Bupropion (Wellbutrin)

• Bupropion is structurally very similar to phenylethylamine (amphetamine and diethylpropion), which are potent stimulants
• Bupropion inhibits the re-uptake of norepinephrine (NE) and dopamine neurotransmission without any significant direct effects on serotonin neurotransmission (this makes it one of the few only non-serotonergic antidepressants)
• Bupropion also has effects on the dopamine reward pathways (blockade of neuronal re-uptake of dopamine and norepinephrine, and inhibition of nicotinic acetylcholine receptors), which makes it useful as an agent in smoking cessation.
• The major metabolite, hydroxybupropion, is present at levels 10-20 times higher than bupropion itself and blocks only NE reuptake

• In overdose: few deaths have been reported – usually through seizures (1/3 of all overdose), bradycardia, cardiac arrest
• Overdose symptoms include sinus tachycardia, hypertension, GI symptoms, hallucinations, and agitation

• Major depressive disorder
• Tobacco use disorder
• Off-label as an adjunctive treatment to reverse antidepressant-induced sexual dysfunction or to augment anti-depressant efficacy in partial responders and non-responders to other medications.^[1]
• For some it has been used as an attention-deficit/hyperactivity disorder treatment adjunct

Bupropion comes in three formulations, the most convenient form (XL) was released in 2003 that allowed for once daily dosing.^[2]

• Seizure disorder (due to lowered seizure threshold)
• Eating disorder, (a higher incidence of seizures was found in patients treated for bulimia with bupropion IR)
• Alcohol or benzodiazepine withdrawal
• MAOi in last 14 days
• Abrupt discontinuation of ethanol or sedatives (due to lowered seizure threshold)
• Hypersensitivity in the past

• Caution is warranted in patients with a predisposition to psychosis

• Bupropion levels are increased by CYP 2B6 inhibitors
• Bupropion increases levels of CYP 2D6 substrates (e.g. - aripiprazole)
  • Bupropion is often combined with venlafaxine, which may increase levels of venlafaxine (it is a 2D6 substrate)
• Carbamazepine, phenytoin, and phenobarbital all induce the metabolism of bupropion, resulting in lower bupropion levels
• May rarely cause CNS toxicity when used with lithium, including seziures
• Need to wash out MAOIs for 14 days before starting bupropion, as MAOIs increase risk of acute bupropion toxicity
• Can cause delirium with other prodopaminergic drugs
• Metoprolol may increased risk of sinus bradycardia
• Levodopa and amantadine, higher incidence of neuropsychiatric adverse effects when combined with bupropion (e.g. - confusion, agitation, delirium, tremor, ataxia, dizziness)
• Nicotine patches, combined use can increase blood pressure (need to monitor)

• Headache, constipation, dry mouth, insomnia, dizziness, tremor, tinnitus, agitation, nausea and vomiting, tic exacerbation (in youth) are the most common adverse events
  • There can be increased blood pressure as well
  • 10-29% experience insomnia, dry mouth, nausea, constipation
• Among the newer antidepressants, bupropion has the lowest incidence of sexual dysfunction, weight gain, and somnolence (<10% sexual side effects)
• For those with severe anxiety or panic disorder, bupropion is a bad choice: up to 50% of people can get worsening anxiety!
  • So don't use as first line for depression with anxious features, or if you suspect anxiety
• Less likely to precipitate mania in bipolar I than tricyclics

• Bupropion can cause in rare cases hallucinations, delusions, catatonia, delirium, word-finding difficulties, memory impairment
• In select cases, bupropion appears to be associated with the induction of psychotic symptoms in addition to the precipitation or worsening of an existing psychotic syndrome. The literature is incomplete and in some cases contradictory.^[3][4]
• Bupropion-associated delayed onset urticaria (rashes) have been reported in the literature.^[5]
  • In most of these cases, patients improve after discontinuing the medication, and could undergo a rechallenge of bupropion at lower doses.
  • Even rarer, case reports of true anaphylactic reactions have been reported.^[6]

• Seizures are associated with bupropion but are reported rarely.
  • Under 300 mg a day, the risk is 0.05% (about the same as other antidepressants), but doses over 450 mg, the risk of seizures increases to 0.4%.^[7]
• Risk factors include: history of seizures, alcohol use disorder, benzodiazepine withdrawal history, central nervous system diseases, head trauma, and epileptiform discharges on EEG.

• Bupropion's potent CYP 2D6 antagonism is often forgotten by clinicians!
• There is no discontinuation syndrome (or very small risk) in bupropion.
• At therapeutic doses, bupropion may actually reduce the QTc interval,^[8] and can be used in patients with ventricular arrhythmias or who are on QTc prolonging medications.^[9]
• If insomnia is marked, take the afternoon dose earlier in the afternoon, but at least 8 hours after the first daily dose
• Unlike most other antidepressants, bupropion does not suppress REM sleep.
• Bupropion is relatively weight neutral
• Since it is structurally very similar to stimulants, bupropion can have abuse potential when crushed, injected intravenously, or snorted.
• Bupropion is one of the few antidepressants that is thought to have a lower risk for open-angle glaucoma.^[10]
  • SSRIs are associated with a risk for glaucoma.^[11]

• Tox & Hound – Illbutrin