workshop on child and adolescent psychopharmacology

CHILD & ADOLESCENT PSYCHOPHARMACOLOGY

CHILD & ADOLESCENT PSYCHOPHARMACOLOGY

Devashish Konar Consultant Psychiatrist & Director, Mental Health Care Centre, Kolkata , IndiaPh: +91 9434009113 +91 9732221712

Workshop on

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AT THE OUTSETChildhood and adolescence is a period of extraordinary biological, psychological and social growth. However, at such times, individuals are also vulnerable to disruptions of healthy development. WHO survey (2006) indicates an early life onset: 50% of all adult psychiatric disorders have manifested by age 14, with 75% manifesting by age 24. Two thirds of pediatric-onset psychiatric disorders are moderate or severe, and most continue into adulthood. So early identification and appropriate treatment of psychiatric disorders as early as possible to preserve healthy development and to reduce individual suffering and societal burden is important.

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Sorel E. (2013). , 21st Global Mental Health. Jones & Bartlett Learning. P. 1

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WHAT BRINGS US HERE ?There has been a definite surge in the knowledge based on the research over last two decades in the field of prescribing for children and adolescents with psychiatric problem. In low resource countries where trained personnel are few and building a team for complete care is still a distant dream, prescribing psychotropic medicines rationally becomes the most important task.Adequate skill to identify the conditions, to be able to advise the required investigations, select proper medicine, having idea about pharmacokinetics and pharmacodynamics, to know the proper dose and titration schedule and being aware of the side effects and drug interactions should be the most sought after knowledge. We would also like to know when and how to stop medicine.

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CASE VIGNETTE -1A child of 11 years sleeping excessively, yawning when awake, nagging, clinging, irritable, demanding & destructive. Illness started following a brief febrile illness. Had earlier similar episode 8 months back.

What would you specifically want to know about this case?- History of bipolarity in the family- Thyroid status(+)

(-)

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HOW DO YOU MANAGE?

Take proper historyPsycho-education about bipolarityStart treatment with QuetiapineAdd LithiumIf depression persists can think of adding SSRI All medicines to be built up slowFrequent follow up visitsSupport yourself with investigation related to treatment like metabolic profile, renal profile and Lithium levelPlan prolonged follow-up5

CASE VIGNETTE -27 years child low intelligence, restless, inattentive, sleeps little, has history of febrile seizure.How do you select a drug if you need to ?MethylphenydateClonidine - build up dose slowly

- Pulse and Blood pressure monitoring

- Again build up slow6

CASE VIGNETTE -35 year child does not adjust well with others, cries a lot, throws tantrums, indulges in repetitive activities with his favorite toys. Hits himself when disturbed by others.Treatment:Multisystemic treatment approach: Family education, behavior shaping, speech therapy, occupational therapy, and educational planning.No specific medications are used in treating the core symptoms of autism, although some recent studies using low-dose Risperidone show some promise.7

CASE VIGNETTE -414 years boy, does not allow others in his room, keeps his room stuffed with apparently useless things. He studies a lot and is of normal intelligent with relatively below average performance. Of late he has started washing more. Treatment: Cognitive behavior therapy along with pharmacotherapy.

Drugs:SSRI in relatively high dose. Buildup slowAmong tricyclics: ClomipramineAugmentation with a typical antipsychotic like Aripiprazole8

CASE VIGNETTE -5A 7 year child presents with blinking and clearing his throat repeatedly, is slow in all activities and has difficulty in completing his home work. Patients father has Obsessive Compulsive Disorder.After doing physical examination, Eye & ENT checkup you will diagnose him Tourette Disorder.

Treatment:

Alpha-adrenergic medication such as Clonidine or GuanfacineAtypical antipsychotic HaloperidolAnti obsessive drugs if obsession is prominent.9

CASE VIGNETTE -615 Year girl admitted for a suicide attempt Argued with a friend and was very upset following which she attempted hanging.After the discharge parents reported no obvious depressionIn the follow up visit parents reported that she was hesitant in coming to Psychiatrists clinic because she feared if cameras in doctors office were recording her.On inquiry it was found that she also believed several of the boys in her school were following her. TREATMENT:Initially you might have thought of her suffering from depression but this is actually a psychotic process and you would like to treat her with antipsychotics.10

CASE VIGNETTE -78 year child under treatment of neurologist presents with Leviteracetam induced depression.

