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Rapid Responses: Rapid Responses published:
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correction: this could be low DHEA...
- James M. Howard (18 February 2005)
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Cognitive changes could be explained by reversible acute sedative effects
- Erick H Turner (20 February 2005)
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Agitation in patients with dementia
- Zafeer H.K Barki (9 March 2005)
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Quetiapine for Lewy Body
- B. Andrew Farah (14 March 2005)
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Safety and efficacy of atypical antipsychotics in the treatment of patients with behavioural symptoms of dementia
- Peter Paul De Deyn (17 March 2005)
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The Cognitive Decline Associated with Quetiapine in Alzheimer’s disease
- ARUNRAJ BALAKRISHNA KAIMAL, MRCPsych, UMA VISWANATHAN NAIR, SHO IN PSYCHIATRY (12 April 2005)
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Quetiapine and cognitive decline: apply caution
- Ajit K Shah (16 April 2005)
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Mechanisms of cognitive decline
- Simon R Wright (19 April 2005)
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Confusion around the scales and interpretation of the results
- Thomas Marshall (21 April 2005)
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Conclusion based on insufficient power
- Lena Palaniyappan, Gill Pinner, Consultant Psychiatrist for Older People (6 May 2005)
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Rivastigmine - thoughts of a journal club
- Jonathan C Haynes, Stuart Nicholl, Anoop Devasahayam, Emma Kelson, Daniel Hirsch (9 May 2005)
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Concerns regarding the article
- JANAKIRAMAN RAGURAMAN (23 August 2005)
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James M. Howard, independent biologist Fayetteville, Arkansas, U.S.A.
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"In 1985 I suggested low DHEA could result in Alzheimer's disease. While controversial, this hypothesis has since been supported. A case may be made that low DHEA is connected to AD. While I could not find research connecting quetiapine with DHEA, quetiapine reduces prolactin which is a direct stimulator of DHEA and quetiapine reduces cortisol which has been interpreted to indicate that quetiapine shuts down the HPA axis. I suggest the negative effects of quetiapine on individual with AD is due to the shutdown of DHEA." Competing interests: None declared |
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Erick H Turner, Medical Director, Mood Disorders Program Portland VA Medical Center, Portland, Oregon 97201 USA
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On first glance, it would appear alarming that quetiapine administration could be associated with cognitive decline. Rather than concluding that these are irreversible changes, it seems at least equally likely that the cognitive changes observed could be explained by reversible acute sedative effects of quetiapine. Quetiapine is known to be strongly antihistaminic. According to the package insert, the rate of sedation was observed to be 18% for quetiapine versus 8% for placebo. The corresponding numbers for rivastigmine are 5% versus 3%. In this study, quetiapine administered twice daily. Although the total daily dose of 50 to 100 mg/day might seem low in comparison to the typical doses given in clinical trials to younger patients with schizophrenia and mania, these are not trivial geriatric doses. It seems that these geriatric patients could have experienced sufficient sedation from the morning doses of 25 to 50 mg (in addition to the overall effect of chronic dosing) to cause a significant effect on their cognitive performance. To test the hypothesis that an irreversible cognitive effect had occurred, and to remove the confound of acute sedation, one could retest the patients after they had undergone a washout. To test the hypothesis that acute sedation can affect performance on cognitive testing, one might test patients receiving twice daily dosing of nonpsychotropic sedating medications such as diphenhydramine or hydroxyzine. Competing interests: I am on the speaker's bureau for AstraZeneca. |
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Zafeer H.K Barki, Staff Psychiatrist at Birmingham VA Medical Center BIrmingham, AL-35244, USA
