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ADHD: Non-Stimulant drugs Or Other drugs Or Second-line drugs

ADHD: Non-Stimulant drugs Or Other drugs Or Second-line drugs. MRM. دكتر محمد رضا محمدي. فوق تخصص روانپزشكي كودك و نوجوان استاد روانپزشكي و رئيس مركز تحقيقات روانپزشکی و روانشناسی دانشگاه علوم پزشكي تهران بيمارستان روزبه Email: moham m adimr@tums.ac.ir.

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ADHD: Non-Stimulant drugs Or Other drugs Or Second-line drugs

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  1. ADHD: Non-Stimulant drugs Or Other drugs Or Second-line drugs MRM

  2. دكتر محمد رضا محمدي فوق تخصص روانپزشكي كودك و نوجوان استاد روانپزشكي و رئيس مركز تحقيقات روانپزشکی و روانشناسی دانشگاه علوم پزشكي تهران بيمارستان روزبه Email: mohammadimr@tums.ac.ir

  3. تعريفاختلال نقص توجه و بيش فعالي بر اساس DSM – IV-TR Attention Deficit Hyperactivity Disorder (ADHD) عبارت است از يك الگوي مقاوم نارسایی ونقص توجه و بيش‌فعالي كه با تكرار و شدت بيشتر از كودكان سالم و مشابه از لحاظ سن و جنس بروز مينمايد .

  4. ADHD is defined • Inattentiveness • disorganised, forgetful, does not invest effort • brief and changing activities • Hyperactivity • depending on context • Impulsiveness • action without reflection

  5. Prevalence of disorder • IRAN • Tehran: 3%-5% • Children 8.6 % –Adolescent 8.3 % • Khorramabad: 3%-6% • Other Studies: 2 % -20 %

  6. Principles of psychological treatment • Identify specific problems • Analyze contingencies (events) • Enhance adult attending • Teach effective instruction • Token economy • Time-out + rapid novel rewards • Self- management

  7. Interventions in the classroom • Proximity to teacher • Managed transitions • Letting off energy • Classroom aide • operant conditioning • peer advice • Rule government • Clarity of goal • speed of feedback

  8. Treatments • Education • Cognitive-Behavior therapy • School modification • Triple P: Positive Parents Program Psychopharmacology • Stimulant drugs • Other drugs • Non-Stimulant drugs Or Second-line drugs

  9. Medication types • Stimulant drugs: • Methylphenidate • Dexamphetamine • Adderall • Extended-release MP

  10. Why is Methylphenidate (Ritalin) effective in ADHD? Its mechanism(s) of action are not understood • Most commonly prescribed psychoactive drug in children. • In the USA, 4-6 million children are treated with methylphenidate every day. • Has been used for over 40 years for ADHD.

  11. Why stimulants fail • They are not being taken Extended release; education; motivational • The dose is wrong Monitor dose range to High dose; distribute; second stimt. • Adverse effects limit benefit Manage symptomatically; modify dose • The diagnosis is wrong • The disorder is refractory Second-line drugs; CBT approaches

  12. عوارض جانبي ريتالين با شيوع كمتر:-سردرد، سرگيجه ، تهوع ، درد معده ، افزايش ضربان قلب. - درد قفسه سينه ، درد مفاصل ، حركات غير ارادي بدن. -  بثورات پوستي ، كهير ، اكيموز -   تب بدون دليل شناخته شده نادر:تاري ديد ، تشنج ، تغيرات خلقي ، گلو درد ، پسيكوز شايع : 1- كاهش اشتها 2-كاهش وزن بدن 3-عصبانيت و پرخاشگري 4-اشكال در به خواب رفتن

  13. SSRIs • Fluoxetine • Citaloprame • sertraline

  14. Trial evidence • Atomoxetine • Haloperidol • Imipramine • Clonidine • Bupropion • Pemoline • Nicotine • Carbamazepine

  15. Few Trial • Guanfacine • Moclobemide (MAoI) • Venlafaxine • Risperidone

  16. Antidepressants • Imipramine 20-100 mg • Amitriptyline 20-100 mg • Desipramine 20-100 mg • Nortriptiline 10-50 • Bupropion 75-300 • Clomipramine 25-100 • Tranylcipromine 5-15 • Clorgyline 5-20 • Pargyline

