An Overview of Psychiatric Medicine in Children and Adolescents

1. An Overview of Psychiatric Medicinein Children and Adolescents Kevin T. Kalikow, MD Author of Kids on Meds: Up-to-Date Information About The Most Commonly Prescribed Psychiatric Medications www.kevinkalikow.com

2. 3 Learner Objectives • This session will help participants: • Know the risks and benefits of the ADHD medicines • Know the risks and benefits of the medicines used to treat depression and anxiety disorders • Understand some of the controversies surrounding the psychiatric medicines used to treat children and adolescents

3. With medicine’s promise,it’s tough to do nothingOur Goal:The Responsible Use of Psychiatric Medicines in Children

4. An Overview of Our Overview • Thinking Psychopharmacologically • Stimulants, Strattera & Alpha agonists • SSRI’s & other Antidepressants • Atypical Anti-psychotics • Mood Stabilizers • Sleep Medicines • The decision to medicate

5. Disclaimers & Disclosures • Assumes a thorough evaluation • Will use generic &brand names • About the speaker • Conservative by nature • Clinician by trade • Disclosures Books published by WW Norton Your Child in the Balance: Solving the Psychiatric Medicine Dilemma Kids on Meds: Up-to-date Information About the Most Commonly Prescribed Psychiatric Medications

6. Brand/generic names of some commonly used meds mph=methylphenidate; MAS=mixed amphetamine salts; amph=amphetamine

7. Thinking Psychopharmacologically • How are medicines classified & named? • Historical reasons (ie atypical antipsychotics) • Synaptic effects (ieSSRI’s) • Molecular structure (ieTricyclicantidepressants) • Effects at different organ systems (ie Stimulants) • Targeted Disorder (ie Antidepressants) • In short: no particular system for naming meds • That might change

8. “...a rose by any other name would smell as sweet”(Juliet, circa 1594) • Names do not limit a medicine’s function • Antidepressants are used for anxiety • Antipsychotics are used for explosive anger • Mood stabilizers are used for Bipolar Disorder

9. This is Your BRAIN (please multiply by about a gazillion)

10. Thinking Psychopharmacologically • How do psychiatric medicines work? A REALLY simplisticoverview: • Stimulants increase DA in synapse • Strattera increases NE in synapse • SSRI’s increase serotonin in synapse • Wellbutrin increases DA & NE in synapse • Effexor increases NE & serotonin in synapse • Atypicals block DA receptors DA=dopamine NE=norepinephrine

11. Don’t Read This! • “…the consensus of binding studies suggests that” aripiprazole (Abilify) is a • High-affinity partial agonist at dopamine D2s, D2L, D3 and serotonin 5-HT1A receptors • High-affinity antagonist at serotonin 5-HT2A and 5-HT2B receptors • Moderate-affinity weak partial agonist at the 5-HT2C receptor • High-affinity weak partial agonist at the 5-HT7 receptor • Also, has moderate affinity at alpha1A, alpha1B, alpha2C adrenoreceptors and histamine H1 receptors (Kessler, AJP, 9/07)

12. Once They Hit the Blood Stream Highway… Medicines are like adolescents- they go where you don’t want them to and do what you don’t want them to.

13. What is that little yellow book? Some classic disorders have proven treatments. Unfortunately… most patients have not read an evolving DSM.

14. Deciding to Treat WEIGH the risks and benefits of medicine vs. the risks and benefits of other treatments vs. the risks and benefits of “no treatment”

15. Benefits?No Treatment Benefits Everyone&Many Don’t Respond Fully

16. Evaluating Benefits • Case studies thru DBPC (Double Blind Placebo Controlled) • Promising case reports often fail in DBPC trials • Beware of the drug du jour! • Results replicated? • Do your patients fit diagnostic criteria? • Beware of extrapolating from adult research • Remember the Tricyclics! • Parent’s approach: “If the shoe fits, wear it”

17. Evaluating the Risks of Medicine First do no harm but Untreated psychiatric disorders have risk

18. Evaluating the Risks of Medicine • Probability of risk from medicine • Probability of risk from placebo (nocebo effect) • Probability of risk in general population • Severity of side effect-mild, moderate, severe • Short term side effects • Long term side effects • Just remember…LIV

19. Evaluating the Risks of Medicine • Side effects depend on: • Age of patient • Dose of medicine • Duration of medicine • Metabolism of medicine • Cytochrome P450: fast vs slow metabolizers • Example: atomoxetine (Strattera)-larger effect & more side effects in slow metabolizers(Michelson, ’07) • Combination of medicines

20. A Riddle When is a side effect a therapeutic effect? The story of Obetrol

21. Thinking Psychopharmacologically • FDA indication vs “off label” • FDA requires 2 controlled studies, side effect data, etc. • FDA indicates medicine for age group and disorder • “Off-label”: Using medicine for non-FDA indication • What about generics? • Last point: • Don’t assume med is taken as prescribed OR at all

22. FDA-Approved for ADHD • Stimulants • Amphetamines • Methylphenidate • Strattera (atomoxetine) • Alpha Agonists • Intuniv (guanfacine extended release) • Kapvay (clonidine extended release) • All patients do not respond to all treatments

