Abstract
Objective: Bupropion is often categorized as a newer generation antidepressant and assessed with serotonin reuptake inhibitors as a lower risk than older tricyclic antidepressants (TCAs). The objective of this study was to compare outcomes in adolescent suicide from ingestions between bupropion and TCA medications.
Study design: An analysis of the National Poison Data System for exposures coded “suspected suicide” in adolescents (age: 13–19) was undertaken for the years 2013–2016 and included TCAs or bupropion. We compared clinical effects, therapies and medical outcomes.
Results: Over the four-year period there were 2253 bupropion and 1496 TCA adolescent suspected suicide calls. There was a significant linear increase in bupropion ingestions over the four years. Across all years, there were on average 189.2 (95% CI: 58.1–320.4; p = .01) more ingestions of bupropion than TCA. When comparing bupropion to a TCA, ingestions of bupropion were significantly more likely to be accompanied by seizure (30.7% vs 3.9%; p < .01), to be admitted (74.8% vs 61.6%; p < .01) and medical outcomes to be coded as a major outcome (19.3% vs 10.0%; p < .01). The number of cases with death or major clinical outcome for both increased over the four-year period. Ingestions of bupropion were less likely to have hypotension (2.7% vs 8.0%; p < .01) and less likely to be intubated (5.6% vs 16.4%; p < .01) as compared to ingestions of TCA.
Conclusions: Adolescents who overdose on a single medication in a suicide attempt with bupropion have a statistically significant higher incidence of major outcomes and seizures. The risks of bupropion as a potential means of suicidal gesture by overdose must be considered, and weighed against its benefits and side effect profile when choosing an appropriate agent for the treatment of depression in adolescents.
Keywords:
Introduction
Adolescent ingestions represented approximately 10% of the over 2 million calls each year to the national poison centers in the United States. The majority of these were intentional ingestions [Citation1]. Unfortunately, the most common reason for ingestions in this age group is for self-harm. A recent study showed a decade of trends in adolescent suicidal ingestions and found that over-the-counter medications were most commonly used, but psychotropic medications including antidepressants and antipsychotics ranked in the top five most common agents [Citation2].
In early 2004, the Federal Drug Administration issued its first public health advisory about the increased risk of suicidality specifically in adolescent and young adults, on all currently available antidepressants, which included bupropion [Citation3]. Within 6 months of this initial public health announcement the advisory committee recommended adding a black-box warning for all antidepressants. Although bupropion now shares this Black Box warning with all antidepressants, since its release, the prescription patterns of medications for adolescent depression have changed with decline in SSRI usage [Citation3]. Currently, bupropion has Food and Drug Administration-approved indications for the treatment of major depressive disorder, smoking cessation, seasonal affective disorder, and as an adjunct agent for weight-loss when co-formulated with naltrexone. Often bupropion is used in the adolescent population, and may be preferred by some physicians and patients, as an agent more likely to improve energy and result in weight loss – a frequent issue in adolescent self-image and mental health [Citation4]. A report of medication errors that examined drug errors for antidepressants found that bupropion was the second most common antidepressant that has issues when providers initiate therapy [Citation4]. This is a concerning finding as bupropion has also been shown in the past to cause significant side effects when incorrectly taken or ingested for self-harm including a high prevalence of neurologic toxicity [Citation5].
Several factors make bupropion use in the adolescent population an important area for closer scrutiny. Emergency departments across the United States have seen steady increases in annual pediatric psychiatric visits [Citation6,Citation7]. Of the available medications to treat depression the SSRIs are the most common antidepressant used, and the use of tricyclic antidepressants (TCAs) has decreased due to poor adherence from side effects [Citation8]. The usage of bupropion has increased due to the perception that its side effect profile is more tolerable. The objective of this study was to analyze trends in bupropion intentional ingestions for self-harm, and compare this with the clinical effects produced by overdoses of TCAs. Many providers may avoid the use of TCAs due to the side effects and complications associated with ingestions, however we hypothesize that bupropion when ingested as an overdose in adolescents, may have substantial adverse clinical effects.