  17. α2-Agonists • Guanfacine 0.5-4.0 • Clonidine 0.05-0.3

  18. miscellaneous • Buspirone 5-30 • Diphenhydramine 75-150 • Nicotine (only adult) 7-21 mg patch • Modafinil100-400 mg

  19. Anticonvulsants • Carbamazepine 50-800 (serum level) • Valproate 50-600 (serum level) • Phenytoin 50-300

  20. Antipsychotics • Thioridazine 25-150 • Halopridol 0.5-5 • Chlorpromazine 25-150 • Risperidone 0.25-2

  21. Precursors • Tryptophan (precursor of serotonin) 70-100 • Tyrosine • (precursor of dopamine & norepinephrine) 100-400 • Phenyalanine (precursor of dopamine & norepinephrine) 100-400 • Levo-DOPA (precursor of dopamine & norepinephrine) • Deanol (precursor of acetylcholine) >500

  22. Others • β Blockers Propranolol 10-100 Caffeine 100-450

  23. Clinical Trial in Iran • Theophilline3/4 mg/kg/day • Ritalin + ZN 55 mg/day • Selegiline 5-10 mg • Pasipay 0.04 mg/kg/day • Modafinil 100-400 mg

  24. Clinical Trial in Iran • Ginkgo Biloba 240-600mg • Buspirone 5-10 mg • Bupropion 37.5-150 mg

  25. 1- Mohammadi, M.R., Ghanizadeh, A., Alaghband-rad, J., Tehranidoost, M., Mesgarpour, B., Soori, H.Selegiline in comparison with methylphenidate in attention deficit hyperactivity disorder children and adolescents in a double-blind, randomized clinical trial(2004) Journal of Child and Adolescent Psychopharmacology, 14 (3), pp. 418-425. Cited 16 times. 2- Mohammadi, M.R., Kashani, L., Akhondzadeh, S., Izadian, E.S., Ohadinia, S.Efficacy of Theophyllinecompared to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents: A pilot double-blind randomized trial(2004) Journal of Clinical Pharmacy and Therapeutics, 29 (2), pp. 139-144. Cited 16 times.

  26. 3- Mohammadi, M.R., Mostafavi, S.A., Keshavarz, S.A., Eshraghian, M.R., Hosseinzadeh, P., Hosseinzadeh-Attar, M.J., Kooshesh, S.M.A., Chamari, M., Akhondzadeh, S.Melatonin effects in methylphenidate treated children with attention deficit hyperactivity disorder: A randomized double blind clinical trial(2012) Iranian Journal of Psychiatry, 7 (2), pp. 87-92. Cited 2 times. 4- Mohammadi, M.-R., Hafezi, P., Galeiha, A., Hajiaghaee, R., Akhondzadeh, S.Buspirone versus methylphenidate in the treatment of children with attention- deficit/ hyperactivity disorder: Randomized double-blind study(2012) ActaMedicaIranica, 50 (11), pp. 723-728. Cited 1 time.

  27. 5- Mohammadi, M.-R., Kazemi, M.-R., Zia, E., Rezazadeh, S.-A., Tabrizi, M., Akhondzadeh, S.Amantadine versus methylphenidate in children and adolescents with attention deficit/hyperactivity disorder: A randomized, double-blind trial(2010) Human Psychopharmacology, 25 (7-8), pp. 560-565. Cited 9 times. 6- Mostafavi, S.A., Mohammadi, M.R., Hosseinzadeh, P., Eshraghian, M.R., Akhondzadeh, S., Hosseinzadeh-Attar, M.J., Ranjbar, E., Kooshesh, S.M.A., Keshavarz, S.A.Dietary intake, growth and development of children with ADHD in a randomized clinical trial of ritalin and melatonin co-administration: Through circadian cycle modification or appetite enhancement?(2012) Iranian Journal of Psychiatry, 7 (3), pp. 114-119. 

