Assessment of lisdexamfetamine on executive function in rats: A translational cognitive research.

Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: a medium-term evaluation of cost benefits.

BACKGROUND: We earlier reported an open study of 50 unipolar and bipolar treatment resistant depressed patients indicating that psychostimulants may have differential superiority for the melancholic depressive sub-type. We designed an extension study to examine cost benefits of psychostimulants more closely for those only with melancholic depression. METHOD: The sample comprised patients clinically diagnosed with melancholic depression who had failed to respond to and/or experienced significant side-effects with at least two antidepressants. Data were collected for 61 unipolar and 51 bipolar II patients receiving a psyschostimulant for a mean interval of 69 weeks. Benefits and side-effects were assessed. RESULTS: Effectiveness ratings were similar across unipolar and bipolar sub-sets. Psychostimulants were judged as 'very' effective for 20% of patients and 'somewhat' effective for 50%. Forty percent judged the psychostimulant as being 'as effective' or as 'superior' to previously prescribed antidepressants, and worthy of being maintained. Significant side-effects were experienced by 40% of patients, requiring medication to be ceased in 12%. Twenty percent of the bipolar patients experienced a worsening of highs. LIMITATIONS: The study was uncontrolled and retrospective, no formal rater-completed or patient-completed interval measures of severity were completed, while diagnostic judgments about melancholic depression and bipolar disorder were clinically judged. CONCLUSIONS: This open study suggests that psychostimulants may be efficacious antidepressant options for managing unipolar and bipolar melancholia, often seemingly having very rapid onset and generally requiring only low doses, and arguing the need for controlled studies in melancholic patients.

Behavioral assessment of high-dose amphetamine withdrawal: importance of training and testing conditions.

Chronic d-amphetamine-treated rats were given twice daily injections at a dose of 7.5 mg/kg for 2 weeks. Acute amphetamine and saline groups of rats were given saline treatments during this time, except that for the acute group the final injection was 7.5 mg/kg d-amphetamine. Acute and chronic amphetamine groups habituated to the locomotor activity testing apparatus showed increases in both distance traveled and repetitive movement time that lasted up to 6 h following the final injection. When animals were not habituated to the activity test apparatus, however, a significant decrease in repetitive movement time was noted for the chronic amphetamine group 24-54 h following the final amphetamine injection; no differences were observed for distance traveled when the locomotor activity apparatus was novel. Swim test immobility time was assessed twice following the last injection, with the second test following the first by approximately 24 h. During the first test, decreases in immobility were observed for both chronic and acute amphetamine groups, 6-12 h following the last injection. However, during the second test, decreases in immobility time were observed only for the chronic amphetamine groups 36-72 h following the final injection. These results indicate that 24 to 72 h after the end of the chronic amphetamine regimen a withdrawal effect was observed for both repetitive movement time in the locomotor activity test and immobility time in the swim test. The withdrawal effect was observed only for the locomotor activity groups for whom the test apparatus was novel, and only during the second test of immobility time for the swim test groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Methods for the assessment of abuse liability of psychomotor stimulants and anorectic agents in humans.

Although stimulant drugs have been available and abused for centuries, it is only recently that procedures for evaluating their liability for abuse have been developed. This methodological development relies on several converging assessment procedures, combining to reveal the resultant profile of effects. The first of these, drug self-administration, is based on the principle that those drugs which can serve as reinforcers, maintaining behavior leading to their delivery, have a high liability for abuse. In addition, the more traditional approach to measuring abuse liability has been through assessing self-reported effects in which standardized questionnaires are used. A variant of this, a drug 'liking' scale has also been used. A third focus of measurement has been the accuracy with which subjects can identify the drug they have been administered, with some laboratories developing procedures for training subjects to discriminate specific substances. The profile of effects obtained with a specific compound can then be compared to the profile obtained with prototypic stimulants such as amphetamine or cocaine. The extent to which these profiles are similar would predict relative liability for abuse. This paper describes the data collected for amphetamine and concludes that the most accurate assessment of abuse liability is obtained when an unknown drug is compared to a drug with abuse liability using as many of these measures as possible.