The common distinction between first- and second-generation antipsychotics has no scientific basis and should be dropped, according toa paper in The Lancet. A meta-analysis of 150 double-blind studies found little evidence that newer, so-called atypical antipsychotics are more effective than older drugs for symptoms of schizophrenia, MedPage Today writes.
The researchers also found that, although newer drugs induced fewer extrapyramidal effects (including tremor, slurred speech, restlessness, movement disorders, among other things) than Haldol, which is also known as haloperidol, this did not occur when compared with low-potency first-generation agents.
"Second-generation antipsychotic drugs differ in many properties" - including structure and mode of action as well as clinical effects - "and are not a homogeneous class," the researchers concluded. "Improper generalization creates confusion and, as a result, the classification (of first- versus second-generation agents) might be abandoned."
In an accompanying editorial, two British researchers went further, calling the notion that newer agents are more effective or safer than older drugs "spurious." "As a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost effective," wrote Peter Tyrer of Imperial College in London and Tim Kendall of the National Collaborating Centre for Mental Health in London.
Both groups of researchers emphasized the findings do not mean that all antipsychotics are alike. Instead, they wrote "this meta-analysis provides data that clinicians could use for individualized treatment of patients with schizophrenia based on efficacy, side-effects, and cost of antipsychotic drugs."
In their analysis, for each efficacy and adverse-effect outcome they studied - overall symptoms, positive symptoms, negative symptoms, depression, extrapyramidal effects, weight gain, and sedation -- there was no clear pattern favoring newer over older drugs. Although they did find that four second-generation agents - Clozaril, Zyprexa, Risperdal and Solian, which is not approved in the US - were significantly more effective than older drugs.
The researchers wrote their findings differed from some earlier meta-analyses partly because they excluded open-label studies that "systematically favored second-generation drugs."
More than half the studies they did include had a different type of bias - Haldol was used as the comparative drug, according to Tyrer and Kendall. And this has a high rate of extrapyramidal effects compared with other first-generation drugs. The result, they suggested, was to make the side effect profile of the newer drugse look better than if other comparators had been tested instead.
The researchers said that most of the second-generation drugs "have not been shown to be better than low-potency first-generation antipsychotic drugs (for extrapyramidal effects), and we noted a robust superiority based on more than two studies only for" Clozaril.
Weight gain is more of an issue for second- than first-generation drugs, they found. In studies using Haldol as the comparator, Abilify and Geodon did not lead to more weight gain. There was no difference in weight gain between any second-generation drug and other older agents, they found. For sedation, no clear pattern emerged to separate first- from second-generation agents.
Many of the results of the meta-analysis echoed those of the prospective CATIE study, in which three newer agents were compared with perphenazine. The researchers wrote that the use of a comparator other than haloperidol in the CATIE trial was a major strength and should be repeated in future studies.
The National Institute of Mental Health funded the analysis. Stefan Leucht reported relationships with Sanofi-Aventis, Bristol-Myers Squibb, Lilly, Johnson & Johnsons' Janssen, Lundbeck, and Pfizer. Other study authors reported no potential conflicts of interest. Kendall reported involvement in an ongoing update of the schizophrenia guideline for the UK' National Institute for Health and Clinical Excellence. Tyrer reported no potential conflicts of interest.
27 Comments
Unless I am missing something, the study suggests that 4 second generation drugs have demonstrated superiority over 1st generation Haldol thus the title seems somewhat misleading.
Most recalcitrant schizophrenic patients are prescribed multiple medications during the course of their treatment. The key is to find one drug or a cocktail that provides enough symptomatic control that it makes the side effects seem manageable. Physicians assess the studies that were used to gain approval, other published trials, and experience in their own patients with antipsychotics to guide their prescribing protocols, and I don't see this study changing that.
Hi Jim,
You raise a good point. I struggled with the headline, given the study results and the various comparisons between the two groups of drugs. I settled on this headline because it appeared, to me, to sum up the conclusions. I admit that headlines can be imperfect, but based on the study and editorial, this is what I took away. And I attribute it to the study; it's not my own opinion.
Hope this helps, ed
This is a very confusing report. First they say that the second generation products offer no advantage to first generation products. Then, as Ed writes, "they did find that four second-generation agents - Clozaril, Zyprexa, Risperdal and Solian, which is not approved in the US - were significantly more effective than older drugs." As I understand it, the majority of patients on second generation drugs are on Zyprexa and Risperdal. Side effect aside (given that both first and second generation products each have significant, but differing side effects), aren't more patients better off using "more effective" products?
