Cytogenetic Effects of Chronic Methylphenidate Treatment and Chronic Social Stress in Adults with Attention-Deficit/Hyperactivity Disorder

S. Kittel-Schneider; S. Spiegel; T. Renner; M. Romanos; A. Reif; S. Reichert; J. Heupel; L. Schnetzler; H. Stopper; C. Jacob

doi:10.1055/s-0035-1569361

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2016; 49(04): 146-154
DOI: 10.1055/s-0035-1569361

Original Paper

Cytogenetic Effects of Chronic Methylphenidate Treatment and Chronic Social Stress in Adults with Attention-Deficit/Hyperactivity Disorder

S. Kittel-Schneider

¹Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany

^*S. Spiegel and S. Kittel-Schneider are shared first authors

,

S. Spiegel

²Institute of Toxikology, University of Würzburg, Würzburg, Germany

^*S. Spiegel and S. Kittel-Schneider are shared first authors

,

T. Renner

³Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Tübingen, Tübingen, Germany

,

M. Romanos

⁴Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany

,

A. Reif

¹Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany

,

S. Reichert

⁴Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany

,

J. Heupel

⁴Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany

,

L. Schnetzler

¹Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany

,

H. Stopper

²Institute of Toxikology, University of Würzburg, Würzburg, Germany

^#H. Stopper and C. Jacob are shared last authors

,

C. Jacob

⁵Department of Psychiatry and Psychotherapy, Hospital of Nürtingen, Nürtingen, Germany

^#H. Stopper and C. Jacob are shared last authors

› Author Affiliations

Abstract

Introduction: Methylphenidate (MPH) is widely used to treat childhood and adult attention-deficit/hyperactivity disorder (ADHD). However, there are still safety concerns about side effects in long-term treatment. The aim of this study was to assess cytogenetic effects of chronic MPH treatment in adult ADHD and to find out if chronic social stress is attenuated by medication and to investigate whether chronic psychosocial stress leads to mutagenic effects by itself.

Methods: Lymphocytes for micronucleus assay and saliva samples for cortisol measurement were collected from adult ADHD patients and healthy controls. Stress exposure of the last 3 months was assessed by TICS (Trier Inventory for Chronic Stress).

Results: We could not detect an influence of MPH treatment on cytogenetic markers. ADHD patients displayed significantly higher chronic stress levels measured by TICS compared to healthy controls which were influenced by duration of MPH treatment. ADHD patients also showed significantly lower basal cortisol levels.

Discussion: We could corroborate that there are neither cytogenetic effects of chronic stress nor of chronic MPH intake even after several years of treatment.

