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JAMA Psychiatry May 2024Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts...
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.
Topics: Humans; Female; Pregnancy; Central Nervous System Stimulants; Prenatal Exposure Delayed Effects; Child; Attention Deficit Disorder with Hyperactivity; Adolescent; Adult; Young Adult; United States; Neurodevelopmental Disorders; Methylphenidate; Autism Spectrum Disorder; Male; Middle Aged; Pregnancy Complications; Cohort Studies; Amphetamine; Dextroamphetamine; Medicaid
PubMed: 38265792
DOI: 10.1001/jamapsychiatry.2023.5073 -
Frontiers in Endocrinology 2023Children with acquired hypothalamic obesity, e.g. following treatment for pediatric craniopharyngioma are at great risk for metabolic syndrome, cardiovascular health... (Randomized Controlled Trial)
Randomized Controlled Trial
Children with acquired hypothalamic obesity, e.g. following treatment for pediatric craniopharyngioma are at great risk for metabolic syndrome, cardiovascular health problems and premature mortality. Treatment for acquired hypothalamic obesity has thus far been disappointing. Several interventions were reported to be partially successful, including dextro-amphetamine and GLP-1R agonists, although results in acquired hypothalamic obesity are conflicting. Disruption of signaling through the melanocortin-4 receptor (MC4R) pathway results in hyperphagia and severe early-onset hypothalamic obesity. Recently, the MC4R agonist setmelanotide has shown promising results in children with genetic forms of hypothalamic obesity; POMC, PCSK1 and LEPR. Patient quotes such as "we have our family life back" illustrate the magnitude of the effect. Targeted hormone replacement therapy with a MC4R agonist for acquired hypothalamic obesity could be a game-changer. Preliminary results of setmelanotide treatment in 14, mostly pediatric, patients with acquired hypothalamic obesity are promising. The FDA has recommended that a prospective, randomized, blinded trial be conducted over a 12 months treatment period, comparable to pivotal trials for other obesity drugs. It may be discussed whether setmelanotide should be regarded as an obesity drug or whether it may be envisioned as an agent for hypothalamic substitution therapy. In this commentary we discuss the trial that is currently recruiting patients with acquired hypothalamic obesity.
Topics: Humans; Child; Prospective Studies; Obesity; alpha-MSH; Obesity, Morbid; Hypothalamic Diseases
PubMed: 38239988
DOI: 10.3389/fendo.2023.1307889 -
Journal of Pharmacy Practice Jan 2024Recent epidemiological data has shown a sharp increase in stimulant use among older adults, which is notable as older adults may be especially vulnerable to their...
Recent epidemiological data has shown a sharp increase in stimulant use among older adults, which is notable as older adults may be especially vulnerable to their cardiovascular effects. Results of recent studies have shown an increase in cardiovascular events among older adults using stimulants; however, little data exists comparing cardiovascular safety of these agents head-to-head. To determine if the incidence of serious cardiovascular events, including myocardial infarction (MI), stroke/transient ischemic attack (TIA), or arrhythmia, are different in patients taking amphetamine/dextroamphetamine compared with patients taking methylphenidate. Methods: Retrospective chart review of veterans 50 years and older at the Veterans Affairs North Texas Health Care System (VANTHCS) who were first prescribed a stimulant between 2015 and 2021. The primary outcome was the difference in composite cardiovascular events between amphetamine/dextroamphetamine and methylphenidate. Secondary outcomes were the composite cardiovascular endpoints compared individually (MI, stroke/TIA, or arrhythmia). Hazard ratios were calculated based off of a time-to-event analysis displayed using a Kaplan-Meier curve for primary and secondary outcomes. 466 veterans were screened for inclusion, 30 were excluded, and 436 were included. There was no difference found in composite cardiovascular events between the 241 veterans in the amphetamine/dextroamphetamine group and the 195 veterans in the methylphenidate group with 12 (5%) vs 8 (4.1%) events respectively ( = .6635). There was also no difference in time-to-event analysis ( = .4966). In elderly veterans, there was no difference found in incidence of major cardiovascular events with the use of amphetamine/dextroamphetamine compared with methylphenidate.
PubMed: 38237603
DOI: 10.1177/08971900241229111 -
Reproductive Sciences (Thousand Oaks,... May 2024Concerns have been raised about potentially irreversible brain damage and damage to the neuroendocrine system during development when treating...
