Piracetam Therapy Does Not Enhance Cognitive Functioning in Children with Down Syndrome

ARTICLE Piracetam Therapy Does Not Enhance Cognitive Functioning in Children With Down Syndrome

Nancy J. Lobaugh, PhD; Vladimir Karaskov, MD; Vicki Rombough, MA; Joanne Rovet, PhD; Susan Bryson, PhD; Rachel Greenbaum, MA; Robert H. Haslam, MD; Gideon Koren, MD

Background: Piracetam is widely used as a purported Main Outcome Measure: The difference in perfor- means of improving cognitive function in children with mance while taking piracetam vs while taking placebo Down syndrome. Its efficacy, however, has not been rig- on tests assessing a wide range of cognitive functions, in- orously assessed. cluding attention, learning, and memory.

Objective: To determine whether 4 months of pi- Results: Eighteen children completed the study, 4 with- racetam therapy (80-100 mg/kg per day) enhances cog- drew, and 3 were excluded at baseline. Piracetam therapy nitive function in children with Down syndrome. did not significantly improve cognitive performance over placebo use but was associated with central nervous sys- Design: A randomized, double-blind, placebo-con- tem stimulatory effects in 7 children: aggressiveness trolled crossover study. (n=4), agitation or irritability (n=2), sexual arousal (n=2), poor sleep (n=1), and decreased appetite (n=1). Participants and Methods: Twenty-five children with Down syndrome (aged 6.5-13 years) and their caregiv- Conclusion: Piracetam therapy did not enhance cogni- ers participated. After undergoing a baseline cognitive as- tion or behavior but was associated with adverse effects. sessment, children were randomly assigned to 1 of 2 treatment groups: piracetam-placebo or placebo-piracetam. Arch Pediatr Adolesc Med. 2001;155:442-448

IRACETAM is a member of the Down syndrome is associated with de- class of drugs known as noo- velopmental delay, and affected children tropics, which are generally generally attain mental and cognitive ca- thought to enhance cogni- pacity in the range of mild to moderate men- From the Rotman Research tive function in instances of tal retardation. Interest in using piracetam Institute of Baycrest Centre for Pbrain dysfunction. Putative mechanisms to improve cognitive function in children Geriatric Care and University of action differ depending on the disease with Down syndrome surged in North of Toronto (Dr Lobaugh); the process being modeled and include en- America after the television program Day Division of Clinical hanced membrane fluidity,1 increased neu- One was nationally broadcast on January 19, Pharmacology and Toxicology rotransmitter release (eg, dopamine),2 pro- 1995. In this program, claims were made that (Drs Karaskov and Koren and tective effects on specific receptors (eg, piracetam therapy improved cognitive func- Ms Greenbaum), the glutamate),3 increased blood flow,4 en- tion in a child with Down syndrome. This Department of Psychology hanced corticosteroid function,5 and ef- was followed by television reports on De- (Dr Rovet and Ms Greenbaum), 6 and the Division of Neurology fects on calcium channel function. Pi- cember 20, 1996 (Nightline), and on Au- (Drs Bryson and Haslam), The racetam has been administered to patients gust 21, 1997 (48 Hours), and widespread Hospital for Sick Children; the dissemination of anecdotal evidence through Departments of Paediatrics For editorial comment Internet newsgroups. For example, par- (Drs Rovet and Haslam), see page 438 ents of a 6-year-old girl indicated that Pharmacology (Dr Koren), “...herconcentration and awareness have Pharmacy (Dr Koren), with diverse clinical conditions such as improved. Her speech has improved to the Medicine (Drs Lobaugh, stroke,7 Alzheimer disease,8-12 and devel- point that she is finally saying phrases and Haslam, and Koren), and opmental dyslexia.13-15 However, re- sentences; improvement is slow but she is Psychology (Dr Rovet), University of Toronto; and the search on the efficacy of piracetam and re- finally making some” (May 1995). An 11- Department of Psychology, lated compounds to ameliorate cognitive year-old boy became “healthier, happier, has York University (Ms Rombough deficiencies in these populations, and in more energy, pays attention better, is grow- and Dr Bryson), Toronto, animal studies, has frequently produced ing like crazy...absolutely full of energy” Ontario. small or inconsistent results.16 (January 1999). Partially in response to

