In addition to improving memory, and so much more …

Galantamine Enhances Sleep
And that’s especially good for seniors who
are far more likely to experience sleeping problems

By Will Block

To sleep, perchance to dream — ay, there’s the rub.
 —  Hamlet, William Shakespeare

E pidemiologic studies show that approximately 50% of the elderly have sleep problems. Many of these are serious, affecting physical and mental health along with social functioning.1 Moreover, sleep problems are often unrecognized in later life, and thus inadequately dealt with in clinical practice.

Among the elderly, sleep disturbances are compounded by dementia, meaning that if you are over 65 years of age you may be experiencing sleep problems, and if you’ve developed dementia, your problems are more likely to be worse.

One Commonly Shared Problem

Overall, the prevalence of sleep disturbance in dementia patients ranges from 25 to 64%, depending on the type and stage of dementia, age, gender, and comorbidities.2 It is worth noting that there is one commonly shared pattern, and that is the irregular sleep-wake rhythm, a circadian disorder characterized by an absence of the sleep-wake cycle’s circadian synchronization.2 In other words, you’re tired when you don’t want to be, and restless when you try to sleep.

It is thought that the mechanisms of circadian rhythm disturbance include suprachiasmatic nucleus (SCN) circadian pacemaker damage, pineal gland and melatonin secretion alterations, and reduced zeitbeigers (“cues” for wakefulness, such as the use of light, “But, soft! what light through yonder window breaks”) and decreased input to the SCN.

Melatonin and Mixed Modalities

Included in the options for treatment are sleep/wake scheduling, light therapy, melatonin, physical and social activity, and mixed modality, which constitutes the most effective method in treating irregular sleep-wake rhythm according to some clinicians.

There is controversy in the choice of pharmacologic interventions — such as sleeping pills — with little evidence supporting their long-term effectiveness. Plus there are multiple side effects. Thus, sleeping pills should be approached with caution and restricted to short-term therapy, if at all. Even then, each individual must be matched to the therapy used to achieve a temporary desirable outcomes.


The prevalence of sleep disturbance
in dementia patients ranges from
25 to 64%.


Good things can be said for melatonin, 5-HTP, tryptophan, and other nutrients (see “Better Sleep May Mean Longer Life — Research suggests that those who sleep well may have a survival advantage” in the March 2003 issue, and “The Durk & Sandy Way to a Quiet Mind™ for Sleep or Daytime Calmness” in the September 2007 issue). These supplements can be particularly good for long-term use because they provide primary provisions for functional sleep. But other issues may arise — especially with age and dementia — that require added support.

Can Cholinesterase Inhibitors Help Sleep?

In a new report, researchers evaluated the influences of cholinesterase inhibitors (ChEIs) on sleep patterns and disturbances during a 6-month observational study.3 Three different cholinesterase inhibitors were used: galantamine (from 8 mg to 16 mg to 24 mg), donepezil (from 5 mg to 10 mg), or rivastigmine band (from 5 cm2 to 10 cm2), depending on the preferences of the clinicians. These were given to 87 mild to moderate stage dementia patients who were not on cholinesterase enzyme inhibitors or memantine regimens. The dose of each drug and nutrient was gradually increased every 2 – 4 weeks until reaching the tolerated maximum dose.

Fifty-five dementia patients (63.2 %) completed the study. Twenty-three elderly subjects, who had normal cognitive functions, were included in the study as the control group. The cognitive functions of the control group were evaluated using the mini – mental state examination — a commonly used dementia test — and the subjects whose scores were ≥ 28 were included in the study (a score of 30 represents cognitive normality). Subjects who had comorbidities and medication that could impair sleep were not included.

Does Galantamine Boost Cognitive Speed?

Dementia is a condition in which a person has significant difficulty with living his/her life because of problems with thinking and memory. However, dementia is not a single disease. It’s an overall term — like “heart disease” — that covers a wide range of medical conditions, including Alzheimer’s disease.

Dementias are caused by abnormal brain changes that result in a decline in thinking skills, aka cognitive abilities, severe enough to impair daily life and independent function. They also affect behavior, feelings and relationships. Brain changes that cause dementia may be temporary, but they most often become permanent and worsen over time, leading to increasing disability and even a shortened lifespan.

