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Dr. Bob is Robert Hsiung, MD,
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Posted by David Mirtzer on July 29, 2000, at 2:33:39
My pdoc now has me on 450 mg Serzone + 20 mg Celexa. So far so good, but I think he's being a little cavalier in saying that Serotonin Syndrome is nothing to worry about with this combo. I'd really appreciate a second opinion.
I read about an SS death from adding low-dose trazodone while weaning off of Prozac. Well, as I understand it, Serzone is a derivative of trazodone. And Celexa is the most serotonin-selective of all the SSRI's. So I'm very uncomfortable with the Serzone/Celexa combo.
Thanks in advance,
DM
Posted by Cam W. on July 29, 2000, at 10:38:46
In reply to CAM or anyone: Serzone + Celexa Risky?? , posted by David Mirtzer on July 29, 2000, at 2:33:39
David - Serzone/Celexa combination is relatively safe. Paraphrasing Sunnely, there are 2 main reasons that serotonin syndrome can occur:
1) Using two antidepressants that have pharmacodynamic interactions that both increase serotonin by different mechanisms. This is seen when an MAOI and SRI are taken together. The MAOI stops the metabolic breakdown of serotonin, by blocking the enzyme (monoamine oxidase - MAO). This increases the amount of serotonin between nerve cells (at the synaptic gap).
Also, a SRI blocks the reuptake of serotonin into the presynaptic neuron (the nerve cell from which the serotonin is released). The reuptake mechanism is the body's way of conserving and recycling serotonin, so that more serotonin doesn't need to be manufacutured. By blocking serotonin's reuptake, the body is forced to produce more serotonin (one of the symptoms of depression is decreased serotonin levels in the body). This process, like the MAOI action, also increases serotonin in the synaptic gap.
So, in this situation, you have 2 drugs working 2 different ways to increase serotonin levels in the synaptic gap. The reuptake mechanism and MAO are responsible for clearing serotonin from the synaptic gap. When you block both of these clearing mechanisms, serotonin levels are dramatically increased, and thus dramatically increasing the risk of acquiring serotonin syndrome.
2) The other way serotonin syndrome can occur is through a pharmacokinetic drug interaction. One way this occurs is when one drug either causes the increased or decreased production of liver enzymes (especially the enzymes of the cytochrome P450 metabolic enzyme system). This is what is happening between trazodone and Prozac. The Prozac (and it's major active metabolite norfluoxetine) strongly inhibits the cytochrome enzymes classified as CYP-2D6, CYP-2C19, and CYP-2C9 and, to a lesser extent, CYP-3A3/4 and CYP-1A2. The Prozac can cause decreased levels of these enzymes, thus the metabolism of other drugs by these systems "may" be slowed; resulting in increased levels of these other drugs when "normal" doses are taken. Some other CYP enzyme systems have been found to be inhibited by Prozac, but they are not really involved with the metabolism of any of the current drugs in humans. Celexa does not inhibit cyctochrome enzymes to any clinically significant amount (slight, probably clinically insignificant, inhibition of CYP-2D6 and CYP-2C19).
Serzone is also a potent inhibitor of CYP-3A4 and to a lesser extent CYP-2D6 and CYP-1A2. Trazodone may inhibit CYP-2D6, but probably not to any significant extent, clinically. Serzone, trazodone, Prozac, and Celexa, all increase serotonin levels in the same way; by blocking the reuptake pump. This is unlike combining a SRI with a MAOI; in which serotonin is increased by 2 different mechanisms.
Serzone, trazodone and Prozac not only inhibit the above enzyme systems, they are also metabolized by them to varying degrees (as is Celexa - mainly by CYP-2C19, CYP-3A4 and, to a lesser extent CYP-2D6). The reason that a combination of Prozac and trazodone caused a fatal serotonin syndrome is because of the dosages of the drugs (especially trazodone) that were used in this case. Trazodone (small doses - 25-50mg) is often used with Prozac when sleep problems occur. The problem is when you begin to use higher doses of these 2 drugs (especially the trazodone). The use of these two drugs together "may" cause a large increase in the amount of trazodone in the body and this can result in a number of cardiac problems (tacycardias and fibrillations) which can result in a heart attack. The serotonin levels are raised in this case, possibly exhibiting serotonin syndrome signs, but also trazodone (and Serzone) can block muscarinic receptors, possibly resulting in some of these heart problems.