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 PARTICIPANTS AND METHODS baseline physical and cognitive assessment. All children were assessed with the Stanford-Binet Intelligence Scale, 4th Edi- STUDY DESIGN tion,17 to establish mental age equivalents, and the cognitive test battery was also administered. Children were ex- This study used a double-blind, placebo-controlled de- amined by a physician, and a medical history was obtained sign consisting of a baseline assessment and two 4-month from the parents. Testing was divided into two 3- to 4-hour treatment arms (Figure 1). To control for maturation ef- sessions, with a break for lunch and additional breaks as fects, 2 treatment orders were used. Children were ran- needed. domly assigned to receive piracetam in phase 1 and placebo in phase 2 (piracetam-placebo) or placebo in phase 1 PRIMARY OUTCOME MEASURES: and piracetam in phase 2 (placebo-piracetam). Cognitive COGNITIVE TEST BATTERY evaluations were conducted at the end of each phase while the children were in school. Baseline assessments were con- The 14 tests selected for this study were culled from a vari- ducted at the end of the 1996-1997 school year, phase 1 ety of standardized tests and experimental paradigms and testing occurred at the end of the fall 1997 term, and phase broadly covered the following functional domains: atten- 2 testing occurred near the end of the spring 1998 term. tion, learning and memory, perceptual abilities, executive This study was approved by the research ethics board at function, and fine motor and visuomotor skills. Additional The Hospital for Sick Children in Toronto, Ontario. criteria were that the tests be suitable for children with Down syndrome and show minimal or no learning or practice ef- PARTICIPANTS fects with repeated administration. Brief descriptions of the The target sample size (N=25) was chosen to allow detec- tasks are listed in Table 1, and full descriptions can be ob- tion of large performance differences (0.8 SD) between the tained from the authors. The standardized tests in the bat- piracetam and placebo phases with power of 80% and ␣=.05. tery are typically used to assess children in the 3- to 5 year- A large effect size was chosen because most reports in the popu- old age range, and the remaining tests have been used in 3- to 5-year-old children (eg, see Johnson18) or patients with lar press have indicated immediate and substantive effects of 19 piracetam treatment in children with Down syndrome. Down syndrome (eg, see Dalton ). The child’s effort on each Moderate- to high-functioning children with Down syn- task was monitored by the tester using a 5-point rating scale drome (aged 6.5-13 years) were recruited through pediatri- (5=fully compliant and 1=noncompliant). cians and Down syndrome support groups throughout south- ern Ontario. Initial interviews with the child’s parent(s) and SECONDARY OUTCOME MEASURES: PARENT teacher determined the child’s general health and cognitive AND TEACHER QUESTIONNAIRES abilities. Exclusion criteria were hearing, vision, language, or other physical or cognitive limitations that would interfere Parents and teachers completed standardized question- with their ability to complete the test battery; known prob- naires at each test phase (Table 2). Parent question- lems in swallowing capsules; use of piracetam during the pre- naires provided 80 items that assessed activity levels, so- vious 6 months; and concurrent use of megavitamins. cial behavior and well-being, stress, parenting and family issues, and the child’s temperament. Teacher question- BASELINE SCREENING ASSESSMENT naires provided 24 items that assessed activity levels, learning, and social behaviors in the school environment. Twenty-five children passed the initial telephone screening and were invited to The Hospital for Sick Children for Continued on next page

