NY Times Article comparing Antipsychotics

[Anasazi23]

New York Times; September 20, 2005
Little Difference Found in Schizophrenia Drugs
By BENEDICT CAREY
A landmark government-financed study that compared drugs used to treat schizophrenia has confirmed what many psychiatrists long suspected: newer drugs that are highly promoted and widely prescribed offer few - if any - benefits over older medicines that sell for a fraction of the cost.

The study, which looked at four new-generation drugs, called atypical antipsychotics, and one older drug, found that all five blunted the symptoms of schizophrenia, a disabling disorder that affects three million Americans. But almost three-quarters of the patients who participated stopped taking the drugs they were on because of discomfort or specific side effects.

One of the newer drugs, Zyprexa, from Eli Lilly, helped more patients control symptoms for significantly longer than the other drugs. But Zyprexa also had a higher risk of serious side effects - like weight gain - that increase the risk of diabetes.

The study, released yesterday and to be published Thursday in The New England Journal of Medicine, was widely anticipated because it is by far the largest, most rigorous head-to-head trial of the newer antipsychotics conducted without significant drug industry financing. The new drugs account for $10 billion in annual sales and 90 percent of the national market for antipsychotics.

The findings may not significantly alter the prescribing patterns of doctors in private practice, who often do not have to worry about cost, psychiatrists said. But they are likely to have an enormous effect on state Medicaid programs, many short on funds in part because of the high cost of schizophrenia drugs.

Several states, including Kentucky, West Virginia and Maine, have limited access to newer drugs, which cost 3 times to 10 times more than the older drugs. "The new study presents an opportunity but also a risk," said John Goodman, president of the National Center for Policy Analysis, a policy research group based in Dallas, which estimates that Medicaid programs spend at least $3 billion a year on antipsychotics, more than for any other drug class.

"The opportunity is to lower the cost of these drugs," Dr. Goodman said. "The risk is that state Medicaid programs use this excuse to entirely deny some patients access to more effective and more expensive drugs which work for those patients."

The government study set out to judge each drug by how long patients and their doctors continued the therapy, a criterion rarely used in studies by drug makers but crucial in real-world practice. People with schizophrenia struggle with delusional thoughts, private voices, blunted emotions and other symptoms, and most try multiple drugs in trying to avoid severe side effects.

The researchers, led by psychiatrist Dr. Jeffrey Lieberman, then at the University of North Carolina and now at Columbia University, recruited 1,493 people with the disorder and assigned them to receive one of five drugs: Risperdal, from Johnson & Johnson; Seroquel from AstraZeneca; Geodon from Pfizer; Zyprexa; and an older drug,perphenazine.

After 18 months, the researchers found, 64 percent of the patients taking Zyprexa had stopped, and at least 74 percent had quit each of the other medications. The most common reasons were that the drug was not effective, the patient could not tolerate taking it, side effects like sleepiness and weight gain or neurological symptoms like stiffness or tremors.

Doctors' concerns about neurological side effects in particular have sped the switch to newer schizophrenia drugs over the last decade. Studies have shown that these medications carry a lower risk than the older drugs of tardive dyskinesia, a disorder that causes tics, lip-smacking and other involuntary movements.

But the study found that at more modest doses, the older drug, perphenazine, while just as effective, was not significantly more likely to cause neurological symptoms. Dr. Lieberman said that there was no reason to believe that modest doses of other older drugs, like Haldol, would perform differently.

The patients on Zyprexa were less likely to be hospitalized because their condition worsened than those taking the other drugs, the study found. But these patients also gained the most weight, adding an average of two pounds a month while on the drug, and their lipid levels increased more than those of people on the other drugs. Weight gain and elevated lipids are risk factors for diabetes.

In the doses used in the study, a month's supply of perphenazine costs about $60, compared with $520 for Zyprexa, $450 for Seroquel, $250 for Risperdal and $290 for Geodon, according to Drugstore.com.

"Probably the biggest surprise of all was that the older medication produced about as good an effect as the newer medications, three of them anyway, and did not produce neurological side effects at greater rates than any of the other drugs," said Dr. Lieberman in an interview.

Dr. Robert Baker, who directs the neuroscience group at Eli Lilly, said that he was pleased with the findings. He said the weight gain and other side effects of Zyprexa were "very consistent with what we've seen in our studies" and that the company tells doctors about these symptoms.

"I think what we can conclude from this study is that there is no one-size-fits-all treatment for schizophrenia," Dr. Baker said.

Spokesmen for Johnson & Johnson and AstraZeneca said that the study supported their drugs and the importance of tailoring treatment to individual patients. "The efficacy results for Risperdal did not demonstrate the full efficacy of Risperdal because many patients in the trial received doses that were too low," Dr. Ramy Mahmoud, of Janssen Pharmaceutica, the unit of Johnson & Johnson that makes Risperdal, said in an e-mail message.

One thing that all agreed on was that the current state of schizophrenia treatment leaves a lot to be desired, and that the field longs for new and different drugs.

"The message is the glass is half full," Dr. Lieberman said. "The drugs work but they are not satisfactory to many patients, and three-quarters of the people in our study voted with their feet and discontinued the drugs."

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[gilgul]

I'll second this, Anasazi.

