Behavior and Motor Activity Response
`in Hyperactive Children and
`Plasma Amphetamine Levels Following
`a Sustained Release Preparation
`
`Gerald L. Brown, M .D., Michael H. Ebert, M.D.,
`Edwin j. Mikkelsen, M.D., and Robert D. Hunt, M.D.
`
`Abstract. Amphetamine has been clearly documented to be an efficacious treatment for
`tablet, and sustained-release
`hyperactive children. Recently, pharmacokinetics of elixir,
`pr ep arations have been studied in hyperactive children. Sustained release has been
`thought to prov ide a prolonged clinical response. In this study , nin e hyperactive children,
`selected by specific exclusion-inclusion criteria, were admi nistered single oral do ses of
`sustained -release d-amphetamine and placebo ; plasma levels, beh avioral response, and mo(cid:173)
`tor activity were observed in double-blind design . The results, as with the earlier studies, in(cid:173)
`d icate that significant clinical response is not observed beyond 4 hou rs and that responses
`occur onl y du ring the abso rptio n phas e and are not correlate d with specific plasma levels of
`d- amphetarnine.
`
`J ournal of the American Academy of Child Psychiatry, 19:225-239, 1980
`
`Amphetamines have been used for over 40 years (Bradley, 1937) to
`treat child ren with aggressive , impulsive behavioral disturbances.
`Double-blind placebo-controlled studies of the effects of d-am(cid:173)
`phetamine on hyperactive children (HAC) have confir med its ef(cid:173)
`ficacy (Greenberg et al., 1972; Arnold et al., 1972; Conners et al.,
`
`Dr. Brown is in the Biological Psychiatry Branch, National Institute of Mental Health, Bethesda,
`Maryland. Dr. Ebert is in the Laboratory of Clinical Science, Nat ional Institute of Mental Health,
`Bethesda, Maryland . Drs. Mikk elsen and Hunt are currently in the Child Study Center, Yale Univer(cid:173)
`sity, New Haven, Connecticut; f ormerly, Biological Psychiatry Branch and Laboratory of Clinical
`Science, NIMH, Bethesda, Maryland .
`R eprints may be requestedfro m Dr. Gerald L. Brown, Nat ional Institutes of Health, Clinical Center,
`Room 3N204, 9000 Rockville Pike, Bethesda, MD 20205.
`Acknowledgment: Assistance in analysis of data, Marcia D. M inichiello, R esearch Assistant, and
`Kathleen j. Powers, Laboratory Assistant.
`0002-7138/80/1902-0225 $0 1.30 Q 1980 Ameri can Academy of Child Psychiatry.
`
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`226
`
`Gerald L. Brown et al.
`
`1972; Huestis et al., 1975 ) and its use as a standard for compari(cid:173)
`son in pharmacotherapeutic trials.
`In normal prepubertal boys,
`Rapoport et al. (1978) ha ve described cogn itive and behavioral
`responses to d-amphetamine similar to th ose observed in HAC.
`Recent studies have reported some of th e pharmacokinetic charac(cid:173)
`teristics oj d-amphetamine in HAC; e .g., apparent elimination
`half-life, X ± SEM, 6.8 ± 0.5 h (Brown et aI., 1977 , 1978, 1979a,
`1979b). Sustained-release d-amphetamine has been shown to be re(cid:173)
`leased at a slower rate than tablets and to ha ve a similar half-life in
`adults and animals (Bec ke tt and Tucker, 1966; Rosenet aI., 1967 ;
`Brown et aI., 1979b); this characteristic ha s been thought to be rel(cid:173)
`evant to attaining a prolonged clinical response in HAC (Wender,
`1971; Gross and Wilson, 1974; Safer and Allen, 1976; Ross and
`Ross, 1976; Cantwell and Carlson, 1978). This study was under(cid:173)
`taken to review pharmacokinetic differences between tablets and
`sustained-release d-amphetamine following single-dose administra(cid:173)
`tion. Clinical responses from tablets and elixir by similar methodol(cid:173)
`ogy also are compared to these results.