Key words

stress - adult attention-deficit/hyperactivity disorder - cortisol

Full Text

References

References
1 Faraone SV, Sergeant J, Gillberg C et al. The worldwide prevalence of ADHD: is it an American condition?. World Psychiatry 2003; 2: 104-113
2 Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 2005; 57: 1215-1220
3 Biederman J, Petty CR, Woodworth KY et al. Adult outcome of attention-deficit/hyperactivity disorder: a controlled 16-year follow-up study. J Clin Psychiatry 2012; 73: 941-950
4 Kessler RC, Adler L, Barkley R et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006; 163: 716-723
5 Kessler RC, Berglund P, Demler O et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593-602
6 Jacob CP, Romanos J, Dempfle A et al. Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 2007; 257: 09-317
7 Jacob CP, Gross-Lesch S, Reichert S et al. Sex- and subtype-related differences of personality disorders (Axis II) and personality traits in persistent ADHD. J Atten Disord 2014;
8 Gross-Lesch S, Dempfle A, Reichert S et al. Sex- and subtype-related differences in the comorbidity of adult ADHDs. J Atten Disord 2013;
9 Isaksson J, Nilsson KW, Nyberg F et al. Cortisol levels in children with attention-deficit/hyperactivity disorder. J Psychiatr Res 2012; 46: 1398-1405
10 Freitag CM, Hanig S, Palmason H et al. Cortisol awakening response in healthy children and children with ADHD: impact of comorbid disorders and psychosocial risk factors. Psychoneuroendocrinology 2009; 34: 1019-1028
11 Wilson CB, Ebenezer PJ, McLaughlin LD et al. Predator exposure/psychosocial stress animal model of post-traumatic stress disorder modulates neurotransmitters in the rat hippocampus and prefrontal cortex. PLoS One 2014; 9: e89104
12 Lataster J, Collip D, Ceccarini J et al. Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: a positron emission tomography study using [(1)(8)F]fallypride. Neuroimage 2011; 58: 1081-1089
13 Lucas LR, Wang CJ, McCall TJ et al. Effects of immobilization stress on neurochemical markers in the motivational system of the male rat. Brain Res 2007; 1155: 108-115
14 Suridjan I, Boileau I, Bagby M et al. Dopamine response to psychosocial stress in humans and its relationship to individual differences in personality traits. J Psychiatr Res 2012; 46: 890-897
15 Mizrahi R, Suridjan I, Kenk M et al. Dopamine response to psychosocial stress in chronic cannabis users: a PET study with [11C]-+-PHNO. Neuropsychopharmacology 2013; 38: 673-682
16 Prather AA, Epel ES, Arenander J et al. Longevity factor klotho and chronic psychological stress. Transl Psychiatry 2015; 5: e585
17 Fiedorowicz JG, Jancic D, Potash JB et al. Vascular mortality in participants of a bipolar genomics study. Psychosomatics 2014; 55: 485-490 Epub 2014 Feb 6
18 Casey DA, Rodriguez M, Northcott C et al. Schizophrenia: medical illness, mortality, and aging. Int J Psychiatry Med 2011; 41: 245-251
19 Black DW, Warrack G, Winokur G. Excess mortality among psychiatric patients. The Iowa Record-Linkage Study. JAMA 1985; 253: 58-61
20 Spencer TJ, Faraone SV, Tarko L et al. Attention-deficit/hyperactivity disorder and adverse health outcomes in adults. J Nerv Ment Dis 2014; 202: 725-731
21 Dalsgaard S, Ostergaard SD, Leckman JF et al. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015; 385: 2190-2196
22 Mikolajczyk R, Horn J, Schmedt N et al. Injury prevention by medication among children with attention-deficit/hyperactivity disorder: a case-only study. JAMA Pediatr 2015; 169: 391-395
23 Bihlar Muld B, Jokinen J, Bolte S et al. Long-term outcomes of pharmacologically treated versus non-treated adults with ADHD and substance use disorder: a naturalistic study. J Subst Abuse Treat 2015; 51: 82-90
24 El-Zein RA, Abdel-Rahman SZ, Hay MJ et al. Cytogenetic effects in children treated with methylphenidate. Cancer Lett 2005; 230: 284-291
25 Walitza S, Werner B, Romanos M et al. Does methylphenidate cause a cytogenetic effect in children with attention deficit hyperactivity disorder?. Environ Health Perspect 2007; 115: 936-940
26 Stopper H, Walitza S, Warnke A et al. Brief review of available evidence concerning the potential induction of genomic damage by methylphenidate. J Neural Transm 2008; 115: 331-334
27 Walitza S, Kampf K, Artamonov N et al. No elevated genomic damage in children and adolescents with attention deficit/hyperactivity disorder after methylphenidate therapy. Toxicol Lett 2009; 184: 38-43
28 Walitza S, Kampf K, Oli RG et al. Prospective follow-up studies found no chromosomal mutagenicity of methylphenidate therapy in ADHD affected children. Toxicol Lett 2010; 193: 4-8
29 Stopper H, Schupp N, Fazeli G et al. Genotoxicity of the neurotransmitter dopamine in vitro. Toxicol In Vitro 2009; 23: 640-646
