Posted by Tomatheus on December 28, 2005, at 14:38:54
In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by linkadge on December 28, 2005, at 11:03:31
Linkadge,
See below for my responses...
> Its funny. They probably don't see new MAOI's as advances over Nardil/Parnate, but yet they're willing to release SSRI after SSRI.
Yeah, in terms of introducing medications that might actually produce clinically significant benefits in treatment-resistant patients, it really doesn't make sense why more MAOIs haven't been pursued. However, you know as well as I know (or probably better) that the drug companies are more interested in making meds that will maximize their profits than those that could potentially help a relatively small group of treatment-resistant patients. I'm not saying at all that these small groups of patients are insignificant, but the drug companies obviously don't stand to make as much money off of meds that that are targeted toward a subgroup of depressed patients as they do from so-called "blockbuster" meds that they can market to all patients with depressive disorders, patients with other psychiatric conditions, and patients who just feel "down" for a short period of time as a result of circumstances in the lives. And of course, if the drug companies can claim that a particular class of drugs is safe -- and if they have the power to discredit anyone who dares to suggest otherwise -- they can succeed at at getting people with a wide range of depressive symptoms (including those that can be directly attributed to "depressing" life circumstances) to request these drugs from their doctors. Because the capacity of the irreversible MAOIs (including the selective MAO-A inhibitors clorgyline and Lilly 51641) to potentiate hypertensive crises has been well-known for decades, it would be impossible for the drug companies to market them as "safe." This of course would translate into a low profit potential from such medications.
I should also probably clarify that Lilly 51641 is actually not a "new" MAOI, but a medication that Lilly began pursuing in the mid-1960s. Lilly 51641 was studied experimentally until the late 1970s, but I have not been able to find any information to indicate to what extent (and for how long) Lilly was actually trying to pursue the drug for commercial use. But considering that Lilly is a commercial drug company, it would make sense that they were trying to pursue it at one point. It seems likely that that Lilly decided against pursuing it as a commercial drug because of its ability (like that of clorgyline) to potentiate hypertensive crises. According to Lotufo-Neto et al. (1999), "Clorgyline is an irreversible enzyme inhibitor, and has some liability to cause hypertensive crises in the face of high substrate concentrations, despite its selectivity (Laux et al., 1995, as cited in Lotufo-Neto et al.). Thus, clorgyline was not considered to represent much of an advance over the nonselective MAOIs and was not vigorously pursued."
> Where I do think that mixed MAO-A/B inhibitors have the advantage over MAO-A inhibitors is in the subset of people who gain a significant antidepressnat effect from increased PEA neurotransmission.
>
> Some doctors have detected low PEA neurotransmission in certain subsets of depression. Depression that is accompanied by low energy, cravings, poor attention and other features.I think you could be right.
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 & Breakfield, 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.
> These people are not going to get major help from SSRI, SNRI's, and probably never will.
I agree.
Tomatheus
==
PRIMARY SOURCE 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.
Hotamisligil, G. S., & Breakfield, X. O. (1991). Human monoamine oxidase A gene determines levels of enzyme activity. American Journal of Human Genetics, 49, 383-92.
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.
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.
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.
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.
SECONDARY SOURCE REFERENCE
As cited in Lotufo-Neto et al. (1999): Laux, G., Volz, H. P., & Möller, H. J. (1995). Newer and older monoamine oxidase inhibitors. A comparative profile. CNS Drugs, 3 (Suppl 2), 145-58.
poster:Tomatheus
thread:591969
URL: http://www.dr-bob.org/babble/20051221/msgs/592784.html