Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.38125.465579.55 (Published 08 July 2004) Cite this as: BMJ 2004;329:75
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Sir,
Lee et al (1) have reviewed the literature about the use of atypical
antipsychotic drugs (AADs) for treating behavioural and psychological
symptoms of dementia (BPSD) and have observed that AADs are being used
with increasing frequency for this indication. Their conclusion is that
typical and atypical antipsychotics have similar effectiveness for this
clinical indication with no difference in the respective adverse event
profile.
In the discussion of adverse events related to AADs, Lee et al. (1)
have not mentioned the increased risk of cerebrovascular adverse events
(2) that has been found in elderly people with dementia receiving
olanzapine or risperidone (3-fold increase). A two-fold increase of
mortality in this population has been found too (2).
In Italy, there is a widespread off-label use of AADs for BPSD. For
this reason, in March 2004 the Italian Ministry of Health has issued a
“Dear Doctor letter” to discourage this off-label use and to underscore
this risk of cerebrovascular adverse events (3).
One controversy regards the use of quetiapine for BPSD. This AAD has less
literature than olanzapine or risperidone in terms of both effectiveness
and adverse event monitoring. The Italian Ministry of Health admits that
this is the reason why quetiapine has not been contraindicated in the Dear
Doctor letter.
In this scenario, quetiapine could paradoxically benefit from its
lack of literature and there could be an unjustified switch towards
quetiapine of this off-label prescription of AADs. In our view, the
restriction for treating BPSD should have been applied to quetiapine as
well, and the entire off-label use of AADs for BPSD should have been
banned.
REFERENCES
1. Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA.
Atypical antipsychotic drugs in the treatment of behavioural and
psychological symptoms of dementia: systematic review. BMJ. 2004 Jul
10;329(7457):75. Epub 2004 Jun 11.
2. EMEA website.
http://www.emea.eu.int/pdfs/human/press/pus/085604en.pdf accessed on 23
August 2004
3. Italian Ministry of Health website.
http://www.ministerosalute.it/imgs/C_17_notaInf_1_listaFile_itemName_1_f...
accessed on 23 August 2004
Competing interests:
BS has acted as consultant for Eli-Lilly, Italy
Competing interests: No competing interests
Sir,
Lee et al have written an excellent review of published trials
comparing atypical antipsychotics with placebo and with typical
antipsychotics and found limited evidence that they work in patients with
behavioural and psychological symptoms of dementia (BPSD)(1). They state
that further evidence is required before atypical antipsychotics can be
endorsed in the management of behavioural and psychological symptoms of
dementia.
However, evidence about typical antipsychotics (including
haloperidol) is even more limited (2). In fact, legislation to restrict
antipsychotic prescription was introduced in the United States before
atypical antipsychotics were marketed, as side effects of the former were
considered frequent and severe. Typical antipsychotics have not been
explicitly licenced in most countries for the treatment of BPSD. Evidence
about other drugs is even weaker. Non-pharmacological treatments are
widely considered a first step in the treatment of BPSD, but evidence
about their use is also very limited (3).
Concerns have been raised about the risk of stroke with new
antipsychotics, but the mechanism of this association is unknown and data
about older antipsychotics are been reviewed to find if this is a group
effect or only some antipsychotics increase the risk.
As BPSD increase suffering of patients and their carers, increase the
risk of nursing home admission and increase cost of care, I believe
treatment is needed in severe cases. As good evidence is lacking for every
therapeutic intervention available, atypical antipsychotics are still
standing as a first line treatment of BPSD.
1. Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA.
Atypical antipsychotic drugs in the treatment of behavioural and
psychological symptoms of dementia: systematic review. BMJ. 2004 Jun 11.
2. Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in
dementia. In: The Cochrane Library, Issue 3, 2003. Oxford: Update
Software.
3. Cummings JL. Drug therapy: Alzheimer’s disease. N Engl J Med 2004;
351:56-67.
Competing interests:
The author has received reimbursments by Almirall Prodesfarma, Astra Zeneca, Janssen-Cilag, Novartis and Pfizer (manufacturers of typical and atypical antipsychotic drugs in Spain), for organizing educational programs and speaking; and fees from Janssen-Cilag for consulting.
Competing interests: No competing interests
Sir:
Reportedly, majority of demented patients suffer from multiple
medical and neuropsychiatric diseases as compared to age-matched normal
population. These diseases mainly include hypertension, coronary heart
disease, myocardial infarction, chronic congestive heart failure,
hyperlipaedemia, cerebrovascular accidents and associated disabilities,
diabetes mellitus, chronic renal failure, musculoskeletal disorders,
obesity,liver diseases, dementia, parkinsonism, and other degenerative
diseases of the CNS. Most importantly, individual patient with dementia
has often additional multiple diseases for which they are frequently
prescibed polypharmacy that has more disadvantages than benefits.
