Rad.washington.edu

Fluorine Magnetic Resonance Spectroscopy
Measurement of Brain Fluvoxamine and Fluoxetine
in Pediatric Patients Treated for Pervasive
Developmental Disorders
Wayne L. Strauss, M.D., Ph.D.
Objective: Pediatric populations, includ-
Results: A significant relationship be-
ing those with autistic disorder or other Alan S. Unis, M.D.
creasingly are being prescribed selective age range studied. Brain fluvoxamine con-centration in the children was lower, con- Charles Cowan, M.D.
serotonin reuptake inhibitors (SSRIs). Littleis known about the age-related brain sistent with a lower dose/body mass drugprescription; when brain concentration Geraldine Dawson, Ph.D.
pharmacokinetics of SSRIs; there is a lackof data regarding optimal dosing of medi- cations for children. The authors used flu- were no longer significant. Brain fluoxe- Stephen R. Dager, M.D.
tine concentration was similar betweenage groups; no significant age effects on (19F MRS) to evaluate age effects on whole- brain fluoxetine drug levels remained af- fluoxetine in children taking SSRIs.
tions of brain fluoxetine bioavailability Method: Twenty-one pediatric subjects
and elimination half-life also were similar Conclusions: These findings suggest that
6–15 years old and stabilized with a con- sistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 success- fully completed the imaging protocol.
dren with autistic disorder or other perva- generalized to other pediatric populations.
(Am J Psychiatry 2002; 159:755–760)
Autistic disorder and other pervasive developmental voxamine under double-blind conditions in adults with disorders are characterized by symptoms that can include autistic disorder, found that eight of 15 patients in the flu- repetitive or compulsive behavior, impaired social inter- voxamine-treated group (in comparison to none of 15 in action, and abnormal language development. These dis- the placebo group) responded to active drug treatment.
orders typically manifest in early childhood and result in Fluvoxamine was superior to placebo in reducing repeti- life-long disability. Serotonin-related brain abnormalities, tive behaviors, maladaptive behavior, and aggression, as particularly in autistic disorder, are suggested by reports of well as in enhancing social relatedness and use of lan- low central serotonergic responsivity in this population, guage. Treatment response was not predicted by subjects’ altered brain synthesis of serotonin in autistic boys, and gender, age, severity of autistic behavior, or intellectual more whole-blood serotonin in approximately one-third There has been a substantial increase in the use of SSRIs Evidence of serotonergic abnormalities provides a ratio- in pediatric populations, including those with autistic dis- nale for treatment of autistic disorder or other pervasivedevelopmental disorders with serotonin reuptake inhibi- order or other pervasive developmental disorders (17, 18).
tors or selective serotonin reuptake inhibitors (SSRIs).
However, dose-ranging studies of SSRIs and their corre- Symptomatic improvement during serotonin reuptake in- sponding pharmacokinetics have not been extensively in- hibitor or SSRI treatment has been reported in both open- vestigated in this age range. Indeed, current pediatric dos- label and controlled studies for most dimensions of clini- ing guidelines for all psychotropic drugs are based on cal impairment associated with autism (6–16). One care- limited blood pharmacokinetics data and are primarily fully designed treatment study (7), which evaluated flu- extrapolated from adult dosing studies.
SSRI LEVELS IN PEDIATRIC PATIENTS
The developing field of magnetic resonance spectros- oral diphenhydramine, 25–50 mg, for light sedation 1–2 hours be- copy (MRS) allows noninvasive, in vivo brain pharmacoki- fore the study if their child had previously demonstrated a seda- netic studies of drugs, such as fluvoxamine and fluoxetine, Of the 21 pediatric subjects, 16 successfully completed the that contain fluorine (19F) in their native structure (19). 19F brain drug concentration measurement protocol, while five of the MRS provides an ideal modality for studying brain phar- subjects were not cooperative with the study. Eight of the subjects macokinetics in pediatric patients because it involves no (mean age=11.8 years, SD=3.2, range=7–15) were taking fluvox- ionizing radiation or special labeling of the compound to amine at a mean dose of 77.5 mg/day (SD=42.8, range=25–150) at be measured. Moreover, it is less motion sensitive than a dose-per-body-mass ratio of 1.43 mg/kg (SD=0.62). One subjectwas studied on three separate occasions while taking progres- other magnetic resonance imaging techniques, making it sively higher doses of fluvoxamine (50 mg/day, 100 mg/day, and clinically feasible for studying individuals who may be un- 150 mg/day, each at a consistent dose for more than 1 month); able to remain completely still during examinations. 19F each measurement was treated as an independent data point.
