Psychopharmacological Strategies Employing Guanfacine in an Adolescent Girl with Postural Orthostatic Tachycardia Syndrome and Severe Posttraumatic Stress Disorder

Chief Complaint and Presenting Problem

B. was a 17-year-old adolescent girl, an only child referred by her adoptive mother for admission to a child and adolescent psychiatry inpatient service for violent visual hallucinations of self-harm, intrusive thoughts of self-harm, nightmares, and increasing emotional distress. She had a history of posttraumatic stress disorder (PTSD) secondary to multiple adverse childhood experiences.

History of Present Illness

B. was referred by her mother to the emergency department (ED) of an inner-city teaching hospital for 3 days of increasing emotional distress. B. had experienced occasional nightmares of being harmed by strangers for as long as she could remember, but her nightmares had increased to an approximately weekly occurrence before referral.

B. reported that her violent visual hallucinations and intrusive thoughts of self-harm began when she was walking home from school with friends. She began to experience “vivid visual hallucinations” of slashing her own throat and her head coming off. She reported that she could even feel the blood flowing down her body. She experienced severe disgust and described a feeling of “deep self-hatred.” She reported that she felt the compulsion to cut her own skin off.

B. stated that this was the first time she had ever experienced visual hallucinations this violent, although in the year before referral she had experienced other nonviolent visual hallucinations. She reported that she tends to “space out” in class. When her attention returned, she reported an overwhelming feeling that her teacher was no longer her teacher, and that someone else had taken her teacher's place.

B. also recounted that several months ago, she was looking in the mirror and saw that “another face” that was not hers was on top of hers, as if the face “shifted” and masked her actual face. She became disgusted at this sight and wanted to rip it off. She reported that several times in the preceding year she felt an overwhelming sense that her right arm was not in fact hers, which caused her to want to cut it off. She reported hitting her arm, knowing that she could not remove it. One month before her ED presentation, she reported she had scratched herself until she bled, “to feel something.”

B. reported an extensive trauma history, including losing her biological father to suicide as a small child. As a young child, she also witnessed her biological mother work as a sex worker. After loss of her father, B. was present when her mother attempted suicide. Ultimately, she was present at her mother's murder, the details of which in the present were unclear or difficult for B. to discuss. Subsequently, she experienced sexual abuse by her grandfather and physical abuse by a previous adoptive mother in a foreign country.

She was later adopted by her current adoptive mother in the United States at age 10 years, where she had a safe home. She denied current or recent psychosocial stressors. She reported that the only current stressors were these traumatic memories of her past, as well as frequent nightmares of murders in which she is the victim of and those in which she is involved in committing.

B. also described a feeling of being uncomfortable in her body. She described disliking her appearance and of “feeling fat”, while acknowledging that was maintained a healthy weight. Approximately 6 months before her referral, she reported she began vomiting after meals to make herself lose weight a few times a week for about a month. After reading about possible sequela of self-induced vomiting, she ceased this behavior and began to restrict her food intake and drink more water as a means to promote satiety for some time. She denied engaging in this behavior in the few months before her presentation.

B. was subsequently admitted from the ED to the inpatient child and adolescent service for treatment of severe PTSD symptoms.

Psychiatric History

B. had been cutting her lower extremities since the age of 16 years. Consultation with a psychotherapist in the community resulted in a diagnosis of PTSD and a course of weekly individual psychotherapy. At the time of her referral for hospitalization, her therapist stated that she was in the preparation phase of eye movement desensitization and reprocessing (EMDR) therapy, but that EMDR was not yet started.

There was no history of psychiatric hospitalization, previous suicide attempts, or violence.

Substance Use History

B. reported that she first used cannabis at the age of 15 years in a social settings about once a month with peers. For the few months preceding her hospitalization, her cannabis use increased to once every 2 weeks. She mostly smoked with friends. However, she sometimes began to smoke by herself because she believed it could help with her distress.