30 Howard CD, Daberkow DP, Ramsson ES et al. Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling. Eur J Neurosci 2013; 38: 2078-2088
31 Peraile I, Granado N, Torres E et al. Cocaine potentiates MDMA-induced oxidative stress but not dopaminergic neurotoxicity in mice: implications for the pathogenesis of free radical-induced neurodegenerative disorders. Psychopharmacology (Berl) 2013; 230: 125-135
32 MSR First, Gibbon M, Williams J. Structured Clinical Interview for DSM-IVTR Axis I Disorders. Biometrics Research, New York State Psychiatric Institute 2002 Research version, Non-patient Edition (SCID-I/NP)
33 Christiansen H, Kis B, Hirsch O et al. German validation of the Conners Adult ADHD Rating Scales (CAARS) II: reliability, validity, diagnostic sensitivity and specificity. Eur Psychiatry 2012; 27: 321-328
34 Retz-Junginger P, Retz W, Blocher D et al. Wender Utah rating scale. The short-version for the assessment of the attention-deficit hyperactivity disorder in adults. Nervenarzt 2002; 73: 830-838
35 Margraf J. Diagnostisches Kurzinterview bei psychischen Störungen: Mini-DIPS. Berlin Heidelberg New York: Springer Verlag; 1994
36 Schulz PSW, Becker P. TICS: Trierer Inventar zum chronischen Stress. Hogrefe, Göttingen; Bern, Toronto, Seattle: 2004
37 Fenech M, Chang WP, Kirsch-Volders M et al. HUMN project: detailed description of the scoring criteria for the cytokinesis-block micronucleus assay using isolated human lymphocyte cultures. Mutat Res 2003; 534: 65-75
38 Faul F, Erdfelder E, Lang AG et al. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007; 39: 175-191
39 Morris SM, Petibone DM, Lin WJ et al. The genetic toxicity of methylphenidate: a review of the current literature. J Appl Toxicol 2012; 32: 756-764
40 Bonassi S, Fenech M, Lando C et al. Human MicroNucleus project: international database comparison for results with the cytokinesis-block micronucleus assay in human lymphocytes: I. Effect of laboratory protocol, scoring criteria, and host factors on the frequency of micronuclei. Environ Mol Mutagen 2001; 37: 31-45
41 Senthilkumar CS, Akhter S, Malla TM et al. Increased micronucleus frequency in peripheral blood lymphocytes contributes to cancer risk in the methyl isocyanate-affected population of Bhopal. Asian Pac J Cancer Prev 2015; 16: 4409-4419
42 Nefic H, Handzic I. The effect of age, sex, and lifestyle factors on micronucleus frequency in peripheral blood lymphocytes of the Bosnian population. Mutat Res 2013; 753: 1-11
43 Migliore L, Parrini M, Sbrana I et al. Micronucleated lymphocytes in people occupationally exposed to potential environmental contaminants: the age effect. Mutat Res 1991; 256: 13-20
44 Di Giorgio C, De Meo MP, Laget M et al. The micronucleus assay in human lymphocytes: screening for inter-individual variability and application to biomonitoring. Carcinogenesis 1994; 15: 313-317
45 Karaman A, Aydin H, Geckinli B et al. DNA damage is increased in lymphocytes of patients with metabolic syndrome. Mutat Res Genet Toxicol Environ Mutagen 2015; 782: 30-35
46 Donmez-Altuntas H, Sahin F, Bayram F et al. Evaluation of chromosomal damage, cytostasis, cytotoxicity, oxidative DNA damage and their association with body-mass index in obese subjects. Mutat Res Genet Toxicol Environ Mutagen 2014; 771: 30-36
47 Brod M, Pohlman B, Lasser R et al. Comparison of the burden of illness for adults with ADHD across seven countries: a qualitative study. Health Qual Life Outcomes 2012; 10: 47
48 Brod M, Schmitt E, Goodwin M et al. ADHD burden of illness in older adults: a life course perspective. Qual Life Res 2012; 21: 795-799
49 Hirvikoski T, Lindholm T, Nordenstrom A et al. High self-perceived stress and many stressors, but normal diurnal cortisol rhythm, in adults with ADHD (attention-deficit/hyperactivity disorder). Horm Behav 2009; 55: 418-424
50 Lackschewitz H, Huther G, Kroner-Herwig B. Physiological and psychological stress responses in adults with attention-deficit/hyperactivity disorder (ADHD). Psychoneuroendocrinology 2008; 33: 612-624
51 Raz S, Leykin D. Psychological and cortisol reactivity to experimentally induced stress in adults with ADHD. Psychoneuroendocrinology 2015; 60: 7-17
52 Wender PH, Reimherr FW, Marchant BK et al. A one year trial of methylphenidate in the treatment of ADHD. J Atten Disord 2011; 15: 36-45
53 Marchant BK, Reimherr FW, Robison RJ et al. Methylphenidate transdermal system in adult ADHD and impact on emotional and oppositional symptoms. J Atten Disord 2011; 15: 295-304
54 Lee MS, Yang JW, Ko YH et al. Effects of methylphenidate and bupropion on DHEA-S and cortisol plasma levels in attention-deficit hyperactivity disorder. Child Psychiatry Hum Dev 2008; 39: 201-209
