Wellbutrin

The short version: Wellbutrin is an antidepressant and mild stimulant. Along with SSRIs, it’s one of the usual first choices for depression. People who are very tired or inattentive might prefer Wellbutrin; people who are very anxious might prefer SSRIs. The most common side effects are loss of appetite, feeling “wired”, and having trouble sleeping. My usual regimen is Wellbutrin XR 150 mg for a month, increasing to 300 or 450 in case of partial response. Wellbutrin is also an effective medication to help people stop smoking.

The long version:

Wellbutrin (bupropion) is a commonly used antidepressant. It’s also sold as a stop-smoking aid under the name Zyban.

1. How does Wellbutrin work?

The short answer is “probably something to do with dopamine or norepinephrine or something”. In the vanishingly unlikely chance that you want to read the long answer, here goes.

The standard narrative says that Wellbutrin is an NDRI – norepinephrine and dopamine reuptake inhibitor. This makes superficial sense – it performs both those actions in studies, both of these neurotransmitters are involved in depression, we know reuptake inhibition of depression-related chemicals can treat depression (see: SSRIs), end of story, right?

But there are many other NDRIs. Ritalin and Adderall are both stronger dopamine transporter inhibitors than Wellbutrin is; accordingly, they are both stronger stimulants. But neither is really an antidepressant. I had a patient who was very depressed on Adderall. When I added Wellbutrin in – which should have been a tiny contribution to her overall ND reuptake level – her depression stopped in its tracks. This doesn’t make sense if Wellbutrin is “just another” NDRI.

Also, it’s not super-clear that Wellbutrin is much of an NDRI at all. Ken Gillman points out that we usually consider Zoloft an SSRI (ie selective serotonin reuptake inhibitor, something that doesn’t inhibit reuptake of anything other than serotonin enough for us to care about), but Wellbutrin inhibits dopamine reuptake only about as much as Zoloft does. Weird. Some people try to save this by saying it’s the Wellbutrin metabolite hydroxybupropion that does the NDRI-ing, not Wellbutrin itself. But hydroxybupropion is an even weaker dopamine reuptake inhibitor than Wellbutrin itself. Sure, it’s a better norepinephrine reuptake inhibitor, but we already know NRI alone doesn’t treat depression – just look at reboxetine!

So what is going on? I don’t know of any researchers even working on this question, so I am forced to provide a few pathetic guesses.

Different dopamine reuptake inhibitors bind to the dopamine transporter in different ways, stabilizing it in different configurations. Ritalin and Adderall both stabilize it in an open configuration; Wellbutrin and modafinil stabilize it in a closed configuration. Maybe stabilizing it in an open configuration is more stimulating and a closed configuration is more antidepressant? But modafinil is a pretty normal stimulant and not really an antidepressant, so I don’t think this is it.

There is some discussion that Wellbutrin may be a norepinephrine and dopamine releasing agent along with a reuptake inhibitor. But I think Adderall does this too and it doesn’t make it an antidepressant. Also, these people seem to have put a lot of work into looking at the releasing agent properties of Wellbutrin and if I understand them correctly they’re not sure it has any.

Or maybe Wellbutrin’s other main action, nicotine antagonism, is involved – either synergistically with the NDRI, or on its own. There is circumstantial evidence that nicotine receptor antagonism may treat depression on its own, but this hasn’t really been explored sufficiently. It would not surprise me if this was a major part of what is going on, even though nobody really talks about it.

I tend to think of Wellbutrin as having a completely straightforward stimulant action, plus a somewhat more mysterious antidepressant action.

2. Which should I try first – Wellbutrin or SSRIs?

This is the million dollar question – most people will start with one of these two antidepressants and want to know which.

About a dozen studies compare Wellbutrin and SSRIs head-to-head and generally find no difference on average; both are moderately effective. However, one or the other is still often much more effective for a given individual. I have had patients who have no effect on any SSRI but almost miraculous effects from Wellbutrin, and vice versa. Can we predict beforehand which patients will respond better to which?

Wellbutrin is a mild stimulant, so it has an advantage at treating symptoms like low energy, fatigue, and lack of motivation. It also has no sexual side effects (if anything it increases sex drive) and no weight gain (if anything it makes you lose weight).

