Drug Profile

Bupropion (APLENZIN, FORFIVO XL, WELLBUTRIN SR, WELLBUTRIN XL) is used to control, but not cure, severe depression that is not caused by other drugs, alcohol or emotional losses (such as a death in the family). Bupropion is related to drugs in the amphetamine family (ADDERALL, ADDERALL XR) and to diethylpropion (TENUATE, TEPANIL) but purportedly is not habit-forming. Although bupropion is preferred by some doctors for use in elderly patients,[1] it has not been studied much in such patients.

We have designated bupropion as Limited Use. For patients who need an antidepressant drug, we recommend trying one of the newer selective serotonin reuptake inhibitors (SSRIs) (for example, fluoxetine [PROZAC, SARAFEM, SELFEMRA]) first, as these are the safest antidepressants. If symptoms do not improve sufficiently on an SSRI and remain severe, further treatment with other antidepressants is warranted.

Bupropion can take up to four weeks to be effective. The length of time it takes an antidepressant to work can overlap with spontaneous recovery — recovery that might occur without the use of medications — especially if the depression is situational (for example, caused by a death or other external circumstances). Most people recover from depression with friends, spiritual resources or activities such as exercise, work, reading, play, art and travel. If depression is not overcome by these measures, patients should seek help from mental health professionals, such as therapists or psychiatrists. Antidepressant drugs should be reserved for major depression in which the patient does not respond to psychotherapy alone.

Adverse effects

Weight loss is a common adverse effect of this drug. A number of people become restless when taking bupropion. Also, people aged 60 and older are more likely to experience adverse effects such as heart complications.

In October 2014, the Australian Department of Health Therapeutic Goods Administration, a regulatory agency similar to the Food and Drug Administration (FDA), issued an advisory that the drug product information for bupropion would be updated to include information on reports of cardiovascular adverse events, including 24 heart attacks and five strokes, in patients taking the drug.[2]

Antidepressants and pregnancy

On Aug. 9, 2004, Health Canada, a regulatory agency similar to the FDA, issued a public advisory warning to Canadians that newborns may be adversely affected when their mothers take a selective serotonin reuptake inhibitor (SSRI) and other newer antidepressants during the third trimester of pregnancy. Health Canada reported that some newborns whose mothers took these drugs during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support and tube feeding. The symptoms reported include feeding and breathing difficulties, seizures, muscle rigidity, jitteriness and constant crying. In most cases, the mothers were prescribed newer antidepressants during the third trimester of pregnancy.[3]

An article published in Prescrire International in January 2012 examined the use of bupropion during pregnancy and the increased risk of congenital heart defects in children. The data showed that children born to mothers who used bupropion during pregnancy had an increased risk of cardiac malformations.[4]

Psychiatric behaviors

Patients treated with bupropion should be observed for changes in psychiatric behaviors. These behaviors can include hostility, agitation, depression and suicidality. Most of these symptoms were reported in patients who were currently taking bupropion, but some were also reported in patients after they had stopped taking bupropion.

Seizures

Because the use of bupropion is associated with an increased risk of seizures, doses over 300 milligrams (mg) per day for smoking cessation should not be used. The risk of seizures is also related to patient factors, clinical situation and other drugs taken with bupropion, all of which must be considered when selecting patients for treatment with this drug. Use of bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

The seizure rate associated with doses of sustained-release bupropion up to 300 mg per day is approximately 0.1 percent (1/1,000). This rate was determined during eight weeks of treatment in approximately 3,100 depressed patients. Data for the immediate-release formulation of bupropion revealed a seizure rate of approximately 0.4 percent (4/1,000) in depressed patients treated at doses ranging from 300 to 450 mg per day. In addition, the estimated seizure incidence increases almost tenfold with doses between 450 and 600 mg per day.

Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system tumor, the presence of severe hepatic (liver) cirrhosis and concomitant medications that lower seizure threshold.

Situations associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine or stimulants; use of over-the-counter stimulants and anorectics; and use of oral hypoglycemics or insulin to treat diabetes.

Many drugs (e.g., antipsychotics, antidepressants, theophylline and systemic steroids) are known to lower the seizure threshold. Bupropion should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency of dosing is required, as peak bupropion levels are substantially increased and higher-than-usual accumulation is likely to occur. The dose should not exceed 150 mg every other day in these patients.

Studies show ...

A major meta-analysis (a study that combines data from multiple clinical trials) commissioned by the U.S. Department of Health and Human Services failed to find any significant differences in effectiveness between older antidepressants (such as bupropion) and newer antidepressants (such as SSRIs).

In terms of adverse drug reactions, there was no significant difference between the new and old antidepressants in overall discontinuation rates by patients.[5] (Drug discontinuation rates can be used to compare adverse reactions between drugs.)

Drug Interaction

In 2017, the FDA approved a change to the product label of bupropion that indicated that the blood level of heart drug digoxin may increase when bupropion and digoxin are used together.[7]

Regulatory actions surrounding bupropion

2004: In October, the FDA issued a public health advisory requiring manufacturers to add a black-box warning (see "FDA Black-Box Warning" at the top of this page) to the professional product labeling of all antidepressants. A black-box warning is the strongest type of warning that the FDA can require.

The FDA also required that a Medication Guide be given to patients receiving this drug, to advise them of the risks and of precautions that can be taken. Bupropion is one of a limited number of drugs for which the FDA requires an FDA-approved Medication Guide to be dispensed when the prescription is filled. (Click here to view the WELLBUTRIN Medication Guide.) An FDA advisory committee has unanimously recommended that all prescription drugs be accompanied by such Medication Guides, but at present, less than 5% of drugs are. The other 95% of drugs are accompanied by unregulated, often dangerously incomplete information leaflets not approved by the FDA.

2007: The FDA announced in May that it would require new warnings concerning the increased risk of suicidal thoughts and behavior in young adults ages 18 to 24 during the first one to two months of treatment with antidepressants. The agency required the new warnings to be black-box warnings, printed on the professional product labels for all antidepressants sold in the U.S. The warnings amended an existing black-box warning for children and adolescents.[8]

The FDA-approved professional product labeling for antidepressant drugs sold in the U.S. carries the following statement:

Suicide: The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for Drug X should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

2020: The Medicines and Healthcare products Regulatory Agency (an agency in the U.K. similar to the FDA) issued an advisory that serotonin syndrome has been reported with use of bupropion.[9]

Symptoms of serotonin syndrome include restlessness, hallucinations, loss of coordination, fast heartbeat, increased body temperature, rapid changes in blood pressure, overactive reflexes, diarrhea, coma, nausea and vomiting.