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Tuesday, February 5, 2013

Memantine (aka. Namenda) and bvFTD. Is it beneficial? Maybe


A recent study published February 2013 concludes that, "Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD."

Stop! Whoa! What does all this mean?

To someone who is not trained in interpreting research, it is obvious from the above statement that if you have FTD Mementine will have no beneficial effect, so you should discontinue using it, or not bother taking it. No! No! No! Please read onward...

My brain on a good day ...sorta!
That is not at all what the above really means. Nobody should use this study as a criteria to determine treatment.

 (I certainly hope that future research is not influenced negatively by this study. Given some of the obvious issues with the methodology - how did it get published in The Lancet?- "The journal is stringently edited and peer-reviewed." ...or at least it was at one time. But I digress, as usual...)

What it really means is that in this particular study, using this particular sample of individuals, using this particular measurement criteria, and this particular method of analysis, the differences between the 2 groups were not statistically significant. A totally different concept.

The only way to really get at this is to look at each of these items individually. This will take a little time, and might get somewhat technical. I think it is worth it because it can serve as an example of how to interpret any research study, as well as this one.

(This abstract of 2013 study, as well as one from 2003, are reprinted at the end of this post because that is where they ended up when I was writing this. If you are totally unfamiliar with this research you may want to read them first, and then come back to the beginning. Hey! I have bvFTD. This is an editorial opinion piece, so I can fail to organize it according to whim. It is very difficult for me to put things in the proper sequence sometimes. I am blaming my Dysexecutive Function. That is my story, and I am sticking to it! Some days are better than others, and today was better than most.)

Lets start with the sample. According to the study: Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial.

Right off the bat there is an issue. Nearly 20% of the patients screened elected not to participate because they wanted to continue taking Memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Why? I can only guess, but it seems logical that it was because they were working noticeably well for them, and they did not want to risk being placed in the control group, and receiving a placebo.

So, at the very start of this study it seems to have eliminated 20% of the people who were taking memantine, and felt that it was working effectively. This is, of course, only a guess, and any evaluation would necessarily be subjective, but at the sample size used in this study it would only take 1 or 2 of those 19 individuals to totally change the outcome. These may well represent the population of bvFTD patients for whom Mamentine is a very effective treatment! This is not in any way bad research. It is reported up-front, so it can be included in any interpretation of the results. Though 81 individuals were randomly selected for the study groups, another 19 individuals self-selected themselves out of the study in a decidedly non-random manner.

In delving a little deeper into the study groups it turns out that only 29 individuals with bvFTD actually received memantine! (the others either dropped out or had semantic FTD) According to The Family Caregiving Alliance (FCA) as many as seven million Americans may be afflicted with a form of dementia.  Frontotemporal Dementia may account for 2-5 percent or 140,000 – 350,000 cases of dementia and for as many as 25 percent of pre-senile dementias. OK, what this means is that to select a sample for a study with a 95% confidence level (as in this study) and a confidence interval of plus or minus 3, a sample size of 1064 is necessary. Not 100! Not 86! Not 29! More than 10 times the total number actually tested. Again this is not bad research. Sample size is often a result of availability, and cost. The effect on the study is that it is more likely with an undersized sample to miss a valid result. In general the bigger the sample, the more likely it is to see a small difference.

(If you are interested in "delving deeper" into this study follow the link below, and then select the green link on the upper right of the summary page for The Lancet. Scroll down the Lancet page for many figures and tables excerpted from the original study: http://www.ncbi.nlm.nih.gov/pubmed/23290598)

To get back on-track, the sample size was very small, and may have excluded many of the very people that the study was designed to test.

One last thing about the sample. According to the abstract:  Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy.

The consensus diagnostic criteria for frontotemporal dementia (FTD) by Neary et al.1 are of particular interest because many patients diagnosed with schizophrenia would fit criteria for FTD. All the core diagnostic features of FTD characterize schizophrenia patients with prominent “negative symptoms.” The supportive features of FTD also feature prominently in schizophrenia excepting the physical signs of incontinence, akinesia, rigidity, tremor, and low and labile blood pressure, which occur but infrequently. Primitive reflexes, however, are commonly found. A plethora of studies implicate frontal lobe neuropsychologic impairment as well as both frontal and temporal structural and functional imaging abnormalities in schizophrenia.2 McKenna3 provides the most complete catalogue of the cardinal symptoms and clinical picture of schizophrenia mirroring FTD symptoms.

