Inconvenient truths about antipsychotics should not be swept under the carpet: a response to Goff et al

In my book The Bitterest Pills, I wrote of how many psychiatrists simply do not want to face up to the harms their treatments can produce. This is illustrated by the way the psychiatric establishment tried to avoid the implications of tardive dyskinesia, by suggesting it was a symptom of ‘schizophrenia,’ and ignoring the evidence that tardive dyskinesia involves cognitive impairment. Similarly, when it became obvious that some of the second generation antipsychotics caused massive weight gain and metabolic disturbance, mainstream psychiatric journals published articles suggesting that diabetes was linked with schizophrenia as well.

The suggestion that antipsychotics reduce brain volume is not new. Psychiatrist, Peter Breggin, made this claim over thirty years ago (1), but was dismissed as a crank. Over the last 10 years, however, the evidence has become irrefutable. Some leading members of the psychiatric establishment, like the UK’s Robin Murray, have even publicised their concern about it (2).

Coupled with, and possibly linked to this evidence of harm, doubts have started to mount that the benefits of long-term treatment with antipsychotics have not been as firmly established as is generally believed. The inadequacies of randomised trials of maintenance treatment have been highlighted, and the fact that there is little data on the overall impact of drug treatment when it is taken over the long periods of time that many patients are prescribed it for. Some evidence points towards the possibility that some people may do better if they stop or reduce their antipsychotic tretament, rather than continue on it long-term. These points have been raised by several mainstream psychiatrists (2;3), as well as the usual suspects, including me (4;5)!

The paper by Donald Goff and seven other leading psychiatrists published in the American Journal of Psychiatry on 5th May is an attempt to rebut these concerns and re-establish the good reputation of antipsychotics (6). I am shocked by how the article dismisses concerns about long-term treatment and evidence of brain impacts. It is riddled with distortions, ignores the most pressing criticisms, and is shot through with the unexamined presumption that the multitude of problems currently labelled as schizophrenia or psychosis will one day be revealed to be due to a specific brain abnormality that is targeted by antipsychotics.

While I would not dispute the usefulness of antipsychotics for the treatment of acute psychosis (in many, though not all situations), decades of research into early intervention has not demonstrated that early antipsychotic treatment improves long-term outcomes. Goff et al’s suggestion that the Norwegian Early Detection study (known as the TIPS study) showed improved long-term outcomes with earlier antipsychotic treatment is not borne out by the paper they cite (7). Although the paper shows lower levels of negative symptoms, cognitive and depressive symptoms at the two year follow-up in people from the area with the Early Detection programme compared to those in areas without the programme, baseline data demonstrate that people in the Early Detection area had milder conditions, with fewer negative symptoms to begin with. In fact negative symptoms declined more in people from the area without the Early Detection programme!  Moreover, the Early Detection group showed no benefit in terms of remission, relapse or positive symptoms.

Goff et al state that ‘the effectiveness of maintenance treatment for prevention of relapse has been well established’, but they do not acknowledge how there are no prospective randomised trials of maintenance treatment, only studies of maintenance treatment versus usually sudden withdrawal of maintenance treatment.  Thus they completely fail to address concerns that effects of withdrawal of long-term treatment inevitably confound such studies. They also fail to mention the dearth of long-term data from randomised trials. Only 6 of the 65 trials in Leucht et al’s 2012 meta-analysis lasted longer than one year (8).

They correctly point out that results of naturalistic studies, like Martin Harrow’s long-term follow-up of people from Chicago (9), and the Finnish cohort study (10), are affected by the fact that patients who stop antipsychotics successfully are likely to have less severe conditions. However, they also claim that two other naturalistic studies found ‘improved outcomes in people with schizophrenia in people who continued antipsychotic treatment with those who did not’. Yet the papers cited refer to quite different sorts of studies, with neither presenting any data on global outcomes or social functioning, and only one involving the sort of follow-up periods of the Finnish and Chicago studies. One of the papers referred to looked at rehospitalisation rates within 3 years of antipsychotic discontinuation in a national database (11), and the other looked at mortality rates (12) (also see the extensive critique of this paper by De Hert et al, 2010 (13)).

