Discontinuation of thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7352.1519 (Published 22 June 2002) Cite this as: BMJ 2002;324:1519All rapid responses
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Dear Editor
The article by Dr SJ Davies et al (1) struck a chord with us.
We are a general practice of 5,500 patients and had 11 patients
well controlled on thioridazine, 6 with learning delay and the rest with
mixed mental health problems. We look after two hostels for those with
learning disabilities and some sheltered accomodation , where most of
our patients lived (7/11). Our experience was that it was that in 8
out of the 11 there were significant problems with the changeover,
most notably an increase in agitation, severe in some and
distressing to both carers and patients alike One patient was
admitted to a hospital under a section from February 2001 to May
2001,, another from October 2001 who is still an inpatient, and another
who I had seen 5 times in 2000 had 41 surgery consults in 2001. The
total number of consults for all patients at the GP surgery was 153
for 2000 amd 149 for 2001, but this does not include phone calls, out
of hours contacts and hospital appointments, all of which were
increased.
Infromation re alternative medications was poor. The initial
local suggestion of promazine was not appropriate as it had little
sedative effect , relative tom thioridazine. , We also ran out of it
here in Sheffield and patients had to be prescribed large volumes of
syrup, Only one of the eleven was finally stabilised on it .
I agree with their comments that balancing cardiovascular risk
against the psychological and pharmacological impact of changing drugs
can be difficult but feel that in this case the MCA/CSM guidance,(2)
was too proscriptive to the detriment of our patients , and I believe
our evidence supports theirs, as to the distress caused, by this and
also the substantioal workload. generated in both primary and secondary
care services. As generalists, we felt the guidance was so strong
that we were obliged to change our patients over, as it would be
hard to defend not doing so at that time.
Davies SJC, Cooke LB, Moore AG, Potokar J. Discontinuation of
thioridazine in patients with learning disabilities: balancing
cardiovascular toxicity with adverse consequences of changing drugs. BMJ
2002; 1519-1521. (22 June )
Medicines Control,Agency/Committee on Safety of Medecines. QT
interval prolongation with antipsychotics. Current problems in
pharmacovigilance 2001.1: 27: 4
Paul Driscoll
General Practitioner,
Heeley Green Surgery,
302 Gleadless Rd,
Sheffield
S2 3AJ
0114 2500326
Competing interests: No competing interests
The article by Davies raised some important issues on Thioridazine
discontinuation in Learning Disability population.1
As against the author's experience, we had successful withdrawal of
Thioridazine in our services at Salford district.
We looked at the following issues before withdrawal of Thioridazine:
1.Initial Diagnosis before Thioridazine was prescribed.
2.Duration and dose of treatment.
3.Review of previous psychiatric treatment including attempts to reduce /
stop Thioridazine.
Results indicated that out of 175 patients under the care of a
Learning Disability Psychiatrist, 28 of them received Thioridazine. The
majority (23 patients) received small doses (50 - 100 mg) for many years.
The main indication for use was marked Challenging Behaviour (12
patients).
Based on the above information, a decision was made to gradually
reduce (12 patients) or suddenly stop Thioridazine (16 patients).
Alternative tranquilliser was prescribed for all 28 patients.
Risperidone was the most commonly used atypical antipsychotic because of
some evidence of its effectiveness in challenging behaviour.2
A review of patients' mental state three months after the
substitution of tranquillisers indicated that:
21 patients either remained stable or improved
7 patients deteriorated
These 7 patients subsequently improved, either by a change to a
different psychotropic drug or by adjusting the dose of existing drugs.
No patient required to restart Thioridazine.
Review of previous psychiatric treatment helped us to identify
instances of rebound increase in behavioural problems when Thioridazine
was stopped. It also prompted us to avoid using those Neuroleptics which
were either ineffective or caused unacceptable side effects. Evidence of
rebound aggression on stopping neuroleptics was also observed by Mos et al
.3 This lead us to withdraw Thioridazine gradually in most cases.
In our opinion risk associated with the withdrawal of Thioridazine
was carefully managed and minimised by taking into account the diagnosis,
the dose and duration and consequences of previous reduction in medication
followed by a careful strategy of either gradual reduction or sudden
stoppage with replacement of alternative tranquillisers in appropriate
doses.
