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1. 1-800-RETREAT www.brattlebororetreat.org Paul Boutin, MD April 29, 2009 Introduction toChild and AdolescentPsychopharmacology

2. 2 Did you know? Most uses of psychoactive drugs in children and adolescents are �off label� Little research is available, with the possible exception of stimulant use for ADHD Little research into child psych pathology and diagnosis further add to the questions � and controversies The overwhelming majority of prescriptions are written by primary care providers

3. 3 Classes of Drugs Anti-depressants Anxiolytics Antipsychotics Mood Stabilizers Stimulants

4. 4 SSRIs (selective serotonin reuptake inhibitors) First line treatment for depression and anxiety Blockage of serotonin results in enhanced serononinogeric neurotransmission in the CNS Multiple, mild, side effects possible: GI (nausea, vomiting), CNS (headache, insomnia), sexual, (decreased libido), General (weight loss, increased sweating, rash) Higher doses needed for anxiety Full therapeutic effects delayed 2 to 12 weeks Prozac, Celexa, Lexapro, Zoloft, Paxil, Fluvox SNRI (selective noradrenergic reuptake inhibitors) Less commonly used in children Effexor, Cymbalta Atypical Wellbutrin, Remeron, Trazadone Tricyclics (TCAs) amitryptyline, clomipramine, desipramine, imipramine, nortriptyline, doxepin MAOIs Phenelzine, tranylcypromine Anti-depressants Fuaif [pf qefjwpeow\ Efepw ewkweFuaif [pf qefjwpeow\ Efepw ewkwe

5. 5 Prozac (fluoxetine) First, and still among the most common, SSRIs FDA indications: depression, OCD (both for ages 7 and up) Possible indications: use in younger children, panic, generalized anxiety, bulimia Very long half life; weekly formulation available Usual Dosing: 20-40mg daily Dosing range: 10-80mg daily (higher doses for anxiety) More common side effects: agitation, anxiety Less common side effects: increased suicidality, mania Absolute Contraindications: MAOI use, thioridazine use Relative Contraindications: Bipolar disorder, hepatic disease, seizure disorder

6. 6 Celexa (citalopram) Well tolerated, few drug-drug interactions FDA indications: none for children Possible indications: depression, anxiety disorders Taper on discontinuation Usual Dosing: 20-40mg daily Dosing range: 10-60mg daily More common side effects: agitation, anxiety Less common side effects: increased suicidality, mania Absolute Contraindications: sensitivity to Celexa; MAOI use Relative Contraindications: Bipolar disorder, renal insufficiency, seizure disorder

7. 7 Lexapro (escitalopram) The effective enantiomer of citalopram; highly effective in recent metaanalysis of all antidepressants FDA indications: none for children Possible indications: depression, anxiety disorders Taper on discontinuation Usual Dosing: 10-20mg daily Dosing range: 5-20mg daily More common side effects: agitation, anxiety Less common side effects: increased suicidality, mania Absolute Contraindications: sensitivity to Celexa/Lexapro; MAOI Relative Contraindications: Bipolar disorder, liver insufficiency, seizure disorder

8. 8 Zoloft (sertraline) Higher degree of potency/specificity for serotonin receptors Performed well in the metaanalysis of antidepressants FDA indications: OCD ages 6 and up Possible indications: depression, anxiety disorders Taper on discontinuation Dosing range: 25-250mg daily (higher doses for anxiety) More common side effects: agitation, anxiety Less common side effects: increased suicidality, mania Absolute Contraindications: sensitivity to Zoloft; MAOI, Pimozide Relative Contraindications: Bipolar disorder, seizure disorder

9. 9 Paxil (paroxetine) FDA indications: none for children Possible indications: depression, anxiety disorders Taper on discontinuation; very short half life means this is of greater concern than other SSRIs Usual Dosing: 20-40mg daily Dosing range: 10-60mg daily More common side effects: agitation, anxiety Less common side effects: increased suicidality, mania Absolute Contraindications: sensitivity to Paxil; MAOI, Thioridazine Relative Contraindications: Bipolar disorder, NSAID use (affects platelet aggregation), seizure disorder More highly implicated in studies of increased suicidality