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This is an interesting study but has some limitations, which make it difficult to interpret the results. These limitations are: 1. Agitation is not defined and can mean a number of things. Agitation is a broad term and includes verbal or physical aggression, oppositional behavior, crying etc. This makes it difficult to interpret the results e.g. if a patient who is physically aggressive after treatment with a medication or placebo stops being physically aggressive but instead becomes oppositional and non-compliant, he/she will have shown improvement but would still be considered "agitated". 2. A lot of times the "agitation" is secondary to psychosis, delirium, pain, worsening of physical condition and infections. Unless these underlying/comorbid conditions are treated the response to treatment for agitation is not good. Again we don't know if patients in each of the three groups had any comorbid conditions. In particular psychosis is a predictor of poor outcome. 3. It would have been interesting if higher doses of quetiapine were used as some open label studies done in USA showed effectiveness of quetiapine for treatment for behavioral disturbances in dementia when higher doses (>200mg/day) were used. Competing interests: None declared |
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B. Andrew Farah, Chief of Psychiatry/High Point Health Systems/Clinical Faculty Wake Forest University, NC 320 Boulevard, High Point NC, 27262 USA
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The cognitive decline seen in these study patients is clearly related to disease progression in the face of inadequate therapy rather than a medication induced adverse outcome. At our Memory Disorders Clinic and in our inpatient settings, we routinley initiate memantine with an anticholinesterase inhibior and often see a preservation of functioning rarely seen with cholinesterase inhibitor monotherapy. But, more importantly, quetiapine must be adequately dosed to ameliorate behavioral problems of dementia. Studies have shown effficacey in this population (Quetiapine treatment for behavioral and psychological symptoms in patients with senile dementia of Alzheimer type/Fujikawa T, et al). For Lewy Body dementia, Parkinson's dementia, and mixed types, quetiapine remains a mainstay of treatment due to the lack of motor side effects and reliable benefit with adequate doses - often above 200 mg /day. Competing interests: speaker's panel for Astra-Zeneca |
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Peter Paul De Deyn, Professor University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
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Editor--Ballard reported results from a study evaluating the efficacy of quetiapine and rivastigmine in reducing agitation and aggression in patients with dementia.(1) The authors found no significant reduction in behavioural symptoms with either treatment. Moreover, greater cognitive decline was observed with quetiapine treatment compared with placebo. While I agree with the authors’ conclusion that this small study shows that quetiapine has no significant effect on behavioural symptoms associated with dementia, I cannot agree with the conclusion "...atypical antipsychotics are not effective for the treatment of agitation in people with dementia." Such a generalisation cannot be made on the basis of this study alone. Indeed, positive results from a large placebo-controlled trial of another atypical antipsychotic (risperidone) were reported on reducing aggression associated with dementia,(2) without a negative impact on cognition. This efficacy of risperidone was corroborated in two other large placebo-controlled trials in patients with dementia.(3,4) Dr. Ballard also suggests that risperidone and olanzapine should no longer be used for these patients due to side effects, including cerebrovascular adverse events. I caution that a blanket statement against the use of atypical antipsychotics may inappropriately limit options of treatment. In that respect, recent epidemiology studies have suggested similar risk of cerebrovascular adverse events with alternate treatments, such haloperidol or benzodiazapines, versus risperidone, olanzapine, or quetiapine.(5) The use of atypical antipsychotics for the treatment of behavioural and psychological symptoms of dementia remains an unsettled issue. Meanwhile, patients continue to suffer from symptoms of dementia, and until better or safer treatments are available, drugs that have been shown to be effective with a documented safety profile are the best tools we have to alleviate their symptoms. 1. Ballard C, Margallo-Lana M, Juszczak E, Douglas S, Swann A, Thomas A, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial BMJ 2005; 10.1136/bmj.38369.459988.8F. 2. Brodaty H, Ames D, Snowdon J, Woodward M, Kirwan J, Clarnette R, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003;64:134–143. 3. De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP, Dautzenberg PL, Eriksson S, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53:946–955. 4. Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry 1999;60:107–115. 5. Gill SS, Rochon PA, Herrmann N, Lee PE, Sykora K, Gunraj N, et al. Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. BMJ 2005;330:445. Competing interests: Speaker and consultant for Janssen |
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ARUNRAJ BALAKRISHNA KAIMAL, MRCPsych, SHO IN PSYCHIATRY Ysbyty Gwynedd , Bangor, North Wales, LL57 2PW, UMA VISWANATHAN NAIR, SHO IN PSYCHIATRY
