Bupropion-Induced Myoclonus: Case Report and Review of the Literature

Abstract

Bupropion is an atypical antidepressant agent approved for treating major depressive disorders and prescribed for smoking cessation, attention deficit hyperactive disorder (ADHD), and sexual dysfunction. In a few cases, bupropion was associated with myoclonus. We present a case of a 58-year-old male, a heavy smoker seeking smoking cessation, was prescribed bupropion 150 mg twice daily. The subject doubled the dosage without medical advice. After 3 days of the increased dosage, he started to experience abnormal movements in his upper limbs associated with diffuse facial twitching. Neuroimaging, electrodiagnostic studies, and laboratory exams were unremarkable. Bupropion was discontinued, and clonazepam was initiated. The subject fully recovered within 24 hours. To the authors’ knowledge, only 8 cases of bupropion-induced myoclonus were reported in the literature. Bupropion discontinuation was the most common management. All individuals except 2 cases fully recovered after bupropion withdrawal. The mechanism of bupropion is probably associated with the serotoninergic pathway.

Introduction

Depression or major depressive disorder (MDD) is a common mental ailment worldwide, with an evaluated 3.8% of the population affected. Around 280 million individuals in the world suffer from depression. ¹ One of the drugs used for MDD is bupropion. It is used for depression, smoking cessation, attention deficit hyperactive disorder (ADHD), and sexual dysfunction. Bupropion has several features that distinguish it from other antidepressants: for instance, unlike most antidepressants, it does not usually cause sexual dysfunction, weight gain, or sleepiness. ² While other options like nicotine patches exist, bupropion appears to be more effective than other pharmacological options in improving abstinence among adolescents who smoke in a short-term manner. In the pharmacological treatment of adults with ADHD, extended- or sustained-release bupropion may be an alternative to stimulants. Some of the rarest but serious side effects of bupropion are seizures and myoclonus. ³ Here in our study, we will discuss a case of a middle-aged male who had chronic addiction to smoking for which bupropion was prescribed. After he increased the dose on his own, he developed myoclonus, which was resolved by discontinuing the drug and prescription of clonazepam.

Case Report

A 58-year-old male patient presented for consultation to quit smoking. He was a chronic cigarette smoker with a history of smoking 90 packs per year. He was oriented towards gradual tapering of smoking. As part of his medical and drug history, he was taking enalapril 20 mg twice per day for hypertension and budesonide/formoterol 100/6 mcg for asthma. His family history was negative for psychiatric or neurologic disease. His previous routine labs, electrocardiogram, and physical examination were normal. He was started on bupropion 150 mg 1 tablet twice daily. After a week, the patient did not observe any shift in his willingness to smoke. Therefore, he began taking bupropion 150 mg 2 tabs twice daily. After 3 days on 600 mg/day, he developed abnormal movements in his upper limbs associated with diffuse facial twitching. The patient had no symptoms related to cardiovascular, respiratory, gastrointestinal, or genitourinary systems.

The subject was fully conscious and oriented to time and place. His vital signs were blood pressure: 140/78 mmHg, pulse rate: 98 bpm, temperature: 36 Celsius degrees, respiratory rate: 14 bpm, and O₂ saturation was 99% in the emergency department. Facies were atypical. Neurological examination revealed sudden involuntary jerkings in the distal upper extremities and face, which were exaggerated with action. The myoclonus was symmetric and synchronous in distal upper limbs but asynchronous comparing the limbs to face. No asterixis was observed. Muscle strength was normal, graded 5 (Medical Research Council Muscle Power Scale) all over the 4 extremities. Deep tendon reflexes were normal. Sensory and cranial nerve examinations were negative. There were no cerebellar signs. The remaining physical examination was normal.

Laboratory tests and imaging studies were ordered to exclude serious neurological disorders such as stroke and neurodegenerative diseases. Complete blood count, renal function, liver function, total bilirubin, direct bilirubin, serum electrolytes, erythrocyte sedimentation rate, C-reactive protein, hepatitis serology; hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV), venereal disease research laboratory test (VDRL), human immunodeficiency virus (HIV-1), and (HIV-2) were all within normal levels. Blood glucose was normal. Urinalysis was normal. The cranial computed tomography (CT) scan and brain magnetic resonance imaging (MRI) were unremarkable. Cerebrospinal fluid analysis (CSF) revealed normal findings. Electroencephalography was entirely normal and did not show any background epileptic activity. The electrocardiogram showed no abnormality except that QT was slightly prolonged (480 ms).