  28. 7- Akhondzadeh, S., Mohammadi, M.-R., Khademi, M.Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial [ISRCTN64132371](2004) BMC Psychiatry, 4, art. no. 9, . Cited 69 times. 8- Kahbazi, M., Ghoreishi, A., Rahiminejad, F., Mohammadi, M.-R., Kamalipour, A., Akhondzadeh, S.A randomized, double-blind and placebo-controlled trial of modafinilin children and adolescents with attention deficit and hyperactivity disorder(2009) Psychiatry Research, 168 (3), pp. 234-237. Cited 39 times.

  29. 9- Amiri, S., Mohammadi, M.-R., Mohammadi, M., Nouroozinejad, G.-H., Kahbazi, M., Akhondzadeh, S.Modafinil as a treatment for Attention-Deficit/Hyperactivity Disorder in children and adolescents: A double blind, randomized clinical trial(2008) Progress in Neuro-Psychopharmacology and Biological Psychiatry, 32 (1), pp. 145-149. Cited 37 times. 10- Salehi, B., Imani, R., Mohammadi, M.R., Fallah, J., Mohammadi, M., Ghanizadeh, A., Tasviechi, A.A., Vossoughi, A., Rezazadeh, S.-A., Akhondzadeh, S.Ginkgo bilobafor Attention-Deficit/Hyperactivity Disorder in children and adolescents: A double blind, randomized controlled trial(2010) Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34 (1), pp. 76-80. Cited 24 times.

  30. 11- Zarinara, A.-R., Mohammadi, M.-R., Hazrati, N., Tabrizi, M., Rezazadeh, S.-A., Rezaie, F., Akhondzadeh, S.Venlafaxine versus methylphenidate in pediatric outpatients with attention deficit hyperactivity disorder: A randomized, double-blind comparison trial(2010) Human Psychopharmacology, 25 (7-8), pp. 530-535. Cited 14 times. 12- Akhondzadeh, S., Mohammadi, M.R., Momeni, F.Passifloraincarnata in the treatment of attention-deficit hyperactivity disorder in children and adolescents(2005) Therapy, 2 (4), pp. 609-614. Cited 14 times.

  31. 13- Abbasi, S.-H., Heidari, S., Mohammadi, M.-R., Tabrizi, M., Ghaleiha, A., Akhondzadeh, S.Acetyl-L-carnitine as an adjunctive therapy in the treatment of attention-deficit/hyperactivity disorder in children and adolescents: A placebo-controlled trial(2011) Child Psychiatry and Human Development, 42 (3), pp. 367-375. Cited 6 times. 14- Jafarinia, M., Mohammadi, M.-R., Modabbernia, A., Ashrafi, M., Khajavi, D., Tabrizi, M., Yadegari, N., Akhondzadeh, S.Bupropion versus methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder: Randomized double-blind study(2012) Human Psychopharmacology, 27 (4), pp. 411-418. Cited 4 times.

  32. 15- Mohammadi, M.R., Soleimani, A.A., Farahmand, Z., Keshavarzi, S., Ahmadi, N.A comparison of effectiveness of regulation of working memory function and methylphenidate on remediation of attention deficit hyperactivity disorder (ADHD)(2014) Iranian Journal of Psychiatry, 9 (1), pp. 25-30. 

  33. Conclusions from trial • Medication is more powerful than cognitive behavioural therapy (CBT) • Research treatment better than routine • Many advantages in adding medication to behavioural

  34. Comparison of treatments (1)Meta analysis of 124 trials Pre-post differences in means / SD pre-treatment

  35. Where does drugs bind in the human brain? PET studies show that drugs binds predominantly to striatum in the human brain where it binds to DA transporters.

  36. Pharmacokinetics ofMethylphenidatein Human Brain Methylphenidate when injected intravenously enters the brain rapidly but has a slow clearance

  37. نوروترانسميترها نوروترانسميترهاي متعددي در فيزيوپاتولوژيADHD نقش دارند از مطالعات حيواني مشخص شده كه Locus ceruleus داراي نرونهاي نورآدنرژيك فراوان ميباشد و نقش كليدي در فيزيوپاتولوژي ADHD دارد. اين فرضيه با داروهايي كه نقش مثبت در درمان ADHD دارند يعني محركها تأييد ميگردد. در حقيقت محركها از طريق تأثير بر روي نور اپي نفرين و دوپامينعملمي‌نمايند. محركها مانند ريتالين ودكستروآمفتامين از طريق افزايش كاتكل آمينها (افزايش آزادسازي و جلوگيري از بازجذب آنها) تأثير درماني دارند..

