Researchers Struggle as Placebos Becoming More Effective & Antipsychotics Losing Power


Since the 1960s, the positive response rates to antipsychotic medications have been dropping steadily, according to a meta-analysis published in JAMA Psychiatry by Columbia University and New York State Psychiatric Institute researchers. At the same time, the positive response rates to placebos have been increasing, and antipsychotic medications are therefore appearing less effective in comparison. This situation necessitates re-thinking how clinical trials are done, wrote the researchers, in order to overcome this appearance of ineffectiveness of antipsychotics.

In their study, the researchers wrote that slim drug-placebo differences in drug trials have been increasing the numbers of “failed antipsychotic trials,” which in turn have been increasing “the cost of drug development” and also causing some pharmaceutical companies to reduce their psychiatric research. “Thus, it is imperative to determine what is causing these increased placebo response rates in antipsychotic trials.”

The researchers examined randomized controlled trials (RCT) published between 1960 and July 2013 that compared antipsychotics to placebos or to other comparable medications in adults with schizophrenia or schizoaffective disorder, and that lasted between 4 and 24 weeks.

“(T)he placebo response was shown to be significantly increasing from 1960 to the present,” they wrote. They found that the average placebo-treated patient in an RCT of antipsychotic drugs during the 1960s worsened by 3.5 Brief Psychiatric Rating Scale (BPRS) points. Yet in the 2000s, the average placebo-treated patient improved by 3.2 BPRS points.

Over the same time span, antipsychotic effectiveness dropped significantly. “The average RCT participant receiving an effective dose of medication in the 1960s improved by 13.8 BPRS points, whereas this difference diminished to 9.7 BPRS points by the 2000s.”

“The consequence of these divergent trends,” the researchers noted, “was a significant decrease in drug-placebo differences from 1960 to the present.”

The researchers found that one factor accounting for this trend seemed to be that people with less severe symptoms — who also responded less well to treatment — were being enrolled in clinical trials in more recent years. They also found that when patients and physicians both knew that patients had higher odds of receiving a drug instead of a placebo in drug comparison trials, response rates improved across the board, possibly due to either heightened patient expectation or clinician “rater bias” or both. In addition, they found that the longer clinical trials lasted, the less effective antipsychotics appeared.

In their conclusion, the researchers suggested that efforts could be made to improve “signal detection,” or the appearance of drug effectiveness. Among such advisable changes, they suggested, “would be to recruit more severely ill patients” and “limit study duration to no longer than 8 to 12 weeks.”

The researchers also concluded that clinical trial designs should “dispense with single-blind placebo lead-in periods.” The study did not go into detail on alternative trial designs; however, a 2012 webinar by UNC at Chapel Hill biostatistician Anastasia Ivanova made the same argument. Discussing many of the same antipsychotic drug trials as were later identified in the JAMA Psychiatry study, Ivanova explained that, “The fact that an increasing number of medications are unable to beat sugar pills has thrown the industry into crisis. The placebo effect has become the elephant in the boardroom.” Ivanova then described in detail how the single-blind placebo lead-in design was an effort to remove people who responded to placebos from clinical trials that did not succeed, and should be replaced by a multi-stage trial design that was much more effective at strategically eliminating people who responded to placebos.

(Abstract) Placebo Response in Antipsychotic Clinical Trials (Rutherford, Bret R. et al. JAMA Psychiatry. Published online October 08, 2014. doi:10.1001/jamapsychiatry.2014.1319)

Changing placebo response dilutes antipsychotic trial power (medwire News, October 16, 2014)

Comparing Strategies for Trials with High Placebo Response (Ivanova, Anastasia. ASA Biopharm Section Webinars Archive. August 27, 2012.)


  1. Researchers want to rethink or revise the clinical trials to “overcome the APPEARANCE of ineffectiveness of antipsychotics”?? How about just stating, hey, these neurotoxic poisons that kill you 25 years earlier and shrink your brain do not work!! You are better to chow down on sugar pills which won’t give you TD or super sensitivity psychosis!!

    But instead, they are going to manipulate the trials to get a positive outcome favoring these drugs??

    Weren’t neuroleptics originally created as pesticides used to kill parasites in pigs? Did I read that somewhere or am I confused??