`
`METHODS
`
`Male child re n, ages 60 to 144 month s, were evaluated at the Na(cid:173)
`tional Institute of Mental Health (N IH Clinical Center, Bethesda,
`Maryland) for impulsive, maladaptive social behavior, hyperactivity
`and learning disability. We obtained the community teachers'
`ratings off-me d icatio n by using the 39-item Conners'
`behavior
`Teacher Rati ng Scale (CTRS) (1969). Children and families were
`assessed in a preadmission screening. All research methods and
`procedures were a pproved by the NIMH Institutional Review
`Board (IRB) and the NIH Medical Board.
`i.e.,
`Exclusion cr iteria were:
`(1) "hard" neurological findings ,
`clinical seizure di sorder or any other medical disorder (we scored
`all children for neurological "soft signs" using PANESS)
`(Guy,
`1976); (2) borderline psychosis-as determined by Creak (1961)
`and the proposed DSM-III criteria (197 8); and (3) IQ < 80 on
`WISC-R. Inclusion cr iter ia for the study group were two standard
`deviations (SD) or more, above publish ed (Werry et aI., 1975)
`norms for similarly aged boys on Factor I (conduct problem) or
`Factor IV (hy peractivity) of the CTRS by comm unity teachers' rat(cid:173)
`ings; children were also rated by the NIH t eacher. Eight of nine
`child ren had Facto r I scores> 2 SD ; two of nine had Factor IV
`scores > 1 SD < 2 SD-one of th ese had a Factor II (attention)
`
`Page 2
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`Behavior Response in Hyperactive Children
`
`227
`
`score> 2 SD and the other> 1 SD < 2 SD. Thus, though Factor I
`behavior is prominent in these children, there were no children
`who showed only this behavior. Each child further received a com(cid:173)
`plete medical and psychiatric examination to confirm hyperactivity
`and rule out other conditions during a 5-day inpatient assessment
`before research procedures were initiated. This study group (N =
`9) may be described (X ± SD) as follows: age, 97 ± 25 mos.; weight,
`28.0 ± 11.8 kg; WISC-R IQ (full scale), 97 ± 7; and family in(cid:173)
`come, $17,278 ± $10,814.
`A low monoamine,
`low xanthine, normal salt diet was main(cid:173)
`tained. The controlled diet was necessary: (1) for urinary metabo(cid:173)
`lite studies not reported in this paper; (2) for minimizing variations
`in urinary pH for pharmacokinetic studies of amphetamine; and
`(3) for a standard state of hydration (Beckett et al., 1969; Rowland,
`1969; Axelrod, 1970). Instructions for this diet were given to par(cid:173)
`ents for weekends and those nights when the child was at home.
`Urinary pH was monitored by Ames Dipstix on days when blood
`samples were obtained for d-amphetamine analyses. The mean
`(± SEM) urinary pH was 6.3 ± 0.4 from an average of 2.7
`determinations/patient (range 5.0-7.0). To minimize the number of
`venipunctures, a heparin-lock and armband were utilized to collect
`serial blood samples. Usually a single venipuncture sufficed for
`eight h, though occasionally more than one venipuncture was nec(cid:173)
`essary either for initiating and/or continuing the procedure. Lunch
`was at a fixed time in relation to blood sampling. A standard
`breakfast (9 g protein, 26 g carbohydrate, 15 g lipid), usually 75%
`consumed, was provided between 8:30 and 9:00 A.M. prior to
`baseline blood at 9:00-9:30 A.M. Placebo and amphetamine were
`given in varying order with at
`least three intervening drug-free
`days. Unlike an earlier study (Brown et al., 1979a), plasma samples
`for norepinephrine (NE) and dopamine-,8-hydroxylase were drawn
`at h 1-3 with small sham drawings at h 4-6, thus allowing a similar
`placebo day in which plasma samples were being obtained. We at(cid:173)
`tempted to keep the dose of d-amphetamine as near as possible
`to 0.5 mg/kg, using 5 mg sustained-release capsules (0.48 ± .01
`mg/kg). Environmental variables during the 6 h following single(cid:173)
`dose administration included dissimilar school material and differ(cid:173)
`ent, numbers of children on the unit. Scheduled activities were
`similar, i.e., 1 h for initiating the study, 2 h in the classroom fol(cid:173)
`lowed by three intervals, each for 1 h, for lunch, occupational
`therapy, and art therapy, respectively.