  38. 100 80 60 DAT Occupancy (%) typical dose(0.5 mg/kg) 40 20 0 0.0 0.2 0.4 0.6 0.8 1.0 Dose (mg/kg) Ritalin Binding to Dopamine Transporters Oral MP at therapeutic doses occupies > 50 % DA transporters. Estimated ED50 (dose required to occupy 50% of the DA transporters) corresponds to 0.25 mg/kg.

  39. DA DA DA DA DA DA DA DA DA DA MP MP DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA What are the effects of therapeutic doses of oral MP on extracellular DA? With MP Without MP Hypothesis 1 Autoreceptor activation decreases DA release blunting DA signals. Hypothesis 2 DAT blockade amplifies DA signals.

  40. What are the levels of DA transporter blockade achieved by MP at the doses used therapeutically for the treatment of ADHD? Placebo 20 mg 40 mg MP given orally at therapeutic doses binds very efficiently to DA transporters.

  41. DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA ADHD Without MP ADHD With MP MP’s increase of extracellular DA would amplify the weak DA signals in ADHD subjects. MP Amplification of DA signals would enhance task-specific signaling (DA decreases background firing and increases signal-to-noise in target neurons), improving attention and decreasing distractibility

  42. آدنوزين يك Neuromodulator مهاري نقش آدنوزين بعنوان يكنورومدولاتور مهاري در سيستم اعصاب مركزي در دو دهه گذشتهبيان شده است. مطالعات متعددي بر روي حيوانات بازگو كننده نقش مهاري آدنوزين بر روي بسياري از نوروترانسميترها از جمله نوراپي نفرين و دوپامين است . لذا آنتاگونيستهاي آدنوزين مانند كافئين و تئوفيلين ميتوانند در درمانADHDمؤثرباشند.

  43. انواع آدنوزين آدنوزين بعنوان يك نرومدولاتور در دستگاه عصبي مركزي تقريباً در همه سيناپس‌ها وجود دارد و از طريق گيرنده هاي اختصاصي در سطح سلول اثر ميكند. گيرنده هاي آدنوزين به زير گروههاي A1، A2a، A2b، A3,A4 تقسيم ميشوند. اين گيرنده ها توزيع گسترده اي در CNSدارند و با بسياري از سيستم هاي نوروترنسميتري در تعامل هستند. بر همين مبناست كه تصور ميشود از تركيبات مؤثر بر گيرنده هاي آدنوزين ميتوان در درمان بسياري از اختلالات عصبي رواني استفاده كرد.

  44. DA DA DA DA DA Adenosine DA DA DA DA DA DA DA DA DA DA DA DA DA ِAdenosine: Inhibitory Neuromodulator

  45. مكانيسم اثر تئوفيلين آزاد سازيRitalinاگر مكانيسم اثر داروهاي محرك ماننددوپامين و نور اپي نفرين باشد آنگاه مهاركننده هاي گزانتيني آدنوزين مانندكافئين و بخصوص تئوفيلين ميتوانند كاربرد درماني داشته باشند زيرا آدنوزين اثر مهاري بر روي آزاد سازي دوپامين و نوراپي نفرين دارد؛ لذا مهاركننده هاي آدنوزين مانند تئوفيلين باعث افزايش فعاليت دوپامين و نور اپي نفرين مي شوند. بعبارتي با اما بصورت غير مستقيم؛ لذا در اين مطالعه Ritalin مكانيسم مشابه را با تئوفيلين مقايسه مي كنيم .Ritalinما براي اولين بار اثر بخشي

  46. DA DA DA DA DA DA Theophyline DA DA DA DA DA DA DA DA DA DA DA DA ِTheophyline Mechanism

  47. Thanks

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