A Review of Neonatal Selective Serotonin Reuptake Inhibitor Withdrawal Syndrome
The purpose of this review is to define “neonatal selective serotonin reuptake inhibitor (SSRI) withdrawal syndrome” (NSWS) from a developmental perspective and outline its management strategies as described in the current body of literature, with a focus on pharmaceutical interventions. A literature search was conducted with PubMed, OVID Medline, Google Scholar, Embase, and Web of Science. Search terms included neonatal and SSRI combined with the Boolean operator “AND” coordinated with the terms withdrawal, poor neonatal adaptation, and neonatal abstinence syndrome. Non-pharmacologic interventions include appropriate hydration, nutrition, and providing a quiet and soothing environment for the infant. Most treatment algorithms for neonatal withdrawal syndromes involve in utero exposure to opioids and other psychotropics, and it is rare to find one that outlines specific guidelines for the management of NSWS. Symptomatic pharmacologic management should be individualized to the patient. Potential measures can include the administration of clonidine for tachycardia, hypertension, diaphoresis, and restlessness; phenobarbital for seizures; or chlorpromazine for agitation and irritability. There is generally no role for the use of morphine or methadone in the treatment of NSWS without combined exposure to opioids in utero. Without studies specifically designed to understand NSWS and guidelines on treatment, there is a lack of clarity regarding the management of neonates with this syndrome. There are limited data differentiating NSWS from neonatal opioid withdrawal despite these disease states being caused by different pharmaceutical agents. There needs to be clear and comprehensive guidelines inclusive of newer studies and comparative treatment efficacies to promote evidence-based practices surrounding NSWS.
Introduction
As many as 11.9% of women experience perinatal depression.1,2 Depression is associated with psychological alterations and psychosocial sequelae that can negatively affect pregnancy outcomes independently of drug exposure, such as inadequate maternal weight gain, underutilization of health care resources, smoking, substance use, preeclampsia, and suicide.3 The mainstay treatments for perinatal depression include cognitive-behavioral therapy and antidepressants such as selective serotonin reuptake inhibitors (SSRIs) including fluoxetine, paroxetine, sertraline, citalopram, and escitalopram.4
The National Birth Defects Prevention Registry estimates that approximately 100,000 infants born in the United States each year are exposed to SSRIs during fetal development, and about 70% of women taking SSRIs at conception continue them throughout pregnancy.1 While both perinatal depression and SSRI exposure can affect reproductive outcomes, SSRI treatment may present a more favorable risk-benefit balance than the risks of perinatal depression-related sequelae.2 However, prolonged fetal exposure to SSRIs is associated with physical and psychological signs of withdrawal in up to 30% of newborns.1,5
Controversy persists regarding the appropriate terminology for SSRI withdrawal. As a result, multiple terms have been used in the peer-reviewed literature to describe this condition, including neonatal abstinence syndrome (NAS), neonatal SSRI discontinuation syndrome, neonatal serotonergic discontinuation syndrome, neonatal serotonergic withdrawal syndrome (NSWS), poor neonatal adaptation syndrome, neonatal antidepressant discontinuation syndrome, and neonatal antidepressant exposure syndrome.6–12 The use of multiple and inconsistent terms has led to confusion and a lack of standardization in the literature. Systematic reviews by Fava and colleagues,13 Harvey and Slabbert,14 and Wang and Cosci15 emphasize that, based on the pharmacologic mechanism(s) underlying this condition (reviewed below), SSRI withdrawal rather than discontinuation is the proper terminology.13–15 This article will use the terms neonatal abstinence syndrome (NAS) to refer to withdrawal from in utero drug exposure leading to clinical symptoms, neonatal opioid withdrawal syndrome (NOWS) to refer to neonatal withdrawal from opioid exposure, and neonatal SSRI withdrawal syndrome (NSWS) to refer to neonatal withdrawal from SSRI exposure.
This narrative review aims to define NSWS, discuss its pathophysiology, and outline management strategies described in the current literature, focusing on pharmacologic interventions.
Materials and Methods
A literature search was conducted with PubMed, OVID Medline, Google Scholar, Embase, and Web of Science for articles published between 1995 and 2022. Search terms included neonatal and SSRI combined with the Boolean operator “AND,” coordinated with the terms withdrawal, poor neonatal adaptation, and neonatal abstinence syndrome combined with the Boolean operator “OR.” The explode feature and MeSH terms were used within PubMed and Medline. Articles on NOWS, articles that did not research the neonatal population, and articles not written or translated in English were excluded. Titles and abstracts were reviewed by at least 2 authors for inclusion in the narrative review, and full texts were obtained for relevant articles. Guidance was provided by faculty practitioners with formal training in drug information, medication-use safety and policy, neonatology, and pediatrics. A total of 120 articles were identified. Following the review process, 47 articles were excluded, and 73 articles were included in the final article.