What is called mixed dementia — an association of both Alzheimer disease (AD) and cerebrovascular disease (CVD) — is more common than is commonly believed.1 It is usually under-diagnosed, and its prevalence becomes more common with increasing age.2


Brain changes that cause dementia
may be temporary, but they most
often become permanent and
worsen over time, leading to
increasing disability and even a
shortened lifespan.


Galantamine: Re Quality of Life and Cognitive Speed

To date, most studies have investigated the efficacy and safety of different agents on each condition separately (AD and CVD), even though the association of AD and CVD is well documented in the medical literature. The effects of galantamine on quality of life and cognitive speed, as well its effects when combined with nimodipine — a drug with putative neuroprotective effects in those with subcortical vascular dementia — in AD with CVD (mixed dementia), had not previously been explored, but a new study looked into that.2 Cognitive speed has to do with how fast you can take in information, or the time necessary to capture various data.

In a double-blind, placebo-controlled, multicenter Brazilian trial, researchers studied the effects of galantamine with nimodipine vs. galantamine with placebo in mild to moderate mixed dementia, which the subjects were randomized to receive for 24 weeks. The primary efficacy measures were changes on a Computerized Neuropsychological Battery (CNTB) to measure cognitive speed and Quality of Life Scale in AD from baseline to week 24.

Galantamine Showed Quality of Life and Cognitive Improvement

Twenty-one patients (76 ± 6.2; 15 female and 6 male) received the drug combo (9 got the galantamine/nimodipine) or the nutrient combo (12 got the galantamine/placebo).

In measuring quality of life …

The Quality of Life Assessment Scale for caregivers of patients with Alzheimer’s disease was used. It is a 13-item scale with four possible scores for each question (score 1: poor and score 4: excellent). It evaluates the caregivers’ own perceived quality of life. Total score ranges from 13 to 52. Higher scores represent a better outcome.

In measuring cognitive speed the researchers used …

The Simple Reaction Time, a computerized attention test that evaluates the patient’s reaction time. The number “one” was presented in the center of the computer screen and the patient had to press this number in the response box as quickly as possible. The reaction time, assessed 100 times per patient, was averaged at each time point for each patient e.g., at baseline, Week 8 and Week 24. The patient’s finger was put over button one before the test begun. This test is part of the CNTB.

The Two-Choice Reaction Time Test, a computerized attention test in which the numbers one or five were presented in the center of the computer screen in a random order. The patient had to press the corresponding button in the response box as quickly as possible. The patient’s right finger was put over the button five and the left finger over button one before the test begun. The reaction time, assessed 100 times per patient, was averaged at each time point for each patient e.g., at baseline, Week 8 and Week 24. This test is also part of the CNTB.


Yet quality of life and cognitive
performance showed significant
improvement from baseline when
all galantamine-treated patients
were analyzed.


The Face Recognition Test, a computerized attention test in which ten unfamiliar faces were presented simultaneously on the computer screen for ten seconds to be remembered. After that, a single face was shown and the patient had to press the button “one” if he/she remembered or, otherwise, button “five.” It consisted of a random presentation of ten pre-exposed faces and ten new faces as distracters. The reaction time, assessed per patient, was averaged at each time point for each patient e.g., at baseline, Weeks 8 and 24. This test is also part of the CNTB.



The Word Recognition and Learning Test, a computerized attention test that evaluates the patient’s reaction time. This test is similar to the Face Recognition test procedure using words. The recognition procedure was repeated three times to evaluate a learning effect. The reaction time, assessed per patient, was averaged at each time point for each patient e.g., at baseline, Weeks 8 and 24. This test is also part of the CNTB.

Overall in the study, there were no significant differences observed between groups on primary or secondary measures. Yet quality of life and cognitive performance showed significant improvement from baseline when all galantamine-treated patients were analyzed. So galantamine improved quality of life and cognitive speed.

Galantamine Ups Influence of Cue Validity on Response Speed

What are the mechanisms whereby the cholinergic neurotransmitter system contributes to attentional processing? This remains poorly understood. In a new study, researchers applied computational modeling to psycho-physical data (obtained from a spatial attention task) under a psychopharmacological challenge with the cholinesterase inhibitor galantamine.3 This design allowed them to characterize the cholinergic modulation of selective attention formally, in terms of hierarchical Bayesian inference.


Galantamine was thought to
increase faster updating, and these
psychopharmacological effects
were dependent on the effective
dose of galantamine.


