Wednesday, January 14, 2009

Are "Second-Generation" Antipsychotic Drugs Better?

It might seem that by calling your attention to this post on Dr. Doug Bremner's blog--

--I am being incredibly self-serving, as the post includes a nice plug for HOOKED, which Dr. Bremner has just begin to read. (Hey, better late than never. He's been busy writing his own book as you'll see from his blogsite.) However, read past that and you'll see a useful commentary on an article and editorial that recently showed up in Lancet (cited at end of this post; subscription required to access article).

The so-called first generation antipsychotic medications, of which one of the most widely known is probably haloperidol (Haldol), were reasonably effective in treating the symptoms of schizophrenia and other psychoses--indeed, the arrival of those medications in the 1950s was seen as the main reason why the inmates of the old state psychiatric hospitals could be let out into the community, though what really happened there is a whole different story. However, the doses required to effectively treat serious psychosis, and the life long nature of many psychoses, led to the major downside, the severe side effects resembling Parkinson's disease.

Along came the "second generation" antipsychotics, among which the best known is probably risperidone (Risperdal). The word on the street was that these drugs work as well as, or even better than, their first generation cousins, but are much kinder and gentler in terms of side effects--thus making them worth the high cost (the new kids on the block being brand name while the old guys had gone generic ages ago). The word on the street was dashed recently with revelations that meds like Risperdal were causing humongous weight gain and new onset diabetes among many psychiatric patients.

Leucht and colleagues from Munich set out to do a meta-analysis of all the available studies that compared first-and second-generation drugs directly, and summarized what they had found from 150 such studies. Tyrer and Kendall added a pithy editorial comment.

In typical British fashion, the editorialists do not mince words:

Stefan Leucht and colleagues [suggest] that what was seen as an advance 20 years ago—when a new generation of antipsychotic drugs with additional benefits and fewer adverse effects was introduced—is now, and only now, seen as a chimera that has passed spectacularly before our eyes before disappearing and leaving puzzlement and many questions in its wake.

Importantly, the second-generation drugs have no special atypical characteristics that separate them from the typical, or first-generation, antipsychotics. 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. The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed.

On present evidence from all sources it is difficult not to conclude that the trials of the second-generation antipsychotics seem to be driven more by marketing strategy than to clarify their role for clinicians and patients.

How, ask the editorialists, did the marketers accomplish this subterfuge? The meta-analysis by Leucht et al. shows that the major strategy was first, to always compare the newer drug to haloperidol, known to cause more Parkinsons-like symptoms than others; and second, to choose whenever possible the highest dose of haloperidol to maximize its side effects. (Strategies that Dr. Bremner kindly notes were discussed in HOOKED.)

What all of these authors agree on is that both first- and second-generation (so-called) antipsychotics are a motley crew of individual drugs. Instead of throwing them in wastebasket categories, the smart physician should be carefully distinguishing among them and choosing the right one for each individual patient based on benefits, side effects, and costs.

The tragedy here is that had any of this hot-shot science been invested in issues of clinical importance rather than used as marketing (recall that we are talking about 150 clinical trials, which is not exactly chopped liver), by now we would have a sizeable database on what drug works best for which type of patient, allowing the dedicated doc to choose based on decent evidence. Because the exercise was taken over by marketing hype from the get-go, we are more or less back to square one. "Old drugs bad, new (expensive) drugs good"--maybe an excellent marketing message, but lousy science.

Leucht S, Corves C, Arbter D, et al. Second-generation vs. first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373:31-41, 2009.

Tyrer P, Kendall T. The spurious advance of antipsychotic drug therapy. Lancet 373:4-5, 2009.


Bernard Carroll said...

And now JAMA comes out this week with new information that the so-called atypical new antipsychotic drugs are linked to sudden death just like the early antipsychotic drugs.

Any takers for antipsychotic drugs in treating depression? Just watch the DTC advertisements for Abilify on television.

Bernard Carroll said...

In fairness, data on aripiprazole (Abilify) were not included in the JAMA report that I cited above. Nevertheless, as the saying goes, absence of evidence is not evidence of absence.

Anonymous said...

