[Show abstract][Hide abstract] ABSTRACT: Subjective responses (ie, liking, disliking) to stimulants are thought to be proxies for abuse potential. Greater subjective responses have been documented in formulations that are more rapidly absorbed. However, repeat dosing has not been examined.
Subjective responses on the Drug Rating Questionnaire were compared in 26 healthy adults after administration of short- (immediate-release [IR] methylphenidate [MPH]) and long- (osmotically controlled-release oral delivery system [OROS] MPH) acting stimulant formulations. The second dose was administered 4 hours after initial dosing. All subjects received all 5 conditions (ie, placebo to placebo; IR-MPH to IR-MPH; IR-MPH to OROS-MPH; OROS-MPH to IR-MPH; or OROS-MPH to OROS-MPH) in a double-blind, counter-balanced design on 5 separate days.
Plasma levels and subjective patterns of detection were higher when an IR formulation was administered during the ascending phase of a first-administered long-acting dose (OROS).
These results emphasize the critical role that formulation type (IR vs OROS) and timing of administration (ascending vs descending phase) play when short- and long-acting formulations are coadministered. Such knowledge provides important information for clinicians about the safety and tolerability of the timing of repeat dosing of various permutations of coadministration of MPH formulations.
No preview · Article · Jan 2012 · Postgraduate Medicine
[Show abstract][Hide abstract] ABSTRACT: Pediatric studies of the long-acting formulation (spheroidal oral drug absorption system [SODAS]) of the isomer dexmethylphenidate have shown a dose-dependent efficacy through 12 hours. However, there are no studies of central nervous system (CNS) dopamine transporter occupancies.
Eighteen healthy volunteers underwent positron emission tomography (PET) imaging with C-11 altropane before and after administration of oral doses of SODAS dexmethylphenidate. Each group of 6 subjects received 1 of 3 doses (20 mg, 30 mg, 40 mg) before PET imaging at 1, 8, 10, 12 (20 mg and 30 mg), or 1, 8, 10, and 14 (40 mg) hours after dosing. Transporter occupancy was calculated by standard methods. The study was conducted from January 2007 through December 2007.
For all doses, plasma dexmethylphenidate levels and CNS dopamine transporter occupancies were greatest at 8 hours and decreased over time at 10, 12, and 14 hours. Plasma dexmethylphenidate levels were correlated to dose (P < .003). Mean plasma levels were ≥ 6 ng/mL to at least 8 hours with 20 mg (5.7 ng/mL), 10 hours with 30 mg, and 12 hours (extrapolated) with 40 mg. Dopamine transporter occupancies in the right caudate were 47% at 8 hours with 20 mg, 42% at hour 10 with 30 mg, and 46% (extrapolated) at hour 12 with 40 mg. Dopamine transporter occupancy was significantly correlated with plasma concentration of dexmethylphenidate (P < .001).
These results confirm the study hypothesis that central dopamine transporter occupancy parallels peripheral pharmacokinetic findings in orally administered long-acting dexmethylphenidate in later hours after administration.
clinicaltrials.gov Identifier: NCT00593138.
No preview · Article · Nov 2011 · The Journal of Clinical Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Armodafinil, prescribed principally to treat narcolepsy, is undergoing assessment of therapeutic potential for other neuropsychiatric disorders and medical conditions. The neurochemical substrates and mechanisms of armodafinil are unresolved. We investigated the hypothesis that armodafinil enhances wakefulness by modulating the activities of the dopamine transporter (DAT). With positron emission tomography imaging, we determined DAT occupancy and changes in extracellular dopamine by armodafinil in vivo.
Twelve subjects were enrolled. Plasma armodafinil levels were obtained. In vivo armodafinil occupancy of the DAT in striatum was detected by [¹¹C]altropane and changes in extracellular dopamine were detected by indirect displacement of [¹¹C]raclopride in human subjects at different times after drug administration.
Armodafinil (100 mg by mouth [PO]) occupied striatal DAT (34.0 ± 9.0% at 1 hour, 40.4 ± 9.5% at 2.5 hours, n = 6) and 250 mg occupied striatal DAT (60.5 ± 7.4% at 1 hour, 65.2 ± 6.1% at 2.5 hours, n = 6). In addition, armodafinil was associated with changes in extracellular dopamine (17.8 ± 30.1% [100 mg PO] and 7.0 ± 8.6% [250 mg PO] at 2.5 hours, n = 6).
Occupancy of the DAT and changes in extracellular dopamine in vivo further implicates the actions of armodafinil on DAT as a potential candidate for its therapeutic improvement of wakefulness and other conditions.
Full-text · Article · Nov 2010 · Biological psychiatry
[Show abstract][Hide abstract] ABSTRACT: Few follow-up studies have been conducted of girls with ADHD, and none have followed girls into adulthood. The authors sought to estimate the prevalence of psychopathology in girls with and without ADHD followed into young adulthood.
The authors conducted a longitudinal case-control study of 6- to 18-year-old girls with (N=140) and without (N=122) ADHD ascertained from psychiatric and pediatric sources. At the 11-year follow-up, 96 (69%) of the girls with ADHD and 91 (75%) of the comparison girls were reassessed (mean age=22 years). Participants were blindly assessed by structured diagnostic interviews.
Lifetime and 1-year risks for all composite categories of psychopathology were significantly greater in girls with ADHD grown up relative to comparison girls; lifetime hazard ratios were 7.2 (95% CI=4.0-12.7) for antisocial disorders, 6.8 (95% CI=3.7-12.6) for mood disorders, 2.1 (95% CI=1.6-2.9) for anxiety disorders, 3.2 (95% CI=2.0-5.3) for developmental disorders, 2.7 (95% CI=1.6-4.3) for addictive disorders, and 3.5 (95% CI=1.6-7.3) for eating disorders. For lifetime psychopathology, all six composite categories remained statistically significant after controlling for other baseline psychopathology. Except for addictive disorders, significant 1-year findings remained significant after controlling for baseline psychopathology. The 1-year prevalences of composite disorders were not associated with lifetime or 1-year use of ADHD medication.
By young adulthood, girls with ADHD were at high risk for antisocial, addictive, mood, anxiety, and eating disorders. These prospective findings, previously documented in boys with ADHD, provide further evidence for the high morbidity associated with ADHD across the life cycle.
Preview · Article · Apr 2010 · American Journal of Psychiatry
[Show abstract][Hide abstract] ABSTRACT: While concordance between mother and child report continues to be the gold standard in the assessment of pediatric bipolar disorder, uncertainty develops when a mother's report is not endorsed by the youth. To this end we compared discordant (mother positive and youth negative) and concordant (mother and youth positive) cases.
Subjects were 98 adolescents (12-19 years of age) derived from family studies of bipolar disorder in youth who had both self-reported and mother-reported assessments. Comparisons were made between discordant (n = 35) and concordant (n = 59) cases on a wide range of clinical correlates.
Mothers in both groups reported similar rates of symptoms of mania and depression. Within the concordant group, mothers and youth reported similar rates of symptoms of mania. There were no differences between the concordant and discordant groups in onset, duration, or impairment of mania, rates of psychiatric hospitalization, cognitive variables, or rates of disorders in family members.
The similarities between discordant and concordant reports in symptomatology of mania and depression, rates of comorbidities, treatment needs, and other clinical correlates suggest that a mother-based diagnosis of mania should not be discounted in discrepant cases in which the youth fails to endorse the diagnosis.
No preview · Article · Jun 2009 · Bipolar Disorders