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Neuropsychopharmacology : Official... May 2024The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced... (Randomized Controlled Trial)
Randomized Controlled Trial
The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, p < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (p < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [C]SCH23390 binding; rho = 0.22, p < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r = -0.68, p = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.
Topics: Humans; Male; Adult; Female; Brain; Positron-Emission Tomography; Magnetic Resonance Imaging; Dopamine; Methylphenidate; Double-Blind Method; Young Adult; Raclopride; Central Nervous System Stimulants; Receptors, Dopamine D1; Neural Pathways; Dopamine Antagonists; Brain Mapping
PubMed: 38326458
DOI: 10.1038/s41386-024-01803-8 -
Journal of Attention Disorders Mar 2024Stimulant medications are the main treatment for Attention Deficit Hyperactivity Disorder (ADHD), but overall treatment efficacy in adults has less than a 60% response...
OBJECTIVE
Stimulant medications are the main treatment for Attention Deficit Hyperactivity Disorder (ADHD), but overall treatment efficacy in adults has less than a 60% response rate. This study aimed to identify neural and cognitive markers predictive of longitudinal improvement in response to stimulant treatment in drug-naïve adults with ADHD.
METHOD
We used diffusion tensor imaging (DTI) and executive function measures with 36 drug-naïve adult ADHD patients in a prospective study design.
RESULTS
Structural connectivity (measured by fractional anisotropy, FA) in striatal regions correlated with ADHD clinical symptom improvement following stimulant treatment (amphetamine or methylphenidate) in better medication responders. A significant positive correlation was also found between working memory performance and stimulant-related symptom improvement. Higher pre-treatment working memory scores correlated with greater response.
CONCLUSION
These findings provide evidence of pre-treatment neural and behavioral markers predictive of longitudinal treatment response to stimulant medications in adults with ADHD.
Topics: Adult; Humans; Attention Deficit Disorder with Hyperactivity; Diffusion Tensor Imaging; Central Nervous System Stimulants; Prospective Studies; Methylphenidate; Amphetamine; Treatment Outcome; Cognition
PubMed: 38321936
DOI: 10.1177/10870547231222261 -
Frontiers in Psychiatry 2023Earlier studies exploring the value of executive functioning (EF) indices for assessing treatment effectiveness and predicting treatment response in...
Limited usefulness of neurocognitive functioning indices as predictive markers for treatment response to methylphenidate or neurofeedback@home in children and adolescents with ADHD.
INTRODUCTION
Earlier studies exploring the value of executive functioning (EF) indices for assessing treatment effectiveness and predicting treatment response in attention-deficit/hyperactivity disorder (ADHD) mainly focused on pharmacological treatment options and revealed rather heterogeneous results. Envisioning the long-term goal of personalized treatment selection and intervention planning, this study comparing methylphenidate treatment (MPH) and a home-based neurofeedback intervention (NF@Home) aimed to expand previous findings by assessing objective as well as subjectively reported EF indices and by analyzing their value as treatment and predictive markers.
METHODS
Children and adolescents ( = 146 in the per protocol sample) aged 7-13 years with a formal diagnosis of an inattentive or combined presentation of ADHD were examined. We explored the EF performance profile using the Conners Continuous Performance Task (CPT) and the BRIEF self-report questionnaire within our prospective, multicenter, randomized, reference drug-controlled NEWROFEED study with sites in five European countries (France, Spain, Switzerland, Germany, and Belgium). As primary outcome for treatment response, the clinician-rated ADHD Rating Scale-IV was used. Patients participating in this non-inferiority trial were randomized to either NF@home (34-40 sessions of TBR or SMR NF depending on the pre-assessed individual alpha peak frequency) or MPH treatment (ratio: 3:2). Within a mixed-effects model framework, analyses of change were calculated to explore the predictive value of neurocognitive indices for ADHD symptom-related treatment response.