Hi Atlex,
I tend to agree about some confusion. A bit like 'on one hand this, on the other hand that.' But it seemed interesting enough to put it out there. Again, it didn't make it easy to write a headline either.
Best ed
The confusing results here seem to be a clear illustration of something we've talked about previously on this site: The difficulty in true comparative-efficacy studies. (or comparative toxicity studies) Note that several products DID show positive comparative efficacy data as compared to Haldol. However, the authors are arguing that Haldol is a bad choice because it's side effect profile is generally worse than other "typical" first generation antipsychotics. This makes the second generation drugs appear better than they really are. To me, this pretty clearly illustrates the problem with comparative efficacy studies.
I think what they are trying to say is that drugs like seroquel ( the most expensive sleeping pill prescribed) and Abilify are over priced and over marketed medications. These two drugs are the most expensive in the "class".
Looks like they forgot to mention the CATIE Study of 2006, judging Zyprexa to be the worst of the second generation atypical antipsychotics, causing diabetes and death from profound hyperglycemia, pancreatitis, and the like - a big difference from the lethal problems of the first generation A.A. Add in the deaths from suicide, the deaths of seniors with dementia from heart attacks, and which group is worse?
Just count the number of dead, for a simple comparison. The study may be confusing, but my read of it is that finally academic medicine is starting to tell the truth about these horrible drugs.
Yesterday Condor posted a link to his blog in which he stated that the original Enhance study for Zetia and Vytorin reduced the number of Medicare reimbursements from 90% to 33% for these particular drugs; with that in mind it would seem that this study would have a similar effect on the Medicare rate of reimbursements for anti-psychotic medications other then the 3 FDA approved exceptions cited. It appears more studies are showing that the benefits of new drugs are minimal in comparisons to older existing generic drugs. While I personally believe this to be true, it seems somewhat coincidental that studies now demonstrate very little statistical significance between newer medications and existing generic drugs since medicare is attempting to reduce its costs. In addition, if the new studies are accurate what data was the FDA looking at when it approved the newer class of drugs? Would not the new drugs be introduced through an IND and therefore need to demonstrate a statistically significant improvement from existing medications?
One other item of note, Dr. Leucht, one of the authors of the study, disclosed he has financial ties to several pharmacuetical companies including Lilly (Zyprexa), and Janssen (Risperdal).
No mention was made to any ties to Novartis, the manufacturer of Clozaril.
Hi,
I've been busy posting elsewhere. I'm pretty familiar with this topic and the data and will come back and discuss the comparative efficacy, safety, and regulatory issues sometime over the weekend when I get a chance.
Salmon
Jim asks: "Would not the new drugs be introduced through an IND and therefore need to demonstrate a statistically significant improvement from existing medications?"
Not at all. The mandate of the FDA is to approve safe and effective drugs. Approval does NOT require them to be better than standard of care. In general, the US has relied upon the market to do that. If the drug is no beter than the existing standard of care, then doctors won't prescribe it. It's approved, but it's a flop. (DTC advertising works against this, however, since the "standard of care" drugs are frequently generic so they get hardly any advertising money.)
Clozaril killed my sister. There is no generational distinction there.
The names ‘first generation’ and ‘second generation’ antipsychotics are really a misnomer. In reality they are better classified as predominantly dopamine receptor blockers or predominantly serotonin receptor blockers. In fact a couple of so called ‘first generation’ antipsychotics are structurally and pharmacologically really serotonin receptor blockers for example pimozide which is so cardiotoxic that they kept marketing to only a small subgroup with Tourette’s, and , an antidepressant similar to clozapine that also has cardiotoxicity. Even though these are so called old first generation drugs structurally they each represent one of the two major structural classes of second generation sertotonin receptor blockers with. These differences in structures give rise to differences in effects and in particular toxicity especially among the serotonin blockers, although it should be remembered that there are different structural classes among the dopamine blockers that also give rise to differences in potency and effects at other receptors. For example the phenothiazines have a lot of anticholinergic effects, and thioridazine has a lot of cardiotoxicity similar to the serotonin blockers.