Reprtedly, elderly patients with dementia do manifest behavioral and
psychological manifestations, which are not only distressful to the
patient but also to care givers. These behavioral smptoms are caused by
biological disturbances as well as by environmental factors. Hence, all
patients with dementia may not require psychotropic medications. Only
comprehensive assessment of these demented patients guide whether or not
they need antipsychotics-atypical or traditional. If yes, these drugs
should be given in proper dosages, i.e., 1/3rd to 1/2half adult doses.
Secondly, the need of continuation of such medications in elderly
population should be assessed more frequently and early discontinuation
should be opted.
Both atypical and traditional antipsychotics are equally effective
in elderly population with dementia and moreover there is no additional
advantages of atypical over typical antipsychotics and vise versa. Both
types of antipsychotics have their own adverse effects, which more often
suggest that elderly patients should be managed by milieu manipulations
rather than by being heavily "drugged".
Reference:
Philip E Lee, Sudeep S Gill, Morris Freedman, Susan E Bronskill,
Michael P Hillmer, and Paula A Rochon. Atypical antipsychotic drugs in the
treatment of behavioural and psychological symptoms of dementia:
systematic review
BMJ 2004; 329: 75-0.
Competing interests:
None declared
Competing interests: No competing interests
We read with great interest the recent systematic review on the use
of atypical antipsychotics in the treatment of behavioural and
psychological symptoms of dementia (BPSD) (1). The authors referred to
new adverse events in the introduction and the conclusions section, but
did not specifiy them. We feel it is important that the readers are made
explicitly aware of the recent concerns expressed by the Committee of
Safety of Medicines (CSM) in the united Kingdom. In March of this year the
CSM informed all clinicians that risperidone and olanzapine increase the
risk of strokes by three-fold when used to treat BPSD, and olanzapine
increases the risk by two-fold for mortality when used to treat BPSD (2).
CSM guided clinicians not to use these two drugs in the treatment of BPSD.
These findings were based on pooled-analysis of placebo-controlled and
randomised studies of risperidone (six) and olanzapine (four) for the
treatment of BPSD (Personal communication fron Janssen-Cilag and Lily).
Similar concerns have been previously raised in the United States and
Canada for risperidone (3), but the concerns for olanzapine are entirely
new. Clearly these new concerns have alarmed clinicians as these two drugs
have been widely used in the treatment of BPSD because of their percieved
efficacy and better side-effect profile. It is indeed a pity that these
concerns were not made explicit and the only reference the authors make
about cerebrovascular adverse events pertained to one study (4).
References
1. Lee PE, Gill SS, Freedman M. Atypical antipsychotic drugs in the
treatment of behavioural and psychological symptoms of dementia:
systematic review. 2004; 329: 75-78.
2. CSM. Atypical antipsychotic drugs and stroke.
http:/medicines.mhca.gov.uk/aboutagency/regframework/csm/csmhome/wlht.
Acess 17 May 2004.
3. Smith D, Beier M. Association between risperidone treatment and
cerebrovascular adverse events: examining the evidence and postulating
hypothesis for an underlying mechanism. Journal of the American Medical
Directors Association. 2004; 5: 129-132.
4. Brodaty H, Ames D, Snowdon J. A randomised trial of risperidone in
the treatment of aggression, agitation and psychosis in dementia. Journal
of Clinical Psychiatry. 2003; 64: 134-143.
Competing interests:
Both Dr Shah & Professor Suh have received funding from Janssen to attend meetings
Competing interests: No competing interests
Dear Sir,
In their review article, Lee et al state that "further evidence is
required before" atypical antipsychotics "can be endorsed in the
management of behavioural and psychological symptoms of dementia"(1). It
is of note that of the five randomised trials reviewed, only 3 contained
information on adverse events, and only 2 of these reported on the number
of serious adverse events.
It must be remembered that at present no atypical antipsychotic is
licensed for the treatment of behavioural disturbances in dementia. In
March 2004, after analysing data from randomised placebo-controlled
clinical trials,and finding an approximate three-fold increased risk of
cerebrovascular adverse events in patients taking Risperidone or
Olanzapine compared to placebo, the Committee on Safety of Medicines
advised that Risperidone or Olanzapine should not be used for the
treatment of behavioural symptoms of dementia (2).
Perhaps this is all the evidence needed, but perhaps not.Let us not
forget that all drugs can have serious side effects, and also the
importance of non-pharmacological interventions.