Methods
This was a retrospective observational study using data collected through the National Poison Data System (NPDS). This data is maintained, de-identified, and provided by the American Association of Poison Control Centers. Data are collected when a person or healthcare provider calls one of the US Poison Centers. The data are collected by specialists in poison information at each poison center and entered into a national database in real time using a uniform set of definitions and guidelines. The study population included all calls coded as “suspected suicide” ingestions in patients aged 13–19 years during the years of 2013–2016. Calls were coded by trained nurses and pharmacists after discussion with the caller. Data variables obtained included age, gender, route of ingestion, reason for ingestion, clinical outcome, and substance(s) ingested. Clinical outcome was coded using a priori definitions from the NPDS coding manual for: no effect, minor effect, moderate effect, major effect, or death [Citation9]. Minor effects include symptoms that are the result of the exposure, but are minimally bothersome to the patient. Moderate effects include symptoms that are more pronounced, more prolonged, or more of a systemic nature than minor symptoms. A major effect is when resulting symptoms from the exposure are life threatening or result in significant residual disability or disfigurement. If one of these effects was noted in the database the implication is that the patient had clinical effects that were related to the ingestion. Strict definitions for each clinical outcome can further be found in the NPDS coding manual version 3.1 [Citation9].
Prior to 2013, bupropion was not coded separately, but instead included in “Other Types of TCAs”; therefore, analysis was performed for 2013–2016. Single ingestions of bupropion and single ingestions of a TCA were included; we also included single ingestions of either agent, with only alcohol (ethanol beverage) coded as a second substance. Dual ingestions of both TCA and bupropion together were not included in this analysis, nor were ingestions or either bupropion or TCA with any other medication. The TCAs included amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, and “Other Types of Tricyclic Antidepressant (TCA)”. We looked at clinical effects overall, and clinical effects just in cases coded with more severe outcomes – moderate, major, and death. The most common clinical effects were compared for statistical significance. We also compared specific clinical effects (seizure, tachycardia, and hypotension), therapies used (intubation and vasopressors), and inpatient admission status, between patients ingesting TCA versus bupropion. These clinical effects and therapy groups were selected as likely reliably reported by bedside providers, since vital signs, major occurrences such as seizures and intubations are usually specifically asked about and reported when they occur.
Statistical analysis
Chi-square tests of association were performed to test for these relationships, and Fisher’s exact tests were use in the case of sparse data. Cochran–Armitage test for trends was used to determine if there was an increase in proportion of bupropion versus TCA ingestions over time. Cochran–Armitage tests for trend were also used to determine if the proportion of cases with intubation, vasopressors, seizures, or death/major outcome changed over time within cases of TCA or bupropion ingestions. Linear regression was performed to test for a change in the number of ingestions, intubations, seizures, vasopressors, or death/major medial outcome by year. An interaction term between year and substance ingested was used to test for a difference in the trend over time between substances ingested. All analysis was performed in SAS 9.4 (Cary, NC). All tests were two-sided, and an alpha of 0.05 was used as the threshold for statistical significance.
Results
There were a total of 3749 ingestions reported during the study period including 2253 bupropion and 1496 TCAs (26.5% vs 19.7%; p < .01). The most common TCA ingestion was amitriptyline (). When analyzed by gender, females made up the majority or overdoses in both groups, but men had more bupropion ingestions than TCAs (26.5% vs 19.7%; p < .01). Overall mortality was low (0.3% in each group) with 10 deaths in the overall study group, four in the TCA group and six in the bupropion group ().
Table 1. Distribution of tricyclic antidepressants.
Table 2. Outcomes for TCA and buproprion overdoses in adolescent self harm Poison Center calls.
When considering groups with more than transient minor effects, those coded as moderate or major outcomes or death (MMD) showed different constellations of symptoms (). Of the 10 most common clinical effects coded in this more seriously ill MMD cohort, the TCA group had statistically more notations of conduction disturbances and drowsiness. The bupropion group exhibited more episodes of hallucinations or delusions, single seizures, vomiting, tremor, tachycardia, and hypertension.
