Abstract
Sleep symptoms are important in pediatric PTSD, as disrupted sleep is a risk factor for developing PTSD, and the treatment of PTSD-related nightmares and sleep symptoms is associated with positive outcomes and overall clinical status improvement (Charuvastra and Cloitre 2009). Prazosin, which selectively blocks α-1 adrenoceptors, has recently been examined as a treatment for sleep problems associated with PTSD. Although used for the treatment of other medical problems, evidence-based studies suggest promising outcome for its utilization in treating nightmares and other comorbid sleep disturbances (Raskind et al. 2003; Miller 2008; Taylor et al. 2008; Strawn et al. 2009; Strawn and Keeshin 2011). In a few case reports, as well as in a randomized controlled trial, prazosin has been found to be effective in resolving sleep disorders related to PTSD (Brkanac et al. 2003; Raskind et al. 2003; Cohen et al. 2007; Miller 2008; Taylor et al. 2008; Strawn et al. 2009; Strawn and Keeshin 2011), but most of these studies are in the adult population. The cases we describe illustrate how the core symptoms of PTSD improved by use of other treatment modalities prior to initiating prazosin. However, prazosin was associated with addressing persistent nightmares and sleep disorders that did not respond initially to other treatments. It appears from these cases that prazosin's mechanism of action on sleep symptoms is different from that of other medications used to treat the core symptoms of PTSD. Sleep problems are a common symptom of PTSD and are particularly important to assess and treat as they are associated with PTSD severity (Caldwell and Redeker 2005; Belleville et al. 2009). We present two cases of adolescent patients with improvement in nightmares and other sleep-related symptoms while prescribed prazosin.
Case Presentations
Case 1
A 16-year-old female presented to the outpatient mental health clinic, with a 2 year history of PTSD that included hypervigilance, autonomic hyperarousal symptoms, and being easily startled. At the age of 14, the patient had been violently assaulted with a knife and sexually abused by three unfamiliar older boys. Several months after the trauma, the individual presented with almost daily nightmares of few older boys threatening her. She had difficulties initiating and maintaining sleep, with frequent early morning awakenings. Because of her insecurities and fear of being attacked late at night, she slept during the daytime from noon to 6 p.m.
She had excelled academically prior to the abuse, typically obtaining A and B grades. However, following the trauma her academic performance declined as her grades fell to D and F. She missed many school days and her social functioning also declined. She rarely interacted with friends and did so using only Internet-based social networking. She was largely homebound to avoid certain social situations; being in the presence of a group of males easily triggered memories and distress related to her past sexual abuse. Aside from mild obesity, her physical examination findings were nonsignificant. Weekly individual cognitive behavioral therapy was initiated to treat her condition. Although serotonergic antidepressant agents were offered, she agreed to initiate bupropion instead because of her fear of possible weight gain from the serotonin reuptake inhibitors (SSRIs). Extended release bupropion was initiated and titrated to a maintenance dose of 300 mg daily, with the addition of trazodone 150 mg at night to aid in sleep. After 6 months of medication management and therapy, some of the core symptoms (i.e., intrusion, avoidance, and hyperarousal symptoms) of her PTSD improved significantly. She was able to function better academically and socially, but continued to report persistent nightmares and insomnia. Trazodone was discontinued and prazosin was initiated at 1 mg at bedtime. Within 3 weeks, the nightmares subsided, but the patient continued to sleep during the day instead of at night. After 16 weeks, prazosin was increased to 1 mg in the morning and 2 mg at bedtime, and within 2 weeks of this increase her nightmares subsided and her sleep pattern readjusted to normal as she slept from 10 p.m. to 6 a.m. Her blood pressure and pulse rates were stable with no reported side effects, and her improved sleep was maintained.