MRS work by our group (20–22) has extended the frame- Eight of the subjects (mean age=8.8 years, SD=3.7, range=6–15) work of classical pharmacokinetics by applying a multi- were taking fluoxetine at a mean dose of 10.63 mg/day (SD=8.5,range=1–20), at a dose-per-body-mass ratio of 0.36 mg/kg (SD= compartmental model to calculate the steady-state con- 0.36). Two subjects who were studied while taking fluoxetine were centration, volume of distribution, and elimination half- then restudied after cessation of drug therapy.
life of selected SSRIs in the adult human brain. An emerg- With use of identical 19F MRS methods, brain concentrations ing 19F MRS technique, magnetization transfer spectros- from outpatients under treatment at the University of Washington copy (MTS), has been also used to characterize the inter- Center for Anxiety and Depression for a DSM-IV diagnosis of panic action between bound and free molecules in vivo as a disorder, major depression, or OCD were determined for 13 adults(mean age=44.8 years, SD=17.5, range=18–66) who were taking measure of brain fluoxetine bioavailability in adults (23).
fluvoxamine at a mean stable dose of 231 mg/day (SD=69, range= Magnetization transfer effects, generated by the selective 100–300) for an average treatment duration of 7.5 months (SD=4.2, preexcitation of the bound fraction of a compound with range=2–24) and 15 adults (mean age=51.9 years, SD=11.3, range= subsequent transfer of magnetization to the free fraction, 24–62) who were taking fluoxetine at a mean stable dose of 24.0 cause the partial saturation of the free, or unbound, com- mg/day (SD=7.4, range=20–40) for an average treatment durationof 11.3 months (SD=6.9, range=3–24). Steady-state brain fluvox- ponent. This partial saturation is detected as reduced sig- amine and fluoxetine concentrations for these adults have, in part, nal intensity in the MRS pulse sequence. The 19F MTS been previously published (20–23). Data from one adult subject technique, to our knowledge, has not been used to mea- previously identified as having a metabolic abnormality on the ba- sure drug bioavailability in children.
sis of consistent abnormally high (∼fivefold) brain levels of fluvox-amine (20) were not included in these analyses.
The purpose of this study was to use 19F MRS to mea- Determination of whole-brain drug concentrations were per- sure whole-brain SSRI concentrations and demonstrate formed by using previously published methods (20, 21). In brief, the feasibility of using 19F MTS to characterize the bound all data were acquired by using a GE Signa 1.5-T magnetic reso- portion of SSRIs prescribed to pediatric patients undergo- nance scanner (General Electric Medical Systems, Milwaukee) ing treatment for a diagnosis of autistic disorder or other with version 5.8 software and equipped with a broad-band poweramplifier (General Electric Medical Systems, Milwaukee) and a pervasive developmental disorders. Data acquired from fluorine quadrature birdcage head coil built in our laboratory this pediatric study group were compared to similarly ac- (23). A T1-weighted proton image was acquired with the fluorine quired data from adults prescribed fluvoxamine or fluoxe- coil to ensure proper positioning of the subject’s head in the mag- tine for a diagnosis of major depression, obsessive-com- net. Whole-brain shimming of the magnetic field, to ensure con- pulsive disorder (OCD), or panic disorder.
sistent magnetic field homogeneity, was performed through theproton channel, since the fluorine signal is too weak to allow ade-quate shimming. The 19F MRS pulse sequence was set at 90°, with a pulse width of 500 µsec, a phase cycling of 2, and TR of 1 secondto obtain a fully relaxed spectrum measurement with about 1,000 Twenty-one pediatric patients were referred from the Center averages. Power for the 90° pulse was determined by using a so- on Human Development and Disability or the Department of Pe- dium fluoride phantom and a resistive device designed to load diatrics at the University of Washington for participation in the the coil similarly to a human head. Drug concentration was deter- study. Parents or guardians gave informed written consent, and mined relative to the phantom. Total scanning time was generally older subjects were given the opportunity to provide informed less than 40 minutes. Signal quantification was performed by us- written assent to participate; both procedures were approved by ing a VARPRO-based time-domain fitting program (MRUI, Delft, the institutional review board of the University of Washington.
