Repurposing Low-Dose Clonidine for PTSD in Veterans

Study Overview
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Brief Summary
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Hypothesis: Veterans with PTSD prescribed clonidine will demonstrate improvements in PTSD symptoms, including daytime, nighttime, and sleep-related behaviors.

Detailed Description
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Military veterans with Posttraumatic Stress Disorder (PTSD) suffer emotionally, physically, and socially. They have higher rates of suicide,1 issues with anger/aggression,2 substance use disorder,3 or other life difficulties (e.g., mental health disorders, marriage instability, unemployment).4 However, current first-line treatments are only effective for around half of patients receiving treatment.5,6 This is problematic given that PTSD is relatively common with a lifetime prevalence in US veterans of 10 - 31%3,7 meaning that many military veterans and their families are suffering for lack of effective treatments. PTSD symptoms can be categorized into four clusters: re-experiencing, avoidance, cognitive or mood disturbances, and hyperarousal/reactivity.8 Symptoms may occur during the day or at night, thus disrupting sleep. Many symptoms are thought to be mediated through noradrenergic pathways. Specifically, noradrenergic overactivity may directly or indirectly affect irritability/aggression, hypervigilance, ability to concentrate, startle reactions, and sleep or other nighttime symptoms.9 These nighttime disruptions are especially problematic given that lack of sleep can exacerbate other PTSD symptoms directly or through associations with increased depression, heightened anxiety, and unstable mood/affect.10-12 Selective serotonin reuptake inhibitors (SSRI) are a first-line pharmacotherapy for PTSD, yet SSRIs do not target noradrenergic pathways, have reduced efficacy in veterans,13 and only weakly impact nighttime symptoms.11,14,15 To directly address hyperarousal and sleep, previous studies have tested medications targeting the noradrenergic pathway or sleep interventions, resulting in promising outcomes for a subpopulation of veterans with PTSD.16-27 Studies on prazosin, an antagonist of post-synaptic α1 noradrenergic receptors, have shown promise for veterans with PTSD.16,18 Clonidine is similar to prazosin and is proposed to have similar effects on PTSD; however, whereas prazosin and blocks the effects of norepinephrine, clonidine decreases norepinephrine release 28 and could therefore have greater effects on hyperarousal. Retrospective, open-label studies have suggested that clonidine use is associated with improvement in PTSD.16,17 However, no prospective studies have been published testing the effects of clonidine on PTSD, either in veterans or any other population. Hypothesis: Veterans prescribed clonidine will demonstrate improvements in PTSD symptoms, including daytime, nighttime, and sleep-related behaviors.

Official Title
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Repurposing Low-Dose Clonidine for PTSD in Veterans

Conditions
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PTSD, Posttraumatic Stress Disorder, Sleep

Intervention / Treatment
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* Drug: Clonidine Pill
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old US military veteran Currently has PTSD diagnosis as determined by clinical diagnosing or by the PI Screening score on PCL5 minimum of 40 (per data from previous studies36-38, a PCL5 score of 40 is roughly equivalent to a CAPS score of 30) Scores ≥10 on PCL5 items 1-5 (intrusion) or scores ≥10 on PCL5 items 15-20 From PCL5 questionnaire, must score the following minimum in each of the following categories: 1x score of 2 on Questions 1-5 1x score of 2 on Questions 6-7 2x score of 2 on Questions 8-14 2x score of 2 on Questions 15-20 Has score ≥3 on CAPS nightmare items B2 and E6 Speaks and understands English Willing to come into the clinic as programmed Exclusion Criteria: Pregnant or breastfeeding At Moderate or High risk of suicide based on past month column of the Columbia-Suicide Severity Rating Scale (CSSR-S) screen version - recent. Has acute or unstable mental illness or any cognitive issues which the PI determines would interfere with engagement in the study (e.g., active schizophrenia, uncontrolled bipolar, history of neurocognitive impairment, history of moderate-severe traumatic brain injury) Currently receiving exposure therapy Recently enrolled (<1 month) in other behavioral health therapies (exclusions made at the PI's discretion depending on therapy type and length since admission) Urgent hypertension (BP above 160/100) or symptomatic of hypertension (having a hypertensive emergency) Blood pressure under 100/60 or symptoms of low blood pressure (light headedness, dizziness, heart palpitations, or other symptoms as determined by clinician). Any contraindications to taking clonidine such as: Known hypersensitivity to clonidine History of 2nd or 3rd degree atrioventricular block History of sinus bradycardia History of pheochromocytoma History of Raynaud's phenomenon Stage 5 Kidney disease Recent myocardial infarction (<6 months) History of cerebrovascular disease or recent stoke (<6 months) Have used any of the following drugs in the past 30 days, unprescribed or not used as prescribed: Heroin Other opiates/analgesics Barbiturates Other sedatives/, hypnotics, or tranquilizers Cocaine Amphetamines Cannabis Hallucinogens Inhalants Currently have any of the following diagnoses: Opioid use disorder Cocaine use disorder Alcohol use disorder Cannabis use disorder Sleep apnea diagnosis with verbal indication of non-adherence to treatment Were prescribed clonidine within the last 6 months Any α2 agonist Catapres/Kapvay (clonidine) Aldomet (Methyldopa) Zanaflex (Tizanidine) Intuniv (Guanfacine) Lucemyra (Lofexidine) Any α1-adrenergic antagonist Prazosin Terazosin Doxazosin Silodosin Alfuzosin Tamsulosin Any opiate (e.g., buprenorphine, hydrocodone, oxycodone) Any antipsychotic medication Haldol (haloperidol) Loxitane (loxapine) Mellaril (thioridazine) Moban (molindone) Navane (thiothixene) Prolixin (fluphenazine) Serentil (mesoridazine) Stelazine (trifluoperazine) Trilafon (perphenazine) Thorazine (chlorpromazine) Abilify (aripiprazole) Clozaril (clozapine) Geodon (ziprasidone) Risperdal (risperidone) Seroquel (quetiapine) Zyprexa (olanzapine) Benzodiazepines Cyproheptadine Based on PI or study team assessment is cognitively unable to engage in the study Has a legal guardian