Pathophysiology of NSWS
The underlying pathophysiology of SSRI withdrawal remains incompletely understood, and much of the current evidence is derived from preclinical rodent models. SSRI withdrawal likely results from the sudden lack of available serotonin (5HT) in the synapses of 5HT neurons in the brain, spinal cord, and gut, following adaptive changes in 5HT receptor sensitivity with chronic SSRI exposure.10 The SSRIs increase intrasynaptic 5HT in serotonergic neurons by binding to the high-affinity presynaptic 5HT transporter that is responsible for 5HT reuptake.11,12 The affinity of 5HT transporter for 5HT is decreased, resulting in an immediate increase in synaptic 5HT exposure, and the rapid appearance of typical SSRI adverse effects. In contrast, the antidepressant benefit of SSRIs typically requires 4 to 6 weeks of chronic dosing.11–14
The term neuronal plasticity describes adaptive changes in both synaptic number and function, and may help explain the delay in clinical benefits observed when starting SSRI therapy.14,16 Neuroplasticity appears to be mediated by the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the production of neurotrophic factors such as brain-derived neuropathic factor (BDNF), and glutamate, the primary excitatory neurotransmitter in the brain.16–19 Activation of the HPA axis causes an increase in cortisol secretion, contributing to neuronal atrophy in the prefrontal cortex and hippocampus, and behavioral stress reduces the function of BDNF.17 Chronic SSRI administration increases BDNF expression, enhancing synaptic formation and hippocampal neurogenesis.17 Abrupt SSRI discontinuation causes a sudden, temporary intrasynaptic deficiency of 5HT, inducing a stress response.10,14 Postsynaptic 5HT2C receptors are strongly implicated in regulating behavioral stress responses. Still, evidence also suggests the involvement of HPA axis activation, N-methyl-d-aspartate receptor signaling, and alterations in dopaminergic, adrenergic, and cholinergic transmission.14,20
Notably, the adaptive effects of chronic SSRI exposure on cortisol concentrations have been observed in neonates undergoing SSRI withdrawal.21,22 Pawluski and colleagues21 measured serum cortisol and corticosteroid-binding globulin concentrations in prenatal SSRI exposed (n = 25) and non-exposed (n = 40) neonates born by vaginal or cesarean delivery. Serum cortisol concentrations were significantly higher following vaginal delivery than by cesarean delivery, regardless of SSRI exposure (p ≤ 0.003), but in the subgroup born by vaginal delivery, serum corticosteroid-binding globulin concentrations were significantly higher in the neonates that had been exposed to prenatal SSRIs (p ≤ 0.009). No differences were observed in neonates delivered by cesarean delivery, regardless of SSRI exposure.21 Kieviet et al22 studied hair cortisol concentrations in 25 neonates exposed to prenatal SSRIs who developed withdrawal, 40 exposed neonates who did not develop withdrawal, and 105 neonates without prenatal exposure. The association of SSRI withdrawal and elevated hair cortisol concentrations was only evident in female neonates, with higher concentrations in those with withdrawal than those without withdrawal (p = 0.04).22
Clinical Presentation and Diagnosis
NSWS can present as a constellation of autonomic nervous system, central nervous system (CNS), and gastrointestinal (GI) symptoms that vary in severity based on gestational age, comorbidities, the SSRI characteristics (e.g., dose, protein-binding capacity, half-life, presence of active metabolites, and other pharmacokinetic parameters), and additional maternal risk factors such as duration of SSRI use and polydrug use during pregnancy.6–8 The onset of symptoms varies based on the pharmacokinetics of the SSRI used. The onset of symptoms typically occurs shortly after birth or within the first few days of life. Neonates who do not have symptoms within the first 48 hours are extremely unlikely to become symptomatic. A shorter drug half-life and longer time since last maternal serotonin norepinephrine reuptake inhibitor (SNRI) or SSRI ingestion are associated with an earlier onset of symptoms in the neonate. Symptoms of NSWS resolve hours to days after birth.7 In contrast, neonates with NOWS present with symptoms within 72 hours of birth or as late as 5 to 10 days after birth and can last 1 week to 6 months.