B. reported that she drank alcohol about once a month and only in social settings. She denied all other substance use.

Developmental History

Developmental history before age 10 years was unknown, including details of pregnancy, birth, and milestones. Adoptive mother reported no obvious developmental delay at age 10 years.

Educational History

B. was junior in high school in regular education in a public school system without an individualized educational plan. She performed well in school.

Social History

B. lived in a major metropolitan area with her adoptive mother. She reported plans to attend college to study law and to study abroad. She reported enjoying calling her friends on the phone. Before her adoption and relocation to the United States, she lived in an orphanage in a foreign country and had an extensive history of trauma.

Family History

Birth father died by suicide when B. was a few months old. Birth mother, a sex worker, had made a suicide attempt. Birth mother was murdered under uncertain but assumed criminal circumstances.

Medical History

B. had a history of childhood-onset asthma but had been asymptomatic for years. She had a history of migraines that she continued to experience occasionally. She was under the care of an outpatient neurologist for the migraines at the time of admission. She had been prescribed sumatriptan but had not used it in months.

B. was diagnosed with postural orthostatic tachycardia syndrome (POTS) at the age of 13 years. She described feeling dizzy, sweaty, and nauseated occasionally when standing up from a seated position. At the time of hospitalization, B. had not experienced symptoms of POTS within the past 3 years. She described that this created nervousness about making sudden movements, and worry that the symptoms would happen outside of home. B. reported she was instructed drink more water when this started, but she did not find this to be helpful. At the time of hospitalization, she believed that she had “outgrown” POTS, and that its symptoms would not return.

Medication History

A few weeks before hospitalization, B. was referred to a psychiatrist in the community. She was started on sertraline 12.5 mg daily that was increased to 25 mg daily for PTSD. She was started on olanzapine for sleep, but it was discontinued when her appetite increased, hydroxyzine 25 mg daily was started for insomnia with fair effect. At the time of her admission, her regimen consisted of sertraline 25 mg in the morning and hydroxyzine 25 mg in the evening.

Mental Status Exam

Upon initial examination, B. was a well-groomed adolescent appearing her stated age, lying in an ED stretcher with a blanket over her entire body. She was cooperative and revealed no psychomotor agitation or retardation. Her speech was normal volume, rate, tone, and prosody. She described her mood as “okay.” Her affect was full range, euthymic, and congruent to mood. Her thought process was linear, organized, and goal directed. Her thought content on initial assessment was significant for alluding to her prior traumatic experiences but not wanting to discuss them in detail. She denied suicidal or homicidal ideation. There were no perceptual disturbances. Insight and judgment were fair. Cognition was grossly intact.

Hospital Course

B. was admitted voluntarily to the child and adolescent psychiatry inpatient unit. Routine admission laboratory screening, including thyroid stimulating hormone, basic metabolic panel, and complete blood count with differential, was all unremarkable. Urine toxicology was negative. SARS-CoV-2 testing was negative.

On admission, the decision was made to continue sertraline to target PTSD symptoms. (See Table 1 for medication administration schedule.) Her standing hydroxyzine 25 mg was discontinued and switched to as-needed use. On hospital day 2, B. was erroneously given sertraline 100 mg instead of sertraline 50 mg as intended. She and her guardian were notified, and she denied any side effects from the error.

Table 1.

Medication Administration Schedule

Hospital day	Sertraline	Guanfacine	Trazodone	Other
1 (11/3)	25 mg			Hydroxyzine 25 mg
2	100 mg			Hydroxyzine 25 mg
3	75 mg	1 mg		Influenza vaccine 2021–2022
4	75 mg (6 am) 50 mg (6 pm)	1 mg		Hydroxyzine 25 mg Acetaminophen 650 mg
5	100 mg	1 mg		Ibuprofen 400 mg
6	100 mg	1 mg		Ibuprofen 400 mg
7	100 mg	2 mg	Trazodone 50 mg	Mirtazapine 7.5 mg Acetaminophen 650 mg
8	100 mg	2 mg	Trazodone 50 mg
9	100 mg	2 mg	Trazodone 50 mg	Acetaminophen 650 mg
10	100 mg	2 mg	Trazodone 50 mg

On hospital day 3, the decision was made to discontinue hydroxyzine 25 mg as needed, given that B. was still reporting trouble sleeping. Extended release (ER) guanfacine 1 mg at night was started for PTSD symptoms and insomnia and consideration of diagnosed hyperadrenergic POTS. B.'s sertraline was increased to 75 mg and then 100 mg daily on hospital day 5 and kept at this dose for the remainder of the hospitalization.