Bupropion was withdrawn, and clonazepam 2 mg 3 times per day was started. After 6 hours of the first clonazepam dose, the patient’s motor symptoms significantly improved. After 24 hours, the patient was symptom-free, and clonazepam was tapered for 2 mg 2 times per day for 2 days. Afterwards, it was tapered for 2 mg once per day for 4 days. Afterwards, clonazepam was withdrawn. After 1 and 6 months, the patient did not exhibit any abnormal movement symptoms or signs.

Discussion

Bupropion was first studied in the 1960s and was approved as an antidepressant by the food and drug administration (FDA) in 1985. In this context, due to many case reports of bupropion-induced seizures, the drug was withdrawn in 1986. Nevertheless, the risk of seizures was found to be dose-dependent, and bupropion was re-introduced in 1989 with a recommended lower dose in immediate-release formulations. ²

Bupropion is an atypical antidepressant inhibiting norepinephrine and dopamine reuptake (Figure 1). Thus, common antidepressant-associated side effects such as sexual dysfunction, sedation, and weight gain are not associated with bupropion therapy. ⁴ The typical antidepressants such as fluoxetine, venlafaxine, or paroxetine are well-known to cause sexual dysfunction as a side effect. However, co-administration with bupropion was found to decrease this effect. ⁵ Also, bupropion is known to cause weak serotonergic activity. Serotonin syndrome was described in a 62-year female who was taking both bupropion and sertraline, a selective serotonin reuptake inhibitor (SSRI). ⁶ Like other antidepressant drugs, bupropion lowers the seizure threshold although bupropion has higher rates of seizures compared to other antidepressants. The seizure can occur even if the patient is on anticonvulsants such as benzodiazepines. ⁷ It has also been hypothesized to antagonize nicotinic acetylcholine receptor function. ³ However, its clinical efficacy in smoking cessation was inconclusive in a recent trial. ⁸

Figure 1.

Bupropion mechanism of action. It inhibits norepinephrine (NE) and dopamine (DA) uptake. It has a weak serotonin (SE) reuptake inhibitor activity.

So far, bupropion has been reported to cause myoclonus in 8 cases in the literature (Table 1). The average age was 44 ± 13 years old. All cases except 1 were females. In most cases, bupropion was prescribed for depression and/or anxiety. Four cases developed myoclonus on usual doses for depression or anxiety.^6,9–11 In the other 4 cases, in which patients aged less than 40 years, overdose was the cause that myoclonus and other adverse effects occurred. In 3 of them, the symptoms developed within 1 to 2 hours.^12–15 Discontinuation of bupropion was the basic management in all cases. Two cases of the overdosed individuals needed gastric lavage and/or activated charcoal administration to reduce the absorption of the massive, ingested dose.^14,15 At least 1 anti-epileptic drug was prescribed to control abnormal movements in 7 cases. Clonazepam, lorazepam, and levetiracetam were the antiepileptic drugs that were most used.

Table 1.

Reported Cases of Bupropion-Induced Myoclonus.