Klinger and Merlob7 divide the presenting signs and symptoms of NSWS into 4 domains, with an initial period of CNS depression, followed by CNS hyperactivity, GI disturbances, and respiratory symptoms (Table). The CNS depression phase commonly includes hypotonicity and poor sucking reflex, while the period of CNS hyperactivity often includes hypertonicity, restlessness, tremor, high-pitched or continuous crying, and disturbed patterns of sleep. Occasional autonomic nervous system signs and symptoms include temperature instability, diaphoresis, nasal congestion, and skin mottling. Common GI signs and symptoms include vomiting or regurgitation, poor feeding, and an uncoordinated sucking reflex, while respiratory difficulties commonly include tachypnea.7 Notably, in utero SSRI exposure has been shown to increase the risk of premature delivery and neonatal intensive care unit (NICU) admission.23 Yang and colleagues23 studied 214 pregnant women: 41 receiving an SNRI or SSRI, 79 with a mood disorder not treated with an antidepressant, and 79 control subjects. Compared with control subjects, newborns of mothers taking SNRIs or SSRIs were more likely to be premature (24.5% vs 8.9%; mean birth weight, 3304.3 ± 704.4 vs 3546.3 ± 567.8 g), have a 5-minute APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) score lower than 8 (6.2% vs 0%), and require NICU admission (33.3% vs 10.3%).
Approximately 2% of women taking an SSRI during their second- or third-trimester pregnancy are also using an opioid, 17% a sedative or hypnotic, and approximately 9% a benzodiazepine.8 Concomitant use of such drugs with SSRIs has been shown to increase the severity score of NSWS and the need for NICU admission during management.24–27 Symptoms commonly observed with both NSWS and NOWS include high-pitched cry, tremor, poor feeding, and loose stool. Restless sleep, increased muscle tone, hyperactive Moro reflex, exaggerated sucking, disturbances (fever, sweating, frequent yawning or sneezing, and nasal stuffiness or flaring), and tachypnea are more commonly observed with NOWS, although they can present in a newborn with NSWS.5,28 One key symptom that is more often seen in NSWS than in NOWS is persistent pulmonary hypertension.7 Another consideration in differentiating possible NSWS from other etiologies such as serotonin syndrome or acute neonatal encephalopathy is the mother’s medication history. A thorough medication reconciliation should be one of the first steps in assessing neonates with symptoms similar to NSWS, to distinguish symptoms from other disease states and medication withdrawals.10
The Finnegan Neonatal Abstinence Scoring Tool (FNAST) was developed to diagnose withdrawal in infants prenatally exposed to opioids, but has also been used to assess and track the progression of neonatal symptoms in SSRI-exposed infants.6,7 The Finnegan scoring system comprises 4 categories (CNS, Respiratory, GI, and Other symptoms), and classifies a score of 8 or above as severe, 4 to 7 as mild, and 0 to 3 as normal. Forsberg et al6 modified the Finnegan scoring system to monitor 205 neonates exposed to SSRIs in utero, and the modified Finnegan scoring system is now the most commonly used monitoring tool in the United States.5–7 This modified scoring system breaks down symptoms by organ class: CNS (21 points), Respiratory (6 points), GI (9 points), and Other (4 points). If the Finnegan score is ≥8, the neonate requires pharmacologic treatment. However, there are several limitations to using the Finnegan scoring system in the setting of NSWS. The clinical evidence to validate the cutoff score of 8 to necessitate pharmacologic intervention is lacking. The Finnegan score is often used to guide the management of NSWS simply because a validated instrument specific to NSWS is lacking, but results should be interpreted with caution.
