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© 2001 American Society for Clinical Oncology Immediate Neurocognitive Effects of Methylphenidate on Learning-Impaired Survivors of Childhood CancerFrom the Divisions of Neurology, Neuro-Oncology, Behavioral Medicine, and Endocrinology, Departments of Pharmaceutical Sciences, Biostatistics and Epidemiology, Diagnostic Imaging, Radiation Oncology, and Hematology-Oncology, St Jude Children’s Research Hospital; Department of Pediatrics, University of Tennessee College of Medicine; and Departments of Electrical and Biomedical Engineering, University of Memphis, Memphis, TN. Address reprint requests to Raymond K. Mulhern, PhD, Division of Behavioral Medicine, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105; email: raymond.mulhern{at}stjude.org
PURPOSE: To test if methylphenidate (MPH) has an objective beneficial effect on immediate performance on tests of neurocognitive functions among learning-impaired survivors of childhood acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT). PATIENTS AND METHODS: From July 1, 1997 through December 31, 1998, 104 long-term survivors of childhood ALL or a malignant BT completed neurocognitive screening for learning impairments and concurrent problems with sustained attention. Eligibility criteria for the MPH trial included an estimated intelligence quotient greater than 50, academic achievement in the 16th percentile or lower for age in reading, math, or spelling, and an ability to sustain attention on a computerized version of the Conners’ Continuous Performance Test (CPT) in the 16th percentile or lower for age and sex. Of the 104, 32 (BT, n = 25; ALL, n = 7) were eligible on the basis of these a priori criteria for a randomized, double-blinded, placebo-controlled trial of MPH. The patients ingested a placebo (lactose) or MPH (0.6 mg/kg; 20 mg maximum) and repeated selected portions of the screening battery 90 minutes later. RESULTS: Compared to the 17 patients randomized to the placebo group, the 15 patients randomized to the MPH group had a significantly greater improvement on the CPT for sustained attention (errors of omission, P = .015) and overall index (P = .008) but not for errors of commission (indicative of impulsiveness) nor reaction times. A trend for greater improvement in the MPH group on a measure of verbal memory failed to reach statistical significance. No trend was observed for MPH effectiveness in improving learning of a word association task. No significant side effects from MPH were observed. CONCLUSION: MPH resulted in a statistically significant improvement on measures of attention abilities that cannot be explained by placebo or practice effects.
ACUTE LYMPHOBLASTIC leukemia (ALL) and malignant brain tumors (BT) are the two most frequently diagnosed childhood cancers, accounting for more than 50% of all cases of pediatric cancers. Due to the inherent risk of CNS relapse in ALL, and due to the obvious location of BT, these patients necessarily receive therapy directed at the CNS. As a result, long-term survivors in both groups of patients are at risk for late neuropsychologic and cognitive deficits, especially impairments of intellectual development.1,2 Oftentimes, these deficits are of sufficient severity to impair future academic performance, employability, and quality of life.3-5 There is an emerging consensus that the declines in mental ability, intelligence quotient (IQ), and academic achievement observed in childhood cancer survivors are due to the inability to acquire new information, secondary to one or more cognitive processing deficits involving attention, short-term memory, speed of mental processing, visuo-motor coordination, or sequencing abilities.6-11 Contemporary theories of cognitive development conceptualize attention abilities as critical functions within the learning process, which are themselves organized in a hierarchic structure.12,13 A basic attention disability reported among survivors of ALL and brain tumors seems to be an inability to sustain attention, defined by the ability to maintain a consistent state of behavior vigilance and persistence for an extended period of time. Similar problems are noted in a subset of otherwise normally developing children diagnosed with attention deficit hyperactivity disorder (ADHD). A large body of research over the past 30 years documents the effectiveness of stimulant medications, most often methylphenidate (MPH), in improving attention abilities among children with ADHD in the laboratory and across other settings (eg, home, school).14 In general, strong dose-response relationships are seen, with improvements in most cognitive functions occurring at higher doses, both in the laboratory and in school and home situations.15 The most consistent and significant benefits of MPH are found on measures of vigilance and sustained attention, and evidence of improvements in reaction time, paired-associate learning, and perceptual efficiency are also common.16-18 However, positive effects of MPH on "higher order" cognitive functions, such as problem solving or language processing, have been less frequently found. When academic learning improves coincident with administration of MPH, it seems that improvements in attention and concentration abilities caused by MPH are responsible because these abilities enhance efficiency on academic tasks.18 To our knowledge, there are only two brief reports in the literature discussing the use of MPH in children with learning problems believed to be secondary to their cancer treatment. DeLong et al19 treated 12 children surviving malignant BT or ALL for 6 months to 6 years (median, 23 months). Their results indicated that eight children had a "good" response, two had a "fair" response, and two had a "poor" response. In another report, Torres et al20 treated six children who had received cranial radiation therapy (CRT) 3 to 12 years earlier for malignant BT. At a consistent dose of 0.3 mg/kg MPH, they found no significant immediate or delayed