    All these studies keep surfacing: the drugs do not work; the drugs create the illnesses and symptoms they are supposed to “treat”; the drugs are toxic to brain and body.

    So, why are “doctors” still prescribing poisons? To create perpetual patients whose mental and physical health declines as they “need” more drugs.

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    • To my knowledge Neuroleptics were accidentally found.
      They had bizarre treatments for M.I. in the past.
      One was immersion in cold water. They did not want the victim to shiver. The alienist/psychiatrist were told of this new poison that stopped shivering. The patients did not shiver when given the poison.
      Then they decided the patient did not need the cold water treatment, the patients symptoms (bad behaviour) have gone away ( the patients brain was no longer functioning).

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  2. I also find it strange that the ineffectiveness of medications relative to placebo is seen as a problem that must be solved by means of ever-more-clever experimental design, rather than as a finding that should be understood in its own right.

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  3. Since human biology has not changed over this timespan the actual effectiveness of placebo and neuroleptics have not changed either. Only the clinical perceptions have changed. The wishful thinking in the earlier years of the efficacy of neuroleptics has been tempered by the increasing scepticism of researchers doing these studies producing more candid and honest results than in the past.

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  4. Here they go – I sniffed it out already when all these papers on placebo response (and how to “eliminate bias”) started coming out. Here goes your evidence based medicine when you don’t like what the evidence tells you.

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  5. Since the 1960s…Think hard, neuroleptics have only been around on the psych ward since the mid 1950s. That’s 5 or 10 years versus the 50 or 60 some years that “the placebo effect” has strengthened so significantly in. The response rate to neuroleptics has been dropping steadily. Yeah, probably with the increased usage of neuroleptics.

    Look at the silver lining, all you researchers out there. All these years of drug research and development have produced a stronger placebo. If only you could market it.

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  6. It is likely that the increased placebo effect has resulted from increased social expectation that drugs will be effective against “mental health problems,” which is exactly what we should expect to happen. I guess it’s the downside of the impressive (if almost completely dishonest) marketing effort that’s pushed these drugs to the top of the sales charts. But I’m with AxqYi – any real scientist would see this trend as a result. And I also agree with Frank (as I usually do) – the decreasing impact of neuroleptics probably is a result of exactly what Bob is outlining in his book – more people have used them for longer periods of time, so they become less effective.

    The recommendation to shorten trial times in order to eliminate placebo effects is particularly troubling to me. These people are not scientists!!!!

    —- Steve

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    • Hi Steve,

      I certainly agree with you that these are not scientists looking for the truth, but instead technicians aiming at making drugs look good so they can be marketed, who are simulating science for that purpose! There should be a name for someone in a career like that – not a very nice name…..

      People are being told to stay on hazardous drugs for life when it is difficult to show that those drugs are better than placebo in getting their intended result for more than a few months – the concern should be about the welfare of the recipients of the drugs, not about trying to create a “successful outcome” for the drug in the study……

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  7. Agreed, Steve

    they make it so simple – if you don’t like the results, change the parameters so you get the results you desire.

    I’m sure they could get positive therapeutic results for a whole range of DSM diseases with heroin, cocaine, marijuana, ice and ecstasy in RCTs if they selected their cohort, limited trial duration and managed dosages. And they possibly wouldn’t have the problem of high drop out rates to contend with either.

    Not science, but then…….neither is psychiatry.

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  8. Surely improvement on a placebo is an emotional response, and therefore the fact that placebos tend to illicit improvement is further indication that these ‘disorders’ are an emotional issue. Of course if you give the sufferer something that makes them devoid of all emotion you may see an initial improvement. But it can’t last, because the cause remains un-addressed, and you have now added a host of adverse effects to compound the original issue.

    ‘The results aren’t saying what we want them to say – we need to change how we get the results.’

    ‘We aren’t getting enough people diagnosed – we need to broaden the diagnostic criteria.’

    ‘Some of our diagnoses are being challenged – we need to make up some new ones.’

    ‘Too many people don’t fit neatly into any particular diagnostic criteria – just label them with something and add NOS’

    ‘The drugs don’t work but we mustn’t admit it – call the patient ‘treatment resistant’.’

    ‘The drugs’ effects are intolerable but we mustn’t admit it – call the patient ‘non-compliant’.’

    The name Ron is looking for is possibly ‘Lying Bastards.’

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