23. A Short History of the Stimulants • 1937: benzedrine, a form of amphetamine • originally for treatment of… (TAKE A GUESS) • Dr. Bradley reports “spectacular” improvement in school performance, with greater drive, comprehension and accuracy of work. • Late ‘50’s: Interest increases & more so in ’80’s • 1990’s: Increased use with longer acting forms • Today: many forms, but few real advances

24. Forms of Stimulants • Tablets-immediate release • Beads-extended release • Examples: Ritalin LA, Adderall XR • Beads in capsule release med at 2 different times • Some Others • OROS (Concerta) • Skin Patch (Daytrana) • Long-acting liquid (Quillivant XR) • & some newbies…

25. Some New Stimulants • Evekeo-d,l amphetamine tablets • Zenzedi-d-amphetamine tablets • Adzenys XR-extended release orally disintegrating d.l amphetamine tablets • Procentra-liquid d-amphetamine • Dyanavel XR-extended release liquid d, l amphetamine • Aptensio XR-extended release d, l MPH capsules • Quillichew-chewable MPH tablets • Companies try to have curve w/ hier serum level late in the day, otherwise get lower effect

26. Long Acting (Extended Release) Stimulant Caps • Advantages • Long duration • Improved compliance • Can be opened & sprinkled (except Concerta) • Difficult to abuse (ie-crush/snort/shoot) • Disadvantages • Don’t trust the expected durations • Irritability experienced by some (esp’ly very young?) • Can’t take late in day or if need short duration (but can match with tablets)

27. Stimulant Equivalents • At equivalent doses, all stimulants are equal • Methylphenidate 10 mg ~ Amphetamine 5 mg • MPH ir5 mg ~ Concerta 18 mg • Vyvanse 30 mg ~ Adderall XR 10 mg ir=immediate release MPH=methylphenidate

28. How Stimulants Work • Increase synaptic NE & DA in prefrontal cortex…& other areas?? • NE: increase attention to the important • DA: decrease attention to the unimportant • Methylphenidate • Blocks NET & DAT for reuptake of NE & DA • Amphetamine • Blocks reuptake AND enters synaptic vesicles causing release of NE & DA from stored sites AND blocks uptake into vesicle AND is MAOI • MPH & Amph work differently • ~70% of patients respond to first stimulant tried • ~90% of patients respond to one of the two • But real mechanism might be DA & NE modulating GLUTAMATE NET=norepinephrine transporter NE=norepinephrine DAT=dopamine transporter DA=dopamine

29. Clinical Effect of Stimulants • Strongest effect: Diminish impulsivity & hyperactivity • Strong effect: Improve focus; tasks more interesting • Also: • Improve social skills •  aggression (Blader, ’13), emotionallability(Merwood, ‘14) • Improved academic performance (short, ?long, term) • Improve teens’ driving, decrease cig initiation… REMEMBER Stimulants improve the attention of those with and without ADHD

30. The Effectiveness of Stimulants

31. Benefit of Stimulants in ADHD • MPH & Amphetamine • FDA approved for use in children • Over 200 controlled studies proving efficacy • MTA Study • Preschool ADHD Treatment Study (PATS) • Comorbid disorders complicate tx & require more than stimulants alone • Don’t forget non-pharm treatments for non-core ADHD symptoms • HA & Inatt’n might need diff doses(Stein, Ped, ’03)

32. MTA Study of the Treatment of ADHD • N=579 at multiple sites • First follow up at 14 months • Four Treatment Groups • Combo Tx (Methylphenidate & Behavioral Tx) • Methylphenidate (MPH) Only • Behavioral Tx Only • Community Care (The MTA Cooperative Group, AGP, 1999, p. 1073)

33. MTA Response Rates(% normalized at 14 months)

34. Initial Conclusions of the MTA • Combo Tx best & MPH better than Behavioral Tx • But, MPH must be used at: • Sufficient dose (avg ~30 mg/day, not 20 mg) • Sufficient dosing (avg=3 times daily, not 2) • Sufficient follow up (monthly, not 2X/yr for 17 min’s) • With sufficient contact with school staff • Behavioral tx beats MPH in kids w/ anxiety

35. 8 Year Follow up of MTA • Initial presentation is better predictor of adolescent functioning than initial tx status • Severity of ADHD symptoms • Conduct problems • Intellect • Social advantage • Strength of response to any tx • ADHD kids don’t do as well as non-ADHD kids • Meds at 6-8 yrs did not improve functioning over no meds, ex. math achievement (Molina, JAACAP, 5/09)

36. Other Benefits of Stimulants? • Lower rate of criminality(Lichtenstein, ‘12) • ~1/3 decrease in criminality while taking meds • Lower smoking rates in adolescents(Hammerness, ‘13) • Rate in medicated ADHD adol’s ~7% • Rate in unmedicated ADHD adol’s ~20%

37. Stimulants in Special Populations • PDD • Lower response rate than ADHD • More side effects than ADHD • Preschoolers (PATS, JAACAP, ’06) • Lower response rate than older children • More side effects than older children • Better at lower dose • Drug Abusers • Treat the abuse, then the ADHD