The most worrying thing about the Goff et al paper, however, is the minimisation of the evidence that antipsychotics produce brain shrinkage. First the authors claim that shrinkage of brain grey matter has been shown to be part of schizophrenia. They trot out the old adage that brain differences were detected long before the introduction of antipsychotics. The paper they cite here is a post mortem study published in 1985, long after antipsychotics had been introduced (14). The air encephalography studies that properly pre-date the introduction of antipsychotics involved long-term institutionalised patients who had been heavily treated with various sedative drugs along with physical treatments such as ECT and insulin coma therapy. Although these are commonly referred to as evidence that people with schizophrenia have smaller brains and larger brain ventricles, in fact the only two which had proper control groups showed no difference between brains of people with schizophrenia and brains of people without (15;16).

In any case, the presence of differences between the brains of people with schizophrenia and controls does not establish that there is progression of brain volume loss, which is what has been clearly demonstrated in people and animals taking antipsychotics. There are no studies that show progressive brain changes in people with diagnosed schizophrenia or psychosis in the absence of antipsychotic treatment. The authors cite one report from a group in Edinburgh suggesting progressive brain loss in people at ‘high risk of psychosis’ prior to receiving antipsychotic treatment (17). However, this study finds subtle changes in some regions in a very small number of patients, not the cortex-wide loss of grey matter observed in people and animals taking antipsychotics.

Goff et al also cite a paper which showed decreases in grey matter volume in eight people following antipsychotic discontinuation compared to eight people who continued taking antipsychotics. However, the changes were localised to the putamen and nucleus accumbens, components of the basal ganglia, which other studies have shown to be enlarged during treatment with antipsychotics. Far from concluding that the study is evidence ‘that volume changes reflect progression of illness’ as Goff et al suggest (P 5), the authors of the discontinuation paper concluded that ‘discontinuation reverses effects of atypical medication’ (18).

When describing the animal studies that show antipsychotic induced brain volume reductions (19;20), Goff et al suggest that ‘the relevance of findings in rodents and monkeys to the treatment of psychosis in humans is unclear, both because of species related differences, and because animals lack the pathophysiology of schizophrenia. It is possible that antipsychotics have deleterious effects on normal brain, but protective effects in the presence of schizophrenia-related neuropathology’ (P 6). Anything is possible, but this is just a leap of faith, and one that is completely at odds with the Hippocratic oath to ‘first do no harm!’ Monkeys and rats were chosen for these studies because of their similarities to human biology. There is no good reason at present to assume that the effects demonstrated in these animals would not occur in a similar species i.e. us! And there is no evidence that antipsychotics have different effects on the brains of people with and without schizophrenia – although of course such evidence would be very difficult to obtain. I agree with Goff et al that these changes have not been definitively linked with effects on actual mental functioning, and that we need further data on this, but as they correctly suggest, ‘most but not all’ current studies show that brain volume reductions are correlated with decreased intellectual performance.

I still think antipsychotics can be useful, and that the benefits of treatment can outweigh the disadvantages, even in the longterm for some people. However, it does no one any service to pretend that they are innocuous substances that somehow magically transform (hypothetically) abnormal schizophrenic brains back to normal. Psychiatrists need to be fully aware of the detrimental effects of antipsychotics on the brain and body. They also need to acknowledge the way these drugs make life so miserable for many people, even for some who might have been even more distressed were they to be without them, something that is well described in Miriam Larssen-Barr’s recent blog on the Mad in America website. Psychiatrists need to support people to evaluate the pros and cons of antipsychotic treatment for themselves and to keep doing this as they progress through different stages of their problems. To do this psychiatrists need to be able to acknowledge the real nature of these drugs, and not sweep inconvenient truths under the carpet!

Reference List

(1)    Breggin P. Hazards to the Brain. New York: Springer Publishing Company; 1983.

(2)    Murray RM, Quattrone D, Natesan S, van Os J, Nordentoft M, Howes O, et al. Should psychiatrists be more cautious about the long-term use of antipsychotics? British Journal of Psychiatry 2016;209:361-5.

(3)    Leucht S, Heres S, Hamann J, Kane JM. Methodological issues in current antipsychotic drug trials. Schizophr Bull 2008 Mar;34(2):275-85.

(4)    Moncrieff J. Antipsychotic Maintenance Treatment: Time to Rethink? PLoS Med 2015 Aug;12(8):e1001861.

(5)    Whitaker R. Mad in America. Cambridge, MA: Perseus Publishing; 2002.

