Posted by alan2102 on October 11, 2007, at 11:09:08
Medical Hypotheses
Volume 65, Issue 6, 2005, Pages 1005-1009
doi:10.1016/j.mehy.2005.08.013
Copyright © 2005 Elsevier Ltd All rights reserved.
Editorial
If 'atypical' neuroleptics did not exist, it wouldn't be necessary
to invent them: Perverse incentives in drug development, research,
marketing and clinical practiceBruce G. Charlton
Editor-in-Chief, Medical Hypotheses, University of Newcastle upon
Tyne, NE1 7RU, UKAvailable online 22 September 2005.
Summary
Perverse incentives in drug development, research, marketing and
clinical usage can be illustrated by considering the example of
the so-called 'atypical' neuroleptics which have grown to become a
standard -- indeed expanding -- part of psychiatric practice
despite their probable inferiority to older sedative agents. There
is now ample evidence to suggest that neuroleptics (aka.
anti-psychotics and major tranquillizers) are dangerous drugs, and
patients' exposure to them should be minimized wherever possible.
This clinical imperative applies whether neuroleptics are of the
traditional type or atypical variety, albeit for different reasons
since the traditional agents are neurotoxic, while atypicals are
mainly metabolic poisons. Usage of traditional neuroleptics seems
indeed to be declining progressively, but the opposite seems to be
happening for 'atypicals', and new indications for these drugs are
being promoted. Yet the atypical neuroleptics are a category of
pharmaceuticals which are close to being un-necessary since there
are safer, cheaper and pleasanter substitutes, such as
benzodiazepines and the sedative antihistamines (e.g.
promethazine). If 'atypical' neuroleptics did not exist, it would
not be necessary to invent them. Analysis of how such expensive,
dangerous and inferior drugs as the 'atypicals' have nevertheless
come to dominate clinical practice casts light on the perverse
incentives which now motivate the pharmaceutical industry in an
era of massive state regulation. The lack of positive incentives
to deploy off-patent drugs is longstanding, but there is a new
disincentive in the widespread but erroneous belief that only
randomized controlled trials (RCTs) can provide valid 'evidence'
of effectiveness. Consequently, those who control RCTs now control
clinical practice. It sometimes makes commercial sense to develop
and market new drugs that are inferior to existing agents, since
new drugs are patent-protected and can be promoted on the back of
a mass of new RCTs funded and 'owned' by the pharmaceutical
corporations. The current regulatory and patenting situation,
therefore, requires major reform if drug efficacy and patient
safety are to become higher priorities. Given that psychiatric
practice is apparently 'locked-in' to prescribing atypicals, and
if (as seems likely) most informed individuals would wish to avoid
neuroleptics for themselves and their loved-ones except as a last
resort; then in the short-term it may be wise for patients and
their families to explore the possibilities of increased
self-management of psychiatric problems using over-the-counter
drugs, such as the sedative antihistamines. In the long-term,
there need to be legal reforms to change the regulatory and
commercial framework of incentives relating to drug development.
These might include new forms of short-term re-patenting of old
drugs.Article Outline
: Neuroleptics to suppress agitated or psychotic behaviour
: Replacing traditional neuroleptics -- the 'atypicals'
: Psychiatry 'locked-into' atypical use
: Why not use sedative antihistamines? Because those who
control RCTs control practice
: Self-management for clinical self-defense, reshaping
incentives for therapeutic progress
: ReferencesNeuroleptics to suppress agitated or psychotic behaviour
The perversity of currently operative incentives in the drug
development, research, marketing and clinical use can be
illustrated by considering the example of the so-called 'atypical'
neuroleptics, which have grown to become a standard part of modern
psychiatric practice. Atypicals represent a backward step in
therapeutics, probably being no more effective, much more
dangerous, and greatly more expensive than already-existing
agents. The policy-implications derive from the fact that the
atypical neuroleptics have emerged in the most advanced modern
societies, and in a context of extreme pharmaceutical regulation.