Traditionally, the counterbalancing advantage of SSRIs has been that they help anxiety more. Certainly SSRIs are an excellent medication for treating anxiety disorders, obsessive-compulsive disorder, and irritability even without comorbid depression, so it would make sense to use them in anxious/obsessive/irritable depression. Wellbutrin is a mild stimulant, and stimulants tend to make anxiety worse (think of how jittery and nervous you can get if you have too much coffee). So it would be reasonable to argue that SSRIs are better for depression comorbid with anxiety – which is at least half of depression cases.

But studies don’t really bear this out. A meta-analysis of anxious depression found that the SSRI advantage was very small – 59% of anxious depressives improved on Wellbutrin compared to 65% on SSRIs. Wellbutrin patients also saw decreases in anxiety almost as great as SSRI patients. There is probably some truth to the SSRI-for-anxiety rule – I do see a few patients get more anxious on Wellbutrin, and the studies did show a 6% advantage – but it probably isn’t as big as we thought.

Since Wellbutrin lacks some troubling SSRI side effects and is not too much worse even in SSRIs’ core competency of anxiety, is it a strictly superior first choice of antidepressant for the average person? Possibly not – a large meta-analysis found that patients discontinued Wellbutrin due to side effects more often than SSRIs, which doesn’t really fit its side-effect-free reputation. Most likely this is people who feel too jittery and and anxious due to its stimulant effects. On the other hand, discontinuation studies are usually only a few weeks. Possibly discontinuing Wellbutrin after two days because you hate it immediately is a great outcome compared to staying on an SSRI for six months and then realizing you have no sex life. I continue to use both antidepressants first-line, with particular cases decided by individual patient characteristics, though I’m trying to have more of a bias towards Wellbutrin when all else is equal.

Here are a few other scattered findings:

– Wellbutrin is better for people with high levels of inflammation as measured by an inflammatory marker called c-reactive protein. It’s probably not worth getting your c-reactive protein measured just to determine what antidepressant to put you on, but some people will have gotten this measured already on standard lab tests.

– Since obese people generally have more inflammation and higher CRP, Wellbutrin will probably be better for obese people. Wellbutrin also helps with weight loss, a second reason that it should be a strong first choice for this demographic.

– Patients with subclinical ADHD (ie ADHD that isn’t enough of a problem to need a real stimulant) might benefit from Wellbutrin, since it is a mild stimulant and will have some efficacy against ADHD. This has not been officially proven via study but is common-sensically true.

– Patients with former amphetamine addictions tend to do well on Wellbutrin, because these people are preselected for having very strong positive reactions to amphetamines. Wellbutrin is a distant amphetamine relative which is not itself addictive, so these people can benefit from whatever strong positive reaction they have safely. I’m basing this one on common sense, experience with a few patients, and wild extrapolation from a few studies like this one.

– Wellbutrin is a very effective stop-smoking medication, so if a depressed person smokes you might as well give them Wellbutrin, and kill two birds with one stone.

– These people claim that highly-driven overachievers do better on Wellbutrin, but their study seems very sketchy to me. I think it’s plausible that highly-driven overachievers generally like stimulants, because they help you achieve more and are less likely to make you tired. I think this is more than sufficient to explain the effect they mention, in the unlikely chance that it wasn’t just a statistical fluke.

Here’s a summary of reasons to prefer one drug or the other:

Wellbutrin:
– You want more motivation and energy
– You want to lose weight
– You are worried about sexual side effects
– You are worried about antidepressant withdrawal
– You have trouble paying attention and staying organized
– You want to quit smoking

SSRIs:
– You want to be less anxious
– You want less intense emotions
– You are worried about having trouble sleeping
– You don’t like feeling overstimulated

3. What’s the difference between Wellbutrin IR, SR, and XR?

IR is immediate release and lasts about five hours per dose. SR is sustained release and lasts about eight hours a dose. XR (sometimes called XL?) is extended release and lasts about twelve hours a dose.

IR is designed to be taken three times a day. SR is designed to be taken twice a day. XL is designed to be taken once a day.

Isn’t taking something once a day more convenient than taking it two or three times a day? Generally yes, about 90% of the Wellbutrin I prescribe is XL, and you should probably start with XL unless you have some strong reason not to.

If you find you have trouble sleeping (either you can’t fall asleep, or your sleep is restless and you wake up a lot during the night) on Wellbutrin XL, you might want to try switching to Wellbutrin SR. Probably what’s happening is that you metabolize Wellbutrin unusually slowly, so your supposedly-twelve-hour dose of Wellbutrin XL is actually lasting you twenty-four hours or longer, and so your body is full of stimulants all night and you can’t sleep. If you take SR, the supposedly-eight-hour SR will probably last you twelve or sixteen hours – long enough to have medication in your body all day, short enough that you can still sleep at night.