(6)    Goff DC, Falkai P, Fleischhacker WW, Girgis RR, Kahn RM, Uchida H, et al. The long-term effects of antipsychotic medication on clinical course in schizophrenia. American Journal of Psychiatry 2017;ajp.psychiatryonline.org.

(7)    Melle I, Larsen TK, Haahr U. Prevention of negative symptom psychopathologies in first-episode schizophrenia. Arch Gen Psychiatry 2008;65:634-40.

(8)    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.

(9)    Harrow M, Jobe TH, Faull RN. Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Psychol Med 2012 Oct;42(10):2145-55.

(10)    Moilanen JM, Haapea M, Jaaskelainen E, Veijola JM, Isohanni MK, Koponen HJ, et al. Long-term antipsychotic use and its association with outcomes in schizophrenia: the Northern Finland birth cohort 1966. Eur Psychiatry 2016;36:7-14.

(11)    Tiihonen J, Walhbeck K, Lonnqvist J, Klaukka T, Ioannidis JP, Volavka J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006 Jul 29;333(7561):224.

(12)    Tiihonen J, Lonnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009 Aug 22;374(9690):620-7.

(13)    De Hert M, Correll CU, Cohen D. Do antipsychotic medications reduce or increase mortality in schizophrenia? A critical appraisal of the FIN-11 study. Schizophr Res 2010 Mar;117(1):68-74.

(14)    Bogerts B, Meertz E, Schonfeldt-Bausch R. Basal ganglia and limbic system pathology in schizophrenia: a morphometric study of brain volume and shrinkage. Arch Gen Psychiatry 1985;42:784-91.

(15)    Storey PB. Lumbar air encephalography in chronic schizophrenia: a controlled experiment. Br J Psychiatry 1966 Feb;112(483):135-44.

(16)    Peltonen L. Pneumoencephalographic studies on the third ventricle of 644 neuropsychiatric patients. Acta Psychiatr Scand 1962;38:15-34.

(17)    McIntosh AM, Owens DC, Moorhead WJ, Whalley HC, Stanfield AC, Hall J, et al. Longitudinal volume reductions in people at high risk of schizophrenia as they develop psychosis. Biol Psychiatry 2011;69:953-8.

(18)    Boonstra G, van Haren NE, Schnack HG. Brain volume changes after withdrawal of atypical antipsychotics in patients with first episode schizophrenia. J Clinical Psychopharmacology 2011;31:146-53.

(19)    Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. 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 Sep;30(9):1649-61.

(20)    Vernon AC, Natesan S, Modo M, Kapur S. Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation. Biol Psychiatry 2011 May 15;69(10):936-44.

 

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7 thoughts on “Inconvenient truths about antipsychotics should not be swept under the carpet: a response to Goff et al

  1. Thank you so much for this article! I have the inpression that the Norwegian program TIPS operates with diagnosing at least some of the patients after they had startes the medikation With «antipsychosis» tablets. Of course then – the study is Worth nothing. I often wonder – how do People that defend much of the quasiscientific aproach feel? Dag Coucheron Norwgian psychiatrist Psychoanalyst With 50 years exsperiance.

    Sendt fra E-post for Windows 10

    Fra: Joanna Moncrieff Sendt: Sunday, May 7, 2017 kl. 5:33 PM Til: dag.coucheron@gmail.com Emne: [New post] Inconvenient truths about antipsychotics should not beswept under the carpet: a response to Goff et al

    joannamoncrieff posted: “In my book The Bitterest Pills, I wrote of how many psychiatrists simply do not want to face up to the harms their treatments can produce. This is illustrated by the way the psychiatric establishment tried to avoid the implications of tardive dyskinesia, “

  2. I diagnose psychosis re Goff et al and the treatment is Olanzapine. If they refuse… sorry but it’s going to have to be a CTO.

  3. It’s so ludicrous. If psychiatrists were made to take these drugs themselves, there would be no need for any studies, indeed, they would not be capable of doing any studies. They would all be drooling, twitching, falling over and slouching around like demented Mr and Mrs blobbies trying to remember what planet they are on, or if indeed it is a planet they are on. You only have to wait in a psychiatric hospital to see the harrowing looks, obesity and twitching blankness of people on antipsychotics to know they are being damaged.

    People do all kind of insane things for money, including pumping really toxic drugs into people – this was clear to me when I counted the number of really up market cars in the car park of a psychiatric hospital in an area that is amongst the most deprived in the UK, those Mercs are owned by the psychiatrists and managers not the patients – and then deluding themselves into believing they are ‘treating’ people.