Treatment:Liaise with the treating neurologist. Ideal would be to withdraw the drugs and place the child on some other antiepileptic by cross titration.If depression does not remit SSRI may have to be given building up slowly under adequate antiepileptic coverage11

CHRONOLOGY OF PROGRESS:

In 1997 US Congress authorized FDA to grant additional 6 months of drug exclusivity in return for conducting specific studies in children.More recently, FDA authorized to require industry to conduct specific pediatric investigations when off-label use in children can be anticipated. Best Pharmaceuticals for Children Act, mandates the final study reports of industry sponsored trials be posted on the FDA website.Research Units on Pediatric Psychopharmacology (RUPPs) under the leadership of NIMH have formed. Research relevant to child psychopharmacology increased remarkably since then.

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Vitiello B. (2006). An update on publicly funded multisite trials in pediatric psychopharmacology, Child and Adolescent Psychiatric Clinic of North America Volume 15, P. 1-12

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IMPORTANT THINGS TO KEEP IN MINDChildren need to be studied separately for their own data. Children are not half, quarter or one-tenth adults. Simple body weight basis of drug dose fixation is not adequate. Pharmacodynamics and Pharmacokinetic considerations are important. Long term deleterious effects have to be kept in mind. Avoid extrapolating. There are risks inherent in extrapolating from adult data. Knowledge of essential differences between child and adult psycho-pharmacology should always guide a prescribing physician.

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COMMON CONDITIONS REQUIRING PHARMACOTHERAPIES

Anxiety DisorderObsessive Compulsive DisorderAutism Spectrum DisorderAttention Deficit Hyperactivity Disorder Conduct disorder or Oppositional Defiant DisorderChildhood SchizophreniaProdromal SchizophreniaDepressionMania Tic DisordersSleep DisordersEnuresisEncopresisSubstance Use Disorders14

Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningAripiprazole (SGA)10 and older for bipolar disorder, manic or mixed episodes; 13 to 17 for schizophrenia; 6 to 17 for irritability associated with autistic disorder2-10 mg/dayBlack Box Warning for Aripiprazole: Not approved for depression in under age 18. Increased risk of suicidal thinking and behavior in short-term studies in children and adolescents with major depressive disorder and other psychiatric conditions.

AT-A-GLANCE: PSYCHOTROPIC DRUG INFORMATION FOR CHILDREN AND DOLESCENTS15

Magellan Health- Appropriate Use of Psychotropic Drugs in Children and Adolescents. Preston et al 2015, Child and Adolescent Clinical Psychopharmacology Made Simple (Third Edition), New Harbinger Publication, Inc.

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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningHaloperidol (FGA)3 and older0.15-0.5 mg/kg/dayOther precautions for haloperidol: May cause sedation, orthostatic hypotension, photosensitivity, constipation, dry mouth, prolactin elevation.Olanzapine (SGA)Ages 13 to 17 as second line treatment of manic or mixed episodes of bipolar disorder and schizophrenia Start with 2.5-5mg qhs5-15 mg

AT-A-GLANCE: PSYCHOTROPIC DRUG INFORMATION FOR CHILDREN AND DOLESCENTS

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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningQuetiapine (SGA)13 and older for schizophrenia; 10 to 17 for treatment of manic and mixed episodes of bipolar disorder.25-300 mg/dayRisperidone (SGA)13 and older for schizophrenia; 10 and older for bipolar mania and mixed episodes; 5 to 16 for irritability associated with autism.Usually 1-2 mg/ day; Max : 3 mg/day-children; 6 mg/day adolescents

AT-A-GLANCE: PSYCHOTROPIC DRUG INFORMATION FOR CHILDREN AND ADOLESCENTS17


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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningThioridazine (FGA)2 and older3 mg/kg/dayBlack Box Warning for Thioridazine: Dose-relatedprolongation of QTc interval may cause torsade depointes-type arrhythmias and sudden death. Userestricted to schizophrenia resistant to standard antipsychotic drugs.



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Antidepressant Medications (also used for anxiety disorders)Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningClomipramine (TCA)10 and older (forOCD only)Used for OCD >10yrs: Max: 3 mg/kg/day up to 100 mg/day in first 2wk; upto 200 mg/day



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningEscitalopram (SSRI)12 and older For 12-17 (for majordepressivedisorder)5-10 mg/day Max: 20mg/day Taper dosegradually to D/CBlack Box Warning for Escitalopram: As with any other SSRi. Not to be used in children under 12 years of age.

