Posted by Adam on May 25, 2000, at 15:07:16
In reply to Re: Risperidone and Serzone and Anger (oh my), posted by PeterJ on May 19, 2000, at 2:36:56
I have been so busy lately that I scan Psychobabble pretty much based on the "new" flags, and often find myself going back to earlier dates first (before I scroll down) to follow a thread.
So I feel a bit like a clod to see a thread discussing almost precisely the same thing I'm talking about in another, totally unrealated thread.
Anyway, Peter, the stuff I've read is in almost complete accord with what you have discussed here. I have also considered the effects of Welbutrin, since I was taking that shortly before I was taking Serzone (nefazodone). However, for instance, most of what I have read seems to indicate that while risperidone is a 2D6 substrate, it shouldn't inhibit 2D6. It is true that the conventional wisdom on such interactions isn't always up to date with the science, but I couldn't find evidence that risperidone would raise the levels of mCPP. Serzone, as you have said, is thought to inhibit CYP450-3A, which metabolizes 9-hydroxyrisperidone (RISP > 9-OH-RISP via 2D6). Inhibition of 3A might be a problem vis a vis risperidone if risperidone concentrations are not closely monitored. I read also that RISP and 9-OH-RISP have about the same pharmacologic activity. I remember that one paper, where the author hypothesised that genetic differences in CYP450-2D6 could cause wide variations in the RISP to 9-OH-RISP ratio, but since both compounds do about the same thing, clinical outcome isn't as highly affected as one would expect by such deficiencies.
Also, it is true that RISP blocks certain serotonin receptors, but at lower doses, it blocks primarily certain dopamine receptors (D4 is the biggie, I think). I'm not sure if it is known what blood level of RISP correlates with dopamine receptor specific doses, and if such a thing could be carefully titrated in the case of drug interactions. Do you know?If one were, say, deficient in CYP450-2D6 (and about 10% of the caucasian population is thought to be), and were taking both nefazodone and risperidone, that could be a really bad thing. If one is responding poorly to nefazodone (a potential indicator of 2D6 deficiency?), and then throws risperidone into the mix, it seems you've got an anxiogenic drug mixed with a higher risk for extrapyramidal symptoms from the other. A dangerous coctail, perhaps?
What do you think? This actually didn't dawn on me until just now. It would blow my "risperidone+nefazodone is better than clozipine+nefazodone" theory right out of the water (if there aren't other holes in it) at least in some circumstances.
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> Drug interactions are of two types. Pharmacokinetic interactions occur when one drug affects the levels of the other drug or its metabolites in your body. Pharmacodynamic interactions occur when the effects of one drug add of subtract from the effects of another drug.
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> Combining risperidone and nefazadone has the potential of both kinds of interactions. It's not necessarily a bad combination, but it's a complicated one and it may explain your anger symptoms.
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> Nefazadone is metabolized by an enzyme called Cytochrome p450 3A. This enzyme converts the Nefazodone to another compound call mCPP (meta-chlorophenylpiperazine). mCPP is a metabolite of several psychiatric drugs and has unique and powerful effects on the brain which have been extensively studied. These studies (mostly at the National Insitututes of Health and also at Yale and other universities) involve giving people mCPP intravenously or orally and noting the effects in various conditions. One observation that has been made is that intravenous infusion of mCPP often causes feelings of anger. This is particularly common in people with certain anxiety disorders. Oral ingestion of mCPP is not as potent but may induce anger as well. If someone is taking Nefazodone and is experiencing unexpected anger, it is very possible that mCPP is the cause.
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> There has been no study of the effects of risperidone on the levels of mCPP produced by nefazadone, but the underlying biochemistry does suggest the possibility of an interaction.
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> First of all, while the enzyme that produces mCPP is Cytochrome P450 3A (known as CYP 3A for short) the enzyme that gets rid of the mCPP is another Cytochrome called P450 2D6 (CYP 2D6).
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> Nefazodone---[by CYP 3A]---> mCPP ----[by CYP 2D6]---> Inactive Metabolites
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> The important fact is that risperidone inhhibits CYP 2D6. So by taking risperidone you could block the breakdown of the anger-causing mCPP. Now risperidone is not a very powerful 2D6 inhibitor, and you are taking a small dose, so the effects might not be pronounced. But there is another drug interaction to take into acount as well. Not only would the risperidone increase the levels of mCPP, but the nefazodone may increase the levels of the risperidone.
