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Bupropion: pharmacology and

therapeutic applications
Kevin F Foley†, Kevin P DeSanty and Richard E Kast

A total of 17 years after its introduction, bupropion remains a safe and effective
antidepressant, suitable for first-line use. Bupropion undergoes metabolic transformation to
an active metabolite, 4-hydroxybupropion, through hepatic cytochrome P450-2B6
(CYP2B6) and has inhibitory effects on cytochrome P450-2D6 (CYP2D6), thus raising
concern for clinically-relevant drug interactions. Common side effects are nervousness
CONTENTS
and insomnia. Nausea appears slightly less common than with the SSRI drugs and sexual
Formulations & dosing dysfunction is probably the least of any antidepressant. Bupropion is relatively safe in
Pharmacokinetics overdose with seizures being the predominant concern. The mechanism of action of
& metabolism bupropion is still uncertain but may be related to inhibition of presynaptic dopamine and
Adverse effects norepinephrine reuptake transporters. The activity of vesicular monoamine transporter-2,
Bupropion in overdose the transporter pumping dopamine, norepinephrine and serotonin from the cytosol into
Drug–drug interactions presynaptic vesicles, is increased by bupropion and may be a component of its
mechanism of action. Bupropion is approved for use in major depression and seasonal
Neuropharmacology of
bupropion affective disorder and has demonstrated comparable efficacy to other antidepressants in
clinical trials. Bupropion is also useful in augmenting a partial response to selective
Approved uses
serotonin reuptake inhibitor antidepressants, although bupropion should not be combined
Common unapproved uses with monoamine oxidase inhibitors. It may be less likely to provoke mania than
Speculative uses antidepressants with prominent serotonergic effects. Bupropion is effective in helping
Expert commentary people quit tobacco smoking. Anecdotal reports indicate bupropion may lower
Five-year view inflammatory mediators such as tumor necrosis factor-α, may lower fatigue in cancer and
may help reduce concentration problems.
Key issues
Information resources Expert Rev. Neurotherapeutics 6(9), 1249–1265 (2006)

References
Affiliations
†
Author for correspondence
University of Vermont, Department
of Medical Laboratory and
Radiation Sciences
302 Rowell Building, Burlington,
VT, 05405, USA
Tel.: +1 802 656 2506
Fax: +1 802 656 2191
kffoley@uvm.edu
KEYWORDS:
antidepressant, bupropion,
depression, pharmacology,
smoking cessation
Bupropion is a low molecular weight compound
(formula weight of HCl salt = 276.2), which has
been in therapeutic use as an antidepressant since
1989. Its basic mode of action remains
unknown. Much evidence points to modulation
of dopaminergic and noradrenergic signaling.
The use of bupropion (Wellbutrin®, Wellbutrin
SR®, Wellbutrin XL® and Zyban®, GlaxoSmith-
Kline) in depression, smoking cessation, and var-
ious off-label treatments appears to be growing.
This paper is a review of bupropion’s clinical
spectrum of action, basic pharmacology and cur-
rent position in drug therapy and offers a poten-
tial mode of action based on the reviewed data.
Formulations & dosing
Bupropion is currently available in several oral
tablet formulations. Immediate-release (IR)
tablets are inexpensive and available worldwide
from several generic manufacturers. Marketed
in 75 and 100 mg strengths, original recom-
mendations were for three-times daily admin-
istration, although twice daily dosing is com-
monly used. Sustained-release (SR) tablets,
available generically and as proprietary Well-
butrin SR, are available in 100, 150 and 200
mg and are easier for some patients to tolerate
at twice daily dosings. Some patients will expe-
rience jitteriness on one formulation but not
on the other. The most recent formulation is
an extended-release (XL) tablet available only
as proprietary Wellbutrin XL 150 and 300 mg,
designed for once-daily administration. In
general, patients are started at low initial daily
doses for several days and then titrated
upward. The IR formulation is typically

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Foley, DeSanty & Kast
started at 100 mg once daily, and uptitrated as tolerated and
needed at weekly intervals. Unusually sensitive patients, and
these often include nonpsychiatric patients being prescribed
bupropion for smoking cessation, can be started at 50 mg once
daily (half the 100 mg IR tablet). However, it is important to
note that bupropion tablets are not currently scored and are
film-coated, making the splitting of tablets difficult. There is
no generic 50 mg tablet currently available. We would recom-
mend that manufacturers of bupropion score tablets or provide
a 50 mg tablet. The SR formulation is given once daily for a
week before increasing to twice daily administration. Avoiding
doses in the evening may help if sleep disturbances occur. The
maximal daily dose approved by the US FDA is 400 mg for the
SR formulation and 450 mg for the IR and XL formulations.
Dose reduction should be utilized in patients with mild-to-
moderate hepatic dysfunction and avoidance should be consid-
ered in those with severe hepatic dysfunction. The total daily
dose should remain the same when converting between the
three bupropion formulations as these products are considered
bioequivalent [1].
Pharmacokinetics & metabolism
Hepatic cytochrome P450 (CYP)2B6 catalyzes hydroxylation of
the side chain tert-butyl group of bupropion to form an active
metabolite hydroxybupropion, FIGURE 1. Two less active metabo-
lites, threohydrobupropion and erythrohydrobupropion, are
formed through reduction of the side chain ketone group. The
roles of the latter two metabolites in the clinical effects are
unknown. Less than 1% of bupropion is eliminated in the urine
as unchanged drug. The majority of parent drug and metabolites
are eliminated in the urine as glycine conjugates [1,2].
Intestinal absorption of bupropion is reported to be close to
100% [1]. This is not surprising given bupropion’s small molec-
ular weight and lipid solubility. However, absolute oral bioa-
vailability (absorbed bupropion that does not undergo first pass
metabolism in the liver) is unknown because no intravenous
formulation has been tested. According to the manufacturer,
studies in rats and dogs suggest absolute bioavailability may be
approximately 5–20% [3]. The bioavailability of bupropion
itself is not necessarily clinically relevant if, as some currently
believe, the hydroxybupropion metabolite has an equal or
greater antidepressant effect to that of bupropion.
Time to peak plasma level (Tmax) is 1.5 h for the IR formula-
tion, 3 h for the SR formulation, and 5 h for the XL formula-
tion [1]. Mean maximal plasma concentration (Cmax) after a sin-
gle 150 mg SR dose in healthy nonsmoking adults was 143
ng/ml in one study and 91 ng/ml in a separate study [3,4]. The
steady state Cmax of bupropion SR is reported at approximately
160 ng/ml in healthy male adults. The Tmax of the hydroxybu-
propion metabolite after a single SR tablet is 6 h. The steady
state Cmax of hydroxybupropion is 7–10 times higher than
bupropion [1,3]. Bupropion and its hydroxybupropion metabo-
lite are 84% plasma protein bound at concentrations up to
200 µg/ml [3,5]. The apparent volume of distribution (Vd/F) is
reported to be 19 l/kg at steady state [1].
1250
Bupropion’s pharmacokinetic profile is best fitted to a two-
compartment model as evidenced by it’s biphasic plasma con-
centration-time curve. A distribution phase in adults occurs
with a mean half-life of 3.5 h [3]. The terminal elimination
phase of bupropion has a mean half-life of 18 ± 3 h after a sin-
gle 150 mg dose in adults [4]. The steady state half-life in adults
on a 150 mg twice-daily regimen is 21 ± 9 h. Similarly,
hydroxybupropion metabolite has a half-life of 20 ± 5 h [1].
Therefore, steady state plasma levels of bupropion and its main
metabolite will occur after 5–7 days of administration. In con-
trast, the threohydrobupropion and erythrohydrobupropion
metabolites have elimination half-lives of 37 ± 13 and
33 ± 10 h, respectively, thus taking longer to reach steady state.
Bupropion and its metabolites display linear pharmacokinetics
at steady state within the 150–450 mg daily dose range [1,3,5].
The apparent oral clearance (Cl/F) of bupropion following
chronic dosing in adults is reported to be approximately
160 l/h [3]. The fact that this experimental value exceeds
hepatic blood flow indicates extensive first-pass metabolism
and low oral bioavailability. There is a three- to ten-fold inter-
individual variability in bupropion and hydroxybupropion
Cmax and area under the plasma time–concentration curve
(AUC) [6]. Tobacco smoking has no significant impact on the
pharmacokinetics of bupropion [4,7].
The major cytochrome P-450 isozyme responsible for
bupropion metabolism is CYP2B6 and bupropion hydroxyla-
tion through this enzyme is considered a selective marker of
CYP2B6 activity [8]. The most abundant drug metabolizing
enzyme, CYP3A4, does not appear to have a significant role in
the metabolism of bupropion [9]. CYP2B6 is a polymorphic
drug metabolizing enzyme such that the metabolism and,
hence, systemic exposure to parent drug and metabolites may
vary widely depending on an individual’s genotype. Both in
vitro and in vivo pharmacokinetic data exist that describe varia-
bility based on CYP2B6 genotype [6,10,11]. For example, a popu-
lation and nonparametric pharmacokinetic analysis of 121
healthy male volunteers assessed the influence of various
CYP2B6 alleles on clearance and AUC values of bupropion and
hydroxybupropion. Despite an approximately tenfold enzy-
matic variability in this homogenous group, there was a unimo-
dal distribution of bupropion AUC values indicating no ultra-
rapid or deficient metabolizers. Six distinct alleles were
identified on the basis of five genetic polymorphisms in the
coding region of the CYP2B6 gene. The CYP2B6*1 wild-type
allele was present in 54.5% of participants. Those with at least
one CYP2B6*4 allele demonstrated a 1.6-fold higher bupro-
pion clearance compared with the wild-type CYP2B6*1 allele
and higher hydroxybupropion:bupropion plasma ratios [6]. One
criticism of this study is that alcohol use was not taken into
account as a potential confounder as this activity is reported to
influence CYP2B6 expression and catalytic activity [10].
CYP2B6 is expressed in the brain at a lower level than the
liver [12,13]. However, the distribution in the brain is not
homogenous, leaving the possibility for localized high expres-
sion in discrete brain regions where bupropion and its
Expert Rev. Neurotherapeutics 6(9), (2006)
 Bupropion

CH3
A O O
CH3
O
NH NH
N CH3
CH3
CH3 CH3
CH3 CH3
CH3
Cl
Bupropion Diethylpropion Methcathinone

CH3
CH3

HO O H
NH2 N
NH
CH3
CH3 CH3
Cl

Cl
Hydroxybupropion Amphetamine Methamphetamine

NH2
B

OH
HO
HO
NH2 HO

NH2
HO HO N
Norepinephrine Dopamine Serotonin H

Figure 1. (A) Structure of bupropion and other compounds, which share its 1-phenylpropan-2-amine core structure. Also shown is hydroxybupropion,
the major active metabolite. (B) The endogenous monoamine neurotransmitters.

metabolites may exert their pharmacologic action. The high-
est expression is found in astrocytes whereas significant
amounts are also found in the dentate gyrus and layers II–VI
of the cortex [12]. It is plausible that baseline and environmen-
tally-regulated expression of CYP2B6 in the brain may have
an influence on the efficacy and toxicity of bupropion. For
example, the expression appears highest in those who are
smokers and alcoholics. This finding has been used to
describe variability in the treatment effect of bupropion on
smoking cessation [12,14]. Although CYP2B6 polymorphisms
may predict altered nicotine cravings and higher relapse rates,
it is not evident that this is related to changes in bupropion
pharmacokinetics. At least one trial suggests a role for
CYP2B6 polymorphisms on smoking cessation success in a
placebo group but no role of the polymorphism on response
rate could be established in the bupropion treatment group. A
criticism of this study is that plasma bupropion and nicotine
levels were not evaluated and it is difficult to assess the role of
altered pharmacokinetics of bupropion in smoking cessation
in light of the fact that CYP2B6 is also a major metabolizing
enzyme for nicotine [14].
An appropriate study addressing the influence of a CYP2B6
phenotype on the safe and effective bupropion dose for an individ-
ual patient is lacking. Previous knowledge of a patient’s expected
plasma levels of bupropion and hydroxybupropion may be useful
in predicting efficacy and toxicity on a given dosage regimen. It
may, at least partly, explain why some individuals develop seizures
at the upper end of therapeutic doses, while others can ingest large
quantities without effect [15,16]. Perhaps selective accumulation of
the hydroxybupropion metabolite in a rapid CYP2B6 metabolizer
may be to blame but it is not yet known if bupropion, hydroxybu-
propion, both, or neither are responsible for inducing seizures in
humans. Additionally, there may be a combination of genotypic
differences at both the site of action and metabolic pathways that
determine bupropion’s variable efficacy and toxicity in humans
but this has not yet been demonstrated [17].
Adverse effects
Bupropion is generally well-tolerated. The most common adverse
effects during initial treatment are dry mouth, constipation, head-
ache, nausea, agitation, insomnia and weight loss [2,18]. In clinical
practice the most common cause of stopping bupropion is