Since bvFTD is so very difficult to diagnose the criteria used to select the subjects for testing is crucial. It appears that the Neary test developed in 1998 was used in conjunction with some form of brain imaging. As indicated above, the Neary test does not differentiate well between schizophrenia and bvFTD. More recent criteria are available, and many studies now require a PET Scan to determine a diagnosis. The Neary test isn't wrong, but it may not be the best test available today.

Lets move on to the way the researchers measured the changes. According to the abstract:  Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analyzed by intention to treat.

Looking at the last one first - a quick explanation of exactly what "intention to treat" means is probably in order as it is "researcher jargon" for a specific methodology. There is nothing wrong with it, except when a lot of people drop out of a study. In this study 5 people, or about 6% of the sample, quit the study before completing it.

According to my research, an intention to treat (ITT) analysis of the results of an experiment is based on the initial treatment assignment and not on the treatment eventually received. ITT analysis is intended to avoid various misleading artifacts that can arise in intervention research such as non-random attrition of participants from the study or crossover. ITT is also simpler than other forms of study design and analysis because it does not require observation of compliance status for units assigned to different treatments or incorporation of compliance into the analysis. Although ITT analysis is widely employed in published clinical trials, it can be incorrectly described and there are some issues to its application.

Medical investigators often have difficulties in accepting ITT analysis because of clinical trial issues like missing data or adherence to protocol.

To address some of these issues, many clinical trials have excluded participants after the random assignment in their analysis, which is often referred to as modified intention-to-treat analysis or mITT. Trials employing mITT have been linked to industry sponsorship and conflicts of interest by the authors.

After all of that, Intention to treat is a valid, and accepted method of analysis though it has some flaws which can introduce error in the outcome of a study. Just be aware that it may introduce error, so any conclusions are subject to interpretation. In this study the drop out rate was not too large, and any error introduced would probably influence the results by over-emphasizing any differences.

When I first read the abstract for this study, I was a little surprised at the tests that were chosen to measure the results. Here is why. According to the study the total NPI score and clinical global impression of change (CGIC) wre used to measure the results.

As for my own case of bvFTD, and always keeping in mind that every case is different, I would not expect to see any difference in my own personal test score after only 26 weeks, or even 32 weeks. Of course some days are better than others! In fact, I would bet that most people who suffer from bvFTD, and are in the earlier stages of the progression, would show little or no change on these particular tests. But, since the CGIC requires input from a caregiver it effectively eliminates anyone who is in the earliest stages of bvFTD, and able to still remain self-sufficient. Well? Aren't the individuals who are still able to function without a caregiver the ones who have the most at stake in stopping or slowing the progression of the disease? Duh! Sad, but - DUH! The definition of a garegiver, and the severity of the symptoms to start with were not addressed in the abstract, so it is unclear what if any affect this would have on the outcome.

The Clinical Global Impression rating scales are commonly used measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders (Guy, W., 1976). Many researchers, while recognizing the validity of the scale, consider it to be subjective as it requires the user of the scale to compare the subjects to typical patients in the clinician experience. (This particular test is probably of little use in determining the affects of Memantine as shown in the results of the 2003 study on Alzheimer's patients which is included at the end of this post for reference.)

The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.

The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.

The Clinical Global Impression - Efficacy Index is a 4 point × 4 point rating scale that assesses the therapeutic effect of the treatment as 1, unchanged to worse; 2, minimal; 3, moderate; 4, marked by side effects rated as none, do not significantly interfere with patient's functioning, significantly interferes with patient's functioning and outweighs therapeutic effect.

My basic issue with using this as a measure is that for those of us with bvFTD every day is different. There are some days when I cannot function at all, others where I can barely get by, and many more where I appear to be within the broad range of what is considered normal. The clinician only sees the patient on a few days, and for only a few hours, and talks to them on the phone a couple times during the study period. With all of the variance in symptoms from day-to-day I question the validity of this type of subjective observational measurement. A less subjective measure, and one not as prone to be influenced by daily fluctuations in symptom severity would be preferred - at least by me. (Wouldn't a study comparing PET Scans over 2 years be WAY better!)