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> Risperidone's metabolism is very complicated and would take me several pages to explain. In a nutshell, risperidone is metabolized by both the CYP 3A enzyme and the CYP 2D6 enzyme. However the 2D6 enzyme mainly converts risperidone to another compound (OH)-risperidone that has the same effects as risperidone itself. To set in motion the process of actually deactivating risperidone you need the 3A enzyme. This 3A enzyeme takes the dumbell shaped risperidone molecule and literally breaks it in half. But, and here is the key, nefazodone is a very potent inhibitor of CYP 3A. So taking nefazodone slows down the breakdown of risperidone.
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> This is the theoretical basis of the interaction. There has only been one published case I have seen that actually looked at levels of risperidone in someone taking nefazodone. That paper estimated that nefazodone doubled the levels of risperidone in the blood. However, this paper, which also described other interactions of risperidone, did not give much detail, such as the amount of nefazodone taken, and the amount of mCPP was not studied at all.
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> So that's the pharmacokinetic interaction. Nefazodone may increase the levels of risperidone and risperidone may increase the levels of mCPP.
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> There is also a possible pharmacodynamic interaction. Both risperidone and nefazodone interact with a number of receptors in the brain. Risperidone blocks serotonin and dopamine receptors, and may also block certain adrenergic receptors. Nefazodone blocks serotonin recoptors and uptake sites, and also blocks adrenergic receptors. mCPP stimulates serotonin receptors and may block some adrenergic receptors. There's a lot going on there, but the end result is any of these drugs can cause some degree of stimulation which could in some situations manifest itself as anger. (I could try to figure out which receptor specifically involved, but honestly there are so many involved that anyone picking one out as the cause would be guessing.) Risperidone can be used to treat psychosis, that does not mean it is not an activating drug. It can be activating, especially in low doses.
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> So what's the bottom line of all this? Well, I think you did the right thing in lowering the risperidone dose. Since risperidone and nefazodone can potentially increase each other's levels (and that of mCPP) and intensify each other's effects you may have been getting more of each than it seemed from your dose levels. Judging from the one published case, dropping the dose by 1/2 is about right.
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> You were concerned about whether such a low dose of risperidone could be effective. Risperidone can actually be surprisingly effective in small doses. While schizophrenic patients may need 6-8mg or more, people with anxiety and mood disorders like you have often respond to less. 0.5mg is a low dose, but there are reports of effectivnesss of such doses in bipolar patients. Elderly people and people with Parkinson's also repsond to very low doses (0.25mg and up). In your case, the drug interactions might mean that 0.5mg is as powerful as 1 or 2 mg would be. If the anger goes away you could try going back to 1mg in the future if needed.
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> So the short term answer is to cut back the dose of either the risperidone or the nefazodone. Hopefully you will be able to find a dose which relieves your depression without exacerbating anger. If you can't find such a dose, the next step would be to consider other antidepressants such as SSRIs or other anti-anger medications such as Lithium, propranolol, clonidine, etc. While some antidepressants may cause transient anger as they activate a person, this almost always goes away with time. Be cautious with the drug Trazodone as it also produces mCPP, and with Buspirone, as it produces a similar compound called 1-PP which can cause anxiety and agitation.
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> I am confident you will be able to find a treatment that will help in the long run causing excessive anger. It may be hard to hold on in the meanwhile, but you can do it.
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> P.S. You and your doctor did a good job of suggesting mCPP as a possible factor in the anger. Very few doctors are familiar with these studies. I happen to know about it because I did research into this area after experiencing mCPP and 1-PP related side effects years ago. I also have done studies on risperidone metabolism although I have not taken that drug. I know several of the world's leading authorities on mCPP and risperidone metabolism and in fact I can remember suggesting the possibility of a risperidone-nefazodone interaction before it was actually reported in the literature. (I'm here mainly as someone who is also ill, but I also have an academic background in biochemistry which comes in handy sometimes.)
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> Peter.
poster:Adam
thread:32301
URL: http://www.dr-bob.org/babble/20000517/msgs/34625.html