Concerns have been raised about potentially irreversible brain damage and damage to the neuroendocrine system during development when treating attention-deficit/hyperactivity disorder with lisdexamfetamine (LDX), a norepinephrine dopamine reuptake inhibitor. This study aims to elucidate the potential adverse effects of LDX on the male reproductive system due to its widespread use and potential for abuse. In this study, adult male rats were randomized into control and LDX groups. Thirty milligrams per kilogram LDX was administered orally for 3 weeks. After isolation of epididymal spermatozoa, the rats were euthanized and testicular tissues were collected for stereological and molecular analyses. The LDX group showed a decrease in sperm motility and an increase in DNA fragmentation compared to the control group. There was also a dramatic decrease in testosterone in the LDX group. Testicular expression of caspase-3 and TNF-α was significantly increased in the LDX group. According to our findings, prolonged use of LDX leads to reduced sperm quality. It also induces apoptosis, inflammatory response, and pathological changes in the testicular tissue. What we have observed in this study is noteworthy but requires further investigation, particularly in people who use LDX over a longer period of time.
Topics: Animals; Male; Apoptosis; Spermatozoa; Lisdexamfetamine Dimesylate; Testis; Sperm Motility; Rats, Sprague-Dawley; Inflammation; Rats; Testosterone; DNA Fragmentation; Caspase 3
PubMed: 38228974
DOI: 10.1007/s43032-023-01449-9 -
Cognitive, Affective & Behavioral... Apr 2024Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during...
Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.
Topics: Amphetamine; Humans; Animals; Male; Electroencephalography; Adult; Young Adult; Double-Blind Method; Mice, Inbred C57BL; Motivation; Female; Central Nervous System Stimulants; Mice; Alpha Rhythm
PubMed: 38168850
DOI: 10.3758/s13415-023-01150-z -
Journal of Psychiatric Research Feb 2024ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related... (Randomized Controlled Trial)
Randomized Controlled Trial
Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement.
BACKGROUND
ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation.
METHODS
Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels.
RESULTS
Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri).
CONCLUSIONS
These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.
Topics: Adult; Humans; Lisdexamfetamine Dimesylate; Attention Deficit Disorder with Hyperactivity; Dextroamphetamine; Treatment Outcome; Double-Blind Method; Central Nervous System Stimulants; Decision Making
PubMed: 38101205
DOI: 10.1016/j.jpsychires.2023.11.037 -
Journal of Clinical Psychopharmacology
Topics: Humans; Lisdexamfetamine Dimesylate; Binge-Eating Disorder; Bipolar Disorder; Central Nervous System Stimulants; Treatment Outcome
PubMed: 38100783
DOI: 10.1097/JCP.0000000000001799 -
BMJ Open Dec 2023Attention deficit hyperactivity disorder (ADHD) affects 5%-10% of paediatric population and is reportedly more common in children with type 1 diabetes (T1D),...
Lisdexamphetamine versus methylphenidate for paediatric patients with attention-deficit hyperactivity disorder and type 1 diabetes (LAMAinDiab): protocol for a multicentre, randomised cross-over clinical trial in an outpatient telemedicine-supported setting.
INTRODUCTION
Attention deficit hyperactivity disorder (ADHD) affects 5%-10% of paediatric population and is reportedly more common in children with type 1 diabetes (T1D), exacerbating its clinical course. Proper treatment of ADHD in such patients may thus provide neurological and metabolic benefits. To test this, we designed a non-commercial second phase clinical trial comparing the impact of different pharmacological interventions for ADHD in children with T1D.
METHODS AND ANALYSIS
This is a multicentre, randomised, open-label, cross-over clinical trial in children and adolescents with ADHD and T1D. The trial will be conducted in four reference paediatric diabetes centres in Poland. Over 36 months, eligible patients with both T1D and ADHD (aged 8-16.5 years, T1D duration >1 year) will be offered participation. Patients' guardians will undergo online once-weekly training sessions behaviour management for 10 weeks. Afterward, children will be randomised to methylphenidate (long-release capsule, doses 18-36-54 mg) versus lisdexamphetamine (LDX, 30-50-70 mg). Pharmacotherapy will continue for 6 months before switching to alternative medication. Throughout the trial, the participants will be evaluated every 3 months by their diabetologist and online psychological assessments. The primary endpoint (ADHD symptom severity, Conners 3.0 questionnaire) will be assessed by a blinded investigator. Secondary endpoints will include HbA1c, continuous glucose monitoring indices and quality-of-life (PedsQL).
ETHICS AND DISSEMINATION
The trial is approved by Bioethical Committee at Medical University of Lodz and Polish regulatory agency (RNN/142/22/KE, UR/DBL/D/263/2022). The results will be communicated to the research and clinical community, and Polish agencies responsible for healthcare policy. Patient organisations focused on paediatric T1D will be notified by a consortium member. We hope to use the trial's results to promote collaboration between mental health professionals and diabetes teams, evaluate the economic feasibility of using LDX in patients with both diseases and the long run improve ADHD treatment in children with T1D.
