Stimulant Reduces Apathy in Alzheimer's Disease

 What is your doctor doing to counter the apathy they caused by not having 100% recovery protocols? Your responsibility is to demand a straight answer.

Stimulant Reduces Apathy in Alzheimer's Disease

Twice daily methylphenidate showed modest effect size

by Judy George, Senior Staff Writer, MedPage Today September 27, 2021

Treatment with methylphenidate (Ritalin), a stimulant approved for attention deficit-hyperactivity disorders (ADHD) and narcolepsy, led to a small to medium reduction in apathy in people with Alzheimer's disease, the phase III ADMET 2 trial showed.

At 6 months, methylphenidate 10 mg twice daily led to a larger decrease on the 12-point Neuropsychiatric Inventory (NPI) apathy scale compared with placebo, with a mean difference of -1.25 points (95% CI -2.03 to -0.47, P=0.002), equivalent to a Cohen d of 0.365, reported Jacobo Mintzer, MD, MBA, of the Ralph H. Johnson VA Medical Center in Charleston, South Carolina, and co-authors.

This effect was first seen 2 months after starting treatment and was sustained over 6 months, the researchers wrote in JAMA Neurology.

On the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), a co-primary endpoint, methylphenidate did not show a statistically significant difference over placebo but trended favorably, the researchers noted.

There were no treatment differences in cognitive measures, or in activities of daily living or quality-of-life scores. No new safety signals emerged with methylphenidate treatment.

"Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers," Mintzer and colleagues wrote. "Clinicians should be aware of the small to medium treatment effects sizes and the lack of effect on activities of daily living."

Apathy affects anywhere from 20% to 90% of people in the dementia stages of Alzheimer's disease, noted Carolyn Fredericks, MD, of Yale University in New Haven, Connecticut, in an accompanying editorial. "Despite the severity of apathy's impact on patients with dementia and their caregivers, it is notoriously difficult to treat, and no therapies to date have proven to be effective," she wrote.

"The magnitude of the effect of methylphenidate reported in this trial is likely to be of clinical significance for many patients and represents the first phase III randomized clinical trial showing efficacy of any treatment for apathy in Alzheimer's disease," Fredericks pointed out.

"While methylphenidate will not be an option for those individuals with medical or psychiatric contraindications to stimulants, the present study demonstrates that it is generally safe and well tolerated for the target population," she added.

Two smaller trials of shorter duration, including the first ADMET study, showed that methylphenidate led to positive outcomes in treating apathy in Alzheimer's disease, with minimal adverse events.

In ADMET 2, Mintzer and co-authors studied 200 patients clinically diagnosed with Alzheimer's disease, mild to moderate cognitive impairment, and frequent or severe apathy from August 2016 to July 2020, assigning 99 participants to methylphenidate 10 mg twice daily and 101 people to placebo.

People with major depression or significant agitation, aggression, delusions, or hallucinations were excluded from the study. Participants had a median age of 76, and two-thirds were men.

Two co-primary outcomes were prespecified: mean change in NPI apathy score and odds of improved ADCS-CGIC rating, both assessed from baseline to 6 months. A significant result for either outcome indicated efficacy.

NPI apathy scores had the largest decrease in the first 100 days, favoring methylphenidate (HR 2.16, 95% CI 1.19-3.91, P=0.01).

At 6 months, ADCS-CGIC ratings improved for 43.8% in the methylphenidate group and 35.2% in the placebo group (OR 1.90, 95% CI 0.95-3.84, P=0.07).

More people in the methylphenidate group reported weight loss of more than 7% during the trial. Of 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile emerged between treatment groups.

"Many study participants were taking acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and other antidepressants, and/or memantine [Namenda] at the time of participation; the authors found no confounding effects of these medications on the study's primary outcomes," Fredericks observed.

"Apathy in the context of Alzheimer's disease often occurs without concomitant depressed mood and is not simply a symptom of depression," she wrote. "That said, depression is also common both in older adulthood and as a neuropsychiatric symptom of Alzheimer's disease, and it can be difficult to untangle which patients are experiencing Alzheimer's disease-related apathy, Alzheimer's disease-related depression, or co-occurring late-life major depression."

ADMET 2 has limitations, Fredericks noted: it did not assess whether methylphenidate meaningfully relieved caregiver burden and relied on "notoriously nonspecific" clinical criteria for Alzheimer's diagnoses, not biomarkers. Future studies should assess methylphenidate treatment on specific forms of apathy, she added.

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

Funding was provided by the National Institute on Aging.

