Serotonin Toxicity Versus Withdrawal: Clonidine One Size Fits All?

Abstract

Serotonin discontinuation syndrome (SDS) can result in a constellation of symptoms exhibited by infants exposed to selective serotonin reuptake inhibitors or other psychotropic drugs during pregnancy. Currently, there is no consensus regarding the pharmacologic management of SDS. We report our experience with clonidine for the management of a term infant with poor neonatal adaption. The infant exhibited biphasic symptoms of acute toxicity at birth and a plateauing of symptoms, followed by subsequent withdrawal symptomatology requiring the use of clonidine in doses up to 4 mcg/kg/dose every 3 hours for control of symptoms. The 38-week gestation Caucasian male infant was born to a mother with major depressive disorder, which was managed with sertraline, trazodone, venlafaxine, and buspirone throughout her pregnancy. The infant exhibited severe hypertonia at delivery and continued to have hypertonia, tremors, hypoglycemia, and feeding issues upon admission to the NICU. The initial Modified Finnegan Neonatal Abstinence scores were extremely elevated, and clonidine was started at 1 mcg/kg/dose every 3 hours and then the dose was titrated up to 4 mcg/kg/dose. This is the first report documenting the use of clonidine to manage serotonin toxicity at birth followed by subsequent neonatal withdrawal associated with maternal antidepressant drug use during pregnancy.

Introduction

Affective disorders are among the most common mental health disorders in women of childbearing age.^1,2 Selective serotonin reuptake inhibitor (SSRI) use during the first trimester has been associated with congenital defects, while use during the third trimester has been associated with a constellation of postnatal toxicity and withdrawal symptoms. Antenatal SSRI exposure has also been reported to result in comorbidities such as hypoglycemia, feeding difficulties, CNS symptoms, and an increased frequency of respiratory disorders, including persistent pulmonary hypertension.^3,4 Differentiating symptoms of toxicity from those of withdrawal from SSRIs in the newborn is challenging in itself, but further complicating matters is the frequent poly-drug exposure with numerous antidepressant agents with additive effects on the serotonin system. Little is known about the degree and significance of this additive and potentially synergistic effect, particularly in the newborn CNS.

Serotonin discontinuation syndrome (SDS) describes the constellation of withdrawal or discontinuation symptoms exhibited by neonates exposed to psychotropic drugs during pregnancy. The ability of these psychotropic agents to cross the placental barrier results in poor neonatal adaption after discontinuation.¹ In neonates, it is difficult to discern if the symptoms exhibited postnatally are those of serotonin toxicity or serotonin withdrawal. Withdrawal symptoms and toxicity symptoms are largely overlapping and include jitteriness, tachypnea, hypertonicity, temperature instability, and diarrhea.⁵ These symptoms can be of varying degrees. Symptoms related to toxicity typically appear within the first 12 hours, while withdrawal symptoms typically emerge within the first 48 hours postnatally. Most symptoms have been described as short-lived but may persist for the first 2 to 6 days of life. Typically, symptoms require only supportive treatment; however, severe symptoms may warrant intervention.¹

Currently, there is no accepted consensus on the management of newborns with SDS. Adults who develop SSRI withdrawal following abrupt discontinuation of therapy are usually managed with reinitiation of the SSRI followed by a slow taper. Clearly this is not an option in the neonate, particularly if the symptoms are actually due to serotonin toxicity, which could further exacerbate the symptoms. Management of SSRI toxicity in adults with serotonin toxicity includes therapies such as benzodiazepines and cyproheptadine; however, currently there are no recommendations for management of newborns with SDS.⁶ A limited number of reports exist on the management of serotonin withdrawal syndrome in the neonate, describing use of haloperidol, chlorpromazine, and phenobarbital; however, no consensus on management exists.⁷

We report the treatment of a newborn with poor neonatal adaption who exhibited biphasic symptoms of acute toxicity at birth and a plateauing of symptoms, followed by subsequent withdrawal symptomatology. This is the first report documenting the use of clonidine to effectively manage discontinuation syndrome in the newborn.

Case

A 38-week Caucasian male infant was born via spontaneous vaginal delivery to a 37-year-old gravida 2, para 1 mother with a history significant for major depressive disorder. During pregnancy, the mother was managed with sertraline (200-mg tablet daily), trazodone (150-mg extended-release tablet daily), venlafaxine (150-mg extended-release tablet daily), and buspirone (5-mg tablets three times daily). Maternal history also included current nicotine use (5 cigarettes daily) and a prior history of alcohol, cocaine, and ecstasy abuse, although use during pregnancy was denied. The delivery was uncomplicated; however, the infant exhibited severe hypertonia and no spontaneous respirations. Resuscitation was performed, and a dose of naloxone was administered, given the maternal opioid exposure during labor and delivery. The infant was resuscitated at delivery, with Apgar scores of 1, 6, and 7, and was immediately transported to the NICU on continuous positive airway pressure (CPAP) via Neopuff.