`Double-blind behavioral ratings by the same research assistant
`
`Page 3
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`

`228
`
`Gerald L. Brown et al.
`
`using the 10-item abbreviated CTRS (ABCTRS) (Conners, 1973)
`were done on all blood sampling days between 15-30 min following
`the hourly blood drawing. Likewise, on all study days motor
`activity was automatically and continuously recorded with a newly
`developed acceleration-sensitive device (Colburn et al., 1976a,
`1976b). Unlike the initial tablet study (Brown et al., 1979a) with 1 h
`activity summations, but similar to the elixir study (Brown et al.,
`1977), the motor activity summations in the current study were 15
`min at baseline and following each hourly blood sampling. Motor
`activity counts for consecutive 7.5 min intervals were stored in a
`memory cell for periods up to 32 h and read out from a PDP-II
`minicomputer. The interval
`length and sensitivity of this device
`may be adjusted in order to adapt it to the level and kind of move(cid:173)
`ment disorder being studied or to a specific protocol design. An
`impulse generated by a movement is amplified, routed, and stored
`in a time-sequence memory location. The entire apparatus is 4 x 6
`x 1 ern and weighs 75 g. Activity monitors can be calibrated with
`each other. The ambulatory motor activity monitor was worn in a
`vest pocket over the thoracic dorsal area (special vests fitted to
`each child). Motor activity data intervals were taken consistently
`during each hour.
`Levels of d-amphetamine in plasma were determined by a
`radioimmunoassay (RIA). The assay relies on competitive bind(cid:173)
`ing between amphetamine (in the plasma of the subject) and
`radiolabeled amphetamine to an antibody raised to a metham(cid:173)
`phetamine-bovine serum complex. The assay was adapted by Ebert
`et al. (1976) from a technique of Cheng et al. (1973). The antibody
`to methamphetamine does not distinguish amphetamine and
`methamphetamine. Neither does it cross-react significantly with
`the major metabolites formed from amphetamine in man (benzoic
`acid, hippuric acid, parahydroxyamphetamine, norephedrine, or
`parahydroxyephedrine). The midpoint of the standard curve was
`1.6 ng, and the minimal detectable dose was 100 pg. Assays were
`performed directly, in duplicate, with 0.1 cc of plasma. The intra(cid:173)
`assay coefficient of variation is 6.9% and the interassay coefficient
`of variation is 12.3%. In the same laboratory, both RIA and gas
`chromatography-mass spectrometry (GC-MS) were used to mea(cid:173)
`sure amphetamine plasma levels; a highly significant multiple cor(cid:173)
`relation coefficient was found (R = 0.98223). RIA samples were
`run in duplicate, while GC-MS samples were run singly. Since
`more error is inherent
`in RIA values, RIA was regressed on
`
`Page 4
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`

`

`Behavior Response in Hyperactive Children
`
`229
`
`GC-MS. Although GC-MS was 1.9 times more sensitive than RIA,
`for most purposes, the convenience of the RIA method outweighs
`the technical superiority of the GC-MS (Powers and Ebert, 1979).
