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ADHD, Co-morbidities Local Perspectives

ADHD, Co-morbidities Local Perspectives. AHMAD ALMAI, M.D. HEAD OF CHILD AND ADOLESCENT PSYCHIATRY, BSP,SKMC. OBJECTIVES. ADHD as Co-morbid Condition Local Data Nonstimulant Treatment of ADHD. ADHD IN ARABIAN GULF MEDIA. الجمعـة 17 ذو القعـدة 1432 هـ 14 اكتوبر 2011 العدد 12008

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ADHD, Co-morbidities Local Perspectives

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  1. ADHD, Co-morbiditiesLocal Perspectives AHMAD ALMAI, M.D. HEAD OF CHILD AND ADOLESCENT PSYCHIATRY, BSP,SKMC

  2. OBJECTIVES • ADHD as Co-morbid Condition • Local Data • Nonstimulant Treatment of ADHD

  3. ADHD IN ARABIAN GULF MEDIA • الجمعـة 17 ذو القعـدة 1432 هـ 14 اكتوبر 2011 العدد 12008  اضطراب «فرط الحركة وتشتت الانتباه» يصيب 15% من أطفال السعودية العلاج الطبي أثبت نجاح 90% من الحالات • يمكن للأسر التعرف على إصابة أبنائها بفرط الحركة بملاحظة شدة الحركة والاندفاعية وتشتت الانتباه («الشرق الأوسط») • جدة: أسماء الغابري تختلف نسبة نشاط الأطفال وتركيزهم واتباعهم للتعليمات من طفل لآخر، وعلى الرغم من هذا التفاوت الطبيعي، فإنه توجد نسبة من الأطفال يصعب تواصلها مع المجتمع وتكوين أصدقاء، إلى جانب النشاط الحركي الشديد الذي يسبب الإنهاك من قبل المحيطين له، واللجوء معه إلى أساليب قد تصل للعنف أحيانا للحد من هذا النشاط، وإرغامه على اتباع التعليمات.إلى ذلك، شخص أطباء في علم النفس والمخ والأعصاب هذا السلوك المضطرب عند هذه الفئة من الأطفال إلى اضطراب عصبي يسمى «اضطراب فرط الحركة وتشتت الانتباه» الذي يعد اضطرابا عصبيا بيولوجيا يصيب الأطفال. • وتشخيص اضطراب فرط الحركة وتشتت الانتباه يتشابه مع • أنواع أخرى من الاضطرابات العصبية، لذ • يصعب على الكثير من الأطباء تشخيصه، عدا الأطباء ذوي • الخبرة والمطلعين باستمرار على الأحداث الطبية والمتميزين. • ويرى الاختصاصيون أنه يمكن للأسرة أن تكتشف إصابة أحد • أبنائها بهذا الاضطراب من خلال التركيز على مدى شدة وحدة • الأعراض، والفترات والظروف التي يظهر فيها السلوك غير • المناسب، الذي يظهر في أعراض ثلاثة (فرط الحركة - الاندفاعية • - تشتت الانتباه) ولا تكون ظاهرة فقط على الطفل وإنما مهيمنة على • سلوكه، لدرجة أنها تؤثر سلبا على حياته من النواحي العلمية • والسلوكية والاجتماعية.وأكدت الدراسات أن نسبة الإصابة في • السعودية تقدر بـ15 في المائة، فيما بينت آخر دراستين عن • الاضطراب؛ الأولى في المنطقة الشرقية، أن متوسط الإصابة • في الدمام يقدر بنسبة 16.7 في المائة، والأخرى في الرياض، • تقدر بنسبة 12.6 في المائة.وعن كيفية تشخيص المرض • ، توضح الدكتورة سعاد يماني استشارية المخ والأعصاب و • رئيسة مجموعة دعم اضطراب فرط الحركة وتشتت الانتباه في • مستشفى الملك فيصل التخصصي ومركز الأبحاث في الرياض، • أنه ليس هناك اختبارات مخبرية أو أشعة لتشخيص اضطراب • فرط الحركة وتشتت الانتباه، مشيرة إلى أنه لا بد أن يتم التشخيص • من قبل مختص قادر على القيام بعملية التشخيص والعلاج كطبيب الأعصاب أو النفسية أو اضطرابات النمو. • السبت 10-09-2011 07:28 مساء غذاء أكثر توازنا لمعالجة فرط الحركة لدى الأطفال  أشارت دراسة نشرتها مجلة "بيدياتريكس" الأميركية الاثنين إلى أن غذاء أكثر توازنا قد يفيد الأطفال مفرطي الحركة الذين يعانون قصورا في الانتباه وفرط الحركة، في حال فشلت العقاقير أو العلاجات الأخرى في حل هذه المشكلة. وبحسب العلماء الذين راجعوا الدراسات الأخيرة حول هذا الموضوع، يصعب تقييم منافع الحميات القائمة على المكملات الغذائية أو التي تستثني بعض المنتجات الغذائية. وقد يكون مفعول هذه الأنظمة الغذائية "وهميا" ليس إلا. وبالتالي، ينبغي اعتبار العلاجات الغذائية المتعلقة بقصور الانتباه وفرط الحركة علاجات بديلة، بحسب الدراسة التي أعدها أطباء من كلية الطب في شيكاغو. وكتب الأطباء في الدراسة أن "التركيز بشكل أكبر على حث الأهل والأطفال على اعتماد نظام غذائي سليم وتجنب الأغذية التي تعزز قصور الانتباه وفرط الحركة قد 