claims such as these, piracetam has gained widespread use line assessment and were not enrolled; their verbal rea- among children with Down syndrome. Although thou- soning age equivalents (2.5-3.0 years) were significantly sands of children are believed to presently receive the drug, lower than those of the study children. Four enrolled chil- no well-designed studies testing the efficacy or assessing dren withdrew during the course of the study: 3 had dif- the adverse effects of piracetam therapy have been pub- ficulty swallowing the capsules and withdrew during phase lished in the peer-reviewed medical literature. 1 and the fourth required heart surgery in phase 2 (pla- Unbiased assessment of the effects of piracetam cebo condition). Baseline demographics and perfor- therapy in Down syndrome, beneficial or harmful, is of mance on the Stanford-Binet Intelligence Scale for the 22 great importance. Most of the media reports have indi- enrolled children are shown in Table 3. cated that cognitive functions such as learning, memory, and attention improve rapidly with the use of pi- PRIMARY OUTCOME MEASURES: racetam. To test these claims, we designed a random- COGNITIVE TEST BATTERY ized, double-blind, placebo-controlled crossover study. Of the 87 items selected for analysis, 22 reflected easier components of the tasks. These items had no variability RESULTS because all children had perfect performance, and they were not analyzed further. Raw scores while taking pi- PARTICIPANTS racetam and placebo for the 65 remaining variables were Twenty-five children were invited to participate based analyzed. To aid visualization of the magnitude of the on telephone screening, and 18 were included in the fi- differences between the piracetam and placebo arms across nal sample. Three children could not complete the base- tests, all raw scores were converted to z-score differ-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 TEST ADMINISTRATION to treatment order was confirmed on the baseline data using between-group analysis of variance (SPSS version The cognitive battery was administered by the same tester 10.0; SPSS Inc, Chicago, Ill; piracetam-placebo vs (V.R.) at all visits to ensure the best possible rapport with placebo-piracetam). The primary analyses were repeated- the children. The 14 tests were divided into three 25- measures analyses of variance, with treatment phase (pi- minute blocks. No more than one 15-minute task was in racetam vs placebo) as the repeated measure. Cases with each block. To control for the order of test administra- missing data were excluded on a test-by-test basis, which tion, 3 block orders were created and children were ran- was necessary for only 5 tests (Go/No-Go, n=15; Stroop domly assigned to 1 of the 6 possible combinations. Chil- Color/Shape, n=16; Stroop Color/Word, n=10; Delayed dren received breaks between each block and as otherwise Match-to-Sample, n=17; and Animal Pegs, n=17). necessary. Parents sat in a nearby room and were brought Huynh-Feldt–adjusted probabilities30 were used to evalu- into the test room only when poor compliance interfered ate the significance of the repeated-measures factors. The with testing or the child’s verbal responses were not readily strength of all statistical results is indicated by ␩2, which understood. indicates the proportion of total variability attributable to the factor. MEDICATION PREPARATION, ADMINISTRATION, AND MONITORING ADDITIONAL ANALYSES OF PRIMARY OUTCOME MEASURES Piracetam was donated in powder form by Medisca Phar- maceuticals (St-Laurent, Quebec) and was encapsulated in The children’s ages fell naturally into 2 nonoverlapping age gelatin capsules at The Hospital for Sick Children. Chil- groups: younger (n=8; mean [SE] age, 8.0 [0.3] years; range, dren received piracetam, 80 to 100 mg/kg per day, in 3 doses 7.0-8.9 years) and older (n=10; mean [SE] age, 11.4 [0.3] 8 hours apart. Placebo was starch and was encapsulated and years; range, 10.0-13.0 years). To ensure that no treat- administered in the same manner. To monitor adverse ef- ment effects were being masked by differences in age at base- fects and establish compliance, parents were interviewed line, additional analyses were conducted separately for on a weekly to biweekly basis during both treatment arms younger and older children. by a physician. Parents also were asked to note any sub- Based on telephone interviews with parents, we identi- stantial behavioral or cognitive changes (positive or nega- fied a subset of children (n=11) for whom the parents indi- tive) during each treatment arm in a diary provided to them. cated some cognitive improvement during piracetam treat- Psychologists involved in testing the children were masked ment (eg, “sharper,” “attentive,” “brighter,” or “more to drug status; to ensure safety, a team of physicians who focused”). (Two parents indicated cognitive improvement did not participate in the measurement of outcome was un- during placebo treatment, one of whom indicated adverse masked. cognitive effects during piracetam treatment. No parent indicated decreased cognitive performance with placebo use.) PRIMARY DATA ANALYSIS The “improvement” group was analyzed separately to determine whether parents’ anecdotal comments corresponded to Across the 14 tests, 87 dependent variables were identified, any measurable improvement due to piracetam use. (The dia- including measures such as the number of correct re- ries provided to the parents were not completed consis- sponses and errors (eg, perseverations, omissions, and false tently and were not analyzed.) Finally, performance of indi- alarms), reaction times, and the number of trials to the first vidual children was examined to determine whether any child correct response. The effectiveness of the randomization demonstrated beneficial effects while taking piracetam.