`
`RESULTS
`
`The results of the CTRS behavior ratings performed by the chil(cid:173)
`dren's community teachers, for whom the scale was intended, are
`shown in table 1. The community teachers' ratings on Factors I, II,
`and IV were generally higher than the NIH teachers' ratings. HAC
`group ratings by community teachers were significantly different
`from norms on Factors I, II, and IV (p < .001); but ratings by
`the NIH teachers were significantly different only for Factor IV
`(p < .01) (two-tailed t-tests). Factor II has been shown to have a
`smaller z score (2.16) than Factors land IV (2.54 and 3.22, respec(cid:173)
`tively) (Werry et al., 1975) in HAC vs. normals and might thus be
`thought to be less sensitive in differentiating HAC from normal
`children. As a further evaluation of the exclusion-inclusion criteria
`used for this study and other studies in this research program, we
`obtained a Spearman rank-order correlation relating community
`and NIH teachers' ratings from 42 children screened for several
`studies. Correlation for both Factors I and IV are significant (Fac(cid:173)
`tor I, rs = 0.43, P < .01; Factor II, r s = -0.04, ns; Factor IV, r, =
`
`Table I
`
`Behavioral Rating Characteristics
`Connors's Teacher Rating Scale Factor Scores (X ± SD)
`
`N H
`
`3 9
`
`43
`
`I
`
`Factor
`II
`
`IV
`
`1.21 (.39)
`
`1.60 (.58)
`
`1.56 (.65)
`
`2.53 (.51)'
`1.34 (.48)
`
`2.85 (.65)'
`1.54 (.48)
`
`3.48 (.60)'
`2.20 (.65)·
`
`0.43·
`
`-0.04
`
`0.37.1
`
`Norms'
`
`Study Group"
`Community Teacher
`NIH Teacher
`
`Community Teacher versus
`NIH Teacher (r,)·
`
`a Werry et aI. (1975).
`two-tailed t-test.
`b Study Group versus Norms,
`c Spearman rank-order correlation coefficients.
`.I p < .05.
`e P < .01.
`f P < .001.
`
`Page 5
`
`

`

`230
`
`Gerald L. Brown et al.
`
`0.39, P < .01). The data reported here are consistent with the z
`scores cited above.
`Peak plasma levels occurred between 3-8 h (X ± SEM = 65.7 ±
`7.1,70.2 ± 7.9,65.8 ± 7.8,64.8 ± 8.8,68.6 ± 7.6, and 64.1 ± 9.5
`ng/ml, respectively). Plasma levels of d-amphetamine in individual
`children differed threefold at 1 h, fivefold at 2 h, threefold at h 3
`and 4, and two and one-halffold thereafter. The coefficients of
`variation (CV = SD/X expressed as a percent) of d-amphetamine
`plasma levels during the absorption phase at h 1-8 are 38, 42, 32,
`34,36,38,31, and 39%, respectively.
`Figure 1 shows the behavioral response to a single dose of
`sustained-release d-amphetamine compared with placebo. There
`was a significant difference between drug and placebo ABCTRS
`t = 3.00, P < .01).
`ratings at h 2 (paired t-tests:
`In HAC,
`the
`
`AMPHETAMINE BLOOD LEVELS AND BEHAVIOR RATINGS
`ON SUSTAINED RELEASE
`
`80
`
`OJm
`
`I~
`
`2.5 <5
`:xl
`:xl
`2.0 ~
`
`ZG
`
`>
`
`1.5 CJ)s
`
`OJ
`1.0 (")
`-l
`:xl
`~
`
`N=9
`
`1 Placebo
`I
`--- ---- '"
`I
`,,---- <., 1
`
`1-....--.-:*':7:*-",-__
`
`'
`
`I
`
`- - - --
`
`234
`TIME (hours)
`
`5
`
`6
`
`EE70
`
`zo~
`
`60
`
`l
`
`~~
`
`50
`
`uzo
`u 40wz
`
`30
`
`~~
`
`Ia.
`~ 20«
`10
`
`«~
`
`~a
`
`.
`
`Page 6
`
`

`

`

`

`232
`
`Gerald L. Brown et al.
`
`All t-tests were one-tailed because a large majority of HAC have
`a positive response to amphetamine (Millichap, 1973) or no re(cid:173)
`sponse. The very few children who have a negative response are
`often considered borderline psychotic (excluded from this study)
`prior to medication (Wender, 1971).
