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50-year Old Schizophrenia Drug as Good as Newer Drugs

Comparison of the effects of 5 medications for schizophrenia:

1)  High rate of discontinuation because of side effects and failure to control symptoms

2)  Olanzapine was SLIGHTLY better as per duration of saying on the medication and incidence of hospitalization, but was associated with substantial weight gain and metabolic changes.

3)  Perphenazine, in use since the 50s, performed as well as the newer medications, and it sells for a fraction of their costs.

4)  The effect upon movement (Thorazine shuffle) occurred at about the same rate for all medications (this effect is a selling hype for the new generation of drugs)


Conditions:  1,400 participants at 57 sites around the country, duration 18 months, 5 medications compared.  Almost 3/4th of the patients switched

from the first medication to one of the others.






NIMH Study To Guide Treatment Choices for Schizophrenia

A large study funded by NIH's National Institute of Mental Health (NIMH) provides, for the first time, detailed information comparing the effectiveness and side effects of five medications — both new and older medications — that are currently used to treat people with schizophrenia. Overall, the medications were comparably effective but were associated with high rates of discontinuation due to intolerable side effects or failure to adequately control symptoms. One new medication, olanzapine, was slightly better than the other drugs but also was associated with significant weight-gain and metabolic changes. Surprisingly, the older, less expensive medication used in the study generally performed as well as the newer medications. The study, which included more than 1,400 people, supplies important new information that will help doctors and patients choose the most appropriate medication according to the patients' individual needs. The study results are published in the September 22 issue of the New England Journal of Medicine.  "The study has vital public health implications because it provides doctors and patients with much-needed information comparing medication treatment options," said NIMH Director Thomas R. Insel, M.D. "It is the largest, longest, and most comprehensive independent trial ever done to examine existing therapies for this disease."


Schizophrenia, which affects 3.2 million Americans, is a chronic, recurrent mental illness, characterized by hallucinations, delusions, and disordered thinking. The medications used to treat the disorder are called antipsychotics. Previous studies have demonstrated that taking antipsychotic medication is far more effective than taking no medicine, and that taking it consistently is essential to the long-term treatment of this severe, disabling disorder. Although the medications alone are not sufficient to cure the disease, they are necessary to manage it.


In the $42.6 million CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial [$30,400/patient], researchers directly compared an older medication (perphenazine), available since the 1950s, to four newer medications (olanzapine, quetiapine, risperidone, and ziprasidone), introduced in the 1990s. The purpose of the study was to learn whether there are differences among the newer medications and whether the newer medications hold significant advantages over the older medications; these newer medications known as atypical antipsychotics, cost roughly 10 times as much as the older medications.


The size and scope of the trial, with more than 1,400 participants at 57 sites around the country, its 18-month duration, and its inclusion of a wide range of patients in a variety of treatment settings ensure that the findings are reliable and relevant to the 3.2 million Americans suffering from schizophrenia.


At the beginning of the study, patients were randomly assigned to receive one of the five medications. Almost three quarters of patients switched from their first medication to a different medication. The patients started on olanzapine were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer than patients taking other medications. However, patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those study participants taking the other drugs.


Contrary to expectations, movement side effects (rigidity, stiff movements, tremor, and muscle restlessness) primarily associated with the older medications, were not seen more frequently with perphenazine (the drug used to represent the class of older medications) than with the newer drugs. The older medication was as well tolerated as the newer drugs and was equally effective as three of the newer medications. The advantages of olanzapine — in symptom reduction and duration of treatment — over the older medication were modest and must be weighed against the increased side effects of olanzapine.


Thus, taken as a whole, the newer medications have no substantial advantage over the older medication used in this study. An important issue still to be considered is individual differences in patient response to these drugs.

Several factors, such as adequacy of symptom relief, tolerability of side effects, and treatment cost influence a person's willingness and ability to stay on medication.  "There is considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another," said Jeffrey Lieberman, M.D., CATIE's Principal Investigator and Chair of The Department of Psychiatry, Columbia University and Director of the New York State Psychiatric Institute.


