder; RCT = randomized controlled trial; REM = rapid eye movement; SDB = sleep disordered breathing; SSRI = selective serotonin reuptake inhibitor; TBI = traumatic brain injury; TCA = tricyclic antidepressant; VA = Department of Veterans Affairs.

ACKNOWLEDGMENTS

Author Contributions:

Drafting of manuscript: F. B. Schoenfeld.

Critical review of manuscript for important intellectual content: J. C. DeViva, R. Manber.

Financial Disclosures: The authors have declared that no competing interests exist.

Funding/Support: This material was unfunded at the time of manuscript preparation.

Submitted for publication November 12, 2011. Accepted in revised form January 9, 2012.

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[108.] Neylan TC, Lenoci M, Samuelson KW, Metzler TJ, Henn Haase C, Hierholzer RW, Lindley SE, Otte C, Schoenfeld FB, Yesavage JA, Marmar CR. No improvement of posttraumatic stress disorder symptoms with guanfacine treatment. Am J Psychiatry. 2006;163(12):2186-88. [PMID:17151174] http://dx.doi.org/10.1176/appi.ajp.163.12.2186

[109.] Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A, Thompson CE, Dobie DJ, Hoff D, Rein RJ, Straits Troster K, Thomas RG, McFall MM. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003;160(2):371-73. [PMID:12562588] http://dx.doi.org/10.1176/appi.ajp.160.2.371

[110.] Raskind MA, Peskind ER, Hoff DJ, Hart KL, Holmes HA, Warren D, Shofer J, O'Connell J, Taylor F, Gross C, Rohde K, McFall ME. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. 2007;61(8):928-34 [PMID:17069768] http://dx.doi.org/10.1016/j.biopsych.2006.06.032

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[112.] Ruff RL, Ruff SS, Wang XF. Improving sleep: initial headache treatment in OIF/OEF veterans with blast-induced mild traumatic brain injury. J Rehabil Res Dev. 2009;46(9):1071-84. [PMID:20437313] http://dx.doi.org/10.1682/JRRD.2009.05.0062

ResearcherID: Frank Schoenfeld, MD: D-5867-2012

Frank B. Schoenfeld, MD; (1) * Jason C. DeViva, PhD; (2) Rachel Manber, PhD (3)

(1) San Francisco Department of Veterans Affairs (VA) Medical Center; University of California San Francisco, School of Medicine, San Francisco, CA; (2) VA Connecticut Health Care System, West Haven, CT; University of Connecticut School of Medicine, Farmington, CT; and Yale University School of Medicine, New Haven, CT; (3) Stanford University School of Medicine, Stanford, CA

* Address all correspondence to Frank B. Schoenfeld, MD; VA Medical Center 4150 Clement St (116A), San Francisco, CA 94121; 415-221-4810, ext. 3102; fax: 415-750-6921.

Email: Frank.schoenfeld@va.gov

http://dx.doi.org/10.1682/JRRD.2011.09.0164

** Pigeon WR, Edinger JD, Epstein DR, Germain A, Haynes P, Martin JL, Mellman TA, Neylan TC, Raskind MA, Ross RJ, Woodward SW, Zayfert C. Report of the Meeting of the Expert Panel on Sleep Disturbance and Combat Trauma. Rochester (NY); 2010.

*** Pigeon WR, Edinger JD, Epstein DR, Germain A, Haynes P, Martin JL, Mellman TA, Neylan TC, Raskind MA, Ross RJ, Woodward SW, Zayfert C. Report of the Meeting of the Expert Panel on Sleep Disturbance and Combat Trauma. Rochester (NY); 2010.

**** Pigeon WR, Edinger JD, Epstein DR, Germain A, Haynes P, Martin JL, Mellman TA, Neylan TC, Raskind MA, Ross RJ, Woodward SW, Zayfert C. Report of the Meeting of the Expert Panel on Sleep Disturbance and Combat Trauma. Rochester (NY); 2010.
Table 1.
Summary of studies of imagery rehearsal and cognitive-behavioral
therapy for insomnia and nightmares in trauma survivors and
individuals with posttraumatic stress disorder (PTSD).