Confounding factors can also play a role in a drug interaction between Prozac and trazodone (or Serzone). Factors like the condition of a person's heart and the natural amount of the different cytochrome enzymes that the person naturally produces (some people who are extra sensitive to some drugs have been found to be lacking the normal complement of some of the enzymes - slow metabolizers - due to a genetic lack of genes to make a certain enzyme).
The drug interaction between Serzone and Celexaa would be as follows. Serzone may inhibit some of Celexa's metabolism and, to a much, much lesser extent, Celexa may inhibit some of Serzone's metabolism. Increased levels of Celexa do not have the heart problems that are seen with increased levels of trazodone. This drug interaction should have little clinical significance.
Also, judging from your description of your doctor's response to your concerns of serotonin syndrome, he has already taken the above information into account and has been following your reactions to the 2 drugs (increased drug concentration is usually manifested by increased side effects).
In short, most people (possibly >98%) will have absolutely no problem taking this combination together at normal to low doses (as you are).
Hope this helps - Cam.
Posted by David Mirtzer on July 29, 2000, at 21:38:27
In reply to Re: CAM or anyone: Serzone + Celexa Risky?? » David Mirtzer, posted by Cam W. on July 29, 2000, at 10:38:46
> David - Serzone/Celexa combination is relatively safe. Paraphrasing Sunnely, there are 2 main reasons that serotonin syndrome can occur:
>
> 1) Using two antidepressants that have pharmacodynamic interactions that both increase serotonin by different mechanisms. This is seen when an MAOI and SRI are taken together. The MAOI stops the metabolic breakdown of serotonin, by blocking the enzyme (monoamine oxidase - MAO). This increases the amount of serotonin between nerve cells (at the synaptic gap).
>
> Also, a SRI blocks the reuptake of serotonin into the presynaptic neuron (the nerve cell from which the serotonin is released). The reuptake mechanism is the body's way of conserving and recycling serotonin, so that more serotonin doesn't need to be manufacutured. By blocking serotonin's reuptake, the body is forced to produce more serotonin (one of the symptoms of depression is decreased serotonin levels in the body). This process, like the MAOI action, also increases serotonin in the synaptic gap.
>
> So, in this situation, you have 2 drugs working 2 different ways to increase serotonin levels in the synaptic gap. The reuptake mechanism and MAO are responsible for clearing serotonin from the synaptic gap. When you block both of these clearing mechanisms, serotonin levels are dramatically increased, and thus dramatically increasing the risk of acquiring serotonin syndrome.
>
> 2) The other way serotonin syndrome can occur is through a pharmacokinetic drug interaction. One way this occurs is when one drug either causes the increased or decreased production of liver enzymes (especially the enzymes of the cytochrome P450 metabolic enzyme system). This is what is happening between trazodone and Prozac. The Prozac (and it's major active metabolite norfluoxetine) strongly inhibits the cytochrome enzymes classified as CYP-2D6, CYP-2C19, and CYP-2C9 and, to a lesser extent, CYP-3A3/4 and CYP-1A2. The Prozac can cause decreased levels of these enzymes, thus the metabolism of other drugs by these systems "may" be slowed; resulting in increased levels of these other drugs when "normal" doses are taken. Some other CYP enzyme systems have been found to be inhibited by Prozac, but they are not really involved with the metabolism of any of the current drugs in humans. Celexa does not inhibit cyctochrome enzymes to any clinically significant amount (slight, probably clinically insignificant, inhibition of CYP-2D6 and CYP-2C19).