Dr. Pernia Arshad
Consultant in Learning Disability Psychiatry,
Meadowbrook,
Department of Psychological Medicine,
Stott Lane
Salford
M6 8HD
Dr. Mary Marcos
Senior House Officer in Psychiatry
Dr. B.Sridharan
Specialist Registrar in Psychiatry
References:
1.Simon J C Davies, Leila B Cooke, Alan G Moore, and John
Potokar.Discontinuation of thioridazine in patients with learning
disabilities: balancing cardiovascular toxicity with adverse consequences
of changing drugs. BMJ 2002 : 324: 1519-21. (22nd June 2002)
2.Vander Ben Borre R. Risperidone as add- on therapy in behavioural
disturbances in mental retardation: a double blind placebo-controlled
Cross- over study. Acta Psychiatrica Scandinavica 1993: 87, 167-71.
3.Mos,J., Van Aken, H.H., Van Oorschot,R. & Olivier,B. Chronic
treatment with Eltoprazine does not lead to tolerance in its anti-
aggressive actions, in contrast to Haloperidol. European
Neuropsychopharmacology 1996 : 6, 1-7.
Competing interests- None
Competing interests: No competing interests
BMJ readers may be interested in this reply from the Medicines
Control Agency to my last letter
MCA ref: HPO2690 8 July 2002
Dear Dr. Murray,
Thank you for the copy of your response to the article by Davies et
al in the BMJ 324:1519-1521 entitled ‘Discontinuation of thioridazine in
patients with learning disabilities: balancing cardiovascular toxicity
with adverse consequences of changing drugs’ published on June 22 2002.
The wording which was issued from the Medicines Control Agency (MCA)
can be found as follows: 1) MCA Press release, 2) Message from Professor
Alasdair Breckonridge, Chairman of CSM, 3) Advice on prescribing
information and 4) DOH on the following web links:
1.
http://www.mca.gov.uk/whatsnew/pressreleases/thioridazinepressrelease.htm
2. http://www.mca.gov.uk/mca/csm/thiolet.pdf
3. http://www.mca.gov.uk/mca/csm/thisspc.pdf
4. http://www.doh.gov.uk/cmo/cemcmo200018.pdf
The website which you have cited in your response
(http://www.doh.gov.uk/cmo/cmo00_18.htm) is the only one to contain the
garbled english that you have highlighted. As all the others are
consistent with the original communications cascaded from the MCA we do
not know how this has happened. We will notifiy the DOH of this dichotomy
in their website.
The points that you have raised in your response about gradual
withdrawal and that were also highlighted in the original BMJ article are
well made. Should any similar issues arise in the future then such points
and suggestions will be taken into account when seeking advice from the
CSM and will be important features of future communications.
The communication issues arising from the restriction of thioridazine
have provoked numerous comments for future consideration and we are
grateful to you for your contribution.
Yours sincerely,
Dr. A. Horsfall
Scientific Assessor
Pharmacovigilance
Post Licensing Division
Competing interests: No competing interests
Until the Committee on Safety of Medicines (CSM) restricted the use
of Thioridazine in 2000, it was the most widely used anti-psychotic in the
UK, with 50 million years’ of safe patient use world-wide. In Scotland in
1999, there were 250,808 prescriptions dispensed in primary care (hospital
data not available, but CSM reports it was the most widely used anti-
psychotic in hospital as well). This dropped to 39,177 in 20012.
Is Thioridazine safer, cheaper and more effective than alternative
anti-psychotic drug treatments for anxiety, agitation, mania and
hypomania? There is simply not enough evidence to answer this because
thioridazine has been very widely used for 30 years – before the days of
rigorous Randomised Controlled Trials. Lack of evidence is not evidence of
no benefit. Conversely, there is only evidence of a handful of adverse
cardiac events, some of which may not have been directly caused by
Thioridazine, or may have been due to combination with other drugs. While
the reported cardiac deaths are lamentable, it appears that Thioridazine
is very much safer than other effective drugs such as Aspirin, which
continues to be sold over the counter.
Even if there is some under-reporting of adverse events, there is far
more practical evidence of long-term safety for Thioridazine compared to
much more expensive and much less tried and tested drugs. A recent JAMA
study3 noted that many new drugs have a high rate of serious side-effects
which go undetected until late in post-marketing surveillance. CSM needs
to balance these relative risks.
