2. Bupropion: Still hazy

These commentaries are based on Dr Gillman’s peer reviewed scientific papers, see Publications

Bupropion: Still hazy after all these years


This note on Bupropion BUP (Wellbutrin etc.) is an update about some new data that is helping to ‘lift the veil of ignorance’ a little further, although there is still uncertainty about BUP’s metabolites and their activity and actions.

An easily accessible and good review of the general & clinical features of BUP, by Flavio Guzman, is here

So, forty years on and: ‘still hazy after all these years’.

Apologies to Paul Simon.

BUP has been in use as an antidepressant since <1980, it was actually patented by Burroughs Wellcome around 1969 (1-3). It is used widely in the USA, but much less elsewhere, which attests to the wide variation in the perception of its effectiveness. It is probably fair to class it (and/or its metabolites) as a weak anti-depressant (this note does not address its use in smoking cessation). There are several recent updates of its usefulness in depression (4-7).

Neuropharmacological profile

It is probably not a clinically significant reuptake inhibitor for noradrenaline (because it does not affect the pressor response to tyramine (8, 9)), and is definitely not a significant SRI (it does not pose a risk of ST if combined with Parnate, which it would do if it was a significant SRI). That fits with the Ki at NAT & SERT is unmeasurably low. At the DAT Ki is around 500 nM, which would generally be regarded as insignificant and unlikely be of clinical consequence (10), and see PDSP database, but there is no Ki data publically available for HBUP: I would be astonished if it had not been assayed, but those results have been withheld.However, the KI is not the last word on whether or not a drug is effective and despite this low Ki value there is still a possibility that it has significant activity from raising dopamine.

PET studies indicate low DAT binding of around 20% (11-14), and much the same for hydroxy-bupropion (radafaxine) (15), which was, apparently studied clinically for bipolar disorder, depression, obesity, fibromyalgia, and neuropathic pain (Australasian Drug Information Service (2008). However, none of these studies have seen the light of day and we are none the wiser.

So, its main ‘action’ is as a very weak dopamine reuptake inhibitor; weaker in vitro than sertraline whose Ki is around 25 nM, vs BUP at 500nM (16) (and sertraline is called a selective serotonin reuptake inhibitor!). However, and that may be a big ‘however’, it has many metabolites and until recently knowledge about their concentrations and activities in humans (as opposed to rats etc.) was even more incomplete. My previous concern that it might be active at the VMAT transporter seems unfounded (17), but it is conceivable that one of the metabolites is. Re VMAT2 see: here


Insofar as it may well be a ‘pro-drug’, much of the research about it may be unhelpful. This is because most studies are done short-term and often do not fully reveal the activity of metabolites (either at receptors, transporters or CYP450 enzymes) that may take a while to build up to therapeutic levels and may also be quite different in animals to humans. So when a drug has activity that is mainly due to its metabolites, rather than the parent compound, research about it may be misleading. Ascher et al. suggested in 1995 that hydroxy-bupropion HBUP might be the main active metabolite (18) and that is discussed further in a more recent review by Carroll et al. (19). It is only more recently that the concentrations and activities of the metabolites, and the determination of which ones might be the most significant, has been slightly more revealing (20): bupropion is probably better classified as a prodrug, in other words, an agent whose activity resides mainly its metabolites.

It has recently been further clarified that bupropion is metabolised by CYP2B6 (20-24). 2B6 is the most polymorphic P450 sub-type so therapeutic drug monitoring (TDM) of blood levels may be useful (25).

Hydroxy-bupropion is present in the blood at a level ten or more times higher than the parent compound (25). However, GSK ceased research on the hydroxy metabolite, which they named ‘radafaxine’, due to ‘poor test results’. It was, apparently, studied clinically for bipolar disorder, depression, obesity, fibromyalgia, and neuropathic pain (Australasian Drug Information Service (2008). However, none of these studies seem to have seen the light of day, so, we are none the wiser.

We cannot know what any of this really means, or what data the drug company decided not to share, perhaps because sharing it would have diminished the perception of the likely effectiveness of bupropion itself.


BUP itself seems to be more toxic (seizures) than hydroxy-bupropion (26), causing, especially, seizures in a small proportion of cases if used in higher (therapeutic) doses. Remember, seizures delayed its rollout until 1989 at the lower, and currently recommended dose range of < 450 mg (27).

About half of BUP over-doses have seizures (28), which are brief and self-limiting (i.e. do not usually require treatment). Sertraline is the only AD I am aware of that inhibits 2B6 and may reach levels sufficient to affect BUP conversion to HBUP which could increase BUP toxicity (23, 26). It may be best to avoid combinations of SERT and BUP especially if TDM is not available.

Importance of DA in depression

Readers may appreciate that I think the role of DA in depression has been considerably neglected and under-appreciated.

In animals, even low doses of DA antagonists and DA depleting drugs, like reserpine and tetrabenazine (TBZ), mimic aspects of the depressive syndrome: they impair reward-related behaviours and promote selection of low reward choices (29-34). In such animal models DRIs, including BUP, attenuate such impairment, whereas inhibitors of NAT and SERT have no effect; in fact SRIs make it worse (17, 35, 36).

TBZ and reserpine induce depressive-like symptoms and ‘fatigue’ in humans (37-40). This is why I think it is insane to use DA antagonists such as quetiapine etc. to attempt to augment treatment response in refractory depressions. Theory, and animal data, predict that is doing the exact opposite of the increase in DA that is required. The clinical evidence that quetiapine augmentation actually has substantial benefits is very poor. It sure as hell does not improve drive, motivation and energy — and that is what patients with severe depression need improved.

In his comprehensive review ‘The myth of reserpine-induced depression’ Baumeister (41) notes that the evidence for precipitating typical depressive syndromes is poor, but that the evidence for the induction of ‘psychomotor retardation, agitation and lassitude’ is rather better. A dimensional interpretation of the role of neurotransmitters in the genesis of the depressive syndrome would suggest that is exactly what we would expect, and it fits with the other evidence presented above (has everyone forgotten Van Praag? (42, 43)). It may be that in susceptible patients, perhaps with a genetic predisposition, lowering dopamine may be sufficient to facilitate a full-blown depressive episode, but most individuals experience lassitude-like symptoms.


Even the very modest DA reuptake inhibitor potency of BUP, which would not normally be considered significant, may in fact be clinically useful, since it seems to have modest drive and motivation improving effects. These are a key component of severe depression and one which is poorly addressed by ADs, other than Parnate. Also, drive and motivation may be made worse by SRIs via their DA lowering effect.


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