the Netherlands). Aged-adjusted literature values for brain vol- The pediatric group met DSM-IV criteria for autistic disorder or ume were used as a correction factor for calculating brain con- other pervasive developmental disorders through diagnostic centrations, since it was not feasible to measure individual brain evaluation by an experienced, university-based clinician (A.S.U., volumes because of technical limitations using the fluorine coil to C.C., or G.D.). All subjects were being treated with either fluvox- acquire high-resolution proton images (24, 25).
amine or fluoxetine and had been taking a consistent daily dose MTS was performed to characterize brain drug binding for a for a minimum of 6 weeks before the study. Exclusion criteria in- subgroup of four pediatric subjects taking fluoxetine. Data are in- cluded treatment with other medications, identified genetic con- cluded for one subject studied in the steady state and 2 weeks af- ditions in which autistic behavior is symptomatic (e.g., fragile X ter drug discontinuation. The MTS methods were identical to syndrome), uncontrolled seizures, or contraindications to mag- those used in a previously published study of adults (23). In brief, netic resonance scanning, such as metal implants or claustropho- the MTS pulse sequence consisted of a 90° hard pulse of 500-µsec bia. Parents or guardians were given the option of administering duration and 0.5-second TR, with and without a train of three sat- STRAUSS, UNIS, COWAN, ET AL.
TABLE 1. Demographic and Clinical Characteristics of Pediatric Patients With Autistic Disorder or Other Pervasive Develop-
mental Disorders Who Took Fluvoxamine or Fluoxetine
a Subject was studied on separate occasions while taking different doses.
uration pulses centered at –3000 Hz and 0.2 msec before the 90° The dose-per-mass relationship between the pediatric pulse. The magnitude of MTS contrast was calculated as a signal and adult subjects did not differ significantly for fluoxe- depression with the preparation pulses.
tine prescriptions (mean=0.36 mg/kg, SD=0.36, versus Statistical handling of the data employed independent t tests to compare pediatric and adult data for each medication separately; mean=0.31 mg/kg, SD=0.14) (t=0.40, df=21, p=0.69). Cor- assumptions of equal variance were met. Additional analyses respondingly, the average brain concentration of fluoxe- were performed by using Pearson’s r to evaluate the relationship tine was similar between the two age groups (mean=4.54 between age and brain measurements for each medication across µM, SD=3.33, versus mean=5.04 µM, SD=2.54) (t=0.41, df= the age range studied. All data are presented as means and stan- 21, p=0.69). When corrected for dose per mass, the brain ratios for concentration per dose per mass remained sim- ilar between the groups (mean=15.66 µM/mg per kg, SD=6.89, versus mean=17.49 µM/mg per kg, SD=9.56) (t=0.48, A whole-brain fluorine signal could be quantified for all subjects, with the exception of three pediatric patients A significant correlation between brain concentration who were taking fluvoxamine at doses between 25 and 50 and dose of medication was found both for fluvoxamine mg/day and who had 19F MRS signals below the level of (r=0.71, df=20, p=0.001) and fluoxetine (r=0.46, df=23, p= quantifiable detection (<0.75 µM). Individual pediatric 0.03). For fluvoxamine, a positive correlation observed be- subjects’ brain concentrations of fluoxetine and fluvoxa- tween age and brain concentration (r=0.52, df=20, p=0.02) mine, also calculated in relationship to dose per body no longer reached significance when brain fluvoxamine concentration was adjusted for the effects of dose per The dose-per-mass relationship for the fluvoxamine mass (r=0.41, df=20, p=0.08). For the combined pediatric prescriptions was lower in the pediatric group than in the and adult groups, this relationship between brain fluvox- adult group (mean=1.43 mg/kg, SD=0.62, versus mean= amine concentration per dose per mass and age is shown 2.94 mg/kg, SD=0.78) (t=5.02, df=21, p=0.001). Consistent in Figure 1. No relationship was found between age and with this, the average brain fluvoxamine concentration in brain fluoxetine concentration (r=0.12, df=23, p=0.55), nor the pediatric subjects was lower than that observed for was there a relationship between age and the ratio for adults (mean=2.74 µM, SD=0.83, versus mean=7.22 µM, brain concentration per dose per mass (r=0.15, df=23, p= SD=2.66) (t=4.29, df=18, p=0.001). When brain concentra- tion was corrected for the effects of dose per mass, the ra- Fluoxetine data were acquired after discontinuation of tio of the concentration per dose per mass in the pediatric the medication by two pediatric subjects. Brain fluoxetine group was not significantly different from that for the concentration had fallen by 93% at 5 weeks after discon- adults (mean=1.91 µM/mg per kg, SD=1.03, versus mean= tinuation of medication for one subject (subject 4), and 2.56 µM/mg per kg, SD=0.71) (t=1.68, df=18, p=0.11).