Upon admission to NICU, the infant continued to have hypertonia, tremors, hypoglycemia, and feeding issues. He was small for gestational age (third percentile) and physical assessment was significant for intrauterine growth restriction. His immediate symptoms included tremors, myoclonic jerks, mottling, and a hyperactive Moro reflex. This resulted in a Modified Finnegan Neonatal Abstinence score of 19.⁸ Within the first 10 hours of life, the Finnegan scores dropped to 9 with nonpharmacologic interventions; however, at 15 hours of life the infant's Finnegan scores began to rise dramatically to 16, necessitating pharmacologic intervention. Clonidine was chosen to manage these symptoms at an initiation dose of 1 mcg/kg every 3 hours. Over the next few days, the Finnegan scores rose, peaking at 19 approximately 72 hours post-delivery, requiring titration of the clonidine up to a dose of 4 mcg/kg/dose every 3 hours (Figure 1).

Figure 1.

Finnegan score trend while receiving respective doses of clonidine and lorazepam.

While on the 4 mcg/kg/dose every 3 hours, the patient developed episodes of bradycardia, with the HR dipping to 80 beats/min (Figure 2). The ECG at this time was negative for QT prolongation; however, because of the concern regarding clonidine contributing to the bradycardia, the dose was titrated down to 3 mcg/kg/dose, and a test dose of midazolam was administered to manage persistent hypertonia. The infant exhibited a dramatic drop in Finnegan scores following midazolam administration (Figure 1); thus, adjuvant therapy with lorazepam (0.05 mg/kg/dose every 6 hours) was initiated on day of life 5 and clonidine was continued at 3 mcg/kg/dose every 3 hours.

Figure 2.

Infant heart rate at differing clonidine doses.

The Finnegan scores improved gradually over the next 12 days, allowing weaning and discontinuation of the lorazepam (Figure 1). Over the remainder of his hospitalization the clonidine was slowly weaned by approximately 10% of the total daily dose every 48 hours based on Finnegan scores and clinical presentation. The clonidine dose was not weaned if there were more than 2 consecutive Finnegan scores of >8 in the last 24 hours. Over the course of 38 days, the patient was weaned to a dose of 1.5 mcg/kg/dose (6 mcg every 8 hours). The patient was discharged home on day of life 44 on a clonidine dose of 1.5 mcg/kg/dose every 8 hours with close follow-up in the high-risk clinic for continued weaning at home.

Discussion

Differentiating the symptoms of serotonin toxicity from those of withdrawal in a neonate is challenging. In adults, symptoms of serotonin toxicity include confusion, fever, shivering, diaphoresis, ataxia, hyperreflexia, myoclonus, and diarrhea. In neonates, the typical CNS and gastrointestinal symptoms exhibited include crying, jitteriness, tremor, feeding difficulties, diarrhea, reflux, and sneezing.^7,9 Immediately after delivery, our patient developed severe hypertonia, tremors, and jitteriness, which is consistent with toxicity, particularly given the maternal use of numerous agents that increase serotonin. Unfortunately, we did not obtain a serum sertraline concentration, which would have allowed a more definitive diagnosis. However, the relatively abrupt onset of elevated neonatal abstinence Finnegan scores would lend to the argument that this was likely toxicity because withdrawal symptoms usually present at a later time because of the prolonged half-life of these agents. We believe the exposure to numerous agents acting on the serotonin system in this case amplified the symptoms of toxicity. Clonidine suppressed many of these initial symptoms related to toxicity by inhibiting sympathetic outflow, as evidenced by the drop in Finnegan scores.

On the third day of life, the patient exhibited elevated Finnegan scores, requiring aggressive titrations of the clonidine dose. We believe this second phase of symptomatology observed in our patient represented serotonin withdrawal. We believe that treatment with clonidine when the withdrawal symptoms presented may have masked the true severity of the withdrawal symptoms. Although the exact mechanism has yet to be elucidated, it is theorized that the 5-HT and norepinephrine (NE) systems are responsible for the symptoms associated with SSRI discontinuation. When exposed to SSRIs for an extended period of time, the increase in the synaptic concentrations of serotonin results in a downregulation of postsynaptic receptor. Additionally, inhibitory 5-HT tone on NE neurons is increased, which decreases the firing activity of NE neurons.¹⁰ Therefore, when there is no longer inhibitory tone because of drops in serotonin concentrations (as would occur with SSRI withdrawal), then one sees the increased hyperadrenergic drive. It is unknown if SSRI withdrawal occurs through this same mechanism in the immature brain of the newborn; the long-term effects on the developing brain are unknown as well.¹⁰