    I have dyskinesia, I eat with a spoon because of the amount of times I’ve stabbed my mouth with a fork. Today I had to sign my name to something and made a right mess of it. I’ve come to terms with going through the rest of my life with this, but I’ll be damned if these idiots called psychiatrists are going to get away with it. And sorry I associated Mr and Mrs Blobby with psychiatrists.

  4. It’s not difficult to find all this stuff….

    https://www.justice.gov/opa/pr/johnson-johnson-pay-more-22-billion-resolve-criminal-and-civil-investigations

    ‘J&J Subsidiary Janssen Pleads Guilty to Misbranding Antipsychotic Drug’

    “The complaint further alleges that J&J and Janssen were aware that Risperdal posed serious health risks for the elderly, including an increased risk of strokes, but that the companies downplayed these risks. For example, when a J&J study of Risperdal showed a significant risk of strokes and other adverse events in elderly dementia patients, the complaint alleges that Janssen combined the study data with other studies to make it appear that there was a lower overall risk of adverse events.”

    “one physician who worked on the study cautioned Janssen that “[a]t this point, so long after [the study] has been completed … we must be concerned that this gives the strong appearance that Janssen is purposely withholding the findings.”

    “The complaint also alleges that Janssen knew that patients taking Risperdal had an increased risk of developing diabetes, but nonetheless promoted Risperdal as “uncompromised by safety concerns (does not cause diabetes).” When Janssen received the initial results of studies indicating that Risperdal posed the same diabetes risk as other antipsychotics, the complaint alleges that the company retained outside consultants to re-analyze the study results and ultimately published articles stating that Risperdal was actually associated with a lower risk of developing diabetes.”

    “The government’s complaint also contains allegations that Janssen paid speaker fees to doctors to influence them to write prescriptions for Risperdal. Sales representatives allegedly told these doctors that if they wanted to receive payments for speaking, they needed to increase their Risperdal prescriptions.”

    https://www.theclarkfirmtexas.com/texas-risperdal-lawyer

    “Johnson & Johnson is facing over 18,500 lawsuits involving Risperdal (risperidone), an anti-psychotic drug linked to the development of breasts on young boys. Trials have ended in juries awarding victims $500,000 to $70 million.”

    http://www.genengnews.com/gen-news-highlights/astrazeneca-to-pay-520m-settlement-in-seroquel-lawsuit/78565333

    “AstraZeneca is still denying allegations that it actively marketed the antipsychotic drug Seroquel for off-label indications but will pay $520 million to resolve the civil suit brought about by federal and state entities. The monetary settlement, confirmed by the Departments of Justice and Health and Human Services’ Health Care Fraud Enforcement Action Team (HEAT), will be split between the federal government and the state Medicaid programs and District of Columbia, with the government receiving just shy of $302 million.”

    “Lilly Settles With 18,000 Over Zyprexa”

    “Including earlier settlements over Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who said they were injured by the drug.”

    “Documents provided to The New York Times last month by a lawyer who represents mentally ill patients show that Lilly played down the risks of Zyprexa to doctors as the drug’s sales soared after its introduction in 1996. The internal documents show that in Lilly’s clinical trials, 16 percent of people taking Zyprexa gained more than 66 pounds after a year on the drug, a far higher figure than the company disclosed to doctors.

    The documents also show that Lilly marketed the drug as appropriate for patients who did not meet accepted diagnoses of schizophrenia or bipolar disorder, Zyprexa’s only approved uses. By law, drug makers may promote their drugs only for diseases for which the Food and Drug Administration has found the medicines to be safe and effective, though doctors may prescribe drugs in any way they see fit.”

    “In its statement, Lilly said the settlement did not change its view that Zyprexa is a safe and effective treatment for mental illness.”

  5. Thank you very much for this article, Mrs Moncrieff. In my opinion, it’s right there in the very first sentence: “…psychiatrists simply do not want to face up to the harms their treatments can produce”.
    This statement also points to the solution of the problem. If psychiatric patients were to have the same rights as any other patients, they wouldn’t be locked up, receive treatment or be forced to take medications against their will. As far as I can see, this is a human rights issue. When the human rights of psychiatric patients are finally recognised, there will be no reason not to develop a rational view on the use of psychotropic medication. I expect that view would turn out to be similar to the one you have already proposed.

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