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Foley, DeSanty & Kast
jitteriness or an unpleasant state variously described as a crazy feel-
ing. Bupropion is notable among antidepressants in that lower
sexual dysfunction is seen during treatment than with any other
single antidepressant or antidepressant class [19].
Bupropion was withdrawn in 1986 shortly after US FDA
approval because of new-onset seizures in four out of 55
bulimic patients in a clinical trial [20]. The drug was reintroduced
in 1989 at a lower dose range and currently has contraindica-
tions for use in patients with seizure history, eating disorders or
those undergoing ethanol or other CNS depressant withdrawal
[2,18]. The drug is considered to pose the same risk of seizures as
other antidepressants when used at recommended doses [21,22].
The risk is estimated at 0.1% with daily doses below 300 mg
and increases to 0.4% with daily doses up to 450 mg. There is a
tenfold increase in seizure risk when daily doses exceed
450 mg [2]. Interestingly, bupropion has been shown to possess
some antiseizure activity in mice but only at low doses [23,24].
In clinical trials, dose-limiting side effects are usually related
to bupropion’s stimulatory effects. For example, in a series of
depression trials, agitation was reported in 3% at 300 mg daily
and in 9% at 400 mg daily versus only 2% in the placebo
group. Likewise, insomnia occurred in 11% and 16% of
patients at 300 mg and 400 mg daily doses, respectively, versus
6% in placebo [2]. Dry mouth, also a potential dose-limiting
effect, occurs with 16% incidence versus 7% in placebo with
100–400 mg/day [25]. These effects are likely related to peak
plasma concentration, which may occur within 1–5 h after a
dose, depending on the formulation used [1]. In clinical trials,
the discontinuation rate owing to adverse events is reported to
be approximately 7% [25–27]. This discontinuation rate appears
no different than other second generation antidepressants,
such as the selective serotonin reuptake inhibitors (SSRIs) [28].
The predominant qualitative difference appears to be the lack
of somnolence and sexual dysfunction with bupropion in con-
trast to these other agents. Nausea, which occurs in approxi-
mately 15% of patients, is similar in occurrence to that
reported with the SSRIs [29]. Unlike the tricyclic antidepres-
sants (TCAs), bupropion is devoid of anticholinergic action
[18,30]. Most adverse effects with bupropion occur in the initial
weeks of therapy and become less apparent over time. Side
effects, if bothersome, are easily treated by switching antide-
pressants but for some this is a poor option. Insomnia can
often be addressed by standard sleep hygiene measures and
hypnotic medicine use. Trazodone, benzodiazepines and zolpi-
dem are commonly used to combat bupropion-induced
insomnia. In our experience zolpidem and related sleep aids
are associated with more next day cognitive and motor effects.
We have found that quetiapine or olanzapine are good options
for sleep induction with bupropion users. If a benzodiazepine
is preferred, lorazepam can be used.
The controlled-release formulations are advertised to be bet-
ter tolerated than the IR tablets, although no direct comparison
study to address this contention exists in the published litera-
ture. The SR formulation is usually dosed twice daily, however,
many patients avoid taking doses late in the day to prevent
1252
interference with sleep. In contrast, the XL formulation is taken
once daily in the morning. It’s main differences may be a lower
Cmax and more delayed time to Cmax [1,31].
Bupropion in overdose
Antidepressants are used in those people who tend to have sui-
cidal drives, therefore a discussion of toxicity in overdose is par-
ticularly important. The introduction of the SSRIs in the late
1980s and early 1990s was significant, as these drugs have
earned a reputation of relative safety in overdose. This is in con-
trast to the well-known toxicities of TCAs that resulted in many
overdose deaths from their introduction in the 1950s, until
their decline in use with SSRI introduction in the 1990s [32].
Current popular press and patient concerns surround the
potential of antidepressants to create, provoke or exacerbate
suicidal feelings and actions. This is not a new story. Prior to
antidepressants it was recognized that emergence from a melan-
cholic depression was a particularly dangerous time in that
patients regain some previously absent motivation as they start
to recover and then act on suicidal drives. All antidepressants
are thought to have some potential to provoke a switch to
mania in predisposed people and mania is a well recognized risk
for suicide. A direct engendering of new suicidal drive by any
antidepressant is conceivable. However, the link between sui-
cide and antidepressants is controversial. There is currently no
strong evidence supporting this linkage in the literature and a
causal link between antidepressant use and suicidality in chil-
dren remains weak. Presently, increased use of bupropion and
other antidepressants are associated with lower suicide rates [33].
Unlike the well-recognized toxicity present in TCA overdose
(anticholinergic crisis, arrhythmia, and obtundation), bupropion
overdose patients can present with vague symptomology.
Depending on the level of ingestion there may be varying degrees
of agitation, stimulation, tachycardia, nausea/vomiting, seizures,
agitation, hallucinations and tremor [34,35]. Several case reports
cite cardiac conduction delays as well [36–38]. It is difficult to
attribute any of bupropion’s toxicities to a hyperdopaminergic
and/or hyperadrenergic state as one may expect based on the
drug’s presumed dopamine and norepinephrine uptake blockade.
It is possible that sodium channel blockade may account for
some of the cardiac conduction effects at high doses [38].
Some may argue that bupropion shares the same safety fac-
tor as the SSRIs in overdose [39]. This argument is supported by
several case reports and retrospective analyses describing the
clinical manifestations of bupropion overdose. For example, a
retrospective analysis examining 385 cases of intentional bupro-
pion overdoses reported to the Texas Poison Center during
1998 and 1999 revealed only two deaths. Patients with co-
ingestants were not excluded from this analysis. Tachycardia
was the most frequently reported symptom occurring in 23%
of cases. A total of 11% of all patients (41 out of 385) had sei-
zures whereas 41% (41 out of 99) of those classified with signif-
icant clinical effects had seizures. The majority of seizures were
reported within 6 h of ingestion and were most common with
doses greater than 2500 mg of bupropion alone or when a
Expert Rev. Neurotherapeutics 6(9), (2006)

stimulant was co-ingested. In most cases seizures were self-lim-
iting and caused no permanent damage. Benzodiazepines were
most often initiated to successfully control the seizures [35].
Perhaps a better indication of the clinical toxicity of bupro-
pion is to examine patients without significant co-ingestants. A
review of bupropion-only exposures reported to the Toxic
Exposure Surveillance System (TESS) from 1998 through 1999
revealed 7348 cases, of which 33% were intentional. A total of
35% (2561 out of 7348) experienced no effects whereas 15%
(1071 out of 7348) had minor effects. The clinical effects of
bupropion lasted less than 24 h in 85% of patients with symp-
tomatic exposures. The most commonly reported clinical
effects included tachycardia, vomiting, lethargy and agitation.
A total of 6% (418 out of 7348) of patients exhibited seizure
activity. In contrast, when examining only the 2247 sympto-
matic patients, 19% had seizure activity. There was a 15% sei-
zure incidence when the exposure was intentional whereas less
than 1% seizure incidence was documented following uninten-
tional exposure. The difference in seizure incidence between
these groups likely resulted from the presumed large difference
in amount of bupropion ingested. The most significant finding
is that only five deaths out of 7348 bupropion-only exposures
were noted in the 1998 and 1999 TESS database. All five
deaths appeared to result from intentional exposure with an
unknown amount of bupropion. These patients exhibited seizures
and eventual respiratory and cardiac arrest [39].
Drug–drug interactions
The potential for pharmacologic interactions with bupropion
has been the previous focus particularly in relation to
co-administration of drugs which lower the seizure threshold,
such as antipsychotics, tramadol, theophylline and other anti-
depressants [1,2]. Increased emphasis on pharmacokinetic inter-
actions is due, in part, to the recent appreciation of the abun-
dance and variability of CYP2B6, the major metabolizing
enzyme of bupropion [6,10,12,40]. The effect of either CYP2B6
inhibition or induction is potentially clinically significant. For
example, the antiplatelet drugs clopidogrel and ticlopidine are
potent CYP2B6 inhibitors [41,42]. The AUC and Cmax of a single
bupropion 150 mg dose was evaluated in 12 healthy male vol-
unteers following 4 days of therapeutic clopidogrel or ticlopi-
dine doses. A 68% decrease in the hydroxybupropion:bupro-
pion ratio was observed following clopidogrel and a 90%
decrease occurred following ticlopidine. The majority of the
ratio decrease was attributed to a decrease in hydroxybupropion
formation. Only a moderate increase in the AUC and Cmax of
bupropion occurred, thus indicating metabolism may have
occurred through an alternative pathway in the presence of
CYP2B6 inhibition. As the elimination half-life of bupropion
did not change, despite the increase in Cmax, it was suggested
that the interaction was at the level of hepatic first-pass versus
the elimination phase [42]. The clinical implication of this phar-
macokinetic interaction was not evaluated in this small study.
However, treatment failure is plausible if the formation of the
hydroxybupropion metabolite is a necessary entity in the
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Bupropion
clinical efficacy of bupropion. A study of clopidogrel and ticlo-
pidine on steady state bupropion pharmacokinetics and tolera-
bility would be a logical follow-up to this single-dose analysis,
in order to fully ascertain the clinical significance of the interac-
tion and whether dose adjustments are necessary. For now, the
clinician should monitor patients closely when co-administering a
CYP2B6 inhibitor with bupropion.
Another significant concern regarding bupropion metabo-
lism is the fact that CYP2B6 is an inducible enzyme. Cigarette
smoking, alcohol, phenobarbital and carbamazepine are some
examples of CYP2B6 inducers and their concurrent use may
lead to increased production of the hydroxybupropion metab-
olite [1]. Further prospective, in vivo, human studies are
needed to assess the true clinical significance of CYP2B6-
inducing agents on bupropion. However, these variations may
account for the requirement of starting with 50 mg daily for
some patients.
Bupropion is an inhibitor of CYP2D6 despite not being a
substrate for this enzyme and this may lead to clinically signifi-
cant drug interactions with CYP2D6 substrates [43–45]. The in
vitro 50% inhibitory concentration (IC50) of bupropion and
hydroxybupropion for inhibition of CYP2D6-mediated dex-
tromethorphan (25 µM) O-demethylation in human liver
microsomes is 58 and 74 µM, respectively [46]. For comparison,
the IC50 of the SSRIs, paroxetine and fluoxetine, for dex-
tromethorphan O-demethylation (25 µM) is reported at 2.85
and 0.24 µM, respectively, when using a similar in vitro
method (i.e., without inhibitor preincubation) [47]. The inhibi-
tory activity of bupropion on CYP2D6 has also been observed
in vivo when utilizing dextromethorphan as a probe. Kotlyar
and colleagues demonstrated that 17 days of bupropion treat-
ment in extensive CYP2D6 metabolizers resulted in decreased
CYP2D6 activity in all patients and conversion to a poor
metabolizer phenotype in six out of 13 patients on the basis of
increased urinary dextromethorphan/dextrorphan ratios. No
change occured in patients who were pretreated with placebo
[43] . The mean dextromethorphan/dextrorphan ratio increased
from 0.012 ± 0.012 at baseline to 0.418 ± 0.302 after bupro-
pion treatment (p < 0.0004). The results of this study appear
to question the in vitro data that classifies bupropion as a rela-
tively weak CYP2D6 inhibitor. The authors suggest the rela-
tively high in vitro IC50 value for CYP2D6 inhibition may have
resulted from the methodology utilized (i.e., lack of a bupro-
pion pre-incubation period). The in vivo data may be consist-
ent with bupropion acting as a time-dependent, mechanism-
based CYP2D6 inhibitor [43]. This contention, of course,
requires further study.
At present, we recommend close monitoring of patients
requiring coadministration of CYP2D6 substrates, particu-
larly highly extracted oral drugs with narrow therapeutic
indexes and drugs that may lack alternative metabolic path-
ways. The manufacturer specifically cautions of potential
interaction with various antidepressants (e.g., desipramine,
sertraline), antipsychotics (e.g., thioridazine, haloperidol),
β-blockers (e.g., metoprolol) and type 1C antiarrhythmics
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Foley, DeSanty & Kast
(e.g., flecainide, propafenone) and suggests initiating these
drugs at the lower end of the dose range in the presence of
bupropion. This precaution is based, in part, on a study that
demonstrated bupropion pretreatment significantly increased
the Cmax (twofold), AUC (fivefold), and half-life (twofold) of
desipramine in 15 healthy male subjects [2].
Bupropion is contraindicated in conjunction with monoam-
ine oxidase inhibitors (MAOIs). The recommendation is to wait
14 days following MAOI discontinuation [2]. The hypothetical
concern is an increase in monoamines (serotonin, norepine-
phrine and dopamine) owing to concurrent uptake blockade
and inhibition of monoamine metabolism at neuronal synapses.
Clinical cases of this interaction with bupropion have not been
published to date. This is puzzling considering the many case
reports of MAOIs interactions with TCAs and SSRIs [48–52].
Neuropharmacology of bupropion
Bupropion is an aminopropiophenone with a chemical struc-
ture dissimilar to SSRIs, or TCAs, but slightly similar to the
endogenous monoamine neurotransmitters dopamine and
norepinephrine (FIGURE 1). Bupropion contains a phenyl-isopro-
pyl-amine structure, which is also found in other psychoactive
compounds, as shown in FIGURE 1. This chemical backbone is
also present in the drug diethylpropion, which is marketed as
an appetite suppressant. Considering its structural similarity,
one might suspect that bupropion can decrease appetite in
patients. Although, some studies have shown weight loss with
bupropion [53], our observation is that bupropion is weight
neutral and is not an effective weight-loss adjuvant over time.
The chemical backbone of bupropion is also seen in the abused
stimulants methcathinone, methamphetamine and ampheta-
mine. Despite sharing this structural motif, bupropion, in our
experience and in experimental studies [54] does not have signif-
icant abuse potential. Bupropion is generically available as a
racemic mixture and is dispensed as the HCl salt. Studies in
mice have demonstrated that the enantiomers of bupropion do
not differ significantly in their efficacy [55]. However, there does
appear to be important enantiomeric effects of the hydroxybu-
propion metabolite, as studies on rat synaptosomes in vitro
found 20 times greater dopamine and norepinephrine trans-
porter inhibition for one hydroxybupropion enantiomer (2S,
3S) [56]. These authors also found significant inhibition of a nico-
tinic acetylcholine receptor by this same enantiomer.
The mechanism of action of bupropion remains elusive.
Bupropion was first synthesized by Wellcome Research Labora-
tories and was patented in 1974 [57]. Its effects in vivo were
reported in 1977 and it was discovered that bupropion did not
elicit the stereotyped behavior commonly seen with ampheta-
mine-type stimulants and had a dose that was lethal for 50% of
test subjects (LD50) of more than 500 mg/kg orally when tested
in rodents [57]. Interestingly, bupropion does not have a high
affinity for monoamine receptors or transporters. It does not
inhibit any of the isoforms of monoamine oxidase [57]. Impor-
tantly, bupropion, unlike structurally related stimulants, has
not been shown to evoke transporter-mediated release of
1254
monoamines [58]. The ability to provoke neuronal release of
monoamines via transporter efflux is a property of transporter
substrates, such as amphetamine but has not been attributed to
bupropion [59,60].
Dopamine, norepinephrine & serotonin inhibition
Initially bupropion’s actions were assumed to result from inhi-
bition of dopamine reuptake transporters. The IC50 values for the
inhibition of [3H]monoamine uptake into rat brain synaptosomes
was initially reported as 6.5 ± 0.6 µM for the norepinephine
transporter, more than 1000 µM for the serotonin transporter
(TABLE 1) and 3.4 ± 0.4 µM for the dopamine transporter [57].
These values are quite high when compared with other antide-
pressants, which typically have IC50 values in the low nM
range. Our laboratory has measured bupropion’s effect on
cloned, human transporters in vitro and found IC50 values of
1.37 ± 0.14 µM for the norepinephrine transporter,
1.64 ± 0.28 µM for the dopamine transporter and
28.69 ± 1.83 µM for the serotonin transporter. These values
are not too dissimilar from those published for the rat. How-
ever, it is interesting to note that we did not find a large differ-
ence in activity between the norepinephrine and dopamine
transporters, although the lower activity at the serotonin trans-
porter was confirmed. Data obtained by others has paralleled
these findings and bupropion is now commonly considered a
dual norepinephrine and dopamine reuptake inhibitor [61].
Relative affinities of bupropion and other chemically similar
compounds for monoamine transporters are shown in TABLE 1.
Although the data in TABLE 1 were obtained using different
methods and species (rat or human) a general trend can be
seen in that bupropion and chemically similar compounds all
have less affinity for serotonin transporters compared with
norepinephrine and dopamine transporters (TABLE 1).
The idea that bupropion is now viewed as a dual uptake
inhibitor rather than a predominantly dopamine transporter
specific inhibitor warrants discussion. Many drugs which are
touted as being specific or selective for a given monoamine
transporter usually have high affinities for other transporters as
well and are really only modestly selective. When used in vivo,
the specificity for many monoamine transport inhibitors may
be over-rated. For example, the SSRI paroxetine has good
affinity (<50 nM) for the human norepinephrine transporter
and the SSRI sertraline, has a similar affinity for the dopamine
transporter [62]. It is interesting that we are willing to call
bupropion a dual norepinephrine/dopamine uptake inhibitor
when its IC50 values are approximately 1 µM, yet we use the
term ‘serotonin-selective’ for drugs which have nM affinity for
other monoamine transporters. Evidence that the SSRIs do
have important effects at sites other than their primary site of
action is demonstrated by a recent study showing that mice
lacking the norepinephrine transporter do not respond to
SSRI drugs [63]. This study supports the notion that antide-
pressants have multiple modes of action and cannot simply be
explained by activity at one transporter, surely bupropion fits
this description.
Expert Rev. Neurotherapeutics 6(9), (2006)

