Trade names: Elontril, Wellbutrin, Zyban
Active substance name before 2000: amfebutamone
The active ingredient bupropion is a β-ketoamphetamine derivative.
Bupropion belongs to the cathinones, a derivative group of amphetamines, which have an additional ketone group compared to amphetamines.
It is not classically classified as a stimulant, although - like nicotine and caffeine - it has a stimulating effect.
Bupropion does not require a prescription for narcotics.
During treatment, a urine drug test for amphetamine and methamphetamine may be positive. Taking the drug before driving in the Czech Republic is therefore not recommended.
1. Mode of action of bupropion¶
Bupropion is active in its own right and is metabolized to hydroxybupropion, threohydrobupropion and erythrohydrobupropion. All are potent noradrenaline reuptake inhibitors. Hydroxybupropion, for example, can reach up to 16 to 20 times the concentration of bupropion.
The plasma half-life of bupropion and hydroxybupropion is around 20 hours.
Bupropion is almost completely absorbed. The bioavailability is reduced to 5 to 20 % by first-pass metabolism. The bioavailability of sustained-release (SR) bupropion is similar to that of immediate-release (IR) bupropion, while that of extended-release (ER) bupropion is slightly lower. Bupropion SR and bupropion ER have higher Tmax values.
1.1. Dopamine and noradrenaline reuptake inhibition¶
Bupropion acts as a dopamine and noradrenaline reuptake inhibitor. In rats, the effect distribution of dopamine : noradrenaline is 2:1
As a result, bupropion increases dopamine levels in the nucleus accumbens in rats, thereby modulating reward and dependence stimulation.
In humans, however, the DAT affinity of bupropion appears to be very weak (DAT occupancy of 14%), so it is questionable whether bupropion actually has a relevant effect as a dopamine reuptake inhibitor in humans at the usual dosage. In contrast, DAT occupancy was found to be 85% in rhesus monkeys and 35% in rodents
Since dopamine is also taken up by the noradrenaline transporter in the PFC (even slightly more than noradrenaline), we hypothesize that bupropion (similar to atomoxetine) could also increase dopamine in the PFC in humans in this way.
These findings could conclusively explain why bupropion is less successful in practice as an ADHD medication compared to stimulants, which also address the DAT in humans.
Bupropion reduces the activity of noradrenergic neurons in the locus coeruleus, which influence sleep and arousal.
1.2. Dopamine and noradrenaline release¶
Bupropion also has a weak dopamine and noradrenaline-releasing effect.
1.3. Inhibition of nicotinic acetylcholine receptors (nAChR, nicotinic receptors)¶
Bupropion is a non-competitive antagonist of several nicotinic acetylcholine receptors (AChR).
1.4. TNF-alpha levels reduced¶
Bupropion reduces the TNF-alpha level.
1.5. No / minimal serotonergic effect¶
According to one view, bupropion had a minor serotonergic effect. According to another view, bupropion does not have a serotonergic effect.
1.6. OCT2 inhibitor¶
Bupropion acts as a selective OCT2 inhibitor at therapeutic levels. OCT1 and OCT3 are significantly less inhibited.
For the presentation of OCT, see *Dopamine degradation by organic cation transporters (OCT) *in the article Dopamine reuptake, dopamine degradation
1.7. Retardation and duration of action¶
Bupropion is available on the market in various prolonged-release forms.
While Wellbutrin XR has such a long duration of action that taking it once a day is sufficient, Zyban, with its shorter duration of action, is intended to be taken twice a day. In comparison, IR had to be taken three times a day.
Graph of the different blood level curves in the steady state of bupropion IR, SR and XR.
2. Effectiveness of bupropion for ADHD¶
In summary: Bupropion can be helpful in higher doses for ADHD, but should only be used as monotherapy when all other stimulants have failed. A particular benefit could be the prolongation of single doses of amphetamine medication that are too short.
In individual cases, bupropion can be a helpful addition to medication with stimulants. When used as a combination medication for ADHD, a much lower dosage is required than would be usual when used as an antidepressant. Bupropion may be helpful for ADHD with comorbid depression.
Bupropion has an (even) stronger activating / drive-increasing effect than nortryptiline and is therefore indicated for more severe symptoms of ADHD-I (without hyperactivity). The administration of bupropion to ADHD-HI or ADHD-C sufferers (with hyperactivity) can trigger aggression or jitteriness.
According to three studies, bupropion is said to have a similar effect on ADHD as methylphenidate, while another study found a weaker effect than methylphenidate
An older small prospective study reported moderate to noticeable improvements in ADHD symptoms in 14 out of 19 subjects. 10 subjects continued treatment with bupropion after the test. This should be seen against the background that the comparison still included MAO inhibitors and that since 1990 there has been considerable further development of stimulant medication (retardation and new active ingredients such as lisdexamfetamine). In 2005, bupropion was described as helpful for around half of adolescent and adult ADHD sufferers
Two studies in 30 and 47 adults with AD(HS) with 300 mg and up to 400 mg bupropion/day, respectively, found trends for efficacy of bupropion in ADHD without statistical significance.
