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Methylphenidate toxicity after Roux-en-Y gastric bypass

2016; Elsevier BV; Volume: 12; Issue: 5 Linguagem: Inglês

10.1016/j.soard.2016.03.015

1878-7533

Magdalena Ludvigsson, Arvo Haenni,

Eating Disorders and Behaviors

Obesity, defined as body mass index (BMI)≥30 kg/m2, has become a global epidemic. Obesity is not only a burden per se but also associated with several co-morbidities, such as type 2 diabetes, cardiovascular diseases, and hypertension, and consequently has a high impact on healthcare expenditure. The most effective treatment of obesity, regarding long-term weight loss maintenance, is bariatric surgery, with laparoscopic Roux-en-Y gastric bypass (LRYGB) displaying the most consistent long-term results [[1]Obeid N.R. Malick W. Concors S.J. Fielding G.A. Kurian M.S. Ren-Fielding C.J. Long-term outcomes after Roux-en-Y gastric bypass: 10- to 13-year data.Surg Obes Relat Dis. 2016; 12: 11-22Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with childhood onset characterized by an enduring pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development. The worldwide prevalence of ADHD in adults is approximately 5% in most cultures, with a significant association between ADHD and overweight/obesity [2Polanczyk G. de Lima M.S. Horta B.L. Biederman J. Rohde L.A. The worldwide prevalence of ADHD: a systematic review and metaregression analysis.Am J Psychiatry. 2007; 164: 942-948Crossref PubMed Scopus (2241) Google Scholar, 3Cortese S. Moreira-Maia C.R. St Fleur D. Morcillo-Penalver C. Rohde L.A. Faraone S.V. Association between ADHD and obesity: a systematic review and meta-analysis.Am J Psychiatry. 2016; 173: 34-43Crossref PubMed Scopus (292) Google Scholar]. Regarding the treatment for ADHD, both pharmacologic and psychological interventions exist. The drugs used for treatment of ADHD may be divided into 2 groups: central nervous system (CNS) stimulants such as amphetamine and methylphenidate, and nonstimulants such as atomoxetine and clonidine [[4]Spiller H.A. Hays H.L. Aleguas Jr, A. Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management.CNS Drugs. 2013; 27: 531-543Crossref PubMed Scopus (76) Google Scholar]. Unfortunately, information regarding the effects of LRYGB on ADHD treatment is scant. We report a case of a 40-year-old man with morbid obesity and ADHD. He had been well maintained for>1 year on methylphenidate. Two weeks after LRYGB he became anxious, experienced insomnia, and described a state of paranoia and audial hallucinations, symptoms known to be clinical manifestations of methylphenidate overdose or toxicity [[4]Spiller H.A. Hays H.L. Aleguas Jr, A. Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management.CNS Drugs. 2013; 27: 531-543Crossref PubMed Scopus (76) Google Scholar]. The symptoms disappeared after termination of methylphenidate treatment. Using the keywords “methylphenidate” and “gastric bypass,” no relevant items were found in PubMed database. Although there is general information regarding the weight-lowering effects of CNS stimulants, there is scant information about how rapid weight loss or starvation might alter the medical effects of these drugs. A 40-year-old male patient with morbid obesity, and type 2 diabetes as a co-morbidity, was prescribed methylphenidate in slow-release capsules (Concerta®, Janssen-Cilag) in January 2013 on the indication of ADHD. One year later the dose was adjusted, from 54 mg in the morning and 18 mg at lunch to 54 mg in the morning and 36 mg at lunch, after which he reported an improvement in his ability to mentally focus as well as becoming more tranquil, although he reported some remaining concentration difficulties but also some hyperacusis. In April 2014, 15 months after starting methylphenidate treatment, the patient underwent LRYGB surgery at a total weight of 136 kg and BMI 41 kg/m2. The surgical procedures were uncomplicated, with a hospital stay of 2 days. Antithrombotic prophylaxis for self-administration was prescribed for 12 days of treatment. The patient was given the standard advice regarding meals, and multivitamin supplementation was prescribed. The dose of methylphenidate was unchanged over the surgery. Two weeks after LRYGB the patient asked for a consultation at the psychiatric emergency department because of insomnia and symptoms of stress. Sleeping pills were prescribed, but the methylphenidate dose was left unaltered. The patient himself lowered the dose of methylphenidate to 54 mg in the morning only. A couple of days later he consulted the psychiatric outpatient clinic because of a fear of his fiancée leaving him. The total weight loss after LRYGB was, at that point, 17 kg, 12.5%, representing an excess BMI loss of 31%. The patient told a psychologist about paranoid thoughts and mentioned that he had heard repeated nocturnal telephone signals that he found threatening. The patient was very anxious and agitated, and the administration of