  4. % Visits to Child Psychiatry Clinic, SKMC, March, 2012

  5. Psychiatric Disorders Child Psychiatry Service, SKMC, 2012

  6. ADHD Co-morbidities Children and Adolescents • Oppositional defiant disorder • Conduct disorder • Anxiety disorders • Major depression • Bipolar disorder • Tic disorders • Learning disabilities Jensen P, et al. Archives of General Psychiatry, MTA study; December, 1999

  7. Local Data Retrospective ADHD Co-morbidity studyUAEN:130012 SEHA HospitalsAbu Dhabi

  8. Psychiatric Co-morbidities in Pediatric Bipolar , SKMC, N:60Age 6-17

  9. Heterogeneity of ADHDDifferent subtypes may respond to different treatments

  10. Pharmacotherapy for ADHD Stimulants (FDA approved): - Methylphenidate compounds; Concerta - Amphetamine compounds; Adderall XR, -Prodrug; Lisdexamfetamine (Vyvanse). Nonstimulants: • Atomoxetine (FDA approved) • Antihypertensives (FDA approved ;Guanfacine XR (Intuniv), Clonidine XR (Kapvay) • Antidepressants - Bupropion SR/XL - Tricyclics • Modafinil • Research - Natural agents - Combined - Cholinergic agents Wilens et al. American Psychiatry News 2008

  11. Pharmacotherapy in Adults with ADHD Wilens T Drugs 2003:63:2395-2411

  12. Alpha-2 receptor Norepinephrine Frontal • Attention • Concentration • Other cognitive fxns Arnsten et al. Arch Gen Psychiatry 1996:53:448

  13. Atomoxetine in ADHD • High affinity for norepinephrine reuptake inhibition • Low affinity for other receptors - (cholinergic, histaminic. serotonergic, alpha-1.2 adrenergic) - Few side effects, increased tolerability • Few direct cardiac effects • No abuse liability • Not scheduled (renewable)

  14. Atomoxetine Systematic Review • From 2009-2011, 750 clinical papers have been produced on atomoxetine • Critical SmPC updates have taken place • Atomoxetine has increasing efficacy over time in core ADHD symptoms in children and adolescents • Effect sizes are similar to MPH in treatment-naïve cohorts and metaanalysis that removed confounders • Full clinical benefit may need 12 weeks • Efficacy demonstrated in cohorts with some common comorbidities • Atomoxetine has extensive HRQOL data • Further longer term research is needed to address the crucial aspects of outcomes Bushe and Savill. Journal of Central Nervous System Disease 2011;3:209-17.

  15. Atomoxetine in Children with ADHD plus AnxietyADHD Outcome Dose of ATMX= 1.26 mg/kg day Geller et al. J Am Acad Child Adoles Psychiatry. 2007:46:1119-1127

  16. Atomoxetine: Change in Effect Size 1.0 0.82 0.8 0.72 0.55 0.48 Effect Size (standardized mean differences between the groups) of the ADHD-RS-IV-Parent: Inv total score 0.5 0.27 0.2 Treatment week 0.0 2 4 6 9 12 Montoya et al. Curr Med Res Opin 2009;25(11):2745-54. • Continuous improvement in the atomoxetine group compared to placebo is clearly evidenced by the constantly increasing effect sizes between the groups