The other measure used to asses any changes is The Neuropsychiatric Inventory (NPI), but even then the symptoms, their severity, and their impact are reported by the caregiver so are also subjective. The NPI was developed to assess psychopathology in dementia patients. It evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The severity and frequency of each neuropsychiatric symptom are rated on the basis of scripted questions administered to the patient's caregiver. The NPI also assesses the amount of caregiver distress engendered by each of the neuropsychiatric disorders. A total NPI score and a total caregiver distress score are calculated, in addition to the scores for the individual symptom domains. Content validity, concurrent validity, inter-rater reliability, and test-retest reliability of the NPI are established. Different neurologic disorders have characteristic neuropsychiatric manifestations and distinctive NPI profiles. The NPI is sensitive to treatment effects and has demonstrated the amelioration of behavioral symptoms in Alzheimer's disease by cholinergic agents. The NPI is a useful instrument for characterizing the psychopathology of dementia syndromes, investigating the neurobiology of brain disorders with neuropsychiatric manifestations, distinguishing among different dementia syndromes, and assessing the efficacy of treatment.

So, they take the difference in total scores on a test that measures delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. I can tell you right now I don't have most of these symptoms, and as for the ones which I think I do have I would not expect to see any change in only 6-8 months (Fingers crossed!). At this time, though I do have some outside assistance, I do not have a caregiver. I can be apathetic. I can be irritable (and irritating!). I do not sleep well, and I have gained about 35 pounds in the past year, but not in the past 6 months. The thing is that if you were to look at these criteria a year ago, and compare them to today, I doubt you would see any difference. That, and my total symptoms account for less than half of the total score, so this test really does not measure me very well. I think it is much better suited to more advanced stages of Alzheimer's and other forms of dementia rather than the early stages of bvFTD.

I spent a lot of time writing about the measures because I really question whether these particular tests would pick up on any real difference if it were actually there. These are not bad tests, and they are widely accepted as research measures. In my opinion they are more likely to only identify very large changes, and to totally miss all of the subtle changes in daily living, cognition, and social interactions that occur in a person with bvFTD.

So, in my opinion what this study says is that in this particular study, using this particular sample of individuals, using this particular measurement criteria, and this particular method of analysis, the differences between the 2 groups were not statistically significant. So, if you were a participant in this particular study who received Mamentene you should not expect to see any benefit in taking it that can be measured by the tests used. For all of the rest of us who did not participate in this study, including those who declined to participate, it means absolutely nothing, and more research will be necessary.

Nobody should use this study as a criteria to determine treatment. Mamentine (Namenda) may or may not work for you. If it works, Great! If not... keep looking.

Personally I take both Memantine and Donazepel at about the maximum recommended dosage. It seems to be working for me, at least something seems to be working. I am pretty damn pleased that 3 years after my diagnosis I can still write this post. (Was that an example of disinhibition?)



Here is the abstract of the study:

Lancet Neurol. 2013 Feb;12(2):149-56. doi: 10.1016/S1474-4422(12)70320-4. Epub 2013 Jan 2.
Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial.
Boxer AL, Knopman DS, Kaufer DI, Grossman M, Onyike C, Graf-Radford N, Mendez M, Kerwin D, Lerner A, Wu CK, Koestler M, Shapira J, Sullivan K, Klepac K, Lipowski K, Ullah J, Fields S, Kramer JH, Merrilees J, Neuhaus J, Mesulam MM, Miller BL.
Source

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. Electronic address: aboxer@memory.ucsf.edu.
Abstract
BACKGROUND:

Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD.
METHODS:

We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974.
FINDINGS:

Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI -3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, -0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one).
INTERPRETATION:

Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD.
FUNDING:

Forest Research Institute.


And here is another abstract from a study in 2003 to take a look at. Though not specifically targeted at bvFTD it shows some interesting results, and most importantly regarding cognition - a criteria not measured in the current study! This study shows a benefit in the effect of memantine (20 mg/day) for patients with moderate to severe Alzheimer disease on cognition and functional  but not in the clinical impression of change. Interesting that the tests selected to measure the effects in the current study do not measure cognition, and do include the clinical impression of change.

Cochrane Database Syst Rev. 2003;(3):CD003154.
Memantine for dementia.
Areosa SA, Sherriff F.
Update in

    Cochrane Database Syst Rev. 2004;(4):CD003154.