55 Halmoy A, Fasmer OB, Gillberg C et al. Occupational outcome in adult ADHD: impact of symptom profile, comorbid psychiatric problems, and treatment: a cross-sectional study of 414 clinically diagnosed adult ADHD patients. J Atten Disord 2009; 13: 175-187
56 Biederman J, Monuteaux MC, Spencer T et al. Do stimulants protect against psychiatric disorders in youth with ADHD? A 10-year follow-up study. Pediatrics 2009; 124: 71-78
57 Gonzalez-Cabrera J, Fernandez-Prada M, Iribar-Ibabe C et al. Acute and chronic stress increase salivary cortisol: a study in the real-life setting of a national examination undertaken by medical graduates. Stress 2014; 17: 149-156
58 Hong HJ, Shin DW, Lee EH et al. Hypothalamic-pituitary-adrenal reactivity in boys with attention deficit hyperactivity disorder. Yonsei Med J 2003; 44: 608-614
59 Pesonen AK, Kajantie E, Jones A et al. Symptoms of attention deficit hyperactivity disorder in children are associated with cortisol responses to psychosocial stress but not with daily cortisol levels. J Psychiatr Res 2011; 45: 1471-1476
60 Yehuda R, Engel SM, Brand SR et al. Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 2005; 90: 4115-4118
61 Moss HB, Vanyukov M, Yao JK et al. Salivary cortisol responses in prepubertal boys: the effects of parental substance abuse and association with drug use behavior during adolescence. Biol Psychiatry 1999; 45: 1293-1299
62 Burke AR, Miczek KA. Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacology (Berl) 2014; 231: 1557-1580
63 Chen YH, Lin XX, Chen H et al. The change of the cortisol levels in children with ADHD treated by methylphenidate or atomoxetine. J Psychiatr Res 2012; 46: 415-416
64 Pakdel R, Rashidy-Pour A. Microinjections of the dopamine D2 receptor antagonist sulpiride into the medial prefrontal cortex attenuate glucocorticoid-induced impairment of long-term memory retrieval in rats. Neurobiol Learn Mem 2007; 87: 385-390
65 Chamberlain SR, Muller U, Cleary S et al. Atomoxetine increases salivary cortisol in healthy volunteers. J Psychopharmacol 2007; 21: 545-549
66 Wang LJ, Huang YS, Hsiao CC et al. The trend in morning levels of salivary cortisol in children with ADHD during 6 months of methylphenidate treatment. J Atten Disord. 2012
67 Weizman R, Dick J, Gil-Ad I et al. Effects of acute and chronic methylphenidate administration on beta-endorphin, growth hormone, prolactin and cortisol in children with attention deficit disorder and hyperactivity. Life Sci 1987; 40: 2247-2252
68 Kirschbaum C, Wust S, Strasburger CJ. ‘Normal’ cigarette smoking increases free cortisol in habitual smokers. Life Sci 1992; 50: 435-442
69 Steptoe A, Ussher M. Smoking, cortisol and nicotine. Int J Psychophysiol 2006; 59: 228-235
70 Lillberg K, Verkasalo PK, Kaprio J et al. Stressful life events and risk of breast cancer in 10,808 women: a cohort study. Am J Epidemiol 2003; 157: 415-423
71 Price MA, Tennant CC, Butow PN et al. The role of psychosocial factors in the development of breast carcinoma: Part II. Life event stressors, social support, defense style, and emotional control and their interactions. Cancer 2001; 91: 686-697
72 Price MA, Tennant CC, Smith RC et al. The role of psychosocial factors in the development of breast carcinoma: Part I. The cancer prone personality. Cancer 2001; 91: 679-685
73 Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol 2004; 5: 617-625
74 Steel J, Carney M, Carr BI et al. The role of psychosocial factors in the progression of hepatocellular carcinoma. Med Hypotheses 2004; 62: 86-94
75 Spiegel D, Giese-Davis J. Depression and cancer: mechanisms and disease progression. Biol Psychiatry 2003; 54: 269-282
76 Ranchor AV, Sanderman R, Coyne JC. Invited commentary: personality as a causal factor in cancer risk and mortality – time to retire a hypothesis?. Am J Epidemiol 2010; 172: 386-388
77 Nakaya N, Tsubono Y, Hosokawa T et al. Personality and the risk of cancer. J Natl Cancer Inst 2003; 95: 799-805
78 Jokela M, Batty GD, Hintsa T et al. Is personality associated with cancer incidence and mortality? An individual-participant meta-analysis of 2156 incident cancer cases among 42,843 men and women. Br J Cancer 2014;
79 Laursen TM, Munk-Olsen T, Vestergaard M. Life expectancy and cardiovascular mortality in persons with schizophrenia. Curr Opin Psychiatry 2012; 25: 83-88
80 Chuang HT, Mansell C, Patten SB. Lifestyle characteristics of psychiatric outpatients. Can J Psychiatry 2008; 53: 260-266
81 Schernhammer ES, Laden F, Speizer FE et al. Night-shift work and risk of colorectal cancer in the nurses' health study. J Natl Cancer Inst 2003; 95: 825-828

Supplementary Material

Supporting Information