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, placebo-controlled, blinded crossover
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clonidine Phase<br>Participants will receive clonidine titrations across 6 weeks. Note that this is a crossover design, so patients will move across phases. | Drug: Clonidine Pill<br>* The study will use a flexible-dose adjustment schedule to identify the minimum dose needed to alleviate symptoms while also ensuring acceptable adverse effects. In other words, all subjects will start at the minimum dose (0.1 mg/night). Near the end of every week, each subject will be assessed for symptom alleviation and adverse events by asking the patient two questions from the CAPS-5 (questions B2 and E6. At baseline, each patient will have scored a ≥3 on each of these questions. If one or both scores remain at ≥3 and if any reported adverse events are marked acceptable by both the clinician and subject, then the dosage for the following week will be increased one level according to the titration chart. However, if both scores for these questions are ≤2 and any current adverse events are acceptable, then the dosage will remain the same. Finally, if any adverse events are deemed unacceptable, the clonidine dosage will be reduced to the lowest acceptable daily dosage.<br>|
| Placebo Comparator: Placebo Phase<br>Participants will receive placebo titrations across 6 weeks. Note that this is a crossover design, so patients will move across phases. | Other: Placebo<br>* Blinded placebo capsules will be provided to participants.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Pittsburgh Sleep Quality Index (PSQI) at 6 weeks into phase | Scored 0-21, where higher scores indicate worse sleep quality. | Week 6 of Current Phase | 
| Change from Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) questions B2 and E6 at 6 weeks into phase | Measures PTSD symptoms on sleep, with each question scored 1-4, where higher scores indicate more severe symptoms. | Week 6 of Current Phase | 
| Change from Baseline in PTSD Checklist-Military Version (PCL-5) at 6 weeks into phase | Includes 20 items with a severity score range 0-80. Includes the ability to treat each item rated as 2 = Moderately or higher as a symptom endorsed, which allows following the DSM-5 diagnostic rule which requires at least: 1 Criterion B item (questions 1-5), 1 Criterion C item (questions 6-7), 2 Criterion D items (questions 8-14), 2 Criterion E items (questions 15-20). In general, use of a cutoff score tends to produce more reliable results than the DSM-5 diagnostic rule. | Week 6 of Current Phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Patient Health Questionnaire (PHQ9) at 6 weeks into phase | Scored 0-27, where higher scores indicate greater depression | Week 6 of Current Phase | 
| Change from Baseline in Sleep Diary at 6 weeks into phase | Qualitative differences in the sleep diary responses | Week 6 of Current Phase | 
| Change from Baseline in quality of life scale (Q-LES-Q-SF) at 6 weeks into phase | Scored 16-80, where higher scores indicate greater quality of life | Week 6 of Current Phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTSD, veterans, military, sleep, adrenergic receptor