This situation highlights the unintended, but pathogenic,
motivators which now operate to perpetuate undesirable trends in
clinical practice.The traditional neuroleptics (aka. anti-psychotics or major
tranquillizers) are very powerful agents for controlling agitated
and psychotic behaviour when compared with the drugs in use before
their discovery [1]. The pre-neuroleptic behavioural control
agents had been mainly sedatives (e.g. antihistamines,
barbiturates, bromides and paraldehyde). However, the
neuroleptics, such as chlorpromazine, haloperidol and fluphenazine
decanoate -- are now seen to be neurotoxic. They achieve their
distinctively powerful behavioural control by making patients
Parkinsonian in a dose-dependent fashion, with permanent
neurological disease (tardive dyskinesia) as the long-term
consequence of prolonged high dosages [1], [2], [3] and [4].
Furthermore, it is now apparent that neuroleptics induce
dependence, so that withdrawal tends to provoke psychotic
episodes, and patients who have never taken neuroleptics have a
better prognosis than those who are maintained on them [1], [2]
and [3]. Short-term benefits are achieved at the cost of long-term
harm. On top of this, neuroleptics are notoriously unpleasant.
Indeed, patients hate them, since the emotional effects of
Parkinson's disease include emotional blunting, mental dullness
and demotivation; and sometimes agitated feelings of akathisia
(inner turmoil and physical restlessness). These are not 'side
effects' of neuroleptics, on the contrary they are the core
therapeutic actions of neuroleptics. In a nutshell, neuroleptics
work by causing the psychological symptoms of Parkinsonism [4].So, traditional neuroleptics are exceptionally nasty drugs whose
use should be minimized as a matter of policy, and for which safer
and less unpleasant replacements should be sought. So much is
probably uncontroversial, at least at a personal level among
informed psychiatric scientists, although for structural,
professional reasons this conviction is seldom clearly stated as
such.Replacing traditional neuroleptics -- the 'atypicals'
The main response to this state of affairs has been the
displacement of traditional neuroleptics by a group of drugs
self-styled as 'atypical' neuroleptics, such as clozapine,
risperidone and olanzapine [2]. Clozapine is not a neuroleptic, by
classical definitions [1] and the others of this class are much
weaker neuroleptics than traditional drugs. Because atypicals have
less tendency to cause Parkinsonian symptoms and tardive
dyskinesia than traditional agents, they are consequently less
powerful at suppressing behaviour than traditional neuroleptics;
but atypicals are powerful enough (it turns out) for most
purposes. It seems that in their clinical effect, atypicals are
essentially the pre-chlorpromazine sedative antihistamines,
re-invented and re-packaged for modern times. Indeed, an old
antihistamine such as cyproheptadine might well be counted as
functionally an 'atypical' neuroleptic by today's criteria i.e. it
blocks serotonin 2 and cholinergic receptors, it is (probably,
like many old antihistamines) only weakly anti-dopaminergic, it is
powerfully sedative and it causes weight gain. Yet cyproheptadine,
is an off-patent drug, and available cheaply over-the-counter.But if most of the atypicals are only weakly neurotoxic they are
instead 'metabolic poisons'; having poorly-understood (this poor
understanding itself being a damning indictment of the structural
biases of contemporary psychiatric research) but clearly damaging
effects on various aspects of energy metabolism [2] and [5].
