ADHD: New Meds and New Wrinkles Lisa B. Namerow, M.D. Child and Adolescent Psychiatry Hartford Hospital/Institute Of Living Mental Health Network Associate Professor of Psychiatry and Pediatrics University of Connecticut School of Medicine March 29, 2012 Introduction Although DMS-IV suggests that ADHD symptoms must be present before age 7, they might not be observed or markedly interfere with functioning before developmental tasks exceed capabilities. For some, that might occur in preschool/grade school but for others, not until middle school, high school or beyond. ADHD: Infant/Toddler Years history of excessive perinatal activity difficult to soothe high activity level, high distractibility unable to sit in bouncy chair always on the go play more sensorimotor than symbolic 1
Infant/Toddler Years (cont d) Treatment plan anticipatory guidance reroute energy observe for other areas of developmental difficulties(r/o PDD) attempt to promote goodness-of-fit Thwart ODD? Infant and Toddler Pathways Leading to Early Externalizing Disorders (JAACAP, 2001) Looked at high-risk children with low socioeconomic status At age 5.5, children with comorbid ADHD (ODD, ODD/CD) had mothers with more agression, depression and rejecting patterns of parenting ADHD alone showed no differences from the nonproblem children in terms of maternal characteristics or other risk factors Neuropsychological factors such as executive and verbal functioning deficits seem to add to risk ADHD: Preschool Years excessive motor activity Play remains mechanical, motor-based rather than increasing need for high-stim activities, frequent redirection impulsivity can become a real problem peer play can be impaired aggression may become an issue 2
Treatment Plan: Preschool Years identify profile : hyperactive-impulsive versus inattentive access functional impairment: school, peers, family assess for comorbidities (ODD, anxiety continue to discuss/recommend behavioral interventions consider pharmacotherapy if level of impairment is marked PATS Study (2006): Preschool ADHD Treatment Study Designed to assess methylphenidate efficacy in preschool children Effect size in MTA.9-1.2 75-80% Effect size in PATS (0.4-0.8) in PATS, more side effects & intolerance (11% discontinued) and impact on growth rates All of which suggests a higher threshold for pharmacotherapy Treatment Plan (cont d) Remember: reducing hyperactivity/impulsivity can help maintain developmental trajectory and reduce failure These children can often feel really bad about getting in trouble all the time Although difficult or challenging, they still need the same encouragement/support positive parental feedback but, it is occurs with much less frequency than easy temperament child 3
Comorbidities: Preschool Years r/o more global developmental disorders (MR, PDD s) Consider other learning disorders (expressive language, executive functioning, other language-based or nonverbal (LDL) anxiety disorders mood disorders (Bipolar or Unipolar)) ADHD: School Age (More Classic Presentation) 3 subtypes: hyperactive-impulsive, inattentive, combined-type use of behavioral checklists most appropriate Vanderbilt checklist approved by NICHQ & AAP Assess for comorbidity DSM-IV Criteria for ADHD I. Either A or B: Six or more of the following symptoms of inattention have been present for at least 6 months to a point that is disruptive and inappropriate for developmental level: Inattention Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities. Often has trouble keeping attention on tasks or play activities. Often does not seem to listen when spoken to directly. Often does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions). Often has trouble organizing activities. Often avoids, dislikes, or doesn't want to do things that take a lot of mental effort for a long period of time (such as schoolwork or homework). Often loses things needed for tasks and activities (e.g. toys, school assignments, pencils, books, or tools). Is often easily distracted. Is often forgetful in daily activities. Six or more of the following symptoms of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level: Hyperactivity Often fidgets with hands or feet or squirms in seat. Often gets up from seat when remaining in seat is expected. Often runs about or climbs when and where it is not appropriate (adolescents or adults may feel very restless). Often has trouble playing or enjoying leisure activities quietly. Is often "on the go" or often acts as if "driven by a motor". Often talks excessively. 4