benefit. We are aware of an additional report of adult patients by Meyers et al21 who investigated the effectiveness of MPH in 30 patients with malignant BT who exhibited neurobehavioral deficits of "apathy syndrome" during or immediately after treatment. A single group, dose escalation design (10 to 30 mg bid) was used, using endpoints of clinical benefit or toxicity, whichever manifest first. Pre- and post-MPH neuropsychologic testing demonstrated significant improvements in mood, psychomotor speed, memory, dexterity, and executive functions. In summary, the preliminary data for MPH effectiveness among survivors of childhood cancer with learning problems are sparse and equivocal. The recent data with adults in the acute setting during active treatment are promising. However, we know no randomized controlled trials of MPH with children surviving cancer. The primary goal of the present study was to test the hypothesis that MPH could improve attention abilities among learning impaired children treated for ALL or malignant BT, as tested by measures that would document immediate changes in these abilities. We therefore screened children at risk to identify those with significant learning problems and, using a randomized, double-blinded, placebo-controlled design, assessed patient performance on neurocognitive testing before and after ingestion of MPH or placebo.
Patients To be eligible for participation, patients were required to be 6 to 18 years of age and have been treated at this institution for a malignant BT with chemotherapy and/or irradiation, or treated for ALL on a recent institutional protocol (Total XIIIA).22 In addition, patients were required to have English as their primary language, to have been off therapy and free of cancer 24 months or longer, and to have given written informed consent. Exclusionary criteria included diagnosis of ADHD before cancer treatment; glaucoma; family history of tic disorder; current antidepressant, anxiolytic, antipsychotic, or stimulant therapy; history of substance abuse; or recent history of poorly controlled seizures. The IRB-approved MPH trial was opened on July 1, 1997 and accrual continued until December 31, 1998. Within that time frame, 139 patients with established eligibility were approached for participation of whom 22 (16%) refused. Of the remaining 117, five could not complete the studies because of scheduling problems. Two patients were discovered to have recurrent cancer at the time of screening, one of whom had an abnormal EEG despite having no previous history of seizures. Six additional patients were excluded for lack of a guardian to give consent, incomplete participation in required studies, or enrollment onto a competing protocol, leaving 104 eligible and potentially assessable patients.
Procedures
Day 1 Testing Protocol
Child Behavior Checklist (CBCL).
Patients were excluded from day 2 of the MPH trial if they scored in the clinically suspect range or above (standard score Abbreviated Wechsler Individual Achievement Test (WIAT). To remain eligible for the day 2 MPH trial, the patient was required to be below the 16th percentile for age-matched peers in the general population in one or more academic areas, equivalent to a standard score of 85 (normative mean, 100; SD, 15). The WIAT27 is an individually administered, standardized test of academic achievement with acceptable reliability and validity. This 30-minute test results in age-corrected standard scores based on a large normative sample for reading, spelling, and mathematics achievement. Conners’ Continuous Performance Test (CPT). For patients to remain eligible for the day 2 MPH trial, a score below the 16th percentile for age- and sex-matched peers in the general population was required for the number of errors of omission. This computer-administered test28 measures selective and sustained attention, reaction time, and impulsivity. The CPT has been standardized on normally developing children and adolescents, as well as on those with ADHD, and results in age-corrected standard scores on a number of indices of attention abilities and impulsivity. It is one of the most widely-administered computerized measures used as an aide to diagnosing ADHD, and for monitoring medication effects in children treated for ADHD with MPH. The patient is instructed to watch a series of letters presented one at a time on a computer monitor. The task is to respond by pressing the space bar to all letters except "X." The CPT takes approximately 15 minutes to administer and is computer scored. Errors of omission are defined by failure to respond to letters other than X. Additional scores reflecting errors of commission (failure to withhold responding to the X, indicating impulsivity), reaction time, and an overall index (scores > 11.0 best discriminate children with attention deficits) were also acquired. We used age- and sex-corrected scores for our analyses. California Verbal Learning Test (CVLT). The CVLT29,30 was given as a supplementary measure and performance did not disqualify patients from participation in the day 2 MPH trial. This test measures the rate of verbal learning and recall of a series of common words. Several indices are derived from the patient’s performance by means of computer scoring of the results. We analyzed the list A total recall score, which is a standard score corrected for age of the patient (normative mean, 50; SD, 10). Visual-Auditory Learning Test (VAL). The VAL31 was given as a supplementary measure, and performance did not disqualify patients from participation in the day 2 MPH trial. This test was selected from the Woodcock-Johnson Cognitive Battery as an experimental analog of learning to read. The patient must learn to associate rebus figures with English words, and then read progressively more complicated passages. The patient’s rate of visual-auditory learning of these new associations is the primary outcome measure. An age-corrected standard score was derived from general population norms (normative mean, 100; SD, 15).
