Posted on Thursday 29 August 2013

NIMH Director’s Blog
By Thomas Insel
August 28, 2013

One of the first lessons I received as a psychiatrist-in-training 35 years ago was the value of antipsychotic medications. These medicines have been available for the treatment of psychosis for over half a century, beginning with the prototype first generation drug chlorpromazine [Thorazine] and now extending to some 20 different compounds, including several second-generation medications, often called “atypical antipsychotics.” Symptoms such as hallucinations, delusions, and paranoia are reduced reliably by these drugs. Although these symptoms can be frightening and dangerous for patients, family members, and providers, antipsychotics safely and effectively help people through the crisis of acute psychosis.

However, the long-term management of chronic mental illness is another matter. Recently, results from several studies have suggested that these medications may be less effective for the outcomes that matter most to people with serious mental illness: a full return to well-being and a productive place in society.

That is not to say that people are not remitting or recovering from serious mental illness. An article recently posted online in JAMA-Psychiatry tells an interesting story about medications and recovery. Wunderink and colleagues from the Netherlands report on a seven-year follow-up of 103 people with schizophrenia and related disorders who had experienced a first episode of psychosis between 2001 and 2002. After six months of symptomatic remission following antipsychotic treatment, patients were randomly assigned to either maintenance antipsychotic treatment or a tapering-off and discontinuation of the drug. As expected, the group that stopped taking their medications experienced twice the relapse rates in the early phase of the follow-up. But these rates evened out after a few years, as some patients in the maintenance group also stopped taking their medication. Most important, by seven years, the discontinuation group had achieved twice the functional recovery rate: 40.4 percent vs. only 17.6 percent among the medication maintenance group. To be clear, this study started with patients in remission and only 17 of the 103 patients — 21 percent of the discontinuation group and 11 percent of the maintenance group — were off medication entirely during the last two years of follow-up. An equal number were taking very low doses of medication — meaning that roughly one-third of all study patients were eventually taking little or no medication.
Well what have we here? signs of a spiritual awakening? an alien inhabitation? Is the Jungian analysis mentioned in Insel’s Wikipedia bio finally working after all these years?
For me, there were three remarkable results in this study. First, the groups did not ultimately differ in their experience of symptoms: about two-thirds of each group reported significant improvement in symptoms at seven years. Second, 29 percent of the discontinuation group reported that they had also achieved a healthy outcome in work and family life — a number that should give hope to those struggling with serious mental illness. And finally, antipsychotic medication, which seemed so important in the early phase of psychosis, appeared to worsen prospects for recovery over the long-term. Or, as Patrick McGorry said in an accompanying editorial, “less is more.” At least for these patients, tapering off medication early seemed to be associated with better long-term outcomes.

What does this say about the long-term use of antipsychotics? Are they potentially harmful? Are they necessary for an individual’s entire lifetime? Earlier this year, Martin Harrow and Thomas Jobe reported an analysis of several long-term follow-up studies of people with schizophrenia to determine if antipsychotics, given long-term, facilitate a return to functional well-being. They describe the following pattern across these studies: [a] within the first 6-10 months after discontinuation, 25-55 percent of patients relapse; [b] for those who do not relapse during this period, subsequent relapses are much less frequent even after prolonged periods off medication…
Maybe even two alien visitations? one in Bethesda and another in Melbourne? "Or, as Patrick McGorry said in an accompanying editorial, ‘less is more.’"
These new data on the long-term outcomes for people with “schizophrenia” remind us that 100 years after defining this disorder and 50 years after “breakthrough” medications, we still have much to learn.
No, I don’t really think that either Tom Insel or Patrick McGorry met the Buddha on the road; nor are they likely inhabited by aliens. They’re rational doctors who want to help people, but both have been caught up in a climate that I hope is finally becoming amenable to change.

When Altostrata commented on this blog by Insel, he said, "And this surprise from Tom Insel." and it is a surprise. Some will be surprised that Insel’s so obviously impressed by these articles that implicitly recommend using antipsychotics for acute episodes of psychosis only, and not as maintenance treatment. I wasn’t so surprised by that. I don’t know many psychiatrists who still have the fantasy that the solution to schizophrenia is "keeping people on their meds." That’s more a fantasy in Mental Health Centers where people are frustrated by the chronically relapsing patients – called recidivism. Insel’s usual response to this kind of topic is different, that "we need better drugs." I was instead surprised that these articles caught his attention; that he didn’t say "we need better drugs;" and that he did say "… after ‘breakthrough’ medications, we still have much to learn."

Then I thought of Kopp’s book title "If you meet the Buddha on the Road, Kill Him". The title comes from a Koan attributed to Linji [the founder of the Rinzai sect of Zen] – mirroring the Taoist proverb, "The Tao that can be named is not the eternal Tao." Like many of the paradoxical sayings of Zen and the Taoists, I take it to mean that if you think you’ve found the answer, watch out! There are no the answers, and if you fall for that illusion, you’ll stop learning, stop listening, and get stuck in preaching the gospel of your new the answer.* That’s my complaint about the last thirty years of psychiatry. And that was also the complaint of the people who initiated the changes of the last thirty years in psychiatry.