ences from the grand average. All data are reported as cal on the piracetam and placebo arms (4.6±0.2; range, mean±SE. 4.2-4.9). The differences between the piracetam and pla- Baseline Performance cebo arms on the primary outcome battery are shown in Figure 2, with reaction times and test scores shown in Children were generally compliant during testing, as seen panel A and errors shown in panel B. Only one measure, in a mean effort rating of 4.2±0.2 across all tasks (range, an error measure on the Stroop attention task, reached 2 3.4-4.6). Performance on the standardized tests con- statistical significance (F1,16=5.66, PϽ.03, ␩ =0.26). On curred with mental age equivalents determined from the average, children made 2.1±0.8 errors while taking pi- Stanford-Binet Intelligence Scale. For example, on the Mc- racetam and 3.3±1.2 errors while taking placebo. As Carthy tests, the mean raw scores for Verbal Fluency shown in Figure 2, the differences between the pi- (9.9±1.3), Verbal Memory (10.6±1.1), and Tapping racetam and placebo arms were small, with a maximal (2.4±0.2) are typical for children aged 4.5, 3.5, and 4.0 difference of 0.55 SD. years, respectively. There were no differences at baseline attributable to the randomization to treatment or- SECONDARY OUTCOME MEASURES: PARENT der (PϾ.09 for all). AND TEACHER QUESTIONNAIRES Treatment Effects At baseline, only one of the questionnaire items differed as a function of assignment to treatment order. Parents The children also worked well at the tasks in the 2 test of children in the placebo-piracetam group reported arms of the study. The mean effort ratings were identi- greater feelings of isolation (14.1±0.9) than did parents

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 in the piracetam-placebo group (9.8±0.9; F1,16=11.61, thought problems (Child Behavior Check List: F1,15=4.93, PϽ.01, ␩2=0.42). In the comparison of piracetam and pla- PϽ.04, ␩2=0.25), and poorer attention while taking pi- cebo scores, 6 items from the parent and teacher ques- racetam (Children’s Behavior Questionnaire: F1,15=5.43, tionnaires reached or approached significance (Figure 2C). PϽ.03, ␩2=0.27). Teachers indicated that the children For parents, these indicated improvements in leader- seemed happier (Teacher’s Report Form: F1,11=8.04, 2 2 ship (FACES III: F1,13=4.45, PϽ.055, ␩ =0.26), fewer PϽ.02, ␩ =0.42), had fewer internalizing problems 2 (Teacher’s Report Form: F1,13=8.65, PϽ.01, ␩ =0.40), and 25 Children Potentially Eligible had fewer total problems while taking piracetam Based on Telephone Screening 2 (F1,13=5.01, PϽ.04, ␩ =0.28). We note, however, that all of these differences, although statistically significant, were Baseline Cognitive Evaluation 3 Children Excluded small from a clinical perspective. For example, on the par- as Ineligible ent questionnaire, thought problem scores below 67 are 22 Children Entered Into the Trial not considered clinically significant. Changes of the magnitude found here would not be interpreted by health care