Day 2 Testing Protocol
Methylphenidate (Ritalin) After establishing eligibility for the MPH trial and obtaining separate informed consent for this phase of the study (day 2), patients were examined by a neurologist (S.J.T.), weighed, and randomized to MPH (0.6 mg/kg) or placebo groups. MPH and lactose placebo were prepared at the institution pharmacy using opaque gelatin capsules. MPH dose was rounded to the nearest 2.5 mg, with a 20 mg maximum dose. The capsule was taken orally under the observation of the patient’s parent. Approximately 90 minutes later, the patient was retested with the CPT, CVLT, and VAL, which combined required approximately 30 minutes to complete. Patients, parents, and the staff member performing the tests were blinded as to the MPH or placebo assignment. Patients remained in the hospital for at least 1 additional hour to document any acute side effects.
Statistic Considerations
Of the 104 patients potentially eligible for the MPH trial, intellectual and academic functioning was generally lower than expected among healthy age peers: estimated IQ (mean, 84.9; SD, 20.3), reading achievement (mean, 87.4; SD, 25.1), spelling achievement (mean, 85.6; SD, 26.3), math achievement (mean, 85.1; SD, 23.3). Sixty-six of the 104 were ineligible on the basis of our day 1 psychologic testing criteria: three children had IQ scores less than 50, two children had abnormal anxiety or depression scores, 30 had normal WIAT achievement scores and a normal CPT omissions score, 13 had abnormal WIAT achievement scores but a normal CPT omissions score, and 18 had an abnormal CPT omissions score but normal WIAT achievement scores. Of the remaining 38 patients who were randomized, one was excluded because of an abnormal EEG and one was excluded because of progressive disease. Both of these findings occurred after randomization and the trials were aborted before the patients took the capsules. In addition, two patients failed to cooperate with the testing after taking the capsule, one patient refused to take the capsule, and in one patient the parent withdrew consent. The present report was restricted to the 32 assessable patients who were randomized without prior stratification to either MPH or placebo groups. The MPH group was composed of 15 patients, 8 females and 7 males, who ranged in age from 0.5 to 12.5 years of age at diagnosis (median, 3.5 years), and were 7.7 to 17.0 years of age (median, 11.3 years) at the time of participation. Four of the 15 had been treated for ALL on our institutional protocol (high risk, n = 3; standard risk, n = 1); those with high risk features were given cranial irradiation (18 to 24 Gy).22 The remaining 11 patients had been treated for malignant BT (ependymoma, n = 4; three medulloblastoma, n = 3; astrocytoma, n = 3; peripheral neuroectodermal tumor, n = 1) with chemotherapy (combinations included cis-diamminedichloroplatinum/ vincristine prednisone (VP)-16; carboplatin (carbo)/VP-16 + cyclophosphamide (cyclo)/vincristine, cis-diamminedichloroplatinum/VP-16 + cyclo/VCR; carbo/cyclo/VP-16; or mechlorethamine, vincristine, procarbazine, prednisone), and craniospinal irradiation (24 to 36 Gy) with boost to the tumor bed (45 to 55 Gy), or local radiation therapy (50 to 55 Gy). One patient received 10 mg, two received 15 mg, and the remaining 12 patients received 20 mg MPH (0.6 mg/kg). The placebo group was composed of 17 patients, eight females and 11 males, who ranged in age from 1.1 to 14.7 years of age at diagnosis (median, 4.8 years), and were 6.4 to 17.5 years old (median, 11.8) at the time of participation. Three of the 17 had been treated for ALL on our institutional protocol (high risk, n = 1; standard risk, n = 2)22 and the remaining 14 had been treated for malignant BT (medulloblastoma, n = eight; ependymoma, n = one; germ cell, n = one; oligodendroglioma, n = one; neuroblastoma, n = one; craniopharyngioma, n = one; astrocytoma, n = one) with therapy similar to that in the MPH group. The pre- and postrandomization performance of the MPH and placebo groups is given in detail in Table 1 with change scores summarized in Fig 1.