methylphenidate was terminated completely 20 days after the surgery. He was prescribed promethazine 50 mg in the evening and 25–50 mg as needed in addition to zopiclone at bedtime. After the termination of methylphenidate, the patient reported decreased intensity of anxiety, fading paranoid thoughts, and disappearance of the audial hallucinations. However, 2 weeks later he stated that the previous ADHD-associated symptoms had returned and therefore methylphenidate 36 mg twice daily was reintroduced; however, the same side effects of anxiety and paranoid thoughts returned, and methylphenidate treatment was interrupted. The patient was prescribed sertraline on the indication of depressive symptoms in the end of May 2014. Two months later, at the end of July 2014, the patient was prescribed the nonstimulant atomoxetine, 25 mg in the morning, on the indication of ADHD. The atomoxetine treatment did not have the same positive effect on concentration difficulties compared with the previously prescribed methylphenidate, even though the dose of atomoxetine was doubled. Because of side effects, including nausea and headaches, the atomoxetine dose was reduced, with insufficient effect on the ADHD-related symptoms. For that reason methylphenidate was prescribed again in November 2014, in a low dose, 18 mg every morning, in conjunction with psychologist treatment. After 3 months, in January 2015, the dose of methylphenidate was increased from 18 mg to 36 mg, with a further adjustment in April 2015, to 36 mg in the morning and 18 mg after lunch. In May 2015 the patient and his fiancée reported an improvement in functioning regarding the ADHD-related symptoms without any of the symptoms of insomnia, anxiety, paranoia, or audial hallucinations that he experienced previously when on a higher dose of methylphenidate. There were no indications of unintentional doses of methylphenidate. Neither were there any use of narcotic medications or any indications of alcohol or drug abuse. The patient did not report any difficulties in swallowing the methylphenidate slow-release capsules. This case may indicate new concerns regarding alterations in CNS-active drug action after LRYGB surgery. Within 2 weeks after surgery this patient presented well-known neuropsychiatric symptoms of methylphenidate toxicity when using the same dose of CNS stimulant after LRYGB as previous to the surgery. The literature regarding alterations in methylphenidate pharmacokinetics after bariatric surgery is scant. No reports regarding alterations in serum concentrations of methylphenidate after LRYGB were found. The only publication is about the dissolution of common psychiatric medications, studied in an RYGB in vitro model. Methylphenidate was found to dissolve slightly more in the RYGB model, a median of 80 mg dissolved, compared with 70 mg in the control setting, however, on a statistically nonsignificant level [[5]Seaman J.S. Bowers S.P. Dixon P. Schindler L. Dissolution of common psychiatric medications in a Roux-en-Y gastric bypass model.Psychosomatics. 2005; 46: 250-253Crossref PubMed Scopus (59) Google Scholar]. The recommended dose of methylphenidate is between .3 and 1.5 mg/kg/d [[6]Kooij S.J.J. Bejerot S. Blackwell A. et al.European consensus statement on diagnosis and treatment of adult ADHD: the European Network Adult ADHD.BMC Psychiatry. 2010 Sept 3; 10: 67Crossref PubMed Scopus (620) Google Scholar]. Twenty-two percent of the content of a Concerta capsule is released immediately in the stomach and proximal part of the small intestine. The remaining part of the content is released over 10–12 hours in the small intestine and proximal part of colon [[7]RELIS database 2013; spm.nr 3369 [database on the Internet]. Tromsø, Norway: RELIS Nord-Norge; 2013. Depotformulert metylfenidat etter gastric bypass. Available from: https://www.relis.no/sporsmal_og_svar/6-958?source=relisdb.Google Scholar]. A number of factors after LRYGB might affect the pharmacokinetics. Changes in transit time and acidity as well as other factors have to be taken into consideration when discussing why previous therapeutic doses may contribute to drug toxicity. With the background of>450,000 bariatric procedures perfomed annually worldwide and with ADHD rates higher than ever, there is a need for further studies assessing the effects of different bariatric procedures on the pharmacokinetics of drugs such as methylphenidate [[8]Angrisani L. Santonicola A. Iovino P. Formisano G. Buchwald H. Scopinaro N. Bariatric Surgery Worldwide 2013.Obes Surg. 2015; 25: 1822-1832Crossref PubMed Scopus (1063) Google Scholar]. A patient on medication for ADHD had well-known neuropsychiatric symptoms of methylphenidate toxicity within 2 weeks after LRYGB when using the same dose of CNS stimulant after LRYGB as previous to the surgery. The methylphenidate pharmacokinetics might be altered by LRYGB, and this case report indicates that dose adjustments may be necessary in close connection to the surgery.