One of the hallmarks of institutional corruption is that an institution will regularly act in ways that promote its own interests, even if that means betraying the principles that are supposed to govern that institution. In the world of medical journals, the public assumes that the journal will seek to publish research articles that report on the safety and efficacy of treatments, regardless of whether the findings support common beliefs and practices. In addition, the public assumes that a journal will publish letters-to-the-editor that, when written by knowledgeable people in the field, raise questions about a recent article the journal has published.
Such are the dictates of science. A medical journal is expected to promote an open-minded discussion of treatments, even if findings—or criticisms—threaten conventional beliefs.
In a blog published on September 21, Peter Gøtzsche detailed a letter that he and I had submitted to World Psychiatry, related to an article on the 10-year outcomes of 281 Norwegian patients following a first episode of psychosis. The death rate in that study was quite high (11%), and we thought the authors should have reported in some detail on those deaths in their published article.
I wasn’t surprised by this rejection of our letter. As a non-academic, I really don’t have standing to write a “letter to the editor” of a medical journal, and although Peter Gøtzsche certainly has such standing, I thought there was little chance our letter would be published. There is a long history of editors of psychiatry journals rejecting articles that challenge the merits of psychiatric drugs in a fundamental way, or only accepting such articles if the damaging results are downplayed or presented in an obscure way. In psychiatry journals, the abstracts are nearly always written in a manner that ensures that the conventional wisdom about psychiatric drugs isn’t unduly threatened.
Now we have a new, powerful example of this institutional corruption at work.
As regular readers of Mad in America know, Donald Goff, Jeffrey Lieberman and others recently published a review of the long-term effects of antipsychotics in the American Journal of Psychiatry. Their conclusion was that while there is no good evidence that antipsychotics worsen long-term outcomes, there is good evidence supporting their long-term use. Joanna Moncrieff wrote a blog for MIA criticizing their study, as did Miriam Larsen-Barr, and I wrote a long “MIA Report” on how their review—given their biased presentation of study findings, their cherry-picking of studies, and their dismissal of evidence that told of long-term harm—served as a case study of institutional corruption. Their review was clearly designed to defend their antipsychotics, as opposed to truly investigating their long-term effects.
Their study also triggered the submission of at least two “letters to the editor” to the American Journal of Psychiatry that were critical of the study, one written by Moncrieff and Stefan Priebe, and the other by Robin Murray and five colleagues. While Moncrieff may be known in the world of psychiatry as a “critical psychiatrist,” which might make the editors of the American Journal of Psychiatry eager to reject her submission, Murray is known as one of the foremost authorities on schizophrenia in the world. As such, it is difficult to imagine how the letter he and his colleagues sent could possibly be rejected by the editors at the American Journal of Psychiatry.
But it was rejected, and so was the letter submitted by Moncrieff and Priebe.
I have to confess, this did surprise me. The rejection of Murray’s letter revealed institutional corruption in such stark fashion: Thou Shall Not Criticize Our Drugs. At least not in the pages of the American Journal of Psychiatry.
The American Journal of Psychiatry is published by the American Psychiatric Association. As the journal’s website states, it is the “official publication” of the association. The website boasts that it is the most widely read psychiatric journal in the world.
As such, this is the journal that perhaps has the greatest impact on thinking about psychiatric drugs. Yet, if you look up its mission statement, you find that the journal’s purpose is not, in fact, to provide a scientific review of the merits of psychiatric drugs. Here is what the editors write: “The American Journal of Psychiatry is committed to keeping the field of psychiatry vibrant and relevant by publishing the latest advances in the diagnosis and treatment of mental illness.”
The journal is committed to “keeping the field of psychiatry vibrant,” and to do so by telling of “advances in the diagnosis and treatment of mental illness.” Their stated mission is to advance the guild interests of psychiatry, and from that perspective, it makes perfect sense that the editors rejected Murray’s letter and Moncrieff’s too. The rejection of such critiques serves the journal’s stated mission.