CPT The mean number of errors of omission (failure to respond to letters other than X) for the sample as a whole was 31.3 (SD, 33.3), representing an error rate of 8.8% compared with the expected error rate of 2% in children of similar age in the general population. The extent of improvement in errors of omission was significantly greater for the MPH group than for the placebo group (P = .015; Table 1). The probability of a discordant finding if the trial had been completed as planned was estimated at .028.33 In the MPH group, 14 of the 15 patients showed a decrease in their rate of omissions compared with 10 of the 17 patients in the placebo group. The mean number of errors of commission (failure to withhold responding to the X) for the sample as a whole was 20.8 (SD, 7.4). This represents an error rate of 57.8%, comparable to the expected error rate of 55% among similarly-aged children in the general population. The extent of improvement in errors of commission was not significantly different between the MPH group and the placebo group (P = .62; Table 1). The initial mean reaction time of the sample as a whole was 480.6 milliseconds (SD, 123.7). This value is higher than the 375 milliseconds value expected from similarly-aged children in the general population. The extent of improvement in reaction times for the MPH group was not significantly different from the placebo group (P = .58; Table 1). The initial mean CPT overall index for the sample as a whole was 10.6 (SD, 5.0). More than 90% of similarly-aged children in the general population will have index scores less than 10. Five patients in the MPH group and seven patients in the placebo group had scores more than 11.0, which is the threshold for diagnosis of ADHD. The extent of improvement in the overall index was significantly greater in the MPH group than in the placebo group (P = .008; Table 1). The probability of a discordant finding if the trial would have been completed as planned is estimated at .014.33 Nine of the 15 patients in the MPH group showed some improvement compared with four of 17 in the placebo group.
CVLT
VAL
Acute Side Effects
The present study demonstrates preliminary evidence for the efficacy of MPH in the treatment of attention problems among survivors of childhood ALL and malignant BT. As such, it adds to the limited number of previous reports of MPH treatment in childhood and adult cancer patients.19-21 The use of a randomized, double-blinded, placebo-controlled design represents a significant methodological improvement over previous reports. This design has become the standard for evaluating the efficacy of MPH and other psychoactive drugs among children with ADHD and other psychiatric disorders. Because of the large practice effects noted on some of our tests of memory and new learning, one could significantly overestimate the magnitude of MPH effects in the absence of comparison to a placebo condition. Specifically, we found significantly greater improvement with MPH than placebo in patients’ abilities to sustain attention as well as in their overall index of attention problems. However, patients’ ability to inhibit impulsive responding and reaction times did not improve significantly with MPH compared with the placebo. Patients’ performance on the test of associative learning did not consistently show an advantage with MPH more than placebo. Finally, although there was a trend for verbal memory to show greater improvement with MPH than placebo, the difference failed to reach statistical significance. This diverse pattern of MPH effects suggests that although attention problems may be reduced, other cognitive deficits may not be improved by MPH treatment. There are at least two possible explanations for the potential benefits of MPH for the attention abilities of children surviving cancer after treatment of the CNS. First, one could argue that the effects of MPH are specific to the pathophysiology of CNS therapy-induced brain damage. For example, it is accepted that many of the delayed organ effects of CRT are secondary to ischemia resulting from microvascular damage.34 It is also known from animal models that hypoxic-ischemic injury results in neurochemical alterations of dopamine distribution in the striatum and persistent depression of dopamine (D2) receptors.35,36 However, we are not aware of any data that confirm a reduction in neurotransmitter integrity among children with cancer treated with CNS-directed therapy. To test for the specificity of MPH, one would need to demonstrate a greater effect among patients with attention problems than among comparably treated patients without attention problems. A second, and more tenable explanation, is that MPH effectiveness is