  17. Atomoxetine: Treatment Effect Sizes vs. Placebo Newcorn et al. Am J Psychiatry 2008;165(6):721-30.

  18. Design 8-week open study of ATX in 12 BPD youth (aged 6-17 years) All subjects euthymic on at least one thymoleptic Mean dose = 59 mg/day Outcome 10/12 completers Discontinuation in 2 subjects (hypomania, Suicidality) Improved ADHD (ADHDRS from 39 to 22; p < 0.0001) 67% response by 25% decrease in ADHDRS No significant change in BPD (YMRS from 7.9 to 7.4; p = NS) No significant change in depression scores Other adverse effects: tiredness. Gl, agitation, dizziness Atomoxetine in Bipolar Disorder

  19. Dosing : • - Start at 0.5 mg/kg/day for 2 weeks, then increase to 1.2 • mg/kg/day. After 6 weeks if partial response, increase to • 1.8-2 mg/kg/day • Adverse effects • - Rare hepatic injury (2 cases): advise. LFTs NOT required • - Suicidality (0.37% vs. 0%): black box • - Somnolence, appetite suppression. Gl upset /dyspepsia. • blood pressure / pulse (adults), sexual dysfunction (.adults), • irritability • - Potential drug interactions (lower dose if using with p448 inhibition) Atomoxetine

  20. • Monotherapy (higher likelihood of response as first start ) • Stimulant nonresponders • Stimulant partial responders (monotherapy, adjunctive therapy- no drug interactions with stimulants) • Adverse effects to stimulants • Concerns of stimulant diversion • Comorbid ADHD plus: - Oppositional disorder - Anxiety - Tics - Mood - Substance abuse • Careful in BPD youth: manic activation (ca. 50%) Atomoxetine: When to Use

  21. Clonidineand Guanfacine Alpha agonist agents - Mimics norepinephrine at alpha and beta receptors - Presynaptic alpha-2a (Guanfacine more specific) - Postsynaptic alpha-1. 2 a-c (alpha-2a in PFC) Effect on prefrontal cortex (PFC) - May be dose-dependent effects on pre/post-2a - Largely inhibitory - Modulated by "stress'-dependent release of Nepi - Improves PFC blood flow and functioning in animal models Effect on locus coeruleus Modulate of neurotransmission of other neuronal systems (glutamate, GABA, cholinergic, opioid) Amsten. Li, Biol Psych 2005 Wilens J. Clin Psych. 2006

  22. (Hunt et al. JAACAP 1985: 1986; Prince et al JAACAP 1996) Clonidine (Catapres®) forded Pharmacology: alpha-2a noradrenergic agonist Dosing: 0.05 mg to 0.2 mg up to t.i.d. Efficacy 3 controlled - efficacy for ADHD Multiple open - efficacy in aggression, impulsivity. ADHD-related sleep disorders Comparison: helpful for hyperactivity and impulsivity. Not helpful with attention Side effects: sedation, headaches, depression, rebound hypertension

  23. Clonidine plus Methylphenidate:ADHD plus Tic Disorders Prospective data indicating improved outcome for ADHD (Kurlan et al. Neurology. 2002; Hazel et al. JAACAP. 2003; Palumbo et al. JAACAP. 2007) - MPH + Clon > MPH > Clon > PBO Prospective data indicating improved outcome for tics (Kurlan et al. Neurology. 2002; Hazel et al. JAACAP. 2003: Palumbo et al. JAACAP. 2007) -No worsening systematically of tics vs. PBO No cardiovascular issues in prospective data - No recent "events" reported

  24. (Popper JCAP .1995; Swanson et al JAACAP 1999 Wilens. Spencer JAACAP 1999) Clonidine Controversy • Sudden death in three youths receiving clonidine + MPH • "The degree of confounding factors made these [3] cases uninterpretable' (NIH Special Emphasis Panel on Cardiac Arrhythmias in Children. 8/96) • No association/causality established • No other such cases identified • Common concomitant use of clonidine + beta agonists -Clonidine for drug withdrawal, cocaine overdose -Amphetamines for clonidine overdose

  25. (Popper JCAP .1995; Swanson et al JAACAP 1999 Wilens. Spencer JAACAP 1999) Clonidine Controversy • Sudden death in three youths receiving clonidine + MPH • "The degree of confounding factors made these [3] cases uninterpretable' (NIH Special Emphasis Panel on Cardiac Arrhythmias in Children. 8/96) • No association/causality established • No other such cases identified • Common concomitant use of clonidine + beta agonists -Clonidine for drug withdrawal, cocaine overdose -Amphetamines for clonidine overdose

