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quetiapine (Seroquel)
(update added, but not rewritten, 2/2006; original from 2004)

The Good Side (which outweighs for many patients...)

The Bad Side 

Remember also that any medication can, once in a while, produce a very bad reaction you won't see listed here.  There are many medication websites you can use, as you probably know, for more detailed information. Here's one example


The Good Side

New evidence for Seroquel has now (summer of '04) separated it from the rest of the pack of "atypical antipsychotics" (Zyprexa, Risperidone, Geodon, aripiprazole are the others; and also clozapine but that's a lot more difficult to use so is more of a last-step option).  

Two aspects of this medication, discussed below, now distinguish it from the rest.  Except for these two features, in my view this medication would still be "on hold" waiting for more evidence for its long term effectiveness in bipolar disorder.  Remember, they all have evidence for effectively treating manic symptoms in the short run.  What I've been waiting for is evidence they can act as good long run agents to prevent recurrences of both mania and depression.  For that, we need studies which run at least several months.  A year or more would be nice, but imagine how difficult and costly it is to run a study that long.  (So far, Zyprexa has the record for "longest randomized trial of a mood stabilizer" I know of, at 18 months.Tohen)

Here are two new sets of data on quetiapine, and one other advantage relative to risperidone:

1. New evidence has been presentedCalabrese showing quetiapine has antidepressant effects.  These effects were quite substantial in this new study.  In addition, the design of this study is more solid than some of the other medications studies out there, in that patients were not pre-selected for having "tolerated" quetiapine.  Everyone who was randomized to get quetiapine had never been on it.  That's different than some of the "long-term" data, meaning more than a few weeks, in other studies such as lamotrigine, where the patients who entered the study had already been on the medication, at least for a few weeks, thus selecting patients who could get on and stay on it.  In the quetiapine study, this favorable bias was not present.

How much antidepressant effect?  It looks like a lot, based on the reports from this study released so far.  The main investigator, Dr. Calabrese, also headed the studies of lamotrigine which showed striking antidepressant effects for that drug.  So, he is not new to this area of bipolar disorder, that's for sure.  But, he exclaimed, (mind you, he has surely been funded handsomely for his work with this company):

"This is the first time that an antipsychotic has been shown to have clear antidepressant activity," senior investigator Joseph R. Calabrese, MD, told Medscape in a telephone interview. "Treatment separated from placebo on every outcome. I was surprised to see how large the effect was. It seems to me that this drug is not just an antipsychotic. It separated from placebo on nine of 10 items, compared to olanzapine, which separates from placebo in three items when assessed as a treatment for bipolar depression."Medscape

(For you skeptics, who wonder about Dr. Phelps and his possible funding  by AstraZeneca -- good on 'ya for wondering!   I  just started receiving $ from them yet after working on it for almost a year, as their point of view may allow me to promote my point of view using their money.  Here's my full explanation of how I handle that.)

UPDATE 7/05: Another "real world" research study, with a very long period of observation, was just published.Hardoy This was not "blinded", meaning that both the patients and the doctors knew that Seroquel was being used. However, this study looked at the course of illness when Seroquel was added to other medications, which is how we often end up using it. Although system used to evaluate results was rather crude, it is similar to what doctors like me do: we basically ask ourselves "Is the patient better? How much?"  The results were strong, even though there weren't many patients in the study (21; usually a small sample like this makes it harder to find "statistically significant" results). Relapse rates into some kind of bipolar symptom, including depression, were three times lower with Seroquel compared to before it was added. If we were to find these kind of results in a long-term trial that was randomized  to start, as we have for Zyprexa, then this kind of result would be very impressive. For now, however, it adds just a little more reliability to the impression we doctors who use the stuff have developed: it does indeed seem to work pretty well over time, not just at first. Remember, that's the "holy grail", for now, amongst mood stabilizers -- does it work long term?  

2. The second feature of quetiapine that distinguishes it from some of the other "atypical antipsychotic" options is a possible lower risk of causing weight gain and diabetes, at least compared to Zyprexa.  [Update October 2004: a recent direct study of this issue confirms this relative risk, consistent with the table belowLeslie; although another study does not.Citrome]

Here is a look at the conclusions of the American Diabetes Association (published in a joint statement with the American Psychiatric Association) regarding weight gain (Wt Gn), diabetes risk, and worsening cholesterol levels:

This ADA/APA statement matches well, in my experience, with the average psychiatrist's impression regarding which of these medications are the most likely to cause weight gain.  It didn't take us long to end up ranking them in this order, based on my discussions with colleagues.  The medications really do seem to be different from each other in this way -- despite the FDA having come out in "blanket" form, requiring the same warning from each company in this regard.   I've yet to run across a clinician who did not rank them just as this ADA slide does:  Zyprexa worst; Risperidone and Seroquel intermediate; ziprasidone and aripiprazole probably least risky -- though for them, we have the least experience to be certain about this. 