I read the journal’s mission statement while writing this blog, and it made for an “aha” moment for me. I hadn’t realized before that the American Journal of Psychiatry so bluntly confessed to this guild purpose, but at least we now know, with this rejection of Murray’s letter, that the editors’ protection of this mission is absolute. They will not find space for criticism even if it comes from one of the best-known psychiatrists in the world.
Both Murray and Moncrieff have given Mad in America permission to print the letters submitted to the American Journal of Psychiatry. Here they are:
The letter submitted by Robin Murray and colleagues
Don’t dismiss the adverse effects of long-term antipsychotics in animal studies.
Robin M Murray, Anthony C Vernon, Sridhar Natesan, Jim Van Os, David Taylor, Marta Di Forti
There is almost universal agreement that antipsychotics are useful in the acute care of people with schizophrenia, and that many patients will have to continue to take them for prolonged periods. However, recent evidence indicates that a significant proportion of patients will be able eventually decrease their medication to a minimum or come off the drugs without detriment to their mental health (1).
In their review published on-line in this journal (2), Goff and colleagues downplay the potential harms of long-term “prophylactic” use of antipsychotics. For example, they minimise the formidable evidence that most second generation antipsychotics increase risk of obesity and the metabolic syndrome with all its consequences (3). Furthermore, they dismiss those studies which show that administration of antipsychotics induces brain volume losses in rodent (4) and primate (5) models. Goff and colleagues claim that the relevance of such findings “to the treatment of psychosis is uncertain, both due to species-related differences and because animals lack the pathophysiology of schizophrenia. It is possible that antipsychotics may have deleterious effects on normal brain but protective effects in the presence of schizophrenia-related neuropathology.” This explanation ignores the similarity of the brain changes induced in animals to those seen in patients following long-term antipsychotics (6). Furthermore, it invokes the extraordinary assumption that there exists a “schizophrenia-related neuropathology” which responds to D2 dopamine blockade in the opposite manner to that of the brains of the remainder of humankind.
Goff and colleagues only briefly touch on the extensive evidence that in animals, long-term antipsychotic administration induces supersensitivity of the D2 dopamine receptor. They ignore the detailed studies of Seeman, Kapur and their colleagues (7,8) who noted that on-going antipsychotic exposure in rats and cats induces an increase in D2 receptor numbers, and that the resultant dopamine supersensitivity causes antipsychotics to lose their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance responding. Once again Goff et al avoid the obvious conclusion that D2 dopamine blockade is likely to have a similar effect in the human brain. Furthermore, they fail to cite the recent reports that some partial dopamine agonists such as aripiprazole have less propensity to cause dopamine supersensitivity, and therefore may have clinical advantages in this regard (9).
In pharmacology, animal studies are considered a valuable indicator of what to expect in terms of the effects of a drug in humans. By arguing that those of us who treat patients with antipsychotics have nothing to learn from animal studies, Goff et al appear to have adopted the Creationist creed that humans and animals were created in an entirely separate manner without overlapping neural systems. The wise psychiatrist will take a more balanced view, and work with their patient to slowly reduce the dose of antipsychotic to the minimum level compatible with the patient’s continuing mental health: in a minority, but an important minority, this level will be zero.
1. Murray RM, Quattrone D, Natesan S, et al. Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics? Br J Psychiatry 2016; 209, 361–365.
2. Goff DC, Falkai P, Fleischhacker W, et al. The Long-Term effects of antipsychotic medication on clinical course in schizophrenia. Amer J Psychiatry, AJP in Advance (doi: 10.1176/appi.ajp.2017.16091016)
3. De Hert M, Detraux J, van Winkel R et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nature Rev. Endocrinology, 2012, 8, 114-126
4. Vernon AC, Crum WR, Lerch JP, et al. Reduced cortical volume and elevated astrocyte density in rats chronically treated with antipsychotic drugs – linking magnetic resonance imaging findings to cellular pathology. Biol Psychiatry 2014; 75, 982–90.
5. Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology 2005; 30, 1649–61.
6. Vita A, De Peri L, Deste G, et al. The effect of antipsychotic treatment on cortical gray matter changes in schizophrenia: does the class matter? A meta-analysis and meta-regression of longitudinal magnetic resonance imaging studies. Biol Psychiatry 2015; 78, 403–12.
