PEDIATRIC PSYCHOPHARMACOLOGY

PRESENTER – Dr. Sriram.R, PG MD PsychiatryCHAIRPERSON – Dr. Arul Saravanan, Assistant Prof of Psychiatry

INTRODUCTION

Pediatric Psychopharmacology refers to the study of interaction of drugs with the body and its behavioral effects in children [1]

First reports of psychotropic drug use in adolescents in the 1930’s by Charles Bradley [2]

HISTORY OF PEDIATRIC PSYCHOPHARMACOLOGY

1997- FDA Moderation Act gave incentives for pediatric research on already adult-approved medications [3]

2002- Best Pharmaceuticals for Children Act- an extensive process for studying medications in pediatric populations [3]

2003- Pediatric Research Equity Act authorized FDA to require drug manufacturers to conduct pediatric studies [3]

With these regulations consumers and medical providers have a fairly large database for using these psychotropic medications in children

PHARMACOKINETICS: Pharmacokinetics: constitutes absorption,

distribution, metabolism, and excretion Gastric absorption

Stomach contents are less acidic, so weakly acidic drugs may be absorbed less efficiently

Distribution Most neuroleptics and antidepressants are lipophilic (less body fat)

Antipsychotics, TCA’s and Lithum eliminated more rapidly

Metabolism Increased hepatic metabolic capacity and more efficient renal clearance

BEFORE STARTING MEDICATIONS Physical exam: height, weight, vitals and abbreviated neurological

exam Labs may be required:

CBC, CMP, UA/UDS, TSH Urine HCG in females of reproductive age Fasting lipids and glucose May consider lead level, karyotype and/or specific chromosomal analysis

if MR is suspected

CLASSIFICATION OF DRUGS Each class of drugs has a different way of functioning

in the body [4]:

• Stimulants• Anti-depressants• Anti-psychotics• Mood Stabilizers/Anti-Convulsants• Anxiolytics and Sedatives

STIMULANTS Centrally and peripherally enhance both dopaminergic and

noradrenergic transmission to improve cognitive and behavioral functioning [2]

Methylphenidate (Ritalin), Dextroamphetamine (Focalin), Pemoline (Cylert), Amphetamine-dextroamphetamine (Adderall)

Are the most prescribed psychotropic agents Most commonly used with ADHD [5] Over 200 controlled studies have shown that stimulant

medications are safe and effective [2]

ANTI-DEPRESSANTS Act on central pre- and post-synaptic receptors affect neurotransmitter

release and uptake (i.e. serotonin, norepinephrine, dopamine) [2] 4 main sub-classes: monoamine oxidase inhibitors (MAOIs), tricyclic

(TCAs), selective serotonin uptake inhibitors (SSRIs), atypical anti-depressants

Of these, SSRIs are the most frequently prescribed (i.e. Prozac, Zoloft, Paxil)

Mostly used for major depressive disorder, but also for: OCD, insomnia, ADHD, anxiety disorders [4]

ANTI-PSYCHOTICS Effectively treat psychosis, including hallucinations, delusions,

bizarre behavior, severe agitation [4] Thought to be related to dopamine antagonist properties

2 main classes: traditional and atypical Common anti-psychotics: Olanzapine (Zyprexa), Clozapine

(Clorzaril), Chlorpromazine (Thorazine) Mostly used for schizophrenia, but also for psychotic

depression, mania, autism spectrum disorders, severe aggressive behaviors [15]

MOOD STABILIZERS/ANTI-CONVULSANTS Act through a variety of mechanisms affecting intracellular

processes- still being researched 3 most commonly used: lithium, valproate, and

carbamazepine [2] Lithium is only FDA approved drug for pediatric bipolar

disorder [4] Also used to improve aggressive behavior and conduct disorder

Valproate effectively treats mania in adults and possibly children

Anxiolytics and Sedatives Relatively less evidence compared to the other categories of

medication, but still used with pediatric medications [2] Benzodiazepines have been used for anxiety (GAD) and

panic disorders [15] Buspirone, TCA’s, SSRIs, Beta Blockers, and α-2a agonists [4] Need for more research with children, so not as frequently

used

Miscellaneous Atomoxetine (Strattera)- nonstimulant drug that was

approved for ADHD treatment [9] Thought to inhibit norepinephrine receptors

Clonidine- α-adrenergic agonist used especially for tics and sometimes ADHD and anxiety disorders [13] Reduces sympathetic outflow directly at the brain stem

therapeutic effects

DISORDERS IN CHILDREN ADHD Pediatric Bipolar Depression OCD Schizophrenia Anxiety Autism Anorexia Bulimia nervosa Obesity