To date there is no widespread consensus regarding choice of pharmacologic options when treating neonatal abstinence syndrome (NAS), or, in this case, SDS in clinical practice. The AAP, however, currently recommends either morphine or methadone for first-line treatment of NAS symptoms. The AAP also acknowledges the growing evidence supporting clonidine as both a primary and adjunctive agent, particularly in the context of poly-drug exposure.¹¹

Clonidine is a central α₂-adrenergic receptor agonist. There is a growing body of evidence to support its use in the management of NAS. Cloni-dine appears to tackle the root cause of serotonin discontinuation symptoms by acting directly on pre-synaptic receptors in the midbrain and medulla. Its ability to decrease central catecholamine release results in a reduction in sympathetic outflow, thus targeting many of the autonomic nervous system responses, such as tachycardia and hypertension, that may arise with withdrawal. In addition, clonidine may play a role in managing SDS because of its ability to decrease the neurologic and systemic effects of excessive NE exposure.¹² The ability of clonidine to directly impact symptoms produced by the autonomic nervous system and the effects of NE make it an attractive option for neonates experiencing toxicity and discontinuation syndrome by targeting the root cause of the problem.

It has also been shown that clonidine may have less generalized cytokine suppression, meaning it has less immunomodulatory properties compared with agents like morphine and methadone, along with potential neuroprotective properties. Unlike opioids, which have been shown to elicit neuronal apoptosis, preclinical models have shown that clonidine protects against this neuronal cell death, possibly resulting in improved cognitive outcomes compared with those obtained with opioids.^12–14 Additionally, clonidine has a relatively low risk of significant adverse effects. Adverse effects reported with clonidine include hypotension, rebound hypertension, and bradycardia.

Although previous studies^12,15,16 have not shown clonidine to cause clinically significant bradycardia, our patient developed bradycardia, prompting a dose reduction. Studies to date have used a wide variety of dosing strategies, with most initial doses starting at 0.5 to 1 mcg/kg and with titrations increasing to 12 mcg/kg/day. In this report, the patient was titrated up to 4 mcg/kg/dose every 3 hours (32 mcg/kg/day) based on increasing Finnegan scores and his overall clinical presentation. Of note, our patient did develop episodes of bradycardia, with the HR dipping to 80 beats/min at the 4 mcg/kg/dose every 3 hours (Figure 2). At this time, the dose was titrated down to 3 mcg/kg/dose every 3 hours (24 mcg/kg/day). The maximum dose of 32 mcg/kg/day is higher than the doses previously reported and may have contributed to the development of bradycardia in this patient. Although QTc prolongation was not observed in our patient during his episode of bradycardia, it has been reported with clonidine use, and therefore monitoring is warranted, particularly with increasing doses.

The patient was discharged at 44 days of life on clonidine 1.5 mcg/kg every 8 hours to complete the tapering process on an outpatient basis. Although clonidine can typically be weaned in a shorter period of time compared with other agents used for withdrawal, in this case the patient was discharged home on clonidine to complete the weaning process. The prolonged weaning period could be due in part to the patient requiring higher doses than previously reported for withdrawal because of the compounded effects of multiple antidepressant exposure.^12,15,16

Conclusion

This is the first report of the use of clonidine for the management of SDS in a newborn. The infant exhibited significant discontinuation syndrome and poor adaptation with evidence of acute toxicity at birth and transient improvement, followed by the onset of classical withdrawal symptoms. Treatment with clonidine was initiated at 1 mcg/kg/dose every 3 hours, with titration up to a 4 mcg/kg/dose for control of symptoms. Concerns regarding the development of bradycardia prompted a dose reduction to 3 mcg/kg/dose. The clonidine was continued for the duration of the infant's hospitalization (44 days) and was subsequently weaned on an outpatient basis. Clonidine may provide an alternative treatment option for managing neonates with NAS; however, these patients should be monitored closely for adverse effects. Its ability to directly affect the mechanism causing symptoms associated with SDS and its potential ability to prevent neuronal apoptosis make it a more attractive option for neonates compared with opioid agents.

ABBREVIATIONS

AAP

American Academy of Pediatrics

CNS

central nervous system

ECG

electrocardiogram

HR

heart rate

NAS

neonatal abstinence syndrome

NE

norepinephrine

NICU

neonatal intensive care unit

QT

ECG interval from the QRS complex to the end of the T wave

QTc

corrected QT

SDS

serotonin discontinuation syndrome

SSRI

selective serotonin reuptake inhibitors