Randomized Into Treatment Groups professionals as indicative of either improvement or de- crease on the factor. Scores while taking piracetam and

Piracetam Phase 1 Placebo 3 Children placebo were within the reference range, at 56.3±1.5 and (80-100 mg/kg Daily) 4 mo Withdrew 60.1±1.6, respectively. Similarly, for teachers, the total 4 mo Because of Difficulty problem scores were in the clinically relevant range (Ͼ60) Swallowing at 62.1±2.7 for the piracetam arm and 64.4±2.6 for the Phase 1 Phase 1 Capsules Cognitive Evaluation Cognitive Evaluation placebo arm.

Placebo Phase 2 Piracetam 1 Child ADDITIONAL ANALYSES 4 mo (80-100 mg/kg Daily) Withdrew 4 mo Because of Need for Age at Baseline Corrective Phase 2 Phase 2 Heart Cognitive Evaluation Cognitive Evaluation Surgery To ensure that age-related beneficial effects of piracetam therapy were not being masked in the primary 18 Patients analysis, we examined the data for the younger and older Completed ϫ the Study children separately. Significant treatment age group in- teractions were found for only 3 measures. Older chil- Figure 1. Flow chart of study design. dren had better performance while taking placebo on 2

Table 1. Primary Outcome Measures: Description of Cognitive Test Battery*

Domain Measured† Task Name Brief Task Description Attention Stroop Color/Shape Picture of red ducklings, yellow trees, and green lips; say color (red) or object (chick) Stroop Color/Word See the word “blue” written in red: say the color (red) or the word (blue) Auditory Continuous Performance Task Listen to a stream of letters, hit the space bar when you hear an “A” Visual Continuous Performance Task Hit the space bar when you see the bird in the tree Learning and memory McCarthy: Verbal Memory List/sentence learning McCarthy: Tapping Memory span—auditory/visual WRAML: Verbal Learning List learning and memory WPPSI-R: Animal Pegs White pegs go with chickens, blue pegs go with fish Delayed Match-to-Sample Which symbol was shown before? Perceptual abilities WPPSI-R: Picture Completion What is missing from this picture? Match-to-Sample Baseline: point to symbol Tracking 1, point to 1 symbol Tracking 2, point to 2 sequential symbols Match to sample? Which symbols match? Executive processing Go/No-Go Where is the button? Object Permanence Button hidden, point immediately to location Delayed Object Permanence Button hidden, point to location after delay Spatial Reversal Button hidden, stays on same side until 4 correct, then is moved to the other side Spatial Alternation Button hidden, after every correct trial, side is reversed McCarthy: Verbal Fluency Name words about... Fine motor skills WRAVMA: Draw-a-Design Copying Visuomotor skills WRAVMA: Pegboard Quickly put the pegs in the holes

*McCarthy indicates McCarthy Scales of Children’s Abilities 20; WRAML, Wide Range Assessment of Memory and Learning 21; WPPSI-R, Wechsler Preschool and Primary Scale of Intelligence−Revised 22; and WRAVMA, Wide Range Assessment of Visuo-Motor Abilities.23 †Domains are broadly defined, and some tasks span multiple cognitive domains.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Secondary Outcome Measures: Table 3. Baseline Demographics and Stanford−Binet Parent and Teacher Questionnaires Intelligence Scale Results*