Fluoxetine (SSRI)8 and older5-30 mg/day



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningFluvoxamine (SSRI)8 and older (forOCD only)Maximum doses:Children: 200mg/dayAdolescents:300mg/dayImipramine (TCA)6 and older (forbedwetting)1-5 mg/kg/day;150-250 ng/mL(serum level)



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningSertraline (SSRI)6 and older (forOCD only)

Maximum dose: 200 / mg/day



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningCarbamazepineAny age (for seizures)10-50 mg/kg/day8-12 mcg/mL(serum level)Black Box Warning for carbamazepine: Stevens-JohnsonSyndrome (particularly among Asians), aplastic anemia, agranulocytosis.Other warnings/precautions: neutropenia, hyponatremia,induces metabolism of itself and some other drugs, decreased efficacy of oral contraceptives, teratogenicity,MAOI use within 14 days.

Mood Stabilizing and Anticonvulsant Medications AT-A-GLANCE: PSYCHOTROPIC DRUG INFORMATION FOR CHILDREN AND ADOLESCENTS23


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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningDivalproex Sodium(Valproic acid)2 and older(seizures)Efficacy notestablished forbipolar disorderin children (ages10-17)15-60mg/kg/day50-100 mcg/mL(serum level)Black Box Warning for Divalproex Sodium: Hepatoxicity,teratogenicity, pancreatitis.Other warnings/precautions: urea cycle disorders, multiorganhypersensitivity reaction, thrombocytopenia,withdrawal seizures, suicidal ideation, polycysticovaries.



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningLithium Carbonate/Citrate12 and older300-2,400 mg/day0.5-1.2 mEq/L(serum level)Black Box Warning for Lithium: Toxicity above therapeutic serum levels. Other warnings/precautions: Renal function impairment, polyuria, tremor, diarrhea, nausea, hypothyroid, teratogenic effects. Special risk patients include those with significant renal or cardiovascular disease, severe debilitation, dehydration, sodium depletion.



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningOxcarbazepine4 and older5-30 mg/kg/day(150-1,200 mg/day)Warnings/precautions for Oxcarbazepine: hyponatremia,suicidal ideation.Lorazepam8 and olderUpto 2 mg per dose,every 4-8 hours(max)



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ADHD MEDICATIONS Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningAmphetamine/Amphetamineextended release3 and older/6 and older (XR)40 mg/day max30 mg/day max



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningAtomoxetine.6 and olderChildren: 0.5 mg/kg/dayAdolescents: 40mg/dayBlack Box Warning for atomoxetine: May cause seriouscardiovascular events including sudden death, particularly in those with pre-existing structural cardiac abnormalities or serious heart problems; increase inblood pressure and heart rate; adverse psychiatric events and liver injury.

AT-A-GLANCE: PSYCHOTROPIC DRUG INFORMATION FOR CHILDREN AND ADOLESCENTSADHD MEDICATIONS 28


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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningClonidineimmediate release(IR)/clonidineextended release(ER)IR- not approvedfor childrenER - 6-17 years oldN/AUp to 0.4 mg/dayPulse and BP check upDexmethylphenidate/Dexmethylphenidateextended release6 and older20 mg/day max30 mg/day maxDextroamphetamine3 and older40 mg/day max



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningGuanfacine6 and older27-40.5 kg: 2mg/day40.5-45 kg: 3 mg/day>45 kg: 4 mg/dayWarnings/precautions for Guanfacine: May cause sedationand hypotension. Do not discontinue abruptly.Methylphenidate/MethylphenidateER and ERsuspension6 and older60 mg/day max



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Drug Generic NameFDA Approval Age / IndicationPediatric Dosage / Serum Level when applicableWarning and precautions/ Black Box WarningMethylphenidatelong acting6 and older72 mg/day max



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GENERAL PRINCIPLES OF PRESCRIBING FOR CHILDREN

Formulating principles of prescribing psychotropic medicine in childhood and adolescence is not very simple. Many a time illness does not fully evolve and diagnosis may be difficult. In such cases you may have to target symptoms. Diagnosis can be difficult also because co-morbidity is very common. Begin with less, go slow and be prepared to end with more. Best way to decide the dose is mg/kg per day. This ideally should be child specific data and not the one extrapolated from adults. 32

GENERAL PRINCIPLES OF PRESCRIBING FOR CHILDREN

Mono-therapy is ideal but poly-therapy may often be required. Off-label use may often be necessary. Whether mono-therapy, poly-therapy, or off-label use of medication rationale of including a drug in treatment plan has to have a scientific basis.Regular monitoring of treatment in childhood and adolescence is very important. Allow time for an adequate trial of treatment. Where possible, change one drug at a time. Monitor outcome in more than one setting like home, school and play ground. Education of patient and family, at times, even teacher about medication is essential.

