Bupropion (amfebutamone)

Cardiovascular

The UK Committee on Safety of Medicines has received over 200 reports of chest pain in patients taking bupropion, and a case of myocardial infarction has been reported.

• A 43-year-old man who had smoked up to 20 cigarettes daily for several years and had a family history of heart disease was given bupropion and stopped smoking after reaching the recommended dose (300 mg/day) [ ]. Three days later he developed central chest and arm pain and 1 day later stopped taking bupropion. Three days after this he developed classical symptoms of acute inferoposterolateral myocardial infarction. He was treated with thrombolytic therapy and discharged taking secondary prevention therapy.

It is difficult to know how far bupropion might have contributed to this acute cardiac event. However, continuing vigilance and case–control studies are warranted.

Nervous system

The main concern with the use of bupropion is that in higher dosages it is associated with a risk of seizures (0.4%). Early in 1986, advertising began to appear in advance of the expected release of bupropion in the USA. Abruptly, in March, distribution was halted because of reports of seizures in patients with bulimia. Although the risk is greater than that seen with SSRIs (about 0.1%), data have suggested that bupropion has approximately the same seizure potential as the tricyclic compounds [ ]. However, a higher seizure risk for bupropion than for tricyclic antidepressants has been reported in patients taking bupropion in doses over 450 mg/day [ ]. Furthermore, the manufacturers have noted an increased risk of seizures in patients taking over 600 mg/day in combination with lithium or antipsychotic drugs [ ].

Of 279 patients who presented to a hospital emergency service between 1994 and 1998 with a first tonic–clonic seizure, 17 (6.1%) had seizures that were thought to be drug-related [ ]. The most common drug-induced causes were cocaine intoxication (6/17) and benzodiazepine withdrawal (5/17) followed by bupropion use (4/17). While one bupropion-associated seizure occurred in a 26-year-old woman without any other risk factors, the three other patients (all women) had additional risk factors, such as concomitant treatment with antidepressants that also lower seizure threshold and a history of bulimia nervosa. These results suggest that bupropion is not an infrequent cause of de novo seizures. However, because of the time frame of the study, many of the patients would have been taking standard-release bupropion. It would be of interest to repeat the study now that modified-release bupropion is available.

Bupropion lowers the seizure threshold and can cause paresthesia [ ].

• A 38-year-old woman who was taking olanzapine 10 mg/day and lamotrigine 200 mg/day for a schizoaffective disorder started to take bupropion for a depressive mood swing. After 4 weeks the dose of bupropion was increased to 300 mg/day, at which point she complained of a twitching pain on the left side of her face. There was hypesthesia of two branches of the left trigeminal nerve, the ophthalmic and maxillary branches, and a reduced left corneal reflex. The bupropion was withdrawn and the neurological signs and symptoms disappeared within 8 days. Four weeks later, because of persisting depression, the bupropion was reintroduced; at a dosage of 300 mg/day identical neurological symptoms recurred.

The reason for this unusual reaction is not clear. Bupropion may potentiate dopamine neurotransmission, and dopamine D ₂ receptors modulate trigeminal nerve function [ ].

Bupropion has been reported to mimic transient ischemic attacks [ ].

• A 67-year-old man with a strong history of ischemic heart disease, who had been smoking 20 cigarettes a day for many years, started to take bupropion (100 mg tds) as an aid to smoking cessation. One week later he had episodes of disorientation, a tingling sensation over his body, and roaring sounds in his ears. MRI scanning and angiography showed evidence of previous strokes. His current episodes were ascribed to transient ischemic attacks. He had stopped taking bupropion while in hospital and then restarted it 2 days after discharge, when the same symptoms recurred. He then stopped taking bupropion completely and over the next 9 months had no further neurological episodes.

It is possible that these symptoms were entirely due to bupropion, but more probably the bupropion interacted in some way with the patient’s established cerebrovascular disease.

Bupropion has been associated with extrapyramidal movement disorders [ ] and ballismus has been reported [ ].

• A 42-year-old woman developed ballismus 4 days after increasing her dose of bupropion to 150 mg bd. She had an involuntary urge to move, gross flexion movements of the torso, and slapping movements of her arms. She had no previous history of movement disorders and was taking only occasional sumatriptan for migraine. Bupropion was withdrawn and she was given haloperidol and oxazepam. The movements abated.

It seems likely from this that the dopaminergic effects of bupropion can provoke movement disorders in therapeutic doses in some individuals.

Acute dystonia is a recognized complication of treatment with antipsychotic drugs and it can also occur with SSRIs and the anxiolytic drug buspirone.