`
`DISCUSSION
`
`The mean (± SEM) apparent half-lives for tablet d-amphetamine
`and for sustained-release d-amphetamine (identical doses) obtained
`from an earlier group of seven children studied on two separate
`occasions were not significantly different (6.6 ± .05 and 8.4 ± 1.2
`h, respectively) (fig. 3, Brown et aI., 1979b). In both, apparent
`half-lives were calculated from a least squares linear regression
`analysis done on the plasma disappearance curve of each patient
`over a 30-h interval. For tablet, peak values occurred between h 3
`and 4 (63.6 ± 5.3 and 63.3 ± 6.1 ng/ml, respectively); and for the
`sustained release, peak values occurred between h 3-6 (60.7 ± 7.8,
`62.2 ± 6.2, 61.7 ± 2.2 ng/ml at h 3, 4, and 6, respectively). Sus(cid:173)
`tained release thus gave a somewhat more plateaulike blood level
`during this peak level period. Plasma levels of d-amphetamine in
`individual children differed fourfold at h 1, two and one-halffold
`at h 2, twofold at h 3, and less than twofold at h 4 after tablet and
`threefold at hi, and about twofold at h 2-4 after sustained release.
`Thus, the early absorption of tablets was somewhat more variable
`than that of sustained-release capsules; whereas the variability in
`plasma levels following both was somewhat
`less during h 6-30
`(elimination) as compared to h 1-6 (absorption). The CV of
`d-amphetamine plasma levels during the absorption phase at h 1-4
`were 66, 31, 22, and 24%, respectively, for tablet, and 47,30,34,
`and 25%, respectively, for sustained release. When plasma values
`obtained from tablets and from sustained release were compared
`for similarity in these seven children,
`the intraclass correlation
`coefficients (ICC) of serial plasma d-amphetamine levels on the
`two study days were significant in five of the seven individuals
`.98, P < .01); however, a chi-square test indicat(cid:173)
`(ICC range,
`.52 -
`ed that the seven ICC's did not differ significantly from one an(cid:173)
`other. The pooled ICC was .83. The interchangeability of sets of
`plasma amphetamine values is quite high for a given child, whether
`he receives tablet or sustained release;
`the interchangeability of
`these sets of values is only modestly less than those reported when
`
`Page 8
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`

`Behavior Response in Hyperactive Children
`
`233
`
`individual children are given tablets on two separate occasions
`(Brown et al. , 1979a, 1979b). Thus,
`to the degree that differing
`plasma pharmacokinetics from these two preparations could be ex(cid:173)
`pected to effect differing clinical responses, one would predict only
`modest differences, if any,
`in clinical response. The plasma data
`from this study group are similar to the earlier HAC group given
`sustained-release d-amphetamine. The standard breakfast given to
`the sustained-release study group here reported (and not to the
`earlier group) appears to have little effect on the CV.
`levels of
`The
`apparent
`elimination
`half-life of
`plasma
`d-amphetamine for a goup of 16 HAC (6.8 ± 0.5 h) who received
`tablets (Brown et al., 1979a, 1979b) was considerably less than that
`reported for eight depressed adults (19.4 ± 4.6 h) (Ebert et al.,
`1976; van Kammen and Murphy, 1975). Both groups attained
`peak levels at
`the same time; and both showed the maximal
`behavioral response at
`the same time, h 1-4). The findings of
`Ebert et al. (1976) are consistent with other adult studies when uri(cid:173)
`nary pH is considered (Davis et al., 1971; Kreuz and Axelrod,
`1974). More recent work (Gershon et al., 1979; Nurnberger et al.,
`1979) indicates that normal adult twins show an elimination half(cid:173)
`life of 10.5 h when the diet is controlled and the urinary pH is
`more similar to that of the HAC here reported. Though urinary
`pH differences could account for some of the half-life differences
`between the depressed adults and the HAC, it is very unlikely to
`account for
`the differences between the HAC and the normal
`adults. If HAC do eliminate d-amphetarnine more rapidly than
`normal adults, no explanation is clear currently. The half-life of
`methylphenidate in HAC is 2.6 h, SD ± 0.16 (Hungund et al.,
`1979) as compared to normal adults (approximately 2 h) (Faraj et
`al., 1974). The metabolism of amphetamine is more dependent
`upon liver enzymes than that of methylphenidate. Children and
`adults apparently absorb d-amphetamine and respond behaviorally
`in a similar fashion with regard to time, but adults may eliminate
`the drug more slowly.