Atypical Psychotics And Unsealed Documents

Not long ago, I got the joy and despair of viewing many documents that were initially not to be seen, by order of the Department of Justice, yet found their way on various locations on the internet- specifically, the website: The documents are, or were, in fact, evidence against Eli Lilly entirely representing their decade of deception promoting and over-medicating others with their drug called Zyprexa, which is in a class of medications called atypical anti-psychotics. While a new a new molecular entity by definition, this new class called atypical antipsychotics in fact is chemically similar to the older and typical anti-psychotics that exist, such as Haldol. In many ways, the older antipsychotics are safer as well as being similar in efficacy compared with the atypicals such as Zyprexa. Perhaps this is why Eli Lilly did the things they did because they knew Zyprexa caused perhaps more harm than good for those who took the medication. Of the several available atypical anti-psychotics now available, Zyprexa and Clozaril, which was the first atypical anti-psychotic, are believed to have the most toxic adverse events to those who take these two in this class of medications.
Launched in 1996, Eli Lilly did not appear to consider any adverse effects that may occur to those who take this drug, yet it is believed that there was reason to believe that there should be caution regarding its use. With the belief that the maker of Zyprexa is and will be exonerated from any responsibility related to Zyprexa, many surmise that Eli Lilly was pleased that others were taking Zyprexa , and was confident that they would be exonerated from any responsibility from the adverse effects of the drug.
At the time Zyprexa was granted approval for marketing, the medication was indicated only for schizophrenia and mania that exists in those with bipolar disorder. Schizophrenia has been defined as a disease that causes the sufferer to deviate from true reality, along with visual and auditory hallucinations. Bipolar disorder is another mental disorder where the victim alternates from states of heightened neurokinetics to periods of what can be brutal depression for the sufferer.
Eli Lilly, known in recent years by many for their focus on marketing over science or research, greatly desired and hoped that Zyprexa would be a welcome blockbuster, which is a medication that exceeds a billion dollars a year in sales as a minimum. Likely because of this state of greed of Eli Lilly, they did not consider or evaluate any possible damage this flagship drug may cause others. And Eli Lilly appeared to have constructed the obedient and manipulated sales force presumed to be a necessity for this monetary goal to occur without interference.
Pharmaceutical representatives overall are attractive and young individuals with little if any medical knowledge or training, but are determined to have charming personalities along with a perception of obedience related to the pharmaceutical culture, and this is all Eli Lilly in particular wanted from the members of their sales force. The sales vocation is normally associated to contain members with a high affinity for money, it is believed, so corruptive acts such as off label promotion or overt kickbacks is not typically a consideration of such people, overall, as history has shown. Therefore, if Eli Lilly’s sales representatives who happen to be instructed to sell Zyprexa for dementia or depression, the orders will likely be followed by such promoters. Or if this sales force is instructed to pay specifically targeted doctors large amounts of money for doing little or no work for this money given to such doctors, it still is not a problem for the sales force to maintain their obedience to their corporate God. This is the perception of not only myself, but many others as well.
A few years after Eli Lilly launched Zyprexa, they appeared, according to documents, anxious due to their obvious disappointment regarding the initial prediction that was speculated about the growth of this drug that was not meeting their expectations, so they had meetings throughout the nation, known as ‘plan of action’ meetings, and concluded afterwards that there is great benefit from a monetary paradigm of implementing ‘seeding trials’, as they are a mechanism for generating needed, although fabricated data void of any scientific gain of knowledge. This amazingly was done and implemented afterwards rather overtly. Even more unbelievable is that around this time, the Zyprexa sales force was instructed by Eli Lilly management to seek out clinical trial sites, along with investigators for these trials. One voiced stipulation was that the investigators had to either be Eli Lilly prescribing supporters or high volume prescribers. This protocol described was written internally, along with the etiology for performing these sham clinical trials. Anything in writing can be golden, from an illegal situation such as this.
In addition to the clinical trial plan of action of no scientific benefit identified, Eli Lilly instructed its sales force to utilize inaccurate promotional material that Eli Lilly gave its Zyprexa reps without exception. Even though this material was largely if not entirely false and misleading, which was the intent of Eli Lilly, they encouraged their hired promoters that such material was entirely accurate. To further saturate and corrupt the Zyprexa sales force, they were coerced to blunt assertively what are at this time widely recognized adverse effects of this medication, such as massive weight gain, along with glucose and lipid abnormalities- all of which are dangerous to the user of this medication.