B. received guanfacine ER 1 mg nightly from hospital day 3 to hospital day 6, and on hospital day 7 guanfacine ER was increased to 2 mg nightly. B. continued to report poor sleep, as demonstrated by prolonged sleep latency and waking up during the night. Given persistence of insomnia, trazodone 50 mg standing at night was started on hospital day 7 to promote restful sleep, with rapid improvement in her reported sleep quality. On the same evening, she used an available as-needed order of mirtazapine 7.5 mg that had been available but not used since hospital day 3. Given B.'s rapid symptom relief, concerns surrounding weight gain caused by mirtazapine, and to reduce polypharmacy, mirtazapine 7.5 mg was subsequently discontinued, while trazodone 50 mg was continued for the remainder of the hospitalization.

B. initially reported an “okay” mood though showed an incongruent and constricted affect. Initially she was mostly withdrawn to her room and not engaging in the unit's milieu and activities. As with before admission, she reported nightmares of being chased by a mysterious figure that would awaken her and she would feel panicked. After 3 days of guanfacine, B. reported that her nightmares had resolved.

As sertraline was gradually increased from 25 to 100 mg daily from hospital day 1 to hospital day 5, she began to have a brighter affect. She engaged more in the unit milieu, including group, art, and individual therapy. Her outpatient therapist visited her while she was on the unit and noted that her affect had brightened and that she appeared ready to discuss past trauma that she had been more hesitant to discuss previously. She denied experiencing visual hallucinations while on the inpatient unit.

A nutrition consult was ordered to aid in the assessment of B's nutritional intake given a history of eating disorder symptoms. Her food intake during hospitalization and self-reported intake before hospitalization were deemed to be adequate nutritional intake. Nutritional counseling was provided.

On discharge, B. confirmed sustained improvement of her mood, resolution of intrusive images/flashbacks, and poor sleep. On hospital day 10, B. was discharged with prescriptions for sertraline 100 mg, guanfacine ER 2 mg evening, and trazodone 50 mg evening for continued outpatient care with her psychiatrist and a psychiatric nurse practitioner.

Brief Formulation

B. was a 17-year-old adolescent girl referred for violent visual hallucinations of self-harm, intrusive thoughts of self-harm, feelings of hopelessness and helplessness, and increasing emotional distress for 3 days before admission.

From a biopsychosocial perspective, biological factors include maternal and paternal family history, and medication for adverse effects. Family history was notable for father's suicide, mother's sex worker, and murder. These losses may have increased B.'s risk of mental illness, and may constitute exposures that met criteria for a PTSD diagnosis. The adverse effect of increased appetite from olanzapine although with uncertain real weight gain in the short duration with which it was used before her hospitalization may have hampered B.'s expectations of psychotropic medications, and may have contributed to possible nonadherence.

From a psychological perspective, B.'s trauma may have led to flashbacks and violent hallucinations. PTSD characteristics include problems with concentration, sleep disturbance, and self-destructive behaviors. B.'s loss of both her birth parents in childhood may have predisposed her to maladaptive attachment patterns. The loss of both parents, moving between orphanages, and finally being adopted suggest that B. may not have had consistent caregivers during what could have been her most formative years; these multiple losses may have predisposed her to difficulties with self-regulation and with internalizing parental figures.

B.'s experience of “spacing out” and having moments of feeling that her arm was no longer real may be consistent with derealization and depersonalization episodes. PTSD is characterized by avoidance and hyperarousal. Impulsivity and risky behaviors, such as self-harm and suicidal ideation, can be formulated as modes of avoidance in an elevated response to stress (Brereton and McGlinchey 2020). B.'s nonsuicidal self-injury could, therefore, be formulated as a maladaptive way of easing the distress associated with recall of her trauma and/or associated with her negative self-image.