(CONT D) DSM-IV Criteria for ADHD I. Either A or B: Six or more of the following Often blurts out answers before questions have been finished. Often has trouble waiting one's turn. Often interrupts or intrudes on others (e.g., butts into conversations or games). Some symptoms that cause impairment were present before age 7 years. Some impairment from the symptoms is present in two or more settings (e.g. at school/work and at home). There must be clear evidence of significant impairment in social, school, or work functioning. The symptoms do not happen only during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder. The symptoms are not better accounted for by another mental disorder (e.g. Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder). Based on these criteria, three types of ADHD are identified: ADHD, Combined Type: if both criteria 1A and 1B are met for the past 6 months ADHD, Predominantly Inattentive Type: if criterion 1A is met but criterion 1B is not met for the past six months ADHD, Predominantly Hyperactive-Impulsive Type: if Criterion 1B is met but Criterion 1A is not met for the past six months. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. [ADHD References] The Vanderbilt Tool health & history form for primary care teacher s checklist & parents checklist initial screen includes comorbidities of anxiety, ODD, mood (scoring easy!) impact on learning also documented well does not access for bipolar BUT if child shows multiple comorbidities, consider bipolar Vanderbilt (cont d) follow-up checklists reference ADHD Sx s alone Scoring allows for identification of comorbidities and differentiation of ADHD subtypes What about discrepancy between teacher and parent reports? Anxiety can mediate impulsivity or hyperactivity in unfamiliar settings Remember: Final diagnosis is a clinical one; not from a checklist alone 5
Comorbidity Anxiety Disorders Mood disorders Other disruptive behavior disorders (ODD/CD) Aggression Tourette s Substance Use Disorders Female Vs. Male ADHD Females tend to be more inattentive, less disruptive overall but social impact can still be significant On CPT testing, girls show less impulsivity (MTA, 2001) More associated with LD issues, but less ODD even impulsivity can look different associated with more social butterfly chatter rather than aggression or disruptive behaviors girls with ADHD have higher levels of anxiety, somatic sxs; boys have higher ODD/Conduct Disorders Bipolar vs. ADHD Researchers believe that ADHD and Bipolar can be misdiagnosed symptom overlap but it is likely that there can be comorbidity as well In Bipolar children, rates of ADHD range 75-98% In ADHD inpatients, 22% met criteria for Bipolar (JACAAP, 1996) Nasreen et al., (2000) followed ADHD children into adulthood and noted much lower comorbidity Bottom line: the prevalence of ADHD is clearly much higher than Bipolar and therefore, when hyperactivity, impulsivity is present ADHD will be more likely 6
Bipolar vs. ADHD (cont d) Using a high index of suspicion, bipolar should be considered when: -temper tantrums are marked often lasting 3-4 hours -thought process is markedly irrational, full of violent content and/or threats and may contain hallucinations -speech is often pressured -irritability is a marked finding -there is a strong family history -grandiosity, hypersexuality can be differentiating symptoms (Geller, Carlson and others) School Age: Treatment Plan MTA serves as guideline for treatment efficacy (See Dev and Behav Peds, Feb, 2001) 4 arms: CC, Medmgt, Beh, Comb Medmgt, or Comb clearly superior Comb had interesting effects over time but was mediated by parental attitudes, strategies pharmacotherapy clearly has EBM support for ADHD (meeting full A-level criteria) MTA Study 10-m Followup After Treatment 22-m Followup After Treatment 0 14-m Treatment Stage 14 24 36 Recruitment Screening Diagnosis Random Assignment 579 ADHD Subjects Medication Only 144 Subjects Psychosocial (Behavioral) Treatment Only 144 Subjects Combined Medication & Behavioral Treatment 145 Subjects Community Controls No Treatment from Study Assessed for 24 mo. 146 Subjects Baseline Early Mid- Treatment End Treatmenttreatment (3 m) (9 m) (14 m) Assessment Points Follow-up (24 m) Recruitment of LNCG Cohort Follow-up (36 m) 7
14-Month Outcomes Teacher SNAP-Inattention 3 2.5 Average Score 2 1.5 Time x Tx: F=10.6, p<.0001 Site x Tx: F=0.9, ns Site: F=2.7, p<.02 CC Beh MedMgt Comb 1 0.5 Comb, MedMgt > Beh, CC 0 Assessment Point (Days) 0 100 200 300 400 days Teacher-Rated Inattention (CC Children Separated By Med Use) Key Differences, MedMgt vs. CC: Initial Titration Dose Dose Frequency #Visits/year Length of Visits Contact w/schools Average Score 2.5 2 1.5 1 0.5 0 100 200 300 400 Assessment Point (Days) CC-NO MEDS CC-MEDS BEH MED COMB Nonpharmacologic Interventions family psychoeducation a must behavior therapy should be considered Social skills training if social competency are significant issues 8