The two major classes of the serotonin blockers are a heterocyclic ring system like olanzapine (Zyprexa - Lilly) and an end group that actually looks a lot like serotonin for example risperidone (Riperdal – JNJ). Efficacy wise the heterocyclics and risperidone / paliperidone are about as efficacious as the dopamine blockers like haloperidol. It’s the other serotonin like ‘second generation’ drugs that were not even included in this article that tend to be much less efficacious, for example ziprasidone (Geodon – Pfizer) and aripiprazole (Abilify – Otsuka / BMS). Although Abilify does have a large following for bipolar so it’s possible that some drugs are better for schizophrenia and some for bipolar based on differing effects at different receptors. These serotonin like serotonin blochers are typically called ‘activating’ i.e. in some people they actually make things worse and induce psychosis and violence, so on average when you lump everyone together the average efficacy score in a big study won’t be as good as the average efficacy score for Haldol or Zyprexa. However as far as schizophrenia on average the serotonin blockers are no better than the dopamine blockers although the serotonin blockers also have a lot more really nasty toxicities due to effects on different side receptors (they were actually designed to be really dirty and hit multiple serotonin receptors since we didn’t know which was the right one to target (and we’re still not 100% sure but we’ve narrowed it down). So the idea that serotonin blockers are more efficatious is a myth. It came from the fact that after clozapine was introduced and withdrawn for toxicity there were some people who had no effect from the dopamine blockers but got a very good response to clozapine. Rather than reflecting that the second gen are better drugs on average this probably just reflects the fact that the underlying cause of schizophrenia is different in different people and for these particular people they needed serotonin blockade. For a different subgroup we would expect the opposite and they would only respond to dopamine blockers.
There are also different toxicities and degrees of toxicity among the serotonin blockers that are related to even finer divisions in their substructures. The following list will give you a rough idea:
Clozapine, Olanzapine – phen-fen like cardiac toxicity (when N-demethylated and oxidized), agranulocytosis (N-oxidation) Quietiapine (Seroquel) and Thioridazine – also cardiac toxicity N.B. others also cause cardiotox (risperidone?) but these 4 are particularly nasty Olanapine, clozapine – metabolic symdrome (diabetes, weight gain, lipid problems) Seroquel and Risperdal to a lesser extent Ziprasidone (Geodon) and Zonisamide – Choreoathetosis (commonly otherwise it’s 1:100,000). Remember the woman in NC that CBSnews reported on in Aug 2007 who died due to choking on food and left her for a day or two sitting in a chair while the attendents played cards right in front of the body, and psychosis Hepatotoxicity – Olanzapine and probably others Skeletal Defects most serotonin receptor blockers but to varying degrees
As for Nathan's comment what we do is if a new drug has poor efficacy we do studies comparing it to another drug with poor efficacy, and if there's toxicity we compare it to another drug with lots of toxicity or game the study some other way. (Sometimes a drug has both). If we can show any degree of difference from placebo becasue we've sunk so much money into it we go into FDA ask if we can do the comparisons we want and FDA with a wink and a nod says yes. Then when we come in for the approval either a new reviewer who can be led down the garden path is given it for review or someone who's reliable and will write the review in such a way that we can get an approval without any labeling dings by ignoring the toxicities.
Salmon
Salmon, I could be wrong, but I don't think that the study was alleging that the newer drugs were compared to Haldol in order to be deceptive. Rather, they were likely compared to Haldol because (at the time the studies were performed), that was the best studied and most well-known antipsychotic. My point was that comparative efficacy studies sound great in principle -- but in practice, they are likely to unintentionally give irrelevant and even misleading data.
Nathan,
I understand your point and agree. Comparison to Haldol at especially the supratherapeutic doses used in the studies with Haldol did give a false sense that the Serotonin blockers caused less tardive dyskinesia than ALL Dopamine blockers. It did this by using the worst dopamine blocker in terms of tardive and using extremely high doses.
I was simply taking your point and going even further and showing how what you said is actually utilized by companies to mislead. This is also why this metaanalysis is misleading.
What you really need to do is have multiple head to head comparisons with different drugs and different doses. Unfortunately this is not economically feasible. So the only way we can really get at it is as I'm doing which is understand the basic pharmacology and what receptors cause different pharmacologic effects, know the relative receptor binding for the different drugs and their metabolites, and know the actual exposures under various conditions, e.g. drug interactions, ethnic groups, and then you can actually look for things in the phase I, II, and III studies with intensive clinical monitoring and compare across drugs and see if the your predictions are correct. I find that I tend to be pretty good at making predictions that turn out to be correct years later after many years of clinical use. It's not 100% and I'm loath to say a drug should be dropped from development (unless the toxicity is so bad and so obvious and unfortunately what we do is set up studies to do this and find early symptoms but then cover them up from the FDA). What I'm advocating is for us to come clean and let people know what were know so they can use things appropriately. It's the business decisions to push really toxic things that we know have serious long term toxicities and the current push for preemption to protect ourselves from being responsible for the damage we've caused that I have problems with.