A Bayesian network is a probabilistic graphical model (a type of statistical model) that represents a set of random variables and their conditional dependencies via a directed acyclic graph. For example, a Bayesian network could represent the probabilistic relationships diseases and symptoms (see Fig. 1). Given symptoms, the network can be used to compute the probabilities of the presence of various diseases.

In a placebo-controlled, within-subject, crossover design, 16 healthy human subjects (8 males, 8 females; age range 19 – 30 years; mean age 23.4 years) performed a modified version of Posner's location-cueing task in which the proportion of validly and invalidly cued targets [percentage of cue validity (% CV)] changed over time. All subjects were right-handed and had normal or corrected-to-normal vision. The Posner Cueing Task is a neuropsychological test often used to assess attention. It has been used to measure manual and eye-movement reaction times to target stimuli in order to investigate the effects of covert orienting of attention in response to different cue conditions. A cue indicates the most likely position of a target.

In the study, saccadic response speeds (RS) were used to estimate the parameters of a hierarchical Bayesian model to test whether cholinergic stimulation affected the trial-wise updating of probabilistic “beliefs” that underlie the allocation of attention or whether galantamine changed the mapping from those beliefs to subsequent eye movements.5

A saccade (sa-kad, French for jerk) is a quick, simultaneous movement of both eyes between two phases of fixation in the same direction. The phenomenon can be associated with a shift in frequency of an emitted signal or a movement of a body part or device. The word appears to have been coined in the 1880s by French ophthalmologist Émile Javal, who used a mirror on one side of a page to observe eye movement in silent reading, and found that it involves a succession of discontinuous individual movements.5

Saccadic RS were most plausibly explained as a function of the precision of the “belief” about the causes of sensory input. This finding is in accordance with current Bayesian theories of brain function, and specifically with the proposal that spatial attention is mediated by a precision-dependent gain modulation of sensory input.

The Need for Statistic Analysis

Figure 1. Diagnostics of lung disease: from causes to symptoms using a small bayesian network in BayesiaLab
LEM1504mainarticlefig_274.gif
(click on thumbnail for full sized image)

Scientific studies invariably involve the use of statistics. That’s because the question scientists attempt to answer is the relationship between two (or more) variables. To demonstrate that there is a relationship, the experimenter must show that when one variable changes, the second variable changes, and that the amount of change is more than would be likely from mere chance alone.

Behaviorally, galantamine led to a greater influence of probabilistic context (% cue validity) on response speed than placebo. Crucially, computational modeling suggested this effect was due to an increase in the rate of belief updating about cue validity (as opposed to the increased sensitivity of behavioral responses to those beliefs). In other words, galantamine enhances sensory precision by boosting bottom-up signaling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty.

The researchers discussed these findings with respect to cholinergic effects on hierarchical cortical processing and in relation to the encoding of expected uncertainty or precision. Galantamine was thought to increase faster updating, and these psychopharmacological effects were dependent on the effective dose of galantamine.

Sometimes, people ask me how it is that I’m able to crank up my output at a time when most people my age have retired. In my response, I always say that galantamine (enhanced by the toolkit of correlative boosters) comes to mind.

References

  1. Korczyn AD. Mixed dementia--the most common cause of dementia. Ann N Y Acad Sci. 2002 Nov;977:129 – 34.
  2. 2. Caramelli P, Laks J, Palmini AL, et al. Effects of galantamine and galantamine combined with nimodipine on cognitive speed and quality of life in mixed dementia: a 24-week, randomized, placebo-controlled exploratory trial (the REMIX study). Arq Neuropsiquiatr. 2014 Jun;72(6):411 – 7.
  3. 3. Vossel S, Bauer M, Mathys C, Adams RA, Dolan RJ, Stephan KE, Friston KJ. Cholinergic stimulation enhances Bayesian belief updating in the deployment of spatial attention. J Neurosci. 2014 Nov 19;34(47):15735 – 42.

Beginning and Final Assessment

The Pittsburgh Sleep Quality Index (PSQI) was used for evaluating the sleep quality at the beginning and at the final assessment. This test is a self-rated questionnaire that assesses sleep quality and disturbances over a 1-month time interval. Decreases and increases in PSQI scores were accepted as an improvement or deterioration in sleep disturbances, respectively. Nineteen individual items generated seven “component” scores: 1) subjective sleep quality, 2) sleep latency, 3) sleep duration, 4) habitual sleep efficiency, 5) sleep disturbances, 6) use of sleeping medication, and 7) daytime dysfunction.

