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Background: Stimulant medication is commonly prescribed as treatment for attention-deficit/hyperactivity disorder (ADHD). While we previously found that short-term stimulant-treatment influences apparent cortical thickness development in an age-dependent manner, it remains unknown whether these effects persist throughout development into adulthood. Purpose: Investigate the long-term age-dependent effects of stimulant medication use on apparent cortical thickness development in adolescents and adults previously diagnosed with ADHD. Methods: This prospective study included the baseline and 4-year follow-up assessment of the "effects of Psychotropic drugs On the Developing brain-MPH" ("ePOD-MPH") project, conducted between June-1-2011 and December-28-2019. The analyses were pre-registered (https://doi.org/10.17605/OSF.IO/32BHF). T1-weighted MR scans were obtained from male adolescents and adults, and cortical thickness was estimated for predefined regions of interest (ROIs) using Freesurfer. We determined medication use and assessed symptoms of ADHD, anxiety, and depression at both time points. Linear mixed models were constructed to assess main effects and interactions of stimulant medication use, time, and age group on regional apparent cortical thickness. Results: A total of 32 male adolescents (aged mean ± SD, 11.2 ± 0.9 years at baseline) and 24 men (aged mean ± SD, 29.9 ± 5.0 years at baseline) were included that previously participated in the ePOD-MPH project. We found no evidence for long-term effects of stimulant medication use on ROI apparent cortical thickness. As expected, we did find age-by-time interaction effects in all ROIs (left prefrontal ROI: P=.002, right medial and posterior ROIs: P<.001), reflecting reductions in apparent cortical thickness in adolescents. Additionally, ADHD symptom severity (adolescents: P<.001, adults: P=.001) and anxiety symptoms (adolescents: P=0.03) were reduced, and more improvement of ADHD symptoms was associated with higher medication use in adults (P=0.001). Conclusion: We found no evidence for long-term effects of stimulant-treatment for ADHD on apparent cortical thickness development in adolescents and adults. The identified age-dependent differences in apparent cortical thickness development are consistent with existing literature on typical cortical development.
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Methylphenidate (MPH) is the first-choice pharmacological treatment for treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) across the lifespan. However, it is unclear whether MPH affects cognitive development, while recent (pre-) clinical studies suggest effects on the developing brain. The present randomized, placebo-controlled trial aims to determine whether MPH has short-term, age-dependent effects on cognitive performance in ADHD after a 1-week washout. Effects of 16 weeks MPH treatment were assessed after a one-week washout on cognitive functioning. Boys (age=10-12) and men (age=23-40) with ADHD were assigned to MPH treatment (boys n=25, men n=24) or placebo (boys n=25, men n=24). Outcome measures were working memory, response inhibition, response speed, episodic memory, and delay aversion. Differences in task performances over time (pre-, mid-, and post-treatment, following a 1-week wash-out) were compared between age and treatment conditions with mixed ANOVAs. MPH improved working memory and response speed, but only during treatment. No lasting age*treatment effects were observed post intervention. Overall, the results from the present randomized, placebo-controlled trial show that the effects of MPH on cognition do not extend past treatment in children or adults. While treatment with MPH improves cognition during treatment, these effects appear transient after 16-weeks of treatment. (Title trial: "Effects of methylphenidate on the developing brain"; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3103).
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Trastorno por Déficit de Atención con Hiperactividad , Estimulantes del Sistema Nervioso Central , Metilfenidato , Adulto , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/psicología , Estimulantes del Sistema Nervioso Central/farmacología , Niño , Cognición , Método Doble Ciego , Humanos , Masculino , Metilfenidato/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
Background: Problems with emotional processing are widely reported in individuals with attention-deficit/hyperactivity disorder (ADHD). Although methylphenidate (MPH) effectively alleviates inattention and hyperactivity symptoms in ADHD, its effects on emotional processing and internalizing symptoms have remained elusive. While we previously found that acute MPH administration modulated neural mechanisms underlying emotional processing in an age-dependent manner, the effects of prolonged administration remained unknown. Objectives: Therefore, we investigated: (i) whether prolonged MPH treatment influences neural substrates (amygdala reactivity and connectivity) of emotional processing, and (ii) whether these effects are modulated by age. Methods: The "effects of Psychotropic drugs On Developing brain-MPH" ("ePOD-MPH") randomized controlled trial was a 16-week double-blind, placebo-controlled, multi-center trial with MPH in 50 boys (10-12 years of age) and 49 men (23-40 years of age), all stimulant treatment-naive and diagnosed with ADHD. Participants performed an emotional face-matching task during functional magnetic resonance imaging. We assessed their symptoms of ADHD and internalizing symptoms at baseline, during the trial (8 weeks), and 1 week after the trial end (17 weeks). Results and Conclusions: We did not find effects of prolonged MPH treatment on emotional processing, as measured by amygdala reactivity and connectivity and internalizing symptoms in this trial with stimulant treatment-naive participants. This differs from our findings on emotional processing following acute MPH administration and the effects of prolonged MPH treatment on the dopamine system, which were both modulated by age. Interestingly, prolonged MPH treatment did improve ADHD symptoms, although depressive and anxiety symptoms showed a medication-independent decrease. Furthermore, our data indicate that baseline internalizing symptoms may be used to predict MPH treatment effects on ADHD symptoms, particularly in (male) adults with ADHD.