Abstract
BACKGROUND:

Alzheimer's disease, vascular and mixed dementia are the three commonest forms of dementia affecting older people. There is evidence that the excitatory activity of L-glutamate plays a role in the pathogenesis of Alzheimer's disease and in the damage from an ischaemic stroke. A low affinity antagonist to N-Methyl-D-aspartate (NMDA) type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning.
OBJECTIVES:

To determine the clinical efficacy and safety of memantine for people with Alzheimer's disease, or vascular or mixed dementia.
SEARCH STRATEGY:

Trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 15 April 2003 using the terms: memantin*, D-145, DMAA, DRG-0267. All major health care databases and trial databases within the scope of the group are searched regularly to keep this Register up to date.
SELECTION CRITERIA:

Double-blind, parallel group, placebo-controlled, randomized and unconfounded trials in which memantine was administered to people with dementia.
DATA COLLECTION AND ANALYSIS:

Data were extracted, pooled where possible, and weighted mean differences, standardized mean differences or odds ratios were estimated. Intention-to-treat (ITT) and observed cases (OC) analyses are reported, where data were available.
MAIN RESULTS:

Effect of memantine in patients with moderate to severe Alzheimer's disease: analysis of the change from baseline at 28 weeks gave statistically significant results in favour of memantine for 20 mg/day on cognition (MD: 6.1. 95% CI 2.99 to 9.21, P=0.0001) activities of daily living (MD 2.10, 95% CI 0.46 to 3.74, p=0.01) and in the global clinical impression of change measured by the CIBIC-Plus at 28 weeks (MD -0.30, 95% CI -0.58 to -0.02, p=0.04), in all cases the analysis was the ITT-LOCF population (Reisberg 2000). There were no significant differences between memantine and placebo for the number of drop-outs and total number of adverse effects, but a significant difference in favour of memantine for the number who suffer agitation. Effect of memantine in patients with mild to moderate vascular dementia: analysis of the change from baseline at 28 weeks gave statistically significant results in favour of memantine ( 20 mg/day ) for cognition (MD -2.19, 95% CI -3.16 to -1.21, P=less than 0.0001) but there was no benefit for the clinical impression of change, or for global measures of dementia (MMM300, and MMM500). There were no significant differences between memantine and placebo for the number of drop-outs and total number of adverse effects, but a significant difference in favour of memantine for the number who suffer agitation. Effect of memantine in patients with Alzheimer's disease and vascular dementia at 12 weeks: there was no statistically significant difference between memantine (10 mg/day) and placebo in activities of daily living. There was a benefit in favour of memantine (10 mg/day) compared with placebo at 12 weeks, for the numbers improved in terms of clinical impression of change (60/82 compared with 38/84 - OR 3.30, 95% CI 1.72 to 6.33, P=0.0003) (Winblad 1999). Effect of memantine in patients with vascular dementia, Alzheimer's disease and dementia of non-specified type at 6 weeks: there were beneficial effects on cognition (Ditzler 1991), activities of daily living (Ditzler 1991, Pantev 1993), behaviour (Pantev 1993) and global scales (Gortelmeyer 1992; Pantev 1993; Ditzler 1991) and in global impression of change (Gortelmeyer 1992; Ditzler 1991). There were no significant differences between memantine and placebo for the number of drop-outs and total number of adverse effects, but a significant difference in favour of placebo for the number who suffer restlessness
.REVIEWER'S CONCLUSIONS:

There is a beneficial effect of memantine (20 mg/day) for patients with moderate to severe Alzheimer disease on cognition and functional decline but not in the clinical impression of change. Patifor patients with moderate to severe Alzheimer disease on cognition and functional decline but not in the clinical impression of change. Patients with mild to moderate vascular dementia receiving memantine 20 mg/day had less cognitive deterioration at 28 weeks but again this effect was not clinically discernible. There is a possible beneficial effect on cognition, function and global scales for memantine at 6 weeks in mixed populations. The drug is well tolerated and the incidence of adverse effects is low. More studies are needed.

That's my interpretation. My analysis. My opinion. There ya have it!
Comments are encouraged.

3 comments:

  1. WOW I say WOW again. This should have never been published. It should have been done with people in the early stages and for a much longer period of time to be benificial . These people already had caregivers and could not answer for themselves properly. So it came from a caregivers point of view. Well that is how I see it and Hope that it doesn't harm to many people that read t.

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  2. Thanks for your comment, Cindy.

    Yes, it makes me wonder. Though it is valid to include research at all stages of the disease, it is not valid to generalize the results from a small study which does not include all of those stages. Like you said, "WOW!"

    -Lee

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