ADHD and School Impact on learning is quite variable depending on aymptom impact full psychoeducational evaluation if learning below grade level neuropsychological evaluation if resources are present 504 plan considered vs. IDEA designation Adolescent Years often won t meet the criteria of symptoms present since age 7 clinical impact may not have been apparent earlier because of higher IQ, better organizational skills now the bar for social & academic competence is higher and the attentional deficit is now having greater impact first presentation may be as a mood or anxiety disorder Inattention Symptoms DSM-IV Symptom Domain Difficult sustaining attention Does not listen No follow-through Cannot organize Loses important items Easily distractible and forgetful Common Adolescent/Adult Manifestations Poor time management Difficult initiating/completing tasks, changing to another task when multitasking, required Procrastination Avoids tasks that demand attention Adaptive behavior-self select lifestyle, support staff, ect. 9
Hyperactivity Symptoms DSM-IV Symptom Domain Squirms and fidgets Cannot stay seated Runs/climbs excessively Cannot play/work On the go / driven by a motor Talks excessively Common Adolescent/Adult Manifestations Adaptive behavior-working long hours, selects a lot of activities, multiple jobs, or a very active job Constant activity leading to family tension Avoids situations required low levers of activity because easily bored Symptoms often felt rather than manifested Impulsivity Symptoms DSM-IV Symptom Domain Blurts out answers Cannot wait turn Intrudes/interrupts others Common Adolescent/Adult Manifestations Low frustration tolerance quitting a job, ending a relationship, losing temper, driving too fast Makes quick decisions Interrupts Common Comorbid Psychiatric Disturbances in Adolescents with ADHD Comorbidity Prevalence Among Prevalence in General Adolescents With ADHD Adolescent Population Academic 20-60% 5-15% Impairment Major depressive 9-32% {average 25%} 3-5% Disorder Anxiety disorder 10-40% {average 25%} 3-10% Conduct disorder 20-56% Unknown Oppositional 20-67% {average 35%} 2-16%{average7-8%} defiant disorder Bipolar disorder -6-10% 3-4% ADHD=attention-deficit/hyperactivity disorder. 10
The bio part of a biopsychosocial treatment plan Considered along with school support, outside support Recent NY times article (2012) Always consider nonpharmacologic options first, or at least, along with Utilize the EBM studies, PATS, MTA Consider algorithms Pediatric Psychopharmacology: Non-Diagnostic Considerations Compliance: Can this system (i.e., family and patient) comply with twice a day or three times a day dosing? Past Medical History (i.e., Is there a history of tics, liver disease, cardiac conduction abnormalities, seizures) Need for Medical Monitoring: Will it be a problem for this family if frequent blood drawing is needed? Is there potential for this patient or anyone in the family to use this medication as a substance for abuse? Is there a potential for this patient or anyone in the family to use this medication in a suicidal gesture? New considerations:genomic Testing P450 analysis on 3 isoenzymes has been developed As a review, the P450 system is a series of enzymes in the liver which break down toxins The analysis is based on genomic technology and using whole blood, determines the presence or absence of the allelles that promote the formation of these 3 enzymes In doing so, enzymes can be categorized as normal, deficient, null or ultrarapid in their activity It has been determined by very smart pharmacologists which medications are substrates for which enzymes---some medications can even induce or inhibit the activity of an enzyme 11
DNA-Guided Psychotropic Selection Double and Triple Gene Alterations 45% Frequency of Polymorphisms 2C19 2D6 2C9 2C19 2D6 None No Gene Alterations 9% 2C9 2C19 N=577 LPH Patient Referrals Nov. 2009 2C9 2D6 2C9 2C19 2D6 Single Gene Alterations 46% THE STIMULANTS 12
Ritalin LA: Extended-release Delivery via SODAS Technology SODAS is a trademark of Elan Corporation, PLC Long-acting Methylphenidate Medications Products Concerta Metadate CD Ritalin LA Formulation Technology OROS Diffucaps SODAS Dose 18 mg 27 mg 36 mg 54 mg 20 mg 20 mg 30 mg 40 mg Immediate 22% 30% 50% release 4 mg 6 mg 8 mg 12 mg 6 mg 10 mg 15 mg 20 mg Sustained/ 78% 70% 50% 2nd release 14 mg 21 mg 28 mg 42 mg 14 mg 10 mg15 mg 20 mg Concerta [package insert]. Moutain View, CA: Alza Corporation; 2001. OROS is a registered trademark of ALZA Corporation. Metadate CD [package insert]. Rochester, NY: Celltech Pharmaceuticals, Inc; 2002. Diffucaps is a registered trademark of Eurand. Ritalin LA [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2002. SODAS is a trademark of Elan Corporation, Plc. 13