Look we knew about the mechanism for Phen-Fen's toxicity back during development in the early 1990's and what did we do why in '93 or '94 we got the ICH regulatory requirements so we only had to study 500 people for 6 months and 100 people for 1 year at the very lowest dose. Plus we either didn't do or rigged the metabolism and drug interaction studies. Plus we put reliable people into the FDA who then were promoted into the positions that set the policy on these type of things over the past decade or so. Of course this was all under Janet Woodcock's guidance.
P.S.
Olanzapine was under development at the same time as Phen-Fen and it's clear from the summary basis of approval that Lilly knew.
Now in June 2004 the Alan Brier Lilly's Chief Medical Officer stood up at the NCDEU meeting (sponsored by NIMH regarding psych drugs) and said that lawsuits had gotten their attention. (Ref Trends in Medicine June 2004 page 10).
Plus olanzapine clearly has more cardiac problems with parenteral administration (look at the recent problems and AC meetings with people keeling over a few hours after long acting Zyprexa) and this may be due either to the route or a contaminant from the manufacturing process. Just like occurs with the classic positive control for 5HT2B toxicity monocrotalline. I also remember that there was an FDA AC meeting in Feb 2002 I believe where FDA got this cardiologist from Georgetown University to say it's neurally mediated reflex bradycardia when people fainted and their hearts stopped shortly with Zyprexa (yeah right).
Now we have this push for quality by design (we know what we're doing and don't need to test). Yeah right, just like the amount of melamine formed in the US baby formulae is only 10 times more than the chemists predicted.
Nathan
I stand corrected, I reviewed the CFR and I did not find any references to the fact that an IND must demonstrate superior efficacy over existing medications. I think I may be confusing the requirements for an IND with those of either a Priority Review or Fast Track Approval. I think I recall language to that effect in those instances but I did not check the criteria for either review.
Jim
Lisa, Remember what I said about activation and suicide etc.. with atypical antipsychotics. Now there's information on Prozac with the same wording from 1984 coming from Germany. There will be a program on German TV tomorrow night.
See http://ahrp.blogspot.com/2008/12/german-tv-documentary-big-pharma-ssri.html
Salmon
Alright there I messed up I work at the FDA.
I'm a whistleblower. Why did I post here?
Because I went everywhere I could think of and couldn't stop the killing of children. I went all the way up my command. I went to Woodcock, I went to Von Eschenbach. I went to Congress multiple multiple times. I went to different Senators, I went to different Congressmen, I went to the Justice Department, I went to the FBI, and I saw nothing happening, and every time I went the retaliation just got worse and worse and worse. I openly cc'ed Congress on e-mails and asked them to look into things. I offered documentation of crimes by FDA managers by their own e-mails as well as documentation of crimes by drug company officials. Every drug I and others were working on were being pushed through no matter how dangerous. Then I saw that hundreds of thousands of children and potentially well over a million people were likely going to be maimed or killed in the US alone and our country's economic future potentially being destroyed and I said enough. I come in to work 18 hours straight on a Sunday (June 29th) after I was supposed to be on vacation, so that I could document my objections to why a drug was so dangerous it shouldn't be approved. But I knew that I was already being set up to be forcably halled out the FDA. Then it became apparent that even that wasn't going to stop them from getting rid of me and then approving several different drugs incredibly dangerous drugs.
FDA management put me through hell for years.
They set me up time and time again, trying to get around me then when they realized I'd gone to Congress in Jan 2007 they began to set me up to fire me and the people they assigned to work with me either were in on trying to trip me up or were mislead so that they would unknowingly help. I was even more overworked than before and given impossible tasks like going through 170,000 pages overnight and then being pushed to agree to everything. I had to constantly break vacations and being a religious minority everytime I had leave coming for a religious holiday I knew I was going to be set up so that I couldn't make a deadline and there would be an excuse to use when firing me.
I had other whistleblowers like Andy Mosholder coming to warn me that Laughren had been overheard making arrangements to have me fired, and I have email documentation of being set up by Laughren.
Temple said to my face "The Law is what I say it is".
I personally overheard Temple and Laughren discussing throwing and Advisory Committee vote.
Go look up the stock prices for Solvay pharmaceuticals from Belgium from June 1, 2007 to August 15, 2007. You'll see huge drops in the stock prices around June 4th, July 24th, and August 9th. Each one of those drops 5% or more drops in price has odds of that volume of stock trading by chance of 1 in 12 million to 1 in 33 million, and each one of those stock drops occured immediately after major news inside the FDA. There is simply no other reason for it than insider trading. I went to my boss and I was immediately retaliated against.
I personally had Janet Woodcock yell at me so as to approve a drug that would have killed our soldiers in Iraq if they had actually been exposed to nerve gas, and yes there is documented evidence that they would have been more likely to die. In fact the Senate Select Committee on Intelligence had several years previously been told what I told my management. When Janet lost it and yelled at me in front of nearly 3 dozen witnesses she clearly implicated President Bush in a criminal act.
