1. Psychopharmacology in Children Irving Kuo M.D. Central Arkansas Veterans Healthcare System

2. Psychopharmacology requires a sense of humor. Sometimes, the best use of evidence-based medicine is to remember how little evidence we have. TA Kramer M.D.

3. Psychopharmacology is big business.

4. Psychiatric Medication Use - Antidepressants Antidepressants prescriptions: 1988 – 40 million 1998 – 120 million 2004 – 150 million Antidepressant revenues 1986 - $263 million 2004 - $11.2 billion

5. Psychiatric Medication Use - Antipsychotics Revenues: 1986 - $263 million 2004 - $8.6 billion For last quarter of 2005 – 4/5 drugs that Arkansas Medicaid paid most for were for antipsychotic meds

6. Psychiatric Medication Use – ADHD Medications 2.5 million children and 1.5 million adults prescribed these meds (2005) $3.5 billion in revenues for 2005 Marked increase in prescription since 1999 – advent of new formulations

7. Psychiatric Medication Use - Depakote $886 million dollar sales last year Leader in prescriptions for bipolar disorder

8. The Developing Brain Most brain cells (neurons) are formed by the 2 nd trimester in the fetus. Neuronal migration (movement of neurons to their correct location) begins within weeks of conception. Brain volume is at 95% of adult volume by age 5.

9. The Developing Brain Neurons transmit signals electrically and chemically through synapses. Neurons ondergo myelinization (insulation) and arborization (branching out) - continue throughout childhood and into adolescence/early adulthood. Synapse formation continues throughout ones lifetime

12. The Developing Brain Neurons that are created at birth must be the right ones. Neurons must migrate to the right parts of the brain – orchestrated traffic. Synapses must form once neurons are correctly placed.

13. The Developing Brain Neurons and their synapses are quite changeable or “plastic” – neuroplasticity. Neurons kill/prune themselves – apoptosis. Up to 90% of neurons made during fetal development undergo apoptosis. Apoptitic neurons “fade away” – the body removes sick/damaged cells – survival of the fittest.

14. The Developing Brain At age 6 – more synapses than at any other time. As children grow older – the brain prunes away half of all synaptic connections. Hopefully, the body chooses well which synapses to keep and which ones to destroy. New synapses form and are pruned throughout adulthood at a much slower rate

15. Children are not small adults in how their body handles drugs.

16. As little evidence as there is for psychopharmacology in adults, there’s much less for children.

17. Antidepressants - SSRIs Prozac (fluoxetine) Paxil (paroxetine) Zoloft (sertraline) Luvox (fluvoxamine) Celexa (citalopram) Lexapro (escitalopram)

18. Antidepressants - SSRIs Selective serotonin reuptake inhibitors – increase serotonin available in synapse Takes 2-4 weeks to begin to work Used for depression and anxiety disorders (OCD, panic disorder, PTSD, social phobia) Used for eating disorders, especially bulimia nervosa

20. Antidepressants – SSRIs How well do they work? In ideal studies – 2/3 patients responded Response vs. remission In more “real world” studies – 30% remission rate in adults Only Prozac is approved by FDA for depression in children Prozac, Luvox and Zoloft FDA- approved for OCD

21. Antidepressants – SSRIs How well do they work? Research indicate mixed results in children – some studies show a modest improvement in depressive symptoms, others show no difference when compared to placebo (sugar pill) British study in 2004 – pooled available studies and indicated little to no improvement in children compared to placebo

22. Antidepressants – SSRIs Pharmocokinetic Differences Paxil cleared in children ages 6-17 faster than in adults, although once a day dosing is still recommended. Prozac serum levels were almost twice as high in children than adolescents/adults with same dose – decrease dose for kids

23. Antidepressants – SSRI Adverse events Behavioral activation in children – anxiety, restlessness or agitation Possible switch to mania if patient is really bipolar Amotivational syndrome Possible bleeding complications – easy bruisability

24. Antidepressants and Suicide in Children In 2004, the FDA looked at 24 clinical trial involving 4,400 children and adolescents taking antidepressants for depression and anxiety disorders. Children taking active meds – 4% developed suicidal thoughts/behaviors Children taking placebo – 2% No children in studies committed suicide.

25. Antidepressants and Suicide in Children This led to the FDA “black box” warning on package inserts about a possible link between antidepressants and onset of suicide behavior. Possible explanations: - behavioral activation - manic switch - patient getting better in terms of energy but not mood

26. Antidepressants and Suicide in Children – Conclusions? Antidepressants do help some children – the actual suicide rate in children/adolescents has decreased since the advent of SSRIs. Close monitoring is a must for those on antidepressants – especially initially. Medications should be only a part of a comprehensive treatment plan.