But also, some people find Wellbutrin IR works in a way that other forms of Wellbutrin don’t. I have no good explanation for this. A few other people find that it helps them to take a booster dose of IR at some point along with their regular SR or XR.

How do you convert between IR, SR, and XR doses? The only way I have ever seen anyone do this is using this picture:

How do you know the maximum safe dose if you’re combining different forms? I eyeball that picture and try to make sure nothing I’m doing is making the peak go higher than where I imagine it would be on 450 mg of XR, which I know is the maximum dose. If someone else knows a better way, message me.

4. How do you dose Wellbutrin?

Usually you start with Wellbutrin XR 150 mg for a few weeks to see how you feel and make sure that it isn’t hitting you too hard or overstimulating you. If you feel okay, after a few weeks you go up to Wellbutrin XR 300 mg. Then you wait a few weeks and see if your depression is better. If it’s not better at all, give up on Wellbutrin and try something else. If it’s somewhat better but not perfect, consider going up to 450 mg. If it’s completely better, declare victory and continue that dose.

As mentioned above, you might switch to SR or even IR if you find XR is helping you but making it hard to sleep. If you find XR helps you in the morning, but you get worse in the afternoon, you might add a small dose of IR (maybe 75 mg) in the afternoon as a “booster”.

5. How long does it take for Wellbutrin to work?

This is a confusing question with no clear answer.

I have seen many patients report very strong positive effects from Wellbutrin on their first day taking it. This is probably a pure stimulant effect; stimulants work immediately. And other stimulants like Adderall have a tendency to cause euphoria your first few days taking them, until your body adjusts. I could see the combination of stimulation plus stimulant-induced euphoria looking a lot like successful depression treatment.

The more mysterious longer-term effects of Wellbutrin may take several weeks to kick in. These people say “in the second week”, but I have seen everywhere from immediately to three or four weeks. And if a patient is doing very well on Wellbutrin, I have sometimes seen them do much worse after missing Wellbutrin for just one or two days, so it does seem like day-to-day changes can have an effect.

In general, I warn patients to expect their first few weeks on Wellbutrin to be a roller coaster ride, with an unpredictable pattern of positive and negative effects. These usually stabilize after a few weeks, hopefully into a steady antidepressant effect.

6. What are the most common side effects of Wellbutrin?

The most common side effect is overstimulation – which could feel like jitters, shakiness, fast heartbeat, poor appetite, and trouble sleeping at night. Sometimes these problems go away if you wait a few days; other times they don’t.

6.1. Does Wellbutrin cause withdrawal when you go off it?

All medications can cause a “rebound” effect when you go off them, where you feel slightly worse for a few days. This can be very mild for low doses over short periods, and stronger for high doses over long periods. But Wellbutrin has a very mild rebound effect compared to other medications, and most people in most situations will not notice anything at all. It is probably fair to say in a colloquial sense that Wellbutrin does not cause withdrawal.

6.2. Isn’t there something about Wellbutrin causing seizures?

Very high doses of immediate-release Wellbutrin can cause seizures, which is why we never use them. Now we use reasonable doses of extended release Wellbutrin.

In the 1990s, when Wellbutrin was just discovered, some doctors prescribed very high doses, and some patients had otherwise-unexplained seizures. Studies were done, and it was determined that about 1 in 30 patients receiving 600 mg + daily of Wellbutrin would get seizures during a the first few months of treatment. So doctors lowered the doses they used, and found that about 1/200 patients receiving 450 mg or less got seizures, and only 1/1000 patients receiving 300 mg or less. Sustained release formulations also have about a 1/1000 rate of seizures. This is around the rate at which people have seizures anyway even when they aren’t taking Wellbutrin, so guideline-making bodies have officially pronouned Wellbutrin safe at a dose of 300 mg SR or less a day.

It’s conventional wisdom that Wellbutrin XR is safe up to 450 mg/day, but I can’t find the calculations originally used to decide this, and this doesn’t exactly match what would happen if you naively converted 300 mg of SR into XR. Please email me if you know how this was decided. However it was decided, it definitely works. Wellbutrin (now mostly prescribed in the XR form) currently has one of the lowest seizure rates of any antidepressant, basically indistinguishable from background risk.