there was an 85% decrease in brain fluoxetine concentra- SSRI LEVELS IN PEDIATRIC PATIENTS
FIGURE 1. Relation of Age to Brain Fluvoxamine Concen-
FIGURE 2. Relation of Age to Brain Fluoxetine Concentra-
trationa in Six Pediatric Patientsb and 13 Adults Who Took
tiona in Eight Pediatric Patients and 15 Adults Who Took
Fluvoxamine
Fluoxetine
µM/mg per kg)(
µM/mg per kg)(
Brain Fluvoxamine Concentration
Brain Fluoxetine Concentration
Age (years)
Age (years)
a Adjusted for daily dose per body mass for the combined pediatric a Adjusted for daily dose per body mass for the combined pediatric b Two additional pediatric patients did not have detectable brain lev- els of fluoxamine. One pediatric subject had undetectable brainlevels of fluvoxamine when taking 50 mg/day, but data collected tine are not significantly different from typical adult levels when the subject was taking 100 mg/day and 150 mg/day are in- when corrected for the effects of dose per mass. Overall, in a direct comparison of the two age groups, and in acombination of the age groups for evaluation across an TABLE 2. Drug Concentration Data From Magnetization
extended age range, from childhood to later adulthood, Transfer Spectroscopy (MTS) for Four Pediatric Patients
no clear relationship was observed between age and brain With Autistic Disorder or Other Pervasive Developmental
Disorders Who Took Fluoxetine
SSRI concentrations after adjustment for the effects of dose per body mass. These findings suggest that thera- peutic dosing of fluvoxamine and fluoxetine can be ex- trapolated in relationship to dose per body mass from adult treatment practices and can provide an acceptable treatment approach for the medication management of There was found a significant effect of age on brain con- centration for fluvoxamine, but not fluoxetine; lower brainlevels of fluvoxamine were observed in the pediatric pa- tion for the second subject (subject 8) 4 weeks after dis- tients. However, differences between age groups in brain fluvoxamine concentration on a dose-per-body mass ba- F MTS demonstrated a quantifiable contrast for the sis were not significant, although a weak, nonsignificant fluoxetine signal (mean=9.4%, SD=3.4%, range=5%–14%) correlation with age remained. It is likely that any age rela- (Table 2). There was a significant negative correlation ob- tionship to brain concentration of fluvoxamine primarily served between brain fluoxetine concentration and the reflects the lower dose-per-mass equivalent prescribed for magnitude of MTS contrast (r=–0.92, df=5, p<0.03). In a the pediatric patients than for adults, a difference not ob- comparison of MTS contrast for fluoxetine between data served for fluoxetine. Age-related differences in dosing from the pediatric age group and the previously deter- patterns between the two drugs probably reflect their re- mined adult values (mean=12.5%, SD=5.0%) (23), no sig- spective side effect profiles in pediatric populations.
nificant difference was observed (t=1.2, df=9, p=0.27).