Developmental Review
In regard to the impact NSWS has on development, there has been a reported slight delay (within normal limits) in the achievement of motor milestones in children exposed to SSRIs during gestation, but no differences were observed between the exposed and control groups at 19 months.29 Limited data are available that follow up exposed neonates through puberty, which is a critical neurodevelopmental stage.2
Exposed fetuses tend to have a shorter gestation length than unexposed fetuses, reduced fetal head growth, lower birth weight, pulmonary hypertension, other malformations at birth, and increased risk for social behavioral abnormalities.30,31 Because these are known effects of SSRIs, it has been associated with delays in developmental milestones early in a newborn’s life.32
Some studies have concluded that the differences in development are caused by other factors underlying treatment than the SSRI medication itself.30 To account for different lifestyle environments, one study focused on 45 pairs of siblings with ages ranging from 3 to approximately 7 years, where 1 sibling (mostly second-born) was exposed to SSRIs while their sibling was not. To assess each pair’s intelligence and behavior, the Wechsler Preschool and Primary Scale of Intelligence–Third Edition, Child Behavior Checklist, and Conners Parent Rating Scale–Revised were used. It was found that the intelligence quotients and rates of problematic behaviors were not significantly different. Thus, SSRIs were found not to be neurotoxic.33
The literature is not without limitations; many SSRI neonatal developmental studies include a small number of participants, children younger than 3 years, clinical disorders, and participants from clinics vs the general population.30
Acute Management of Neonatal SSRI Withdrawal Syndrome
The management of NSWS is not well defined in the literature and largely overlaps with the management of NOWS. All neonates with in utero exposure to SSRIs should be observed for at least 48 hours, and a FNAST score should be measured every 8 hours to guide therapy.7,34 Based on limited literature, if the score is ≥8 and the newborn presents with severe symptoms, they should be monitored in a NICU and treated until their NSWS signs and symptoms normalize to a score of ≤3.5,7 Although literature references the use of the FNAST score to guide therapy, there are varying clinical practices owing to the lack of a standard of care for the management of NSWS. Therefore, treatment should be individualized to the patient and targeted to manage the presenting symptoms. Current treatment strategies for symptomatic management include both non-pharmacologic and pharmacologic interventions.
Supportive Measures.
The primary goal of supportive care measures is to ensure the newborn remains comfortable through the withdrawal episodes. Mainstays of care during observation include appropriate hydration, nutrition, and providing a quiet and soothing environment.35 The mother can also swaddle the newborn and increase skin-to-skin contact, which can help improve the infant’s breathing and temperature regulation.36 In addition, breastfeeding in particular, has been theorized to decrease the duration and severity of withdrawal symptoms owing to the presence of SSRIs and their metabolites in breast milk, leading to continued exposure; however, this has not been studied in major trials and is an area for further research.7,36,37 The American College of Obstetricians and Gynecologists strongly recommends against the discontinuation of SSRIs for mental health treatment if the sole concern is the pregnancy or lactation status of the mother, because drug transmission is more limited through lactation than through fetal exposure. Additionally, more severe consequences can result from the abrupt discontinuation of SSRIs.38
Pharmacologic Interventions.
Generally, pharmacologic management should be considered when the FNAST score is ≥8 on 3 consecutive score measurements performed at intervals of 8 hours.7,34 In most cases of NOWS, treatment revolves around controlled re-exposure and tapering of the causative agent.7,39 However, there are no established data on the effects of using an SSRI taper schedule in neonates with NSWS. The following medications discussed in this section are used based on an individualized approach to treat the withdrawal symptoms associated with NSWS rather than to treat the pathology associated with the withdrawal.
Clonidine.
Clonidine has been studied as an adjunctive or monotherapy agent for the treatment of NSWS.38 Clonidine is an alpha-2-adrenergic receptor agonist and is proposed to reduce withdrawal symptoms through a negative feedback mechanism by inhibiting the CNS sympathetic activity. This results in a net reduction in autonomic activity, thus reducing the withdrawal symptoms of tachycardia, hypertension, diaphoresis, restlessness, and diarrhea.37 In case reports, clonidine has been used successfully as a first-line monotherapy agent over conventional agents in neonates exposed only to SSRIs in utero.40,41 The suggested initial dose is 1 mcg/kg, with a maximum dose of 4 mcg/kg administered orally every 3 to 4 hours (in contrast to the frequency for NAS, namely every 3 to 6 hours).40,42 This dosing regimen may vary, but is largely agreed upon in both SSRI and opioid-based NAS treatment studies. Clonidine is not commercially available in a liquid formulation but can be extemporaneously compounded as either a 0.01-mg/mL or 0.02-mg/mL oral suspension or solution from 0.1-, 0.2-, or 0.3-mg tablets. Notably, a 0.1-mg/mL (100 mcg/mL) concentration can be prepared, but this is too concentrated for neonatal dosing and can inadvertently lead to medication errors and patient harm. It is important to note that symptomatic bradycardia was seen in a case report after administering clonidine at a dose of 4 mcg/kg every 3 hours, highlighting the need for careful monitoring of heart rate during initiation.43,44 Symptoms pertaining to alterations in feeding, weight gain or loss, or blood pressure were not seen with significant changes throughout the course of reviewed studies. While benefits were observed, most evidence for this indication comes from case reports, which limits the generalizability of this recommendation.42 However, clonidine remains the most well-supported pharmacologic agent in the management of NSWS.