An RCT in 40 subjects with 2 x 200 mg bupropion SR / day found a good improvement in ADHD symptoms with a responding rate of 76 %.
In children, a double-blind study showed an improvement in ADHD symptoms with bupropion
A small double-blind placebo-controlled crossover study with individual dose optimization of MPH and bupropion in 15 children and adolescents found an equally strong improvement in ADHD symptoms with bupropion as with MPH:
Useful results when used alone for ADHD were only found in practice at quite high doses of 400 to 450 mg / day, which is why the updated European consensus on the diagnosis and treatment of ADHD in adults recommends using bupropion only if neither MPH nor amphetamine medication is effective (double non-responding)
The increased risk of seizures with higher doses of bupropion should be taken into account.. Due to the risk of seizures, bupropion was temporarily no longer approved.
In the case of depression, a hydroxybupropion serum concentration of more than 860 ng/ml should be achieved for a positive response. The therapeutic reference range for depression is between 850 and 1500 ng/ml hydroxybupropion.
3. Breakdown and interactions of bupropion¶
The half-lives are
- Bupropion: 21 hours
- Hydroxybupropion: 20 hours
- Erythrohydrobupropion: 33 hours
- Threohydrobupropion: 37 hours
Excretion takes place primarily in the urine and to a lesser extent in the feces.
Bupropion is primarily converted to hydroxybupropion by CYP2B6. CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP 3A4 contribute slightly to the conversion. Bupropion is degraded by carbonyl reductases to the active metabolites threohydrobupropion and erythrohydrobupropion. Threohydrobupropion and (R)-hydroxybupropion reach plasma levels that are significantly higher than those of bupropion itself. It is assumed that they have therapeutic benefits.
Bupropion also has the metabolites 4′-hydroxybupropion and the corresponding erythro- and threo-4′-hydroxyhydrobupropion.
When taking bupropion, caution should be exercised when administering other drugs that influence CYP2B6. Simultaneous administration of CYP2B6 inhibitors such as clopidogrel or ticlopidine increased the bupropion AUC level by 60 % and 90 % respectively. Concomitant administration of carbamazepine (inducer of CYP2B6 and CYP3A4) reduced the bupropion AUC by 90 % and increased the hydroxybupropion AUC by 50 %.
Although bupropion itself has little or no serotonergic effect, simultaneous administration with serotonergic medication can lead to serotonin syndrome.
Bupropion also acts as an inhibitor of CYP2D6 by reducing its gene expression. If amphetamine drugs or atomoxetine are administered at the same time, these should therefore be dosed lower. Several sufferers who had a too short effect of amphetamine medication reported a successful prolongation of the effect by taking bupropion at the same time.
4. Side effects¶
The risk of seizures when taking bupropion seems to depend on the maximum blood plasma concentration and is therefore higher with IR than with SR and probably lowest with XR.
- Bupropion IR:
- 0.4 % (4/1000) at 300 to 450 mg/day
-
significant increase in risk with even higher doses
- Bupropion SR:
- 0.1 % (1/1000) at 300 mg/day.
- Bupropion XR:
-
SSRI:
Possible side effects of bupropion are (in order of frequency, descending):
- Headache
- Dry mouth
- Sleep disorders
- The blood level at bedtime is lower with bupropion SR than with IR and even lower with XR than with SR
- Nausea
- Loss of appetite
- Weight loss of more than 2 kg
- unlike SSRIs, bupropion is not associated with weight gain
- Excitation states
- States of anxiety
- Constipation
- allergic reactions (anaphylactoid or late reactions, e.g. joint symptoms)
- Increase in blood pressure
- Tinnitus
- Dizziness
- Visual disturbances
- psychotic reactions
Discontinuation side effects were found in 9% (300 mg SR) to 11% (400 mg SR) and are thus considerably rarer than with other SSRIs. With placebo, discontinuation side effects were found in 4%
- Skin rash
- Nausea
- Restlessness
- Migraine
In contrast to SSRIs, bupropion does not appear to impair sexual function
Bupropion SR does not show an increased risk of daytime sleepiness. Bupropion SR shows less daytime sleepiness than placebo and much less daytime sleepiness than SSRIs such as sertraline or fluoxetine, than tricyclic antidepressants or than trazodone.
5. Contraindications¶
Bupropion is contraindicated for
- Hypersensitivity to bupropion or any of the excipients it contains
- Taking other medicines containing bupropion
- current seizure disorder or a history of seizures.
- a known tumor of the central nervous system.
- during an abrupt withdrawal from
- Alcohol
- Medicines if this increases the risk of seizures, e.g.
- Benzodiazepines
- benzodiazepine-like agents
- severe liver cirrhosis
- current or former bulimia or anorexia nervosa.
- when using irreversible monoamine oxidase inhibitors within the last 14 days
- when using reversible monoamine oxidase inhibitors within the last 24 hours
6. Discontinuation of bupropion¶
Slow dosing is recommended.