Mintzer reported being an advisor for Praxis Bioresearch and Cerevel Therapeutics. Other authors reported relationships with NIH, BioXcel Therapeutics, Cerevel, Praxis, Eisai, Kondor Pharma, Eli Lilly, Vaccinex, Functional Neuromodulation, Alzheimer's Therapeutic Research Institute, Alzheimer's Clinical Trials Consortium, Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Gerson Lehrman Group, SVB Leerink, Cerevance, Acadia Pharmaceuticals, Sunovion, FDA, Roche, Ono Pharmaceutical, Biogen, Biohaven, Novartis, Janssen, Genentech, Merck, VA, Cadent Therapeutics, Syneos, Avanir Pharmaceuticals, Athira, Alzheon, MapLight Therapeutics, Premier Healthcare Solutions, and IQVIA.

Primary Source

JAMA Neurology

Source Reference: Mintzer J, et al "Effect of methylphenidate on apathy in patients with Alzheimer disease: The ADMET 2 randomized clinical trial" JAMA Neurol 2021; DOI: 10.1001/jamaneurol.2021.3356.

Secondary Source

JAMA Neurology

Source Reference: Fredericks C "Methylphenidate for apathy in Alzheimer disease -- Why should we care?" JAMA Neurol 2021; DOI: 10.1001/jamaneurol.2021.2942.

 

Scientists show cognitive enhancing drugs can improve chess play

Would this be useful for cognitive decline in stroke rehab? We'll never know since nothing seems to be ever followed up to help stroke survivors.

Scientists show cognitive enhancing drugs can improve chess play

06 March 2017 European College of Neuropsychopharmacology (ECNP)

The first study to both show and measure the effects of cognitive-enhancing drugs such as modafinil, methylphenidate (best known under the trade name Ritalin), and caffeine, on chess play is being published in the March edition of the peer-reviewed journal European Neuropsychopharmacology. This shows significant cognitive improvements for modafinil and methylphenidate, and may have influence how these drugs are used off-label in a range of activities.
The study shows how certain drugs can alter and even improve the way in which the brain processes complex information. As applied to chess (and other fields), this supports the possibility pharmaceutical enhancement giving a player a competitive advantage. The World Chess Federation, FIDE, recognised this by introducing an anti-doping code in 20141.
Now a new double-blind randomised controlled trial by scientists from German and Swedish universities has shown that the cognitive enhancing drugs, modafinil, methylphenidate, and caffeine can improve chess play. Previous research had shown that the drugs could improve cognitive performance when a subject was tired or was performing below his or her optimal performance, but this is the first work to show improvement of cognitive performance even if the subject is performing at a very high level.
The team, led by Professor Klaus Lieb (University of Mainz, Germany) gave 39 male chess players controlled doses of one of the drugs modafinil, methylphenidate, caffeine, or a placebo. They then played a series of rapid, time-limited (15 minutes) games against a chess programme (the popular Fritz 12 programme) which had been matched to the strength of each individual player. This was a 4-day “crossover” study, meaning that the player had who taken modafinil on day 1 would receive a different drug (or placebo) on each subsequent day, and so on. In total the researchers gathered data from over 3000 chess games.
“One of the strengths of this study is that the chess programme provides a reference point to measure the cognitive effect”, commented Professor Lieb, “
They found that all three substances tested caused the players to increase the time needed to decide on a move, meaning that more games were lost as the players ran out of time. However, when the analysis was corrected to take out games lost on time, the team found that both modafinil and methylphenidate significantly increased the players’ scores, whereas caffeine showed a more modest, but not statistically significant improvement.
“We were surprised to see that players on the drugs played more slowly than normal, indicating that their thought processes seemed to be deeper” said Professor Lieb.
He continued:
 “The key to this work is in understanding that players showed an improvement if under less time pressure. The results themselves would be pretty significant in chess terms. For example, both modafinil and methylphenidate gave an improvement coefficient of around 0.05.  If we correct for the slowest players, then the effect would be the equivalent of moving a player from say, number 5000 in the world ranking, to number 3500 in the world ranking. In a single game, the effect is the equivalent of having the white pieces, every time, which give around a 5% better chance of winning.
These differences can be pretty significant in a competitive sport or game. But this work also allows us to put a figure on the way that the use of these drugs can affect the way we think in a range of everyday intellectual activities, such as studying for an exam.”
The researchers stress that the use of these drugs as cognitive enhancers are ‘off-label’ uses, and may have significant side effects, especially with repeated use. As all pharmaceutical substances have risks and benefit, there is little data that compares the benefit of cognitive enhancement against any risk or side effect. They also note that this is a comparatively small study, and requires replication before firm conclusions can be drawn.
Trevor Robbins (Professor of Cognitive Neuroscience at the University of Cambridge), who was once ranked in the top 20 chess players in England, commented:
“Chess involves several higher brain processes including working memory, planning, cognitive flexibility and cognitive control. Drugs such as modafinil have previously been found to enhance performance of such cognitive functions in laboratory based studies of non-sleep deprived volunteers, although sometimes at the cost of prolonging response times.
This work, one of the first to study drug effects on chess, shows that these performance enhancements can translate into real-world activities in this study of chess players who improved their performance, though sometimes at the cost of losing on time. ".
Professor Robbins won the Brain Prize in 2014, which is considered the most important international neuroscience prize.
Professor David Nutt (Imperial College), ex-President of the European College of Neuropsychopharmacology, added:
“We have known for decades that stimulants improve sustained performance through reducing fatigue effects on attention and vigilance. So these current data provide new and controlled data in chess - a test of complex cognitive function.  It’s likely that other stimulants could do the same so this does raise interesting issues for regulators of these activities. Clearly more research is needed”
http://www.europeanneuropsychopharmacology.com/article/S0924-977X(17)30019-6/abstract

