Effects of 12-Week Methylphenidate Treatment on Neurometabolism in Adult Patients with ADHD: The First Double-Blind Placebo-Controlled MR Spectroscopy Study.

Simon Maier,Esther Sobanski,Kathrin Nickel,Thomas Lange,Swantje Matthies,Dominique Endres,Volkmar Glauche,Ludger Tebartz Van Elst,Bernd Feige,Evgeniy Perlov,Katharina Domschke,Barbara Alm,Alexandra Philipsen

doi:10.3390/jcm9082601

Abstract

Attention deficit hyperactivity disorder (ADHD) is a frequent neurodevelopmental disorder that often persists into adulthood. Methylphenidate (MPH) is the first-line treatment for ADHD; however, despite its wide usage, little is known about its neurometabolic effects. Until now, no randomized and blinded clinical trials have been conducted addressing the neurometabolic signals of MPH administration in adults with ADHD. In the current study, the authors investigated how MPH intake and group psychotherapy (GPT) influence brain neurometabolism over the course of three months. The authors hypothesized a decrease in the anterior cingulate cortex (ACC) glutamate concentration following MPH administration. This study was part of a double-blind multicenter trial (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS)) investigating the effects of MPH and GPT in patients with adult ADHD. Using single-voxel magnetic resonance spectroscopy (MRS) of the pregenual ACC and the left cerebellar hemisphere (CHL), we investigated the concentration of glutamate plus glutamine (Glx), N-acetyl-aspartate, creatine, total choline containing compounds, and myo-inositol in patients before and after 12 weeks of treatment. Neither MPH nor GPT significantly influenced the Glx concentration or any of the other metabolite concentrations in the ACC and CHL after 12 weeks. Therefore, contrary to the hypothesis, no change in the prefrontal Glx signal was detected after MPH treatment. Given that MRS does not differentiate between glutamate in the synaptic cleft and in neuronal tissue, MPH-induced down-regulation of glutamatergic neurotransmission in the ACC might only affect the concentration of glutamate in the synaptic cleft, while the general availability of glutamate in the respective neuronal tissue might be unaffected by MPH intake. The observed lack of any MPH-induced normalization in metabolite concentrations is less surprising, considering that the baseline sample did not significantly differ from a healthy control group. Future studies of other regions, such as the basal ganglia, and the use of novel methods, such as whole brain MRS and multimodal imaging approaches, are necessary.

Highlights

Attention deficit hyperactivity disorder (ADHD) is a frequent neurodevelopmental disorder mainly diagnosed in childhood or adolescence [1,2]
In the magnetic resonance spectroscopy (MRS) part of the “Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study” (COMPAS) we investigated neurometabolite concentrations in the pregenual anterior cingulate cortex (ACC) and left cerebellar hemisphere (CHL)
More surprising was the lack of any changes in the glutamate + glutamine (Glx) signal since we had expected a decrease in the Glx concentration in response to MPH intake

Summary

Introduction

Attention deficit hyperactivity disorder (ADHD) is a frequent neurodevelopmental disorder mainly diagnosed in childhood or adolescence [1,2]. Despite the reduction in several symptoms with age, the persistence of some other symptoms into adulthood has brought ADHD into the focus of adult psychiatry [3,4,5]. Difficulties in maintaining attention, hyperactivity and impulsiveness are central symptoms of ADHD in childhood. In about 50% of patients, these symptoms disappear when they reach adulthood, so that the diagnostic criteria are no longer met [6,7]. In patients who are still seriously affected in adulthood, hyperactivity is often reduced, whereas attention deficits, emotional instability, and executive dysfunction persist and can lead to comorbid disorders such as anxiety, depression, and alcohol or drug abuse [1,8,9]. Multimodal treatment includes stimulant medication with methylphenidate (MPH), and psychotherapy and psychosocial interventions [2,7,11,12]

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Results

Discussion

Conclusion