Case 2
A 15-year-old female presented with multiple psychiatric diagnoses including mood disorder not otherwise specified and a learning disability. She had had five previous acute psychiatric hospitalizations between ages 8 and 14, with adjunctive treatment using multiple and adequate doses of different neuroleptic medications, antidepressants, and mood stabilizing agents. At the initial phase of psychiatric evaluation, she presented with symptoms suggestive of PTSD including: being easily startled, hypervigilance, recurrent nightmares of her death, fear of dying, and cognitive difficulties manifested by problems remembering some recent traumatic family events. Palpitations, diaphoresis, and insomnia were associated symptoms. She later revealed ongoing sexual abuse by a family member since she was 8 years of age. Although she reported a history of visual hallucinations of “a man without a face” and auditory hallucinations of a “male voice” instructing her to hurt herself and/or members of her family, she later revealed that she used these statements as an excuse to get out of the house to avoid the perpetrator of the abuse.
During re-evaluation at the outpatient mental health clinic, both the patient and her mother agreed that over the previous 4 weeks, she had been at her “highest level of functioning” since her symptoms had started at 8 years of age. Four weeks prior to the re-evaluation, a family member was arrested by police after the patient disclosed that he had molested her. To treat her PTSD symptoms, sertraline 50 mg was initiated and gradually titrated up to a maintenance dose of 100 mg. After the patient had been on the medication and had received adjunctive cognitive behavioral therapy for 3 months, the core PTSD symptoms subsided. However, she continued having recurrent nightmares of her own violent death and difficulty initiating and maintaining sleep, as she fell asleep at 1 a.m. but woke at least three times during the night before finally waking near 7 a.m. These sleep problems occurred at least four times in an average week. Physically, the patient had no significant medical illness except a past history of an uneventful tonsillectomy and adenoidectomy. Her recent annual medical evaluation by her pediatrician was normal; therefore, prazosin 1 mg at bedtime was initiated and increased to 3 mg at bedtime after 6 weeks. While on prazosin, the sleep-related symptoms significantly subsided after 8 weeks of treatment. Transient dizziness was an initial side effect, which lasted for 1 week but subsided without any further complication.
Discussion
Prazosin possesses high selectivity for α-1 adrenoceptors as opposed to other classical α-adrenoceptor antagonists (Davey 1982; Jaillon 1998; Miller 2008). This sympatholytic drug blocks α-1 adrenergic receptors on vascular smooth muscle, and therefore is used for treating arterial hypertension and congestive heart failure (Davey 1982; Jaillon 1998). These two cases, however, illustrate how prazosin may also be effective for sleep problems associated with PTSD in adolescents. PTSD in children and adolescents frequently presents with anxiety, depression, and/or disruptive behavior and, therefore, is often misdiagnosed, particularly as a mood and/or other type of anxiety disorder (Hamblen and Barnett 2009; Hamblen 2011). Obtaining a detailed history, collateral information, and comprehensive biopsychosocial evaluation of the subject is essential for accurate diagnosis. Early detection of abuse or other trauma is important; trauma- based therapy has proven to be effective in this population (National Center for PTSD 2007; Hamblen and Barnett 2009; Hamblen 2011).
Antidepressant drugs (Davidson et al. 2001; Becker et al. 2007), antiadrenergic agents (Raskind et al. 2003), α-2 adrenergic receptor agonists, clonidine (Harmon and Riggs 1996; Porter and Bell 1999), guanfacine (Horrigan and Barnhill 1996; Horrigan 1996), and the beta blocker; propranolol (Nugent 2007) have been successfully used in the adult population to treat PTSD. Although benzodiazepines have also been used, their long-term effect on cognition and their addiction potential renders them an unfavorable choice in this population. Mood stabilizers and/or antipsychotic agents have occasionally been used off label in treatment resistant cases (Jeffreys 2009). In youth, sertraline failed to show efficacy in two double-blind studies when compared with placebo (Cohen et al. 2007; Robb et al. 2010). In adolescent populations, the core symptoms of PTSD are generally treated with selective SSRIs, especially fluoxetine, paroxetine, and sertraline (Becker et al. 2007).
