PsychoTropicalResearch, serotonin and serotonin syndrome research.
Antidepressants - Bupropion (Zyban)
Antidepressants - Bupropion (Zyban)
Date Created: 28/11/2000 Last Modified: 10/06/2001 This drug has been marketed, and used widely, as an antidepressant in the USA for fifteen years.It's recent introduction to Australia is a testimony to the fact that the availability of drugs owes as much to marketing opportunities as it does to pharmacology. One must assume that the company have decided they are more likely to establish a market niche using the evidence that it is helpful for smoking cessation, rather than as an antidepressant.
It is a uni-cyclic aminoketone derivative with a structure slightly similar to tranylcypromine. Animal tests predict an anti-depressant and stimulatory clinical profile, which is what this drug seems to exhibit in humans. In some ways it is a extraordinary drug because, despite clinical use as an antidepressant for more than a decade, there is still great uncertainty about its activity and mode of action.
It is probably not a clinically significant reuptake inhibitor for either noradrenaline or 5-hydroxytryptamine. It is a weak dopamine reuptake inhibitor; weaker in vitro than sertraline (which is called an selective serotonin reuptake inhibitor). It may also have other pro-dopaminergic activity.
Peak absorption occurs in one to three hours and the half life of the parent compound is 10-20 hours (the metabolites, some of which are active, have a half life of 20-30 hours). It produces a sensitization to it's own action after chronic administration.
It has a stimulant profile as shown by increase in motor activity which is reduced by dopamine blocking drugs. It does not seem to have amphetamine like properties because it has no effect on spontaneous release of dopamine from the synapse. It produces a dose dependent increase in extra cellular DA in the striatum. In keeping with a dopaminergic mechanism it has a "pro sexual effect" which may not be restricted to patients with depression. It has shown efficacy for the improvement of orgasmic function, especially in females, and it produces a reduction in both orgasmic delay and inhibition. Spontaneous orgasms have been reported with the combination with sertraline.
It is interesting to note that another drug under development recently, which produced a similar pro sexual effect, was mysteriously dropped. It was rumored that this was because of pressure from the FDA in America, perhaps as a result of their concerns that it would be 'inappropriately utilised'. Perhaps the FDA decided that society was not ready for an 'aphrodisiac'.
It has only recently been clarified that bupropion is metabolised by CYP2B6 (not 2D6). It may be a weak inhibitor of CYP2D6
As with the tricyclic antidepressants there is great variation in levels of bupropion (and metabolites) with a standard dose, those who get high levels on normal doses may have a higher risk of epilepsy; but blood level monitoring is not usually available.
The product package insert for bupropion has only a brief description of a bupropion-desipramine drug interaction study. It looks like it may have weak, but significant inhibitory action for CYP2D6 and maybe 1A2. Interactions between bupropion and medications with narrow therapeutic indexes, such as tricyclic antidepressants and antiarrhythmics may cause problems.
It seems Bupropion can raise levels of imipramine and desipramine up to 400%. Note that both tricyclic antidepressants and bupropion can lower the seizure threshold. There are few studies, but of 15 extensive metabolizers of the CYP2D6, 300 mg daily raised the plasma levels of desipramine two-fold. A recent (2001) report was of nortriptyline levels elevated by 200%.
It has three major metabolites, but hydroxy bupropion is probably the only one that has significant activity and its blood levels are much higher than the parent compound.
Electrophysiological studies support the concept that it has an action through enhancement of noradrenergic and dopamine pathways (but we cannot be sure this is via re-uptake inhibition).
It may also have an effect on tyrosine hydroxylase activity and there is some suggestion that it may have actions 'downstream' of the synapse, perhaps at a genomic level.
This drug is rated by some US specialists in bipolar disorder as a first line anti-depressant in bipolar patients. The risk of precipitating mania seems to be lower with bupropion and selective serotonin reuptake inhibitors than with most other drugs.
Side effects
The tolerability is good and many practitioners experienced in the use of this drug consider it has less side effects than SSRIs (with which it is sometimes combined to combat their sexual side effects). There are some reports of increased libido.
It does not have activity at post-synaptic serotonin receptors (as do a number of other anti-depressants such as tricyclic antidepressants and mirtazapine). It has no anti-histaminic or anti-muscarinic activity, so it does not cause sedation / dry mouth etc through those mechanisms. It has no activity at alpha 1 receptors and therefore does not cause hypotension.
It does not appear to cause problematic interactions with MAOIs or other types of antidepressants. There is a report suggesting it can interact weakly with CYP450 2D6 and it may raise levels of drugs dependant on 2D6 for their breakdown, eg desipramine (now off the market) and nortriptyline. There is a report of 'delirium' with fluoxetine and bupropion. (see other 'Psychopharmacology Update Notes' re this).
Skin reactions have been reported. Urticarial rashes are associated with angio-oedema and anaphylaxis. Because 50% of urticarial rashes are accompanied by angio-oedema and because of the association of that with anaphylaxis this is considered an indication for cessation of the drug. If the rash is exanthemous or maculo-papular then rechallenge and treatment with antihistamines may be possible. The choice made will relate to the seriousness of the condition being treated and the availability of alternative strategies.
Most common side effects:--
- Insomnia, dry mouth and headache.
- Nausea, vomiting 7% vs 15-20% for SSRIs
- Increased appetite and weight gain, none
- Digestive disturbances, none vs SSRIs common.
The overall side effect burden is estimated as significantly better than SSRIs or nefazodone or mirtazapine.
There have been reports of hepatitis, menstrual irregularities (with short cycles) and amenorrhoea.
Bupropion was unpopular for a while because of the evidence for increased incidence of epileptic seizures which was about 1% overall in trials (risk with TCAs is about 0.1%). Indeed it was withdrawn from the market in USA in 1986 (has your drug rep told you that?) whilst an assessment was conducted; this concluded the risk was 0.44% at doses below 450 mg and 2.2% at doses above 450 mg. It was re-introduced in 88/89. I know of no direct comparisons between bupropion and either TCAs or SSRIs. However it would be wise to warn patients of the higher risk of seizures with bupropion; those with pre-existing risk factors for epilepsy may be best off avoiding it.
Seizures risk factors
- Previous seizures, or head injury
- Heavy alcohol use
- Use with other drugs that lower seizure threshold; eg tricyclic anti-depressants, anti-psychotics, theophyline, corticosteroids.
- During benzodiazepine withdrawal.
The sustained release form now in use appears to carry a significantly lower seizure risk.
The effect on sleep is similar to that of Parnate, in that it tends to worsen it rather than improve it (at least during the early phase of treatment). There is a higher rate of co-prescription with sedatives with bupropion (and SSRIs) than with other antidepressants.
There appears to be no evidence that bupropion is addictive.
Evidence continues to accumulate that it is effective clinically, and cost effective, as an aid to smoking cessation. In a recent large trial cessation rates at 12 months were:--
- 15.6 percent in the placebo group
- 16.4 percent in the nicotine-patch group
- 30.3 percent in the bupropion group (P0.001)
Dosing should be twice daily, in patients who suffer side effects on the usual dose of 300 mg it is worth persisting with the lower dose of 150 mg per day.
It is advisable to use it in conjunction with psychological support and or cognitive behavioural therapy which may multiply its effectiveness. Like treatments for alcohol dependence, use without education and psychological assistance is probably not ideal.
The most recent evidence indicates that bupropion is a nicotinic receptor antagonist. It has significant selectivity between the different subtypes of nicotinic receptors.
All text ©Dr Ken Gillman MRC Psych - PsychoTropical Research®
|Return to the menu at the top of this page|