Can people with known seizure risk (like epileptics) take Wellbutrin? As far as I can tell, the most evidence-based answer is yes – studies consistently show Wellbutrin as used today has one of the lowest seizure rates of any antidepressant, maybe even lower than SSRIs (which aren’t usually though of as able to cause seizures at all). I have heard stories of very knowledgeable neurologists with decades of expertise in epilepsy who are happy to give their epileptic patients Wellbutrin. I’m still too much of a coward to try this myself.

7. If Wellbutrin works for me, how long should I keep taking it?

Wellbutrin does not permanently cure any condition. At best, it suppresses the condition while you are on it. So you will need to be on Wellbutrin until your condition goes away, or you feel ready to deal with it without medication.

The average length of a major depressive episode is between three months and a year, with most sources saying six months. Current guidelines state that if Wellbutrin treats your depressive episode, you should stay on it for about six months, then try stopping to see if your depression has gone away on its own. This suggests some picture of depression episodes “continuing to go on” “below the surface” even when antidepressants have rendered them asymptomatic; I don’t know if anyone actually believes this or whether this is a productive way to think about things. But I think the six-month suggestion is a good rule of thumb.

If you stop Wellbutrin after six months and immediately feel depressed again, then probably you should try again after another six months to a year. If you keep trying this, and every time you get off the medication you get depressed again and again, you may need to stay on it until something changes, or even permanently.

If you’re taking Wellbutrin to deal with depression, anxiety, or other negative emotions caused by life circumstances, you should probably match your course of medication to the course of your life circumstances. For example, if you’re miserable because of your terrible job, and Wellbutrin helps relieve that misery, you should probably stay on it until you can get a less terrible job. After that, you can try stopping it and seeing if your anxiety is better.

If you’re taking Wellbutrin for a trait condition like trait dysthymia – a condition you’ve had most of your life and which just seems to be a part of how you are – then you’ll need to stay on it unless you find some other way to deal with the trait condition. IE if you’re just naturally an unhappy person, and you need Wellbutrin to be able to function without your unhappiness getting in the way, you will need to stay on it until you find some other way of dealing with your unhappiness (lifestyle changes? therapy?)

Some people stay on Wellbutrin forever, and there’s no shame in this.

8. Are there any known long-term side effects from staying on Wellbutrin for many years?

I don’t know of any specific side effects. In general, we are always worried that there may be side effects we don’t know about from staying on a drug a very long time. If all else is equal, you should probably try to be on as few drugs as possible to lower this risk. But we don’t know of any specific risks from Wellbutrin. Wellbutrin came out in the 90s, and the people who have been using it constantly since then – so about 25-30 years – seem fine as far as we can tell.

9. What about Wellbutrin to stop smoking?

It works really well! You should try it!

The mechanism of action here is complicated. Wellbutrin blocks nicotine receptors. You would think that would obviously be involved in it stopping people from smoking, but I’ve seen (implausible) claims that the dopamine and norepinephrine reuptake effects are equally or more important. I’ve also seen claims that it specifically binds to nicotine receptors in a way that prevents them from eliciting dopamine release, which seems pretty on-the-nose for a stop-smoking agent.

I think a fair layman’s explanation would be “Wellbutrin blocks the receptors that detect nicotine and make smoking pleasurable”. But I’ve also heard from many patients that cigarettes seem actively disgusting when they’re on Wellbutrin (including some patients who didn’t know it was a stop-smoking aid when they started taking for depression!) Why would that be? Maybe cigarettes are always disgusting, but you don’t notice when you’re enjoying them? I am interested in hearing from anyone who knows more about this.

How effective is Wellbutrin? Graph from here:

Pretty effective! It more than doubles the percent of quitters who remain abstinent after a year. The percent is still pretty low (20% in this study), but most people need more than one attempt to quit smoking successfully. Maybe a more encouraging way to look at it is that about half of people who successfully stayed off cigarettes for three weeks were able to make it a whole year.

The usual regimen is:

1. Start 150 mg two weeks before your target quit-smoking date
2. Go up to 300 mg one week before your target quit-smoking date
3. Quit smoking
4. Once you’ve been off cigarettes for six weeks, you can consider stopping Wellbutrin
5. If you find that you want to smoke again after stopping Wellbutrin, consider continuing Wellbutrin forever

Is step 5 a little extreme? Shouldn’t we be careful about keeping someone on a medication the rest of their lives? Well, we should be super careful about the possibility that someone might be on tobacco the rest of their lives! Tobacco is so much more dangerous than Wellbutrin that there is no comparison. If there is the slightest chance that staying on Wellbutrin will prevent you from staying on tobacco, then for God’s sake, please take the Wellbutrin.