The hypothalamic–pituitary–adrenal axis is involved in the neuroendocrine responses to stress and is thus believed to play an important role in the neurobiology of PTSD (Newport and Nemeroff 2000; Medina 2008a,b). Subsequent adrenergic modification leads to exaggerated increases in cardiovascular responses to trauma-specific stimuli (Newport and Nemeroff 2000; Medina 2008a,b). This is manifested by an increase in urine, plasma, and cerebrospinal fluid catecholamines and decreases in platelet α-2 adrenoceptors. Unlike individuals with depression, patients with PTSD appear to have low cortisol levels prior to traumatic events (Meewisse et al. 2007; Yehuda et al. 2007). In PTSD, there is an increase in glucocorticoid receptors, strong negative feedback, and hypersuppression of the dexamethasone suppression test (Meewisse et al. 2007; Yehuda et al. 2007). Hence, it is prudent to use medications such as prazosin with pharmacodynamic actions that involve inhibition of the postganglionic action of the sympathetic nervous system (Newport and Nemeroff 2000; Medina 2008a,b). As hyperadrenergic states develop secondary to PTSD, this lipophilic, centrally acting drug showed effectiveness in several case reports (Perry 1994; Strawn et al. 2009; Strawn and Keeshin 2011). It reduces hyperarousability, intrusive thoughts, and nightmares in individuals with acute or chronic PTSD. In this population, high levels of noradrenergic activity occur during rapid eye movement sleep stage, compared with controls. Blocking this activity decreased nightmares and thus rapidly improved PTSD symptoms within the first month of its use. This was observed in both adult and pediatric studies of patients as young as 7 years of age (Brkanac et al. 2003; Fraleigh et al. 2009; Strawn et al. 2009; Strawn and Keeshin 2011). A similar scenario appears to have occurred in the two cases presented previously; the core symptoms of PTSD subsided but the nightmares and sleep disturbances persisted until the patient started prazosin. In an open label study, 12 adult individuals with PTSD showed symptom reduction when prescribed the long-acting hydrophilic α-1 receptor antagonist doxazosin (Jong et al. 2010). A review by Taylor and colleagues suggests that prazosin is a well-tolerated agent for the management of PTSD-related nightmares among adults (Taylor et al. 2008). Prazosin has been suggested as a first-line medication management of nighttime PTSD symptoms, as it was found to achieve better long-term effectiveness and a lower incidence of adverse drug reactions compared with quetiapine in a prospective cohort study of 324 combat veterans (Byers et al. 2010). Prazosin studies in adults include poster presentations, case reports, chart reviews, open-label trials, and randomized placebo-controlled trials, but there are fewer studies in the child and adolescent population (Davey 1982; Miller 2008; Taylor et al. 2008; Strawn et al. 2009). The available empirical data regarding dosing of prazosin in pediatric populations are limited, but extrapolated data from adult dosing suggest starting children at 1 mg at bedtime with an increase of 1 mg per week to a maximum dose of 4 mg in 24 hours (Strawn et al. 2009, 2010; Strawn and Keeshin 2011). In a case report, Fraleigh et al. 2009 reported improvements in PTSD-related nightmares in a 16-year- old male on prazosin 1.5 mg at bedtime. Some studies have suggested adult dosing up to a maximum of 15 mg in 24 hours (Strawn et al. 2010), but caution is required, because prazosin is used to treat hypertension. Consequently, it is essential to monitor the vital signs at a regular rate while patients are on prazosin (Davey 1982; United States Food and Drug Administration 2009). Other common side effects include headache, dizziness, weakness, palpitations, drowsiness, lack of energy and nausea (United States Food and Drug Authority 2009).
Conclusion
The positive outcome of these two cases is in keeping with the previous few studies of prazosin for treatment of PTSD, and, in particular, for sleep-related symptoms, in pediatric populations. Our case report adds to the growing literature suggesting that prazosin is an effective adjunct, promoting rapid symptom recovery in children and/or adolescents with PTSD. Hence, the authors recommend the consideration of this medication in younger populations with severe PTSD-related sleep disorders. Medical contraindications to prazosin include congestive heart failure caused by mechanical obstruction, hypersensitivity to the drug, pregnancy, and narcolepsy. Finally, comprehensive, multicenter, double-blind, randomized, placebo-controlled trials will be helpful to enable understanding of the role and efficacy of prazosin in the management of nightmares and other sleep disturbances associated with PTSD in pediatric populations.
Footnotes
Acknowledgments
The authors thank Drs. Amanda Rush and William Sonis for their assistance.
Disclosures
Drs. Oluwabusi, Sedky, and Bennett disclosed no financial ties or conflicts of interest.