Table 1. Relative affinities of aminopropiophenones and amphetamine for monoamine transporters.
Drug Dopamine transporter
IC50 µM
Bupropion 3.4 (R)
1.64 (H)
Diethylpropion 14.99 (R)
Methcathinone 0.356 (H)
Methamphetamine 0.467 (H)
Amphetamine (+ isomer) 0.034 (R)
IC50: Inhibitory concentration of 50%.
Some values were obtained using rat brain synaptosomes (R), others used cell lines with human transporters expressed (H). Standard deviations are not reported for clarity
and simplicity. Adapted from [157–159].
How can bupropion work as an antidepressant with such
relatively low affinity for monoamine transporters?
Human studies using the positron-emitter [11C]-RT132, which
is selective for the dopamine transporter have demonstrated
that less than 22% of dopamine transporters have bound
bupropion [64]. This is less than would be expected for a drug
whose action is mediated chiefly by dopamine transporter
inhibition. As the authors of this study noted, occupancies of
80% at the serotonin transporter are found when SSRIs are
administered and 50% occupancy at the dopamine transporter
is needed for cocaine’s effects [65,66]. However, it may not be
valid to directly correlate the occupancy of a specific trans-
porter to its effects. For example, both SSRIs and cocaine have
affinities for other monoamine transporters and the effects of
these compounds are not explained exclusively by actions at a
single transporter. Since binding percentages at a single trans-
porter do not explain all the actions of SSRIs or cocaine,
bupropion’s low binding percentage at dopamine transporters
does not necessarily negate a role for this protein in its actions.
As mentioned previously, metabolites of bupropion are known
to be active. Bondarev and colleagues showed that the metabo-
lite S,S-hydroxybupropion has affinity for norepinephrine and
dopamine transporters of 3.85 and 1.02 µM, respectively [67].
Activity of hydroxybupropion is reported to be greater than
bupropion in rodent depression models as well [68]. However, no
single metabolite of bupropion can account for all its actions in
vivo. The relative effects of metabolites on stimulant versus nico-
tinic effects were examined by Bondarev and colleagues. S,S-
hydroxybupropion was similar to bupropion in amphetamine-
substitution tests and both isomers of hydroxybupropion and
hydrobupropion had antagonist effects at α3β4 nicotinic recep-
tors [67]. It is clear that the metabolites of bupropion play a role
in its systemic action and most likely affect the duration of
action since metabolites appear to accumulate in humans [69].
Unlike other antidepressants, bupropion does not appear to
alter CSF concentrations of dopamine and norepinephrine
metabolites [70]. This would suggest a different mechanism of
action than other antidepressants and one that was not
transporter-mediated. However, earlier studies demonstrated
www.future-drugs.com
Bupropion
Norepinephrine transporter Serotonin transporter Ref.
IC50 µM IC50 µM
6.5 (R) >1M (R) [157,159]
1.37 (H) 28.69 (H)
18.10 (R) 311.00 (R) [157]
0.511 (H) 34.6 (H) [158]
0.647 (H) 11.6 (H) [158]
0.039 (R) 0.038 (R) [157]
that when injected into rats, bupropion could prevent dopamine
and norepinephrine depletion caused by 6-hydroxydopamine
[71]. This is strong evidence that bupropion inhibits uptake
in vivo and when considering its effectiveness in animal models
of depression (Porsolt swim test), it seemed clear that bupropion
owed at least part of its physiologic action to inhibition of
dopamine and, to a lesser degree, norepinephrine transporters.
Initial studies with bupropion did not demonstrate the char-
acteristic downregulation of adrenergic receptors that com-
monly occurs with TCAs [58]. Newer studies in rats have now
shown downregulation of β-adrenergic receptors along with
desensitization of norepinephrine-stimulated adenylate cyclase,
however these occur only after chronic, high doses of bupro-
pion [72]. Interestingly, experiments using more acute dosing
showed that bupropion reduced the firing rates of noradrener-
gic neurons in the locus ceruleus [73] but did not alter the firing
rates of serotonergic neurons in the dorsal raphe [72]. Dong and
colleagues showed that chronic bupropion administration
decreased the firing rate of noradrenergic neurons via increased
activation of autoinhibitory α2-adrenoceptors [74].
In contrast to the CSF findings of Little and colleagues, ther-
apeutic doses of bupropion did reduce systemic turnover of
norepinephrine measured in the urine [75]. Decreased turnover
of monoamines can occur when increased levels of neurotrans-
mitters are present in the synaptic cleft. These increases can
then activate presynaptic autoreceptors that serve to decrease
neurotransmitter release. Findings that bupropion reduces
norepinephrine turnover provide further evidence that the drug
is inhibiting the norepinephrine transporter in vivo.
Recent data has also shown that bupropion’s actions at the vesic-
ular monoamine transporter may be important in its action.
Bupropion and methylphenidate have been shown to increase
vesicular monoamine transporter-2 (VMAT-2) uptake and cause a
redistribution of the cytoplasmic VMAT-2 from plasmalemmal,
membrane-associated to a non-membrane-associated fraction [76].
Dopamine, norepinephrine, and serotonin cycle in and out of
neurons and modulate neuronal signaling (FIGURE 2). Neurotrans-
mitters are released via exocytosis from intracellular vesicles stored
in the presynaptic cytosol. The dopamine, norepinephrine and
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Foley, DeSanty & Kast
Presynaptic neuron
VMAT-2 sequestering
neurotransmitters into
synaptic vesicles
N N N N
N N
N
(2) N
N N
N
N N
N
N
N N
N
N
N N
N N
N N
Presynaptic vesicle
Figure 2. Neuronal synapse depicting release of monoamine neurotransmitter with subsequent receptor activation and termination via reuptake
transporters. Possible sites of bupropion action are shown, (1) monoamine reuptake transporters (norepinephrine and dopamine), (2) augmentation of vesicular
monoamine transporter (VMAT)-2. N: Neurotransmitter.
serotonin reuptake transporters transport their respective extracel-
lular neurotransmitters from the extracellular synaptic space, back
into the presynaptic neuron (FIGURE 2). Once back in the cytosol,
the neurotransmitter is free to stimulate intracellular receptors. It
is also available to be catabolized by monoamine oxidase. For
dopamine this catalysis is believed to generate reactive oxygen spe-
cies that can damage neurons. VMAT-2 pumps cytosolic
dopamine, norepinephrine, and serotonin into vesicles of the
respective neurons (FIGURE 2). When VMAT-2 function is
increased, vesicle size is increased [77]; however, neurotransmitter
concentration remains similar in large and small presynaptic vesi-
cles. Diverse bits of evidence, summarized here, suggest that if in
fact bupropion increases VMAT-2 function, this mechanism
could play an important role in its antidepressant mechanism.
Consider the drug amiodarone, a phospholipase inhibitor
used to treat arrhythmias [78]. Amiodarone inhibits VMAT-2
function [79]. It has also been associated with depression [79,80].
Amiodarone binds to the reserpine binding site on VMAT-2
[79]. Reserpine has been used for centuries to treat psychotic ill-
ness and does so successfully but at the price of high morbid
depression generation. Just as reserpine and amiodarone may be
causing depression by inhibiting VMAT-2, it is possible that
bupropion’s ability to enhance VMAT-2 function is important
in its antidepressant mechanism.
1256
Activation of presynaptic receptors
Activation of
postsynaptic receptors
N
N
N N N
N
N N
(1)
Reuptake transporters
terminating synaptic signaling
Postsynaptic neuron
For VMAT-2, dopamine transport is D2 function-dependent.
D2 agonists stimulate dopamine entry into VMAT-2 [81]. Potent
traditional antipsychotic medicines, such as haloperidol and the
neuroleptic group, block dopamine entry into VMAT-2 yet the
newer atypical antipsychotic clozapine does not [81–83]. The older
group of antipsychotic medicines to which haloperidol belongs
have long been thought by psychiatrists as contributing to
depression, anhedonia, or alogia in chronic schizophrenia and the
newer atypical group to which clozapine belongs are considered
not to generate these deficits. This again would suggest that drugs
which inhibit VMAT-2 may generate depression. On the other
hand, drugs which augment VMAT-2 have positive effects. Apo-
morphine is a D2 agonist used to treat Parkinson’s disease and
potently increases VMAT-2 in rat vesicles isolated from the
striatum [82]. There is data indicating that apomorphine is stimu-
lating to sexual drive and function [84]. The lower incidence of sex-
ual side effects associated with bupropion may be owing, in part to
a similar VMAT-2 augmenting mechanism.
Other observations connecting VMAT-2 enhancement with
increased sexual function include the clinical observation that
the dopaminergic agonists used to treat Parkinson’s disease
result in increased sexual desire and function even when the
Parkinson’s itself is not helped. This has been formally reported
[85]. Strong increases are even more common after apomorphine
Expert Rev. Neurotherapeutics 6(9), (2006)

