The Emperor’s Antipsychotic Drugs

Sandra Steingard, MD

I avoid drug reps but I can not stop them from finding me through the mail. Over the past few months, I have received reprints of an article from The American Journal of Psychiatry (1), reporting on a randomized, double-blind, placebo-controlled study of lurasidone from the company that makes this drug.  Since I had it in my hands, I read it. What I found was surprising. Rather than leaving me impressed by lurasidone, it left me wondering what happened with olanzapine (Zyprexa).

In this study, two doses of lurasidone were compared to 15 mg of olanzapine, a widely used antipsychotic, and placebo. The researchers summarized their findings as follows, “Lurasidone was an effective treatment for patients with acute schizophrenia.”

This study followed a typical design of a modern, good quality drug study: it was large – over one hundred people in each group – and it was conducted at multiple centers.  The use of two lurasidone doses allowed the researchers to gather more information about effective dosing.  The use of placebo allowed them to demonstrate that the drug was more effective than an inactive substance. They used olanzapine for “assay sensitivity”;  they wanted to demonstrate that a drug that is known to be effective actually worked in this particular study.  The primary measure of efficacy was change in the PANSS (positive and negative symptom scale) from the start of the study to the 6 week end-point.  This is a scale that has 30 questions about various symptoms of schizophrenia and each question can be rated on a 1-7 point scale.

On the PANSS, the lurasidone 40 mg group improved by 25.7 points, 120 mg by 23.6 points, olanzapine by 28.7 points, and placebo by 16 points.  These difference were statistically significant but I am not sure they are clinically meaningful. The overall difference between the olanzapine group and the placebo group was less than 13 points on a scale on which one can score anywhere from 30 to 210 points.  On the secondary measure, the CGI (Clinical Global Impression) a 7 point scale, the difference was less than half a point.  This is a simple scale that is intended to give a general sense of overall change and although that difference was statistically significant, it is, once again, a change that might not have much impact.

This is an important distinction. With large enough numbers, small differences that are not due to chance can be detected but the difference may not have much salience  from the point of view of the person who is taking the drug.

Irving Kirsch (2) has pointed out that a failing of many modern drug studies in the lack of inclusion of an active placebo.  Studies are designed to be double blind, i.e., neither the person taking the drug nor the person doing the assessments knows who is on active drug and who is on placebo but Kirsch points out that in many studies there is a high likelihood that both subjects and researchers have a guess about who is on what because of the side effects that are both observed and experienced.  These guesses have an impact on outcome.  He argues that we need studies that have an active placebo, i.e., a compound that is not thought to be effective for the symptoms being studied but produces side effects.  Since sedation was a common side effect in this study, a good comparator would be a sedating drug, such as an antihistamine. We often give them to people to help improve sleep. There is some thought among the researchers who worked at Soteria House and with Open Dialogue, that regulating sleep in someone who is psychotic can be enormously helpful.  It would be informative to include the antihistamine, hydroxyzine, for example, as an arm in one of these 6 week antipsychotic drug studies.

I have read a number of reviews of lurasidone (3,4 ) and some of the other newer antipsychotics and there seems to be an under enthusiasm for these drugs. Many of the so-called second generation antipsychotics that came into the market in the past 20 years are off or soon to be off patent so the drug companies will be trying hard to push these newer, more expensive drugs but, at least where I work, I do not see large numbers of psychiatrists flocking to use them.  However, it seems to me that the headline of this study is why olanzapine was not more effective. I would like to see studies that assess the effectiveness of the antipsychotics using active placebos so we can understand and learn more about who can recover without them.

1. Meltzer, HY et al. “Lurasidone in the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo- and Olanzapine- Controlled Study” American Journal of Psychiatry 2011; 168: 957-967.

2. Kirsch, I “The Emperor’s New Drugs” Basic Books,Philadelphia,PA, 2010.

3. Sewell, RA  “Latuda: ‘Procognitive’ or Pro-Profint?”  The Carlat Report Psychiatry 2011; 9 (6) 1-3.

4. “Lurasidone (Latuda)” Biological Therapies inn Psychiatry 2011; 34 (2) 1-2.


  1. Interesting article. It doesn’t seem unlikely that what is driving a lot of the med development and marketing is just money rather than an interest in patient outcomes. For instance, in a recent trial the psychiatrist on the other side testified that in his opinion, although it supposedly has some advantages in bioavailability, Invega is being pushed not for any clinical benefits but primarily because it sells for a lot higher price than Risperidone.

  2. The patients have a disease right? A broken watch is correct twice a day. A person who was once psychotic is always psychotic? Like a broken leg is a broken leg forever?
    How do you know if the patient is still psychotic/still has a broken leg?
    People are constantly changing like the numbers change on a watch.
    Withdrawal from the drugs look like “psychosis”, the patient still has a broken leg.

  3. WOW. Kate Higgins, that’s one of the best, if scathing, denouncements of the LIE of biological psychiatry. I have been drug & shrink free for well over 15 years. Overall, I’m more whole, healthy, and happy than ever! Gee, “doc”, what happened to my “mental illness”, that I would need “drugs” the rest of my life for???…

  4. Why is it that shock doctors owning the companies making ECT machines and calling all the shots about ECT have done all in their power to prevent their machines and practices to be tested by fighting the FDA considering such testing? Reason is that a shock doctor did a study in 2007 proving that ECT does cause brain damage, short term and permanent memory loss, dementia and destroyed lives like the worst psych drugs. So, why are you promoting this deadly ECT treatment while accusing equally deadly drug pushers of being unethical while you hide your own pet barbaric practice you promote with Dr. Healy?