Anna Richman
1 Lee P E, Gill S S, Freedman M, Bronskill S E,Hillmer M P, Rochon P
A .Atypical Antipsychotic drugs in the treatment of behavioural and
psychological symptoms of dementia :systematic review.BMJ 2004;329:75-78
2.Committee on Safety of Medicines : Atypical Antipsychotic Drugs and
stroke CEM/CMO/2004/1
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
Lee et al looked at trials that compared atypical antipsychotics with
placebo and with typical antipsychotics and found limited evidence that
they work in patients with behavioural and psychological symptoms of
dementia. (1)
However neither placebo nor typical antipsychotics have been shown to
help patients with behavioural and psychological symptoms of dementia. (2)
Trials should always compare new treatments with the best available
old treatments. And the treatments that are most likely to be helpful in
patients with behavioural and psychological symptoms of dementia are
carbamazepine and reality orientation. (3, 4)
Lee et al should have drawn greater attention to this in their review
and encouraged future researchers to compare new drugs with proven older
treatments - carbamazepine and reality orientation. Until this happens
patients and their carers will continue to get a raw deal.
Yours Sincerely,
Dr. Kieran Walsh,
Editorial Registrar,
bmjlearning.com
1. Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA.
Atypical antipsychotic drugs in the treatment of behavioural and
psychological symptoms of dementia: systematic review. BMJ. 2004 Jun 11.
2. Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in
dementia. In: The Cochrane Library, Issue 3, 2003. Oxford: Update
Software.
3. Spector A, Orrell M, Davies S, et al. Reality orientation for
dementia. In: The Cochrane Library, Issue 3, 2003. Oxford: Update
Software.
4. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability
of carbamazepine for agitation and aggression in dementia. Am J Psychiatry
1998;155:54–61.
Competing interests:
None declared
Competing interests: No competing interests
I applaud the fine article by Lee et al(1) reviewing the double blind
placebo controlled data on atypical antipsychotic drugs in the elderly. I
would like to suggest that drug induced parkinsonism is likely to have
been underreported in each of the trials cited(2). For example, it was
noted in this review that olanzapine was associated with "abnormal gait."
The article reporting the abnormal gait however reported that "objective
EPS were absent with olanzapine." Based on my personal experience (2) it
is hard to escape the conclusion that the "abnormal gait" was simply a
manifestation of parkinsonism. No other explanation was provided. The
literature on the effects of olanzapine in people with Parkinon's disease
is very clear in demonstrating worsened motor function (4), and elderly
people with dementing diseases, including Alzheimer's disease, dementia
with Lewy bodies and vascular dementia, are highly vulnerable to the
parkinsonian side effects of medications. I suspect that this
underreporting of parkinsonism in the olanzapine study extends to the
reporting in the other studies as well.
1. Lee PE, Gill SS, Freedman M, et al. Atypical antipsychotic drugs in the
treatment of behavioural and psychological symptoms of dementia:
systematic review. BMJ doi:10/1136/bmj.38125/465579.55
2. Friedman JH, Trieschmann MM, Fernandez HF. Parkinsonism in a Nursing
Home-Underrecognition. J Ger Psychiatry 2004;17:39-41
3. Street JS, Clark WS, Kadam DL, et al. Long term efficacy of olanzapine
in the control of psychotic and behavioral symptoms in nursing home
patients with Alzheimer's dementia. Int J Geriatr Psychiatry 2001;16:S62-
70.
4.Breier A, Sutton VK, Feldman PD, Kadam DL, Ferchland I, Wright P,
Friedman JH. Olanzapine in the treatment of dopamimetic-induced psychosis
in patients with Parkinson’s disease. Biol Psychiatry 2002;52:438-45.
Competing interests:
I have received remuneration for consulting, speaking or clinical research from: Astra-Zeneca, Janssen, Lilly, Bristol Myers Squibb, Pfizer
Competing interests: No competing interests
Dear sir/madam,
Your research shows promising results for treating behavioural and
psychotic symptoms in dementia. My concern is, how far we can safely use
atypicals as there is increased evidence of cerebrovasculr events in
people with dementing illness.It is not recommended to use Resperidone and
Olanzapine in dementia.
Competing interests:
None declared
Competing interests: No competing interests
No excess of stroke with risperidona in a Primary Care area
In May 2004, the Spanish Committee on Drugs Safety of Medicines
advised that risperidone should not be used for long periods in elderly
patients suffering from dementia.
We conducted a retrospective study of clinical records of demented
patients over 64 in an urban area (44.800 people, 181 registered cases of
dementia) attached to a Primary Care Centre in Barcelona. We recorded
stroke rates, cardiovascular risk factors, type of dementia, and
demographic data from the whole181 community dwellers with dementia
registered from 1/1/1999 to 15/06/2004.
During the 6 years, we found 5 strokes among the 17 patients on
haloperidol (29, 4%), and 28 cerebrovascular accident among 87 patients
having risperidone (32, 2%). Out of the 61 demented patients untreated 11
(18%) had a stroke. No significant differences were found (p=0, 15). The
groups were similar except for an excess of diabetic patients in the
risperidone group (33% vs. 5, 9%, p=0.021). The average time running on
antipsychotic drugs was 1, 5±1, 6 years without differences within both
drugs. (p=0.33)
We recognize our population is small but the resemblance of risperidona
risk and benefit ratio remains unclear in Primary Care.
Competing interests:
None declared
Competing interests: No competing interests