ADHD

ADHD is the most commonly diagnosed psychiatric disorder of childhood [2]

4.5 million children between 5-17 years of age have been diagnosed with ADHD as of the end of 2006. [6]

• Children with ADHD can experience peer rejection, impulsivity, disruptive behaviors, low self-esteem which can affect their daily life [7]

• If not treated, symptoms can persist into adulthood [2]

Medication has proven to be extremely effective for treating ADHD

Over 200 controlled studies have shown that stimulant medication is safe and effective [2]

Methylphenidate and atomoxetine have repeatedly been found to decrease inattention and hyperactivity [9]

Stimulants for ADHD do not result in substance abuse disorders and may actually have a protective effect against development of substance abuse in adolescence [8] Also protective factor for legal difficulties and poor impulse

control

Concerns that stimulant medication may be responsible for smaller brain structures not well supported [5]

ADHD

Semrud-Clikeman et al. 2008 [7] Compared ADHD kids that have at least some history

of medication (current or past) to ADHD kids that were never exposed to treatment

ADHD children with some history of medication performed significantly better in writing, attention, executive functioning, verbal working memory, and academics. They also had less mood problems and aggressive behaviors.

ADHD children that have been medicated show better functioning even when medicine has been discontinued.

ADHD

Pappadopulos et al. 2004 [11] When reviewing a decade of studies-

stimulant medication has been tested on over 6000 ADHD children substantial evidence showing stimulants are effective at treating ADHD symptoms

ADHD

• Pelham et al. 2002 [12]–Methylphenidate shown to reduce ADHD

treatments in children with normal and low IQ

ADHD Attitudes [5] Parent

Over 90% of parents challenged and were skeptical of the doctor’s recommendation of starting medication

After 2 years- about 80% of parents considered methylphenidate a safe and effective drug

ADHD

• A few parents stopped the medication in between- but all of them restarted treatment because of belief that child performed better on medication

– Child:• After 2 years on stimulant drugs- 86% of kids

considered methylphenidate safe and effective

In the school settings- teachers and school psychologists are working with medical doctors to provide a multinodal treatment for ADHD children [10] Medication combined with psychosocial interventions show

greatest decrease in symptoms

75% of parents believe that the best treatment for ADHD = methylphenidate + psychological support

Behavioral interventions alone did not exert improvement in academic performance, emotional status, and overall functioning [13]

American Academy of Pediatrics announced that stimulant medication should be recommended to improve outcomes in ADHD children [5]

ADHD

Effectiveness of stimulants in children 6 years and older with ADHD [14]

ADHD

PBD children experience moods that alternate between depression and mania episodes

Early onset PBD often starts with depression episode that switches to BD [2] Therefore hard to estimate PBD prevalence

Children with PBD can be extremely harmful to themselves, family, and society

Medication is critical with almost all PBD cases

PEDIATRIC BIPOLAR DISORDER

PEDIATRIC BIPOLAR DISORDER Lithium- only FDA approved drug for treatment of PBD

[15] Clinical Global Assessment Scale score of more than 65 was

achieved by 47% of kids receiving lithium versus 8% of kids on the placebo [11]

Findling et al. 2003 [17] Lithium + divalproex sodium (mood-stabilizer) treatment

produced significant improvements in various areas 47% subjects met criteria for full remission after medication for 20 weeks

PEDIATRIC BIPOLAR DISORDER Kafantaris et al. 2001 [18]

Lithium + Anti-psychotic treatment (Haloperidol) showed improvement of symptoms for adolescents with PBD

Majority of patients showed reoccurrence of symptoms once medication was discontinued

• Biederman et al. 2005 [21]– When given Risperidone (anti-psychotic)- PBD patients

showed 70% response for manic symptoms and 35% for ADHD symptoms.