• A 44-year-old man took bupropion 300 mg/day and buspirone 45 mg/day for depression [ ]. Over 2–3 weeks he developed increasing neck stiffness, with tightening and spasm of the jaw muscles and pain in the left temporomandibular joint. He stopped taking his medications, and all his symptoms resolved over the next 3 weeks. Rechallenge with buspirone (45 mg/day) failed to reproduce the dystonic symptoms. The buspirone was withdrawn and bupropion 150 mg/day was started; the dystonic symptoms did not recur. However, 24 hours after the dose of bupropion was increased to 300 mg/day there was a return of neck stiffness and jaw spasm.

Bupropion has dopaminergic properties, which seem to have played a part in this dystonia. Whether the effect was initiated by concomitant buspirone therapy is unclear, but subsequently bupropion alone was sufficient to produce the dystonic symptoms.

Visual hallucinations and tinnitus have been reported in patients taking bupropion [ ].

Somnambulism has been reported with bupropion [ ].

• A 35-year-old man took bupropion 150 mg bd as part of a smoking cessation program. After 14 days he stopped smoking, after which he noted some increase in mood and appetite. Three days later a friend reported that the patient had telephoned him at 1.00 am, about 2 hours after he had gone to sleep, but the patient had no memory of this. Over the next week he discovered evidence of several episodes of nocturnal eating but again had no recall of getting up at night to obtain food. He stopped taking bupropion and the sleep-walking episodes disappeared and did not recur.

Bupropion promotes slow wave sleep, the sleep stage during which somnambulism is initiated. However, this case was complex, because of the possible interaction with nicotine withdrawal. Nicotine withdrawal is associated with increased appetite and weight gain, and sleep walking can be associated with nocturnal eating.

Psychological, psychiatric

Bupropion potentiates dopamine neurotransmission and at higher doses can cause toxic delirium and psychosis, particularly in patients with a history of psychosis and those taking other dopaminergic medications [ ].

• A 79-year-old man developed a paranoid psychosis with auditory hallucinations during treatment with bupropion (100 mg tds) [ ]. The symptoms remitted with reduction of the dose of bupropion and the introduction of haloperidol 5 mg/day.

Paranoid ideas and hallucinations can occur during the course of a severe depressive episode, but in this case the patient’s mood was gradually improving, so a link with bupropion seems more likely. It seems prudent to dose bupropion conservatively in elderly patients.

• A 35-year-old woman with no history of a psychiatric disorder was given bupropion 300 mg/day for smoking cessation [ ]. After 5 days she developed an acute paranoid state with ideas of reference and fixed convictions concerning her partner’s fidelity. She was also irritable and slightly grandiose. Bupropion was withdrawn and she was given benzodiazepines. She recovered over the next 2 days.

This case suggests that bupropion can rarely cause psychotic symptoms even in people without susceptibility factors, although it is conceivable that this patient might, for example, have had a family history of psychiatric disorder. Bupropion is believed to enhance dopaminergic function, and the psychiatric phenomena experienced by the patient, principally paranoid delusions and elevated mood, are consistent with a hyperdopaminergic state.

In an open trial, two of 16 patients became psychotic and were withdrawn from the study [ ]. A more detailed report of this adverse effect described four of 13 patients who became psychotic during a trial of bupropion; three had a history of psychosis, but none had previously had this response to other antidepressants [ ]. The usual dosage range of bupropion is 300–750 mg/day, and the psychotic symptoms occurred at dosages of 300–500 mg/day. In two cases psychotic symptoms were absent at lower dosages, but in one case the dose was therapeutically inadequate.

Other reports of psychotic reactions and a manic syndrome associated with bupropion have appeared [ , ]. In two of these cases a possible drug interaction with fluoxetine, with inhibition of the metabolism of bupropion, could not be excluded.

Electrolyte balance

Hyponatremia with SSRIs is well described [ ] but has also been reported with other antidepressants, including the selective noradrenaline re-uptake inhibitor reboxetine.

• A 49-year-old woman, who was taking oxcarbazepine for bipolar disorder, developed hyponatremia after also taking bupropion [ ].

Oxcarbazepine can also cause hyponatremia, but in this case the hyponatremia appeared to correlate with the prescription of bupropion rather than oxcarbazepine and was also reproduced by bupropion re-challenge. This case suggests that bupropion can also cause hyponatremia, although it is possible that the presence of oxcarbazepine was necessary for the adverse effect to occur.

Hematologic

Eosinophilia reportedly developed in a 72-year-old woman shortly after she was given bupropion. The eosinophil count fell rapidly after all medications (including glibenclamide and tolmetin) were withdrawn [ ].