Galantamine Overcomes Speechlessness

While preserving your memory, protect your ability to speak …

If you’ve ever experienced a so-called “senior moment” or a “momentary absence” when you don’t know where you are, you have an idea of what aphasia might be like 

Facts do not speak for themselves. They speak for or against competing theories. Facts divorced from theories or visions are mere isolated curiosities. 
— Thomas Sowell, A Conflict of Visions: Ideological Origins of Political Struggles

In British film director Ken Russell’s movie Altered States, Harvard psychophysiologist Dr. Eddie Jessup—a “mad scientist”—conducts experiments on himself with a psychedelic drug and an isolation tank. In searching for his “original self” on one of his research “trips,” Jessup—played by actor William Hurt in his film debut—experiences what we later learn is nothing less than a physiological transformation or genetic regression resulting from his hallucinations. (This is science fiction, of course.) Under the influence of a drug extracted from a mushroom brew used by Hinchi Indians to elicit first memories, Jessup comes out of one experiment bleeding from his mouth and unable to speak. Upon initial examination, an attending physician from a teaching hospital for Harvard Medical School pronounces the cause to be a transient-ischemic-attack-produced type of aphasia or speechlessness.

The Words Will Not Come Out

It is not only mad scientists who must fear losing the ability to speak. If you’ve ever experienced a so-called “senior moment” or a “momentary absence” when you don’t know where you are, you have an idea of what aphasia might be like. In the moments of forgetting, you lose a thought or important knowledge. In an aphasic moment, you lose the ability to speak. The words simply won’t come out.

One of the most common forms of dementia in individuals younger than 65 years is something called frontotemporal lobar dementia (FTLD). Encompassing a spectrum of disorders, FTLD is comprised of three core syndromes: frontotemporal dementia (FTD*), progressive nonfluent aphasia (PA), and semantic dementia (SD). These are clinical, pathological, and genetically mixed disorders in which there is atrophy (the partial or complete wasting away of a part of the body) in the frontal lobe and temporal lobe of the brain, while sparing the parietal and occipital lobes.

* FTD was formerly known as Pick’s disease

What frontotemporal lobar 
dementias have in common are 
behavioral symptoms, 
such as emotionlessness, and 
language symptoms, 
such as speechlessness.

What FTLDs have in common are behavioral symptoms, such as emotionlessness, and language symptoms, such as speechlessness. However, those so afflicted generally have preserved memory function, distinguishing their dementias from Alzheimer’s disease (AD), which always involves memory loss. Other behavioral features common to FTLDs include social inappropriateness, loss of insight, and emotional blunting. In the language realm, FTLDs assault comprehension and object knowledge (aspects of SD) and increase nonfluency and hesitant speech (aspects of PA). The major symptoms of PA are increasing difficulties with the production of speech.

FTLDs Can Be Seen

With the use of magnetic resonance imaging (MRI) of neural tissue, it is possible to show focal atrophy (in specific brain regions) and to exclude other disease causes. When combined with a patient’s history and a physical examination, MRI can help distinguish FTLDs from other common forms of dementia, including AD, Dementia with Lewy Bodies, and vascular dementia. While there is no cure for FTLDs, it is possible to manage symptoms with drugs, including selective serotonin reuptake inhibitors (SSRIs) and antipsychotics, as well as by the nutrient acetylcholinesterase inhibitor (AChEI)galantamine. It is interesting to note that some SSRIs have been associated with causing aphasia.1

Setting New Therapeutic Standards

As previously stated, FTD is one of three neurobehavioral syndromes produced by FTLD. Despite its importance as a cause of dementia, especially in the years before the incidence of AD accelerates, there have been no large scale treatment trials for FTD to determine the efficacy of serotonergic, dopaminergic, or cholinergic therapies. Part of the reason for this is the absence of agreement on standards to facilitate comparison across therapeutic trials.

Toward that goal, in a recent paper the literature on FTD therapeutic trials was reviewed.2 Outlines of general recommendations for standards related to the development of future treatment studies in this disorder were established. Among the drugs suggested for FTD were:

    • Trazodone (an antidepressant)
    • Idazoxan (an antipsychotic enhancer and an antidepressant targeting catecholamines, such as noradrenaline and adrenaline)
    • Lithium plus fluoxetine (a mood stabilizer along with an SSRI antidepressant)
    • Lithium plus paroxetine (a mood stabilizer along with another SSRI antidepressant)
    • Other SSRI antidepressants
    • L-deprenyl [selegiline, a selective monoamine oxidase (MAO) B inhibitor, used for many years for the treatment of Parkinson’s disease]
    • Moclobemide (a MAO inhibitor primarily used to treat depression and social anxiety)
    • Methylphenidate [a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder (ADHD)]
    • Piracetam (a nootropic drug to improve brain function and stimulate the central nervous system)
    • Rivastigmine (an AChEI for decreasing the breakdown of the memory function molecule acetylcholine)
    • Donepezil (another AChEI)
    • Olanzapine (an atypical antipsychotic for the treatment of schizophrenia and bipolar disorder)
    • Risperidone (another atypical antipsychotic used to treat schizophrenia, schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in children with autism)
    • Amantadine (used both as an antiparkinsonian drug and as an antiviral)
    • Guanfacine (an antihypertensive that can be used to control nervous disorders as in muscle twitches, and also used to treat ADHD)
    • Allopurinol [a drug used for aggressive behavior associated with dementia and to treat hyperuricemia (excess uric acid in blood plasma) and its complications, including chronic gout)
    • Bromocriptine (a dopamine agonist used in the treatment of Parkinson’s disease,pituitary tumors, hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.)
    • Galantamine [another AChEI with a triple mode of action (see “Galantamine Dismantles Brain Plaque” in the December 2010 issue)]

Targeting Progressive Aphasia

Of significance, overall behavioral improvement has been reported in FTD for all the above drugs except for piracetam, guanfacine, and galantamine. Nonetheless, galantamine has been shown to operate in the language arena, improving primary progressive aphasia (PPA). In this regard, galantamine appears to be unique, based on randomized controlled trials to date.

Whereas FTD improvement has been reported with the use of paroxetine (Paxil®) and other SSRIs—as well as idazoxan and methylphenidate (Ritalin®)—paroxetine and idazoxan have also been reported to cause a decline in function [as previously indicated, the SSRI sertraline (Zoloft®) has been found to produce aphasia in some subjects] and a marginally significant decline has been reported for methylphenidate.

The Repetition of Meaningless Words

Additionally, in one study calcium EDTA was found to show improvement in FTD.3 The rationale behind this investigation was that the primary defect in Pick’s disease (FTD) is caused by an excess of zinc, and when levels were reduced by EDTA chelation, improvement was seen. This occurred in attention, contact, collaboration, initiative, communication, verbal fluency and comprehension. There was also a reduction in perseveration (the repetition of a particular response, such as a word, phrase, or gesture, despite the absence or cessation of a stimulus), echolalia (the automatic repetition of vocalizations), and verbal stereotypies (the constant repetition of certain meaningless words).

Galantamine has been shown to 
operate in the language arena, 
improving primary progressive 
aphasia.

Returning to the review paper,2 from a total of six FTLD double-blind, placebo-controlled studies—two using idazoxan and group trials using trazodone, paroxetine, galantamine and methylphenidate—experts have struggled to define standards for all clinical trials. Included among these standards are tests for diagnostic criteria, tests of severity, experimental design, and outcome measures.

Galantamine on Trial

At the Cognitive Neurology and Alzheimer Research Centre, St. Joseph’s Hospital, London, Ontario, Canada, galantamine was tried in the two most common varieties of FTLD.4 Up until then, the treatment of FTD has been principally symptomatic, and small randomized or open-label case control studies of neurotransmitters have been inconclusive.

In schizophrenics, galantamine 
increased verbal fluency test 
performance, and “poverty of speech.”

Thirty-six behavioral variety FTD and PPA patients were treated in an open-label period of 18 weeks and a randomized, placebo-controlled phase for 8 weeks with galantamine. At the end, the primary efficacy measures showed no significant differences in behavior or language for the total group. However, galantamine provided a treatment benefit in a subgroup of subjects with PPA in the global severity score. But while detected in the placebo-controlled withdrawal phase, it was not considered significant after correction for multiple comparisons. More favorable, language scores for the PPA group given galantamine remained stable compared to the placebo group, which showed deterioration.

In the conclusion of this study, while it was not effective in the behavioral variety of FTD, there was an efficacy trend with galantamine in the aphasic subgroup, which may be clinically significant. Galantamine was shown to have no safety issues with FTD and PPA patients.

Galantamine Improves Aphasia

One year later, again at St. Joseph’s Hospital in London, Ontario, another study on FTD affirmed galantamine’s benefits for aphasia.5 The researchers also reported that FTD has become recognized as a distinct and relatively common entity encompassing behavioral language (PPA) and extrapyramidal presentations [side effects, such as akinesia (inability to initiate movement) and akathisia (inability to remain motionless)]. Further clinical subdivisions such as SD, and pathological subtypes increase the complexity of diagnosis. Given the relatively younger age of FTD’s onset, the typical presentations of syndromes and focal asymmetrical frontotemporal atrophy on MRI imaging allows experienced clinicians to make the diagnosis confidently as long as the overlap between the syndromes is recognized.

