Piracetam and Down syndrome

1. Lobaugh NJ et al. Piracetam does not enhance cognitive abilities in moderate to high-functioning 7 to 13 year-old children with Down syndrome. Presented at the PAS/SPR meeting in San Francisco May 3, 1999; published in Archives of Ped and Adol Med, April 2001, 155(4):442-448.
   

   "Piracetam, a drug reported to enhance cognitive performance in many neurobehavioural conditions, has become popular in the treatment of children with Down Syndrome (DS). However, reports of its efficacy in DS have been anecdotal, not from evidence-based studies. Some caregivers have noted no effect of piracetam, while others claim substantial improvement in cognitive functioning. To address the need for objective analysis, we conducted a double-blind placebo-controlled crossover study assessing the cognitive and behavioral effects of piracetam in children with DS. Patients and Study Design. Children with DS (n = 25, 13 males, 6.5 - 13 yrs) and their parents participated. The first phase of the study was a baseline cognitive assessment. Children were then randomly assigned to one of two four-month treatment arms: Piracetam. Placebo or Placebo. Piracetam. Children were retested at the end of the two treatment phases. Children received 80-100 mg/kg piracetam per day in capsules. Placebo was administered in the same manner. Test Battery. The test battery included 16 tasks assessing attention, learning, memory, verbal fluency, perceptual and spatial abilities, processing speed, fine motor skills, and executive function. Both standardized and experimental tasks were included. Secondary outcome measures were questionnaires completed by parents and teachers at each of the three phases. Results. Eighteen children (7 - 13 yrs) completed the study, 5 withdrew, and 2 could not complete the battery at baseline testing. The mean mental age for the final sample was 4.2 ± .7 years (Stanford Binet). The 16 tasks yielded 75 measures and the parent and teacher questionnaires had 80 and 24 items, respectively. Piracetam did not show significant effects over placebo on any outcome measure. All significant interactions (p's < 0.05) with drug order or the covariate were examined further to ensure drug effects were not being masked. That analysis did not alter the results. Piracetam administration was associated with CNS stimulatory effects: aggressiveness (n=4), agitation (n =3), sexual arousal, (including masturbation in public, n=2), irritability (n=1), and poor sleep (n=1). Conclusion. Piracetam has received a great deal of attention in the popular press purporting its efficacy in improving cognitive function in children with Down Syndrome. In this study, we were unable to substantiate these claims, even at doses associated with adverse effects. Neither cognitive nor behavioural measures demonstrated improvement under piracetam. Due to the serious adverse effects, it is unlikely that larger doses can be tolerated."
   ©1999 Pediatric Academic Societies

2. Fialho J Dromia and Piracetam: a useful association in the treatment of Down syndrome. Tempo Medico 30:944, 1977. (The original was published in Spanish; an English version was reprinted in a book whose specifics are unknown to me.) 26 children with DS between 3 months and 12 years were given Dromia (mixture of pyriglutine and 5-hydroxytryptophan) alone, and then a combination of Dromia and Piracetam. The children were then evaluated based on their muscle tone, motor development, mental development, speech, affective-social development, scholastic achievement and EEG trace. The author concludes that the combination of the two drugs caused an improvement in all aspects, but especially speech. There were no side effects noted. (Unfortunately, this is a terrible study. There were no controlled subjects, the investigator does not tell how he evaluated the above categories and does not say if the subjects, parents, or investigators were "blinded" as to which children were getting one or both drugs.)
    
3. An unpublished feasibility study was conducted in 1999 at the Kennedy Kriger Institute in Baltimore under the guidance of Dr. George Capone. Five school-aged children with DS were given piracetam and compared to five children with DS not on piracetam. The piracetam was given at 100 mg/kg body weight per day. After six months, the children were assessed for auditory verbal memory, auditory non-verbal memory, visual memory, and spatial working memory. There were no statistically significant differences in the two groups. It should be noted that this was a study that was set up more to prove to the NIH that the study was doable and deserving to be funded on a large-scale basis rather than to prove whether to not piracetam had any measurable effects. A lack of funds kept this study from being carried out to a point where the research could be published.

"Piracetam is a nootropic agent that has been shown to improve cognitive performance in a number of animal model systems. Piracetam is reported to be used widely as a means of improving cognitive function in children with Down's syndrome (DS). In order to provide a preclinical assessment of the potential efficacy of piracetam, we examined the effects of a dose range of piracetam in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for a region of mouse chromosome 16 with homology to human chromosome 21. Daily piracetam treatment at doses of 0, 75, 150, and 300 mg/kg ip was initiated in 6-week-old male Ts65Dn and euploid control mice. Following 4 weeks of treatment, mice were tested in the visible and hidden-platform components of the Morris water maze and were placed overnight in computerized activity chambers to assess effects on overall activity. Piracetam treatment was continued through the 4 weeks of testing. In control mice, 75 and 150 mg/kg/day piracetam improved performance in both the visible- and hidden-platform tasks. Although low doses of piracetam reduced search time in the visible-platform component in Ts65Dn mice, all piracetam doses prevented trial-related improvements in performance in Ts65Dn mice. The 300-mg/kg/day-piracetam dose was associated with a reversal of the nocturnal spontaneous hyperactivity in Ts65Dn. These data do not provide support for piracetam treatment for individuals with DS."

Advocates of piracetam have argued that choline must also be supplemented with piracetam to get any effect, thus explaining the results of the Toronto and Johns Hopkins studies. The main basis for this belief are the following studies:

1. Bartus RT et al. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging Summer;2(2):105-11, 1981. Rats given both choline and piracetam did better on a memory test than on choline or piracetam alone.
2. Platel A et al. Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes. Pharmacol Biochem Behav 21(2):209-12, 1984. Mice did better on memory of their environment with the combination of choline and piracetam than on either separately.
3. Mosharrof AH & Petkov VD. Effects of citicholine and of the combination citicholine + piracetam on the memory. Acta Physiol Pharmacol Bulg 16(1):25-31, 1990. Mice did better with memory retention with the combination of citicholine and piracetam than the compounds separately.
4. Friedman E et al. Clincal Response to choline plus piracetam in senile dementia: relation to red-cell choline levels. New Eng J Med 1981 Jun 11; 304(24): 1490-1. This is actually a "letter" rather than a full paper, and consisted giving 10 patients with presenile dementia piracetam and choline for 7 days in a non-controlled study. 3 of the 10 had "marked improvement" cognitively, but no description of the cognitive tests or whether the testing was blinded is mentioned. The 3 who responded had higher choline red blood cell levels than the 7 who didn't respond.

1. Ennaceur A & Delacour J. Effect of combined or separate administration of piracetam and choline on learning and memory in the rat. Psychopharmacology 92(1):58-67, 1987. Rats given choline alone did better than rats given piracetam alone on memory test, and rats given piracetam and choline together did worse than the other groups.
2. Growdon JH et al. Piracetam combined with lecithin in the treatment of Alzheimer's disease. Neurobiol of Aging 7:269-276, 1986. Piracetam was administered alone or with lecithin (phosphatidylcholine) in a double-blinded test. No effect was seen, with or without lecithin, on cognition or memory test scores.
3. Corona GL et al. Clinical and biochemical responses to therapy in Alzheimer's disease and multi-infarct dementia. Eur. Arch. Psychiatr. Neurol. Sci. 239:79-86, 1989. Patients with either AD or multi-infarct dementia were given either piracetam or piracetam with choline. This was not paired with placebos. Despite biochemical changes, there was no change in memory performance.