7. Samaha AN, Seeman P, Stewart J et al ‘‘Breakthrough’’ dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 2007; 27: 2979–2986.
8. Ginovart N, Wilson AA, Hussey D, et al. D2-receptor upregulation is dependent upon temporal course of D2-occupancy: a longitudinal 11C- raclopride PET study in cats. Neuropsychopharmacology 2009; 34: 662–71.
9. Tadokoro S, Okamura N, Sekine Y, et al. Chronic treatment with aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity psychosis. Schizophr Bull 2012; 38: 1012–20.
R.M.M., J.v.O., and DT have received speaker honoraria from Janssen, Lilly, Otsuka, Servier and Lundbeck, and M.D.F. has received honoraria from Janssen and Lundbeck. D.T. is on the following advisory boards: Servier, Lundbeck and Sunovion, and and has received research funding from Janssen, Lundbeck and BMS. ACV has received research funding from Roche.
The letter submitted by Joanna Moncrieff and Stefan Priebe
Patients deserve more evidence
A response to “The long-term effects of antipsychotic medication on clinical course in schizophrenia” by D.C. Goff, P. Falkai, W.W. Fleischhacker, R.R. Girgis, R.M. Kahn, H. Uchida, J. Zhao, J.A. Lieberman
Goff et al’s recent article highlights that the full risk-benefit ratio of long-term antipsychotic treatment remains uncertain (1). All trials of long-term treatment involve withdrawal of previous treatment, yet antipsychotic withdrawal may induce psychotic symptoms and increase risk of relapse, thus confounding outcomes. Long-term follow-ups and data on other outcomes are also limited. Only six of the 65 trials in Leucht et al’s 2012 meta-analysis lasted longer than one year (2). The only long-term follow-up of a randomised cohort suggests that gradual and supported antipsychotic reduction may lead to better social functioning, with no long-term increase in risk of relapse, although numbers were small (3).
Goff et al. refer to evidence using percentages and group means but doctors are confronted with individuals. Even ignoring the problems with existing studies, numbers needed to treat with antipsychotics suggest individual patients are more likely not to benefit than to benefit. In Leucht et al’s review, three patients need to receive maintenance antipsychotics for one to have a lower chance of relapse attributable to treatment. How do doctors provide the evidence to patients in this situation? How should the possibility of positive effects be balanced with the probability of serious adverse effects and the indications—even if not confirmed—of brain shrinkage, impaired cognition and lower social functioning ?
Patients’ decisions will be influenced by the probabilities of different outcomes and by their personal appraisals of these outcomes. A patient might accept the risk of re-hospitalisation in exchange for the higher chance of a satisfying sex life, for example, and appraisals can obviously change over time. The challenge for research is not to arrive at a generalised recommendation for or against treatment with anti-psychotics, but to provide more detailed evidence to facilitate the informed choice of individual patients. If doctors support patients to take such decisions a more open and trusting therapeutic relationship may be established, making it less likely that patients stop medication on their own.
The United Kingdom’s National Institute for Health Research has funded the first large trial of gradual antipsychotic reduction and discontinuation in people with recurrent psychotic conditions, which will measure social functioning and quality of life as well as relapse (4). This may clarify some questions about long-term antipsychotic treatment. Yet more studies for different patient groups are required to provide the data patients and doctors need to make informed and collaborative decisions.
1. Goff DC, et al. The Long-Term Effects of Antipsychotic Medication on Clinical Course in Schizophrenia. Am J Psychiatry 2017 May 5;appiajp201716091016.
2. Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Davis JM. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 2012;5:CD008016.
3. Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy: Long-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psychiatry 2013 70:913-20.
4. RADAR trial ISRCTN (International Standard Randomised Controlled Trial Number) 2017 Feb 7. http://www.isrctn.com/ISRCTN90298520
Conflict of interest statement:
Both authors are investigators on a research programme funded by the UK’s National Institute for Health Research entitled Research into Antipsychotic Discontinuation and Reduction (RADAR). Details are described in the text, and a reference to the trial registration is supplied.
Neither author has any financial conflicts of interest.