PEDIATRIC BIPOLAR DISORDER Pavuluri et al. 2009 [16]

Lamotrigine is an anti-convulsant commonly used for adult BD Controls glutamate release activates serotonin levels

This study showed that kids on lamotrigine medication showed significantly reduced depressive symptoms and controlled aggression and irritability compared to the placebo group

Previous adverse effect of benign rash only seen in 6% of patients and was quickly treated with no long-term effects

PEDIATRIC BIPOLAR DISORDER PBD can be extremely severe if left untreated Certain researchers today consider it unethical to have a

placebo group for children with PBD because withholding treatment can have drastic long term effects Without medication- high risk for substance abuse, conduct

disorder, suicide, and other co-morbidities [21]

Show symptoms of hallucinations, verbal and physical intrusion, lack of self-control, delusional thinking, possibly assaultive, and more [2]

DEPRESSION Increased rates of depression among kids:

especially in families dealing with divorce, abuse, neglect, bereavement [3] Harvard Medical School study in 2006 found that

childhood depression is increasing by 23% a year

Depression rates and suicide are strongly correlated suicide is the 6th leading

cause of death among children ages 5-14 [22]

DEPRESSION Fluoxetine (SSRI) has been shown to be superior to placebo in many

controlled studies. Emslie et al. 2002 [24] Tao et al. 2009 [26] Fluoxetine medication showed significantly improved results compared to

cognitive behavioral therapy alone [25]

Only FDA approved drug for pediatric depression

Tricyclic antidepressant (Anafranil) and paroxetine (Paxil) have shown some promising results in the treatment of pediatric depression More controlled studies is needed before these drugs can be frequently

distributed for treatment

OBSESSIVE COMPULSIVE DISORDER OCD in children obsessions, compulsions, persistent thoughts,

impulses, or images that are intrusive/inappropriate [14] Causes anxiety & stress Repetitive behaviors are in response to obsession

• 1/3-1/4 of OCD patients had symptoms before the age of 15 [27]

• Symptoms can manifest similar to adult OCD but often differently (i.e. temper tantrums, food restrictions, decreased academic performance) [2]

OBSESSIVE COMPULSIVE DISORDER Of all childhood disorders- OCD has most evidence supporting

pharmacologic treatment & largest number of FDA approved drugs [2]

SSRIs fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft) and clomipramine (Anafranil) are FDA approved for treating childhood OCD (age 6 and up) [2]

Geller et al. 2003 [28] Meta analysis of children with OCD showed significant difference between

children on medication and placebo Clomipramine was shown to be the most superior of the SSRIs [2]

OBSESSIVE COMPULSIVE DISORDER

Wagner et al. 2003 [29] Sertaraline has been shown effective in long term trials

because of significant remission rates and improved functional status in majority of patients

Gellar et al. 2003 [28] Continued paroxetine treatment significantly reduces

pediatric OCD relapse rates compared to the placebo

Is often comorbid with other disorders such as ADHD, tics, anxiety disorders, and PBD [14]

SCHIZOPHRENIA Pediatric schizophrenia is serious disorder that affects cognition and

ability to relate socially with others gross impairment of reality [2] Symptoms include delusions, hallucinations, distortion, disordered

speech and communication, catatonic behavior, intensity of emotions and exaggeration of behavioral control [14]

These children are significantly delayed in their school functioning, relationships, and self care. Again, without medication- can be extremely dangerous to themselves and society.

SCHIZOPHRENIA

Sikich et al. 2004 [30] Schizophrenic children and adolescents between 8-19 years of age

show significant improvement when taking either risperidone, olazapine, and haloperiodol medication

Sikich et al. 2008 [20] First and second generation atypical antipsychotics (molindone,

olanzapine and risperidone) have been shown to significantly decrease pediatric schizophrenia symptoms

Kranzler et al. 2005 [31] Schizophrenic children can often be extremely aggressive Clozapine treatment showed significant clinical improvement for

severely aggressive children

SCHIZOPHRENIA Psychotherapy alone has not been proven to be

effective for treating pediatric schizophrenia Adjunctive psychosocial treatments

(psychoeducation, behaviorally based therapy, cognitive-behavioral therapy) improves symptoms and reduces relapse rates [32]

• If the disorder is at an advanced stage- constant hallucinations and bizarre ideation can take over the child’s life without medication

ANXIETY DISORDERS One of the most commonly diagnosed psychiatric disorders affecting

populations in U.S. and Europe [14] Includes separation anxiety, panic disorder, social phobia, specific phobias, and

generalized anxiety

Not only distress to thought of threat, but also cognitive feelings of losing control, unwelcome or intrusive thoughts, inattention, insomnia, and perceptual disturbances. Affects youth more than adults

because anxiety affects normal physical and mental development

ANXIETY DISORDERS Due to a lack of current research, there are no FDA

approved drugs for the treatment of pediatric anxiety disorders [2]