The CATIE study was led by Lieberman, and co-Principal Investigators Scott Stroup, M.D. (University of North Carolina at Chapel Hill), and Joseph McEvoy, M.D. (Duke University). CATIE was carried out by researchers at 57 sites across the country, including private and public mental health clinics, Veteran's Health Administration Medical Centers, and University Medical Centers, where people with schizophrenia received their usual care.

This New England Journal of Medicine article is the first to report outcomes from the CATIE schizophrenia trial, and addresses many of the primary questions from the study. Future reports will address a multitude of topics (e.g., cost-effectiveness of the medications, quality of life, predictors of response) and will provide a more detailed picture of the interaction between patient characteristics, medication, and outcomes. The information from the CATIE study will inform new approaches for improving outcomes in schizophrenia.


CATIE is part of an overall NIMH effort to conduct "practical" clinical trials that address public health issues important to those persons affected by major mental illnesses in real world settings.

For more information on CATIE, visit


The study results are published in the September 22 issue of the New England Journal of Medicine


Drug companies hype lower side effects for new drugs, but studies fail to support this in comparison with perphenazine


Psychopharmacology (Berl). 1994 Feb;114(1):24-30



A long-term cross-over pharmacokinetic study comparing perphenazine decanoate and haloperidol decanoate in schizophrenic patients.


Dencker SJ, Gios I, Martensson E, Norden T, Nyberg G, Persson R, Roman G, Stockman O, Svard KO.

Department of Clinical Neuroscience, University of Goteborg, Sweden.


The purpose of the study was to investigate clinical and pharmacokinetic parameters concerning perphenazine decanoate (PD) and haloperidol decanoate (HD) with an interval of 3 weeks during a study period of 51 weeks. This was done by using the available drug preparations in chronic schizophrenic patients in a randomised, double-blind, cross-over, multicentre study. In addition, an elimination phase of 6 weeks was added, when no IM injections of the depot drugs were given. Twenty-nine patients in a stable neuroleptic maintenance phase entered the study. The patients were rated during the trial according to the CPRS-SCHZ and CGI scales, the UKU side effect scale and serum concentrations of the drugs and prolactin were monitored. There was no significant difference between the drugs in antipsychotic efficacy or side effects. Thus, the doses were equipotent with regard to the CPRS-SCHZ scores. However, the patients' global improvement rating was higher for PD (52%) than for HD (39%) (P > 0.05). The elimination of both drugs was very slow. No interaction effects between PD and HD were observed. The serum levels of HD were in most patients lower than those recommended for acute-subacute treatment. The mean doses were 117 mg (0.29 mmol), range 20-313 mg PD and 120 mg (0.32 mmol), range 20-350 mg HD. The serum concentrations in nmol/L of perphenazine and haloperidol (week 24) were 0.8-15.9 and 2.3-46.7, respectively.


Study Finds No Best Schizophrenia Drug,  By LAURAN NEERGAARD, AP Medical Writer, 9/19/5
{selected portions of this article, which is based on the NIMH press release}

That one, Eli Lilly & Co.'s Zyprexa, worked slightly better but with a drawback: It was far more likely than leading competitors to cause severe weight gain, leading to high cholesterol, high blood sugar, even Type 2 diabetes. 

The findings are striking considering that perphenazine can cost no more than $50 a month compared with more than $600 for Zyprexa, depending on dose. Indeed, the nation will spend about $10 billion this year on those atypical antipsychotics, said Dr. Thomas Insel, director of the National Institute of Mental Health, which funded the research.
Zyprexa users gained an average of 2 pounds a month. 
Perphenazine, in contrast, didn't cause more of those anticipated movement troubles than the newer drugs — and the newer drugs overall had no substantial advantage, the study concludes