Clinical Review

Evaluation of Clonidine and Prazosin for the Treatment of Nighttime Posttraumatic Stress Disorder Symptoms

Both clonidine and prazosin can be effective treatments for nighttime symptoms 
of posttraumatic stress disorder, but their long-term use may be limited.

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References

Posttraumatic stress disorder (PTSD) remains a significant health concern in veterans and military personnel. Whereas the lifetime incidence of PTSD in the U.S. general population is about 7% to 8%, the estimated prevalence of PTSD in deployed U.S. military personnel is higher than the national average, ranging from 11% to 17%.1,2 These numbers may be even higher, depending on the branch of service, responsibilities within the military, and specific conflict in which the veteran served. For example, one study found that 31% of Vietnam veterans have PTSD, and another recent study has reported PTSD in 28.7% of veterans returning from military service in Iraq and Afghanistan.3,4

Posttraumatic stress disorder treatment guidelines from both the American Psychiatric Association and the VA and DoD recommend the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) as first-line pharmacotherapy for PTSD.5,6 However, SSRIs and SNRIs seem to be largely ineffective for the management of nighttime PTSD symptoms, such as insomnia and nightmares.7,8

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Researchers hypothesize that the sympathetic nervous system plays a significant role in the hyperarousal component of nighttime PTSD. The heightened responsiveness and disruption in restorative sleep seen in PTSD have been attributed to increased activity of norepinephrine in the central nervous system.9 Mechanistically, therapies that attenuate the increased noradrenergic signaling might be effective in the management of nighttime PTSD symptoms.

The body of evidence for the use of adrenergic agents for nighttime PTSD symptoms is growing. Prazosin, a peripherally acting 
α1-adrenergic receptor antagonist, has recently been demonstrated to be effective for nighttime PTSD symptoms in veterans in a series of small, randomized controlled trials.10-12 Data to support the use of clonidine, a centrally acting α2-adrenergic 
receptor agonist, are generally limited, with the most compelling data coming from a population of civilian Cambodian refugees.13,14 A 2007 article by Boehnlein and Kinzie includes a thorough review of the preclinical research, case reports, and early clinical studies that have led to the widespread use of these agents for PTSD despite the lack of FDA approval for this indication.13A previous retrospective review by Byers and colleagues compared the effectiveness and tolerability of prazosin and quetiapine for nighttime PTSD symptoms in veterans.15 The results of that review suggest that α1-adrenergic agents may be equally effective and better tolerated than alternative medication options (ie, atypical antipsychotics) for this purpose. The present study was adapted from this design to report concurrently on the real-world use of clonidine and prazosin for the treatment of nighttime PTSD
symptoms.

Study Objectives

The primary objective of this retrospective chart review was to describe the experience of patients prescribed clonidine or prazosin for the treatment of nighttime PTSD symptoms, including initial effectiveness. The primary endpoint of initial drug effectiveness was documented improvement of nighttime PTSD symptoms in the patient’s chart within 6 months of the date of first prescription. Clonidine or prazosin was categorized as initially effective if a statement such as “frequency of nightmares decreased” or “patient’s nighttime PTSD symptoms have improved” was made within 6 months after initial prescription of the drug.

The secondary objectives of this study were to evaluate the long-term effectiveness and tolerability of prazosin. The endpoints used to assess these outcomes were the 2-year continuation rates of clonidine and prazosin (as a surrogate marker for long-term effectiveness) and the documented reasons for discontinuation of clonidine and prazosin for the treatment of nighttime PTSD symptoms (in order to assess tolerability).

Methods

An electronic database search was conducted to identify the VA Portland Health Care System (VAPHCS) patients with a diagnosis of PTSD who received a first prescription for clonidine or prazosin for nighttime PTSD symptoms from a VAPHCS mental health provider or primary care provider (PCP) from January 1, 2009, to December 31, 2011. Patients were excluded if they had any history of prior use of the drug being initiated, were co-initiated on both clonidine and prazosin (defined as starting the drugs within 30 days of each other), or had a concomitant diagnosis of schizophrenia, bipolar 
disorder, psychotic disorder, or cognitive disorder as defined in the 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Patients with traumatic brain injury (TBI) were excluded only if it could be determined that the event had resulted in lasting cognitive impairment.

Study Population

All patients with a diagnosis of PTSD who received a first prescription for clonidine during the period specified were screened for inclusion; patients with PTSD who were first prescribed prazosin during the same period were randomly sampled to equalize patient populations. This was done to maximize the data set while examining groups of roughly equal size for each drug, as prazosin is used much more commonly than clonidine for nighttime PTSD symptoms at VAPHCS. The patients in each resulting group were screened to determine whether they met inclusion and exclusion criteria. All subjects included were followed for 2 years from the date of the initial prescription.

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