TRIAL REGISTRATION NUMBERS
EU Clinical Trials Register (EU-CTR, 2022-001906-24) and NCT05957055.
Topics: Adolescent; Humans; Child; Attention Deficit Disorder with Hyperactivity; Methylphenidate; Lisdexamfetamine Dimesylate; Diabetes Mellitus, Type 1; Outpatients; Blood Glucose Self-Monitoring; Blood Glucose; Central Nervous System Stimulants; Treatment Outcome; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 38086595
DOI: 10.1136/bmjopen-2023-078112 -
Life (Basel, Switzerland) Nov 2023This review delves into the therapeutic applications of amphetamine-type stimulants such as lisdexamphetamine dimesylate, mixed amphetamine salts,... (Review)
Review
This review delves into the therapeutic applications of amphetamine-type stimulants such as lisdexamphetamine dimesylate, mixed amphetamine salts, 3,4-methylenedioxymethamphetamine (MDMA), dextroamphetamine, and phentermine. These compounds have been investigated for their potential in treating a range of psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), drug dependence, post-traumatic stress disorder (PTSD), and obesity. Lisdexamphetamine dimesylate has shown promise in effectively treating ADHD symptoms in both children and adults. Additionally, it has been explored as a potential treatment for drug dependency and withdrawal, demonstrating encouraging results. Mixed amphetamine salts have also exhibited efficacy in reducing ADHD symptoms in adults. Future research should explore their potential use in treating bipolar disorder and cocaine dependence, considering the associated risks and benefits. MDMA-assisted psychotherapy has emerged as an innovative approach to treating PTSD, leading to sustained reductions in symptoms and even promoting post-traumatic growth. Furthermore, it has shown promise in managing anxiety related to life-threatening illnesses. Dextroamphetamine and phentermine have demonstrated efficacy in treating cocaine and opioid dependence, ADHD, and obesity. However, careful consideration and monitoring by medical professionals are essential due to the potential risks and benefits associated with them. In conclusion, amphetamine-type stimulants present a promising avenue for therapeutic interventions in various psychiatric conditions. Nevertheless, further research is necessary to comprehensively understand their mechanisms of action, dosage requirements, and long-term effects in different patient populations.
PubMed: 38004320
DOI: 10.3390/life13112180 -
Biomedicine & Pharmacotherapy =... Dec 2023Intracranial self-stimulation (ICSS) of the medial forebrain bundle in mice is an experimental model use to assess the relative potential of reward-seeking behaviors....
Abused drug-induced intracranial self-stimulation is correlated with the alteration of dopamine transporter availability in the medial prefrontal cortex and nucleus accumbens of mice.
Intracranial self-stimulation (ICSS) of the medial forebrain bundle in mice is an experimental model use to assess the relative potential of reward-seeking behaviors. Here, we used the ICSS model to evaluate the abuse potential of 18 abused drugs: 3-Fluoroethamphetamine (3-FEA); methylphenidate; cocaine; dextroamphetamine; alpha-Pyrrolidinobutyrophenone (α-PBT); 4'-Fluoro-4-methylaminorex (4-FPO); methamphetamine; larocaine; phentermine; paramethoxymethamphetamine (PMMA); phendimetrazine; N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48); Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB-13); 4-Ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210); Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018); N-(ortho-methoxybenzyl)-4-ethylamphetamine (4-EA-NBOMe); N-[(2-Methoxyphenyl)methyl]-N-methyl-1-(4-methylphenyl)propan-2-amine (4-MMA-NBOMe); and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine (4-MeO-PCP). We determined dopamine transporter (DAT) availability in the medial prefrontal cortex (mPFC), striatum, and nucleus accumbens (NAc) after drug treatment. DAT availability in the mPFC and NAc significantly correlated with the ICSS threshold after drug treatment. Extracellular dopamine and calcium levels in PC-12 cells were measured following drug treatment. After drug treatment, Spearman rank and Pearson correlation analyses showed a significant difference between the extracellular dopamine level and the ICSS threshold. After drug treatment, Spearman rank correlation analysis showed a significant correlation between Ca signaling and the ICSS threshold. A positive correlation exists between the ICSS threshold and DAT availability in the mPFC and NAc provoked by abused drugs. The relative potential of drug-induced reward-seeking behavior may be related to DAT availability-mediated extracellular dopamine levels in the mPFC and NAc.
Topics: Animals; Mice; Dopamine; Dopamine Plasma Membrane Transport Proteins; Nucleus Accumbens; Prefrontal Cortex; Self Stimulation
PubMed: 37948992
DOI: 10.1016/j.biopha.2023.115860