  26. 'Hunt et al JAACAP 1995. Scahill et al Afi CAP 1999) Guanfacine (Tenex®) for ADHD Pharmacology: half-life = 18 hrs (adults) Alpha-2a noradrenergic agonist Dosing: 0.5 mg to 2.0 mg up to t.i.d. Efficacy 1 controlled - efficacy for both ADHD plus tics 2 open studies - efficacy in ADHD Comparison: Similar to clonidine. but better effect on attention, less effect for hyperactivity Side effects: Similar to clonidine but less sedation, more agitation, insomnia, headaches

  27. Based on research from the Arnsten lab. the alpha-2Aadrenoceptor agonist Guanfacine (GFC) developed by Shire Pharmaceuticals for the treatment of ADHD. Guanfacine is tested in a number of additional disorders that Involve weakened PFC function

  28. ADHD-RS: Mean Total Score at Endpoint and Change In LS Mean from Baseline (ITT Population N= 245) Guanfacine ER: Efficacy

  29. Guanfacine Extended-Release in ADHD (N= 324 [51 sites]: 6 weeks active*, mean age 11+3 yrs)

  30. (N= 324 (51 sites) 6 weeks, mean age 11 + 3 yrs) Guanfacine Extended-Release in ADHD • Adverse effects • - Discontinuation rate similar between med and placebo • -Somnolence (27% vs. 12% [placebo]) and fatigue (9% vs. 3%) • Improved after titration • -Headache (21% vs. 11%)

  31. (N= 324 (51 sites); 6 weeks, mean age 11 + 3 yrs) • Monotherapy • Stimulant or nonstimulant nonresponses • Medication partial responders (adjunctive therapy) • - Study of combined Guanfacine XR in suboptimal stimulant responded: • - 9-week study of 75 subjects: target dosing to 4 mg/day • - Improved ADHD in majority of subjects (-16 drop in ADHDRS) • - Tolerable AEs abdominal pain, fatigue and irritability most common • - CV, typically BP/HR dose-dependent decreases, no CV symptoms reported • Adverse effects to stimulants or nonstimulantsComorbid ADHD plus • - Oppositional disorder • - Anxiety • - Tics • - '"Emotional dysregulation' • Potentially younger children (needs to be studied) Guanfacine Extended-Release in ADHD

  32. Bupropion SR/XL(Wellbutrin) • Combined dopaminergic/noradrenergic • mechanism of action • Effective anti-ADHD agent • Effective antidepressant (adults) • Anti-smoking (Zyban)

  33. Bupropion XL in Adults with ADHD:Percent Responders* *>30% reduction from baseline; **p >0.01, p <0.05 Wilens et al. bio psych 2005

  34. Nortriptyline in Pediatric ADHD

  35. • Controlled multisite study of adults with ADHD (N = 98: 5 months) of paroxetine alone or in combination with d-amphétamine (Weiss et al. J Clin Psych. 2006). -Amphetamine effective for ADHD -Paroxetine not effective for ADHD • No clinical evidence of efficacy of SSRIs in ADHD -Helpful with psychiatric comorbidity -Some drug interactions with nonstimulants (e.g.. ATMX. TCAs) -No known drug interactions with stimulants ADHD: Serotonin Reuptake Inhibitors

  36. Modafinil Effects on OverallClinical Response

  37. Adverse Events Reported in > 5% ofModafinil FCT-Treated Patients Only adverse events that occurred more frequently in parents treated with Modafinil FCT than placebo are listed. P< 0001 vs. placebo P= 0042 vs. placebo

  38. Stimulant or nonstimulant non- or partial responders • (monotherapy, adjunctive therapy - no drug interactions • with stimulants) • • Adverse effects to medications • • Concerns of diversion or misuse of stimulants • • Need for renewable agent • • Cardiovascular risk factors (still cautionary in PI) • • Predominately cognitive deficits (e.g., motivation, arousal • of attention) • • Comorbid ADHD (?) • -Oppositional disorder • - Bipolar 'moody (evidence of usefulness in adults» Modafinil: When to Use

  39. Stimulant or nonstimulant non- or partial responders • (monotherapy, adjunctive therapy - no drug interactions • with stimulants) • • Adverse effects to medications • • Concerns of diversion or misuse of stimulants • • Need for renewable agent • • Cardiovascular risk factors (still cautionary in PI) • • Predominately cognitive deficits (e.g., motivation, arousal • of attention) • • Comorbid ADHD (?) • -Oppositional disorder • - Bipolar 'moody (evidence of usefulness in adults» Modafinil: When to Use

  40. www.gcmbhs.org Gulf Child Mental and Behavioral Health Society THANK YOU Questions?

  41. wwwww.themcc-group.ae مؤتمر الطب النفسي للاطفال العالمي الثاني

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