Table 3. Ten most common clinical effects in cases with moderate, major and death (MMD) outcomes.
When looking at the whole dataset of patients including those with minor or no effects those patients with a bupropion ingestion were significantly more likely result in any seizure (single or multiple) (30.7% vs 3.9%; p < .01), have accompanied tachycardia on presentation (67.3% vs 56.6%; p < .01), be admitted to the hospital (73.8% vs 61.6%; p < .01), and have a major clinical outcome coded (19.3% vs 10.0%; p < .01) compared to TCA ingestions. However, patients with a bupropion ingestion were less likely to exhibit hypotension (2.7% vs 8.0%; p < .01) and less likely to be intubated (5.6% vs 16.4%; p < .01) compared to TCA ingestions. There were only 59 co-ingestions with alcohol. There was no difference between bupropion and TCAs with need for vasopressor support (1.3% vs 1.2%; p = .74).
There was an overall increase in both TCA and bupropion ingestion cases where contact with a poison center occurred over the study period; for every progressive year studied, there was a corresponding increase of 70.8 ingestions (95% CI: 12.1, 129.4; p = .03). The proportion of bupropion versus TCA ingestions showed a significant increase during the study period. Bupropion accounted for 51.5% of ingestions between the two groups in 2013 and increased to 61.2% in 2016 (). There was an average of 189.2 more ingestions of bupropion than TCAs each year (95% CI: 58.1, 320.4; p = .01).
Figure 1. Number of suspected suicide ingestions of a single substance (or single substance plus ETOH) in teens. ETOH: ethanol; TCA: tricyclic antidepressant.
A test for trend found that the proportion of patients undergoing intubation, vasopressor support, seizures, or death/major clinical outcome remained stable over time for both bupropion and TCAs. However, the number of cases with death/major clinical outcome increased over time with 27.8 more cases per year (95% CI: 16.8, 38.8; p = .01). There was also noted a trend toward a yearly linear increase in seizure frequency with an additional 36.5 seizures per year (95% CI: −3.4, 76.4; p = .06) (). There was no significant trends for ingestions resulting in intubation or need for vasopressor support.
Figure 2. Single substance and substance with alcohol co-ingestions with major clinical outcomes, death, or seizures. ETOH: ethanol.
Discussion
Bupropion is an antidepressant used in adolescents that when ingested in a suicide attempt has significant clinical effects and a higher percentage of serious outcomes and hospitalizations than TCAs, which has classically been regarded as the highest risk antidepressant in overdose. Two concerning findings of our study are the rising number of calls to poison centers involving bupropion in this age group and the higher occurrence of seizures with overdose of this medication when compared with TCAs. This study shows that bupropion ingestions result in major clinical outcomes in nearly one out of five overdoses in adolescents, with almost a third of patients experiencing a seizure. This information is valuable to prescribing providers in terms of anticipatory guidance to parents of adolescents, and for emergency medicine providers to anticipate clinical events when caring for these patients.
With decreasing prescriptions of TCAs, other medications used for depression such as bupropion, have increased especially in the adolescent population. This usage pattern is not limited to North America. A recent study in Germany showed a decrease in TCA prescriptions from 0.9–0.6 prescriptions per 1000 minors [Citation10]. This study noted the prevalence of antidepressants to be between 1.7 and 2.1 per 1000 minors and approximately 40% of the prescriptions are used off-label. Another recent study across 40 psychiatric centers in 10 Asian countries showed approximately one-third of antidepressant medications being prescribed off-label in children [Citation11]. The uses of bupropion have been reported in the literature for multiple conditions including ADHD and smoking cessation in adolescents or other compulsive behaviors [Citation12–14]. This off-label use for ADHD has increased the overall prescribing rates of bupropion in adolescents.