use [86,87]. Pramipexole is used and is quite effective in the treat-
ment of partially responding depression [88] and when it is used
in this way, we usually see increases in sexual function.
Lithium is one of the oldest medicines currently still in use. It
has well established mood stabilization effects in bipolar disor-
der and is commonly used to augment antidepressants but has
significant antidepressant effects of its own. Chronic treat-
ment of rats, raising their lithium levels to that considered ther-
apeutic in psychiatric patients, doubled VMAT-2 in some sero-
tonergic areas, as well as causing significant VMAT-2 increases
in dopaminergic neurons, while decreasing VMAT-2 in
noradrenergic neurons [89]. This is more evidence of a link
between VMAT-2 and depression. The information above
implicates the importance of VMAT-2 in depression and may
help explain some of bupropion’s mood elevating effects.
We believe that inhibition of dopamine and norepinephrine
reuptake and enhancement of VMAT-2 all contribute to
bupropion’s mechanism of action. Although the affinity for
bupropion and its metabolites for monoamine transporters is
low compared with classic antidepressants, inhibitory concen-
trations should be reached in the CNS at therapeutic doses
based on the drug’s large apparent volume of distribution.
Bupropion also appears to have the ability to modulate neuro-
transmitter release and this may play a role in its actions. If, by
modulating VMAT-2, bupropion increases the amount of nore-
pinephrine, dopamine and/or serotonin released during depo-
larization then inhibiting reuptake of these neurotransmitters
would likely further augment this action.
How does bupropion serve as a smoking cessation aid?
A noteworthy report from Slemmer and colleagues showed
that bupropion was able to block nicotine’s hypothermic,
motor, antinociceptive and convulsive effects in rats [90]. Inter-
estingly, these effects were obtained with systemic or intrathe-
cal injections of bupropion, suggesting the parent compound
is effective in nicotinic modulation. Furthermore, they
showed that bupropion noncompetitively blocks α3β2, α4,
β2 and α7 isoforms of nicotinic acetylcholine receptors
(nAChRs) at therapeutically relevant concentrations. The sig-
nificance of inhibiting α3 subunits, which are expressed in
brain regions associated with pleasure and reward was also
noted by Fryer and colleagues [91]. Building on these findings,
Miller and colleagues found that bupropion inhibits nicotine-
evoked dopamine overflow in rat brain slices by antagonizing
nAChRs in rat striatum and the hippocampus, and that this
effect occurs at concentrations which also inhibit dopamine
and norepinephrine transporter uptake [92]. The monoamine
uptake inhibition effects of bupropion are also thought to be
important in bupropion’s antismoking effects. This is exam-
pled by the fact that nortriptyline, a norepinephrine reuptake
inhibitor and antidepressant, has also been found to be effec-
tive in smoking treatment but significantly less so than bupro-
pion. So as is the case in depression, the mechanism of action
in smoking cessation is complex and not attributable to any
one receptor or transporter. An excellent and recent review
www.future-drugs.com
Bupropion
describing bupropion’s nicotinic actions and its effects in vari-
ous models of addiction and withdrawal has been published
by Warner and Shoaib [93].
Approved uses
Depression
Bupropion is US FDA approved for treatment of major depres-
sive disorder in adults [2]. Trials of varying size and quality have
been published to demonstrate bupropion’s efficacy and safety
in depression versus placebo and other antidepressants in vari-
ous patient populations. Early trials included small numbers of
patients and were typically only 4 weeks in duration [94–97].
Furthermore, doses as high as 600 mg/day were evaluated [94].
Although most patients are administered the 300 mg daily dose
in clinical practice, patients can respond to daily doses of
100–300 mg with little or no evidence of a clear dose-response
effect. For example, an 8-week multicenter evaluation of the
efficacy and safety of bupropion SR demonstrated essentially
no difference between 150 and 300 mg daily doses on mean
improvements in the Hamilton Rating Scale for Depression,
Clinical Global Impression Severity Of Illness Scale and Clini-
cal Global Impressions For Improvement Of Illness Scale [27].
Consistent with this is evidence from an early study that dem-
onstrated a potential inverted curvilinear plasma concentration-
response curve for bupropion. It was noted that a maximum
response was associated with trough plasma levels between 50
and 100 ng/ml. Concentrations above or below this range may
correlate with a poor response [98]. This is in contrast to the
positive linear dose- and concentration-response observed for
smoking cessation with bupropion [99] but is in accordance
with older findings of nortriptyline being effective as an antide-
pressant when plasma levels are between 50 and 150 ng/ml and
efficacy going down as levels depart from this therapeutic
range [100].
Antidepressant therapy should be continued longer than the
typical length of a clinical trial as relapses are common upon dis-
continuation [101,102]. A double-blind, continuation-phase trial
evaluated the safety and efficacy of bupropion SR (150 mg twice
daily; n = 210 vs placebo; n = 213) in decreasing depression
relapse in patients who experienced a previous positive bupro-
pion response in an 8-week open-label phase. The survival curve
favored bupropion SR over placebo when examining the pro-
portion of those who would relapse (i.e., require treatment
intervention) by the end of the 44 week double-blind study
period (log-rank test, p = 0.003; Wilcoxon test, p = 0.004).
Survival estimates indicated 52% of the placebo patients would
require treatment intervention versus 37% of bupropion-treated
patients. The median time to relapse after randomization into
the double-blind phase was 24 weeks with placebo versus at least
44 weeks with bupropion. Statistically significant separation of
the survival curves began at week 12 and was maintained to the
end of the study period. Safety results were also consistent with
previous short-term studies and discontinuation rates from
adverse effects did not differ between bupropion and placebo
groups during the double-blind period [101].
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Foley, DeSanty & Kast
Consistent with other antidepressants, the onset of maximal
benefit with bupropion often requires at least 4 weeks of treat-
ment [1,2]. Several comparative clinical trials with trazodone,
doxepin, amitriptyline and imipramine have shown essentially
equivalent magnitudes of clinical response compared with
bupropion [103–107]. More recent trials have compared bupro-
pion with second-generation agents, such as the SSRIs and
demonstrated no clear efficacy differences [108–110]. Furthermore, a
recent systematic review concluded that no significant differ-
ence exists in the efficacy and tolerability between any of the
various second-generation antidepressants [29].
Based on the stimulant property of bupropion, there is a hypo-
thetical concern for use in patients with an anxiety component to
their depression [111]. A randomized, parallel-group, double-
blind, multicenter trial compared response rates between serta-
line (n = 126) and bupropion SR (n = 122) in relation to base-
line anxiety scores in out-patients with major depressive disorder.
No difference in efficacy or time-to-treatment effect was
observed between the two groups. Baseline Hamilton Anxiety
Score (HAM-A) had no influence on response to bupropion or
sertraline as mean baseline HAM-A scores were identical for
responders and nonresponders in both treatment groups. Fur-
thermore, no evidence for aggravation of anxiety was demon-
strated based on HAM-A scores over the course of the 16-week
trial [112]. Many question if bupropion is itself anxiolytic. In our
experience, increased anxiety while on bupropion is a self-
reported cause for bupropion intolerance, yet bupropion also
appears to lower anxiety in a majority of psychiatric patients.
Why bupropion appears to increase anxiety chronically in a
minority of patients is unknown. SSRIs do not increase anxiety
when used chronically, although they certainly can on initial use.
Common clinical practice is to use SSRIs first if anxiety promi-
nent depression is encountered, however, Rush and colleagues
note that their findings suggest that SSRIs should not be thought
of as more anxiolytic than bupropion and that the clinical deci-
sion to select between bupropion and an SSRI should not rest on
the patient’s level of pretreatment anxiety or on the anticipation
of more rapid or more complete anxiolysis [112]. Our experience
agrees with this statement.
As with other antidepressants, there appears to be a moderate
response rate with bupropion. Response rate is often defined as
a 50% reduction in symptom scores from baseline. It is difficult
to show differences in efficacy between antidepressants as trials
typically have high placebo responses [113,114]. Remission,
defined as a complete absence of symptoms, may be a better
efficacy measure and is reported at a rate of 35–40% in 8-week
clinical trials [115–117]. Remission rate was used to assess the effi-
cacy of an appropriate next-step antidepressant by the
Sequenced Treatment Alternatives to Relieve Depression
(STAR-D) study team. The primary outcome measure was
defined as a score of 7 or less on the 17-item Hamilton Rating
Scale for Depression (HRSD-17); this is the standard threshold
defining depression. Adult out-patients with nonpsychotic
major depression were randomly assigned to sertraline, venla-
faxine XL or bupropion SR after failure to respond to
1258
citalopram or intolerance to citalopram. Remission rates
(approximately 25%) and tolerability were similar in all groups
at the end of the 14-week trial [115].
There is also considerable interest in augmentation therapy
where bupropion is added to an SSRI to potentially enhance
efficacy and possibly decrease sexual dysfunction and adverse
effects of the SSRI [118]. Previous reports on augmentation
strategies to SSRIs included case series with small numbers of
patients and other nonprospective studies. In contrast, a second
randomized trial from the STAR-D Study Team examined the
effectiveness of SR bupropion or the anxiolytic buspirone as
augmentation therapy in patients with nonpsychotic major
depression whom either had intolerance to citalopram or did
not have a remission with citalopram. Bupropion SR treatment
(n = 279) resulted in a 29.7% remission rate versus 30.1% in
the buspirone (n = 286) group, thus indicating no significant
difference in treatment effect (p = 0.93). The mean dose of
bupropion at the end of the study was 267.5 mg/day. Bupro-
pion also produced similar remission rates to buspirone by the
end of the study when assessing the secondary outcomes of
response as defined by a score of less than 6 or 50% or more
reduction in baseline scores from the 16-item Quick inventory
of Depressive Symptomology-Self-Report (QIDS-SR-16). The
authors noted that a greater reduction in QIDS-SR-16 scores
occurred with bupropion (25.3 vs 17.1%, p <0.04), although
this was not a prospectively designated outcome. Of note was a
superior tolerability profile with bupropion compared with
buspirone [116]. This trial does at least support previous conten-
tions that some patients treated with SSRIs that exhibit only a
partial response can be brought to full remission by bupropion
augmentation [119,120].
Bupropion is also commonly added to non-SSRI antidepres-
sants, such as mirtazapine or TCAs but until safety can be
established should not be used with MAOIs. Psychiatrists have
long believed that bupropion is slightly less likely to throw a
depressed patient with bipolar disorder into mania than are
SSRIs and recent research bears this out [121].
Postpartum depression was eased by bupropion [122] but
safety in pregnancy or during breast feeding has not been
clearly established [122,123]. A small study demonstrated no
major malformations but slightly increased spontaneous abor-
tions in the bupropion treated group [124]. Interferon (IFN)
treatment of hepatitis C and some malignancies, such as multi-
ple myeloma commonly results in severe psychiatric side effects,
usually involving depression. IFN-induced depression is
commonly treated and responds to SSRIs and to
bupropion [125].
Seasonal affective disorder
Bupropion has demonstrated effectiveness in the prevention of
seasonal affective disorder (SAD). Three multicenter, placebo-
controlled trials had 1024 SAD patients (70% female) rand-
omized to bupropion XL 300 mg daily or placebo beginning
in the months of September to November. Patients were
excluded if they had been treated for depression since the
Expert Rev. Neurotherapeutics 6(9), (2006)

