It is 8:30 pm at the WV Poison Center and the evening rush is in full-force. I am preparing for a night full of overdoses and medication events to manage when the physician in the emergency department calls with a patient who, “just prior to arrival,” ingested an “unknown amount” of their own Wellbutrin XL 300 mg in a self-harm attempt (attempting pill counts with intentional exposures are not helpful, clinicians are better off assuming all of what was in the bottle, if not more, was ingested).
Gulp, time to buckle up and get ready for a difficult shift.
Throughout my four and a half year career in toxicology, there were certain exposures that immediately increased my anxiety and made me sink in my seat. Words such as antifreeze, windshield wiper fluid, moonshine, button battery, drain opener, colchicine, amlodipine, digoxin, lithium, baclofen, glipizide, methotrexate, hydroxychloroquine, atenolol, propafenone, benzonatate, amitriptyline, clozapine, and bupropion illicit a special sense of dread that still make my hands sweat and heart race. Now in my role as a psychiatric prescriber, some of the same substances I was vigorously working to remove from someone’s body are the ones I am prescribing.
Overdoses on Wellbutrin are one of the many reasons why I expanded my knowledge and continued my education so I could move up the chain and work to prevent. My passion for psychiatry is fueled by the horrific cases I managed and I do so with the patients and their families in mind every single day. I will fight back against mental illness with every fiber of my being until I take my last breath.
Wellbutrin (bupropion), a norepinephrine and dopamine reuptake inhibitor, is one of the most common antidepressants used in psychiatry. I have seen its benefit in relieving depression and its diversity in targeting an array of mental health symptoms. However, because of its favorable side effect profile, tolerability, and diversity, its lethality is massively under recognized in the medical community.
Throughout my education, tricyclic antidepressants were always cautioned as the most lethal psychiatric medication. It is a fact I will not dispute. The evidence is clear, even though TCAs are not near as prevalent today. However, I have managed hundreds of TCA overdoses over the years.
The treatment for a TCA overdose is fairly straightforward. The patient presents with central nervous system depression, hypotension, tachycardia and/or seizures. They are rehydrated, given vasopressors if needed, benzodiazepines for seizures, intubated for airway protection, a 12-lead EKG is performed and aggressive supportive care is underway. If the QRS is greater than 120 msecs, systemic alkalinization with sodium bicarbonate (in D5W, not NS) is initiated, keeping the arterial pH above 7.45, not to exceed 7.55, until the conduction delay is corrected. If the patient’s OTc is greater than 500 msecs, they are given multiple grams of intravenous magnesium. As long as someone does not try to administer activated charcoal (even worse if given through a nasogastric tube), the patient usually does pretty well.
Wellbutrin in overdose is more complex and while it presents similar life-threatening effects, they are much more difficult to treat.
Seizures following a Wellbutrin exposure are expected and the questions will be, how many will the patient have and can they be stopped before the patient goes into cardiac arrest?
It is commonly known Wellbutrin decreases a person’s seizure threshold, but as long as taken as directed, they are rare. This is even more true with the XL formulation (remember immediate release was briefly removed from the market in the 1980s), which is the most commonly used in practice. The problem, however, is the seizure risk markedly increases once the dose exceeds 600 mg. Given Wellbutrin XL is dosed 150 mg to 450 mg per day, as little as a double dose at the FDA approved maximum taken within a 16 hour time period, has the potential to be a medical emergency.
Seizures from a Wellbutrin XL overdose can be significantly delayed. Among the most common questions asked by physicians in the emergency department to the Poison Center is how long do we watch them, do they need admitted, and do they need to be admitted to the ICU? A large majority of drug overdoses can be medically cleared if the patient has been asymptomatic for 6 hours. With Wellbutrin XL, the time of observation is a required 24 hour observation period from the time the patient checks in to the hospital (time of arrival to the hospital is most commonly used to start the observation timer unless the ingestion was directly witnessed). This is because patients who overdose on Wellbutrin XL can be asymptomatic or mildly symptomatic 6 hours post-ingestion. In fact, many patients who overdose on Wellbutrin XL do not begin to have seizures until 6-8 hours post-ingestion. What starts as a tremor or mild agitation, quickly turns life-threatening. If the patient is medically cleared following a standard 6 hour observation period where they are asymptomatic or mildly symptomatic, the risk is they can be discharged before life-threatening effects are witnessed.
The 24 hour observation period for a Wellbutrin XL overdose is something I have personally been screamed at over and I have seen disregarded by providers (yes, I realize the ER is full and there are no beds upstairs). There are multiple case reports where patients have been medically cleared following shorter periods of observation and have gone on to have seizures and subsequent cardiac arrest. I once managed a case where the patient had their first seizure 20 hours post-Wellbutrin ingestion.
Not only are seizures from a Wellbutrin XL overdose delayed, they can be difficult to stop. The obvious concern is for a patient developing status epilepticus and subsequent cardiovascular collapse. I always cautioned providers that it was best to get ahead and to treat any tremor, agitation, or tachycardia (there are case reports on heart rate being a predictor of Wellbutrin-induced seizures) with an intravenous benzodiazepine. It is imperative to give liberal doses of BZDPs because Ativan 1 mg every four hours as needed is not going to be sufficient. I would always urge providers to consult directly with our medical toxicologist for guidance on aggressive benzodiazepine dosing, warning this will exceed standard hospital protocols (and make nurses extremely nervous). The treatment for overdose seizures is benzodiazepines, not traditional anticonvulsants like Keppra or Phenobarbital.