The manufacturers of Thioridazine have raised few objections to the
restricted use of Thioridazine because it is an extremely cheap drug,
costing only a few pence compared with newer anti-psychotics, which may be
up to a hundred times more expensive, as well as having different and
sometimes distressing side-effects. The cost of anti-psychotic
prescriptions has risen sharply in the last two years in Scotland2.
Anecdotally, considerable numbers of patients with hypomania, anxiety
and agitation are having considerable problems in adjusting to a change of
drugs, and, as Davies points out, informed consent may be a problem1.
It would be very helpful if NICE or Health Technology Board for
Scotland reviewed the evidence, risks and benefits of Thioridazine, and
considered more humane guidelines for its future use. It seems quite wrong
to deprive so many patients of a well-tried drug.
1. Davies SJC, Cooke LB, Moore AG, Potokar J. Discontinuation of
Thioridazine in patients with learning disabilities: balancing
cardiovascular toxicity with adverse consequences of changing drugs. BMJ
2002:324: 1519-21.
2. Information from Primary Care information Unit, Information &
Statistics Division, Trinity Park House, Edinburgh EH5 3SQ
3. Lasser K, Allen P et al. Timing of new black box warnings and
withdrawals for prescription medications. JAMA 2002: 287:2215-20
Ann F Bisset
Medical Adviser, Public Health Medicine, Information & Statistics
Division, Trinity Park House, Edinburgh EH5 3SQ
Email: ann.bisset@virgin.net
No competing interests.
Competing interests: No competing interests
Davies et al are right to raise concerns about the discontinuation of
thioridazine in patients with learning disabilities. However, there are
reasons for questioning some of their interpretations of the problems
which have arisen in carrying out advice from the Committee on Safety of
Medicines. Thioridazine’s high anticholinergic activity may be associated
with severe withdrawal syndromes for some people. The Chief Medical
Officer refers to these as “nausea, vomiting, gastric upset, trembling,
dizziness, anxiety, agitation and insomnia, as well as transient
dyskinetic signs or the re-emergence of psychotic symptoms.” ‘Gradual’
withdrawal is advised in pursuance of their avoidance.
Unfortunately, prevalent definitions employed by prescribers refer
to periods of between one week and four weeks as “gradual withdrawal”. For
drugs which may have been taken for decades this is an abrupt and not a
gradual change. In my own observation, discontinuing Thioridazine in
people with learning disabilities after longterm use without a long taper
can have catastrophic effects [1]. Dramatic weight loss, severe
disruption of sleep patterns, pronounced almost incessant agitation and
restlessness with distressed vocalisations are features of these abrupt
withdrawals which may last for months after rapid onset coinciding with
drug discontinuation. Sovner found a similar pattern in his cases of
thioridazine withdrawal, with anxiety and insomnia prominent[2] .
Here is what a veteran pharmacist who spent decades specialising in
psychiatric drugs says about antipsychotic withdrawal, "All the problems,
like benzodiazepines, occur when withdrawal is attempted in a few days or
few weeks"[3] .
There are a number of reasons for suspecting that a proportion of the
patients who had problematic withdrawal from thioridazine in the study by
Davies et al were undergoing withdrawal reactions, with or without
eventual re-emergence of a baseline pathology. One reason is the speed of
onset of disturbed behaviour, one is the appearance of psychotic like
symptoms in people who did not initially have a diagnosis of psychosis,
one is the cases where switching to another antipsychotic did not curtail
the problem behaviours, one is the case of NMS , and finally it would be
surprising if nobody experienced a withdrawal syndrome when after only 37
weeks of antipsychotic treatment even monkeys show disturbed behaviours
after discontinuation for as long as seven weeks before beginning to
return to baseline [4].
This view is also supported by the findings of May et al that “of 23
severely and profoundly mentally retarded adult male patients undergoing
slow "diagnostic" neuroleptic taper, it was determined that at least 60%
could eventually be managed without psychoactive medication. However, many
of these demonstrated a remarkably long, but nonetheless transient, period
of worsening” (my emphasis)[5].