The reformers of 1980, Mel Sabshin, Robert Spitzer, the Saint Louis group, etc. all felt that the psychoanalysts and other psychotherapists had over-valued their models, inflated their results, and had exerted too much influence on American Psychiatry.  They were very taken with the findings from the pharmacotherapies of the 1950s – as well they should have been. An acute schizophreniform psychosis is a formidable event to behold. Seen up close and personal, there’s little question that it needs to be treated, and the idea that it can be ablated in hours to days in a lot of instances would get anyone’s attention. There were other forces in the mix sure enough, but the net result was a radical flip and a love affair with biological treatments as the answer replacing the last the anwer. That idea was irrationally extrapolated and has us back near where we started – offering more than could be delivered. The pharmaceutical industry had a field day with this enthusiastic turn of focus, fanning the flames of hope with a pipeline pouring out lightweight clones disguised as breakthroughs, joined by a chorus of our colleagues who behaved pretty badly.

And Tom Insel of the NIMH has been a part of that problem with his psychiatry-as-clinical-neuroscience sermons and his monocular ideology. But much worse, like the psychiatric leadership in general, he’s run an NIMH that has doled out major treasure to the discredited and the non-productive; he’s inserted and controlled the agendas of researchers rather than following their creative leads; and his silence about rampant corruption in psychiatry has been deafening. He may not pick the grantees. But he should be setting the tone of his organization that does our major funding. He has pandered to industry throughout his tenure, and shows no signs of changing directions.

So I’m surprised and pleased with this article too, even though his insight is into something many of us have known and done for decades – learned from the bench of clinical experience. But it’s going to take a lot more than this wiff of humility and flexibility to change my view that Tom Insel is not going to be a part of substantive and needed changes in the world of psychiatry. He’s too much a part of the problem…

* That, by the way, is neither the interpretation of the Koan nor the message delivered by Kopp’s book – subtitled "The Pilgrimage of Psychotherapy Patients". Its closer to "Don’t look for answers outside yourself." I like both interpretations. I’ll even bet there are some other good ones out there.

    Richard Noll
    August 29, 2013 | 2:51 PM

    Jungian archetypes, extraterrestrial influences — a nice retro ’80s vibe in this piece.

    On another note: Here is a clearly written expression of my own apostacy regarding so much of published research, especially in the social sciences, but with equal relevance to medical research:

    Richard Noll
    August 29, 2013 | 2:57 PM

    Correction: apostasy.

    August 29, 2013 | 4:38 PM
    August 29, 2013 | 5:24 PM

    I Read that article in the NIMH the other day,

    I was thrilled to see a line like “tapering off medication early seemed to be associated with better long-term outcomes.”

    Then disspointed to see a line like “Clearly, some individuals need to be on medication continually to avoid relapse.”

    I like the admission that “reducing the so-called “positive symptoms” (hallucinations and delusions) may be necessary, but is rarely sufficient for a return to normal functioning.”

    Then disspointed to see him use the word ‘relapse’ to describe a feature of a withdrawal syndrome that can’t be told apart from the illness.

    Every other time Dr. Insel writes, it’s almost as if he’s nudging one inch closer to declaring neurology’s apporach the correct one, and psychiatry’s apporach absolutely rediculous (as far as science goes).

    Yet he’s caught between wanting to treat symptoms of ‘mental illness’ while declaring ‘mental disorders’ (groups of symptoms) invallid..

    H’es stuck not acknowledging that psychiatry historically treats illnesses where the (biological) causes are unknown (e.g. neurosyphilis). When psychiatry decided to start offering physical treatments it was like the 17th centuray all over again, horrible injuring or brain disrupting treatments like Insulin shock, electro shock, lobotmoy, and repurposed perpetual dosing of anesthetics (antipsychotics). Mental disorders are just labels for insurance reimbursement, and the symptoms ‘mental disorders’ are made of are just symptoms. Psychotherapy was and still is, the only way to go forward.

    The treatments only ‘work’ by damaging or disrupting the patients brain. The exact same way blood letting works. It looks like it’s working, the patient complains less, but in reality the patient gets sicker.

    So until Dr. Thomas Insel acknowleges the past is the present, and not the past, they’ll keep searching for something that doesn’t exist, and harming people all the same with a forced 17th century approach. Dr. Insel needs to take a full step to neurology and collapse the edifice, or rationalize what’s happened and go back to psychotherapy. Until then, he’s just part of the problem.

    At least that was my take on it. I was really pleased to see the acknowlegements he did make though. It does look like he’s moving towards an eventual epiphany. I really hope he has one.

    August 29, 2013 | 6:12 PM


    Thanks for that article. It would be a good one for all of us to digest. It’s an oft-told tale but he tells it usefully and the dead salmon at the end will live long in memory!. I’m messing with a project right now and computing a lot of p’s and Cohen’s d’s, anova’s, and chi squares. Those things were so clear in statistics classes, but in practice… I’d rather talk Jungian Archetypes. In the drug research world, they hang on to and manipulate these things to the third decimal place, but we’ve continued to struggle with clinical relevance without any resolution – even when people play it straight [on the rare occasions when that happens].