I presented this to various attendings and residents in during my Psychiatry Sub-Internship, and they all agreed. Sure, they said. What else is new? The major concern for most prescribers was that if you get a new patient with schizophrenia or associated long term diseases, if you start with a typical antipsychotic, you are running a long term risk of Tardive Dyskinesia or other dystonias, which further identify and stigmatize long term psychiatric patients. Once they appear, these adverse effects are 75% irreversible upon discontinuation of the drug. Moreover, the typical antipsychotics are generally interchangeable, and if one does not work, they all probably will not work.

Long term effects of atypical antipsychotics are significant, too, though. Zyprexa, Seroquel, Risperdal, Clozaril, and Geodon all have some extrapyramidal side effects, as well as significant glucose intolerance/weight gain/carbohydrate craving effects. Abilify is an unknown quantity in the general prescribing population. The consensus is that it is somewhat activating, so it is good for those patients with psychosis and depressed mood. However, as the article indicates, the financial side effects are quite significant, especially for self-pay or restrictive private health insurances. Also, most antipsychotics have significant subjective effects ranging from grogginess, unclear thinking, difficulty making decisions, difficulty expressing oneself, emotional numbness, etc. that contribute to the noncompliance. Of course in many cases antipsychotics are victims of their own success, as patients believe they are "cured" when the antipsychotic has been working for a few weeks and months, and consequently stop taking the medications.

Altogether I have found the noncompliance rate to be quite a significant factor, especially in rehospitalizations of patients with chronic psychotic diseases. It seems to me that many psychiatrists use a "fire and forget" mentality with these patients, prescribing antipsychotics and then not engaging them in psychotherapy, or unaware of what supportive psychotherapy *really* is, for I have found anxiety to be a major feature of almost all psychiatric patients, and it really must be addressed first before psychoeducation or indeed sometimes even basic conversation can be begun. Most psychotic patients respond much better to true support and building of the patients ego functions, rather than the typical adversarial, condescending, interrogational relationship that I have observed. I believe that a solid rapport with the patient's psychiatrist, as well as regular office visits, would contribute greatly to the reduction of noncompliance among patients with chronic psychotic disorders.

 

[Thewonderer]

Agree with the opinions set forth by the other posters here. This is a true landmark study! A couple comments:

1) Tardive Dyskinesia is a very disturbing side effects. Can you imagine someone started on atypical antipsychotics by the age of 16 years old and develope TD by the age of 25 and have to live with that for the rest of their lives? I read the originial article in NEJM and the whole article totally downplays the importance of TD as side effect. That is probably all due to politics. I mean, recently, the whole metabolic side effects of antipsychotics are the main foucs and will get you grant money. So there is all these hypes (not that they are not important but you cannot simply move onto these newer, sexier side effects, i.e. metabolic syndromes, and forget about the older, forgotten side effects, i.e. TD). This is totally irresponsible.

2) "significant subjective effects ranging from grogginess, unclear thinking, difficulty making decisions, difficulty expressing oneself, emotional numbness, etc. that contribute to the noncompliance."

if you read those lines carefully again, they actually fit the textbook description of the negative symptoms of schizophrenia!!! Nowadays, I am not so certain if all these are the side effects of the medications and not due to the negative symptoms. The only way to find out is, increase the antipsychotic dose and see if those sx's get worse (i.e. side effects of medication) or getting better (i.e. due to schizophrenia).

3) noncompliance rate. We should not be surprised. This is inherent in the field of medicine as a whole. After all, many and I can bet, more than half, of all the cognitively intact patients still refuse to take their antihypertensives and diabetic medicatiosn consistently on an everyday basis. How can we expect schizophrenic patients with all the cognitive impairment to do so consistently? Doctors cannot do it all. We need better and more social workers and case managers even in the outpt setting.

 

[MJD503]

gilgul --- well said! you can come work with me anytime! i'm going to copy your post and save it, maybe pass out a couple select sentences to a few people at work.

meds,meds, meds is what is preached at the state psychiatric facility I work in. Intolerance, condesension and condemnation are a real close second. Our patients are NOT expected to have ego's and should they come in with one, it is gone pretty quickly.

that said, our doctors are overworked and have little time to do more than prescribe meds and attends to crisis'. with 30 chronic patients, it seems that way, from my outside view. it's no wonder patients symptoms often get worse while in the hospital, more chronic and they are often admitted once or twice a year. I used to have dreams of working as a psychiatrist and still do somewhat but working in direct care with the population has made me extremely dissatisfied with the system. The patients, with all their quirks, anxiety and even violence, are not the reason for my burn out rather the system and how it treats these people is the main reason.

back on topic, i took risperidal (2mg so a small dosage) for three years between the ages of 15-18 for a actue psychotic episode resulting from long term untreated severe depression. i gained at least 30 pounds and have been unable to loose but a small portion of it.

i thank god and my psychiatrists with my heart everyday for putting me on the drug and that it actually was effective because it worked wonders and i often doubt i would be alive to tell about it without compassionate care, and to a lesser extent the medication! the only major side effect(dry mouth, constipation or similar do not constitute a major SE to me) that i had was weight gain and light muscle twitching. the latter has been gone since i stopped the drug.