Life-threatening cardiac arrhythmias secondary to a Wellbutrin overdose are not as common as seizures, but widening of both the QRS and QTc intervals can be seen, especially after the patient begins having seizures. As with a TCA overdose, multiple grams of intravenous magnesium are recommended for QTc prolongation in attempt to stabilize the myocardium. However, unlike a TCA overdose, QRS widening secondary to a Wellbutrin overdose is from impaired intracellular communication at the gap junctions, not sodium channel blockade (I look at it like the sodium channels are the door to the hotel room, while the gap junctions are the doors inside hotel rooms that connect rooms). For this reason, systemic alkalinization with sodium bicarbonate is ineffective. I would always tell providers they could attempt it, especially because most overdoses involve co-ingestions, but if the QRS widening is from Wellbutrin, systemic alkalinization will not correct the conduction delay and the patient is at high risk for developing ventricular tachycardia. Once the patient goes into ventricular tachycardia, intravenous lidocaine, intralipids, and prayer are the best options.
There is research to support using intralipid therapy to stabilize patients with a Wellbutrin overdose. However, this treatment is not first-line, and only attempted as a last resort. Often times providers will want to start by giving intralipids, but this approach is far from a guarantee and presents multiple complexities, including the inability to obtain accurate labs after initiated (in other words, it is unlikely to work and you are going to be “flying blind” once you start). Treating an overdosed patient with intralipids should only be performed under direct consultation with a toxicologist.
Back to my example patient in the introduction, when I would receive a call like this, I would often be asked about the use of activated charcoal, among other gastrointestinal decontamination techniques. The use of activated charcoal varies depending on the toxicologist and while it may be seen as a low-risk intervention, that is a misconception. Aspiration pneumonia secondary from vomiting activated charcoal is the last thing any overdosed patient needs and the risk often does not outweigh the benefit. Time of ingestion can be difficult to predict and if activated charcoal is not given within two hours of ingestion, its effectiveness is limited. If the provider was intent on giving AC, I would always remind them the patient needs to be alert enough to drink it, and not currently nauseated or vomiting. Inserting a nasogastric tube to administer AC is inappropriate and greatly increases the risk to the patient for developing aspiration pneumonia. AC is used much more often in Kentucky or Ohio, compared to West Virginia or Pennsylvania (again, it depends on the toxicologist).
Wellbutrin cannot be dialyzed and whole bowel irrigation is not standard treatment (if WBI is being considered, it should only be initiated with direct consultation with a toxicologist). The key to a good outcome following a significant Wellbutrin exposure is aggressive sedation, close cardiac monitoring, and supportive care. Admission to a critical care unit is advised due to the potential for rapid status change and decompensation. If the patient is admitted to a med surge or intermediate care unit, the patient must be on a continuous cardiac monitor and there needs to be an immediate plan in place to move the patient to intensive care. Nurses on non-critical care units taking care of these patients need to be educated about the importance of vigilant and frequent monitoring for agitation, tachycardia, hallucinations, and tremors as these are all symptoms that precede seizures.
The complexities of treating a Wellbutrin exposure include a lengthy period of observation, significantly delayed seizures, and cardiac arrhythmias that can be difficult to treat.
Now after reading above, you may be able to see why Wellbutrin is a villain of the toxicology community. But that is no longer my role and my role is to adequately treat a person’s mental health symptoms. As I detailed above, Wellbutrin is a well-tolerated, effective, and safe medication when taken as directed. I use it on a daily basis with continued success for a myriad of mental health symptoms. Patients like it because it has few side effects and is not a drug that is going to cause them to feel “numb” or sedate. Not only is there no risk of weight gain, but it can help with overeating that can be seen with depression.
I do, however, feel it is imperative providers understand and educate patients about the risks of Wellbutrin. We all know informed consent is a necessity with every medication prescribed, but we need to respect Wellbutrin with the same fervor as we do TCAs, lithium, clozapine, and MAOIs. Remind patients of the importance of once daily dosing, not to split or crush tablets, and ask if they have children in the home. If the patient works night shift, explain they must not exceed their dose in any 24-hour period. Ensure the patient understands medications are properly stored and encourage the use of daily pill boxes to prevent inadvertent double doses.
I disagree with the FDA’s maximum dose of Wellbutrin XL 450 mg daily and believe it should be capped at 300 mg (I will not prescribe above 300 mg daily). Not only does the risk of seizures markedly increase with the dose, a one-time double dose of 450 mg is enough to warrant a trip to the emergency department for 24 hours of medical observation. Let us also remember while Wellbutrin can be used as monotherapy, it is most commonly an augmenting agent used in conjunction with SSRIs. Not all SSRIs are created equal as medications such as Celexa and Lexapro (much higher risk for Celexa), can also cause seizures and cardiac conduction delays. Effexor, an SNRI, is a medication that acts a lot like Wellbutrin in overdose, with similar effects, albeit easier to treat. Rarely do intentional exposures include one single substance (always check serum ETOH, APAP, and ASA levels on any intentional overdose).
In conclusion, my relationship with Wellbutrin will always be a complicated one. But I will continue to use the medication after a thorough risk versus benefit discussion with every patient, maintaining a dosage range of 150-300 mg per day.
As a reminder, this post is not meant to be used as medical advice or for treatment recommendations. If you are a provider managing a case or if you have made a medication error, consult your local Poison Center at 1-800-222-1222. The Poison Center is HIPPA compliant and failure to provide patient information impedes quality care and can result in poor patient outcomes.
This post was written by Richard Gray, PMHNP-BC. The above information is for educational/entertainment purposes and is not intended to be treated as medical advice. If you have questions about a medication you are taking, discuss these questions with your medical provider.