Completed Children Who Questionnaire Questionnaires, No.* Study Children Withdrew Measure (n = 18) (n=4) Parents The Conners’ Parent Rating Scale24 13 Chronological age 9.8 ± 2.0 9.3 ± 2.1 Child Behavior Check List25 14 at baseline (range), y (6.9-12.9) (7.6-12.3) Parenting Stress Inventory26 15 Stanford-Binet age equivalents, y FACES III27 14 Verbal reasoning Temperament: Children’s Behavior Questionnaire 16 Vocabulary 4.8 ± 1.4 4.4 ± 1.0 Comprehension 4.0 ± 1.1 3.4 ± 1.1 Teachers Absurdities 4.5 ± 1.2 3.7 ± 1.1 The Conners’ Teacher Rating Scale28 9 Abstract/visual reasoning Teacher’s Report Form29 12 Pattern analysis 4.6 ± 0.9 4.2 ± 0.9 Copying 3.8 ± 1.1 3.9 ± 1.5 *Only fully completed questionnaires for all 3 test periods were analyzed. Quantitative reasoning 4.9 ± 1.0 4.1 ± 0.6 Short-term memory measures (Tapping and perseverations in Verbal Learn- Bead memory 3.6 ± 0.4 3.8 ± 0.8 ing, PϽ.05), whereas younger children showed no dif- Memory for sentences 3.4 ± 0.8 2.9 ± 0.4 ferences while taking piracetam vs placebo. On the first *Data are given as mean ± SD. trial to correct reversal in the Go/No-Go task, young children were better while taking placebo (4.3 trials) and older children were better while taking piracetam (3.9 trials; COMMENT PϽ.05 for both). Piracetam has received significant attention in the me- Perceived Cognitive Improvement dia for its purported beneficial effects on cognition in children with Down syndrome. Because enhancement has Analysis of the remarks made during telephone inter- been reported on several cognitive functions, we explic- views indicated that 11 parents made some comment of itly designed the present study to capture a wide range improved cognition or attention during the piracetam arm. of cognitive functions and behaviors. Thus, our primary The data for these children were analyzed separately outcome measure incorporated tests of sustained and (mean±SD age, 10.3±0.6 years; range, 7.0-12.4 years). short-term attention and memory; tests that assess pro- None of the cognitive measures reached or approached cessing in the visual and auditory domains; tests that ex- significance in this subsample. amine verbal abilities, such as word fluency and learning and remembering new words; and basic fine motor Individual Cases and perceptual motor skills. The study is strengthened by the addition of a set of standardized parent and teacher Inspection of performance on a case-by-case basis indi- questionnaires to evaluate behavior, temperament, and cated that occasionally individual children showed mean- social and academic performance. The 2 test sessions of ingful changes in performance (improved or worsened primary importance (piracetam and placebo) were con- relative to baseline) on 1 or 2 measures while taking pi- ducted within a single school year, and well within each racetam. However, these effects were not consistent across school term, providing a degree of stability to our mea- children of similar ages or across tasks within a child. surements. It also strengthens the teacher reports, as the same teacher conducted both assessments. Because of the ADVERSE EFFECTS inherent difficulties in assessing changes in cognitive function in cognitively impaired individuals, we were care- Adverse effects during the piracetam phase reported by ful to include tasks that children with Down syndrome caregivers were mostly associated with central nervous could complete. In addition, our screening measures en- system stimulatory effects and were seen in 7 children: sured that the participating children would have suffi- aggressiveness or violent behavior (n=4), agitation or ir- cient capacity to understand and perform all tasks. These ritability (n=2), sexual arousal (n=2), poor sleep (n=1), goals were met for most measurements. and decreased appetite (n=1). In 1 boy (aged 10.6 years The results of this study indicate no consistent or at baseline), previously noted inappropriate sexual and pervasive beneficial effects of piracetam therapy over pla- aggressive behaviors increased during piracetam use and cebo use in these children. Across 3 analyses of the for- were especially disruptive at home and at school. No such mal test battery, 2 measures indicated better perfor- effects were reported in the placebo arm. To ensure that mance while taking piracetam and 2 indicated better the adverse effects were not overshadowing possible ben- performance while taking placebo. For the parent and eficial effects of piracetam treatment, performance was teacher reports, all detected changes were either within analyzed separately for the 11 children not showing be- the reference range or remained in a clinically relevant havioral problems. No beneficial effects of piracetam were range. Given the small number of significant effects and identified, and the 2 groups did not differ from each other the mixed nature of the findings, we conclude that there on any measure. is no strong evidence to indicate that piracetam use im-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A Strp Effect (A) B Strp Shape E (A) ∗ Strp Shape RT (A) Strp Reverse Shape E (A) Strp Shape Diff RT (A) Strp Color RT (A) Strp Other Shape E (A) Strp Color Diff RT (A) Strp % Shape E (A) Strp Word Name RT (A) Strp Color E (A) Strp Word Name Diff RT (A) Strp Word Color RT (A) Strp Reverse Color E (A) Strp Word Color Diff RT (A) Strp Other Color E (A) AudCPT FA RT (A) Strp % Color E (A) AudCPT Hit RT (A) AudCPT No. of Hits (A) Strp Name E (A) VisCPT Hit RT B1 (A) Strp Other Name E (A) VisCPT Hit RT B2 (A) Strp % Name E (A) VisCPT No. of Hits B1 (A) VisCPT No. of Hits B2 (A) Strp Word Color E (A) VisCPT FA RT (A) Strp Other Word Color E (A) VisCPT Hit RT (A) Strp % Word Color E (A) VisCPT No. of Hits (A) Verbal Memory (M) AudCPT No. of Holds (A) Tapping (M) AudCPT No. of Doubles (A) VLearn Learning Score (M) AudCPT No. of Omissions (A) VLearn Memory Score (M) VLearn Max (M) AudCPT No. of FA (A) VLearn % Max (M) VisCPT No. of Doubles (A) VLearn Mean Learned (M) VLearn Recalled – Learned (M) VisCPT No. of Omissions (A) VLearn % Recalled (M) VisCPT No. of FA (A) VLearn Storage (M) VLearn Failures (M) VLearn No. of Words T1 (M) VLearn No. of Words T2 (M) VLearn Perseverations (M) VLearn No. of Words T3 (M) Verbal Fluency Perseverations (E) VLearn No. of Words T4 (M) VLearn Repeats on T2 (M) VLearn Repeats on T3 (M) VLearn Repeats on T4 (M) Animal Pegs Time (M) ∗ C CBCL: Thought Animal Pegs (M) DMTS % (M) FACES: Leader ∗ Picture Completion (P) CBQ: Attention Spatial Reversal (E) Spatial Alternation No. Correct (E) Spatial Alternation 1st Correct (E) Spatial Alternation No. Sequential (E) ∗ Verbal Fluency (E) TRF: Happy Draw-a-Design (FM) ∗ TRF: Internal Pegs Dominant (FM) ∗ Pegs Nondominant (FM) TRF: Total