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We examined if manualized cognitive behavioral therapy (CBT) was more effective than Treatment As Usual (TAU) for clinically depressed adolescents within routine care. This multisite Randomized controlled trail included 88 clinically depressed adolescents (aged 12-21 years) randomly assigned to CBT or TAU. Multiple assessments (pre-, post treatment and six-month follow-up) were done using semi-structured interviews, questionnaires and ratings and multiple informants. The primary outcome was depressive or dysthymic disorder based on the KSADS. Completers, CBT (n = 19) and TAU (n = 26), showed a significant reduction of affective diagnoses at post treatment (76% versus 76%) and after six months (90% versus 79%). Intention-to-treat analyses on depressive symptoms showed that 41.6% within CBT and 31.8% within the TAU condition was below clinical cut-off at post treatment and after six-months, respectively 61.4% and 47.7%. No significant differences in self-reported depressive symptoms between CBT and TAU were found. No prediction or moderation effects were found for age, gender, child/parent educational level, suicidal criteria, comorbidity, and severity of depression. We conclude that CBT did not outperform TAU in clinical practice in the Netherlands. Both treatments were found to be suitable to treat clinically referred depressed adolescents. CBT needs further improvement to decrease symptom levels below the clinical cut-off at post treatment.
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Terapia Cognitivo-Conductual/métodos , Adolescente , Adulto , Niño , Humanos , Países Bajos , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
Methylphenidate (MPH) improves behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Its effects on sleep, however, are insufficiently known, as trials with MPH in medication-naive children were so far restricted to relatively short trial durations. Here, we assessed effects of prolonged MPH treatment on sleep in medication-naive boys in a 16-weeks double-blind, placebo controlled, multicenter clinical trial with immediate-release MPH (ePOD-MPH trial, NTR3103). Seventy-five medication-naive boys, aged 10-12 years, were screened for eligibility using ADHD DSM-IV criteria. Sleep was assessed using actigraphy, diaries and questionnaires prior to randomization, in week 8, and 1 week after trial end. Fifty boys (mean age 11.4y, SD 0.9) were randomized to MPH or placebo. Linear mixed model analysis demonstrated a significant time-by-treatment interaction effect (p = 0.007) on sleep efficiency. Post-hoc analyses demonstrated that the two groups did not differ from each other (p = 0.94) during treatment (week 8), but that sleep efficiency was significantly improved in the MPH (p = 0.005), but not placebo group (p = 0.87) 1 week after trial end. The lack of MPH's negative effects on sleep during treatment differ from most previous studies and could be explained by the relatively long trial duration in our study and the medication-naive status of our sample; suggesting that evaluating sleep problems only shortly after treatment onset presents an incomplete picture, because it might not be representative for sleep quality after longer treatment periods. Our findings of improved sleep after trial end could be due to rebound effects or longer-term effects of MPH treatment and therefore require replication. CLINICAL TRIAL REGISTRATION: Central Committee on Research Involving Human Subjects (an independent registry, identifier NL34509.000.10) before enrollment of the first subject and The Netherlands National Trial Register, identifier NTR3103.