Atypicals tend to cause physiological damage, such as glucose
intolerance, diabetes and perhaps pancreatitis; gross weight gain
and cardiac conduction problems. Atypicals are also associated
with significantly increased mortality, from a variety of causes
[6] and [7]. (Clozapine, notoriously, causes lethal blood
dyscrasias, requiring continuous monitoring.) These side effects
occur in the context of long-term prescription for psychiatric
disorders which are often self-limiting and rarely fatal [1] and
[2].Perhaps the main useful lesson from the emergence of the
'atypical' (i.e. weak) neuroleptics is that psychiatrists did not
actually need to make all of their agitated and psychotic patients
Parkinsonian in order to suppress their behaviour. Atypicals are
highly sedative agents. Apparently, the kind of sedation provided
by the 'atypicals' is sufficient for behavioural control in most
instances. This should not have been a surprise, since sedation
was the standard method of controlling agitation and acute
psychoses before the emergence of neuroleptics and in situations
where neuroleptics were not available (e.g. in the Eastern Bloc
and underdeveloped countries) [1], [2] and [8]. Indeed, the value
of sedation should not be underestimated. Sedation is not merely a
relatively safe way of controlling agitated behaviour; sedation
also provides a potentially 'curative' benefit for psychotic
patients with a causative element of delirium [4]. Sleep has
profoundly restorative qualities where sleep disturbance is severe
and prolonged, as is the case for many psychotic patients. In sum,
drugs which promote sleep likely have an 'anti-psychotic' effect,
as well as making patients both feel and function better [4] and
[8].In terms of therapeutic value, it therefore seems likely that
'atypicals' are merely an unusually dangerous way of sedating
patients. In therapeutic terms these drugs therefore represent a
significant backward step. Rationally, the atypicals should now be
dropped and replaced with safer sedatives. Potential
neuroleptic-substitutes which already exist would include
benzodiazepines and sedative antihistamines, such as promethazine
[4] and [8].The situation therefore seems straightforward. Neuroleptics --
whether traditional or atypical -- are toxic and dangerous drugs,
their use should be minimized, and safer alternatives must be
sought as a matter of urgency. This should no longer be a matter
for debate, but for remedial action.Psychiatry 'locked-into' atypical use
Usage of traditional neuroleptics seems indeed to be declining --
albeit without properly explicit transparency of the rationale
[2]. But the opposite seems to be happening for 'atypicals' which
have been increasing in use, and new indications for these drugs
are being promoted -- e.g. for affective disorders, and in very
young children. Given the evidence for the dangers of atypical
neuroleptics, the need to minimize exposure, and the availability
of better substitutes -- why is 'nothing' happening. Why indeed
are ever-more new indications for atypical neuroleptics being
pushed, when they almost always cause physiological damage and
sometimes cause fatalities?A full answer would need to include social attitudes to
psychiatric illness, and the relative powerlessness (lack of
autonomy) of psychiatric patients compared with other patient
groups. But the situation is also illustrative of the incentives
which operate generally in the pharmaceutical industry.
Pharmaceutical companies must make money in order to survive, and
this is usually done by researching and marketing new, relatively
expensive, patent-protected drugs. These incentives lead to the
production and promotion of new drugs even when they are less
effective and/or more dangerous than existing agents. This
clinically-damaging consequence is not simply a matter of 'benign'
neglect of old, off-patent drugs -- but actually a consequence of
the driving imperatives of the system.It is probable that the old antihistamines (for example) would
often provide a safer and less-unpleasant alternative to both
typical and atypical neuroleptics. The atypicals have confirmed
that sedation without Parkinsonism can provide sufficient
behavioural control for at least a significant number of patients
-- the clinical problem is simply to find the safest and best form
of sedation for particular patients [4] and [8]. So, it is
plausible that traditional sedating antihistamines, such as
promethazine, would be sufficient to control acutely agitated
behaviour in many psychotic patients, thereby avoiding the
potential dangers of exposing these patients to either the
traditional or atypical neuroleptics. The balance of potential
harm would almost certainly favor the antihistamines over the
neuroleptics.Why not use sedative antihistamines? Because those who control
RCTs control practiceGiven the powerful reasons for avoiding or minimizing patient
exposure to neuroleptics, it would not be unreasonable to consider
immediately substituting antihistamines for neuroleptics wherever
possible, especially by an initial trial of sedating
antihistamines for newly admitted acutely disturbed psychotic
patients. Since traditional neuroleptics are the most powerful
agents for suppressing agitated behaviour, there may be rare
situations in which their use is unavoidable. But the 'atypical'
neuroleptics can probably always be substituted by safer
sedatives, such as the benzodiazepines or antihistamines.