RESULTS
For a variety of neurocognitive indices, we found a significant pre-post change during treatment, mainly in the MPH group. However, the results of the current study reveal a rather limited prognostic value of neurocognitive indices for treatment response to either NF@Home or MPH treatment. Some significant effects emerged for parent-ratings only.
DISCUSSION
Current findings indicate a potential value of self-report (BRIEF global score) and some objectively measured neurocognitive indices (CPT commission errors and hit reaction time variability) as treatment markers (of change) for MPH. However, we found a rather limited prognostic value with regard to predicting treatment response not (yet) allowing recommendation for clinical use. Baseline symptom severity was revealed as the most relevant predictor, replicating robust findings from previous studies.
PubMed: 38312916
DOI: 10.3389/fpsyt.2023.1331004 -
Child and Adolescent Psychiatry and... Feb 2024Sudan is a Northeast African country, with 61.7% of its population under 24 years. With a large youth population and significant cultural and linguistic diversity,...
BACKGROUND
Sudan is a Northeast African country, with 61.7% of its population under 24 years. With a large youth population and significant cultural and linguistic diversity, Sudan, like most low-income countries, has contributed minimal data to global child and adolescent mental health (CAMH) research. This study aimed to perform the first ever situational analysis of CAMH services and systems in Khartoum State, Sudan.
METHODS
The study focused on Khartoum state and covered the calendar years 2019 and 2020. Using the World Health Organization Assessment Instrument for Mental Health Systems (WHO-AIMS) version 2.2 adapted for CAMH, the study focused on the publically available data sources. Findings were described and presented in tables and figures using the WHO-AIMS template.
RESULTS
The situational analysis found no CAMH-specific policies, no separate budget for CAMH, and no supervising body for CAMH services in Khartoum. Three tertiary mental health hospitals provided CAMH services, all combined with adult mental health services. Essential medicines were available in all facilities, except methylphenidate available only in 3 central pharmacies. There was no free access to essential psychotropic drugs for children and adolescents except in emergency settings. Data about training to primary healthcare providers and the process of referral to specialized services were limited. A school mental health programme existed which provided early identification and management of CAMH problems in schools. The workforce was small and variable across all levels of care. No formal public health awareness campaigns and little evidence of formal intersectoral collaboration on CAMH were identified. A health information system existed, but no CAMH-specific items were reported. Among a handful of publications on CAMH, no national studies on CAMH were identified.
CONCLUSIONS
This situational analysis represented the first systematic collation of data and information about CAMH in Sudan. Findings highlighted some areas of strength, but also many gaps in CAMH services and systems. We acknowledge the need to complement the desktop analysis with in-depth data collection with stakeholders across multiple levels, but hope that this will serve as a first step towards strengthening CAMH services in Sudan and other low-income countries.
PubMed: 38310302
DOI: 10.1186/s13034-024-00707-1 -
European Archives of Psychiatry and... Jun 2024More knowledge is needed about long-term ADHD medication and symptom, daily functioning, comorbidity, and tolerability outcomes. This "Long-term Medication for ADHD... (Observational Study)
Observational Study
More knowledge is needed about long-term ADHD medication and symptom, daily functioning, comorbidity, and tolerability outcomes. This "Long-term Medication for ADHD (LMA) trial" was a prospective observational 2-year trial in children and adolescents aged 6-18 years (extension of 1-year trial). Participants met criteria for DSM-5 ADHD (inattentive or combined), with complex comorbidities; autism spectrum disorder (31%), autistic traits (24%), oppositional symptoms (59%), anxiety (32%), dyslexia/language disorder (16%), borderline intellectual functioning (17%). Medication was individually tailored and followed-up at clinical visits (1, 2, 3, 6, 12, 18, 24 months). Primary outcome: Clinical Global Impression-Severity and Improvement scales (CGI-S, CGI-I). Secondary outcomes: Investigator-rated ADHD-Rating Scale, Weiss Functional Impairment Rating Scale-Parent report (WFIRS-P; Family, School Learning and Behavior, Life Skills, Self-Concept, Social Activities, and Risky Activities domains), comorbidity symptoms and adverse events (AEs). One hundred twenty-eight participants were enrolled (1-year trial only n = 27, LMA trial n = 101). Of these 29 (23%) discontinued, mainly due to AEs (n = 7), moving (n = 7), or no longer needing medication (n = 6). Main AEs were poor appetite, low mood, anxiety, irritability, fatigue. Improvements from baseline to 2 years were large in CGI-S (effect size (ES) 2.28), ADHD-RS (ES 2.06), and moderate to large in WFIRS-P (ES total 0.73, learning 0.4, family 0.67). Overall, the trial showed robust and sustained improvements in ADHD symptom severity and daily functioning over a period of 2 years of ADHD medication in children and adolescents with ADHD and complex comorbidities. Most AEs were mild. Comorbidity symptoms were improved after 1 year, particularly oppositional symptoms, depression, and anxiety.