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In view of the recent reports of Central Nervous System adverse effects associated with a number of atypical antipsychotics the researchers addressed an important issue with a clearly focused research question. Even though RCTs are available to examine a similar question in the cases of risperidone and olanzapine, level 1b or 1c evidence was lacking for Quetiapine. Because of the less Extra Pyramidal Side Effects [EPSE] Quetiapine is almost like an antipsychotic of choice in elderly population, which gives this study a particular validity. Even though this is a very small study, the researchers have done a satisfactory power calculation, giving an allowance for attrition. They have used computer generated block randomization, which is the method of choice to minimise the confounders in a small study. The allocation concealment was done and was reported adequately. It was also reported that the assessors were blind to treatment allocation. Because of these methodological advantages authors stated that it was unlikely that the differences can be explained by any potential confounding factors. However, in spite a good methodology we need to consider few biases and confounding factors especially when the sample size is small. First of all the study population is predominantly women [70 to 90% in all groups]. The behavioural disturbances is equally or more prevalent in male population with Alzheimer’s disease. This could be consideration when we generalise the result in our clinical practice. Quetiapine is a drug, which is specifically used to control the psychotic symptoms in dementia population. When it is used in agitation, which is broadly defined, there is an increased likely hood of adverse reaction compared with potential benefits. It would have been ideal if the researchers had performed a subgroup analysis in the patient group with psychotic symptoms. As discussed by several people in the responses a possibility of sedative effect of Quetiapine, which could act as potential confounder, could also result in a bias. The sedation and possible other side effects of Quetiapine, can be easily identified by an experienced clinician who measures the outcome in the study, which would invalidate the effects of blinding. The use of data in the form of last observation carried forward is of particular concern, when considering the fact that, the patients entering the placebo group had an advantage of increased score by 10, on severe impairment battery at baseline. It is not clear from the paper whether the patients entering Quetiapine group had a mean deterioration from their baseline score by 14.6 or whether this is the difference from the change observed in the placebo group. If it is the first case the baseline difference of 10 becomes more significant. Rather than concluding that Quetiapine should not be used in Alzheimer’s disease patients with behavioural problems, a call for an urgent research in the field with a larger sample size would appear a more logical approach. Meanwhile use of Quetiapine in the same population would warrant a close monitoring of cognitive state and other possible side effects. Competing interests: None declared |
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Ajit K Shah, Consultant Psychiatrist West London Mental Health NHs Trust. Uxbridge Road, Southall, Middlesex, UB1 3EU
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The Committee of Safety of Medicines recently advised clinicians not to use risperidone and olanzapine in dementia because they increase the risk of strokes and olanzapine also increases mortality. Therefore, the randomised double blind study of quetiapine and rivastigmine for agitation in Alzheimer's disease was of great interest. However, the conclusions of the authors are not entirely supported by their data. They conclude that quetiapine should not be used in dementia. However, this study only looked at agitation in Alzheimer's disease (and not other dementias)in institutional settings. Therefore, they cannot generalise to other types of non-cognitive symptoms of dementia (like disorders of perception and thought content), to other types of dementias and to patients residing at home. Interpretation of their data is also difficult. The power calculation was based on efficacy of the active treatments and not their side-effect profile (like cognitive impairment). Moreover only 46 (50%) and 49 (53%) of subjects completed the severe impairment battery for cognitive evaluation at week 6 and week 26 respectively. Therefore, any association between quetiapine and cognitive impairment may be spurious due to Type 1 statistical error, particularly as no effort was made to correct for multiple comparisons. Moreover, surprisingly rivastigmine, an established cholinesterase inhibitor, showed no efficacy for improving cognition; this too may have been a spurious finding due to small numbers and type 2 statistical error. The findings of this study should be interpreted cautiously until further studies with adequate power to examine effects on cognition are conducted. It would be a pity to throw the baby (quetiapine) out of the bath water after one study with insufficient power when psychogeriatricans have already lost the authority to prescribe two other atypicval antipsychotics (risperidone and olanzapine)in dementia. Competing interests: None declared |