The corrosive promotion of Zyprexa by Eli Lilly continued as this dangerous medical corporation continued their efforts by intentionally altering certain Zyprexa articles by essentially rewriting them, followed by being reviewed internally and not externally by those who are called, 'regulators'. The purpose was to stimulate what Eli Lilly believed was clearly absent, which was much needed commercial interest related to Zyprexa. It unfortunately worked to a noticeable degree.
Then it came time to essentially buy benign support groups, if not create these front groups, in hopes that this would improve the growth of Zyprexa. One example is that Eli Lilly paid the American Diabetes Association for their assistance in obtaining endocrinologist consultants, which is a medical specialty that treats, among other things, diabetes. To reduce any possibility of an unexpected contingency doing this, they went ahead and hired a good sized team of diabetes educators. In 1999, Eli Lilly altered a Zyprexa report that originally illustrated the glucose problem with the medication, and did so with deliberate intent and reckless disregard for others. Eventually, the American Diabetes Association became quite the critic of Eli Lilly because of their harmful behavior regarding Zyprexa.
As a sidenote, amazing alliances between Eli Lilly and the Bush administration have existed as well. George H.W. Bush became an Eli Lilly director after leaving the CIA and lobbied to infect third world countries with Lilly medications. He also did his best to maximize tax breaks further for this industry that now employs both himself and his political affiliation. In fact, many members of this administration have some connection with Eli Lilly. It seems to be a revolving door issue once again. One could speculate that the Zyprexa campaign continued for so long because of the relationships the maker of the drug had and has with other powerful people.
The next related psychotic tactic (pun somewhat intended) Eli Lilly created was an advisory board paid well by this company to focus on the progressing concerns of Zyprexa. This tactic did work briefly, but did not change the view of the drug by the medical community in any way perceptually regarding their embellished drug.
Understandably, the health care professionals in the medical community began to get vexed and irritated by Eli Lilly’s deceptive and overtly destructive promotional tactics regarding Zyprexa- which included the company’s own speakers that were utilized in the past expressing concerns overtly. Such events materializing resulted in many ways Eli Lilly being ostracized was because of their disregard for those they are obligated to serve in the medical community, which are those in need of restoration of their health.
Perhaps most disturbing and harmful was the Eli Lilly's intentional holding of crucial safety information related to Zyprexa even before the drug was even approved. For example, Eli Lilly’s Zyprexa representatives were instructed without doubt to neutralize the legitimate concerns doctors may have about Zyprexa, if not outright fear regarding this deadly drug they now perceived as being a clear reality. The representatives were in agreement of continuing to dodge or neutralize legitimate concerns about Zyprexa, with the promise of Eli Lilly’s management team to fill their wallets more if they maintain obedience regarding this directive that caused harm in the form of such physiological disorders as metabolic syndrome associated with Zyprexa, yet the sales force still denied the association due to the insistence of their employer. Essentially, the Zyprexa representatives with Eli Lilly were trained, perhaps aggressively, to disarm negative perceptions about Zyprexa, even though these perceptions continuously proved to be valid. This deeply troubled many Zyprexa representatives, as at this point they were aware of the dangers of the drug they were promoting in order to maintain employment.
Also, and of no great surprise, off label promotion with Zyprexa if not other products by Eli Lilly was a norm within the organization and certainly encouraged by Eli Lilly's management team. Encouraging doctors to prescribe Zyprexa for depression is one example. Amazingly, reflecting back on the behavioral flaws by Eli Lilly for quite some time, they did not alter their method of business even though there was a strong perception regarding this company being both aggressive and greedy, and likely criminal in the way they chose to conduct their business. And depression was not the only off label claim with Zyprexa. Eli Lilly considered such criminal acts as off label promotion as ‘redefining the market’. This is yet another example of their absurdity. The overt demonstration of profits over patients is clearly absurd and inexcusable in any situation.
In the year 2000, Eli Lilly greatly expanded what was called their long term care sales force to increase the utilization of Zyprexa intake in the elderly. This, as a reminder, is deadly- as Zyprexa is harmful to older citizens- specifically pneumonia and eventual premature death result from Zyprexa intake in this patient population. At the same time, Eli Lilly developed a strategy to neutralize the obvious weight gain associated with Zyprexa with other patient populations.
Yet in the year 2002, Eli Lilly was having financial disappointments, which again did not shock many. So to stay in form, they went on a mission to develop speakers to align with them and to not educate others, but to pacify other doctors in hopes that their problems with Zyprexa would disappear. After the speaker episode, Eli Lilly had the audacity to claim that Zyprexa was indeed the best in the class of atypical antipsychotics. Such a statement appears psychotic, to say the least. And now the market for atypicals is about 5 billion a year, so there seemed to be no end as to what Eli Lilly might try next. Also in this year our FDA called Eli Lilly ‘a sponsor’. I find that a bit disturbing. As disturbing as the covert meetings Eli Lilly had with the FDA as well. Well, if you are going to have a friend-that is the right one. Eli Lilly also bribed select reporters to speak or annotate favorably about Zyprexa, evidence suggests.