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Several diffusion tensor imaging (DTI) studies in attention deficit hyperactivity disorder (ADHD) have shown a delay in brain white matter (WM) development. Because these studies were mainly conducted in children and adolescents, these WM abnormalities have been assumed, but not proven to progress into adulthood. To provide further insight in the natural history of WM maturation delay in ADHD, we here investigated the modulating effect of age on WM in children and adults. 120 stimulant-treatment naive male ADHD children (10-12 years of age) and adults (23-40 years of age) with ADHD (according to DSM-IV; all subtypes) were included, along with 23 age and gender matched controls. Fractional anisotropy (FA) values were compared throughout the WM by means of tract-based spatial statistics (TBSS) and in specific regions of interest (ROIs). On both TBSS and ROI analyses, we found that stimulant-treatment naive ADHD children did not differ in FA values from control children, whereas adult ADHD subjects had reduced FA values when compared to adult controls in several regions. Significant age × group interactions for whole brain FA (p = 0.015), as well as the anterior thalamic radiation (p = 0.015) suggest that ADHD affects the brain WM age-dependently. In contrast to prior studies conducted in medicated ADHD children, we did not find WM alterations in stimulant treatment naïve children, only treatment-naïve adults. Thus, our findings suggest that the reported developmental delay in WM might appear after childhood, and that previously reported differences between ADHD children and normal developing peers could have been attributed to prior ADHD medications, and/or other factors that affect WM development, such as age and gender.
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Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , Imagen de Difusión Tensora , Sustancia Blanca/diagnóstico por imagen , Adulto , Factores de Edad , Análisis de Varianza , Anisotropía , Estudios de Casos y Controles , Niño , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Adulto JovenRESUMEN
In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant treatment-naive patients with ADHD (N = 35 boys; N = 46 men) and 23 healthy control subjects (N = 11 boys; N = 12 men). In ADHD patients, we also measured amygdala reactivity 90min after an acute oral challenge with MPH (0.5mg/kg). Mean amygdala reactivity was analyzed for all subjects using a repeated measures analysis of variance (ANOVA). Whole-brain maps were analyzed for the patients only. At baseline, we found a age*diagnosis effect approaching significance (p = 0.05) in the right amygdala due to lower reactivity in children with Attention Deficit/Hyperactivity Disorder (ADHD) vs. controls (-31%), but higher reactivity in adults with ADHD vs. controls (+31%). MPH significantly reduced right amygdala reactivity in all patients, resulting in further reductions in children. In the left amygdala, reduction of amygdala reactivity was confined to adult ADHD patients whereas there was no change in children with ADHD. MPH-induced decrease of amygdala reactivity in adults might be a promising avenue for managing emotional dysregulation when replicated for chronic MPH treatment.
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Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/diagnóstico por imagen , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/administración & dosificación , Metilfenidato/administración & dosificación , Adulto , Factores de Edad , Mapeo Encefálico/métodos , Niño , Método Doble Ciego , Emociones/efectos de los fármacos , Emociones/fisiología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Estimulación Luminosa/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
IMPORTANCE: Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. OBJECTIVES: To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status. INTERVENTIONS: Treatment with either methylphenidate or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses. RESULTS: Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03). CONCLUSIONS AND RELEVANCE: We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up. TRIAL REGISTRATION: identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Dopamina/metabolismo , Metilfenidato/uso terapéutico , Receptores Dopaminérgicos/efectos de los fármacos , Adulto , Factores de Edad , Niño , Cuerpo Estriado/irrigación sanguínea , Cuerpo Estriado/efectos de los fármacos , Método Doble Ciego , Giro del Cíngulo/irrigación sanguínea , Giro del Cíngulo/efectos de los fármacos , Humanos , Cuidados a Largo Plazo , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/irrigación sanguínea , Red Nerviosa/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Tálamo/irrigación sanguínea , Tálamo/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of different approaches to determine whether there are related findings in humans. METHODS/DESIGN: Animal studies were carried out to investigate age-related effects of psychotropic drugs and to validate new neuroimaging techniques. In addition, we set up two double-blind placebo controlled clinical trials with MPH in 50 boys (10-12 years) and 50 young men (23-40 years) suffering from ADHD (ePOD-MPH) and with FLX in 40 girls (12-14 years) and 40 young women (23-40 years) suffering from depression and anxiety disorders (ePOD-SSRI). Trial registration numbers are: Nederlands Trial Register NTR3103 and NTR2111. A cross-sectional cohort study on age-related effects of these psychotropic medications in patients who have been treated previously with MPH or FLX (ePOD-Pharmo) is also ongoing. The effects of psychotropic drugs on the developing brain are studied using neuroimaging techniques together with neuropsychological and psychiatric assessments of cognition, behavior and emotion. All assessments take place before, during (only in case of MPH) and after chronic treatment. DISCUSSION: The combined results of these approaches will provide new insight into the modulating effect of MPH and FLX on brain development.