In Parkinson disease patients, 
galantamine was shown to improve 
verbal fluency or “wordfulness.”

Of the three variants of FTLD—SD, PA, and FTD—FTD is the most prevalent, being typified predominantly by character change and disordered social conduct. A variety of pathologies may underlie these syndromes, yet it is the location of the pathology rather than the type that dictates the clinical features of the disease. Several medications have been investigated to measure efficacy of treatment in FTD, often with mixed results. In yet another Ontario, Canada study—this one at the Baycrest’s Kunin-Lunenfeld Applied Research Unit—researchers reviewed these findings and suggested future directions that researchers might take to enhance treatment.6

Final Words and Improved Speech

In seemingly unrelated areas, galantamine has been found to be of value for speech-related problems. In one study, galantamine was associated with significantly greater improvements in schizophrenics in what was described as “continuous performance task (CPT) errors of commission and verbal fluency test performance.”7 [Emphasis added] (See “Galantamine May Help in Schizophrenia” in the October 2004 issue, and also see “Galantamine Used to Help Schizophrenia Patients” in the September, 2002 issue.) More recently, it was found that galantamine can improve speech in schizophrenia,8 and another recent study suggests that galantamine my treat “poverty of speech” in schizophrenia.9

Galantamine would seem to be 
valuable for those who cherish the 
preservation of language.

A recent double-blind, placebo-controlled pilot study tested the ability of galantamine to improve cognitive dysfunction in minimally symptomatic bipolar disorder. The study followed 30 patients for three months and found that galantamine increased fluency.10 In another double-blind, placebo-controlled study with AD patients, galantamine appeared to help with fluency.11 In the study, 78 patients over the age of 55 were given a metal-protein-attenuating compound that increases toxic oligomerisation of amyloid-beta (Aβ) in AD. Normally that would accelerate the effects of AD, but when the subjects were given galantamine for at least four months, less degeneration was seen and two executive tests showed significant improvement over placebo, one of which indicated a greater facility with words.

Wordfulness

To bring us back to Altered States, galantamine was given to 16 Parkinson’s disease patients in their 70s, nine of whom were suffering from hallucinations.12 By the end of the study, seven of the nine experiencing hallucinations were improved. There were also trends showing improvement in verbal fluency or “wordfulness.” Would Dr. Jessup’s outcome been different if Harvard Medical had then had galantamine in its arsenal?

While the evidence is still not all in by any means, galantamine would seem to be valuable for those who cherish the preservation of language. Given its other virtues, and if the evidence holds up and continues to compile, you can add yet another reason to make it a part of your supplement regimen.

References

  1. Prodan CI, Monnot M, Ross ED. Behavioural abnormalities associated with rapid deterioration of language functions in semantic dementia respond to sertraline. J Neurol Neurosurg Psychiatry 2009 Dec;80(12):1416-7.
  2. Freedman M. Frontotemporal dementia: recommendations for therapeutic studies, designs, and approaches. Can J Neurol Sci 2007 Mar;34 Suppl 1:S118-24.
  3. Richard J, Constantinidis J, Tissot R. Calcium EDTA treatment of Pick’s disease. Nouv Presse Med 1978; 7:1304.
  4. Kertesz A, Morlog D, Light M, Blair M, Davidson W, Jesso S, Brashear R. Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord 2008;25(2):178-85.
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  7. Allen T, McEvoy JP, Keefe R, Levin E, Wilson W. Galantamine as an adjunctive therapy in the treatment of schizophrenia. Presented at 11th Congress of the International Psychogeriatric Association (IPA), Chicago, IL, Aug 17-22, 2003.
  8. Ochoa EL, Clark E. Galantamine may improve attention and speech in schizophrenia. Hum Psychopharmacol 2006 Mar;21(2):127-8.
  9. Galletly C. Recent advances in treating cognitive impairment in schizophrenia. Psychopharmacology (Berl) 2009 Jan;202(1-3):259-73.
  10. Ghaemi SN, Gilmer WS, Dunn RT, Hanlon RE, Kemp DE, Bauer AD, Chriki L, Filkowski MM, Harvey PD. A double-blind, placebo-controlled pilot study of galantamine to improve cognitive dysfunction in minimally symptomatic bipolar disorder. J Clin Psychopharmacol 2009 Jun;29(3):291-5.
  11. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW; PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2008 Sep;7(9):779-86. Erratum in: Lancet Neurol 2009 Nov;8(11):981.
  12. Aarsland D, Hutchinson M, Larsen JP. Cognitive, psychiatric and motor response to galantamine in Parkinson's disease with dementia. Int J Geriatr Psychiatry2003 Oct;18(10):937-41.