`The earlier study of the response of HAC to a single dose of
`d-amphetamine (0.45 ± .02 mg/kg) also showed that significant
`behavioral and motor activity responses occurred during the ab(cid:173)
`sorption phase (h 1-4) and did not correlate with plasma am pheta(cid:173)
`mine levels (Brown et al., 1979a). A later replication study of the
`response of a different group of 14 HAC to a single dose of
`d-amphetamine elixir (0.5 mg/kg) with armboard, heparin-lock,
`
`Page 9
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`

`234
`
`Gerald L. Brown et al.
`
`and placebo blood study days (as in this study) showed results simi(cid:173)
`lar to the tablet study as well as reliable results within the same
`group of children (similar drug study conditions on two separate
`occasions) (Brown et al., 1977). ABCTRS ratings are somewhat de(cid:173)
`pendent upon interactions between children;
`though the ratings
`themselves were done consistently on both amphetamine and pla(cid:173)
`cebo study days, interactions between children were not consistent
`across all intervals on a given study day. Lack of behavioral effects
`postpeak amphetamine levels (h 5 and 6) could possibly be due to
`the decreased behavioral rating on placebo days at those time inter(cid:173)
`vals, whereas the return of disruptive behavior on amphetamine
`days is less than baseline for the postpeak intervals; but the likeli(cid:173)
`hood of a type II error in this small N sample is reduced by our
`having used one-tailed t-tests. The preferable statistical analysis to
`employ in such a study would be an analysis of variance to assess
`drug effect,
`time effect, and their possible interaction, as well as
`the avoidance of a possible occasional significant difference by
`paired t-test from chance alone. However, difficulties in obtaining
`com plete serial sets of data for all children studied (particularly be(cid:173)
`havior) determined the choice of paired t-tests.
`When the earlier absorption-elimination study of tablet and
`sustained-release amphetamine is compared to the current study
`(see figs. 1, 2, and 3), it is clear that the peak plasma level occurs
`later and lasts longer with sustained-release (up to h 8), though this
`later occurrence and more plateaulike peak plasma level
`is not
`accom panied by a longer period of significant response to the
`medication (in fact, the significant response appears to be shorter).
`Additionally, the earlier and more significant responses to tablet,
`and particularly to elixir, may further indicate that clinical re(cid:173)
`sponse is related to absorption. The pharmacogenetic studies of
`Gershon et al. (1979) in normal adult twins indicate that the period
`of maximal behavioral change occurs within h 1 after intravenous
`d-amphetamine despite a mean elimination half-life of greater
`than 10 h. Behavioral response thus appears unlikely to be a sec(cid:173)
`ondary response to plasma amphetamine level. These authors
`suggest that genetic variation in the amount of releasable cate(cid:173)
`cholamines, susceptibility of cellular and vesicular membranes to
`amphetamine, or sensitivity of postsynaptic receptor sites may, in
`part, explain this profile of response. Pharmacokinetic data for
`methylphenidate in HAC mayor may not be consistent with that
`of d-amphetamine. Hungund et al.
`(1979) suggest that the low
`
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`236
`
`Gerald L. Brown et al.
`
`"behavioral" and pharmacological half-life of methylphenidate is
`coincidental. Whether the differences in behavioral parameters be(cid:173)
`ing measured contribute to an understanding of the mechanism of
`response for methylphenidate and d-amphetamine is unclear
`(Sprague and Sleator, 1977).