Topics: Humans; Child; Attention Deficit Disorder with Hyperactivity; Adolescent; Male; Female; Comorbidity; Central Nervous System Stimulants; Prospective Studies; Outcome Assessment, Health Care; Autism Spectrum Disorder; Methylphenidate
PubMed: 38280948
DOI: 10.1007/s00406-023-01744-1 -
Addiction Neuroscience Dec 2023Depression and attention deficit hyperactivity disorder are known to be comorbid. Treatment of these commonly coexisting diseases typically involves the combined...
BACKGROUND
Depression and attention deficit hyperactivity disorder are known to be comorbid. Treatment of these commonly coexisting diseases typically involves the combined prescription of methylphenidate (MP), a psychostimulant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI). MP and cocaine have similar mechanisms of action and this study examined the effects of chronic treatment of MP combined with FLX on cocaine consumption in rats.
METHODS
Four groups of rats received access to drinking solutions of water (control), MP (30/60 mg/kg/day), FLX (20 mg/kg/day), or the combination of MP (30/60 mg/kg/day) plus FLX (20 mg/kg/day), during 8 h per day for one month. Following these drug treatments, rats were allowed to self-administer cocaine for 14 days.
RESULTS
Our results showed that, during the first week of cocaine self-administration, the MP-treated rats had significantly greater numbers of active lever presses (plus 127%) and increased consumption of cocaine compared to the control rats. In contrast, during week two of cocaine self-administration, the rats treated with the MP + FLX combination showed significantly more lever presses (plus 198%) and significantly greater cocaine consumption (plus 84%) compared to the water controls.
CONCLUSION
Chronic oral treatment during adolescence with the combination of MP plus FLX resulted in increased cocaine use after 2 weeks of cocaine self-administration in rats. These novel findings suggest that the combined exposure to these two drugs chronically, during adolescence, may produce increased vulnerability towards cocaine abuse during young adulthood.
PubMed: 38274857
DOI: 10.1016/j.addicn.2023.100127 -
BMJ Neurology Open 2024Acute brain injury can lead to states of decreased consciousness, that is, disorder of consciousness (DoC). Detecting signs of consciousness early is vital for DoC...
Detecting signatures of consciousness in acute brain injury after stimulation with apomorphine and methylphenidate: protocol for a placebo-controlled, randomized, cross-over study.
INTRODUCTION
Acute brain injury can lead to states of decreased consciousness, that is, disorder of consciousness (DoC). Detecting signs of consciousness early is vital for DoC management in the intensive care unit (ICU), neurorehabilitation and long-term prognosis. Our primary objective is to investigate the potential of pharmacological stimulant therapies in eliciting signs of consciousness among unresponsive or low-responsive acute DoC patients.