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Simon R Wright, Consultant Psychiatrist for Older People Rotherham General Hospital South Yorkshire
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I read with interest the postulated mechanisms of cognitive decline in this study. BDNF reduction is mentioned and the authors speculate the "accelerated accumulation of core pathological substrates". I find it difficult to believe that as these pathological processes have been developing many years before symptoms emerge that in 6 weeks quetiapine could produce such a profound effect. Is it known that quetiapine is an antagonist at the TrkB receptor in the human brain causing alterations in synaptophysin and Tau protein gene expression? I note the authors quote a rat cerebellar model which may not equate with human cortex, hippocampal or neocortical especially in the context of severe neurodegenration as in late stage Alzheimer's disease. Another thought is why do so many studies show higher doses (around 200mg) of quetiapine are better in dementia in general. Is it because only at these doses does quetiapine have a positive cognitive effect via it's actions on elevating dopamine levels in the neocortex? Pehaps at lower doses it is just sedative as others have suggested. I myself have seen patients at all stages of Alzheimer's disease respond well across a wide dose range to this drug, but I also agree it is not without its porblems in those it does not help with oversedation and postural hypotension being often marked. Competing interests: I have received educational grants and honoraria from Astra Zeneca |
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Thomas Marshall, Consultant LD Psychiatry The Rutson, High Street, Northallerton, DL7 8EN
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Overall, the quality of this paper is very high. I am confused around the way changes in the scales are reported. I assume that the SIB score increases as the cognitive impairment worsens.It would be clearer to say this than that "the change in the severe impairment battery score from baseline was estimated as an average -14.6 points lower". This means the score was 14.6 points higher in those recieiving Quetiapine and thus worse.This sounds clearer than -14.6 lower! I assume that the agitation scale increases with increasing agitation, so the scores in the table represent an improvement for all three arms of the trial. I cannot figure out whether when the difference between quetiapine vs placebo is reported as 3.5 this means less or more agitated on quetiapine. I believe the conclusions are overstated. The study does not show that Quetiapine is ineffective for agitation. It shows there is no statistically significant difference compared to placebo. However, the confidence intervals cross the line of no difference, so the study is not powerful enough to demonstrate that Quetiapine does not work. The classic error of confusing abscence of evidence for evidence of abscence has occured. Also, in what the study adds it is suggested that all atypical antipsychotics and central cholinesterase inhibitors are ineffective. The study only involved one of each of these two classes of drugs so this extrapolation is not justified. The study clearly shows that quetiapine causes cognitive decline, as the confidence intervals do not cross the line of no difference. Overstating the conclusions and a lack of clarity around the scales undermines a fine study which should make psychiatrists hesitate to use antipschotic drugs in this patient group. Competing interests: None declared |
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Lena Palaniyappan, Senior House Officer Sheila Gibson Unit, Bramwell, Chilwell Lane, Nottingham NG9 3DU, Gill Pinner, Consultant Psychiatrist for Older People
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Ballard et al (1) have suggested that neither quetiapine nor rivastigmine is effective in the treatment of agitation in people with dementia in institutional care. More than this they go on to suggest that quetiapine is associated with significant cognitive decline and recommend that this drug should not be used to treat people with dementia. We feel that the following points are worth considering before coming to that conclusion. Firstly, although the power calculation used may be sufficient for the purpose of assessing the primary outcome measure of effect on agitation by the two drugs against placebo, this is not valid for the secondary outcome measure of effect on cognition. Indeed this sample size