**5. Clinical treatment**

consolidation of fear conditioning (e.g., [96–102]). In addition to its roles in mediating fear memory and fear responses, the amygdala is important in the regulation of behavioral, physiological, and neuroendocrine responses to stress [103–105] and it appears to be a vital interface between stressful events, stressful memories, and their impact on sleep and arous-

The amygdala has a strong influence on REMS (e.g., [106–110]), which can be significantly altered by stress [48, 111, 72]. However, there is also evidence that the amygdala can influence all sleep-wakefulness states [107, 109, 110, 112]. This influence most likely involves amygdalar projections to thalamic, hypothalamic, and brainstem target regions [113] that are involved in the control of sleep and arousal. These include direct projections via the central nucleus of the amygdala (CNA; e.g., [114–118]) and the lateral division of the bed nucleus of the stria terminalis (reviewed in [113, 119]), the sources of the major descending outputs of the

The functional role of the amygdala in mediating the effects of stress on sleep has been demonstrated. For example, blocking inactivation of the CNA with microinjections of gammaaminobutyric acid (GABAA) antagonist, bicuculline, immediately following IS can eliminate the reduction in REMS commonly seen following IS [95]. Moreover, blocking inactivation of CNA can alter brain activation, as indicated by c-Fos (a marker of neuronal activity) in a manner consistent with the reduced effect on REMS. That is, there was a reduction in c-Fos activity in the locus coeruleus (LC), an area implicated in the regulation of REMS [120], consistent with enhanced REMS. By comparison, inactivation CNA with microinjections of the GABAA agonist, muscimol, did not significantly alter the reduction of REMS or c-Fos

In addition to its role in the acquisition and consolidation of fear conditioning (e.g., [96–102]), the basolateral nucleus of the amygdala (BLA) also appears to be critical for determining how and whether fear memories impact sleep. For example, the corticotropin-releasing factor antagonist, antalarmin, administered into BLA of rats prior to IS training blocked both ISinduced reductions in REMS and the formation of memories that alter sleep without blocking fear memory as indicated by contextual freezing [53]. By comparison, global inactivation of BLA with microinjections of muscimol prior to IS blocked the post-training reduction in REMS seen in vehicle-treated rats and attenuated contextual freezing and subsequent reductions in REMS [121]. Together, these data indicate that BLA plays a significant role in regulating the initial effects of stress and fear on sleep and in mediating the subsequent effects of fearful

Stressor controllability is an important determinant of the effects of stress and stress-related memories on sleep. The mPFC is a critical region in the perception of control and in mediating the consequences of stress [122–124]. For example, blocking activation of the vmPFC with muscimol in rats presented with escapable shock produced failure in escape learning and greater fear conditioning [124]. By comparison, activation of vmPFC with picrotoxin, a GABAA antagonist, prior to IS promoted later escape learning in rats provided an opportunity

amygdala to brainstem regions linked to the regulation of REMS.

26 A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice

activation in LC that can be produced by IS.

to escape shock in a shuttle box [124].

al.

memories.

Studies of the first-line treatments of PTSD, both psychotherapeutic and pharmacological, have rarely examined the effectiveness of these therapeutic modalities for PTSD-related sleep symptoms. This is especially concerning given the evidence for clinically significant residual sleep problems during and following PTSD treatment [127, 128]. In addition, persistent insomnia and recurrent nightmares can compromise treatment responses to empirically supported PTSD interventions.

#### **5.1. Psychotherapy**

The most widely accepted psychotherapies for PTSD are cognitive behavioral treatments (CBTs) and include PE and cognitive processing therapy (CPT) [129]. Galovski and colleagues [130] found that both PE and CPT were effective in reducing global sleep disturbance in adult, female rape survivors; however, sleep impairment remained clinically significant in both groups despite an overall improvement in PTSD symptoms. Gutner and colleagues [128] examined the long-term effects of CPT and PE on sleep disturbance. Similar to previous studies [130, 131], they found significant improvements in waking PTSD symptoms but no remission of the sleep disturbance.

CBT for insomnia (CBT-I) is a brief intervention aimed at improving overall sleep quality [132, 133]. It includes instruction in stimulus control (in order to reduce negative associations with the bed and bedroom) and sleep restriction (in order to increase sleep drive by first limiting, and then gradually raising, the amount of time allowed in bed); cognitive restructuring (to identify and challenge inaccurate beliefs that interfere with sleep); education in sleep hygiene; and relaxation training (to minimize physical and mental tension around sleep onset) [132, 134].

CBT-I may be beneficial for insomnia in PTSD. In a randomized clinical trial (RCT) of CBT-I compared to a waitlist control in a community sample in treatment for PTSD, the CBT-I group had a superior response on measures of sleep amount and quality [135]. However, both groups reported reductions in PTSD symptom severity and post-traumatic nightmares, limiting any conclusions that can be drawn about the therapeutic elements of CBT-I specifically.

Imagery rehearsal (IR) [136–138] is a form of CBT that targets recurrent nightmares. There is evidence that it promotes increased mastery of nightmare content and experience [139]. IR protocols share the following basic steps: choosing a repetitive nightmare, rescripting it during waking, and imaginally rehearsing the new dream script at bedtime. Two recent meta-analyses of predominantly uncontrolled trials of IR reported large effect sizes for nightmare frequency and sleep quality as well as overall PTSD symptomatology [137, 140]. However, a RCT in Vietnam War veterans with chronic, severe PTSD suggested that IR may hold no advantage over a comparison treatment with elements of CBT-I [141]. In a meta-analysis of studies of CBT-I combined with IR, a large gain in sleep quality was reported, but there was no significant improvement in PTSD severity and the nightmare disturbance [140].

#### **5.2. Pharmacotherapies**

The selective serotonin reuptake inhibitors (SSRIs) have the strongest evidence base among pharmacotherapies for PTSD [142, 143]. The use of selective norepinephrine-serotonin reuptake inhibitors (SNRIs), in particular venlafaxine, is also supported by clinical guidelines [142]. However, there is little evidence that insomnia and recurrent nightmares in PTSD respond to either the SSRIs or the SNRIs.

The tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) have not been studied in large RCTs in PTSD [144]. There is only weak support for the usefulness of these classes of psychotropic medication in controlling recurrent nightmares [145]. Considering the prominent REMS suppressant effect of the MAOIs and the evidence that most nightmares emerge from REMS, a methodical investigation of the MAOIs is warranted [145].

The atypical antipsychotic drugs have been minimally studied as a treatment for PTSD. One small placebo-controlled trial of adjunctive olanzapine for combat-related PTSD non-responsive to an SSRI found a greater improvement in sleep, as measured by the Pittsburgh Sleep Quality Index [146]. However, a larger study in veterans showed no significant effect of adjunctive risperidone [147]. There have been no completed RCTs of other medications in this class.

Little is known about the treatment of insomnia in PTSD with benzodiazepines, commonly used to treat other forms of insomnia [148]. Clonazepam, the mainstay of pharmacological treatment for REMS behavior disorder, could have a role in managing excessive movement during sleep in PTSD, a topic for future research. One RCT of the non-benzodiazepine receptor agonist eszopiclone reported greater improvements in PTSD symptoms including sleep disturbance [149].

As noted above, there is strong support for the alpha-1 adrenocepter antagonist prazosin as a treatment for the nightmare disturbance in PTSD. Four placebo-controlled trials of prazosin, two in veterans, one in active-duty US service members, and one in civilians, support its efficacy [12, 150–152]. Prazosin must be administered continuously to avoid the recurrence of nightmares. It is not known whether there could be a lasting beneficial effect after drug discontinuation.