Comparison of Extended-release Methylphenidate Dosage Forms Mean d,l-methylphenidate plasma levels (ng/ml) 20 15 10 5 Ritalin 20 mg BID Concerta 54 mg Metadate CD 60 mg (3 x 20 mg) Ritalin LA 40 mg 0 0 5 10 15 Gonzalez MA, et al. Int J Clin Pharmacol Ther. 2002;40:175-184. Data on file, Novartis Pharmaceuticals. Time (h) Vyvanse Not biologically active until cleaved during the GI absorption process Reportedly has a continuous absorption that enhances duration of action Can be swallowed whole or sprinkled in water Less rebound? Daytrana Transdermal absorption Lasts 9 hours Needs to be placed and removed every day alternating sites Less ups and downs? 14
Long-acting stimulants: The good news Less chance of abuse Greater chance of compliance Less chance of stigmatizing due to trips to the school nurse Less chance of rebound Less chance of ups and downs Long-Acting Stimulants: The Bad News May have greater potential for weight loss May have greater potential for agitation:? More potent May have greater chance for sleep disturbance Take home: tolerance of short-acting stimulants does not assure tolerance of long-acting preparations but the longacting agents offer some clear advantages if well-tolerated The nonstimulants 15
Strattera: The first NRI A completely different class of medication for ADHD, a norepinephrine reuptake inhibiter Not a controlled medication The first nonstimulant approved by the FDA for age 6 and over for ADHD Works by establishing a steady state, so needs to be taken daily rather than as needed Yet, seems to have a rapid onset of action 16
Alpha 2 Agonists Mechanism: alpha 2 stimulants cause the presynaptic noradrenergic receptor to decrease sympathetic output over time, this is a brake on the release of norepinephrine. Approved for HTN in adults but used in children for treatment of tics, ADHD, and aggression. Guanfacine ER (Intuniv) A long acting version of Tenex May have less sedation FDA approved for ADHD in children over 6 Would assess tolerance by using short-acting first, then converting Comes in 1mg, 2mg, 3mg, 4mg Kapvay (clonidine) FDA approved as an adjuvant to stimulant meds Dosed twice per day Possibly less sedation than its short acting version, clonidine 17
Medication Management: ADHD (Texas Algorithm, July, 2005) ADHD ADHD with MDD ADHD with Anxiety ADHD with tics ADHD with aggression ADHD alone 18
ADHD with tics 19
ADHD with Aggression Medical workup and monitoring EKG???: Let s talk: JAACAP, October 2011) Baseline bp, pulse, ht, weight Subsequent vital signs at each visit Impact on growth?: let s talk again Two Case Illustrations: Case #1 14 y/o male currently in 9 th grade athletic, A-student presents for evaluation of depression History reveals 1-year history obsessional intrusive worries regarding academic work, tests, basketball practice MSE reveals almost rigidly anxious, tearful young man 20
Case #1 (cont d) parents revealed no past history or family history initially but when questioned.psychologist saw pt in 7 th grade for ADHD thought he met criteria, but parents felt it wasn t an issue & grades were high also very (+) family history of OCD diagnosis: OCD with underlying ADHD treatment: target OCD first then ADHD Case #2: Adolescent ADHD 13 y/o 8 th grade female presented with grades, motivation, sadness In reviewing all prior grades, there was no history of learning or attentional difficultness by teacher comments or conferences when questioned, family did reference she always has her head in the clouds when she isn t being a social butterfly DX: Depressive Disorder, NOS with R/O for ADHD TX: target depression first then ADHD College - Age May also be first presentation With transition lack of home-based structure support, need for higher-level executive functioning attentional symptoms may become first apparent Response to a friend s Ritalin does not make the diagnosis but might suggest need for further review Would suggest a neuropsychological if adolescence or college is first presentation of ADHD and had never before been considered or documented 21
Take Home Points although fairly straightforward in some individuals, ADHD can be elusive in others think developmentally sometimes, symptoms are not clinically apparent until the tasks become challenging enough some of these symptoms contribute to success given the demands of the 21 st century (Does this then contribute to the promotion of the genes?) Take home points (cont d) Literature supports that the natural untreated course of ADHD places a child or adolescent at high risk for comorbidities such as substance use disorders, Anxiety, Depression, ODD/Conduct Disorder or a sense of failure Take Home Points (con t) Adults can often find a nitch that works for their individual strengths/weaknesses But the first 18-21 years of life can be a real challenge The push for identification and treatment of ADHD is NOT meant to simply pathologize normal variants of behavior but rather to promote an at-risk child s developmental trajectory 22
23