has been significantly reduced as the study rightly excludes the most severely impaired patients. The remaining sample size is unlikely to be sufficient to confidently demonstrate this. This is supported by the fact that the cholinesterase inhibitor, rivastigmine, was no better than placebo in cognitive outcome, a somewhat unexpected outcome for a cognitive enhancer. Needless to say, it is well established that cognitive benefits do occur with rivastigmine, even in the more severely demented groups - which again suggests the questionable significance of results about cognitive impairment in such a small sample. Current evidence would suggest that accelerated cognitive decline may not be a specific problem with quetiapine alone, but a wider problem with both classes of antipsychotics (2), though a similar study demonstrated as a secondary outcome measure, that atypical antipsychotic risperidone compared favourably against haloperidol in not causing significant cognitive decline (3). This is the first published RCT data for quetiapine in the treatment of agitation in severely demented patients and did not demonstrate efficacy in this instance. Neither did it show efficacy for agitation using rivastigmine. However, there are RCT studies that do show efficacy of both atypical (4) and typical (5) antipsychotics and cholinesterase inhibitors(6) in BPSD. So the effect may be restricted to certain target symptoms and may vary on the stage of illness i.e. these findings may not be replicated over the whole range of patients and symptoms seen in clinical practice. Although this study is a useful addition to the evidence base around the use of atypical antipsychotics and cholinesterase inhibitors for BPSD in severe dementia, further evidence needs to be gathered, including their usefulness at different stages of illness and the range of symptoms labelled BPSD. The evidence for quetiapine causing acceleration of cognitive decline is not convincing as the sample size is too small to draw firm conclusions, but again it is an area that would benefit from further investigation. Overall it seems that the clinical implications are over stated. References: 1. Ballard C, Margallo-Lana M, Juszczak E, Douglas S, Swann A, Thomas A, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial BMJ 2005;330: 874 2. McShane R, Keene J, Gedling K, Fairburn C, Jacoby R, Hope T. Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up. BMJ 1997;314: 266-70 3. De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP, Dautzenberg PLJ, Eriksson S, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53: 946- 55. 4.Brodaty H, Ames D, Snowden J, Woodward M, Kirwan J, Clarnette R, et al. A randomized placebo controlled trial of risperidone for the treatment of aggression, agitation, and psychosis in dementia. J Clin Psychiatry 2003;64: 134-43 5. Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc 1990; 38: 553-563 6. Finkel SI. Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease. Clinical Therapeutics. 26(7):980-90, 2004 Jul. Competing interests: None declared |
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Jonathan C Haynes, Specialist Registrar Weston super Mare, Stuart Nicholl, Anoop Devasahayam, Emma Kelson, Daniel Hirsch
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On behalf of a small local journal club, I write to express concern that this paper made headline claims that are likely to affect practise, but without sufficient levels of evidence. 1. We cannot conclude that the patients are representative, as we are not given information about recruitment. 2. The main use of rivastigmine is in the mild-moderate demented population, and yet these patients were excluded from the ongoing cognitive monitoring and analysis 3. There is a significant risk of Type II error, casting significant levels of doubt onto the claim that rivastigmine is as effective as placebo. We consider the headline clinical implications attached to the paper to be hasty, and potentially dangerous if practise is changed without further evidence. Competing interests: None declared |
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JANAKIRAMAN RAGURAMAN, SHO DN2 5LT
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Though the study has been done well, I feel that it has not adequately provided evidences to support that the rivastigmine is not helpful in dementia. The study considers only severe degree of dementias and has not explained if the samples were adequately screened and ruled out of any co-morbid psychiatric problems. I feel that the sample size is less despite considering that there will be more drop outs in severe degree of dementias. There are no comments about the raters who evaluated (for agitation and cognitive assessments) the patients at 6 and 26 weeks. There is no adequate supportive data to explain that quitapine is ineffective in agitation. (Although it explains that it is not statistically significant) Competing interests: None declared |
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