3. Noting that quetiapine and risperidone appear to be in roughly the same risk-category, is there any reason to prefer one over the other?  Risperidone has one major advantage, and one disadvantage, in this comparison.

The advantage:  it is less sedating.  I'm told the quetiapine sedation will diminish over several weeks and that one strategy to cope with this is to push the dose higher faster (there actually is an explanation for this, having to do with histamine receptor blocking, just as Benadryl does).  I haven't tried that yet; up to now I've just held back or slowed down on dosages when faced with this side effect.  By starting with 25 mg, or sometimes even with 12.5 mg, I've usually been able to keep the sedation from being a limiting factor; it fades almost to zero in nearly everyone, over about 4-7 days at each dose step.  

The disadvantage: risperidone can cause some muscle problems, called EPS; and it can cause an increase in a hormone called prolactin.  The EPS side effect limits how high one you can push the dose, whereas with quetiapine, the dose can go quite high without any clear increase in side effects, except for that sedation business, which one can work around. The prolactin increase appears to be almost solely a risperidone problem.  Quetiapine has been repeatedly shown not to do this, with the exception of two case reports (searched 8/2005) when used with an antidepressant as well.venlafaxine,mirtazapine  Prolactin increases can interrupt normal menstrual function and, less commonly, cause breast milk secretion.  The risks that might go along with continued high levels of prolactin have not been well studied.

The Bad Side

Obviously there was some bad in the "good" you've heard thus far:  quetiapine is associated, at least to some degree, with weight gain;  and a risk of developing diabetes. 

From that bipolar depression study discussed above, here are common side effects by dose, relative to placebo:

Side Effect

600 mg 300 mg placebo
Dry Mouth 41% 44% 8%
Sedation 32% 30% 6%
Dizzy 23% 17% 8%
Constipation 11% 12% 4%
Weight gain after 8 weeks 1.6 kg/  3.5 lbs 0.4 kg/  1 lb 0.1 kg/  0.2 lbs

Are there any other long-term risks?  People who get a good response to the medication and are likely to stay on it for a long time need to know about tardive dyskinesia, a serious movement problem that can continue even when the medication has stopped.   With the new atypical antipsychotics,  tardive dyskinesia appears to be very uncommon, but along with weight gain and diabetes, it is one of the big long-term risks of this class of medications.

Drug Interactions
Quetiapine is a little more susceptible to interactions with other medications than many other psychiatric medications.  Whereas most of our tools require no adjustments when used with other medications, this one requires a little thinking.  While so far, we do not have evidence of interactions with most of the medications we use, here are three which matter.  Mind you, if one starts out low and goes up slowly on the quetiapine dose,  then even if quetiapine levels are doubled by the other medication, this should not be a problem.  The patient would simply respond at a dose lower than one would expect. Or, side effects might turn up at lower doses, making the necessary dose increases impossible.

However, in one case below, the opposite occurs: quetiapine levels are lowered so far when the patient is already taking carbamazepine, it would be nearly impossible to get satisfactory quetiapine levels. One would need far more than the average doses to get the usual benefits from this medication.

Update 2/2006: Interaction with Depakote
A recent study indicates that people who are taking valproate (Depakote) have much higher quetiapine levels for a given dose: 77% higher.Aichhorn This study was not "prospective", meaning that they didn't measure levels on quetiapine alone, then measure them again when combined with valproate. Instead, they just compared levels between patients who were or were not also on valproate. So these data are not "for sure", but very suggestive that there is a significant interaction between these two medications. Think of it this way: if you're also on valproate (Depakote), you can get your Seroquel level much cheaper -- with less than half the dose you might otherwise require! Of course the other way around is important too: if you're on Depakote, you may not require a very high dose of Seroquel and might need to start lower and go up a little more slowly to know where you will get the best result.  Note the words "may" and "might" in that sentence, please. 

Update 11/2007: Interaction with fluvoxamine (Luvox)
If a patient is already taking this antidepressant, quetiapine levels will be nearly twice as high for a given dose of quetiapine than one would have expected.Castberg

Update 11/2007: Interaction with carbamazepine (Tegretol, Equetro)
In 39 patients taking both carbamazepine and quetiapine, quetiapine levels were 86% lower than in patients not taking carbamazepine.Castberg Wow -- only about 10% of the dose achieved compared to what one would expect; that is not very much.  In order to get to average quetiapine blood levels, a patient taking carbamazepine would have to take many times the average quetiapine dose. Just doubling or even tripling the dose would not get a patient back to average, according to these data.

Indeed, the results of this study suggest that using quetiapine in patients already taking carbamazepine may be quite futile.  Upon reading this study, I could not immediately think of a patient of mine who did not respond to quetiapine while taking carbamazepine, but I'll bet I have several.  I will avoid using this combination in the future.