10. 10 Luvox (fluvoxamine) FDA indications: OCD in children 8 and up Possible indications: depression, anxiety disorders Now rarely used; did not do well in metaanalysis Taper on discontinuation Usual Dosing: 50-300mg (upper 200mg children) daily Dosing over 50mg should be in divided doses More common side effects: agitation, anxiety Less common side effects: increased suicidality, mania Absolute Contraindications: sensitivity to Luvox; MAOI, Thioridazine, terfenadine, astemizole, pimozide, cisapride use Relative Contraindications: Bipolar disorder, liver disease, seizure disorder

11. 11 SNRIs Effexor (venlafaxine) and Cymbalta (duloxetine) Combination of serotonin and norepinephrine reuptake inhibition FDA Indications: none in children/adolescents Possible Indications: depression, anxiety disorders, neuropathic pain Dosing not well known for children. Effexor 75-225mg daily, divided dosing; extended release version available Cymbalta 20-60mg daily Taper Effexor slowly on discontinuation Absolute Contraindication: hypersensitivity, MAOI Relative Contraindication: bipolar, seizure disorder, HTN (Effexor) Side Effects: sexual, GI, agitation, sweating

12. 12 Atypical Antidepressants Wellbutrin (bupropion) Decreases seizure threshold. Do not use for bulemic patients. Discontinue with taper. No FDA indication in children. Possibly effective in treating ADHD, depression. Dosing 75-225mg children, 150-400mg teens, divided dosing. Exists in extended-release formulation. Higher doses for ADHD treatment (to 450mg daily) Also used to augment SSRI treatment, or in patients with manic tendencies Remeron (mirtazapine) No FDA indication in children. Possibly effective in treating epression, anxiety disorders Dosing 15-45mg at bedtime Highly sedating, associated with weight gain Desyrl (trazadone) Anti-depressant generally used as a sleep aid, sometimes for migraine treatment No FDA indications in children Side effect of priapism Dosing 50-400mg daily

13. 13 Tricyclic Antidepressants Block the reuptake of norepinephrine and serotonin Clinical Concern over toxicity, especially cardiac. There have been reports of sudden death Especially concerning in overdose Greatly decreased use since the advent of the SSRIs Only FDA indications are for OCD for Anafranil (clomipramine) and enuresis for Trofranil (imipramine) Possible indications: depression, anxiety disorders, ADHD, migraine, neuropathic pain Other TCAs include: Elavil (amitryptyline), Norpramine (desipramine), Pamelor (nortriptyline), Sinequan (doxepin) Generally dosed in the 50-200mg daily range

14. 14 Monoamine Oxidase Inhibitors Block the deactivation of monoamines (including serotonin, norepinephrine and dopamine) Almost no use in children given potential toxicity and strict diet guidelines Must follow a tyramine-free diet, or face life threatening hypertension Greatly decreased use since the advent of the SSRIs No FDA indications in children/adolescents Include: Nardil (phenelzine), Parnate (tranylcypromine), selegiline

15. 15 Anxiolytics/Sedatives Benzodiazepines Long-term use not recommended in children/adolescents High incidence of idiosyncratic, activating disinhibition High abuse and addiction potential; increases as more short-acting May inadvertently teach increased helplessness, the feeling that anxiety will only pass with a pill, if used on an as needed basis Long-acting: Klonopin (clonazepam) [0.5-4mg daily, divided], Valium (diazepam) [2-10mg daily, divided], Librium (chlodiazepoxide) Intermediate-acting: Xanax (alproazolam) [0.5-2mg daily, divided] Short-acting: Ativan (alprazolam) [0.5-8mg daily, divided], Halcion (triazolam), Restoril (temazepam), Serax (oxazepam), Versed (midazolam) FDA indications in children: seizures, sleep terrors, sleepwalking, procedural sedation, insomnia (<2 weeks only) Possible indications: Anxiety disorders, Bipolar disorder, aggression, tics Side Effects: sedation, disinhibition, addiction, withdrawal seizures, hallucinations