38. Starting & Stopping Stimulants • Start at the lowest dose • Increase every ~3-5 days tilclear benefit or side eff • 1st determine dose, then determine duration • Dr K’spreference for young kids-begin w/ immedrel • Should school staff be “blind” to med status? • Use on weekends-at least initially • Decr’d effect, esp’lyXR’s? Try drug holidays to regain ascending serum level curve

39. Side effects of Stimulants • Stomach aches & headaches • Slight increase in pulse & blood pressure • Decreased appetite • Insomnia • “Mood” changes, incl’g rebound, “zombieism”, etc. • Controversial topics • Sudden cardiac death • Height/weight concerns-any drug holiday helps • Tics • Addiction vs misuse

40. Strattera (atomoxetine) • Selective norepinephrine reuptake inhibitor • So, increases attention to the important • Might help decrease anxiety, not depression • Dose is weight-dependent • Takes 3-4 wks or longer • ADHD: Response rate ~50% • PDD: less effective than in ADHD • Most Common Side Effects • Sedation • GI-nausea, vomiting, abd pain,  appetite,  weight

41. Alpha-2 agonists (see Hirota, JAACAP, ‘14) • Types: • Clonidine: Catapres, Kapvay • Guanfacine: Tenex, Intuniv • FDA approved for children • Guanfacine extended release (as Intuniv) for ADHD • Clonidine extended release (as Kapvay) for ADHD • Both Int & Kap approved as adjunct to stimulants for ADHD • Approved as anti-hypertensive in adults • Effect •  hyperactivity/imp= inatt’n (&  ODD sx’s a bit) • Other uses of alpha-2 agonists in children • Tourettes • Insomnia

42. Alpha-2 agonists • How they work? • Affect NE presynaptically • So increase attention to the important • Differences • Clonidine-shorter acting than guanfacine • Clon.: binds more varied receptors, so more side effects • Side effects • Sedation-greater with clonidine • Decrease pulse/BP, so monitor, esp’ly if also on stimulants • Possible small  in QTc interval, so monitor in at risk kids • Rebound hypertension, if stopped abruptly

43. Treatments of Depression • Therapy: CBT, IPT, DBT, psychodynamic, etc. • Selective Serotonin Reuptake Inhibitors • “Novel” anti-depressants • ieWellbutrin (bupropion),Effexor (venlafaxine) • Tricyclic anti-depressants (TCA’s) • Monoamine Oxidase Inhibitors (MAOI’s) • Electroconvulsive Therapy (ECT)

44. Selective Serotonin Reuptake Inhibitors (SSRI’s) • Types • Prozac (fluoxetine) • Zoloft (sertraline) • Paxil (paroxetine) • fluvoxamine (or extended release Luvox) • Celexa (citalopram) • Lexapro (escitalopram) • FDA approval • OCD: fluoxetine, sertraline, fluvoxamine • Depression: fluoxetine, escitalopram

45. SSRI’s-Good fer what ails ya? • Uses in Children & Adolescents • Depression • OCD • Anxiety Disorders: Separation Anxiety Disorder, Social Anxiety Disorder, Generalized Anxiety Disorder • Selective Mutism • Panic Disorder • Premenstrual DysphoricDisorder • Bulimia • Not Anorexia • Not PTSD • Not Trichotillomania (but possibly clomipramine)

46. How Do SSRI’s Work? • Party line: Inhibit reuptake of serotonin, somore opportunity to bind to postsynaptic receptor sites • Research: Activate birth of new neurons? (Anacker, Molec Bio, 7/11) • Do SSRIspermanently affect the brain? • If so, for better or worse?? (see next slide) • Metabolism: mostly P450 enzymes, esp’ly 2D6 • Watch for interactions • Half life: mostly ~15-24 hours, but not fluoxetine

47. What We Don’t Know!! • 16 young monkeys: ½ stressed & ½ not stressed • ½ of each group given fluoxetine for 1 year • PET scans 1 ½ yrs after fluoxetine stopped • FLU treated monkeys: increased serotonin transporter • Apply to humans?? (Shrestha, AJP, ‘14)

48. Dosing of SSRI’s • Start Low & Go Slow • Minimizes side effects, especially early activation • Can’t tell which dose will be effective • If no response after ~6-8 weeks, change meds? • Goal is remission to minimize relapse

49. SSRI’s: All Hype or Is There Proof? • Proof of Benefit (selected studies) • Bipolar Depression? Not so fast! Avoid if Bipolar I. • Except olanzapine/fluoxetine combo in adults • Depression • Treatment for Adolescent Depression Study (TADS) (JAMA, 2004) • Anxiety Disorders • RUPP Study (NEJM 4/26/01) • OCD • Pediatric OCD Treatment Study (POTS) (JAMA 10/27/04)

50. TADS: response at 12 weeks • Combo Tx (FLU & CBT) 71% • FLU only 60% • CBT only 43% • Placebo 35% FLU=fluoxetine CBT=Cognitive Behavioral Therapy Response=50% drop in symptoms by clinician’s rating scale response