Attention deficit/hyperactivity disorder is one of the most common neurodevelopmental disorders. The pathophysiology is thought to involve noradrenaline and dopamine. The role of dopamine transporter (DAT) was evaluated in imaging studies using mostly dopamine reuptake inhibitors. Atomoxetine is a selective noradrenaline reuptake inhibitor. Here we report the results of a pilot study conducted to evaluate changes in striatal DAT after 8 weeks of atomoxetine treatment. Our results suggest that 8 weeks of atomoxetine treatment may change striatal DAT bioavailability as measured via SPECT but that change was not correlated with genotype or clinical improvement

Ali Evren Tufan

Aynur Pekcanlar Akay

Burak Baykara

Gamze Capa Kaya

Handan Özek

Hatice Durak

Mine Sencan Eren

Neslihan Inal Emiroglu

Sevay Alsen

Suha Miral

Turkan Ertay

Yesim Ozturk

Yusuf Demir

Neuropsychiatric Disease and Treatment

English

PubMed

Ozturk, Yesim

ÇAPA KAYA, GAMZE

ERTAY, TÜRKAN

BAYKARA, HÜSEYİN BURAK

AKAY, AYNUR

ALŞEN GÜNEY, SEVAY

Tufan, Evren

Durak, Hatice

Miral, Suha

Emiroglu, Neslihan Inal

Eren, Mine Sencan

Oezek, Handan

Demir, Yusuf

Dokuz Eylul University Research Information System

Atomoxetine treatment may decrease striatal dopaminergic transporter availability after 8 weeks: pilot SPECT report of three cases