Reference	Sex, Age (Years)	Indication for Bupropion	Dose and Frequency of Bupropion	Time from Starting of Bupropion Until Initial Myoclonic Symptoms	Management of the Case	Follow Up	Special Note
Hohler and Hartmann 2002 9	M, 54	Depression	N/A	Three weeks	Bupropion discontinuation	Complete recovery after 2 weeks. Asymptomatic at 6 months	Patient had evidence of peripheral neuropathy and was on amitriptyline
Munhoz 2004 6	F, 62	Depression	300 mg daily	Five weeks	Discontinuation of bupropion. Cyproheptadine 4 mg 4 times a day and clonazepam 2 mg twice a day were started for 5 days. Fluoxetine 10 mg a day was rechallenged on day 10	On three-week follow up, complete recovery	Patient was also on sertraline, piracetam and venlafaxine. She presented as serotonin syndrome (SS) with cognitive-behavioral and neurologic changes. There was transaminases elevation and QT interval prolongation. All psychiatric drugs were discontinued upon admission
Gupta and Lang 2010 10	F, 69	Depression and anxiety	200 mg daily	N/A	Bupropion discontinuation	Complete recovery after bupropion discontinuation	Patient was also on citalopram, clonazepam, risperidone and rosuvastatin. Neither of citalopram nor risperidone withdrawal reduced the symptoms. A trial of L-dopa didn’t help
Lin et al 2012 13	F, 30	Suicide attempt	N/A	One hour	Sodium bicarbonate, cyproheptadine, and lorazepam	Permanent symptoms of pallidal necrosis 7 weeks after admission	Patient consumed bupropion, venlafaxine, and lorazepam for a month. She presented with manifestation suggestive of serotonin syndrome. MRI scan revealed bilateral pallidal necrosis 7 weeks after admission
Mendonca et al 2015 14	F, 38	Suicide attempt	6 grams	Two hours	Gastric lavage followed by administration of activated charcoal. Diazepam and phenytoin for generalized seizures. Thiopental induced coma for resistant seizures	Complete resolution of seizures and myoclonus after 24 hours	Patient ingested 110 grams of alcohol in addition to 6 grams of bupropion. She had agitations, hallucinations, ECG changes, metabolic acidosis, myoclonus and then developed seizures. She had aspiration pneumonia as a secondary complication
Xiang and Phillips 2018 15	F, 15	Intentional overdose	6.6 grams	Two hours	Activated charcoal and Golytely (at 500 mL/h). Lorazepam and levetiracetam load	Full recovery of myoclonus and seizure after 24 hours	Patient had smoked marijuana before bupropion ingestion. She also developed generalized seizure which was controlled with levetiracetam
Goodman 2021 12	F, 23	Intentional overdose	NA	NA	Levetiracetam, lorazepam, midazolam, and vasopressors	Complete resolution within 3 hours. Discharged on 10th day	Patient developed burst suppression in addition to new-onset myoclonic seizures
Simpson et al 2022 11	F, 59	Anxiety	N/A	N/A	Levetiracetam 500 mg daily	Transient improvement after weeks followed by loss of benefit	Patient had history of autoimmune and thyroid diseases and was also on levothyroxine and amlodipine. There was a positive ANA and centromere antibodies. TPO antibodies were elevated
Riaz et al	M, 58	Smoking cessation	300 mg twice a day	Three days	Bupropion withdrawal. Initiation of clonazepam	Complete resolution after 24 hours. One and 6 months follow up were free	Patient was on 150 mg twice per day for smoking cessation. He increased the dose to 300 mg twice per day and after 3 days he developed myoclonus

Abbreviations: M: male; F: female; MRI: magnetic resonance imaging; ECG: electrocardiography; ANA: anti-nuclear antibodies; TPO: thyroid peroxidase.

In a 38-year-old female who ingested around 6 grams of bupropion, resistant seizures occurred. Diazepam and phenytoin failed to control the generalized seizures. It was controlled with thiopental-induced coma. ¹⁴ Cyproheptadine was prescribed in 2 cases. Sodium bicarbonate was prescribed in 1 case of serotonin syndrome with metabolic acidosis. ¹³ Complete resolution of the myoclonus was achieved in 6 of the 8 cases. Two individuals did not have a full recovery. One developed pallidal necrosis 7 weeks after admission. ¹³ Noteworthy, this patient had consumed a one-month prescription of 300 mg bupropion, 150 mg venlafaxine and 3 mg lorazepam 3 days later. Transient hypoxia was thought to cause bilateral pallidal necrosis. However, toxicity due to bupropion and/or venlafaxine couldn’t have been excluded. ¹³ And, the other case showed transient improvement on antiepileptic medication levetiracetam followed by loss of benefit. ¹¹ This patient had history of autoimmune and thyroid diseases and despite being clinically and biochemically euthyroid then, autoimmune process underlying the myoclonus couldn’t have been excluded as the physicians hadn’t involved an immunotherapy. ¹¹

In our case, bupropion was prescribed for smoking cessation. The patient developed myoclonus 3 days after he increased the dose from 150 mg twice daily to 300 mg twice daily. Bupropion discontinuation and clonazepam initiation were prescribed and appropriately controlled the case. The patient achieved full recovery on follow-up. The patient was 58 years old and developed myoclonus shortly after an increase in the usual dose. This may raise the need for clarification of the risk of developing myoclonus and other adverse effects of bupropion based on patients’ age, sex, comorbidities, history of neurological diseases, and drug co-administration. Thus, doses should be adjusted on a case-by-case basis.

Conclusion

Bupropion was known to cause myoclonus at high doses or long-term use. The myoclonus is usually self-limited and resolves after bupropion discontinuation. However, anti-epileptic drugs may be prescribed to fasten the recovery or in cases of persistent seizures. We believe this to be the first case report of bupropion toxicity that develops shortly (3 days) on 600 mg bupropion without concomitant use of other antidepressant or neuropsychiatric drugs. Thus, physicians should be aware of that possibility even in patients without any comorbidities or drug intake, and patients should be informed of the possible side effects.

ORCID iDs

Asad Riaz https://orcid.org/0000-0002-3765-7335

Hossam Tharwat Ali https://orcid.org/0000-0001-8077-5911