Davies et al remark that, “Although the adverse consequences for the
seven patients who stopped taking thioridazine could be viewed as being
attributable to poor management of change, the clinicians involved felt
they had little option but to follow the Committee on Safety of Medicines'
advice”. A significant defect in that advice was its characterisation of
“gradual withdrawal”. Strangely, when that advice appears as from the
Committee’s Chair, Professor Alan Breckenridge, (online) it is thus:
“When discontinuing thioridazine a gradual reduction in dosage over
several weeksone to two weeks is recommended “[sic][6] . Did someone
alter the original statement and replace “several weeks” with “one to
two”? If so, they may be responsible for widespread distress, often
leading to “prescribing cascades”[7] . An ideally slow taper would be no
faster than 10% every two to three months, especially after chronic use of
thioridazine or other neuroleptics.
footnotes
1.Murray DKC 1999, “Potions Pills and Human Rights”, Good Autism
Practice April 1999, pp.1-13.
2.Sovner,R. 1995, “Thioridazine withdrawal induced behavioral
deterioration treated with clonidine: Two case reports”. Mental
Retardation, 33, 221-225.
3.Stuart Baker http://www.apana.supanet.com/links.htm
4. Amore M, Zazzeri N. 1995 Neuroleptic malignant syndrome after
neuroleptic discontinuation. Prog Neuropsychopharmacol Biol Psychiatry
;19(8):1323-34
5. May P, London EB, Zimmerman T, Thompson R, Mento T, Spreat S. 1995
“A study of the clinical outcome of patients with profound mental
retardation gradually withdrawn from chronic neuroleptic medication.”
Ann Clin Psychiatry. Dec;7(4):155-60.
6. www.doh.gov.uk/cmo/cmo00_18.htm
7. See Webb, OJ. 1996, Medication use patterns in IHC community
homes. NZ Fam Physician; 23: 4-6. and Murray DKC 1999, “Potions Pills and
Human Rights”, Good Autism Practice April.
Competing interests: No competing interests
Dear Sirs,
As a sufferer of schizophrenia, I am delighted that The Committee on
Safety of Medicines restricted the indications for thioridazine, although
FDA gave similar recommendations 6 months earlier in United States. In
Sweden, for instance the Medical Product Agency (MPA) has done nothing to
restrict it's use and they have recently told me that such decisions are
based on national adverse effect reports and it is difficult to get enough
evidence to make such restrictions. In Sweden, year 2001 20 % of the Drug
Committees recommended thioridazine against psychosis, which seems not
very appropriate regarding the risk of cardiac side effects and the fact
that schizophrenia seems to have an increased cardiac mortality.1
Concerning this article, it is naturally very interesting although
the number of patients involved seems rather small. The results, however,
suggests that the majority can change to a less harmful drug and also the
general importance of a careful choice of drugs to the group of learning
disabilities. In some countries, I am sure that this group of patients are
often treated by GP:s, who might lack this awareness.
What I lack in this article is the strategy they adopted with the
patients that had problems to change from Mallorol. At Schizophrenia sites
on Internet, I often meet desperate family members of schizophrenia
patients that wants advice how to convince him/her to comply with the
medication and care. The usual advice is buy the book "I Am Not Sick, I
Don't Need Help! Helping the Seriously Mentally Ill Accept Treatment: A
Practical Guide for Families and Therapists" by Xavier Amador, Ph.D., with
Anna-Lisa Johanson. After a year or so of recommending this book, I have
started to wonder, if the care have read it and what strategy they uses in
such cases. Doctors have prescribed drugs for several houndred years, but
still is not able to treat patients that refuse medication. This suggests
that more education and research should be directed to the problem with
non-compliance and it is especially urgent in schizophrenia.
Yours truly
Sir Nil
Founder of the site: Whisper - about schizophrenia
Information source, Meeting point,Whistle-blower
http://hem.passagen.se/sir.nil/
1. Allebeck, P
Schizophrenia: A life shortening disease
Schizophrenia Bullentin, 1989, 15: 81-89
Competing interests: No competing interests
Editor-
I am sure that many clinicians like me would have relished the article by
Dr.Davies et al as they have voiced their views regarding the use of
Thioridazine in day to day clinical practice.(ref:1)
It was a time when the committee on Safety of Medicines restricted the
licensed indications for thioridazine, when not only the patients but also
professionals including GPs were expressing their anguish at the decision
made.
It is interesting to note that the National Institute for Clinical
Excellence (NICE)(ref:2)has now come out with the guidance on the use of
newer (atypical) antipsychotic drugs for the treatment of Schizophrenia.