• Full bibliographic informationTitle: Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: a double-blind, randomised controlled trial
  
  Journal: European Neuropsychopharmacology March 2017
  
  Authors: Andreas G.Frankea, Patrik Gränsmark, Alexandra Agricola, Kai Schühlea, Thilo Rommel, Alexandra Sebastian, Harald E.Ballóg, Stanislav Gorbulev, Christer Gerdes, Björn Frank, Christianuckes, Oliver Tüschera, Klaus Lieba
  
  
  DOI: 10.1016/j.euroneuro.2017.01.006

Researchers urge caution in prescribing commonly used drug to treat ADHD - Methylphenidate(Ritalin)

Research from 1998 suggests that this might be helpful in stroke rehab. Not that I think any doctor in the world is using it but for us stroke survivors this could have been important if we had a strategy that followed up promising research. But we have crap for stroke leadership.

Methylphenidate(Ritalin) and stroke rehab - 1998

 Researchers urge caution in prescribing commonly used drug to treat ADHD - Methylphenidate(Ritalin)

Authors of new Cochrane Review remain uncertain about effect of widely used medicine on ADHD symptoms, despite large amount of research. Some evidence of increased sleeplessness and loss of appetite leads researchers to encourage more caution in use of methylphenidate.

The Cochrane Library publishes one of the most comprehensive assessments to date on the benefits and harms of a widely prescribed drug used to treat Attention Deficit Hyperactivity Disorder (ADHD).

ADHD is one of the most commonly diagnosed childhood disorders and can continue through adolescence into adulthood. Symptoms include difficulty focusing attention and remaining “on task”, excessively impulsive behaviour, and extreme hyperactivity. It is estimated to affect about 5% of children, and diagnosis is based on clinical judgement rather than objective diagnostic markers.

Methylphenidate, more commonly known by its brand names - Ritalin®, Concerta®, Medikinet®, and Equasym®, amongst others - has been used to treat ADHD for more than 50 years. A team of Cochrane researchers has carefully evaluated and summarized the findings from all of the available randomized trials of this widely used drug.

This new Cochrane Review includes data from 185 randomized controlled trials involving more than 12,000 children or adolescents. The studies were conducted mainly in the US, Canada, and Europe, included males and females from ages 3-18, and all compared methylphenidate with either a dummy pill or no intervention.

When researchers combined data from identified trials, they found that methylphenidate led to modest improvements in ADHD symptoms, general behaviour, and quality of life. Analysis of adverse effects showed that children were more likely to experience sleep problems and loss of appetite while taking methylphenidate. However, the researchers’ confidence in all results was very low: it was apparent from assessing the included trials that it would have been possible for people involved in the trials to have been aware of which treatment the children were taking. In addition, the reporting of results was not complete in many of the trials, and for some analyses there was variation among trial results.

Based upon this information, the researchers urge clinicians to be cautious in prescribing methylphenidate, and to weigh up the benefits and risks more carefully.

The team of 18 researchers was led by Professor Ole Jakob Storebø, Clinical Psychologist from the Psychiatric Research Unit in Region Zealand, Denmark. He says, “This review highlights the need for long-term, large, better-quality randomized trials so that we can determine the average effect of this drug more reliably.”