The elimination half-life of fluoxetine and its metabo- Discussion
lites from the adult brain has been estimated, based onlimited observations, to be approximately 16 days or To our knowledge, this is the first study to systemati- longer (26, 27). The rate of brain clearance of fluoxetine cally evaluate the effects of age on brain steady-state con- and its metabolites that was observed for the two pediatric centrations of SSRIs in humans. Our findings, from a subjects in this study suggests that the brain elimination group of pediatric patients with a diagnosis of autistic dis- half-life of fluoxetine is not prolonged in this age group.
order or other pervasive developmental disorders, sug- Our preliminary findings of a similar brain elimination gest that pediatric brain levels of fluvoxamine and fluoxe- time course for pediatric subjects as has been observed for STRAUSS, UNIS, COWAN, ET AL.
adults after fluoxetine discontinuation are consistent with children with these disorders (30, 31; unpublished data of the similar brain concentrations achieved between age Dager et al.), it is uncertain how generalizable our findings groups on a dose-per-body mass basis. However, from the are to other pediatric populations undergoing treatment small number of subjects studied, we cannot exclude the with SSRIs. An additional consideration is that individual possibility that the kinetics of drug uptake or clearance in brain volume measurements were unavailable for the sub- the brain may vary as a function of age until additional in- jects in this study. If the pediatric group had greater brain vestigations are carried out to systematically address these volumes, reported to be approximately 10% larger among a group of 3–4-year-old children with autistic disorder or Age-related effects on the plasma pharmacokinetics of other pervasive developmental disorders (31), then we antidepressants, which typically are metabolized more would have overestimated brain drug concentrations by rapidly by children and more slowly by older adults, have using typical age-adjusted values for brain volumes. How- provided a clinical rationale for upward dose adjustments ever, this is an unsettled issue, since recent findings sug- for children that may sometimes far exceed adult daily gest that early brain enlargement may occur from acceler- doses prescribed on a dose-per-mass basis (28). Hepatic ated brain growth among very young children with clearance of medications is more efficient in children be- autism, which plateaus at about 5 years of age (30) and be-fore the minimum age of entry into this study.
cause of the disproportionate size of their livers relative tobody size. However, fluvoxamine and fluoxetine are pref- Findings from this study may help to provide a brain erentially distributed from plasma into brain tissue be- pharmacokinetic basis for current dosing strategies in pre- cause of their high lipophilicity, which results in approxi- scribing SSRIs to pediatric patients. We found that chil-dren and adolescents with autistic disorder or other per- mately 20-fold higher brain concentrations that would vasive developmental disorders attained similar brain substantially lessen the impact of hepatic clearance on levels of fluvoxamine and fluoxetine on a dose-per-body steady-state brain levels (22). The substantial concentra- mass basis, as did adults treated for anxiety disorders or tion gradient between brain and plasma may also account major depression. Thus, a reasonable target dose range for for observations that combined plasma fluoxetine and prescribing fluvoxamine and fluoxetine in pediatric popu- norfluoxetine concentrations, when adjusted for dose- lations may be determined by scaling adult doses in rela- per-mass relationships, are similar between pediatric and adult populations (unpublished data from Eli Lilly andCompany).
Received July 19, 2001; revision received Jan. 4, 2002; accepted Prior work making use of MTS in conjunction with 19F Jan. 14, 2002. From the Center on Human Development and Disabil- MRS quantification of fluoxetine in the adult brain (23) has ity, the Center for Anxiety and Depression, and the Departments ofBioengineering, Psychiatry and Behavioral Sciences, Pediatrics, Psy- demonstrated the use of this technique to better under- chology, and Radiology, University of Washington; and the Children’s stand brain bioavailability of psychotropic drugs. These Hospital and Medical Center, Seattle. Address reprint requests to Dr.
preliminary 19F MTS findings in pediatric patients are con- Dager, Center for Anxiety and Depression, University of WashingtonSchool of Medicine, 4225 Roosevelt Way, N.E., Suite 306-C, Seattle, sistent with work in adults (23) that found an inverse rela- WA 98105-6099; [email protected] (e-mail).
tionship between brain drug concentration and MTS con- Supported by a Bristol-Myers Squibb Neuropharmacology Post- trast. This inverse relationship implies saturable binding of doctoral Fellowship from the National Alliance for Autism Research(to Dr. Strauss), an unrestricted grant from Solvay Pharmaceuticals, fluoxetine in both pediatric and adult brains; the bioavail- and a project grant (HD-34565) from the Neurobiology and Genetics ability of the drug is proportional to brain concentration.
of Autism program at the National Institute of Child Health andDevelopment.
Several potential limitations of the study design may have influenced our results. For example, the time to reachbrain steady state in pediatric patients has not been estab- References
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