preceding winter. The dose began at 150 mg daily and then
increased after 1 week unless the investigator deemed the
patient intolerable of the 300 mg dose. The patients were fol-
lowed until spring and then 8 weeks after treatment discontin-
uation. Patients were withdrawn from the study if they had a
major depressive episode recurrence. The occurrence of a
major depressive episode was defined as a score of 20 or more
on the Structured Interview Guide for the Hamilton Depres-
sion Rating Scale (SIGH-SAD) during two visits (1-week
apart) or on clinical grounds from Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition criteria inde-
pendent of SIGH-SAD score. Each of the three studies dem-
onstrated superiority of bupropion XL over placebo as demon-
strated by a lower recurrence of seasonal major depression;
Study A; 19% versus 30% (p = 0.026), Study B; 13% versus
21% (p = 0.049) and Study C: 16% versus 31% (p < 0.001).
This translated to a relative risk reduction of 44% for the three
studies. A total of 80% of patients attained the 300 mg daily
target dose of bupropion XL or placebo. These studies were
the first randomized trials to demonstrate effectiveness in pre-
venting a major depressive episode in patients when beginning
the medication before the onset of such episodes [126].
Bupropion as a smoking cessation aid
Bupropion is US FDA approved for use in those attempting to
quit smoking [3]. Bupropion was the first non-nicotine agent
used to aid smoking cessation and is still considered to be the
first choice for non-nicotine intervention. There are many
reports describing the efficacy of bupropion in clinical trials.
One recent report analyzed data from 1070 subjects from two
similar double-blind randomized clinical trials of bupropion
versus placebo and found that bupropion prolonged the time
between quitting and relapse regardless of gender [127]. Another
recent study showed that when used in medical professionals for
7 weeks, bupropion was superior to placebo by 10%
(50 vs 40%) [128]. A smaller study of 47 patients found that
patients receiving bupropion had lower daily cigarette consump-
tion at the time of hospital admission before elective surgery
[129]. A randomized, multicenter, double-blind trial randomized
707 smokers to bupropion (300 mg daily) or placebo for 7
weeks along with behavioral counseling. Continuous smoking
abstinence rates were significantly higher in the bupropion
group (n = 527) compared with placebo (n = 180) at both week
7 (46 vs 23%; p < 0.001) and at month 12 (21 vs 11%;
p = 0.002) [130]. To our knowledge there have been only two
studies which showed bupropion to be ineffective. Killen and
colleagues showed that in adolescent smokers, a nicotine patch
plus bupropion was not significantly better than a nicotine
patch plus placebo [131]. A single-center Veterans Affairs trial in
2004 was performed using 244 smokers (93% male), half of
whom received a 7-week course of bupropion and all of whom
received transdermal nicotine replacement and 3 months of cog-
nitive-behavioral counseling. Although there was a trend
(p = 0.23) towards efficacy at 3 months, bupropion did not sig-
nificantly increase smoking cessation rates in this population
www.future-drugs.com
Bupropion
[132]. Despite these last two trials, most trials with bupropion
have shown it to be moderately effective as an aid to smoking
cessation. Interestingly, a history of depression is not a factor in
the efficacy of bupropion. A recent study of 784 smokers
showed that bupropion use resulted in increased smoking absti-
nence compared with placebo and efficacy was independent of a
past history of major depressive disorder [133]. An interesting
study examining the effects of bupropion on depression symp-
toms in patients trying to quit smoking found that smokers who
received bupropion were more likely to experience a decrease in
depressive symptoms during treatment [134]. This suggests the
drug may be ideal for dual therapy in this population.
An excellent review by Warner and Shoaib reviews data con-
cerning bupropion’s antismoking effects and concluded that
bupropion’s principal mode of action seems to be in the allevia-
tion of withdrawal symptoms following smoking cessation but is
not very effective at acutely reducing smoking (just as it is not
effective at acutely reducing depression). Although bupropion is
effective when used alone or combined with a nicotine
patch [135], it is often coupled with behavioral counseling in tri-
als. There have been few studies which compare bupropion
alone with other smoking cessation methods. A very recent, ran-
domized, double-blind, controlled trial compared bupropion
with nortriptyline and placebo, with all groups receiving cogni-
tive behavior therapy [136]. This study found that treatment with
bupropion resulted in better 6-month smoking cessation rates
compared with nortriptyline or placebo. Chronic bupropion can
be used in people with lung disease who can’t or don’t want to
quit smoking. The number of cigarettes smoked/day goes down
during bupropion treatment even in absence of intent to stop or
cut down tobacco use [137]. Given its relatively low cost, moderate
efficacy and tolerability and the massive morbidity generated
worldwide by ongoing tobacco use, the use of bupropion to help
patients quit smoking is recommended.
Common unapproved uses
Bupropion is commonly used by psychiatrists to treat sexual dys-
function (in any of the three domains, desire, arousal and
orgasm) induced by SSRI treatment, yet formal studies have not
always confirmed the activity of bupropion in this use [138]. Some
studies have shown increases in desire in absence of improvement
in the other two domains [119]. Non-medication, nondepression
related hypoactive sexual desire was improved in a small study of
premenopausal women [139].
Bupropion has many anecdotal reports of benefit to a wide
range of psychiatric ills not currently thought of as directly
depression related (but may in fact be so). It was noted to
reduce laboratory administered methamphetamine high and
cued craving scores [140], and it lowered gambling behaviors in
more than half the cohort of people with problem gambling
[141]. Apathy can be the primary manifestation of depression or
present as a problem when the person reports no sad feelings or
despair or negative affect of any sort. This is occasionally
treated with bupropion and a series of three patients success-
fully so treated was just reported [142]. Bupropion lowered
1259
Foley, DeSanty & Kast
restless legs syndrome in three patients [143]. Possibly related is
the study of periodic leg movements of sleep showing SSRI
induced increases not seen with bupropion [144].
Attention/concentration problems are common in school and
at the workplace. These problems referred to as attention deficit
disorder, or attention deficit hyperactivity disorder, are commonly
treated with methylphenidate or dextroamphetamine. Bupropion
has shown some activity significantly beyond placebo in helping
concentration problems [145] but all trials were uncontrolled with
respect to possible antidepressant effects. Although entry subjects
in all trials met criteria for concentration problems and depression
was excluded, there is the problem of nondepressed depression.
Sadness without traditional signs of depression, such as sleep dis-
turbance, loss of interests, appetite problems or diurnal variation
in mood, can occur with poor concentration alone as external
manifestation. Psychiatrists commonly see sadness, as well as for-
mally defined depression, responding to SSRI and other antide-
pressants including bupropion. Therefore, to be properly control-
led, the concentration enhancing experiments, for bupropion, as
well as for the stimulants, must have the control group on an
antidepressant too.
Bupropion SR dosed at 150–300 mg/day has demonstrated
efficacy in the treatment of neuropathic pain in a single-center,
double-blind, placebo-controlled crossover study of 41 nonde-
pressed patients. Mean daily pain score was improved begin-
ning in week 2 of active treatment and was maintained through
the 6-week treatment period. Pain symptoms were significantly
superior to placebo at week six. Pain symptom scores then
returned to baseline level within 2 weeks after crossover to
placebo. Overall, 73% reported improved or much improved
pain-relief with bupropion, whereas 90% reported no change
or worse pain with placebo treatment [146]. Although the results
are encouraging, a large multicenter trial is needed to better
assess the true benefit, if any, in the neuropathic pain popula-
tion. Furthermore, it seems prudent to have a trial that com-
pares bupropion with established neuropathic pain
treatments as well.
Based on its stimulant properties some have suggested bupro-
pion to be beneficial in treatment of various fatigue syndromes.
In fact, small uncontrolled studies have shown reduced cancer-
related fatigue [147,148]. It has also been used for depressed
patients with residual or SSRI induced fatigue [149]. In general
practice, psychiatrists tend to think of bupropion when a
depression has prominent apathy, anhedonia or alogia and tend
to steer away from bupropion in agitated depression.
Speculative uses
Tumor necrosis factor (TNF)-α, is a 17 kDa circulating signal-
ing molecule that is thought to play crucial roles in constructive
immune responses and ontogeny, but when overexpressed is
thought to be a growth factor for some cancers and contribu-
tory to inflammatory diseases, such as rheumatoid arthritis and
Crohn’s disease. Isolated reports of remission during bupropion
treatment of TNF mediated illnesses, such as recurrent oral
aphthous ulceration [150] and Crohn’s disease [151,152] have
1260
appeared and bupropions use has been suggested in these and
some cancers, such as multiple myeloma [153] and chronic lym-
phocytic leukemia [154], where TNF is believed to play promi-
nent pathogenic roles. A single mouse study did document
TNF lowering by bupropion [155] and a single case report of a
chronic hepatitis B patient, whose TNF went down after start-
ing bupropion and who lost hepatitis B surface antigen shortly
thereafter [156]. So bupropion may have some anti-inflamma-
tory activity or biasing of immune system away from T helper
(Th)-1 oriented responses toward Th2 biased responses. This
matter is far from proven though. Until the potential for
bupropion to lower TNF and IFN-γ can be confirmed or
refuted, bupropion should not be used in active infection.
Expert commentary
Bupropion remains a safe and useful antidepressant 17 years
after its introduction. Bupropion’s mechanism of action has
been studied for years and although insights have been gained,
no clear single mechanism can explain all its actions. Much of
its action is presumed to occur via the active metabolite,
hydroxybupropion. Bupropion is thought to achieve antide-
pressant effects by virtue of dopamine and norepinephrine
transporter inhibition and possibly via VMAT-2
enhancement [72,76]. Some evidence indicates serotonergic
transmission is enhanced during bupropion treatment,
although its side-effect profile is quite unlike those seen with
SSRI use. Bupropion’s clinical spectrum in affective disorders
appears diverse and recent US FDA approval for seasonal affec-
tive disorder is one example of the continued usefulness of this
drug. It appears that many patients can be successfully started
on this medication with careful attention to starting dose so as
to avoid adverse effects in subgroups of sensitive patients. Addi-
tional trials are pertinent to identify particular populations with
other psychiatric disorders that can benefit from bupropion.
Furthermore, controlled trials are also needed to determine if
bupropion has clinically useful anti-inflammatory actions (e.g.,
lowering TNF and IFN-γ synthesis). Overall, bupropion is an
effective antidepressant with comparable efficacy to SSRIs but
with a better sexual side-effect profile.
Five-year view
Depression and related psychiatric disorders continue to be a
burden on society and bupropion will remain a useful therapy
for a large portion of this population. It will likely continue to
be used as an augmenting agent with SSRIs and other second-
generation antidepressants, in order to treat resistant forms of
depression. The application of bupropion in smoking cessation
has enjoyed some success and is still an area of ongoing
research. It is likely that ongoing efficacy and pharmacoge-
nomic studies with bupropion will allow for a better under-
standing of how to treat nicotine addiction and explain why
certain patients are unsuccessful with this treatment. Overall,
the myriad of uses for bupropion and its proven effectiveness in
approved uses ensures this drug will remain a useful therapeutic
tool in the future.
Expert Rev. Neurotherapeutics 6(9), (2006)
 Bupropion

Information resources Shoaib describe the possible antismoking effects of bupropion in

There are several articles which describe the mechanisms of
bupropion in greater detail. Much of the original data and
descriptions of bupropion are reported in the paper by Soroko
and colleagues [57]. Kirchheiner and colleagues [6] describe
CYP2D6 polymorphisms with regard to bupropion. Warner and
great detail [93]. Hansen and colleagues report on the safety and
efficacy of antidepressants and provide a valuable paper for com-
paring bupropion and SSRIs [29]. The 1995 reviews by Ascher
and colleagues and Ferris and colleagues although somewhat
dated, are also recommended for further reading [58,72].