METHODS
In a placebo-controlled, randomised, cross-over setting, we evaluate the effect of methylphenidate and apomorphine in 50 DoC patients with acute traumatic or non-traumatic brain injury admitted to the ICU. Patients are examined before and after administration of the trial drugs using (1) neurobehavioural scales to determine the clinical level of consciousness, (2) automated pupillometry to record pupillary responses as a signature for awareness and (3) near-infrared spectroscopy combined with electroencephalography to record neurovascular coupling as a measure for cortical activity. Primary outcomes include pupillary dilations and increase in cortical activity during passive and active paradigms.
ETHICS
The study has been approved by the ethics committee (Journal-nr: H-21022096) and follows the principles of the Declaration of Helsinki. It is deemed to pose minimal risks and to hold a significant potential to improve treatment options for DoC patients. If the stimulants are shown to enhance cortical modulation of pupillary function and neurovascular coupling, this would warrant a large multicentre trial to evaluate their clinical impact.
DISSEMINATION
Results will be available on EudraCT, clinicaltrialsregister.eu and published in an international peer-reviewed journal.
TRIAL REGISTRATION NUMBER
EudraCT Number: 2021-001453-31.
PubMed: 38268756
DOI: 10.1136/bmjno-2023-000584 -
BJPsych Open Jan 2024The efficacy of probiotics as a therapeutic alternative for attention-deficit hyperactivity disorder (ADHD) remain unclear. (Review)
Review
BACKGROUND
The efficacy of probiotics as a therapeutic alternative for attention-deficit hyperactivity disorder (ADHD) remain unclear.
AIMS
To investigate the effectiveness of probiotics for symptoms of ADHD and identify possible factors affecting their efficacy.
METHOD
Randomised placebo-controlled trials were identified through searching major databases from inception to April 2023, using the main keywords 'probiotics' and 'ADHD' without limitation on languages or geographic locations. The outcome of interest included improvement in total symptoms of ADHD, symptoms of inattention and hyperactivity/impulsivity, and drop-out rate. Continuous and categorical data were expressed as effect sizes based on standardised mean differences (SMDs) and odds ratios, respectively, with 95% confidence intervals.
RESULTS
Meta-analysis of seven trials involving 379 participants (mean age 10.37 years, range 4-18 years) showed no significant improvement in total symptoms of ADHD (SMD = 0.25; = 0.12), symptoms of inattention (SMD = 0.14; = 0.3) or hyperactivity/impulsivity (SMD = 0.08; = 0.54) between the probiotic and placebo groups. Despite non-significance on subgroup analyses, there was a large difference in effect size between studies using probiotics as an adjunct to methylphenidate and those using probiotics as supplementation (SMD = 0.84 0.07; = 0.16), and a moderate difference in effect size between studies using multiple strains of probiotics and those using single-strain regimens (SMD = 0.45 0.03; = 0.19).
CONCLUSIONS
Current evidence shows no significant difference in therapeutic efficacy between probiotics and placebos for treatment of ADHD symptoms. However, albeit statistically non-significant, higher therapeutic efficacies associated with multiple-strain probiotics or combining probiotics with methylphenidate may provide direction for further research.
PubMed: 38268113
DOI: 10.1192/bjo.2023.645 -
Progress in Neuro-psychopharmacology &... Apr 2024Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and...
Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and psychomotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2 receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attentional and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally induced attentional and psychomotor dysfunction in children more broadly.
Topics: Humans; Child; Adolescent; Rats; Animals; Methylphenidate; Manganese; Attention; Attention Deficit Disorder with Hyperactivity; Cognitive Dysfunction; Central Nervous System Stimulants
PubMed: 38266866
DOI: 10.1016/j.pnpbp.2024.110949 -
Cognitive, Affective & Behavioral... Apr 2024The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and...
The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.
Topics: Animals; Central Nervous System Stimulants; Atomoxetine Hydrochloride; Attention; Male; Rats; Methylphenidate; Nicotine; Amphetamine; Ketamine; Photic Stimulation; Adrenergic Uptake Inhibitors; Serial Learning; Reaction Time; Visual Perception; Rats, Sprague-Dawley
PubMed: 38253774
DOI: 10.3758/s13415-023-01152-x