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© 2015 Akay et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)  License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.phpNeuropsychiatric Disease and Treatment 2015:11 2909–2912Neuropsychiatric Disease and Treatment Dovepresssubmit your manuscript | www.dovepress.comDovepress 2909S h o rT  r e p o rTopen access to scientific and medical researchopen Access Full Text Articlehttp://dx.doi.org/10.2147/NDT.S87359Atomoxetine treatment may decrease striatal dopaminergic transporter availability after 8 weeks: pilot SpeCT report of three casesAynur pekcanlar Akay1Gamze Capa Kaya2,3Burak Baykara1Yusuf Demir2,3handan Özek1Sevay Alsen1Mine Sencan eren2,3Neslihan Inal emiroglu1Turkan ertay2,3Yesim ozturk4Suha Miral1hatice Durak2,3evren Tufan41Department of Child and Adolescent psychiatry, 2Department of Nuclear Medicine, 3Department of pediatrics, Dokuz eylul University Medical Faculty, Izmir, 4Department of Child and Adolescent psychiatry, Abant I.zzet Baysal University, Bolu, TurkeyAbstract: Attention deficit/hyperactivity disorder is one of the most common neurodevelop-mental disorders. The pathophysiology is thought to involve noradrenaline and dopamine. The role of dopamine transporter (DAT) was evaluated in imaging studies using mostly dopamine reuptake inhibitors. Atomoxetine is a selective noradrenaline reuptake inhibitor. Here we report the results of a pilot study conducted to evaluate changes in striatal DAT after 8 weeks of atomoxetine treatment. Our results suggest that 8 weeks of atomoxetine treatment may change striatal DAT bioavailability as measured via SPECT but that change was not correlated with genotype or clinical improvement.Keywords: neuroimaging, dopamine, noradrenaline, SLC6A3 protein, human, pragmatic clinical trial, pilot studyIntroductionCatecholaminergic neuro-transmission, especially involving dopamine (DA) and noradrenaline (NA), is thought to be mostly responsible for the pathogenesis of attention deficit/hyperactivity disorder (ADHD).1 The contribution of presynaptical dopamine transporter (DAT) has been suggested by imaging studies that evaluated the efficacy of treatment with DA reuptake inhibitors such as methylphenidate.2 Atomoxetine, a selective inhibitor of the presynaptic noradrenaline transporter, with a very low affinity for DAT is a nonstimulant approved for the treatment of ADHD.3 Because noradrenaline transporter is primarily responsible for the clearance of DA in prefrontal cortex, atomoxetine treatment increases both extracellular NA and DA in the prefrontal cortex, but NA in other regions.4 Although the effects of atomoxetine on striatal DAT function in rodents have been studied previously, data on patients is scarce.5 Here, we report post-treatment changes in Tc-99m TRODAT-1 brain SPECT of three adolescents (one of whom was female aged 158 months with ADHD inatten-tive type; two were male aged 167 and 175 months with ADHD combined type) who received atomoxetine treatment for 8 weeks.Patients and methodsThe patients were selected from adolescent (12–17 years old) patients with suspected ADHD who applied to the Child and Adolescent Psychiatry Outpatient Department of Dokuz Eylul University Medical Faculty between December 2013 and February 2014. The patients had to be treatment naïve and free of medical, neurological, and psychiatric comorbidities. All prospective patients and parents were informed of the study procedures Correspondence: evren TufanDepartment of Child and Adolescent psychiatry, Abant I.zzet Baysal University, Golkoy, 14280 Bolu, TurkeyTel +90 532 526 9416email tevrenus@yahoo.comJournal name: Neuropsychiatric Disease and TreatmentArticle Designation: Short ReportYear: 2015Volume: 11Running head verso: Akay et alRunning head recto: Atomoxetine may decrease striatal DATDOI: http://dx.doi.org/10.2147/NDT.S87359 Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 137.108.70.14 on 21-Jan-2020For personal use only.Powered by TCPDF (www.tcpdf.org)                               1 / 1Neuropsychiatric Disease and Treatment 2015:11submit your manuscript | www.dovepress.comDovepress Dovepress2910Akay et aland only patients providing written assent whose parents provided written informed consent were included in the study. The study was approved by the Institutional Review Board of Dokuz Eylul University and all study procedures were in accordance with the Declarations of Helsinki and local laws and regulations. ADHD diagnoses were made based on DSM-IV-TR criteria via Turkish version of the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version, which was found to be valid and reliable previously.6 All patients were right handed and treatment-naïve with an IQ level .80 (confirmed with Turkish version of Wechsler Intelligence Scale for Children-Revised).7 Genotypes and atomoxetine doses of patients are listed in Table 1.Mean CGI-ADHD-severity for all patients was five (significantly impaired) at visit 1. Baseline Du Paul ADHD Questionnaire total scores were 28, 28, and 20, respectively. Neurological examinations, magnetic resonance imagings, and electrocardiograms were normal. After the baseline SPECT, each subject’s dose was individually titrated in accordance with the clinical response. Starting dose was 0.5 mg/kg titrated within 4 weeks up to 1.6 mg/kg. The patients were seen weekly at the dose adjustment phase, and then monthly. Height, weight, pulse, blood pressure, side effects, Du Paul ADHD Questionnaire, and CGI-ADHD-severity scale were assessed at visits.Tc-99m TRODAT-1 was obtained by the Institute of Nuclear Energy Research (Taipei, Taiwan). SPECT was performed at the baseline and at the 8th week (under treatment). Radiochemical purity of Tc-99m TRODAT-1 was exceeded 95% when tested by high-performance liquid chromatography. Three hours after the injection of 444-814 MBq Tc-99m TRODAT-1, brain images were obtained using a gamma camera (Philips Forte A–Z Gamma Camera, Holland, the Netherlands). The range of activi-ties for the tracer varied due to differing body weights of patients (range =38.5–73.0 kg). A total of 128 frames were acquired in 128×128 matrices, 30 s/frame, 1.46 zoom, and 360°. Transaxial slices were transformed into plane images. Regions of interest were drawn on the right and left basal ganglia and the localization of cerebellum as the background. The two consecutive transverse slices showing the highest uptake in the basal ganglia were selected. Mean counts per pixel were used. Mean corrected activity in the Table 1 Genotypes and atomoxetine dosages of patients in a pilot study to evaluate the effect of atomoxetine on striatal DAT availabilityPatient 1 Patient 2 Patient 3BaselineDAT 10/9 10 10DrD4 4/3 4 7/4CoMT G/G G/G G/AAtomoxetine (mg/day) 25 36 36endAtomoxetine (mg/day) 60 100 85Abbreviations: DAT, dopamine transporter; DrD4, dopamine receptor type 4; CoMT, catechol-o-methlytransferase.Figure 1 Tc-99m TroDAT-1 SpeCT image of one of the patients before (A) and after (B) treatment with atomoxetine. Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 137.108.70.14 on 21-Jan-2020For personal use only.Powered by TCPDF (www.tcpdf.org)                               1 / 1Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.comDovepress Dovepress2911Atomoxetine may decrease striatal DATbasal ganglia was calculated as follows: (basal ganglia-background)/background. The images were evaluated visually and semi-quantitatively as above the scalp activity, equivalent to scalp activity, and below the scalp activity by involvements observed in the basal ganglion. Wilcoxon signed-rank test and Spearman’s rank order correlation were used in analyses. P-value was set at 0.01.Results and conclusionIn the visual, semi-quantitative analysis (Figure 1), there was a decrease in baseline availability of DAT after 8 weeks of atomoxetine treatment in both right and left basal ganglia (pre =1.09±0.96 and post =0.97±0.11 for left basal ganglia, pre =1.05±0.13 and post =0.86±0.14 for right basal ganglia, P,0.01). Du Paul Total scores at end point were 18, 12, and 17, respectively. The effects of dopamine transporter 1, dopamine receptor type 4 and catechol-O-methlytransferase were explored with separate analyses, which were all nonsignificant (Wilcoxon signed-rank test, P.0.01). An exploratory analysis of correlation between CGI-S scores and DAT availability was not significant (Spearman’s rank order test, P.0.01).To conclude, in this pilot study, we observed that 8 weeks of treatment with atomoxetine may change DAT bioavail-ability as evaluated via Tc-99m-TRODAT-1, however, this change may not be affected by the genotype of patients and did not correlate with clinical improvement. These observa-tions should be interpreted as exploratory and hypothesis generating, rather than conclusions.Previously, it was reported that DAT binding was higher in adults with ADHD and the reduction in DAT binding with methylphenidate treatment correlated with clinical improvement.8 Also, genotype of patients was reported to affect the magnitude of DAT reduction in patients with ADHD receiving treatment.9 The discrepancy between our results and those reported previously may be due to differ-ing age ranges, treatments, and imaging characteristics of the patients.The sample size of this pilot trial was too small, and there was no control group to compare a placebo effect. Hetero-geneous subtypes of ADHD and sexes may also be limita-tions and our finding may also be an artifact. We believe the probable effect of atomoxetine on DAT availability should be evaluated with further studies.AcknowledgmentsThis study is partially supported by Dokuz Eylul University Research Committee, Fogarty MH/DD program, and the Institute of Nuclear Energy Research (INER, Taipei, Taiwan).Author contributionsAll authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in either drafting the article or revising it critically for important intellectual content; and gave final approval of the version to be published.DisclosureAPA is a member of the Advisory Board of Janssen and Lilly Pharmaceutical Companies, all other authors have no conflicts of interest to disclose.References1. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57:1313–1323.2. La Fougère C, Krause J, Krause KH, et al. Value of 99mTc-TRODAT-1 SPECT to predict clinical response to methylphenidate treatment in adults with attention deficit hyperactivity disorder. Nucl Med Commun. 2006;27(9):733–737.3. Heal DJ, Smith SL, Kulkarni RS, Rowley HL. New perspectives from microdialysis studies in freely-moving, spontaneously hypertensive rats on the pharmacology of drugs for the treatment of ADHD. Pharmacol Biochem Behav. 2008;90:184–197.4. Arnsten AF. Toward a new understanding of attention-deficit/hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs. 2009;23(Suppl 1):33–41.5. Del’Guidice T, Lemasson M, Etiévant A, et al. Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice. Psychopharmacology (Berl). 2014;231(1): 109–122.6. Gokler B, Unal F, Pehlivanturk B, Cengel Kultur E, Akdemir D, Taner Y. Okul Çağı Çocukları için Duygulanım Bozuklukları ve Şizofreni Görüşme Çizelgesi-Şimdi ve Yaşam boyu Şekli-Türkçe Uyarlamasının Geçerlik ve Güvenirliği. [Reliability and validity of schedule for affective disorders and schizophrenia for school age children-present and lifetime version – Turkish version (K-SADS-PL-T)]. Turkish J Child Adolesc Psychiatry. 2004;11:109–116.7. Savasir I, Sahin N. Wechsler Çocuklar İçin Zeka Ölçeği-Gözden Geçirilmiş Formu Elkitabı. [Manual for the Wechsler Intelligence Scale for Children – Revised (WISC-R)]. Ankara: Turkish Pscyhology Association Publications; 1995.8. Dresel S, Krause J, Krause KH, et al. Attention deficit hyperactivity dis-order: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med. 2000;27(10): 1518–1524.9. Szobot CM, Roman T, Hutz MH, et al. Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity. Synapse. 2011;65(2):154–159. Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 137.108.70.14 on 21-Jan-2020For personal use only.Powered by TCPDF (www.tcpdf.org)                               1 / 1Neuropsychiatric Disease and TreatmentPublish your work in this journalSubmit your manuscript here: http://www.dovepress.com/neuropsychiatric-disease-and-treatment-journalNeuropsychiatric Disease and Treatment is an international, peer-reviewed journal of clinical therapeutics and pharmacology focusing on concise rapid reporting of clinical or pre-clinical studies on a range of neuropsychiatric and neurological disorders. This journal is indexed on PubMed Central, the ‘PsycINFO’ database and CAS, and is the official journal of The International Neuropsychiatric  Association (INA). The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.Neuropsychiatric Disease and Treatment 2015:11submit your manuscript | www.dovepress.comDovepress DovepressDovepress2912Akay et al Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 137.108.70.14 on 21-Jan-2020For personal use only.Powered by TCPDF (www.tcpdf.org)                               1 / 1

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Atomoxetine treatment may decrease striatal dopaminergic transporter availability after 8 weeks: pilot SPECT report of three cases

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