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Taylor D, Paton C, Kapur S. (2012) The Maudsley Prescribing Guidelines in Psychiatry, Eleventh Edition, John Wiley & Sons Ltd., UK, Chapter 5, P. 349-350

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BRAIN CHANGES ASSOCIATED WITH DEVELOPMENT

It is important to study the developing brain which provides important clues for successful prescription. Brain undergoes dramatic developmental changes which involve, among others, the very neurotransmitter systems upon which psychotropic drugs act. In human brain synaptic density is highest in the first 3 years of life, then gradually declines through synaptic pruning to reach adult levels at about 10 years of age. The cerebral metabolic rate rises rapidly until 3 to 4 years after birth, remains high until about 9 years of age, and declines to adult level in late teen years.

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DOPAMINE RECEPTOR SYSTEM

The density of dopamine receptors increases in striatum after birth, peaks at about 3 years of age, and starts declining thereafter till adulthood. The incidence of drug induced dystonia and bradykinetic reaction diminish strikingly with maturation from ages 10 to 19 years, to adulthood. One neurotransmitter may have multiple effects on different systems during development. Neuroleptic induced akathisia is less common in children. Neuroleptic withdrawal dyskinesias are more common in children.

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SEROTONIN SYSTEM

Animal studies suggested that immature organisms may lack the full capacity to upgrade a 5-HT-receptor-coupled response. This may explain the documented differences, in clinical response to antidepressants, in studies comparing children & adolescents to adults.

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PHARMACOKINETICS

There are few things specific in pediatric pharmacology which need to be kept in mind. The large liver-total body ratio- e.g. children need higher dose of Phenytoin Sodium. Greater renal clearance, e.g. children tolerate higher dosage of Lithium. Children are uniquely sensitive to some medications and develop side effects that are less or rarely seen in adults, e.g., Lamotrizine induced Steven Johnson Syndrome more common in children, idiosyncratic hepato-toxicity associated with Valproic acid seem to occur exclusively in children.

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ABSORPTIONStomach contents of children tend to be less acidic than those of adults. Acidity of stomach determines the rate of absorption. Another factor determining absorption from the gut could be the intestinal micro flora. Young children usually have fewer types of micro-organisms. Some drugs, such as chlorpromazine, are metabolized in the gut wall. It may perhaps contribute to resistance to Phenothiazine, may necessitate large dose in case of children.

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FIRST PASS METABOLISM

Once absorbed through the gut, there is a first pass through the liver before the drug is distributed around the body. In general, young children have particularly active livers. They are proportionately large, to their body weight. They are very efficient at conjugating and metabolizing many drugs, including Antidepressants and Phenothiazines. Rapid hepatic clearance reduces the bioavailability of an orally administered drug.

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DISTRIBUTIONMost psychotropic drugs get distributed in the extra cellular fluid of the body. The relative volume of extra cellular water is high in young children. During development it tends to fall while fat content rises. The most rapid changes during development are in the first year of life and after puberty in girls. Accordingly, young children may have a dose of drug distributed in a larger volume than will apply in adult life. This factor also tends to reduce bioavailability during childhood.

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BLOOD-BRAIN BARRIERThe blood-brain barrier tends to be more permeable in children than in adults. In theory, this factor will increase the bioavailability of drugs in children. It will, to some extent, be countered by greater amounts of protein entering the cerebrospinal fluid which will reduce the bioavailability of any drug that binds to protein, such as anticonvulsants.

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EXCRETIONRate of excretion may be different in children, example being Lithium Carbonate. Rate of excretion decides half-life (t), dosage schedule, and time to reach steady state.

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BEDSIDE CLINICAL GUIDELINESAt the starting point, while recommending psychotropic drugs, complexities of pharmacokinetic and pharmacodynamic factors have to be considered. Later in every case it is necessary to titrate the dose against the desired clinical response. Whenever possible, blood levels should be done. Some of them are very useful in monitoring the optimum dose of the drugs, e.g., Lithium and Anticonvulsants.

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PREVENTIVE MEASURES TO AVOID DRUG INTERACTION:Obtain a detailed medication history including OTC drugs. Young patients constitute high risk group. So, use drugs with minimum interaction potential. Avoid poly-pharmacy, whenever possible. Educate patients, including written instruction, when appropriate. Keep detailed, up-dated references on important potential drug interactions.