16. 16 Anxiolytics/Sedatives Buspar (buspirone) Non-benzodiazepine anxiolytic, studied almost exclusively in adults Not sedating, no abuse potential Multiple CNS targets No FDA indications for those under 18. Possible indication for anxiety disorders. Dosing 20-40mg daily in divided doses. Contraindications, side effects, similar to SSRIs (except no known increase in suicidality Novel benzodiazepine receptor agonists Ambien (zolpidem), Sonata (zaleplon) [5-10mg daily, at bedtime] Lunesta (eszopiclone) [2mg daily, at bedtime] Highly sedating, used only for insomnia. Do not have the muscle/coordination effects of benzodiazepines, no effect on seizures. No FDA indication for children/adolescents. Very little pediatric data, and not endorsed for use in children

17. 17 Anxiolytics/Sedatives Beta blockers Propranolol, atenolol, etc No FDA indication in child psychiatry used for anxiety, especially performance related anxiety Also used to control rage episodes Chloral Hydrate FDA indication for pre-op sedation those <18. Potential toxicity and withdrawal syndrome if used long term Still used for sleep on an outpatient basis in extreme cases Melatonin Endogenous hormone, used to reset sleep pattern when given before bedtime Little oversight of production, thus quality concerns. Dosing varies: 1-10mg Some concern for interaction in various hormonal axes Rozerem (remelteon) is a synthetic, melatonin receptor agonist

18. 18 Antihistamines First generation antihistamines cause sedation and impart an anxiolytic effect, by antagonizing acetylcholine and histamine receptors Relatively side effect free, aside from sedation, anticholinergic effects Benedryl (diphenhydramine) Used as a sedative agent and to treat the dystonic side effects of antipsychotic medication Dosing from 25-300mg daily, in divided doses Vistaril (hydroxazine) Used as an short-term anxiolytic � the only FDA indication for antihistamine use for a primary psychiatric disorder Dosing from 10-100mg daily in divided doses Periactin (cyproheptadine) Some evidence that Periactin helps with nightmares and disturbed sleep seen in PTSD Also some feel Periactin increases appetite and it has been used in treating anorexia nervosa

19. 19 Antipsychotics Divided into two groups, typical (first generation) and atypical (second generation) antipsychotics, they were originally designed to treat thought disorders Typical antipsychotics are older medications, that frequently had the side effect of dystonia. They also did not treat negative symptoms (such as apathy) very well Atypical antipsychotics are newer, less likely to cause dystonia, and are felt to treat negative symptoms better All act on dopamine receptors, atypicals also at serotonin receptors As atypicals were seen to be safer drugs, their uses began to extend beyond treatment of thought disorders to encompass treatment of tic disorders, mood stabilization and aggression Typical antipsychotics are still used, sometimes when a patient fails atypical treatment, but also as serious side effects (largely metabolic) have been seen with the atypicals The prototypical first generation drugs are Haldol (haloperidol) and Thorazine (chlorpromazine), but include Moban (molindone), perphenazine and fluphenazine. The second generation drugs are Zyprexa (olanzapine), Risperdaal (risperidone), Geodon (ziprazidone), Seroquel (quetiapine), Abilify (aripiprazole) and Clozaril (clozapine)

20. 20 Typical Antipsychotics Haldol (haloperidol) Most commonly used of the typical antipsychotics FDA indication for psychosis and Tourette�s for 3 years up, as well as explosive aggression if psychosocial intervention and other meds have failed High rates of akasthesia, dystonia, EPS (Parkinsonism) and long-term risk of tardive dyskinesia (possibly permanent involuntary movements) Dosing: 1 to 20mg daily, higher doses divided Moban (molindone) Recently found to be as effective, in treating early onset psychosis, as a selection of atypicals, when tolerance was taken into account Weight neutral, no QTc effect FDA indication for psychosis for 6 years and older Dosing 50-225mg daily Thorazine (chlorpromazine) FDA indications for severe behavioral issues or psychosis 6 months & older Lowers seizure threshold Dosing range 50-600mg daily, depending on level of psychosis/aggression