Co-author Camilla Groth MD added, “This review shows very limited quality evidence for the effects of methylphenidate on children and adolescents with ADHD. Some might benefit, but we still don’t know which patients will do so. Clinicians prescribing methylphenidate must take account of the poor quality of the evidence, monitor treatment carefully, and weigh up the benefits and adverse effects."

Another co-author, Dr Morris Zwi, Consultant Child & Adolescent Psychiatrist added, “This evidence is important for health professionals and parents of children with ADHD. Our expectations of this treatment are probably greater than they should be, and whilst our review shows some evidence of benefit, we should bear in mind that this finding was based on very low-quality evidence. What we still need are large, well-conducted trials in order to clarify the risks versus the benefits for this widely used treatment.”

The researchers have also urged that clinicians and families should not rush to discontinue using methylphenidate. Dr Zwi added, “If a child or young person has experienced benefits without experiencing adverse effects, then there may be good clinical grounds to continue using it. Patients and their parents should discuss any decision to stop treatment with their health professional before doing so.”

An abridged version of the Cochrane Review will appear in the BMJ later this week.
http://doi.wiley.com/10.1002/14651858.CD009885.pub2

• Full bibliographic informationFull citation:"Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)." Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, Rosendal S, Groth C, Magnusson FL, Moreira-Maia CR, Gillies D, Buch Rasmussen K, Gauci D, Zwi M, Kirubakaran R, Forsbøl B, Simonsen E, Gluud C. CRG: Developmental, Psychosocial and Learning Problems Group. Cochrane Database of Systematic Reviews 2015, Intervention review. DOI: 10.1002/14651858.CD009885.pub2
  URL Upon publication: http://doi.wiley.com/10.1002/14651858.CD009885.pub2

‘Smart’ Drugs Alter Developing Brain

Whom is going to research if these cognitive enhancing drugs help a survivors recovery?  This is from the Dana Foundation so I expected a much more complete story.  After my next stroke I will find some way to get them because this:
Maybe Ritalin from this research in 1998.
The article here:
‘Smart’ Drugs Alter Developing Brain 

At Neuroscience 2012, Barbara Sahakian, a psychiatrist at the University of Cambridge, led a rousing discussion regarding the ethics surround the use of so-called "smart" drugs, or drugs that improve attention, memory, wakefulness and cognitive capabilities. In her talk, Sahakian highlighted that the number of young students and professionals using such drugs is only growing-and stressed the pros and cons of such use must be discussed in the context of both the individual and society at large. It was one of the most talked about speeches at the conference that year.
Certainly, cognitive enhancement, by any means, remains a controversial issue. But Julian Savulescu, the Uehiro Chair in Practical Ethics at the University of Oxford, says, on the whole, there is a lot of benefit to cognitive enhancement. He says that the ability to enhance memory and learning, even through the use of drugs, offers healthy people not only the ability to improve their academic performance but also their overall well-being and life success. And that, he argues, provides an economic benefit to society at large.
"I think there are a lot of good reasons to take 'smart' drugs. Overwhelmingly, there are a weight of reasons in favor of taking them," he says. "There are only two good objections to it that I see. One is that their use may be potentially exacerbating social injustice. But I think that's easily addressed by making sure people have basic access to them in the same way they have access to basic education. The second objection is one of safety. That they might be risky and we just don't know the long-term effects of their use. And that's a scientific question that needs to be answered."
To date, there has been a serious lack of research concerning the effects of these drugs, many of which are available without a prescription over the Internet, in healthy individuals. A recent review from researchers at the Drexel University College of Medicine suggests the use of cognitive enhancing drugs may have unintended and quite negative consequences, particularly in young brains.
- See more at: http://www.dana.org/News/Details.aspx?id=115099#sthash.7ShljdNO.dpuf

 At Neuroscience 2012, Barbara Sahakian, a psychiatrist at the University of Cambridge, led a rousing discussion regarding the ethics surround the use of so-called "smart" drugs, or drugs that improve attention, memory, wakefulness and cognitive capabilities. In her talk, Sahakian highlighted that the number of young students and professionals using such drugs is only growing-and stressed the pros and cons of such use must be discussed in the context of both the individual and society at large. It was one of the most talked about speeches at the conference that year.

Certainly, cognitive enhancement, by any means, remains a controversial issue. But Julian Savulescu, the Uehiro Chair in Practical Ethics at the University of Oxford, says, on the whole, there is a lot of benefit to cognitive enhancement. He says that the ability to enhance memory and learning, even through the use of drugs, offers healthy people not only the ability to improve their academic performance but also their overall well-being and life success. And that, he argues, provides an economic benefit to society at large.