Other Pharmacologic Agents.
Other medications have been considered adjunctive agents to control symptoms associated with NSWS, but their use is limited by the lack of data in NSWS. Chlorpromazine has been used to decrease autonomic overactivity and promote sedation, making it beneficial in attenuating CNS symptoms associated with SSRI withdrawal.45–48 Common side effects associated with chlorpromazine that may affect the newborn include sedation, anticholinergic effects, and QTc prolongation.47 As a result, blood pressure, heart rate, and heart rhythm must be closely monitored. Owing to the adverse events associated with chlorpromazine and its need for extensive monitoring, it has fallen out of favor as a treatment option for NOWS. Evidence suggests that patients treated with chlorpromazine as a sedative for NOWS have higher rates of treatment failure, leading to its unfavorable use, but the same cannot be determined for NSWS owing to insufficient literature.48,49
Symptomatic pharmacologic management of NSWS may also include the administration of phenobarbital to control seizures, irritation, or convulsions. Phenobarbital is a barbiturate used as first-line therapy for neonatal seizures, given its high efficacy, low cost, and favorable adverse effect profile.47 The recommended phenobarbital dosing strategy varies considerably.45,50,51 However, significant adverse effects associated with phenobarbital include CNS and respiratory depression, as well as irritability, hyperactivity, and long-term adverse neurodevelopmental outcomes particularly in children. While respiratory depression may be avoided with therapeutic drug monitoring, phenobarbital’s other adverse effects cannot, which resulted in its falling out of favor for treating NSWS.47,52–55 Other antiepileptic medications have been studied for efficacy in controlling neonatal seizures, such as levetiracetam, but further research is needed to explore these alternative antiseizure agents in the setting of NSWS.56 Evidently, data support the clinical utility of phenobarbital in managing seizures associated with NSWS, but the risks must be carefully evaluated prior to its use.
Treatment for Mixed Neonatal Opioid and SSRI Exposure.
In the case of neonatal withdrawal from polypharmacy exposure to opioids and SSRIs, morphine and methadone can be used to promote analgesia and sedation. Morphine is a short-acting natural opioid, compared with methadone, which is a longer-acting synthetic opioid.57 Some studies show that neonates with NAS, inclusive of those with NSWS, are treated with morphine or methadone owing to in utero opioid exposure or polysubstance exposure to opioids and SSRIs. However, no studies currently exist providing clinical evidence of the use of morphine or methadone in the standalone setting of NSWS.37,57–63 Relevant side effects of methadone and morphine that limit their use are GI disturbances, poor feeding, CNS depression, respiratory depression, and general signs of rebound.21,62,64,65 Other opioid subsidiaries, including paregoric elixir and tincture of opium, were historically the drugs of choice but have since fallen out of favor owing to concerns for patient safety and the lack of standardization for their formulation composition.57,62,66 There is a lack of concrete evidence for opioid use in NSWS without opioid co-exposure, and by weighing the risks and benefits of opioids, these treatment options should be reserved for NSWS symptomatic management only if the mother’s medication history reveals that the neonate had a polysubstance in utero exposure to opioids and SSRIs. While phenobarbital is of key consideration for treating symptomatic seizures, it is also important to note its role in a mixed presentation. The use of phenobarbital has been traditionally preferred for non-opiate–related NAS, targeting symptoms of CNS irritability.50 Owing to the adverse overdepressant effects, such as decreased sucking reflex, and its ethanol-ethanol–containing commercially available formulations, resulting in potential adverse effects toward neurodevelopmental outcomes in infants, it has since fallen out of favor as a first-line agent.50,67
Clinical Trials and Research
As of the writing of this article, only 24 studies exploring NAS are registered in ClinicalTrials.gov. After excluding studies exploring NAS due to opioid use disorder, 1 study focused on the pharmacologic management of NAS in the context of SSRI exposure in utero. Challenges in studying this patient population include difficulty in recruitment during the COVID-19 pandemic, difficulty obtaining parental consent, and lack of a consensus on nomenclature. As SSRI use in mothers is becoming more prevalent, there is a substantial need for further research on developmental changes related to SSRI use, in addition to more effective treatment options for NSWS.