>
> Serzone is also a potent inhibitor of CYP-3A4 and to a lesser extent CYP-2D6 and CYP-1A2. Trazodone may inhibit CYP-2D6, but probably not to any significant extent, clinically. Serzone, trazodone, Prozac, and Celexa, all increase serotonin levels in the same way; by blocking the reuptake pump. This is unlike combining a SRI with a MAOI; in which serotonin is increased by 2 different mechanisms.
>
> Serzone, trazodone and Prozac not only inhibit the above enzyme systems, they are also metabolized by them to varying degrees (as is Celexa - mainly by CYP-2C19, CYP-3A4 and, to a lesser extent CYP-2D6). The reason that a combination of Prozac and trazodone caused a fatal serotonin syndrome is because of the dosages of the drugs (especially trazodone) that were used in this case. Trazodone (small doses - 25-50mg) is often used with Prozac when sleep problems occur. The problem is when you begin to use higher doses of these 2 drugs (especially the trazodone). The use of these two drugs together "may" cause a large increase in the amount of trazodone in the body and this can result in a number of cardiac problems (tacycardias and fibrillations) which can result in a heart attack. The serotonin levels are raised in this case, possibly exhibiting serotonin syndrome signs, but also trazodone (and Serzone) can block muscarinic receptors, possibly resulting in some of these heart problems.
>
> Confounding factors can also play a role in a drug interaction between Prozac and trazodone (or Serzone). Factors like the condition of a person's heart and the natural amount of the different cytochrome enzymes that the person naturally produces (some people who are extra sensitive to some drugs have been found to be lacking the normal complement of some of the enzymes - slow metabolizers - due to a genetic lack of genes to make a certain enzyme).
>
> The drug interaction between Serzone and Celexaa would be as follows. Serzone may inhibit some of Celexa's metabolism and, to a much, much lesser extent, Celexa may inhibit some of Serzone's metabolism. Increased levels of Celexa do not have the heart problems that are seen with increased levels of trazodone. This drug interaction should have little clinical significance.
>
> Also, judging from your description of your doctor's response to your concerns of serotonin syndrome, he has already taken the above information into account and has been following your reactions to the 2 drugs (increased drug concentration is usually manifested by increased side effects).
>
> In short, most people (possibly >98%) will have absolutely no problem taking this combination together at normal to low doses (as you are).
>
> Hope this helps - Cam.Does it ever! Thank you so much for providing such a clear and detailed (and very interesting) response.
DM
Posted by CraigF on August 10, 2000, at 17:53:17
In reply to Re: CAM or anyone: Serzone + Celexa Risky?? » Cam W., posted by David Mirtzer on July 29, 2000, at 21:38:27
I'm switching from Serzone and Celexa, but taking both at the same time for now as a safety net.
Will the Serzone interfere with the benefits of Celexa? I'm feeling terrible amounts of dread in the morning (like I'm waking for my own execution)and feel groggy and hopeless throughout the day.
I remember the edgy morning feeling from Prozac years back, but not this bad. Also, I'm not getting much of a boost during the day. The obsessional thinking has definitely dipped, but I'm fairly unhappy. I've only been taking Celexa for two weeks (in the a.m.)as of this upcoming Sat. and I still take 450 mg Serzone at night.
Any suggestions would be great!!
Posted by Cam W. on August 10, 2000, at 18:55:05
In reply to Re: CAM or anyone: Serzone + Celexa Risky?? , posted by CraigF on August 10, 2000, at 17:53:17
Craig - It sounds like your neurotransmitter receptors (esp. serotonin and norepinephrine) are readjusting to the Celexa and you are getting a good jolt of serotonin to your system. The reuptake block of serotonin in the gap between nerve cells is greater with Celexa. This increases serotonin in the gap and thus, you are probably getting a stronger response. This should abate in another week or so.
When does your doctor want to start weaning from the Serzone? A slight reduction of the Serzone may help alleviate some of the symptoms that you are experiencing. Ask your doctor about this.
Hope this helps - Cam
This is the end of the thread.
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