But numerous medications have shown promising results: SSRIs: such as Fluoxentine have shown notable symptom

reduction with minimal side effects [10] Benzodiazepines: such as Clonazepam is useful in short-

term treatment (i.e. used to ensure child attends school) [2] α-2a Agonists: help with symptoms

of hyperautonomic arousal (i.e. palpitations) Tricyclic antidepressants [14]

OTHER DISORDERS There are several studies show evidence of psychotropic medication

decreasing symptoms in other disorders: Autism [2]

SSRIs, anti-psychotic (haloperidol, thioridazine), α-2a agonists, anticonvulsants, stimulants

Anorexia nervosa [33] Atypical antipsychotics (olanzapine), appetite enhancers, mood stabilizers

Bulimia nervosa [33] Anti-depressants, Tri-cyclic anti-depressants, SSRIs (fluoxentine)

Obesity [33] Anti-depressants, appetite suppressants

DRUG DOSAGES AT A GLANCE

TERATOGENIC RISKS OF PSYCHOTROPICS

Category A - Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

Category B - Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Category C - Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category D - There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category X - Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

CLINICAL MONITORING OF PSYCHOTROPICS IN CHILDREN

REFERENCES1) Orkin, B. G. (2002). The use of atypical antipsychotic agents for nonpsychotic disorders in children and adolescents. Doctoral dissertation, ProQuest

Information and Learning Company, Ann Arbor, MI.2) Cheng, K., & Myers, K. M. (2005). Child and adolescent psychiatry: The essentials. Baltimore: Lippincott Williams & Wilkens.3) Emslie, G. J. (2009). Understanding Placebo Response in Pediatric Depression Trials. American Journal of Psychiatry, 166(1), 1-3.4) Brown, R. T., & Sammons, M. T. (2002). Pediatric psychopharmacology: A review of new developments and recent research. Professional psychology,

research and practice, 33(2), 135-147.5) Berger, I., Dor, T., Nevo, Y., & Goldzweig, G. (2008). Attitudes Toward Attention-Deficit Hyperactivity Disorder (ADHD) Treatment: Parents' and Children's

Perspectives. Journal of Child Neurology, 23(9), 1036-1042.6) (2009). Retrieved April 14, 2009, http://www.cdc.gov/7) Semrud-Clikeman, M., Pliszka, S., & Liotti, M. (2008). Executive Functioning in Children With Attention-Deficit/Hyperactivity Disorder: Combined Type

With and Without a Stimulant Medication History. Neuropsychology, 22(3), 329-340.8) Wilens, T. E., Faraone, S. V., Biederman, J., & Gunawardene, S. (2003). Does Stimulant Therapy of Attention-Deficit/Hyperactivity Disorder Beget Later

Substance Abuse. Pediatrics, 111(1), 179-185.9) Spencer, T., Heilgenstein, J. H., Biederman, J., Faries, D. E., Kratochvil, C. J., Conners, K., et al. (2002). Results from 2 proof-of-concept, placebo-

controlled studies of Atomoxetine in children with attention-deficit/hyperactivity disorder. The Journal of Clinical Psychiatry, 63(12), 1140-1147.10) Abrams, L., Flood, J., & Phelps, L. (2006). Psychopharmacology in the schools. Psychopharmacology in the schools, 43(4), 493-501.11) Pappadopulos, E. A., Guelzow, T. B., Wong, C., Ortega, M., & Jensen, P. S. (2004). A review of the growing evidence base for pediatric

psychopharmacology . Child and Adolescent Psychiatric Clinics of North America, 13(4), 817-855.12) Pelham, W. E., Hoza, B., Pillow, D. R., Gnagy, E. M., Kipp, H. L., Greiner, A. R., et al. (2002). Effects of methylphenidate and expectancy on children with

ADHD: behavior, academic performance, and attributions in a summer treatment program and regular classroom settings. Journal of Consulting and Clinical Psychology, 70(2), 320-325.

13) Abikoff, H., Hechtman, L., Klein, R., Gallagher, R., Fleiss, K., Ectovitch, J., et al. (2004). Social Functioning in Children With ADHD Treated With Long-Term Methylphenidate and Multimodal Psychosocial Treatment. Journal of the American Academy of Child & Adolescent Psychiatry, 43(7), 820-829.