    Authors               Treatment                  Treatment
                       Sample/Control

Cook et al.,      124 VN veterans w/PTSD/     Same model as Forbes
2010 [54]         "sleep and NM management"   et al. [51]
                  control intervention

Davis & Wright,   17 trauma survivors w/      Three 120 min groups;
2007 [55]         NMs, most diagnosed w/      ERRT; participants
                  PTSD, delayed treatment     "encouraged to utilize
                  control                     relevant themes" to
                                              change nightmares; SH/
                                              SC/PMR

Forbes et al.,    12 VN veterans w/PTSD,      Six 90 min groups; group
2001 [51]         no control                  dis- cussed potential NM
                                              changes; goal was
                                              "alterations that pro-
                                              mote mastery or control"

Germain et al.,   7 adult crime victims       One 90 min session;
2007 [72]         w/PTSD, no control          "participants No
                                              significant change were
                                              instructed to change NM
                                              they had had in any way
                                              they wanted"; SC/SR w/
                                              workbook

Krakow et al.,    169 women w/ PTSD from      Two 180 min group
2000 [49]         sexual assault, wait list   sessions, 1 60 min group
                  control                     session; "change NM any
                                              way you wish"

Krakow et al.,    60 females "predominantly   Same as Krakow et al.
2001 [50]         consisting of sexual        [49]
                  assault survivors w/
                  PTSD," treatment as usual
                  control

Krakow et al.,    62 assault or crime         Three 180 min group
2001 [64]         victims w/PTSD, no          sessions, 1 60 min group
                  control                     session; instruc- tions
                                              to change NM "any way
                                              you wish"; SH/SC/SR

Long et al.,      37 male veterans in PTSD    Six 90 min sessions,
2011 [74]         program, no control         "cognitive- behavioral
                                              skills for sleep
                                              management," exposure to
                                              original NM; imagery
                                              rescripting based on
                                              ERRT of Davis & Wright
                                              [55]

Lu et al., 2009   15 veterans w-PTSD and      Same model as Forbes
[53]              trauma-related NMs at       et al. [51]
                  least weekly, no control

Nappi et al.,     35 veterans experiencing    Four or five 60 min
2010 [52]         significant distress from   individual or 120 min
                  recurrent NMs, most diag-   group sessions;
                  nosed w/PTSD, no control    instructions to change
                                              NM "any way you wish"
                                              but "identify and
                                              elaborate on an
                                              alternative, neutral,
                                              and/or pleasant
                                              ending...that [would]
                                              not elicit negative
                                              affect or include
                                              distressing content"

Swanson et al.,   8 veterans w/ PTSD & poor   Ten 90 min groups; 5
2009 [61]         sleep, no control           sessions CBTI, 5
                                              sessions IR that
                                              "rewrote the nightmare
                                              to address core themes"

Ulmer et al.,     22 veterans w-PTSD          Six 60 min individual
2011 [73]         diagnosis, positive         sessions, 3 session of
                  screen for sleep            IR instructing
                  disorder, endorse-ment of   participants to "change
                  NMs; "usual care" control   NM in any way they
                                              liked"; 3 sessions of
                                              SC/SR/SH/CR

    Authors                Sleep                    Nightmare
                          Results                    Results

Cook et al.,      No significant             No significant
2010 [54]         change                     change

Davis & Wright,   Improvement on             Decreased NM
2007 [55]         questionnaire subscale,    frequency, intensity
                  restfulness after
                  waking

Forbes et al.,    Not measured               Decreased target NM
2001 [51]                                    frequency, intensity;
                                             no change in other
                                             NMs

Germain et al.,                              No significant
2007 [72]                                    change

Krakow et al.,    Improvement on             Decreased NM
2000 [49]         questionnaire              frequency, nights
                                             w/NMs

Krakow et al.,    Improvement on             Decreased NM
2001 [50]         questionnaire              frequency, nights
                                             w/NMs

Krakow et al.,    Improvement on two         Decreased NM
2001 [64]         questionnaires             frequency, nights
                                             w/NMs

Long et al.,      Increased total sleep      Decreased NM
2011 [74]         time                       frequency

Lu et al., 2009   No significant change      Decreased NM
[53]                                         frequency, nights
                                             with NMs

Nappi et al.,     Improvement in one         Decreased NM
2010 [52]         questionnaire, no          frequency, intensity
                  change on another

Swanson et al.,   Large effect sizes on      Large effect sizes
2009 [61]         self-monitoring & ques-    on NM frequency,
                  tionnaire measures         distress

Ulmer et al.,     Significant improve-       Decreased NM
2011 [73]         ments on self-monitor-     frequency
                  ing & questionnaire
                  measures

    Authors                 PTSD
                      Symptom Results

Cook et al.,      No significant
2010 [54]         change

Davis & Wright,   Decrease in
2007 [55]         symptom severity,
                  rate of diagnosis

Forbes et al.,    Decrease in
2001 [51]         symptom severity

Germain et al.,   Decrease in
2007 [72]         daytime intrusions &
                  arousal

