Posted by Tomatheus on January 14, 2006, at 15:11:55
In reply to Re: Looking for a Diagnosis, Medicine Input » Tomatheus, posted by HKristina on January 12, 2006, at 13:08:58
Heather,
I'm sorry for taking so long to get back to your post. My responses are below...
> Am I right to assume that you noticed that I no longer have the hypochondriasis or panic attacks and that you believe that I would benefit from Nardil due to the fact that a particular profile of people happen to have a neuropsyiological need that is congruent to the solution a MAOI provides?Yes, I did notice that you described the occurrence of panic attacks and the symptoms of hypochondriasis (as well as the social anxiety and the excessive alcohol consumption) as psychiatric events that have since come to pass. Judging from your post, it seems pretty clear from my perspective that your psychiatric condition is manifesting itself primarily as depression. But I just thought that it would be helpful to examine the course of your illness as it has unfolded over time, especially so I could illustrate the fact that most of the primary symptoms associated with your various diagnoses are those that tend to respond reasonably well to MAOIs.
Now with respect to the second part of your question...
On occasion, I read posts here on Psycho-Babble and other discussion forums (mostly here, though) from patients whose symptomatic profiles, illness trajectories, and medication responses seem to be consistent with a certain genetically determined biochemical abnormality. But because there is so much uncertainty surrouding the causes of psychiatric illnesses in general -- and even more uncertainty on my part about any potential underlying pathologies because one can only understand another person's illness so well just from reading a discussion board posting -- I basically always refrain from suggesting that another person's illness might be caused, at least in part, by a specific abnormal variant in a given gene. But I've never had anyone ask me if I think that they might have a "neuropsyiological need that is congruent to the solution" that a suggested medication might provide (or anything along those lines). I'm assuming that you asked me this question because you wanted my honest response. So, considering that my honest response is what you're looking for, that's what I'm going to give you. But remember that I'm just a patient -- not a doctor or researcher -- and that my ideas are basically just hypothetical, even though there is some evidence in the scientific literature to support my ideas.
I've never said this before on this forum, and it would take me far too long to explain what I'm about to say in any amount of detail (plus, it would end up including more personal information about myself than I would prefer to provide here), but I have for some time suspected that the underlying cause of my psychiatric illness is the abnormally high production of monoamine oxidase A (MAO-A), the enzyme that metabolizes serotonin and norepinephrine in their respective neurons. Another structurally similar enzyme, monoamine oxidase B (MAO-B) is specific in its metabolism of benzylamine and phenylethylamine (Lotufo-Neto et al., 1999). Neuronal dopamine is believed to be metabolized primarily by MAO-A under normal conditions, but by both MAO-A and MAO-B when neuronal dopamine levels are abnormally high (Fornai et al., 1999).
Nardil and Parnate, the two MAOIs approved for the treatment of depression in the United States, are mixed inhibitors in that they inhibit both types of MAO at both high and low doses. Selegiline, which is used primarily in the treatment of Parkinson's disease, is preferential in its inhibition of MAO-B, but loses some of this preferentiality at higher doses. It is expected that a transdermal form of selegiline (Emsam) will be approved for the treatment of depression soon -- possibly as early as next month. There currently are not any MAOIs available for commercial consumption in the United States that are highly preferential in their inhibition of MAO-A. But moclobemide, a reversible inhibitor of MAO-A, is available in more than 50 countries worldwide (Lotufo-Neto et al., 1999). Unlike the aforementioned MAOIs, which are all irreversible in their inhibition of the MAO enzymes, moclobemide only binds to MAO-A temporarily before eventually losing its grip on the enzyme, so to speak. The irreversible inhibitors bind to MAO-A and MAO-B for the life of the enzymes, and the clinical effects of this irreversible inhibition (from just a single dose) can be felt for approximately two weeks. With moclobemide, the clinical effects of a sinle dose last approximately 16 hours in comparison. So, even though moclobemide might seem like the perfect medication for individuals with abnormally high levels of MAO-A, it is much less potent than the irreversible MAOIs. Furthermore, when Müller et al. (2002) investigated the relationship between moclobemide responsiveness and the genetic variants that encode for abnormally high MAO-A production, they did not find a statistically significant correlation between the two variables. If it is indeed true that the overproduction of MAO-A is at the root of my psychiatric illness (which is mostly depressive in nature), then my experience with moclobemide would be consistent with the findings of Müller et al. (2002). When I took moclobemide, I felt a slight antidepressant response during my first three to four days on the medication, but I felt next to nothing after that.
