Bupropion (Wellbutrin)

Bupropion (Trade name: Wellbutrin) is an antidepressant in the norepinephrine dopamine reuptake inhibitor (NDRI) class used in the treatment of major depressive disorder and as a smoking cessation agent in tobacco use disorder (Bupropion SR [Trade name: Zyban]).

Pharmacokinetics of Bupropion

Absorption T-max of about 5-6 hours for both bupropion SR and XL. Taking bupropion with food has no clinically significant effect.
Distribution Protein-binding is 84% for bupropion and similar for hydroxybupropion
Metabolism Bupropion is rapidly and extensively metabolized in the liver by CYP 2B6 in the liver to three active metabolites, the most important of which is hydroxybupropion.
Elimination Renally (urine)
Half-life 21 hrs for bupropion SR; up to 37 hrs for active metabolite

Bupropion: Cytochrome P450 Metabolism

Substrate of (Metabolized by) 2B6
Induces
Inhibits 2D6 (potent!)
  • 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

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

Dosing and Formulations for Bupropion

Bupropion Intermediate-release (IR) Bupropion Sustained-release (SR) Bupropion Extended-release (XL)
Tradename Wellbutrin Zyban Wellbutrin XL
Frequency Requires TID dosing Requires BID dosing Once daily dosing, but pill cannot be cut, or else it loses its efficacy
Starting Dose (Depression) - - • 150 mg PO daily, then increase to 300 mg qDay on day 4.
• May increase to 450 mg daily after more than 4 weeks, if no clinical improvement observed at 300 mg daily.
Starting Dose (Smoking Cessation) - • Start 1-2 weeks before quitting smoking at 150mg PO qAM for 3 days
• Then increase to 150mg PO BID for 7-12 weeks
• Treatment can last up to 6 months.
-
Max Dose Wellbutrin IR 100 mg TID Wellbutrin SR 150 mg BID Wellbutrin XL 300 mg once daily
Tapering There is no discontinuation syndrome associated with bupropion. There is no discontinuation syndrome associated with bupropion. There is no discontinuation syndrome associated with bupropion.
  • 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
  • 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]
  • 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 400 mg, the risk of seizures increases to 0.4%.
  • 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 associated with bupropion.
  • At therapeutic doses, bupropion may actually reduce the QTc interval,[5] and can be used in patients with ventricular arrhythmias or who are on QTc prolonging medications.[6]
  • If insomnia is marked, take the PM 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.
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