27. Atypical Antipsychotics Clozaril (clozapine) – not much in kids Risperdal (risperidone) Zyprexa (olanzapine) Seroquel (quetiapine) Geodon (ziprasidone) Abilify (aripiprazole)

28. Atypical Antipsychotics – Indications/Uses Psychosis Disorganized behavior Bipolar disorder Tics More controversial but increasing: ADHD ADHD Conduct disorder Conduct disorder Pretty much any behavior we don’t like Pretty much any behavior we don’t like

29. Atypical Antipsychotics – Indications/Uses Recent Vanderbilt University study – 5-fold increase in antipsychotic use in children for ADHD Feeling among prescribers that atypicals are safer than the old generation antipsychotics Don’t have the neurologic side effects of typical agents (or less frequent)

30. Atypical Antipsychotics – Mechanism of Action Block dopamine receptors – antipsychotic action Block serotonin receptors – prevent extrapyramidal side effects, reduce negative symtoms of schizophrenia Pharmacokinetics have not been studied in children very much – seems to be similar to adults

31. Atypical Antipsychotics – Adverse Effects Extrapyramidal effects - acute dystonic reaction - akathesia (restlessness) - Parkinson-like symptoms Tardive dyskinesia These are less common in the atypical antipsychotics but still possible

32. Atypical Antipsychotics – Adverse Effects Weight gain/obesity Increase blood sugar (diabetes) Increase lipids (cholesterol/triglyceride levels) Sedation Increase prolactin levels – amenorrhea, galactorrhea, breast enlargement (males) Cardiovascular - arrhythmias

33. Atypical Antipsychotics – Conclusions? Effective in treatment of psychosis, tics, and behavioral problems where nothing else helps (i.e. developmental disorders) Increasing use in ADHD and conduct disorders without basis in literature Side-effects are not trivial – weight gain, metabolic – in a population where obesity is an increasing problem Neurological side-effects still possible – who know what are the long-term CNS impact on kids

34. ADHD Medications – stimulants Ritalin, Concerta (methylphenidate) Dexedrine (dextroamphetamine) Adderall (mixed amphetamine salts)

35. ADHD Medications – stimulants Mechanism of Action Effect dopamine (DA) and norepiniphrine (NE) in the frontal lobes and other parts of the brain Increase release of DA and NE in neurons Block reuptake of DA and NE Basically increase DA concentration in synapses

36. ADHD Medications – stimulants Numerous studies point to significant efficacy over placebo in treatment of ADHD – in children and now in adults Rate of prescriptions for children is actually leveling off, but increasing for adults (adult ADHD) – 140% increase from 2004 to 2005

37. ADHD Medications – stimulants Pharmacokinetics Immediate release stimulants are rapidly absorbed by the gut – this can be increased by food Immediate release stimulants begin to act 30 minutes after ingestion and effect last 3-5 hours Recent introduction of long-acting stimulants with delayed delivery system – once a day dosing

38. ADHD Medications – stimulants Adverse Events Sleep problems Decreased appetite JitterinessHeadache Cardiovascular effects

39. ADHD Medications – stimulants Cardiovascular effects February 9, 2006 – FDA voted to have “black box” warnings added to labeling of stimulants warning about the cardiovascular risks of stimulants Sudden heart failure seen in children Concern that adults with preexisting cardiac problems could be at increased risk when taking stimulants

40. ADHD Medications – stimulants Cardiovascular effects Increase heart rate and blood pressure Committee feeling that stimulant prescribing needed to be “slowed down.” Fear surrounding increased utilization in adults

41. ADHD Medications – Stimulants Conclusions? Effective in treating ADHD – both in children and adults Side-effects are not trivial Monitoring of BP and heart rate as well as baseline and follow-up EKGs

42. Mood Stabilizers Lithium Depakote (sodium valproate) Tegretol (carbamazepine) Topomax (topirimate) Lamictal (lamotrigine)

43. Mood Stabilizers – Depakote Indications/Uses Anticonvulsant – adults and children > 10yo Bipolar disorder Migraine headaches – adults Behavioral problems in adults and kids secondary to brain damage PTSD

44. Mood Stabilizers - Depakote Most frequently prescribed medication used for bipolar disorder Increasing pediatric use for mood and behavioral control – impulsive and aggressive behaviors Increase GABA in brain – inhibitory effects

45. Mood Stabilizers – Depakote Pharmacokinetics After absorption (slowed by food), reaches peak blood level in 3 hours Half life in children – 7 hours Half life in adults – 13 hours Liver metabolism – kids under 10 yo have 50% greater clearance than in adolescents/adults Multiple drug-drug interactions

46. Mood Stabilizers – Depakote Adverse Events GI effects – nausea, vomiting, indigestion – can improve with food Weight gain/increased appetite Neurological – tremor, sedation, cognitive slowing, ataxia – may be dose related Decrease platelets in blood – increase bleeding Acute pancreatitis – rare Hair loss

47. Mood Stabilizers – Depakote Liver toxicity Fatal liver failure seen – 29/1,000,000 patients between 1987-1993 Highest risk at age 2 or younger High risk in children with mental retardation, receiving other anticonvulsants, or are developmentally delayed Not indicated in children < 10 yo

48. Mood Stabilizers – Depakote Conclusions? Lots of experience with kids since it was used as a seizure med in the pediatric population Effective in adult bipolar disorder Used off-label in kids – can be effective for aggressive/impulsive behaviors Multiple side effects – tough med to take Not for kids under 10 yo because of potential fatal liver problems

49. Psych Meds in Kids Conclusions? Very little supportive evidence for efficacy (except stimulants in ADHD) Many known side-effects Unknown effects – long term on the developing brain and body Overused? – recent study of child psychiatrists show that 9/10 of their patients are on meds Need much more than meds to help kids