Social factors include B's immigration to the United States, acculturation, and English as a second language. Moving to the United States during the formative years of her development likely posed additional challenges of integration into a new community while B. was forming her identity. Likewise, possible cultural differences between the cultures of her home country and the United States may have added additional challenges in navigating the psychological stages of development.

Multiaxial Diagnoses

I: PTSD with dissociative symptoms

Major depressive disorder, recurrent, severe, without psychotic symptoms

Cannabis use disorder, in early full remission

Alcohol use disorder, in early full remission

Unspecified eating disorder (resolved)

II: Deferred

III: Asthma, mild intermittent (resolved)

Migraine disorder

Postural orthostatic tachycardia syndrome

IV: Acculturation

V: Global assessment of functioning: 50.

Discussion

Introduction

POTS is an autonomic disorder characterized by an increase in heart rate of 30 beats per minute (bpm) or greater upon 10 minutes of standing in adults, and an increase in heart rate of 40 bpm or greater in individuals from ages 12 to 19 years (Freeman et al. 2011). Patients with POTS also experience symptoms of orthostatic intolerance including lightheadedness, weakness, diaphoresis, tremor, anxiety, exercise intolerance, and syncope, and these symptoms are generally relieved in the supine position (Kizilbash et al. 2014).

POTS is estimated to affect 0.1%–1% of the U.S. population; affected individuals are primarily adolescents and young adults, with females comprising 80% of all patients (Arnold et al. 2018; Fedorowski 2019). Adolescents with POTS generally report symptom onset ∼1 or 2 years after puberty, with a median age of onset at 13 years; symptoms are commonly precipitated by a febrile illness such as mononucleosis or influenza, and they often by the end of adolescence (Boris 2018). Many adolescents may avoid engaging in normal teenage activities out of fear of exacerbating their symptoms (Kizilbash et al. 2014). POTS can cause significant functional impairment in adolescents, including decreased tolerance of academic settings, social and athletic activities, and lead to depression and anxiety (Chen et al. 2020).

Cardiovascular considerations

The most common cardiovascular challenges encountered in patients with POTS are hypovolemia and blood pressure changes. There are three main subtypes of POTS in children and adolescents (hypovolemic, neuropathic, and hyperadrenergic), and they are all relatively equally distributed in the population (Thieben et al. 2007).

In hypovolemic POTS, low blood volume causes a compensatory increase in heart rate and causes vasoconstriction. These patients tend to have low levels of renin and aldosterone, which normally would be elevated in hypovolemia.

In neuropathic POTS, sympathetic denervation of vasculature in the lower extremities leads to vasodilation and excessive blood redistribution to the legs and reflex tachycardia.

In hyperadrenergic POTS, excess norepinephrine leads to increased sympathetic activity, and orthostatic hypertension may be seen in these patients due to baroreceptor dysfunction (Raj 2006; Zhang et al. 2020).

Psychiatric considerations

Several studies have found that adolescents with POTS experience mild to moderate levels of self-rated depression and anxiety and a diminished quality of life (Raj et al. 2018). Depressive and anxiety symptoms are positively correlated with specific orthostatic intolerance symptoms, such as chest discomfort, difficulty concentrating, and depression (Raj et al. 2018).

However, several studies have found that adults with POTS did not experience a higher lifetime prevalence of depression, anxiety, or panic disorder, and that the orthostatic symptoms associated with anxiety disorders such as palpitations, difficulty breathing, and dizziness were caused by the POTS itself rather than a separate psychiatric condition (Raj et al. 2009). It appears that the depression and anxiety experienced by individual with POTS are related to the psychological impact of living with a chronic medical condition, as the quality-of-life deficits experienced are similar to those of patients with heart failure and COPD (Moon et al. 2016; Raj et al. 2018).