21. 21 Zyprexa (olanzapine) Medium potency Excels in treating psychosis, at the price of extreme metabolic side effects (weight gain, elevated glucose, cholesterol, triglycerides) FDA indications: none for children Possible indications: psychosis, mood stabilization, augmentation of antidepressants, tics, agitation/aggressive behaviors Dosing range: 2.5-20mg daily Some work being done on treating the metabolic effects with Metformin

22. 22 Risperdal (risperidone) High potency Also excels as an antipsychotic, but at the expense of higher rates of dystonia, some metabolic effects, and prolactinemia FDA indications: Agitation in autism Possible indications: psychosis, mood stabilization, tics, agitation/aggression Dosing range: 0.25-6mg daily, in divided doses Monitor prolactin levels, and metabolic markers May require anticholinergic treatment (Benedryl, Cogentin) for dystonic reaction

23. 23 Seroquel (quetiapine) Low potency Less effective in treating psychosis, but frequently used for its sedating effects Notable metabolic effects FDA indications: none for children Possible indications: agitation, mood stabilization, tics, psychosis Dosing range: 25-800mg daily, in divided doses Short half-life, may need many doses in a day Extended release formulation available Used for insomnia, and as needed anxiolytic

24. 24 Geodon (ziprazidone) Medium potency Most notable for need to monitor EKGs, due to possible lengthening of the QTc interval FDA indications: none for children Possible indications: psychosis, tics, mood stabilization, agitation/aggression Dosing range: 20-160mg daily, divided doses Has the potential for metabolic effects, as well

25. 25 Abilify (aripiprazole) Medium potency Initially marketed as having low likelihood of metabolic effects � this may or may not be true in all cases FDA indications: none for children Possible indications: psychosis, mood stabilization, tics, agitation/aggression Dosing range: 10-30mg daily

26. 26 Clozaril (clozapine) Medium potency Highly effective as an antipsychotic, working when many other medications have failed Used as a last resort due to slow titration and monitoring schedules, secondary to the serious side effect of neuropenia Also has seizures as possible side effect Low rates of dystonia, but high rates of metabolic effects FDA indications: none for children Possible indications: psychosis, mood stabilization, tics, agitation/aggression Dosing range: 25-900mg daily Requires scheduled (and reportable, to a registry) WBC/ANC

27. Mood Stabilizers This is not a uniform group of medications, but are varied medications used to modulate manic and depressed mood states Can refer to the antipsychotics, anticonvulsants or lithium Among the anticonvulsants Depakote (valproic acid), Tegretol (carbamazepine), Trileptal (oxcarbazeine), Lamictal (lamotrigine) are frequently used Neurontin (gabapentin) and Topomax (topiramate), although used, have not been shown to work well as mood stabilizers. 27

28. 28 Eskalith, Lithobid (lithium) Naturally occurring salt, in the same chemical family as sodium, likely changing the flow of sodium in neurons The only mood stabilizer to show decreased risk of suicide (in adults) FDA indications: manic episodes, ages 12 and up Possible indications: mania in younger children, aggression Dosing range: determined by blood levels, narrow range between therapeutic and toxic levels Typical doses would be 1200-1800mg daily in divided doses. Extended release formulation still requires dosing twice daily Side effects are multiple: GI upset, thirst, tremor (all somewhat common); kidney, thyroid and cardiac effects Requires labs for monitoring: therapeutic level, thyroid functioning, electrolyte levels, kidney function High risk in overdoes, requires hemodialysis