Conclusions
Despite the available literature on NSWS, much remains unclear regarding treatment strategies, awareness of this condition, and high-quality evidence and guidelines. With the rise in social media–led awareness of and initiatives on mental health—hoping to reduce the stigma surrounding this disorder—more women are finding guidance and empowerment through online support groups and forums to seek professional help for their perinatal depression.68 With the increased prevalence of psychiatric diagnoses among women of childbearing age, we may observe rising trends in both SSRI use as well as NSWS. Specifically during the COVID-19 pandemic, rates of depression diagnoses among pregnant women were higher than among postpartum women, even though rates for both of these population groups increased over time.69 Importantly, with greater willingness to accept treatments for depression during pregnancy, there has been a rise in antidepressant use among women from 10.6% to 13.8% over a decade.70 Diving deeper, retrospective data show that between 1996 and 2005, antidepressant use increased from 2.0% to 7.6%, with SSRIs in particular from 1.5% to 6.2%.71 Because SSRIs are first-line pharmacologic agents used for the management of depression in pregnant women, these agents are greatly used, leading to an increasing prevalence of risk for NSWS.72
Much remains unknown about the burden of NSWS, its natural course, and effective therapies. Part of the uncertainty lies in the confusing terminology used for neonatal withdrawal syndromes. Currently, the all-encompassing term of NAS includes the use of various substances that may precipitate neonatal withdrawal. Expenditure in NAS is known to be costly, with the average cost per infant estimated at $22,552. Compounded with the financial burden, more vulnerable populations who rely on Medicaid or are without insurance are reported to have the highest incidence.73 NSWS can be assumed to contribute to this cost, but the exact details have not been previously explored. Furthermore, the rise of polypharmacy approaches to depression therapy may complicate diagnosis and management. Pregnant women with depression may initiate SSRI therapy on a background of other medications for additional comorbidities, thus blurring the relationship between SSRI use and neonatal development.39 Additional factors to be considered include the lack of long-term studies that reliably follow up patients for delayed outcomes affected by changing environments and dysfunctional caregivers.37 Considering these points, there is a need for clear and comprehensive guidelines inclusive of more recent studies and comparative treatment efficacies to promote evidence-based practices surrounding NSWS.
Furthermore, there is immense overlap in the literature for terminology related to withdrawal associated with SSRIs, opioids, and other psychotropics despite these agents being used for distinct disease states. A simplified standard disease state name would facilitate delineating the different withdrawal settings and assist with various treatment options. Therefore, there is a need to agree on a specific name for withdrawal syndrome specific to SSRIs, such as the proposed neonatal SSRI withdrawal syndrome (NSWS). The distinction in naming could provide a clearer target for treatment research moving forward. Current research tends to group SSRI and SNRI use in pregnant women, further greying the specificity to SSRIs. In the same path, studies could be easily compared with a new modality for a diagnostic tool specific to this syndrome. Without studies specifically targeting populations with NSWS, there is limited literature for practitioners to provide care for affected neonates. They may also struggle to provide adequate context to affected patients regarding the potential risk of SSRI use during pregnancy.
The methodologic limitations of published studies introduce heterogeneity and uncertainty in the proposed NSWS pathophysiology and treatment models. The scope of this review was limited to SSRIs and did not include other agents such as SNRIs or atypical antidepressants that may be implicated in NAS. The objective in this limitation was to avoid generalized conclusions on the efficacy of SSRI and SNRI treatment when the studies used had a mixed tendency to group the 2 together or study only SSRIs. Given the involvement of vulnerable populations, most pathophysiologic models of SSRI withdrawal syndromes are rooted in animal models, which may not translate fully to human patients. Furthermore, the observational nature of most human NSWS studies introduces information bias in possible misclassification of antidepressant exposure, thus biasing estimates of NSWS sequela—recall of SSRI use may be increased in response to serious neonatal adverse effects. Finally, bioethical concerns complicate the prospective or interventional analysis of NSWS natural history; however, prospective analysis of treatment modalities may be reasonable given the lack of a single standard of care for treatment.
The path to better understanding NSWS requires clearer terminology, a mechanistic understanding of pathophysiology, and a more rigorously explored treatment algorithm. Currently, adaptive changes in 5HT receptors, cortisol concentrations, and synaptic function within the neonate are proposed as pathophysiologic changes contributing to NSWS. The current diagnosis and treatment determination is based on a modified FNAST scoring system, and treatment targets supportive measures using phenobarbital, clonidine, and, alternatively, chlorpromazine. Additional research for SSRI-individualized regimens is required to better understand the mechanistic patterns of withdrawal, and subsequently individualized treatment patterns to SSRI-related cases, from the generalized patterns currently recommended for NAS.
Contributor Notes