Notably, a case report of a 19-year-old woman with PTSD developed orthostatic intolerance symptoms consistent with POTS including >125 bpm heart rate after table tilt, palpitations, and lightheadedness after the traumatic event; the authors suggest that central sympathetic activation after a traumatic event can trigger the development of POTS through a disturbance to the intracardiac neural network (Meyer et al. 2015). PTSD has been linked to decreased baroreceptor sensitivity, causing excess sympathetic activation and leading to autonomic dysfunction, possibly including POTS, although no studies have been done identifying PTSD as a risk factor for POTS specifically (Brudey et al. 2015).

Treatment of PTSD

There are several options for pharmacological treatment of PTSD in children and adolescents, including selective serotonin reuptake inhibitors (SSRIs), alpha- and beta-adrenergic blockers, antipsychotics, and mood-stabilizing agents (Cohen et al. 2010).

Propranolol, a nonselective beta-blocker, was found to reduce intrusive and hyperarousal symptoms in children with PTSD (Auxéméry 2012). Prazosin, an alpha-1 antagonist, has been shown to decrease nightmares and sleep disturbances in pediatric patients with PTSD in various case reports as systematically reviewed in 2017 (Akinsanya et al. 2017) and in subsequent retrospective (Hudson et al. 2021) and prospective (Ferrafiat et al. 2020) studies. Guanfacine, a selective alpha-2A agonist, can be used to reduce symptoms of PTSD, such as impulsivity and avoidance behaviors, by decreasing sympathetic activation of the central nervous system; studies have reported that guanfacine can decrease intrusive, avoidant, and hyperarousal symptoms in children and adolescents with PTSD (Connor et al. 2013; Anderson et al. 2020).

There are important cardiovascular considerations with each of these three pharmacological options. Propranolol use in children has been associated with bradycardia, hypotension, dizziness, and Raynaud phenomenon (Patel et al. 2018). Adverse effects of prazosin include orthostatic hypotension and reflex tachycardia; a study done on the effects of prazosin in children with PTSD found that a quarter of patients reported dizziness, anxiety, and headaches after prazosin administration (Keeshin et al. 2017). Lastly, although guanfacine has been found to decrease blood pressure and heart rate in children, these decreases in one large-scale study were found to be minimal and did not lead to any clinical symptoms, including orthostatic hypotension (Biederman et al. 2008).

SSRIs are currently the only medication class that is Federal Drug Administration (FDA) approved to treat pediatric PTSD; however, there are many drawbacks to SSRI treatment of PTSD, including their delayed onset of effect; efficacy studies have generally reported discouraging results (Keeshin and Strawn 2014). For these reasons, exploring the complications of propranolol, prazosin, and guanfacine in the treatment of patients with both PTSD and POTS merits consideration.

Conclusion

Clinical studies have demonstrated trauma-focused psychotherapies as efficacious for the treatment of PTSD in children and adolescents (Deblinger et al. 2015). Although there are medications that are FDA approved for treatment of PTSD in adults, no such medications have been identified for treatment of PTSD in children and adolescents.

The empirical literature regarding the use of medication for treatment of PTSD in childhood and adolescence can be expanded, which would ideally lead to more evidence for specific medications for youth who suffer from PTSD. This case report suggests that the use of guanfacine in an adolescent with POTS is safe and may not worsen POTS symptoms. It provides a potential approach to utilize guanfacine to reduce PTSD symptoms including intrusive and hyperarousal symptoms, and nightmares. Guanfacine in combination with an SSRI may help to reduce the frequency and intensity of PTSD symptoms in children.

Disclosures

B.J.C. is on the scientific advisory board of Teva/Nuvelution, received honoraria from the American Academy of Child and Adolescent Psychiatry, and Partners Healthcare and the Psychiatry Academy. She has received research support from Neurocrine Biosciences and NIMH, Emalex, and Teva/Nuvelution. She is cochair of the medical advisory board of the Tourette Association of America (TAA), and on the speakers' bureau for the TAA-CDC Partnership. The other authors have no other disclosures.