Krakow et al.,    Decrease in
2000 [49]         symptom severity

Krakow et al.,    Decrease in
2001 [50]         symptom severity

Krakow et al.,    Decrease in
2001 [64]         symptom severity

Long et al.,      Decrease in
2011 [74]         symptom severity

Lu et al., 2009   Decrease in
[53]              symptom severity

Nappi et al.,     Decrease in
2010 [52]         symptom severity

Swanson et al.,   No significant
2009 [61]         change

Ulmer et al.,     Decrease in
2011 [73]         symptom severity

CBTI = cognitive/behavioral therapy for insomnia; CR = cognitive
restructuring; ERRT = exposure, relaxation, and rescripting therapy;
IR = imagery rehearsal; NM = nightmare; SC = stimulus control; SH =
sleep hygiene; SR = sleep restriction; PMR = progressive muscle
relaxation; VN = Vietnam; w/= with.

Table 2.
Summary of pharmacologic treatment for insomnia and nightmares in
trauma survivors and individuals with posttraumatic stress disorder
(PTSD).

  Pharmacologic           Study                   Sleep
      Agent               Design                 Results

SSRIs               Multiple large       Overall improvement
                    RCTs w/sertra-       in sleep quality
                    line, paroxetine,    but w/significant
                    & fluoxetine.        individual variation.
                    Small open trial
                    w/fluvoxamine.

Venlafaxine         Large RCT            Not reported in
                    (Davidson et al.).   Davidson et al.
                                         No difference
                                         compared w/placebo
                                         in large pooled
                                         analysis study.

Mirtazapine         Small controlled     Not reported in
                    trial (Davidson      Davidson et al.
                    et al.).             Not reported in
                    Large case series.   case series.

Nefazodone          Small uncon-         Improved sleep
                    trolled clinical     maintenance,
                    trials. One trial    total sleep time,
                    included             & SWS.
                    polysomnography.

Trazodone           Small RCT w/         Decreased midsleep
                    polysomnography      awakenings, increased
                    (Roth et al.).       sleep maintenance
                    VA survey of         & SWS.
                    effects upon         Improved sleep
                    insomnia.            disruption for 88%
                                         of pts.

TCAs                Three small          Little information
                    RCTs.                about benefit for
                                         sleep.

MAOIs               Phenelzine is        Phenelzine improved
                    most studied         sleep in open trial.
                    MAOI. Small
                    RCT & open
                    trials.

Prazosin            RCTs in veteran      Significant improvement
([[alpha].sub.1]-   (Raskind et al.)     in sleep quality.
adrenergic          & civilian popula-   Large effect size
receptor            tions (Taylor        (d = 1.0).
antagonist)         et al.).             Significant increase
                                         in total sleep time.

Guanfacine          Small RCT in         No difference in
([[alpha].sub.2]-   veterans w/PTSD      sleep quality
adrenergic          (Neylan et al.).     compared w/placebo.
receptor agonist)

BZs                 Placebo-             Ineffective in
                    controlled cross-    improving sleep
                    over trial w/6       quality.
                    combat veterans
                    (Cates et al.).

BZ Receptor         Large 6 mo RCT       Significant improvement
Agonists            w/eszopiclone        in sleep
                    for primary          onset, awakenings,
                    insomnia             total sleep time, &
                    (Krystal et al.).    quality of sleep.
                    Case series of       Improved insomnia.
                    3 combat veterans
                    w/PTSD.

Antipsychotic       Multiple RCTs        Olanzapine improved
Agents              as adjunctive        sleep. Risperidone
                    agents PTSD          study did not report
                    Tx. Risperidone      sleep results.
                    largest RCT          Quetiapine improved
                    (Krystal et al.).    sleep.
                    Chart review
                    for adjunctive
                    use of quetiapine.

  Pharmacologic               NM                     PTSD
      Agent                Results                 Results

SSRIs               Limited data             Significant overall
                    from large RCTs.         Sx improvement
                    Fluvoxamine              w/modest effect
                    helped relieve           size in large RCTs.
                    combat-related
                    dreams.

Venlafaxine         Not reported in          Significant
                    Davidson et al.          improvement in
                    No difference            re-experiencing,
                    compared w/ placebo      avoidance/numbing
                    in large pooled          but not hyperarousal
                    analysis study.          Sxs.

Mirtazapine         Not reported in          More effective than
                    Davidson et al.          placebo on some
                    Reduced frequency        measures of PTSD.
                    & intensity of NMs
                    in case series.

