I recently read The NIMH-CATIE Schizophrenia Study: What Did We Learn? by Jeffrey Lieberman, MD, and T. Scott Stroup, MD, MPH. The article was published in the American Journal of Psychiatry 168:8, August 2011.
Here are two quotes:
“When the CATIE study was designed in 1999-2000, the prevailing opinion of researchers and clinicians alike was that the newer (second-generation) antipsychotic drugs were vastly superior to the older (first-generation) antipsychotic drugs in efficacy and safety. This largely reflected the results of studies sponsored by the manufacturers of the new drugs…, marketing messages of pharmaceutical companies and the hopes of many who wanted better treatments.”
“CATIE helped to demonstrate that, although the introduction of second-generation antipsychotic drugs brought new options for treatment of psychosis, the major advance many had hoped for remains elusive.”
Let’s take a look at the first passage. Essentially what’s being said is that by about the year 2000, psychiatric researchers and practitioners believed that the second-generation neuroleptics were vastly superior to the older drugs in effectiveness and safety.
The CATIE study debunked these beliefs, as is acknowledged clearly in the second quote.
EFFECTIVENESS AND SAFETY
Here is a list of the second-generation neuroleptics introduced prior to the year 2000 with the main adverse effects associated with the use of each drug as listed in the 2001 PDR.
- Clozapine, Clozaril (1989). Adverse effects: agranulocytosis (black box); seizures (black box); orthostatic hypotension (black box); neuroleptic malignant syndrome; tardive dyskinesia; akathisia, etc…
- Risperidone, Risperdol (1994). Adverse effects: extrapyramidal disorders; akathisia; aggressive reaction; joint pain; weight gain, etc…
- Olanzapine, Zyprexa (1996). Adverse effects: neuroleptic malignant syndrome; tardive dyskinesia; akathisia; weight gain; postural hypotension; joint pain; extremity pain, etc…
- Quetiapine, Seroquel (1997). Adverse effects: neuroleptic malignant syndrome; tardive dyskinesia; orthostatic hypotension; seizures; hypothyroidism; cholesterol and triglyceride elevations; etc…
Each entry in the PDR is a verbatim copy of the manufacturer’s FDA-approved labeling information and is updated annually. It is clear, from the adverse effects listed with each of these products, that the respective manufacturer acknowledged clearly that there was a real danger of serious and potentially irreversible adverse effects.
With the exception of clozapine, the manufacturers also acknowledged that their efficacy data was based on very short-term trials.
- risperidone 3 weeks
- olanzapine 6 weeks
- quetiapine 6 weeks
The entry for olanzapine (Zyprexa) stated explicitly:
“The efficacy of ZYPREXA was established in short-term (6-week) controlled trials of schizophrenic inpatients…
The effectiveness of ZYPREXA in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use ZYPREZA for extended periods should periodically re-evaluate the long-term usefulness of the drug for this individual patient… [emphasis added]
ZYPREXA is indicated for the short-term treatment of acute manic episodes associated with Bipolar I Disorder.
The efficacy of ZYPREXA was established in two placebo –controlled trials (one 3-week and one 4-week), with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or, without psychotic features…
The effectiveness of ZYPREXA for longer-term use, that is, for more than 4 weeks treatment of an acute episode, and for prophylactic use in mania, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use ZYPREXA for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient…” [emphasis added]
Against this background, it’s difficult to afford much credence to the assertion of Drs. Lieberman and Stroup that the responsibility for psychiatrists’ false beliefs that these products were vastly superior to the old drugs in efficacy and safety can be laid at the feet of pharma.
It is noteworthy that Drs. Lieberman and Stroup mention not only industry sponsored studies, but also pharma’s “marketing messages.” [emphasis added]
This strikes me as an extraordinary admission. America is the birthplace of aggressive marketing, and we all know how successful it can be in the selling of cars, vacuum cleaners, etc… But for a group of people, who routinely claim that they are a bona fide medical profession, to admit that they were duped by tawdry marketing ploys raises serious concerns about their credibility and competence.
Drs. Lieberman and Stroup are defending psychiatry’s overly zealous adoption of the newer drugs by blaming the pharmaceutical companies’ misleading research and commercials. But the much more fundamental issue is: why did psychiatrists believe these messages despite the fact that the PDR entries for the drugs in question provided abundant justification for caution and restraint?
It’s difficult to avoid the suspicion that the various largesse showered on psychiatry by the pharma industry might have played some part.
It’s also clear that psychiatrists’ love affair with these drugs and their vulnerability to pharma marketing continue to this day.
In the third quarter of 2013, the second-generation neuroleptic Abilify (aripiprazole), with over $1.5 billion in sales, was not only the best selling neuroleptic drug in the US, it was the highest grossing of all prescription drugs. It was also the most heavily promoted neuroleptic in 2011 (the last year for which I can find data), and accounted for 38% of neuroleptic promotional spending.
However, there is nothing in the current PDR entry, which is available online, to suggest that it is any safer than the other products. All the usual second-generation neuroleptic adverse effects are listed, including tardive dyskinesia, akathisia, weight gain, metabolic problems, neuroleptic malignant syndrome, etc… There are also two black box warnings: increased mortality in dementia-related psychosis; and increased suicide risk in children and young adults.
In addition, efficacy studies were limited to 6 weeks.
So in 2011, we had Drs. Lieberman and Stroup blaming pharma advertizing for psychiatry’s misplaced enthusiasm for the newer neuroleptics, while side-stepping the obvious corollary: that psychiatrists were taken in by these promotions. Now, two years later, the problem is still with us. Psychiatrists apparently are still responding positively to the marketing messages; and neuroleptic drugs, which in former times were barely a blip on the sales charts, are now acquiring blockbuster status.