29. 29 Depakote (valproic acid) Anticonvulsant First alternative to lithium studied (in adults); possibly functions by decreasing neuronal excitability FDA indications: none for children, aside from seizure prophylaxis Possible indications: mood stabilization, agitation/aggressive behaviors Dosing range: weight based, and monitored by blood levels Typical dose for an average teen around 1000mg per day, in divided doses Side effects include liver toxicity, pancreatitis and thrombocytopenia. Should monitor with regular blood work Cannot be used in pregnancy

30. 30 Tegretol (carbamazepine) Anticonvulsant Less common use due to side effect profile FDA indications: none for children, aside from seizure control Possible indications: mood stabilization, agitation/aggressive behaviors Dosing range: 800-1200mg daily, in divided doses, titrated to therapeutic dose (induces its own metabolism) Also requires blood monitoring, for therapeutic level; hematological, electrolytes, kidney and liver monitoring Side effects include: blurred vision, clumsiness, nausea/vomiting More serious side effects of liver and kidney failure, aplastic anemia, leukopenia

31. 31 Trileptal (oxcarbazepine) Anticonvulsant FDA indications: none for children, aside from seizure control Possible indications: mood stabilization, agitation/aggressive behaviors Dosing range: 900-1200mg daily, in divided doses, titrated to therapeutic dose Side effects similar to Tegretol, but not as common/serious

32. 32 Lamictal (lamotrigine) Anticonvulsant, not related to other anticonvulsant drugs FDA indications: none for children, aside from seizure control Possible indications: mood stabilization, especially in controlling depression; agitation/aggressive behaviors Dosing iIs started at 12.5 or 25mg daily, and titrated slowly to avoid Stevens-Johnson syndrome (toxic epidermal necrosis) Typical dose is 200mg daily

33. Stimulants Stimulant medications are well-studied and effective for ADHD management Multiple formulations exist, that result in varied coverage over time All have FDA indications for child/adolescent ADHD (and narcolepsy) All the formulations have the same side effect profile: decreased appetite (with association of slowed growth), agitation, insomnia Many of the formulations have notable abuse potential All are schedule II drugs; written monthly refills 33

34. Stimulants Short-acting 4 to 6 hour coverage: Adderall (mixed amphetamine salts): 5-40mg daily, divided Dexedrine (dextroamphetamine): 5-60mg daily, divided doses Focalin (dexmethylphenedate), 10-20 mg daily divided doses Ritalin(methylphnedate): 10-60 mg daily, divided doses Extended-release (~50% immediate and 50% extended release) 8 hour coverage: Metadate CD (methylphenedate): 20-60mg daily Ritalin LA (methylphenedate): 10-60mg daily 10-12 hour coverage: Adderall XR (mixed amphetamine salts): 10-20mg daily Concerta (methylphenedate): 18-72mg daily 34

35. Stimulants Transdermal Daytrana (methylphenedate): 10-30 mg daily One patch daily, remove in evening Some skin irritation Placement issues (so child does not remove) Prodrug Vyvance (lisdexamfetamine): 20-70mg daily Metabolically converted to dexamphetamine, lessened abuse potential 35

36. Non-Stimulants Strattera (atomoxetine) SNRI. Same side effect profile as antidepressants FDA indication for treatment of ADHD. No abuse potential Dosing: 40-100mg daily, single dose or divided Provigil (modafinil) FDA indication for narcolepsy Possible indication for ADHD Dosing: 200mg daily in the morning Alpha adrenergic agents Originally antihypertensives, requires monitoring of blood pressure, must taper on discontinuation No FDA indications, outside of HTN Possible indications: ADHD, tics, aggression Clonidine: 0.05- 0.3mg in divided doses Reports of sudden cardiac death when used with stimulants Guanfacine: 1-3mg in divided doses 36

37. References Pediatric Psychopharmacolgy: Fast Facts Daniel F. Connor, MD, and Bruce M. Meltzer, MD More medically focused Helping Parents, Youth and Teachers Understand Mediations for Behavioralamd Emotional Problems Mina K.Dulcan, MD Oriented to the non-medical audience 37