Key issues

• Bupropion remains a safe and effective antidepressant, as well as being an effective smoking cessation aid.
• For sensitive patients, bupropion can be started at 50 mg once daily and then increased at 50 mg increments every week, as
tolerated and as needed, up to a maximum of 200 mg sustained release (SR) twice daily, at least 8 h apart. However, bupropion
tablets are not scored and splitting tablets into 50 mg doses may be difficult for patients, in which case 75 mg once daily, must
be prescribed.
• The recommended starting dose is 100 mg once daily (immediate release [IR] or SR) or 150 mg once daily of the extended release
(XL) preparation.
• The recommended maximum daily dose is 450 mg for IR and XL, 400 mg for SR in divided doses. Although formal studies on the use
of low dose quetiapine (25 or 50 mg at bedtime) or olanzapine (2.5–5 mg at bedtime) in nonbipolar depression as a sleep aid are
lacking. In our experience these agents are preferable to benzodiazepines or zolpidem for the treatment of bupropion’s insomnia
and jitteriness side effects.
• Seizure risk of bupropion goes up rapidly after 450 mg/day and in those undergoing CNS depressant withdrawal.
• Bupropion is relatively safe in overdose with seizures being the primary concern.
• Bupropion should not be used together with or within 2 weeks of monoamine oxidase inhibitors.
• Bupropion is a cytochrome P450 (CYP)2D6 inhibitor and may result in alterations in the clinical effects of CYP2D6 substrates.
• Bupropion is metabolized in large part through CYP2B6, such that inducers and inhibitors of this metabolic pathway may alter
bupropion and hydroxybupropion plasma concentrations.
• Bupropion appears to be equally effective as several selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants
based on results of comparative clinical trials.
• Bupropion may be useful as augmentation therapy to a SSRI for depression.
• Evidence indicates that bupropion is somewhat less likely to induce a switch to mania than are SSRIs.
• Bupropion is associated with fewer sexual side effects compared with SSRI treatment.
• Although unproven, bupropion may have anti-inflammatory properties. This might make bupropion a particularly good first choice
in treating depression with comorbid Crohn’s disease, rheumatoid arthritis or other illnesses associated with tumor necrosis
factor-mediated pathology.

References 5 Findlay JW, Van Wyck Fleet J, Smith PG selective marker of human cytochrome
et al. Pharmacokinetics of bupropion, a P450 2B6 catalytic activity. Drug Metab.
1 Jefferson JW, Pradko JF, Muir KT.
novel antidepressant agent, following oral Dispos. 28(10), 1222–1230 (2000).
Bupropion for major depressive disorder:
administration to healthy subjects. Eur. J. 9 Faucette SR, Hawke RL, Shord SS et al.
pharmacokinetic and formulation
Clin. Pharmacol. 21(2), 127–135 (1981). Evaluation of the contribution of
considerations. Clin. Ther. 27(11),
1685–1695 (2005). 6 Kirchheiner J, Klein C, Meineke I et al. cytochrome P450 3A4 to human liver
® Bupropion and 4-OH-bupropion microsomal bupropion hydroxylation.
2 Wellbutrin XL Prescribing Information.
pharmacokinetics in relation to genetic Drug Metab. Dispos. 29(8), 1123–1229
GlaxoSmithKline, Research Triangle Park,
polymorphisms in CYP2B6. (2001).
NC (2006).
Pharmacogenetics 13(10), 619–626 (2003). 10 Hesse LM, He P, Krishnaswamy S et al.
3 Zyban® Prescribing Information.
7 Stewart JJ, Berkel HJ, Parish RC et al. Pharmacogenetic determinants of
GlaxoSmithKline, Research Triangle Park,
Single-dose pharmacokinetics of bupropion interindividual variability in bupropion
NC (2006).
in adolescents: effects of smoking status and hydroxylation by cytochrome P450 2B6 in
4 Hsyu PH, Singh A, Giargiari TD et al. gender. J. Clin. Pharmacol. 41(7), 770–778 human liver microsomes. Pharmacogenetics
Pharmacokinetics of bupropion and its (2001). 14(4), 225–238 (2004).
metabolites in cigarette smokers versus
8 Faucette SR, Hawke RL, Lecluyse EL et al. 11 Martin H, Beaune P, de Waziers I. Human
nonsmokers. J. Clin. Pharmacol. 37(8),
Validation of bupropion hydroxylation as a CYP2B6: expression, inducibility and
737–743 (1997).

www.future-drugs.com 1261
Foley, DeSanty & Kast
catalytic activities. Pharmacogenetics 9(3),
295–306 (1999).
12 Miksys S, Lerman C, Shields PG et al.
Smoking, alcoholism and genetic
polymorphisms alter CYP2B6 levels in
human brain. Neuropharmacology 45(1),
122–132 (2003).
13 Gervot L, Rochat B, Gautier JC et al.
Human CYP2B6: expression, inducibility
and catalytic activities. Pharmacogenetics
9(3), 295–306 (1999).
14 Lerman C, Shields PG, Wileyto EP et al.
Pharmacogenetic investigation of smoking
cessation treatment. Pharmacogenetics
12(8), 627–634 (2002).
15 Spiller HA, Ramoska EA, Krenzelok EP
et al. Bupropion overdose: a 3-year multi-
center retrospective analysis. Am. J. Emerg.
Med. 12(1), 43–45 (1994).
16 Pesola GR, Avasarala J. Bupropion seizure
proportion among new-onset generalized
seizures and drug related seizures
presenting to an emergency department. J.
Emerg. Med. 22(3), 235–239 (2002).
17 Lerman C, Shields PG, Wileyto EP et al.
Effects of dopamine transporter and
receptor polymorphisms on smoking
cessation in a bupropion clinical trial.
Health Psychol. 22(5), 541–548 (2003).
18 Horst WD, Preskorn SH. Mechanisms of
action and clinical characteristics of three
atypical antidepressants: venlafaxine,
nefazodone, bupropion. J. Affect. Disord.
51(3), 237–254 (1998).
19 Clayton AH, Pradko JF, Croft HA et al.
Prevalence of sexual dysfunction among
newer antidepressants. J. Clin. Psychiatry
63(4), 357–366 (2002).
20 Horne RL, Ferguson JM, Pope HG et al.
Treatment of bulimia with bupropion: a
multicenter controlled trial. J. Clin.
Psychiatry 49(7), 262–266 (1988).
21 Johnston JA, Lineberry CG, Ascher JA
et al. A 102-center prospective study of
seizure in association with bupropion.
J. Clin. Psychiatry 52(11), 450–456 (1991).
22 Dunner DL, Zisook S, Billow AA et al. A
prospective safety surveillance study for
bupropion sustained-release in the
treatment of depression. J. Clin. Psychiatry
59(7), 366–373 (1998).
23 Tutka P, Barczynski B, Wielosz M.
Convulsant and anticonvulsant effects of
bupropion in mice. Eur. J. Pharmacol.
499(1–2), 117–120 (2004).
24 Tutka P, Mroz T, Klucha K et al.
Bupropion-induced convulsions:
preclinical evaluation of antiepileptic
drugs. Epilepsy Res. 64(1–2), 13–22
(2005).
1262
25 Settle EC, Stahl SM, Batey SR et al. Safety
profile of sustained-release bupropion in
depression: results of three clinical trials.
Clin. Ther. 21(3), 454–463 (1999).
26 Fava M, Rush AJ, Thase ME et al. 15 years
of clinical experience with bupropion HCl:
from bupropion to bupropion SR to
bupropion XL. Prim. Care Companion
J. Clin. Psychiatry 7(3), 106–113 (2005).
27 Reimherr FW, Cunningham LA, Batey SR
et al. A multicenter evaluation of the
efficacy and safety of 150 and 300 mg/d
sustained-release bupropion tablets versus
placebo in depressed outpatients Clin. Ther.
20(3), 505–516 (1998).
28 Gartlehner G, Hansen RA, Carey TS et al.
Discontinuation rates for selective
serotonin reuptake inhibitors and other
second-generation antidepressants in
outpatients with major depressive disorder:
a systematic review and meta-analysis.
Int. Clin. Psychopharmacol. 20(2), 59–69
(2005).
29 Hansen RA, Gartlehner G, Lohr KN et al.
Efficacy and safety of second-generation
antidepressants in the treatment of major
depressive disorder. Ann. Intern. Med.
143(6), 415–426 (2005).
30 Cusack B, Nelson A, Richelson E. Binding
of antidepressants to human brain
receptors: focus on newer generation
compounds. Psychopharmacology (Berl.)
114(4), 559–565 (1994).
31 Davidson JR, Connor KM. Bupropion
sustained release: a therapeutic overview.
J. Clin. Psychiatry 59(Suppl. 4), 25–31
(1998).
32 Isbister GK, Bowe SJ, Dawson A et al.
Relative toxicity of selective serotonin
reuptake inhibitors (SSRIs) in overdose.
J. Toxicol. Clin. Toxicol. 42(3), 277–285
(2004).
33 Gibbons RD, Hur K, Bhaumik DK et al.
The relationship between antidepressant
medication use and rate of suicide. Arch.
Gen. Psychiatry 62(2), 165–172 (2005).
34 Shepherd G. Adverse effects associated with
extra doses of bupropion. Pharmacotherapy
25(10), 1378–1382 (2005).
35 Shepherd G, Velez LI, Keyes DC.
Intentional bupropion overdoses. J. Emerg.
Med. 27(2), 147–151 (2004).
36 Curry SC, Kashani JS, LoVecchio F et al.
Intraventricular conduction delay after
bupropion overdose. J. Emerg. Med. 29(3),
299–305 (2005).
37 Paris PA, Saucier JR. ECG conduction
delays associated with massive bupropion
overdose. J. Toxicol. Clin. Toxicol. 36(6),
595–598 (1998).
38 Wenger TL, Cohn JB, Bustrack J.
Comparison of the effects of bupropion
and amitriptyline on cardiac conduction in
depressed patients. J. Clin. Psychiatry
44(5 Pt 2), 174–175 (1983).
39 Belson MG, Kelley TR. Bupropion
exposures: clinical manifestations and
medical outcome. J. Emerg. Med. 23(3),
223–230 (2002).
40 Lang T, Klein K, Fischer J et al. Extensive
genetic polymorphism in the human
CYP2B6 gene with impact on expression
and function in human liver.
Pharmacogenetics 11(5), 399–415 (2001).
41 Turpeinen M, Nieminen R, Juntunen T
et al. Selective inhibition of CYP2B6-
catalyzed bupropion hydroxylation in
human liver microsomes in vitro. Drug
Metab. Dispos. 32(6), 626–631 (2004).
42 Turpeinen M, Tolonen A, Uusitalo J et al.
Effect of clopidogrel and ticlopidine on
cytochrome P450 2B6 activity as measured
by bupropion hydroxylation. Clin.
Pharmacol. Ther. 77(6), 553–559 (2005).
43 Kotlyar M, Brauer LH, Tracy TS et al.
Inhibition of CYP2D6 activity by
bupropion. J. Clin. Psychopharmacol. 25(3),
226–229 (2005).
44 Guzey C, Norstrom A, Spigset O. Change
from the CYP2D6 extensive metabolizer to
the poor metabolizer phenotype during
treatment with bupropion. Ther. Drug
Monit. 24(3), 436–437 (2002).
45 Weintraub D. Nortriptyline toxicity
secondary to interaction with bupropion
sustained-release. Depress Anxiety.13(1),
50–52 (2001).
46 Hesse LM, Venkatakrishnan K, Court MH
et al. CYP2B6 mediates the in vitro
hydroxylation of bupropion: potential drug
interactions with other antidepressants.
Drug Metab. Dispos. 28(10), 1176–1183
(2000).
47 Bertelsen KM, Venkatakrishnan K,
Von Moltke LL et al. Apparent mechanism-
based inhibition of human CYP2D6 in
vitro by paroxetine: comparison with
fluoxetine and quinidine. Drug Metab.
Dispos. 31(3), 289–293 (2003).
48 Diamond S, Pepper BJ, Diamond ML et al.
Serotonin syndrome induced by
transitioning from phenelzine to
venlafaxine: four patient reports. Neurology
51(1), 274–276 (1998).
49 Weiner LA, Smythe M, Cisek J. Serotonin
syndrome secondary to phenelzine-
venlafaxine interaction. Pharmacotherapy
18(2), 399–403 (1998).
50 Graber MA, Hoehns TB, Perry PJ.
Sertraline-phenelzine drug interaction: a
Expert Rev. Neurotherapeutics 6(9), (2006)

