NI,
Your first point is a good one. The second one, which dealt with the subject I had initally brought up I'm not sure I can totally concur with though.
First, there are major differences between the products which act through serotenergic effects, including ssri antidepressants and dexfenfluramine(redux) and fenfluramine(pondimin). The fens likely increase presynaptic serotonin(5-HT) release while having many other effects in the whole serotenin system which are yet unknown. The mechanisms of action for appetite suppression aren't totally clear, as there are effects on glucose utilization as well as effects on the 5-HT sytstem. These 5-HT effects may be mediated in many ways, whether they be affecting levels, turnover rates, specific receptor sites, etc, and truly where it all occurs is unknown. The relationship between the glucose utilization and 5-HT system hasn't been clarified that I'm aware of, and there are also stimulant type effects, as well, leading to the potential for addiction, as well as having depressing effects, loss of efficacy with 5-ht blocking drugs which lower 5-HT levels in the brain, and the risk for exacerbation or even causing psychosis, agitation, and depression(more so with alcoholics).
None of this is the case with the ssri antidepressants. Their primary mechanism involves blockade of uptake(no such thing as reuptake actually, but calling them ssui antideps has a suicide sounding abbreviation, which wouldn't help marketing any). They are all effective for depression, panic disorder, ocd, and many other problems at times, including anorexia and bulimia. The likely main reason for the effects for the eating disorders include the associations with depression and ocd(obsessive-compulsive disorder), as there is a very high rate of ocd traits in these patients. They have been well studied, and there are no similar findings of exacerbation of psychosis, depression, etc., as well as no findings of regular heart effects of any kind, one of the main benefits over the older tricyclics. The primary risk for problems psychiatrically is for an overshoot in treating the depression, causing mania, primarily in those with bipolar depression. Actually, luvox has been indicated for ocd in kids 8 y/o and above, and likely the others will follow suit eventually. The types of symptoms seen as well as treated, and the side effect profiles are totally different. In many ways, they are totally opposite on their effects, especially psychiatrically(hence, neurologically). There is no way to say that ssri antidepressants actually increase 5-HT peripherally per se,as blocking uptake doesn't lead to a long lasting increase, but rather a change in the balance, and maybe even a reduction, as seen by the GI and sexual side effects which are commonly seen. They do not share many qualities with the fens actually, so I see the mention/possible accusation of ssri antideps causing the same problems as a real stretch and extremely unlikely.
Keep in mind that there are many ways the 5-HT system can work, and many products affect it. Sansert(methylsergiside), the headache med, serves as a post-synaptic 5-HT antagonist, and likely increases the risk for cardiac valvular fibrosis or thickening, more similar to the fen risk claims. It also can lead to retroperitoneal fibrosis if used longer than 6 months. There may be more in common with this mechanism.
LSD has partial post-synaptic agonist qualities, primarily 5-HT2, something which I suspect may occur to a lesser degree with the fens, and something which is blocked with the newer antipsychotic agents such as risperdal and zyprexa. 5-HT 3 antagonists include odansetron(for nausea with chemotherapy) and propulcid(the bigger and better version of reglan for GI treatment).
Also, the fen-phen plan can block the efficacy of ssri antipressants in treating depression, and the risk for toxic 5-HT syndrome is actually quite low, although there, as with mixing 2 ssri s or other associated products. Actually, the likeliest cardiac risk of the 5-HT antidepressants is for anafranil, but likely for non-5-HT reasons. Keep in mind that Toxic 5-HT syndrome is very rare, and not truly comparable to neuroleptic malignant syndrome in many ways. The first is far more rare, and usually a lot easier to treat, especially if caught early on, such as with periactin. The risk for TSS is there regardless of the dose, but increases with more med. This doesn't mean ssri antidepressants can't be combined, however, as they can, but very carefully. High doses, or combining with a low-dose of another, are commonly needed in ocd, and usually without ever seeing a sign of TSS. NMS with antipsychotics, as well as tardive dyskinesia and extrapyramidal symptoms are far bigger concerns.
I agree that the NEJM article overstated, but there is sufficient reason reason to be concerned and investigate further. The risk may not be as tiny as you alluded, even though it likely isn't huge either. However, the shops set up by many docs after hours to provide fen-phen weren't done with nearly enough medical care or monitoring, and now this will have to occur, combined with the negative publicity, there is little likelihood of redux thriving at this time, although it may still yet bring in reasonable revenues. The fact that people were looking for a quick fix is quite accurate however. Everybody jumped on the bandwagon due to the fact that it looked like an easy answer for obesity treatment, something which doesn't happen for many other medicines. The other question is just how many who have had cardiac valvular effects truly need immediate repair, vs. simple monitoring and d/c of the drug upon abnormal findings, with the possibility of reversal of the initial damage with early d/c.
One other aspect is the lovan issue. Yes, LLY attempted to get approval for obesity with this name for prozac, much as Glaxo has for Zyban for tobacco craving reduction(actually wellbutrin 150 SR, an antidepressant), but it appears any weight loss is usually early on, and not necessarily maintained. As a matter of fact, often the reverse happens over time,not at all typical of the fens. The likely reason for efficacy in this area with ssris, such as prozac, would be weight gain secondary to depression, or effects secondary to an obsessive compulsive component, which may yet be helpful in some with obesity, but a good clinical picture will need to be maintained.
My apologies for the very long-winded post.
Okay.......done with this hardcore science stuff...it's a holiday. Not looking to be antagonistic in any way, simply discussing, and I appreciate the good discussion you bring up, as well as the interest in information you clearly have. Have a nice holiday weekend.
Regards,
Marshall |