Why Janet? Why would you potentially throw the war and kill our soldiers? Just so some drug company can make some money?
Everything I said here about drug toxicity is based on publicly available information and I can prove it, and yes I did figure it out on my own based on what I googled at home.
So Dr. Von Eschenbach want to fire me. Go ahead. I'm ready to take this to the Supreme Court if I can. Not that I trust that they'll rule according to original intent. The First Amendment has been gutted by the courts for Federal Employees and others. I was threatened for going to Congress and I have documents that I believe show that I was being set up to be fired. In fact I was afraid I was being set up to be placed in a mental institution and forcably drugged. The FDA even sent a Senator, a Senator a message that I broke the law and that the Senator broke the law in receiving information I sent on crimes by FDA officials. All the while the person they told me to talk to about it appears to have known that it wasn't true and that I was within the law.
I take these drugs and my child takes these drugs and I couldn't read the labeling myself and figure out what was appropriate. Even looking into FDA's own files I couldn't find enough information. There was absolutely no excuse for approving drugs without adequate studies so we can't even tell how it's broken down and so we can warn people about lethal interactions. I came to the point where I couldn't trust anything coming out of the FDA and I couldn't protect my own life. My father died from heparin and I was afraid for my own children.
I take following the law very seriously and it's only because of the gravity of the situation and that I exhausted every other channal that I could think of that finally made me go public even if it was anonymously. Even then I tried my best to stay within the law as best I could.
Isn't that what the First Amendment is for? To be able to protect our own lives and our families' lives.
One day the nightmare will end. We are all relying on those who swim upstream.
Big wheel keep on toinin, Proud Mary keep on boinin, And were rolling, rolling Rolling on the river
TMAP and the 2nd generation antipsychotics are the biggest scam of the century.
It's very nice to see that the foundation is crumbling on this.
And it's very nice to see that men such as pharmalot are not afraid to stand strong against the dope pushers.
Could it boil down to little more than that there had to be some kind of active ingredient or else Dr. Bizarros magic juice would have been sussed for a block of chalk or sugar.
The behavioral health nazi's always push these drugs based on the bio-chemical imbalance myth because the APA who raises their hands or not on symptoms, often votes(invents symptoms) after a new drug has been invented. The reasoning is that they rely upon drug company funding. If you think about it, real diseases always have a known cause, and not a fictitious one used to make the drug company rich.
Kevin,
Please do not make baseless accusations. Biochemical alterations have been well documented in some psychiatric diseases. Whether these are a cause in some people or simply a symptom of a more basic problem in many more is immaterial at this point. It was a useful 'myth' to help break down stigmas that it was the patient's own fault and they could control things if they really wanted to. I agree that it was likely abused to get people to use drugs inappropriately but it did have a valid use to allow people to stop blaming themselves for something that they had only partial control over, without going into a detailed lecture and saying ultimately we don't know for sure. I say partial control because for some illnesses many people can minimize the symptoms to various degrees by various nondrug techniques, although not everyone, and not all the time. Some people do not need drugs at all and can use non-drug techniques, and some people need drugs for only a short time so that they can get things under control and then apply non-drug techniques, and some people will always need the drugs. It is this last group that we are especially oversold on, especially in children.
As for real diseases having known causes, essential hypertension is probably one of the most common diseases, yet by definition it has no known cause.
Let's not be so antipharmaceutical that we ignore the facts. There is a lot wrong with the pharmaceutical industry and with the FDA. I certainly have raised my voice and have serious concerns about medication misuse and the hiding of the truth regarding both safety and efficacy information. I believe that many people have been victimized by pharmaceutical companies and even by dishonest psychiatrists. I've observed dishonest psychiatrists ever since I first worked in the field. But there are honest people in psychiatry, people who have been misled and realize it. Let's try to get at the truth and not broadbrush everything and say everything is wrong. Just as we should not broadbrush and say the industry and FDA is completely benevolent either, because that leads to preemption and greater motivation to go on hurting people.
Salmon
Opinions are my own.
As a person who has been on both new and 'old' anti psychotics, I can truthfully say that both work equally well, both cause weight gain (over 75lbs in 20 yrs), however I became both pre diabetic and had a bout with psuedo parkinsonism on the new drugs. Also, the cost of new anti psychs is atrocious - around $1500.00 or more a month for Geodon vs $4.00 a month for Tegretol. Somehow I don't think the extra expense is worth the health risk. I will have blood work and watch for tardive darkinsesia and still be able to pay my bills.