Naturally, in the long-term, the balance of benefits and harm
between sedatives and neuroleptics would need to be quantified by
formal clinical trials in various situations and patient groups.However, such a shift in practice -- however desirable from the
perspective of patients -- cannot and will not happen without the
development of new positive incentives to develop novel uses for
old drugs. The lack of marketing effort, and consequent
underusage, for old, off patent drugs is nothing new. But what is
new is the erroneous belief that the only valid source of evidence
regarding drug effectiveness comes from randomized controlled
trials -- particularly very large mega-trials [9] and [10]. This
ignorant over-valuation of RCTs has reached the point where those
who control randomized trials control clinical practice.It is widely believed, and at the highest levels of policy, that
RCT evidence is an uniquely 'unbiased' methodology because of the
use of randomization. Yet mega-trial RCTs are not
hypothesis-testing science, but instead a method of measuring the
effect-size of therapies -- and their meaning depends on what is
being measured and how [10]. Therefore, RCTs do not constitute
transparent, explicit information about therapies; but always
require contextual interpretation [11]. Nowadays, the most
influential contextual interpretation occurs within the
constraints of marketing imperatives, which enable the biases of
RCTs to be exploited by those who control them. The distorting
effects of highly-selective subject recruitment, methodological
specificity (e.g. choice of dosages and outcome measures),
together with selective reporting and publicity (driven by
marketing rather than scientific considerations), render RCTs just
as bias-prone as any other clinical research methodology -- and
much more damagingly so since their universal generalizability is
assumed [11].An unintended-consequence of ignorantly over-valuing and
misapplying RCTs is that drugs for which large quantities of
recent randomized trial data are lacking have become -- de facto
-- unusable, even when the use of these agents is supported by a
coherent body of pharmacological, clinical and historical evidence
as is the case for using sedatives in agitation and acute
psychosis [8].The pervasive misunderstanding and misinterpretation of RCTs among
policy-shapers is another explanation why modern psychiatric
practice is apparently 'locked-in' to the status quo of using
ever-more atypical neuroleptics, no matter how harmful this
situation may be, and how much preventable misery, disease and
death this practice may be causing. Psychiatrists, as individuals,
may be aware of the problems of 'atypical' neuroleptics, may
indeed wish to stop using them and try something else; but other
types of practice are all-but-indefensible under present
conditions. Presumably this nightmarish situation will continue
until the patents on atypicals lapse, and a new generation of
expensive patent-protected agents has emerged with an accompanying
mass of RCT data to backup their mass marketing. The irony is
that, as things stand, any replacement drugs may be (even) worse
than the atypicals.Self-management for clinical self-defense, reshaping incentives
for therapeutic progressIn the immediate term, it seems plausible that already-existing,
cheap, sedative drugs offer realistic hope of being safer, equally
effective and subjectively less-unpleasant substitutes for
neuroleptics in many patients (although precise epidemiological
measures of their relative safety and effectiveness are lacking).
If we were to apply the test of choosing what treatment we would
want for ourselves or our relatives with acute agitation or
psychosis, knowing what we now know about neuroleptics, I think
that many people (perhaps especially psychiatric professionals)
would wish to avoid neuroleptics except as a last resort. And we
would probably not wish to wait a decade or so for the
accumulation of a mass of randomized trial data (which may never
emerge) before making the choice of less dangerous and unpleasant
drugs.Since psychiatrists cannot or will not stop using neuroleptics,
the implication may be for more widespread and better informed
self-management of psychosis [12] -- including more informal
management by families of their members with psychiatric problems.
Unless prescription-only agents are obtained using the internet,
this probably suggests a greater use of 'over-the-counter' (OTC)
drugs which can be purchased from a pharmacist. For instance,
there are many sedative antihistamines which are available OTC and
without prescription. Potentially, it might become as common for
people to self-manage or prevent milder episodes of psychotic
agitation or hypomania using sedating antihistamines, as it
currently is to self-manage milder forms of depression and anxiety
using St John's Wort/Hypericum [12].But self-management -- while probably useful -- is insufficient.