The sum of scores for these seven components yields one global score. The last five questions include the assessment of the bed partner about the subject and were not included in the scoring. Sleep habits (time of going to bed, awakening time, sleep latency, total sleep time), frequency of sleep problems during the night, sleep quality, use of sleep medicine and the daytime awakening problems are the parameters evaluated by the test. The test measures the sleep quality within the last month, graded out of 21, and scores of 5 and above indicate a poor sleep quality.


Sleeping pills should be
approached with caution and
restricted to
short-term therapy.


Sleep Improvement

Galantamine is frequently used in early and mid-stage Alzheimer’s disease. Sleep disturbances in Alzheimer’s disease (AD) are prolonged sleep latency, decreased deep sleep, daytime sleepiness, decreased rapid eye movement (REM) sleep, “sun-downing” (a psychological phenomenon associated with increased confusion and restlessness in patients with some form of dementia, including AD), and frequent and long awakening during sleep.


ChEIs change the sleep pattern
through prolonging the REM time.


Significant Improvement with Galantamine

A significant decrease in PSQI scores was detected in the galantamine group after treatment, representing significant improvement. Rivastigmine and donepezil failed to significantly alter the PSQI. Among dementia patients who had a poor sleep quality (n=36), the rate of improvement in sleep disturbance was 81.8% in the galantamine group, 75% in the rivastigmine, and 50% in the donepezil group.

Acetylcholine is important in the maintenance of the sleep pattern and consolidation of memory during REM sleep.3 ChEIs change the sleep pattern through prolonging the REM time. In several studies, donepezil reportedly increased REM sleep, and was associated with an improvement of cognitive functions. [See reference #3; other references omitted.]

In rats, galantamine was superior to both donepezil and memantine (which impaired sleep pattern) and led to sleep disorders. Galantamine did not impair sleep. Another report determined that donepezil significantly increased the sleep latency in transgenic rat models. Donepezil not only decreased non-REM sleep, but also impaired the sleep quality.

In the current study, the highest improvement rate was found with galantamine in dementia patients who had a poor sleep quality. The researchers wrote, “Galantamine may be the first choice of cholinesterase inhibitor in mild to moderate dementia patients in terms of improving sleep quality.” In another study by the same authors, galantamine significantly improved sleep disorders compared to donepezil in dementia patients.4 Numerous other studies have found that galantamine is not only safe for sleep, but is ­sleep positive.


“Galantamine may be the first choice
of cholinesterase inhibitor in mild to
moderate dementia patients in terms
of improving sleep quality.”


Three Galantamine Mechanisms of Sleep Enhancement

Galantamine’s advantageous effect on sleep has been explained by three different mechanisms. First, galantamine has lower ChEI effect than others. Second, plasma levels of galantamine are high during daytime and low at night, which may contribute to the desired cholinergic activity after treatment that mimics physiological circadian rhythms. Third, the function of the hypothalamopituitary axis (HPA) is affected by cholinergic neurotransmission disorder. Cholinergic activity of galantamine may repair the sleep pattern by restoring regular functions of the HPA axis, impairment of which is associated with cognitive disorders and insomnia.

With all of the positive things that we know about galantamine, including its positive effects on memory and cognition, now we can add one more — galantamine is a sleep enhancer. Three cheers for galantamine!

References

  1. Rodriguez JC, Dzierzewski JM, Alessi CA. Sleep Problems in the Elderly. Med Clin North Am. 2015 Mar;99(2):431 – 439.
  2. Zhou QP, Jung L, Richards KC. The management of sleep and circadian disturbance in patients with dementia. Curr Neurol Neurosci Rep. 2012 Apr;12(2):193 – 204.
  3. Naharci MI, Ozturk A, Yasar H, Cintosun U, Kocak N, Bozoglu E, Tasci I, Doruk H. Galantamine improves sleep quality in patients with dementia. Acta Neurol Belg. 2015 Mar 17. [Epub ahead of print] PubMed PMID: 25777522.
  4. Naharcı MI, Bozoglu E, Kocak N, Doruk H. Analysis of the efficiencies of galantamine and donepezil on sleep disorder in patients with dementia. 2011 Bull Clin Psychopharm. 21(4):339 – 44.
  5. Javal É Essai sur la physiologie de la lecture. Annales d’Oculistique. 1878;80:61 – 73.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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