To briefly summarize a few of the studies that I have read concerning abnormally high MAO-A production, I am going to paste a paragraph that I wrote in a post that I made a few weeks ago (http://www.dr-bob.org/babble/20051221/msgs/592784.html):
[==beginning of pasted paragraph==]
I also think that there is a subgroup of individuals who stands to benefit from the selective inhibition of MAO-A. Studies that have measured MAO-A levels in cultured skin fibroblasts and placentas have found that levels of the enzyme vary "over 50-fold" among control individuals (Hotamisligil & Breakefield, 1991). Furthermore, variants of the MAO-A gene that encode for abnormally high levels of the enzyme have shown statistically significant associations with major depression and sleep disturbance in males (Du et al., 2004); depressed suicide in males (Du et al, 2002); major depression in females (Schulze et al., 2000); panic disorder in females (Deckert et al, 1999); anxiety disorders, agoraphobia, and specific phobias in females (Samochowiec et al., 2004), and ADHD in children (Domschke et al., 2005; Jiang et al., 2001). In my opinion, it seems possible that in some individuals, the genetic tendency to produce abnormally high levels of MAO-A could be just one of multiple genetic abnormalities that contributes to their illness. And the relationship between the abnormally high MAO-A levels and the ways in which the associated psychiatric illnesses manifest themselves does seem to be different in males than it is in females. This could be because the MAO-A gene is located on the X chromosome, because of estrogen's ability to influence MAO-A activity MAO-A activity (Chakravorty et al., 1997), or possibly both. But it seems clear that there are some individuals whose psychiatric symptoms are at least partially mediated by genetically determined high levels of MAO-A. Furthermore, MAO-A activity has been reported to rise significantly with aging (Hotamisligil et al., 1991), indicating that the selective inhibition of MAO-A may be beneficial in treating geriatric depression. So, between the genetic tendencies to produce abnormally high levels of MAO-A and the potential that hormonal differences could also influence MAO-A levels, there is little doubt in my mind that there are some individuals (note: I'm not saying *all* individuals) who would benefit from a potent selective inhibitor of MAO-A.
[==end of pasted paragraph==]
As you can see, the diagnoses and primary symptoms that you described in your posts match up pretty closely with the illnesses that have shown statistically significant associations with variants of the MAO-A gene that encode for abnormally high enzyme production in females. Can I say with 100 percent certainty that you have one of these high-activity variants of the MAO-A gene? Of course not; I have neither the know-how nor the technology to give you a genetic test. But the likelihood that your psychiatric condition might be mediated by abnormally high MAO-A levels seems likely enough from my perspective that I think it would probably be a good idea to try an MAOI.
Ideally (and hypothetically), the best way to counteract abnormally high MAO-A production would be to use a medication that just inhibits MAO-A. Actually, it would be even better in theory to use gene therapy, but that's another story. But unfortunately, even if you do produce abnormally high MAO-A levels and have the means to obtain moclobemide from outside the U.S., it would be my prediction that you would not be responsive to moclobemide -- remember that Müller et al. (2002) found no statistically significant relationship between patients who responded to moclobemide and those with the high-activity variants of the MAO-A gene. And even though clorgyline -- an irreversible MAOI known for being highly preferential to MAO-A over MAO-B -- is still used in animal research, it was never developed commercially and is no longer even produced for human consumption in research studies (SLS, 2000). So, if you're looking for an MAO-A inhibitor that actually produces the therapeutic effects associated with enzyme inhibition (i.e., not moclobemide), that basically leaves you with Nardil and Parnate. In other words, this means that you're basically going to have to settle for a medication that inhibits both MAO-A and MAO-B to a significant extent.