`Studies in rats of the effect of methamphetamine on NE metabo(cid:173)
`lism and behavior demonstrate that methamphetamine (5.0 mg/kg)
`inhibits reuptake and increases normetanephrine levels in the first
`several hours postdrug administration. In these experiments, in(cid:173)
`creases
`in normetanephrine, a metabolite that
`reflects extra(cid:173)
`neuronal metabolism of NE, correlate highly with the behavioral
`response to methamphetamine (Cook and Schanberg, 1970). When
`rhesus monkeys were assessed behaviorally after single oral doses
`of d-amphetamine (0.32 and 1.0 mg/kg), maximal behavioral ef(cid:173)
`fects were seen prior to the peak plasma level of amphetamine at
`times when the plasma level was twofold lower than that which was
`subsequently attained (Downs and Braude, 1977). The mechanism
`of the decreased response to later similar levels of d-amphetarnine
`(from a single dose) in plasma may be related to depletion of
`catecholamine stores, to replacement by a "false neurotransmitter"
`metabolite of amphetamine (Kopin, 1968a, 1968b), or to alteration
`in receptor sensitivity (Bunney and Murphy, 1975).
`to whether
`The most
`important
`clinical question relates
`sustained-release d-arnphetamine actually does lead to a prolonged
`clinical response. Despite the literature th at raises this prolongation
`as a possibility, these data would not support such a conclusion, nor
`would the pharmacokinetic-clinical response data in previous stud(cid:173)
`ies. Gross and Wilson (1974) suggest
`that variable absorption
`- "delayed and incomplete"-may account for some of the varia(cid:173)
`tion in clinical response; however, our data suggest modest varia(cid:173)
`tion within the group during the absorption phase. Earlier data
`suggest less variation during the early absorption phase for sus(cid:173)
`tained release than for tablet, as well as more plateaulike plasma
`levels during the peak level period; both preparations show some(cid:173)
`what less variability during h 6-30, as compared to the early hours
`during the absorption phase. Thus,
`the variability in absorption
`and elimination between sustained release and tablet appear to be
`either unrelated to the observed clinical response in this study, or
`the slower rate of absorption for the sustained release may relate to
`a later onset and less significant clinical response vs. the response
`observed after tablet. Safer and Allen (1976) found that at least
`
`Page 12
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`Behavior Response in Hyperactive Children
`
`237
`
`10% of HAC who take 15 mg sustained-release spansules as a
`beginning dose will experience insomnia. Our study did not pro(cid:173)
`vide for systematically observing differences between tablet and
`spansule response in the evening hours. Insomnia has sometimes
`been a clinical complaint on the evening of the several single-dose
`studies; such appears to have been dose-related, but not prepara(cid:173)
`tion-related. The period during which absorption and elimina(cid:173)
`tion are in equilibrium (peak plasma level) clearly does last longer
`for the spansules than for the tablets at the same dose. Thus, for
`some children, this prolonged peak plasma level might relate to in(cid:173)
`somnia,
`though one could also hypothesize less of a "rebound
`effect"-an effect that is sometimes felt to be observable clinically,
`but which has not been documented in a controlled study. Should
`the clinical response be related to a necessary rate of absorption
`and be unrelated to the peak plasma level per se and its duration,
`then the earlier studies would not lead one to predict a prolonged
`response. These data would not suggest that there is any general
`advantage in single-dose sustained-release capsule vs. a tablet at
`8:00 A.M. and 12:00 P.M., since there is no evidence that any
`pharmacologically induced therapeutic effect can be obtained be(cid:173)
`yond 4 hours from the oral administration of a single dose (0.5
`mg/kg) of d-amphetamine to HAC.
`In conclusion,
`this study of sustained-release d-amphetamine,
`like earlier single-dose amphetamine studies in hyperactive chil(cid:173)
`dren, shows significant behavior and motor activity responses
`to the medication only during the absorption phase, and these
`responses are not correlated with specific plasma levels of d(cid:173)
`amphetamine. Furthermore, despite pharmacokinetic differences
`between elixir, tablet, and sustained release, all at the same dose,
`there is no evidence that a prolonged clinical response results
`from the use of the sustained-release preparation.
`
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