Bupropion, which is available in both immediate and sustained release forms, can result in clinical presentation including seizures, hallucinations, agitation [Citation15,Citation16]. Serotonin syndrome may occur rarely when ingested with other agents. One recent report on bupropion ingestions showed that significant clinical effects occurred in 26% of cases, and approximately 11% of patients experienced seizures [Citation17]. Our data show a higher proportion of seizures. A major difference is that our study was isolated to adolescents. The previous study included ages 12–57 (mean age of 30) raising the concern that adolescents as opposed to adults are at higher risk for seizures. Future data prospectively collected may help to identify higher risk populations that can improve the appropriate selection of patients for bupropion use.
Our data highlight that among the more common clinical findings in patients with bupropion overdose is the risk of seizure experienced by almost a third of our patients. In a report from 37 toxicology centers evaluating drug-induced seizures in children, the authors identified antidepressants as the most common agents for drug-induced seizures; bupropion being the leading drug overall, followed second by anticholinergic agents [Citation18]. This study also noted that all bupropion ingestions in their study resulted from intentional self-harm. This further highlights the importance of careful patient selection for use of bupropion as well as very extensive anticipatory guidance to patients and their families.
One of the most challenging issues with bupropion ingestions is the timing for observation until medical clearance. This mainly originates from the risk for delayed onset of seizures. While the onset can vary with preparation ingested, the more commonly prescribed extended-release preparations pose a risk for delayed seizures. A recent study evaluated the incidence and onset of seizure in overdoses of extended-release bupropion [Citation19]. The study found that over a 3-year period, 31.6% of patients with an extended-release ingestion had a seizure with timing ranging from 0.5 to 24 h post-ingestion. In particular, 32% had an initial seizure at greater than 8 h from the time of ingestion and overall almost half of the patients went on to have recurrent seizures. The authors did find that patients initially exhibiting tremors, hallucinations, and tachycardia were at higher risk for seizure, however many patients without these initial manifestations of central nervous system toxicity may still experience a seizure [Citation19]. This unfortunately highlights the need for prolonged monitoring in what is often perceived as a stable and alert patient either in the emergency department or as an in-patient for up to 24 h. In our study three-quarters of all bupropion ingestions were admitted. Medical toxicology consultation or contact with a regional poison centers may help on patient disposition but even many patients with no warning signs exhibit late onset seizures, making the standard course to have a prolonged observation of these patients.
This study has a number of limitations. Inherent to any administrative database is the fact that data are recorded based on the caller’s degree of detail in providing information. While obvious events such as intubation, seizures, and vasopressor use are usually accurately reported, more subtle events such as agitation or hallucinations can be more likely underreported or overlooked by the reporting caller. The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org/) maintain the national database of information logged by the country’s 57 poison centers (PCs). Case records in this database are from callers: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance. Exposures do not necessarily represent a poisoning or overdose. The AAPCC are not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s). In this study, the true incidence of bupropion ingestions over time is most likely underrepresented as the data rely on a provider to call the poison center. This study only included patients coded as suspected-suicide and although coded by trained individuals this may have missed a portion of patients. Lastly, the timing of seizure in patients was not available in the database to further discuss the timing and necessary periods of observation.
Conclusion
This study shows that in cases of adolescents overdosing on an antidepressant medication reported to a regional poison center, clinical outcomes with major effects in bupropion exceeded those of TCAs over the four-year period 2013–2016. Use of either agent or calls to poison centers concerning them is rising. Notably adolescent suicidal ingestions of bupropion more frequently experienced a seizure than TCAs. While all antidepressants carry a similar black box warning for close vigilance of suicidality in adolescents and young adults, careful selection of patients at risk for suicidal gestures should be weighed when prescribing bupropion as its outcome in an overdose can be significant, and often underappreciated as to its morbidity. These potential risks of bupropion overdose must be considered in choosing an agent for treatment of depression in adolescents.
Disclosure statement
The authors have no conflicts of interest relevant to this article to disclose.
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References
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