I've been taking Nardil for a little more than three months, and now that I'm at 75 mg/day, I actually feel like remisssion is within reach. I'm actually trying a rather unorthodox strategy right now to try to maximize Nardil's antidepressant effect (most likely the effects of MAO-A inhibition) without having to feel what I would I would describe as a sort of negative energy that I sometimes overpowers the antidepressant effect (possibly the effects of MAO-B inhibition). I can't say for sure that my strategy will work out, but I'm optimistic about it. I'll write more about this strategy after I give it enough time to evaluate my responsiveness to it. If my strategy doesn't work out, I could always try augmenting the Nardil with another medication (I'm thinking that Lamictal would be the best choice for this) to see if that might also help me get that antidepressant effect without getting that "negative energy." The point I'm trying to make in describing my current situation is that even though Nardil and Parnate might not provide the exact effect that you're looking for, you might be able to tweak your treatment strategy for either MAOI in such a way that it might make remission possible.
Tomatheus
==
REFERENCES
Chakravorty, S. G., & Halbreich, U. (1997). The influence of estrogen on monoamine oxidase activity. Psychopharmacology Bulletin, 33, 229-33.
Deckert, J., Catalano, M., Syagailo, Y. V., Bosi, M., Okladnova, O., Di Bella, D., et al. (1999). Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Human Molecular Genetics, 8, 621-24
Domschke, K., Sheehan, K., Lowe, N., Kirley, A., Mullins, C., O'Sullivan, R., et al. (2005). Association analysis of the monoamine oxidse A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: Preferential transmission of the MAO-A 941G allele to affected children. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 134B, 110-14.
Du, L., Bakish, D. Ravindran, A., & Hrdina, P. D. (2004). MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males. NeuroReport, 15, 2097-2101.
Du, L. Faludi, G., Palkovits, M. Sotonyi, P., Bakish, D., & Hrdina, P. D. (2002). High activity-related allele of MAO-A gene associated with depressed suicide in males. NeuroReport, 13, 1195-1198.
Fornai, F., Chen, K., Giorgi, F. S., Gesi, M., Alessandri, M. G., & Shih, J. C. (1999). Striatal dopamine metabolism in monoamine oxidase B-deficient mice: A brain dialysis study. Journal of Neurochemistry, 73, 2434-40.
Hotamisligil, G. S., & Breakefield, X. O. (1991). Human monoamine oxidase A gene determines levels of enzyme activity. American Journal of Human Genetics, 49, 383-92.
Jiang, S. Xin, R., Lin, S. Qian, Y., Tang, G., Wang, D., et al. (2001). Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes. American Journal of Medical Genetics (Neuropsychiatric Genetics), 105, 783-88.
Lotufo-Neto, F., Trivedi, M., & Thase, M. E. (1999). Meta-analysis of the reversible inhibitors of monoamine oxidse type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology, 20, 226-47.
Müller, D. J., Schulze, T. G., Macciardi, F., Ohlraun, S., Gross, M. M., Scherk, H., et al. (2002). Moclobemide response in depressed patients: Association study with a functional polymorphism in the monoamine oxidase A promoter. Pharmacopsychiatry, 35, 157-58.
Samochowiec, J. Hajduk, A. Samochowiec, A., Horodnicki, J., Stepien, G., Grzywacz, A., et al. (2004). Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Research, 128, 21-26.
Schulze, T. G., Müller, D. J., Krauss, H., Scherk, H., Ohlraun, S., Syagailo, Y. V., et al. (2000). Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder. American Journal of Medical Genetics (Neuropsychiatric Genetics), 96, 801-03.
SLS. (2000, October 2). Re: clorgyline - the agony and the ecstasy >> rogdog. Message posted to http://www.dr-bob.org/babble/20000926/msgs/45699.html
poster:Tomatheus
thread:597152
URL: http://www.dr-bob.org/babble/20060108/msgs/599067.html