serotonin syndrome reaction. Ann.
Pharmacother. 28(6), 732–735 (1994).
51 Otte W, Birkenhager TK, van den
Broek WW. Fatal interaction between
tranylcypromine and imipramine. Eur.
Psychiatry 18(5), 264–265 (2003).
52 Bhatara VS, Bandettini FC. Possible
interaction between sertraline and
tranylcypromine. Clin. Pharm. 12(3),
222–225 (1993).
53 Kaplan LM. Pharmacological therapies for
obesity. Gastroenterol. Clin. North Am.
34(1), 91–104 (2005).
54 Griffith JD, Carranza J, Griffith C et al.
Bupropion: clinical assay for amphetamine-
like abuse potential. J. Clin. Psychiatry 44,
206–208 (1983).
55 Musso DL, Mehta NB, Soroko FE et al
Synthesis and evaluation of the
antidepressant activity of the enantiomers
of bupropion. Chirality 5, 495–500 (1993).
56 Damaj MI, Carroll FI, Eaton JB et al.
Enantioselective effects of hydroxy
metabolites of bupropion on behavior and
on function of monoamine transporters
and nicotinic receptors. Mol. Pharmacol.
66(3), 675–682 (2004).
57 Soroko FE, Mehta NB, Maxwell RM et al.
Bupropion hydrochloride ((+/-) α-t-
butylamino-3-chloropropiophenone HCl),
a novel antidepressant agent. J. Pharm.
Pharmacol. 29, 767–770 (1977).
58 Ferris RM, Beaman OJ. Bupropion: a new
antidepressant drug, the mechanism of
action of which is not associated with
down-regulation of postsynaptic
β-adrenergic, serotonergic (5-HT2),
α2-adrenergic, imipramine and
dopaminergic receptors in brain.
Neuropharmacology 22, 1257–1267 (1983).
59 Eshleman AJ, Henningsen RA, Neve KA,
et al. Release of dopamine via the human
transporter, Mol. Pharmacol. 45, 312
(1994).
60 Johnson RA, Eshleman AJ, Meyers T et al.
[3H]substrate-and cell-specific effects of
uptake inhibitors on human dopamine and
serotonin transporter-mediated efflux.
Synapse 30(1), 97–106 (1999).
61 Stahl SM, Pradko JF, Haight, BR et al.
A review of the neuropharmacology of
bupropion, a dual norepinephrine and
dopamine reuptake inhibitor. Prim. Care
Companion J. Clin. Psychiatry 6, 159–166
(2004).
62 Owens MJ, Knight DL, Nemeroff CB
Second-generation SSRIs: human
monoamine transporter binding profile of
escitalopram and R-fluoxetine. Biol.
Psychiatry 50, 345–350 (2001).
www.future-drugs.com
63 Cryan JF, O’Leary OF, Jin SH et al.
Norepinephrine-deficient mice lack responses
to antidepressant drugs, including selective
serotonin reuptake inhibitors. Proc. Natl
Acad. Sci. USA 101, 8186–8191 (2004).
64 Meyer JH, Goulding VS, Wilson AA et al.
Bupropion occupancy of the dopamine
transporter is low during clinical treatment.
Psychopharmacology (Berl.) 163, 102–105
(2002).
65 Meyer JH, Wilson AA, Sagrati S et al.
Serotonin transporter occupancy of five
selective serotonin reuptake inhibitors at
different doses: an [11C]DASB positron
emission tomography study. Am. J. Psychiatry
161, 826–835 (2004).
66 Volkow ND, Wang GJ, Fowler JS et al.
Blockade of striatal dopamine transporters by
intravenous methylphenidate is not sufficient
to induce self-reports of “high”.
J. Pharmacol. Exp. Ther. 288, 14–20 (1999).
67 Bondarev ML, Bondareva TS, Young R. et al.
Behavioral and biochemical investigations of
bupropion metabolites. Eur. J. Pharmacol.
474, 85–93 (2003).
68 Martin P, Massol J, Colin JN et al.
Antidepressant profile of bupropion and
three metabolites in mice. Pharmacopsychiatry
23(4), 187–194 (1990).
69 Perumal AS, Smith Tm, Suckow RF. Effect of
plasma from patients containing bupropion
and its metabolites on the uptake of
norepinephrine. Neuropharmacology 25,
199–202 (1986).
70 Little JT, Ketter TA, Mathe AA et al.
Venlafaxine but not bupropion decreases
cerebrospinal fluid 5-hydroxyindoleacetic
acid in unipolar depression. Biol. Psychiatry
45(3), 285–289 (1999).
71 Cooper BR, Hester TJ, Maxwell RA.
Behavioral and biochemical effects of the
antidepressant bupropion (Wellbutrin),
evidence for selective blockade of dopamine
uptake in vivo. J. Pharmacol. Exp. Ther. 215,
127–134 (1980).
72 Ascher JA, Cole JO, Colin JN et al.
Bupropion: a review of its mechanism of
antidepressant activity. J. Clin. Psychiatry 56,
395– 401(1995).
73 Cooper BR, Wang CM, Cox RF et al.
Evidence that the acute behavioral and
electrophysiological effects of bupropion
(Wellbutrin) are mediated by a noradrenergic
mechanism. Neuropsychopharmacology 11,
133–141 (1994).
74 Dong J, Blier P. Modification of
norepinephrine and serotonin, but not
dopamine, neuron firing by sustained
bupropion treatment. Psychopharmacology
(Berl.) 155(1), 52–57 (2001).
Bupropion
75 Golden RN, Rudorfer MV, Sherer MA et al.
Bupropion in depression. I. Biochemical
effects and clinical response. Arch. Gen.
Psychiatry 45, 139–143 (1988).
76 Rau KS, Birdsall E, Hanson JE et al.
Bupropion increases striatal vesicular
monoamine transport. Neuropharmacology
49(6), 820–830 (2005).
77 Colliver TL, Pyott SJ, Achalabun M et al.
VMAT-2-Mediated changes in quantal size
and vesicular volume. J. Neurosci. 20(14),
5276–5282 (2000).
78 Harris L, Kimura Y, Shaikh NA.
Phospholipase inhibition and the
electrophysiology of acute ischemia: studies
with amiodarone. J. Mol. Cell Cardiol.
25(9), 1075–1090 (1993).
79 Haikerwal D, Dart AM, Little PJ et al.
Identification of a novel, inhibitory action
of amiodarone on vesicular monoamine
transport. J. Pharmacol. Exp. Ther. 288(2),
834–837 (1999).
80 Odelola AT. More on amiodarone-induced
depression. Br. J. Psychiatry 175, 590–591
(1999).
81 Truong JG, Newman AH, Hanson GR et al.
Dopamine D2 receptor activation increases
vesicular dopamine uptake and redistributes
vesicular monoamine transporter-2 protein.
Eur. J. Pharmacol. 504(1–2), 27–32 (2004).
82 Truong JG, Hanson GR, Fleckenstein AE.
Apomorphine increases vesicular
monoamine transporter-2 function:
implications for neurodegeneration. Eur. J.
Pharmacol. 492(2–3), 143–147 (2004).
83 Hanson GR, Sandoval V, Riddle E et al.
Psychostimulants and vesicle trafficking: a
novel mechanism and therapeutic
implications. Ann. NY Acad. Sci. 1025,
146–150 (2004).
84 Bechara A, Bertolino MV, Casabe A et al. A
double-blind randomized placebo control
study comparing the objective and
subjective changes in female sexual response
using sublingual apomorphine. J. Sex Med.
1(2), 209–214 (2004).
85 Klos KJ, Bower JH, Josephs KA et al.
Pathological hypersexuality predominantly
linked to adjuvant dopamine agonist
therapy in Parkinson’s disease and multiple
system atrophy. Parkinsonism Relat. Disord.
11(6), 381–386 (2005).
86 O’Sullivan JD, Hughes AJ. Apomorphine-
induced penile erections in Parkinson’s
disease. Mov. Disord. 13(3), 536–539
(1998).
87 Courty E, Durif F, Zenut M et al.
Psychiatric and sexual disorders induced by
apomorphine in Parkinson’s disease. Clin.
Neuropharmacol. 20(2), 140–147 (1997).
1263
Foley, DeSanty & Kast
88 Goldberg JF, Burdick KE, Endick CJ.
Preliminary randomized, double-blind,
placebo-controlled trial of pramipexole
added to mood stabilizers for treatment-
resistant bipolar depression. Am. J.
Psychiatry 161(3), 564–566 (2004).
89 Cordeiro ML, Gundersen CB, Umbach JA.
Lithium ions modulate the expression of
VMAT-22 in rat brain. Brain Res.
953(1–2), 189–194 (2002).
90 Slemmer JE, Martin BR, Damaj MI.
Bupropion is a nicotinic antagonist.
J. Pharmacol. Exp. 295, 321–327 (2000).
91 Fryer JD, Lukas RJ. Noncompetitive
functional inhibition at diverse, human
nicotinic acetylcholine receptor subtypes by
bupropion, phencyclidine, and ibogaine.
J. Pharmacol. Exp. Ther. 288, 88–92
(1999).
92 Miller DK, Sumithran SP, Dwoskin LP.
Bupropion inhibits nicotine-evoked
[3H]overflow from rat striatal slices
preloaded with [3H]dopamine and from rat
hippocampal slices preloaded with
[3H]norepinephrine. J. Pharmacol. Exp.
Ther. 302, 1113–1122 (2002).
93 Warner C, Shoaib M. How does bupropion
work as a smoking cessation aid? Addict.
Biol. 10, 219–231 (2005).
94 Feighner JP, Meredith CH, Stern WC et al.
A double-blind study of bupropion and
placebo in depression. Am. J. Psychiatry
141(4), 525–529 (1984).
95 Zung WW. Review of placebo-controlled
trials with bupropion. J. Clin. Psychiatry
44(5 Pt 2), 104–114 (1983).
96 Fabre LF, Brodie HK, Garver D et al. A
multicenter evaluation of bupropion versus
placebo in hospitalized depressed patients.
J. Clin. Psychiatry 44(5 Pt 2), 88–94
(1983).
97 Halaris AE, Stern WC, Van Wyck Fleet J
et al. Evaluation of the safety and efficacy of
bupropion in depression. J. Clin. Psychiatry
44(5 Pt 2), 101–103 (1983).
98 Preskorn SH. Antidepressant response and
plasma concentrations of bupropion.
J. Clin. Psychiatry 44(5 Pt 2), 137–139
(1983).
99 Johnston JA, Fiedler-Kelly J, Glover ED
et al. Relationship between drug exposure
and the efficacy and safety of bupropion
sustained release for smoking cessation.
Nicotine Tob. Res. 3(2), 131–140 (2001).
100 Murphy GE, Simons AD, Wetzel RD.
Plasma nortriptyline and clinical response
in depression. J. Affect. Disord. 8(2),
123–129 (1985).
101 Weihs KL, Houser TL, Batey SR et al.
Continuation phase treatment with
1264
bupropion SR effectively decreases the risk
for relapse of depression. Biol. Psychiatry
51(9), 753–761 (2002).
102 Zajecka JM. Clinical issues in long-term
treatment with antidepressants. J. Clin.
Psychiatry 61(Suppl. 2), 20–25 (2000).
103 Weisler RH, Johnston JA, Lineberry CG
et al. Comparison of bupropion and
trazodone for the treatment of major
depression. J. Clin. Psychopharmacol. 14(3),
170–179 (1994).
104 Feighner J, Hendrickson G, Miller L et al.
Double-blind comparison of doxepin versus
bupropion in outpatients with a major
depressive disorder. J. Clin. Psychopharmacol.
6(1), 27–32 (1986).
105 Mendels J, Amin MM, Chouinard G et al. A
comparative study of bupropion and
amitriptyline in depressed outpatients.
J. Clin. Psychiatry 44(5 Pt 2), 118–120
(1983).
106 Chouinard G. Bupropion and amitriptyline
in the treatment of depressed patients.
J. Clin. Psychiatry 44(5 Pt 2), 121–129
(1983).
107 Branconnier RJ, Cole JO, Ghazvinian S et al.
Clinical pharmacology of bupropion and
imipramine in elderly depressives.
J. Clin. Psychiatry 44(5 Pt 2), 130–133
(1983).
108 Kavoussi RJ, Segraves RT, Hughes AR et al.
Double-blind comparison of bupropion
sustained release and sertraline in depressed
outpatients. J. Clin. Psychiatry 58(12),
532–537 (1997).
109 Feighner JP, Gardner EA, Johnston JA et al.
Double-blind comparison of bupropion and
fluoxetine in depressed outpatients.
J. Clin. Psychiatry. 52(8), 329–335 (1991).
110 Weihs KL, Settle EC Jr, Batey SR et al.
Bupropion sustained release versus paroxetine
for the treatment of depression in the elderly.
J. Clin. Psychiatry 61(3), 196–202 (2000).
111 Zimmerman M, Posternak MA, Attiullah N
et al. Why isn’t bupropion the most
frequently prescribed antidepressant? J. Clin.
Psychiatry 66(5), 603–610 (2005).
112 Rush AJ, Trivedi MH, Carmody TJ et al.
Response in relation to baseline anxiety levels
in major depressive disorder treated with
bupropion sustained release or sertraline.
Neuropsychopharmacology 25(1), 131–138
(2001).
113 Dworkin RH, Katz J, Gitlin MJ. Placebo
response in clinical trials of depression and its
implications for research on chronic
neuropathic pain. Neurology 65(12 Suppl. 4),
S7–S19 (2005).
114 Walsh BT, Seidman SN, Sysko R et al.
Placebo response in studies of major
depression: variable, substantial, and
growing. JAMA 287(14), 1840–1870
(2002).
115 Rush AJ, Trivedi MH, Wisniewski SR et al.
STAR*D Study Team. Bupropion-SR,
sertraline, or venlafaxine-XR after failure of
SSRIs for depression. N. Engl. J. Med.
354(12), 1231–1242 (2006).
116 Trivedi MH, Fava M, Wisniewski SR et al.
Medication augmentation after the failure of
SSRIs for depression. N. Engl. J. Med.
354(12), 1243–1252 (2006).
117 Trivedi MH, Rush AJ, Wisniewski SR et al.
STAR*D Study Team. Evaluation of
outcomes with citalopram for depression
using measurement-based care in STAR*D:
implications for clinical practice. Am. J.
Psychiatry 163(1), 28–40 (2006).
118 Clayton AH, Warnock JK, Kornstein SG
et al. A placebo-controlled trial of bupropion
SR as an antidote for selective serotonin
reuptake inhibitor-induced sexual
dysfunction. J. Clin. Psychiatry. 65(1), 62–67
(2004).
119 Zisook S, Rush AJ, Haight BR et al. Use of
bupropion in combination with serotonin
reuptake inhibitors. Biol. Psychiatry 59(3),
203–210 (2006).
120 Rojo JE, Ros S, Aguera L et al. Combined
antidepressants: clinical experience. Acta.
Psychiatr. Scand. 36(Suppl. 428), 25–31
(2005).
121 Leverich GS, Altshuler LL, Frye MA et al.
Risk of switch in mood polarity to
hypomania or mania in patients with bipolar
depression during acute and continuation
trials of venlafaxine, sertraline, and
bupropion as adjuncts to mood stabilizers.
Am. J. Psychiatry 163(2), 232–239 (2006).
122 Nonacs RM, Soares CN, Viguera AC et al.
Bupropion SR for the treatment of
postpartum depression: a pilot study. Int. J.
Neuropsychopharmacol. 8(3), 445–449
(2005).
123 Gentile S. The safety of newer
antidepressants in pregnancy and
breastfeeding. Drug Saf. 28(2), 137–152
(2005).
124 Chun-Fai-Chan B, Koren G, Fayez I et al.
Pregnancy outcome of women exposed to
bupropion during pregnancy: a prospective
comparative study. Am. J. Obstet. Gynecol.
192(3), 932–936 (2005).
125 Raison CL, Broadwell SD, Borisov AS et al.
Depressive symptoms and viral clearance in
patients receiving interferon-α and ribavirin
for hepatitis C. Brain Behav. Immun. 19(1),
23–27 (2005).
126 Modell JG, Rosenthal NE, Harriett AE et al.
Seasonal affective disorder and its prevention
Expert Rev. Neurotherapeutics 6(9), (2006)