As the new millennium progressed over the next few years, lawsuits became a concern for Eli Lilly regarding Zyprexa. Doing what any responsible corporate entity would most certainly do, the upper management of Eli Lilly had the audacity to blame the media for the way they handled their drug Zyprexa. Around this time, Eli Lilly needed and did hire a public relations firm because of their image crisis that was likely well-deserved. About this same time, Eli Lilly implemented a nationwide program entitled, “Operation: Restore Confidence”. I’m not sure how a fully rational and conscious group of Eli Lilly people could create something so ridiculous and unrealistic considering what has materialized due to their crimes. Equally deviating from reality of Eli Lilly’s behavior is that they actually thought they could increase Zyprexa growth by hammering home astronomical efficacy of Zyprexa and continue on the path they have created.
Another failure to add to what has been annotated so far was when Eli Lilly hired an organization called Lifespan Marketing, who colluded with Eli Lilly to create a brand new market establishing Zyprexa as the standard of care. Maybe Eli Lilly needs to adopt a standard of care for themselves.
At least one human insider within Eli Lilly wanted to let everyone know he did not, nor will he ever forget his experience as a Zyprexa representative with Eli Lilly for years. His name is Shahram Ahari and he aligned with a non-profit advocacy group called Pharmedout after this experience, which was created due to a state settlement from another pharmaceutical company's wrongdoing. Sharam spends his days now making others aware of things such as what you have read so far. I’ve spoken with Shahram, and I admire his assistance with others trying to correct this medical mess. He sacrificed much, and continues to do so.
Eli Lilly appears pathologically persistent in frightening ways: next was a national implementation plan of action which focused on training the Zyprexa sales force to use what was called a J.C.P. study to emphasize the numerous off label benefits of Zyprexa. At the same time, Eli Lilly determined that primary care doctors should be their number one Zyprexa targets for increasing the growth of their drug. With this new focus, the sales force for Zyprexa were somehow convinced to tell doctors that fatigue is really the only side effect that presents itself with Zyprexa use by their patients, which of course is false. Again, citizens are overall not catatonic about such actions if they are aware of them with understanding.
While on this off label role with Zyprexa combined with being void of fair balance regarding presenting this drug to others, Eli Lilly attempted to revive their long term care efforts by taking on Aricept, and Alzheimer’s drug, and encouraged others to switch to Zyprexa. The reaction for this misbehavior was Zyprexa being removed from Medicaid in 2004, according to documents that are authentic, and are available to others.
Allan Reier was the Zyprexa product team leader at this time. He may have developed the unbelievable strategy of visiting psychiatrists to assure them they will not be sued if they prescribe Zyprexa for their patients. Literature and documents prove this strategy was implemented.
So, now we are at a point where Eli Lilly had a flash of reality and preferred no media contact. Gosh, what a surprise. There was also the disclosure of Eli Lilly creating if not funding deceptive front groups to screen others in order to sell more Zyprexa as well- combined with previous efforts regarding such hired groups by this corporation.
The next tactical plan from Eli Lilly was to re-implement blunting techniques regarding Zyprexa. My guess is that they dragged this into a week- long meeting with their sales force. This of course included dodging concerns by doctors that they are normally encouraged to partner with, historically. Such tactical plans of action were associated with such clever names as, ‘Viva Zyprexa’, or Zyprexa Limitless”. Maybe the next one will be ‘Zyprexa Revenue Regression’. Zyprexa for atrophy, maybe?
Another tactic authorized by Eli Lilly was to use those bonafide contract research organizations (CROs) to manufacture safety, health, and outcomes database studies. A deceptive publication plan followed.
CROs are commercial research organizations that include often what may be substandard research investigators to work with the sponsor of such clinical trials. Eli Lilly, as a sponsor, has the ability to alter aspects of such trials for their own benefit. This was done- as they still encouraged as a result children to consume Zyprexa- near a million of them due to an arrangement that Zyprexa will be promoted by the ADD drug Strattera.
As stated earlier, previously sealed and damaging documents got exposed at the end of 2006, and are accessible on the internet and some websites, such as, which is what this article is based upon, overall.
Perhaps the documents should have been exposed immediately instead of being held from public view. Perhaps prosecutors should not keep such information from others due to a collusive relationship with such corporations. One may only speculate as to why this occurs.
Eli Lilly makes over 4 billion dollars a year on Zyprexa, and has made close to 40 billion dollars on their drug so far.

Eli Lilly has had to pay well over a billion dollars for Zyprexa damage to others between 2006 and 2007. The company recently paid the largest one-time payment to settle accusations of their wrongdoing related to Zyprexa. I'm sad to say I'm unconvinced this will change their behavior regarding their tactics. Cynical, perhaps I am. History proves this is often the case.
“Character is what a man is in the dark” --- Dwight Moody
Dan Abshear
Author’s note: What has been written is based upon information and belief.