–1 0 1 –1 0 1 Difference (z Score) Difference (z Score) Figure 2. Mean±SEM differences (and 95% confidence intervals of the differences [horizontal lines]) between the piracetam and placebo arms for all primary outcome measures (A and B) and significant differences from secondary outcome measures (C). A, Measures such as reaction times, total scores, and number correct. B, Measures that reflect task errors such as false alarms, omissions, naming color instead of shape, and perseverations. C, The 6 measures from the parent and teacher questionnaires that approached or reached significance. Positive numbers indicate better performance while taking piracetam and negative numbers indicate better performance while taking placebo. Scores are expressed as z-score deviations from the grand average of piracetam and placebo scores. The letter in parentheses after each measure name indicates whether the measure came from a test designated as primarily reflecting attention (A), memory (M), perceptual abilities (P), executive function (E), or fine motor skills (FM) and are listed as in Table 1. Strp indicates Stroop; RT, reaction time; Diff, difference; AudCPT, auditory continuous performance task; VisCPT, visual CPT; FA, false alarms; VLearn, Verbal Learning; Max, maximum recalled; E, error; B1, B2, blocks 1 and 2; T1-T4, trials 1-4; DMTS, Delayed Match-to-Sample; CBCL, Child Behavior Check List; CBQ, Children’s Behavior Questionnaire; TRF, Teacher’s Report Form; and asterisk, significant differences.