not specific to the type of damage resulting from treatment of the CNS, but rather that it enhances the patient’s ability to compensate for the disruption of normal brain function caused by chemotherapy or CRT. The fact that MPH can enhance arousal and attention in a variety of brain damage syndromes with markedly different etiologies, such as AIDS,37 Alzheimer’s disease,38 and malignant gliomas of the brain in adults,21 in addition to the extensive efficacy literature with ADHD,32 would support the argument for such nonspecific effects. The present study has several methodological issues that limit the generalization of our findings. First, our eligibility criteria were relatively conservative in that we limited enrollment to those patients who had significant and quantifiable deficits in both academic achievement and attention. Other, less severely affected children, such as those with significant attention problems without academic achievement deficits, may also benefit from MPH. Relevant to this point is the tendency for children with less severe ADHD to demonstrate a better response to MPH. A second limitation was our use of a between-groups design that may have constrained our ability to detect subtle differences in patient performance. The use of a cross-over design in which the patient serves as his or her own control would offer greater sensitivity to MPH effects. However, such a design requires a sufficient "washout" interval between ingestions of the capsules and extends the patient encounter from 1 to 2 days, a logistical problem that could not be resolved in the present study. Finally, enrollment of larger numbers of children in subsequent studies will also allow for analysis of response to MPH as a function of patient and treatment characteristics, which was not possible in this preliminary study. In conclusion, the present study provides preliminary support for the efficacy of MPH in improving attention problems among a selected sample of survivors of childhood ALL and malignant BT. Although beyond the scope of the present study, some evidence for ecologic validity of sustained response to MPH is needed to justify routine treatment. Future studies are therefore needed to define a threshold for instituting MPH treatment among childhood cancer survivors, and to establish efficacy of response to MPH in the natural home and school environments.
Supported by grants no. CA20180 and CA21765 from the National Cancer Institute, by a Center of Excellence grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities.
1. Roman DD, Sperduto PW: Neuropsychological effect of cranial irradiation: Current knowledge and future directions. Int J Radiat Oncol Biol Physics 31: 983-998, 1995[Medline] 2. Ris D, Noll RB: Long-term neurobehavioral outcome in pediatric brain tumor patients: Review and methodological critique. J Clin Exper Neuropsychol 16: 21-42, 1994 3. Mostow EN, Byrne J, Connelly RR, et al: Quality of life in long-term survivors of CNS tumors of childhood and adolescence. J Clin Oncol 9: 592-599, 1991[Abstract]
4.
Haupt R, Fears TR, Robison LL, et al: Educational attainment in long-term survivors of acute lymphoblastic leukemia. JAMA 272: 1427-1432, 1994 5. Armstrong FD, Blumberg MJ, Toledano SR: Neurobehavioral issues in childhood cancer. School Psychol Quarterly 28: 194-203, 1999
6.
Rodgers J, Horrocks J, Britton PG, et al: Attention ability among survivors of leukemia. Arch Dis Child 80: 318-323, 1999
7.
Lockwood KA, Bell TS, Colegrove RW: Long-term effects of cranial radiation therapy on attention functioning in survivors of childhood leukemia. J Pediatr Psychol 24: 55-66, 1999
8.
Cousens P, Ungerer JA, Crawford JA, et al: Cognitive effects of childhood leukemia therapy: A case for four specific deficits. J Pediatr Psychol 16: 475-488, 1991 9. Brouwers P, Riccardi R, Fedio P, et al: Long-term neuropsychologic sequelae of childhood leukemia: Correlation of CT brain scan abnormalities. J Pediatr 106: 723-728, 1985[Medline] 10. Mulhern RK, Wasserman AL, Fairclough D, et al: Memory function in disease-free survivors of childhood acute lymphocytic leukemia given CNS prophylaxis with or without 1,800 cGy cranial irradiation. J Clin Oncol 6: 315-320, 1988[Abstract] 11. Brouwers P, Poplack D: Memory and learning sequelae in long-term survivors of acute lymphoblastic leukemia: Association with attention deficits. Am J Pediatr Hem/Onc 12: 174-181, 1990 12. Sohlberg MM, Mateer AD: Introduction to Cognitive Rehabilitation. New York, NY, Guilford, 1989 13. Mirsky AF, Fantie BD, Tatman JE: Assessment of attention across the lifespan, in Mapou RL, Spector J (eds): Clinical Neuropsychological Assessment: A Cognitive Approach. New York, NY, Plenum Press, 1995
14.