We also need to think in terms of optimizing future therapeutic
discoveries. Drug development, research, marketing and therapy are
all subject to perverse structural incentives which -- in the
medium-term -- require substantial re-orientation. The magnitude
of the problem facing policy-makers can be encapsulated by the
observation that -- even if (hypothetically) it happened it be the
proven case that sedating antihistamines were in every way
superior drugs to atypicals -- under current conditions there is
no effective professional motivation in the system of psychiatry
to stimulate the huge shift in clinical practice and clinical
reasoning entailed by their adoption. In particular, with present
incentives, it is extremely unlikely that there will ever be a
significant body of randomized trials of -- say atypical
neuroleptics versus sedating antihistamines in calming agitation,
the treatment of acute psychosis, or for the prevention of manic
or schizophrenic breakdown. And without such a mass of trials (and
the marketing power to push them), then a change to safer
sedatives is very unlikely.In policy terms, there need to be new incentives whereby it
becomes possible to make money from marketing new indications for
old, off-patent drugs and technologies. These incentives need to
be financial if they are to mobilize sufficient resources to
change clinical practice. It will probably be necessary to
consider introducing new forms of short-term licensing and
re-patenting of old drugs, with similar arrangements for clinical
procedures and other medical technologies [13]. This is uncharted
territory -- various ideas will need to be proposed, critiqued and
trialed. But there should be a sense of urgency about tackling the
problem. We are all patients, potential patients and relatives of
patients; so it is in everyone's interests that drug development
and research should continue, and that the incentives which shape
it should be orientated towards optimizing therapeutic benefits.References
[1] D. Healy, The creation of psychopharmacology, Harvard
University Press, Cambridge, MA, USA (2002).[2] R. Whitaker, Mad in America, Perseus Publishing, Cambridge,
MA, USA (2002).[3] R. Whitaker, The case against antipsychotic drugs: a 50 year
record of doing more harm than good, Med Hypotheses 62 (2004), pp.
5-13. SummaryPlus | Full Text + Links | PDF (189 K) | View Record
in Scopus | Cited By in Scopus (12)[4] B. Charlton, Psychiatry and the human condition, Radcliffe
Medical Press, Oxford, UK (2000).[5] D. Healy, Psychiatric drugs explained (3rd ed.), Churchill
Livingstone, Edinburgh (2002).[6] M.G. Morgan, P.J. Scully, H.A. Youssef, A. Kinsella, J.M.
Owens and J.L. Waddington, Prospective analysis of premature
mortality in schizophrenia in relation to health service
engagement: a 7.5 year study within an epidemiologically complete,
homogenous population in rural Ireland, Psychiat Res 117 (2003),
pp. 127-135. SummaryPlus | Full Text + Links | PDF (98 K) | View
Record in Scopus | Cited By in Scopus (7)[7] C. Montout, F. Casadebaig, R. Lagnaoui, H. Verdoux, A.
Phillipe and B. Begaud et al., Neuroleptics and mortality in
schizophrenia: a prospective analysis of deaths in a French cohort
of schizophrenic patients, Schizophr Res (2002), pp. 147-156.
Abstract | Abstract + References | PDF (113 K) | View Record in
Scopus | Cited By in Scopus (19)[8] J. Moncrieff and D. Cohen, Rethinking models of psychotropic
drug action, Psychother Psychosom 74 (2005), pp. 145-153. Full
Text via CrossRef | View Record in Scopus | Cited By in Scopus
(14)[9] D. Healy, Let them eat Prozac, New York University Press, NY,
USA (2004).[10] B.G. Charlton, Fundamental deficiencies in the megatrial
methodology, Curr Control Trials Cardiovas Med 2 (2001), pp. 2-7.
Full Text via CrossRef[11] B.G. Charlton, P.R.A. Taylor and S.J. Proctor, The PACE
(population-adjusted clinical epidemiology) strategy: a new
approach to multi-centred clinical research, QJM 90 (1997), pp.
147-151. Full Text via CrossRef | View Record in Scopus | Cited
By in Scopus (28)[12] B.G. Charlton, Self-management of psychiatric symptoms using
over-the-counter (OTC) psychopharmacology: The S-DTM therapeutic
model - self-diagnosis, self-treatment, self-monitoring, Med.
Hypotheses 65 (2005), pp. 823-828. SummaryPlus | Full Text +
Links | PDF (96 K) | View Record in Scopus | Cited By in Scopus
(3)[13] B.G. Charlton and P. Andras, The future of 'pure' medical
science: the need for a new specialist professional research
system, Med Hypotheses 65 (2005), pp. 419-425. SummaryPlus | Full
Text + Links | PDF (98 K) | View Record in Scopus | Cited By in
Scopus (6)
poster:alan2102
thread:788467
URL: http://www.dr-bob.org/babble/20071009/msgs/788467.html