However, NICE does not recommend change to one of the atypical
antipsychotic drugs if a patient is currently taking typical antipsycotics
that are controlling the symptoms of schizophrenia and are not causing
unacceptable side effects. It is undeniable that it is important to work
with the patient in determining the care and medication following a
discussion on the relative benefits of each of the drugs and their side-
effects.
In that case, will the directives allow clinicians greater flexibility in
their clinical practice to continue established drug regimes with careful
and adequate monitoring?
Dr.V.Murali
Specialist Registrar in Psychiatry
Cossham Hospital,
Bristol
1. Simon JC Davies, Leila B Cooke, Alan G Moore, John Potokar.
Discontinuation of thioridazine in patients with learning disabilities:
balancing cardiovascular toxicity with adverse consequences of changing
drugs. BMJ 2002;324:1519-21
2. NICE Technology Appraisal Guidance - No.43, National Institute for
Clinical Excellence. (www.nice.org.uk)
Competing interests: No competing interests
Discontinuation of thioridazine: guidelines should consider indications of drugs beyond their licens
Editor – The article by Davies et al(1) highlights the difficulties
encountered resulting from thioridazine being restricted due to its
association with prolonged QT interval and cardiac arrhythmia. Several
other drugs e.g. cisapride, droperidol, have been withdrawn for the same
reason. In palliative care, thioridazine and cisapride were of use in the
management of symptoms, usually for an unlicensed indication, as are other
commonly used antipsychotics, e.g. haloperidol and tricyclic
antidepressants, e.g. amitriptyline, that also prolong the QT interval(2).
Given the growing safety concerns relating to prolonged QT and the lack of
information regarding the extent to which it is a problem in palliative
care patients, we routinely carry out an ECG on all new referrals to a
specialist palliative care unit, except those deemed to be imminently
dying. Of 200 patients with cancer, based on EMEA definitions(3), 26
(13%) had prolonged QTc (QT corrected for heart rate) and only 1 (0.5%)
had a seriously prolonged QT of over 500 milliseconds. Compared to those
with normal QTc interval, those with prolonged QTc had a greater
male:female ratio (p=0.001) and a higher incidence of cardiac disease
(p=0.01), otherwise demographics, biochemistry, use of ‘at risk’ drugs,
survival and incidence of sudden ‘unexpected’ death were similar. The
prevalence of prolonged QTc in palliative care patients appears similar to
psychiatric patients (8-23%), higher than reported in non-malnourished
hospital patients (4%) and less than reported in malnourished hospital
patients (23%)(4-6). However, severely prolonged QT appears to be
relatively rare. For any drug treatment, balancing the potential benefit
against the risk of harm is part of the prescribers’ responsibilities and
is aided by an understanding of the magnitude of the risk. We agree with
Davies that guidelines should provide flexibility to continue established
regimes where the benefits outweigh the potential harm but would add that
they also pay cognisance to the sometimes extensive use of these drugs for
indications beyond the license.
No competing interests
1. Davies SJC, Cooke LB, Moore AG et al. Discontinuation of
thioridazine in patients with learning disabilities: balancing
cardiovascular toxicity with adverse consequences of changing drugs.
British Medical Journal 2002; 324: 1519-1521.
2. Haverkamp W, Breithardt G, Camm AJ et al. The potential for QT
prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and
regulatory implications. European Heart Journal 2000; 21: 1216-1231.
3. Anonymous. Points to consider: the assessment of the potential for
QT interval prolongation by non-cardiovascular medicinal products.
European Agency for the Evaluation of Medicinal Products (EMEA); Committee
for Proprietary Medicinal Products: CPMP/986/96.
4. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SHL. QTc-interval
abnormalities and psychotropic drug therapy in psychiatric patients. The
Lancet 2000; 355: 1048-1052.
5. Warner JP, Barnes TRE, Henry JA. Electrocardiographic changes in
patients receiving neuroleptic medication. Acta Psychiatr Scand 1996; 93:
311-313.
6. Da Cunha DF, De Carvalho Da Cunha F, Ferreira TPS et al. Prolonged
QTc intervals on the electrocardiograms of hospitalized malnourished
adults. Nutrition 2001; 17: 370-372.
Competing interests: No competing interests