14) Vitiello, B., Masi, G., & Marazziti, D. (2006). Handbook of child and adolescent psychopharmacology (). New York: Informa HealthCare.15) Ryan, N. D. (2003). Medication treatment for depression in children and adolescents. CNS Spectrums, 8(4), 283-287.16) Pavuluri, M. N., Henry, D. B., Moss, M., Mohammed, T., Carbay, J. A., & Sweeney, J. (2009). Effectiveness of Lamotrigine in Maintaining Symptom

Control in Pediatric Bipolar Disorder. Journal of Child and Adolescent Psychopharmacology, 19(1), 75-82.

17) Findling, R. L., McNamara, N. K., Stansbrey, R., Gracious, B. L., Whipkey, R. E., Demeter, C., et al. (2006). Combination lithium and divalproex sodium in pediatric bipolarity. Journal of the American Academy of Child and Adolescent Psychiatry, 45(2), 142-146.

18) Kafantaris, V., Dicker, R., Coletti, D. J., & Kane, J. M. (2001). Adjunctive Antipsychotic Treatment Is Necessary for Adolescents with Psychotic Mania. Journal of Child and Adolescent Psychopharmacology, 11(4), 409-413.

19) Biederman, J. (2005). Attention-deficit/hyperactivity disorder: a selective overview. Biological Psychiatry, 57(11), 1215-1220.20) Sikich, L., Frazier, J., McClellan, J., Findling, R., Vitiello, B., Ritz, L., et al. (2008). Double-Blind Comparison of First- and Second-Generation Antipsychotics in

Early-Onset Schizophrenia and Schizo-affective Disorder: Findings From the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) Study. American Journal of Psychiatry, 165, 1369-1372.

21) Wilens, T., Biederman, J., Kwon, A., Ditterline, J., Forkner, P., Moore, H., et al. (2004). Risk of Substance Use Disorders in Adolescents With Bipolar Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 43(11), 1380-1386.

22) (2009). Retrieved 14 Apr. 2009, http://www.about-teen-depression.com/depression-statistics.html23) (2008). Retrieved 14 Apr. 2009, http://www.raisinganoptimisticchild.com/statistics.html24) Emslie, G. J., Heiligenstein, J., Wagner, K. D., Hoog, S., & Ernest, S. E. (2002). Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A

Placebo-Controlled, Randomized Clinical Trial. Journal of the American Academy of Child & Adolescent Psychiatry, 41(10), 1205-1215.25) TADS Team (2004) The Treatment for Adolescents with Depression Study (TADS): short-term effectiveness and safety outcomes. JAMA 292:807–82026) Tao, R., Emslie, G., Mayes, T., Nakonezny, P., Kennard, B., & Hughes, C. (2009). Early prediction of acute antidepressant treatment response and remission in

pediatric major depressive disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 48(1), 71-78.27) Oner, O., & Oner, P. (2008). Psychopharmacology of pediatric obsessive compulsive disorder: three case reports. Journal of Psychopharmacology, 22(7), 809-

811.28) Geller, D. A., Biederman, J., Stewart, E., Mullin, B., Martin, B., & Spencer, T. (2003). Which SSRI? A Meta-Analysis of Pharmacotherapy Trials in Pediatric

Obsessive-Compulsive Disorder . American Journal of Psychiatry, 160, 1919-1928.29) Wagner, K., Ambrosini, P., Rynn, M., Wohlberg, C., Yang, R., Greenbaum, M., et al. (2003). Efficacy of Sertraline in the Treatment of Children and Adolescents

With Major Depressive Disorder . The Journal of the American Medical Association, 290(8), 1033-1041.30) Sikich, L., Hamer, R. M., Bashford, R. A., Sheitman, B. B., & Lieberman, J. A. (2004). A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth:

A double-blind, randomized, 8-week trial. Neuropsychopharmacology, 29(1), 133-14531) Kranzler, H., Roofeh, D., Gerbino-Rosen, G., Dombrowski, C., McMeniman, C., Dethomas, C., et al. (2005). Clozapine: Its impact on aggressive behavior among

children and adolescents with schizophrenia. Journal of the American Academy of Child and Adolescent Psychiatry, 44(1), 55-63.32) Rector, N. A., & Beck, A. T. (2001). Cognitive Behavioral Therapy for Schizophrenia: An Empirical Review. The Journal of Nervous and Mental Disease, 189(5),

278-287.33) Powers, P. S., & Bruty, H. (2009). Pharmacotherapy for Eating Disorders and Obesity. Clinics , 18(1), 175-187.

REFERENCES

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