proved cognition in these children, either in the formal taking piracetam, this did not translate into measurable test battery or from parent and teacher reports. beneficial effects of piracetam over placebo. As is typical in clinical trials, some children were The dose of piracetam used by us was within the lost to the study. Because this reduced our sample size range used in adults and in children with dyslexia.13 De- below that needed to detect large effects of the drug, we spite this, potentially serious adverse effects were expe- were careful to examine multiple aspects of the data, in- rienced by 7 of the 18 children while taking piracetam. cluding relaxing the threshold for statistical signifi- This finding excludes the option of dose escalation. cance, to ensure that positive effects of piracetam treat- The results of this study are strikingly different from ment were not being masked. We did not identify even the anecdotal testimonials presented in the popular press. a single case that would suggest the possibility that pi- One possibility that might partially account for the per- racetam therapy generally improved cognition. Most tell- ceived beneficial effects of piracetam therapy might lie ing, perhaps, is that although 11 parents noted that cog- in the stimulatory effects of this medication. This type nitive function seemed to be better when children were of behavioral stimulation could easily be confused with

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 actual cognitive improvement in the absence of objec- functional activity of neurons as a possible mechanism for the effects of noo- tive measures. Especially relevant to parent observa- tropic agents. Neurosci Behav Physiol. 1996;26:507-515. 7. De Deyn PP, Reuck JD, Deberdt W, Vlietinck R, Orgogozo JM, for the Members tions of alertness and better focus, none of our attention of the Piracetam in Acute Stroke Study (PASS) Group. Treatment of acute is- tasks revealed enhanced performance while taking pi- chemic stroke with piracetam. Stroke. 1997;28:2347-2352. racetam over placebo on any measure. In conclusion, the 8. Aguglia E, Caraceni T, Genitrini S, et al. Comparison of teniloxazine and piracetam results of this study indicate that piracetam treatment is in Alzheimer-type or vascular dementia. Curr Ther Res. 1995;56:250-257. associated with adverse effects and does not substan- 9. Di Ianni M, Wilsher CR, Blank MS, et al. The effects of piracetam in children with dyslexia. J Clin Psychopharmacol. 1985;5:272-278. tially enhance cognition or behavior. 10. Gainotti G, Nocentini U, Sena E. Can the pattern of neuropsychological improvement obtained with cholinergic drugs be used to infer a cholinergic mechanism Accepted for publication December 1, 2000. in other nootropic drugs? Prog Neuropsychopharmacol Biol Psychiatry. 1989; This research was supported by the Motherisk Re- 13:S47-S59. search Fund and by a grant from The Scottish Rite, Toronto, 11. Growdon JH, Corkin S, Huff FJ, Rosen TJ. Piracetam combined with lecithin in the treatment of Alzheimer’s disease. Neurobiol Aging. 1986;7:269-276. Ontario. 12. Molloy DW, Guyatt G, Brown G. Effects of oxiracetam on cognition, behaviour Presented in part at the Pediatric Academic Societies/ and activities of daily living in dementia. J Clin Exp Gerontol. 1992;14:217-233. Society for Pediatric Research annual meeting, San Fran- 13. Tallal P, Chase C, Russell G, Schmitt RL. Evaluation of the efficacy of piracetam cisco, Calif, May 3, 1999. in treating information processing, reading and writing disorders in dyslexic chil- The Down Syndrome Association of Toronto, pro- dren. Int J Psychophysiol. 1986;4:41-52. 14. Wilsher CR, Bennett D, Chase CH, et al. Piracetam and dyslexia: effects on read- vided valuable help in recruiting participants for this study. ing tests. J Clin Psychopharmacol. 1987;7:230-237. Piracetam was donated by Medisca Pharmaceuticals. Arthur 15. Ackerman PT, Dykman RA, Holloway C, Paal NP, Gocio MY. A trial of piracetam J. Dalton, PhD, graciously allowed us to use the Dalton/ in two subgroups of students with dyslexia enrolled in summer tutoring. J Learn McMurray Visual Memory Test. We thank Zina Levichek, Disabil. 1991;24:542-549. 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