Committee on Children with Disabilities and Committee on Drugs: Medication for children with attention disorders. Pediatrics 98: 301-304, 1996 15. Rapport MD, Denny C, DuPaul GJ, et al: Attention deficit disorder and methylphenidate: Normalization rates, clinical effectiveness, and response prediction in 76 children. J Am Acad Child Adoles Psychiat 33: 882-893, 1994 16. Rapport MD, DuPaul GJ, Stoner G, et al: Comparing classroom and clinic measures of attention deficit disorder: Differential, idiosyncratic, and dose-response effects of methylphenidate. J Consult Clin Psychol 54: 334-341, 1986[Medline]
17.
Tannock R, Schachar RJ, Carr RP, et al: Dose-response effects of methylphenidate on academic performance and overt behavior in hyperactive children. Pediatrics 84: 648-657, 1989 18. Tannock R, Ickowicz A, Schachar R: Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 34: 886-896, 1995[Medline]
19.
DeLong R, Friedman H, Friedman N, et al: Methylphenidate in neuropsychological sequelae of radiotherapy and chemotherapy of childhood brain tumors and leukemia. J Child Neurol 7: 462-463, 1992 (letter) 20. Torres C, Korones D, Palumbo D, et al: Effect of methylphenidate in the post-radiation attention and memory deficits in children. Ann Neurol 40: 331-332, 1996 (abstr) 21. Meyers CA, Weitzner MA, Valentine AD, et al: Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 16: 2522-2527, 1998[Abstract] 22. Pui C-H, Mahmoud HM, Rivera GK, et al: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92: 311-415, 1998 23. The Psychological Corporation: The Wechsler Intelligence Test for Children, ed 3. New York, NY, Harcourt, Brace, Jovanovich, 1992 24. The Psychological Corporation: The Wechsler Adult Intelligence Scale: III. New York, NY, Harcourt, Brace, Jovanovich, 1997 25. Sattler JM: Assessment of Children: Revised and Updated, ed 3. San Diego, CA, Jerome M. Sattler, 1992 26. Achenbach TM: Manual for the Child Behavior Checklist/4-18 and 1991 Profile. Burlington, VT, University of Vermont, Department of Psychiatry, 1991 27. The Psychological Corporation: The Wechsler Individual Achievement Test. New York, NY, Harcourt, Brace, Jovanovich, 1992 28. Conners CK: The Conners’ Continuous Performance Test. Toronto, Canada, Multi-Health Systems, 1995 29. Delis D, Kramer JH, Kaplan E, et al: California Verbal Learning Test. New York, NY, Harcourt, Brace, Jovanovich, 1994 30. Delis D, Kramer JH, Kaplan E, et al: California Verbal Learning Test: Adult Version. New York, NY, Harcourt, Brace, Jovanovich, 1987 31. Woodcock RW, Johnson MB: Woodcock-Johnson Tests of Cognitive Ability (rev). New York, NY, Riverside Publishing Co, 1989 32. Nelson JC: Sympathomimetics, in Kaplan HI, Saddock BJ (eds): Comprehensive Textbook of Psychiatry, Vol 2 (ed 6). Baltimore, MD, Williams &Wilkins, 1995, pp 2073-2079 33. Tan M, Xiong X, Kutner MH: Clinical trial designs based on sequential conditional probability ratio tests and reverse stochastic curtailing. Biometrics 54: 682-695, 1998[Medline] 34. Menendez JC, Casanova D, Amado JA, et al: Effects of radiation on endothelial function. Int J Radiat Oncol Biol Physics 41: 905-913, 1998[Medline] 35. Kondoh T, Lee SH, Low WC: Alterations in striatal dopamine release and reuptake under condition of mild, moderate, and severe cerebral ischemia. Neurosurgery 37: 948-954, 1995[Medline] 36. Fillour FM, Adair J, Narang N: The temporal evolution of striatal dopamine receptor binding and mRNA expression following hypoxia-ischemia in the neonatal rat. Dev Brain Res 94: 81-91, 1996[Medline] 37. Brown GR: The use of methylphenidate for cognitive decline associated with HIV disease. Int J Psychiatry Med 25: 21-37, 1995[Medline] 38. Jenike MA: Treatment of affective illness in the elderly with drugs and electroconvulsive therapy. J Geriatr Psychiatry 22: 77-112, 1989[Medline] Submitted June 20, 2000; accepted November 20, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
65) on CBCL
-phenyl-2-piperidineacetate hydrochloride. This piperidine derivative acts by releasing stored dopamine from the reserpine-sensitive presynaptic vesicular pool, decreasing dopamine reuptake, and inhibiting monoamine oxidase.
