6. Tyacke RJ, Lingford-Hughes A, Reed LJ, et al. GABAB receptors in addiction and its treatment. Adv Pharmacol. 2010;58: 373Y396. 7. Fronczek R, Baumann CR, Lammers GJ, et al. Hypocretin/orexin disturbances in neurological disorders. Sleep Med Rev . 2009;13:9Y22. Bilateral Gynecomastia in a Preadolescent Boy While Under Treatment With Methylphenidate and Paroxetine To the Editors: M ethylphenidate (MPH) has rarely been reported to be related to gyneco- mastia in subjects with attention-deficit/ hyperactivity disorder (ADHD). 1 Mean- while, selective serotonin reuptake inhibi- tors (SSRIs) have also been reported to be related to gynecomastia. 2Y6 Here, we report a case of a preadolescent boy who devel- oped bilateral gynecomastia after increas- ing his osmotic-controlled release oral delivery system (OROS) MPH to 54 mg/d while under treatment with 36 mg/d of OROS MPH and 20 mg/d of paroxetine for ADHD and social phobia. CASE REPORT A 10-year-old boy with normal de- velopmental history was diagnosed with ADHD inattentive type and social phobia. His weight was 40 kg. He was started with 18 mg/d of OROS MPH and 10 mg/d of paroxetine. In the next visit, 2 months later, his ADHD and social phobia symptoms showed mild to moderate improvement in parents’ and teacher’s reports. He gener- ally tolerated the medications well, and his medication was increased to 36 mg/d of OROS MPH and 20 mg/d of paroxetine. His symptoms showed further improve- ment, and he continued this treatment re- gimen for 1 year without any significant adverse effects. Thereafter, his ADHD me- dication was increased to 54 mg/d because he was considered to develop some level of tolerance to MPH. His weight was 50 kg at that time. In the next visit, 1 month later, his ADHD symptoms showed further im- provement and he reported no significant adverse effects. He continued taking 54 mg/d of MPH and 20 mg/d of paroxetine for a total period of 6 months. He was seen at the end of the sixth month of the combi- nation treatment with 54 mg/d of MPH and 20 mg/d of paroxetine. He was repor- ted to have bilateral gynecomastia that had developed for the last several months (Figure 1, Supplemental Digital Content 1, http://links.lww.com/JCP/A243). He had no pain, tenderness, or galactorrhea. Gy- necomastia was psychologically, physi- cally, and socially disturbing for him and his parents. His weight was 50 kg, and his body mass index was 21.3. Pediatric endo- crinology and surgery consultation were ordered. His physical examination and labo- ratory workup including liver, thyroid, and renal function tests; electrolytes; blood cell count; prolactin; testosterone; estrogen; lu- teinizing hormone; follicle-stimulating hor- mone; and cortisol levels were all within normal limits. He denied using any other medical or herbal medications or substan- ces, or eating unusual foods. There was no known case of gynecomastia in his family. No medical or surgical condition was de- tected to explain the gynecomastia. The gynecomastia was considered to be related to his medications. Methylphenidate and paroxetine were discontinued. No signi- ficant improvement was observed in the gynecomastia after 7 months of medication- free period. His weight was 63 kg, and his body mass index was 24.9. His prolactin, estrogen, and testosterone levels were within normal limits. His family refused any surgi- cal operation for managing the gynecomas- tia. They expected that the gynecomastia would resolve on its own within time. He was advised to do physical/sportive activ- ities and referred to a dietician for weight control. He reported some level of prob- lems with his attention as well as difficulty in concentration and school work after stopping the MPH treatment. He was therefore referred for an academic sup- port program. However, there was no sig- nificant worsening in the social phobia symptoms. The parents gave verbal in- formed consent, and the patient gave his assent for publication. DISCUSSION Prepubertal gynecomastia is character- ized by the presence of palpable unilateral or bilateral breast tissue in boys, without other signs of sexual maturation. Gynecomastia is common in healthy boys in the neonatal period, at early puberty, and with increas- ing age. Neonatal gynecomastia is caused by placental transfer of estrogens and pu- bertal gynecomastia by an imbalance within the breast tissue between estrogens and androgens. With aging, the production of testosterone decreases and the peripheral conversion of androgens to estrogen often rises because of an age-associated in- crease in adipose tissue. During these 3 periods, gynecomastia is considered a normal finding and is often called physi- ologic gynecomastia. 7 Prepubertal gy- necomastia in otherwise healthy boys was reported rarely in the literature. Prepuber- tal gynecomastia may be considered a pathological sign of a possible endocri- nopathy, warranting a thorough history, physical examination, and laboratory workup. However, prepubertal gyneco- mastia is considered idiopathic in most of the cases. 7 Methylphenidate has been the first- line psychopharmacological treatment in children as well as in adolescents with ADHD and results in significant improve- ment in 70% to 80% of affected children. 8 Nausea, decreased appetite, weight loss, and sleep disturbances are among the most frequently reported adverse effects during MPH treatment. 8 Besides these common adverse effects, MPH has also been repor- ted to cause some unusual adverse effects such as hallucinations, 9,10 hypersexuality or inappropriate sexual behaviors, 11 skin eruptions, 12 overactive/psychotic reactions, 9 obsessive-compulsive symptoms, 13,14 and gynecomastia. 1 Ensat et al 1 reported a pre- adolescent boy experiencing ADHD who had been treated with MPH (10 mg/d) since the age of 4 years. At the age of 6 years, unilateral gynecomastia was diagnosed, with an ongoing progression causing an emo- tional burden. Gynecomastia was man- aged by subcutaneous mastectomy at the age of 12 years. Regarding our case, possible medical factors related to gynecomastia were ex- cluded by detailed history and laboratory workup. Gynecomastia, apparently, de- veloped for the last several months after increasing the MPH dosage to 54 mg/d. This condition may raise concern that MPH has been particularly related to develop- ing gynecomastia in this case. Exact pathophysiological mechanisms through which MPH can cause gynecomastia are unknown. Literature and Internet media reviews have shown several case reports of MPH-related gynecomastia, 1,15 but no possible pathophysiological mechanism has been implicated. On the other hand, the neurophysio- logic findings indicate an inhibition of do- paminergic neurotransmission by SSRIs that could be related to several adverse effects such as hyperprolactinemia, extrapyramidal symptoms, sexual and cognitive dysfunc- tion, galactorrhea, mammary hypertrophy, as well as, more rarely, gynecomastia. 4 There have been a number of case re- ports on SSRI-related 2Y6 or antidepressant- related 16Y18 gynecomastia. Gynecomastia was managed by either surgical operation 2 or medication discontinuation 16,18 in some of those cases. Journal of Clinical Psychopharmacology & Volume 34, Number 4, August 2014 Letters to the Editors * 2014 Lippincott Williams & Wilkins www.psychopharmacology.com 537 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.