    August 29, 2013 | 7:42 PM

    Yeah, thanks from too, Richard, that article makes the problems of statistical significance understandable for the lay person. Beautiful website, too.

    I’d like to see you elaborate on the Jungian Archetypes. Just looked up heuristics in the wikipedia, and there Gerd Gigenzer pops up again. Synchronicity? I’d never heard of this guy before.

    August 29, 2013 | 7:43 PM

    I’d like to see Mickey elaborate.. and thanks from me too, Richard.

    Richard Noll
    August 29, 2013 | 8:35 PM

    Mickey, I knew you would appreciate the empathetic dead salmon.

    August 29, 2013 | 10:43 PM

    Clearly, some people need to stay on anti-psychotic medications, for a long time, if not forever. We know this, because they repeatedly stop them and get sick again, and some of them end up ill and violent (they get treatment in the jails), ill and living on the street, or in & out of hospitals. But I think it’s very important that we acknowledge that we don’t know who needs long-term treatment, and who doesn’t, and it’s good that we’ve started to question this. Certainly, there are people who have a single episode of severe mental illness, only to go on to recover and live full lives (with or without medications). In clinical practice, I wish I often wish I had a crystal ball.
    Thanks for the post.

    August 29, 2013 | 11:06 PM

    Insel’s article is good news. I see it as the leaders of Psychiatry actually conducting and reviewing quality science instead of pushing junk science. It does seem true antipsychotic meds can reduce positive symptoms in a short term (along with a lot of unwanted effects), and that folks who do not take them or have less exposure have better functional, long-term outcomes. I am not a huge fan of significance testing everything precisely because the tests are done on stupidly identified outcomes (or outcomes in name only). The real failure of pharm research particularly with antipsychotics was not statistical testing and RCTs, just that conclusions were drawn that did not follow the limits of the methodology of the experiments and their results. There was no evaluation of risk, assessment of value of limiting positive symptoms while decreasing function/wellness vs. tolerating positive symptoms and increasing liklihood of future functionality/wellness. The methodology was not wrong per se, but the questions asked were silly and the answers available were inappropriately used outside of their context. Studies can be designed to assess treatment effect on longer-term functional outcomes, but they aren’t done as often because they are expensive and risky. It doesn’t make it ok to make assumptions like people should spend a lifetime on antipsychotic meds after a psychotic experience and that they should get used to a diminished life because a 6 week study showed that with confidence using significance tests that positive symptoms were reduced significantly (and even with clinical relevance) with use of antipsychotic meds.

    Let’s just hope folks like Insel and health professionals in leadership positions or otherwise conduct and evaluate and apply research findings more critically.

    And for what it’s worth, John Ioannidis, cited in the article Richard posted and a respected methodologist particularly of meta-analyses, also did a study assessing the published experimental and quasi-experimental studies on long-term psychotherapy, and found the evidence for the effectiveness of such treat to be ” limited and at best conflicting.”

    August 29, 2013 | 11:08 PM
    August 29, 2013 | 11:22 PM

    Great article on the well known toxic “side effects” of atypical antipsychotics and all the fraud in marketing and medicine from 2010. The article answers how these horrible drugs became such bestsellers: money! I disagree that anyone should be on these toxic drugs for life.

    August 29, 2013 | 11:26 PM

    Why Most Published Research Findings Are False by John P. A. Ioannidis

    August 30, 2013 | 1:42 PM

    “Maybe even two alien visitations? one in Bethesda and another in Melbourne?”-Mickey

    I gotta go with the “neural prosthesis” theory.

    August 30, 2013 | 7:28 PM

    I made mention of this post at my blog this PM, but not specifically about Insel and antipsychotics. Nice post though here.

    Happy Labor Day, don’t labor too much!

    September 2, 2013 | 2:02 PM


    psychiatry operates in a space within a larger medical space and subject to forces operating throughout the space

    Patents, Profits, and the American People — The Bayh–Dole Act of 1980

    Howard Markel, M.D., Ph.D.

    “The law certainly contributed substantially to the increase in patents awarded to universities over the past three decades — from 380 in 1980 to 3088 in 2009”

    “… many academic researchers assume that Bayh–Dole is an inviolate aspect of doing business.”

    “When the Bayh–Dole Act was written, its aim was primarily to stimulate economic growth by more efficiently mining the untapped scientific riches of hospitals, laboratories, and universities. Much has changed since then.”

    “It’s time for Congress to recalibrate Bayh–Dole. Profits and patents can be powerful incentives for scientists, businesspeople, and universities, but new and ongoing risks — including high prices that limit access to lifesaving technologies, reduced sharing of scientific data, marked shifts of focus from basic to applied research, and conflicts of interests for doctors and academic medical centers — should be mitigated or averted through revisions of the law.”

    N Engl J Med 2013; 369:794-796August 29, 2013DOI: 10.1056/NEJMp1306553

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