Nefazodone          Reduced frequency        Improved overall
                    of NMs.                  PTSD Sxs.

Trazodone           Effect on NMs not        Limited data on its
                    reported in RCT.         effectiveness for
                    Helpful for NMs          overall PTSD Sxs.
                    in 72% of pts.

TCAs                Little information       Amitriptyline &
                    about benefit for        imipramine helped
                    NMs.                     re-experiencing &
                                             arousal but not
                                             avoidant/numbing
                                             symptoms.
                                             Desipramine no
                                             better than placebo.

MAOIs               Little information       MAOIs more
                    about benefit for        effective than
                    NMs.                     TCAs for PTSD
                                             in comparative
                                             review.

Prazosin            Significant reduction    Efficacy for overall
([[alpha].sub.1]-   in frequency and         PTSD Sxs has not
adrenergic          intensity of NMs.        been established.
receptor            Large effect size
antagonist)         (d = 0.94).
                    Significant reduction
                    in frequency of NMs.

Guanfacine          Effect on NMs            No more effective
([[alpha].sub.2]-   not measured.            than placebo for
adrenergic                                   overall PTSD Sxs.
receptor agonist)

BZs                 Ineffective in           No benefit for
                    relieving NMs.           re-experiencing
                                             & avoidance/numbing
                                             Sxs.

BZ Receptor         NMs were not             No reports on
Agonists            studied.                 effectiveness of
                    Improved NMs.            these agents for
                                             overall PTSD Sxs.

Antipsychotic       NMs were not             Olanzapine improved
Agents              studied in olanzapine    overall PTSD Sxs.
                    trial.                   Risperidone did not
                    Quetiapine reduced       reduce overall PTSD,
                    NM frequency by          depression, or anxiety
                    25%.                     Sxs.

  Pharmacologic             Treatment
      Agent               Considerations

SSRIs               VA/DOD CPG
                    recommends SSRIs
                    as 1st line Tx for
                    overall PTSD, including
                    sleep disturbance.

Venlafaxine         VA/DOD CPG
                    recommends venlafaxine
                    as 1st line Tx for
                    overall PTSD.
                    Not recommended by
                    the AASM for Tx of
                    NMs.

Mirtazapine         May be helpful for
                    PTSD-related sleep
                    disturbance, but does
                    carry significant risk
                    for weight gain.

Nefazodone          May be helpful for
                    PTSD-related sleep
                    disturbance. Carries
                    rare but serious risk
                    for hepatotoxicity &
                    is not recommended
                    by AASM for Tx of
                    NMs.

Trazodone           Use is primarily limited
                    to Tx of sleep distur-
                    bance because of side
                    effects at higher doses.
                    Listed in VA/DOD
                    CPG as one of hypnotic
                    agents to consider
                    for PTSD-related
                    sleep disturbance.

TCAs                Not mentioned by VA/
                    DOD CPG as option
                    for Tx of sleep
                    disturbance. Carry
                    risk for cardiac
                    conduction problems &
                    anticholinergic side
                    effects.

MAOIs               Usefulness is limited
                    by side effects & need
                    for dietary restrictions
                    to avoid hypertensive
                    crisis.

Prazosin            Recommended by VA/
([[alpha].sub.1]-   DOD CPG as adjunc-
adrenergic          tive agent for Tx of
receptor            NMs. Recommended by
antagonist)         AASM as 1st line
                    Tx of PTSD-associated
                    NMs.

Guanfacine          Not effective for
([[alpha].sub.2]-   treatment of PTSD,
adrenergic          including sleep
receptor agonist)   disturbance.

BZs                 Not recommended by
                    VA/DOD CPG due to
                    concerns about signifi-
                    cant risk for dependence.

BZ Receptor         VA/DOD CPG suggests
Agonists            using this class of drug
                    as hypnotic agent rather
                    than BZs due to their
                    shorter half-life and
                    lower risk for
                    dependence.

Antipsychotic       VA/DOD CPG
Agents              recommends
                    that all antipsychotics
                    are to be avoided
                    for Tx of sleep
                    disturbance due
                    to their poor risk to
                    benefit ratio for this
                    indication.

AASM = American Academy of Sleep Medicine, BZ = benzodiazepine, CPG =
clinical practice guideline, DOD = Department of Defense, MAOI =
monoamine oxidase inhibitor, NM = nightmare, pts = patients, RCT =
randomized controlled trial, SSRI = selective serotonin reuptake
inhibitor, Sx = symptom, SWS = slow-wave sleep, TCA = tricyclic
antidepressant, Tx = treatment, VA = Department of Veterans Affairs.
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