by anticipatory treatment with bupropion
XL. Biol. Psychiatry 58(8), 658–667 (2005).
127 Wileyto EP, Patterson F, Niaura R. Recurrent
event analysis of lapse and recovery in a
smoking cessation clinical trial using
bupropion. Nicotine Tob. Res. 7, 257–268
(2005).
128 Zellweger JP, Boelcskei PL, Carrozzi L et al.
Bupropion SR vs placebo for smoking
cessation in health care professionals. Am. J.
Health Behav. 29, 240–249 (2005).
129 Myles PS, Leslie K, Angliss M et al.
Effectiveness of bupropion as an aid to
stopping smoking before elective surgery: a
randomised controlled trial. Anaesthesia 59,
1053–1058 (2004).
130 Tonnesen P, Tonstad S, Hjalmarson A. et al.
A multicentre, randomized, double-blind,
placebo-controlled, 1-year study of
bupropion SR for smoking cessation.
J. Intern. Med. 254, 184–192 (2003).
131 Killen JD, Robinson TN, Ammerman S
et al. Randomized clinical trial of the efficacy
of bupropion combined with nicotine patch
in the treatment of adolescent smokers. J.
Consult Clin. Psychol. 72, 729–735 (2004).
132 Simon JA, Duncan C, Carmody TP et al.
Bupropion for smoking cessation: a
randomized Trial. Arch. Intern. Med. 164,
1797–1803 (2004).
133 Cox LS, Patten CA, Niaura RS et al. Efficacy
of bupropion for relapse prevention in
smokers with and without a past history of
major depression. J. Gen. Intern. Med. 19,
828–834 (2004).
134 Lerman C, Niaura R, Collins BN et al.
Effect of bupropion on depression
symptoms in a smoking cessation clinical
trial. Psychol. Addict Behav. 18, 362–366
(2004).
135 Jorenby DE, Leischow SJ, Nides MA et al. A
controlled trial of sustained-release
bupropion, a nicotine patch, or both for
smoking cessation. N. Engl. J. Med. 340,
685–691 (1999).
136 Haggstram FM, Chatkin JM, Sussenbach-
Vaz E et al. A controlled trial of
nortriptyline, sustained-release bupropion
and placebo for smoking cessation:
preliminary results. Pulm. Pharmacol. Ther.
19(3), 205–209 (2006).
137 Hatsukami DK, Rennard S, Patel MK et al.
Effects of sustained-release bupropion
among persons interested in reducing but
not quitting smoking. Am. J. Med. 116(3),
151–157 (2004).
138 DeBattista C, Solvason B, Poirier J et al. A
placebo-controlled, randomized, double-
blind study of adjunctive bupropion
sustained release in the treatment of SSRI-
www.future-drugs.com
induced sexual dysfunction. J. Clin.
Psychiatry 66(7), 844–848 (2005).
139 Segraves RT, Clayton A, Croft H et al.
Bupropion sustained release for the treatment
of hypoactive sexual desire disorder in
premenopausal women. J. Clin.
Psychopharmacol. 24(3), 339–342 (2004).
140 Newton TF, Roache JD, De La Garza R et al.
Bupropion reduces methamphetamine-
induced subjective effects and cue-induced
craving. Neuropsychopharmacology 31(7),
1537–1544 (2005).
141 Dannon PN, Lowengrub K, Musin E et al.
Sustained-release bupropion versus
naltrexone in the treatment of pathological
gambling: a preliminary blind-rater study. J.
Clin. Psychopharmacol. 25(6), 593–596
(2005).
142 Corcoran C, Wong ML, O’Keane V.
Bupropion in the management of apathy.
J. Psychopharmacol. 18(1), 133–135 (2004).
143 Kim SW, Shin IS, Kim JM et al. Bupropion
may improve restless legs syndrome: a report
of three cases. Clin. Neuropharmacol. 28(6),
298–301 (2005).
144 Yang C, White DP, Winkelman JW.
Antidepressants and periodic leg movements
of sleep. Biol. Psychiatry 58(6), 510–514
(2005).
145 Waxmonsky JG. Nonstimulant therapies for
attention-deficit hyperactivity disorder
(ADHD) in children and adults. Essent
Psychopharmacol. 6(5), 262–276 (2005).
146 Semenchuk MR, Sherman S, Davis B.
Double-blind, randomized trial of bupropion
SR for the treatment of neuropathic pain.
Neurology 57, 1583–1588 (2001).
147 Moss EL, Simpson JS, Pelletier G et al. An
open-label study of the effects of bupropion
SR on fatigue, depression and quality of life
of mixed-site cancer patients and their
partners. Psycho-oncology 15(3), 259–267
(2005).
148 Cullum JL, Wojciechowski AE, Pelletier G
et al. Bupropion sustained release treatment
reduces fatigue in cancer patients. Can. J.
Psychiatry 49(2), 139–44 (2004).
149 Marin H, Menza MA. The management of
fatigue in depressed patients. Essent
Psychopharmacol. 6(4), 185–192 (2005).
150 Kast RE, Altschuler EL. Bupropion and
chronic aphthous ulceration. Arch. Dermatol.
141(9), 1167 (2005).
151 Kast RE, Altschuler EL. Remission of
Crohn’s disease on bupropion.
Gastroenterology 121(5), 1260–1261 (2001).
152 Kane S, Altschuler EL, Kast RE. Crohn’s
disease remission on bupropion.
Gastroenterology 125(4), 1290 (2003).
Bupropion
153 Kast RE. Evidence of a mechanism by which
etanercept increased TNF-α in multiple
myeloma: new insights into the biology of
TNF-α giving new treatment opportunities-
the role of bupropion. Leuk. Res. 29(12),
1459–1463 (2005).
154 Kast RE, Altschuler EL. Anti-apoptosis
function of TNF-α in chronic lymphocytic
leukemia: lessons from Crohn’s disease and
the therapeutic potential of bupropion to
lower TNF-α. Arch. Immunol. Ther. Exp.
53(2), 143–147 (2005).
155 Brustolim D, Riberio-dos-Santos R, Kast RE
et al. A new chapter opens in anti-
inflammatory treatment: Bupropion lowers
TNF-α and interferon-γ in mice. accepted
for publication. Int. Immunopharm. (2006)
(Epub ahead of print).
156 Kast RE, Altschuler EL. Tumor necrosis
factor-α in hepatitis B: potential role for
bupropion. J. Hepatol. 39(1), 131–133
(2003).
157 Yu H, Rothman RB, Dersch CM et al.
Uptake and release effects of diethylpropion
and its metabolites with biogenic amine
transporters. Bioorg. Med. Chem. 8,
2689–2692 (2000).
158 Cozzi NV, Sievert MK, Shulgin AT et al.
Inhibition of plasma membrane monoamine
transporters by
β-ketoamphetamines. Eur. J. Pharmacol. 381,
63–69 (1999).
159 Foley K. Aminopropiophenones at the
Norepinephrine Transporter: Structure-
activity Relationships and Behavioral Effects
of Methcathinone Analogs, In: Pharmacology.
East Carolina University School of Medicine,
Greenville, NC, USA (2002)
Affiliations
• Kevin F Foley, PhD
University of Vermont, Department of Medical
Laboratory and Radiation Sciences,
Burlington, 302 Rowell Building, VT 05405,
USA
Tel.: +1 802 656 2506
Fax: +1 802 656 2191
kffoley@uvm.edu
• Kevin P DeSanty, PharmD, PhD
Gaston Memorial Hospital, Department of
Pharmacy, 2525 Court Drive Gastonia, NC
28053, USA
Tel.: +1 704 834 2000
Fax: +1 704 834 3030
desantyk@gmh.org
• Richard E Kast, MD
University of Vermont, Deptartment of Psychiatry
Burlington, VT 05401,
USA
Tel.: +1 802 656 2506
Fax: +1 802 656 2191
REkast@email.com
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