"I think there are a lot of good reasons to take 'smart' drugs. Overwhelmingly, there are a weight of reasons in favor of taking them," he says. "There are only two good objections to it that I see. One is that their use may be potentially exacerbating social injustice. But I think that's easily addressed by making sure people have basic access to them in the same way they have access to basic education. The second objection is one of safety. That they might be risky and we just don't know the long-term effects of their use. And that's a scientific question that needs to be answered."

To date, there has been a serious lack of research concerning the effects of these drugs, many of which are available without a prescription over the Internet, in healthy individuals. A recent review from researchers at the Drexel University College of Medicine suggests the use of cognitive enhancing drugs may have unintended and quite negative consequences, particularly in young brains.

Skin patch improves attention span in stroke patients

So I wonder what else stimulates dopamine receptors? maybe Ritalin from this research in 1998. Doesn't anyone follow previous research? Where is the 1998 research in the stroke therapy protocol? Who has the stroke therapy protocol?
http://medicalxpress.com/news/2012-07-skin-patch-attention-span-patients.html
Hemi-spatial neglect, a severe and common form of inattention that can be caused by brain damage following a stroke, is one of the most debilitating symptoms, frequently preventing patients from living independently. When the right side of the brain has suffered damage, the patient may have little awareness of their left-hand side and have poor memory of objects that they have seen, leaving them inattentive and forgetful. Currently there are few treatment options.
The randomised control trial took 16 patients who had suffered a stroke on the right-hand side of their brain and assessed to see whether giving the drug rotigotine improved their ability to concentrate on their left-hand side. The results showed that even with treatment for just over a week, patients who received the drug performed significantly better on attention tests than when they received the placebo treatment.
Rotigotine acts by stimulating receptors on nerve cells for dopamine, a chemical normally produced within the brain.
Professor Masud Husain who led the study at the Institute of Neurology at UCL says: “Inattention can have a devastating effect on stroke patients and their families. It impacts on all aspects of their lives. If the results of our clinical trial are replicated in further, larger studies, we will have overcome a major hurdle towards providing a new treatment for this important consequence of stroke.
“Milder forms of inattention occur in other brain disorders, across all ages - from ADHD (attention deficit hyperactivity disorder) to Parkinson’s disease. Our findings show that it is possible to alter attention by using a drug that acts at specific receptors in the brain, and therefore have implications for understanding the mechanisms that might cause inattention in conditions other than stroke.”
The work, published in the journal Brain, was funded by the Medical Research Council (MRC) and Wellcome Trust.

Methylphenidate(Ritalin) and stroke rehab

Methylphenidate is used as part of a treatment program to control symptoms of attention deficit hyperactivity disorder (ADHD; more difficulty focusing, controlling actions, and remaining still or quiet than other people who are the same age) in adults and children.

Arch Phys Med Rehabil. 1998 Sep;79(9):1047-50.

Only 13 years old, I wonder what happened to further research.

http://www.ncbi.nlm.nih.gov/pubmed/9749682

Abstract

OBJECTIVE:

To determine the efficacy and safety of methylphenidate in acute stroke rehabilitation.

DESIGN:

A prospective, randomized, double-blind, placebo-controlled study.

PATIENTS AND SETTING:

Twenty-one stroke patients consecutively admitted to a community-based rehabilitation unit.

INTERVENTION:

Three-week treatment of methylphenidate (or placebo) in conjunction with physical therapy. Methylphenidate was started at 5mg and increased gradually to 30mg (15mg at 8:00AM and 15mg at 12:00 noon), and discontinued before discharge.

MAIN OUTCOME MEASURES:

Mood measures included the Hamilton Depression Rating Scale (HAM-D) and Zung Self-Rating Depression Scale (ZDS). Cognitive status was evaluated using the Mini-Mental State Exam (MMSE). Motor functioning was assessed using the Fugl-Meyer Scale (FMS) and a modified version of the Functional Independence Measure (M-FIM). All measures were administered pretreatment and weekly thereafter. Side effects were measured after each increase in dosage and weekly.

RESULTS:

Patients receiving methylphenidate treatment scored lower on the HAM-D (F(1,18)=5.714, p=.028), lower on the ZDS (F(1,18)=4.206, p=.055), higher on the M-FIM (F(1,18)=5.374, p=.032), and higher on the FMS (F(1,9)=4.060, p=.075) than patients receiving placebo.

CONCLUSION:

Methylphenidate appears to be a safe and effective intervention in early poststroke rehabilitation that may expedite recovery.