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SPECIFIC ISSUES RELATED TO PEDIATRIC PHARMACOLOGY:

Now we will come to some of the important issue that are very pertinent in the treatment of children and adolescents. Let us first discuss diagnosis vs. target symptom approach. At times, categorical diagnosis is easy to use; at other times, functionally impairing symptoms control may be a better approach to deal with the clinical situation. Effective pharmacotherapists should be mindful of both the target symptoms and the context and settings in which they occur. 45

Bostic J.Q., Rho Y, (2006) Target symptom psychopharmacology: between the forest and trees, Child and Adolescent Psychiatric Clinic of North America, Volume 15. P. 289-302

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Therapeutic alliance is slightly more complicated in children than adults. In pediatric psychopharmacology specifically, there is always at least a dual alliance, if not more, that must be acknowledged and nurtured. Prescribing clinicians should strive to include both patients and parent / guardian into the working alliance paradigms of goal identification, tasks consolidation, and therapeutic bond establishment.

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Joshi S.V. (2006) Team work: the therapeutic alliance in pediatric pharmacotherapy, Child and Adolescent Psychiatric Clinic of North America, Volume 15, P. 239-262

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Childrens concept about medications is to be acknowledged and respected. They may be concerned about physical properties of the medication itself like name, form, size, and labeling and printing. Then they could be wrong kind of notions about medicine. The patient may believe that only children who are sick or bad have to take medicine. Timing of the dose and frequency (like, morning, evening or during school dosage) have to be kept in mind. Special caution must be taken in using injectable medications for children and adolescents with a history of trauma.

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Joshi S.V. (2006) Team work: the therapeutic alliance in pediatric pharmacotherapy, Child and Adolescent Psychiatric Clinic of North America, Volume 15, P. 239-262

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ISSUES DEMANDING ATTENTIONComorbidity is more a rule than exception in children e.g., Intellectual Developmental Disorder, Autism, ADHD, ODD, Epilepsy, Conduct Disorder, Anxiety Disorder, Depression, they all come in different combinations. Over the last decade, pharmacotherapy in pediatric psychiatry has shown similar, if not more dramatic, trends toward polypharmacy. Here you have to be more cautious because children have more propensity for seizure and EPS.Seizure potential is of special significance in the vulnerable population of children and adolescents.

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DRUG INTERACTIONFluoxetine and Nortryptiline or Amitryptiline, Clozapine and Clomipramine or Bupropion are particularly risky combinations. And then dont forget the long half-life of Fluoxetine which may have its potentiating action long after discontinuing medicine.Some important inhibitors of CYP that are involved in psychotropic drug interactions must be remembered. There is increased risk of serious skin reactions with Lamotrigine when it is co-prescribed with Sodium Valproate, resulting from inhibition of CYP3A4.

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DRUG INTERACTIONConcomitant administration of a beta blocker with a selective serotonin reuptake inhibitor (SSRI) or other antidepressant with potent CYP 2D6 inhibition (i.e., Paroxetine, Fluoxetine, Bupropion, Duloxetine) may result in bradycardia as a result of increased concentrations of the beta blocker. Fluvoxamine is a potent CYP 1A2 inhibitor and can cause clozapine or theophylline toxicity or caffeinism. Children taking atomoxetine who are poor CYP 2D6 metabolizers have a 50% increased risk of seizures compared with extensive CYP 2D6 metabolizers. Coadministration of atomoxetine with a CYP 2D6 inhibitor could potentially result in serious toxicity, especially in patients who are poor metabolizers of CYP 2D6.

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SOME WISE THINGS TO DOIt is always good to have a ready reckoner for checking drug interactions. When advising investigations, if it is not possible to have an adequate battery done, be at least optimum. Adequate investigation may not be feasible due to financial constraints in developing economies but important ones cannot be omitted and safety concerns may never be downplayed. So taking hints from clinical presentation regarding adverse effects may be more important in the context of developing economies.

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CONCLUSION

Before we conclude we must remind ourselves of our basic commitments. We should always try to diagnose the condition to the best of our understanding and ability.Keeping differential diagnosis in mind and careful attention to comorbidities are musts in tailoring a rational prescription for the child. We must remember, pharmacotherapy is only a part of treatment plan. Consideration must be given to all aspect of childs life like psychosocial, educational and family interventions. Assess risks and benefits, have realistic expectations, and, discuss available alternative non-pharmacological treatment.

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CONCLUSION

Obtain an informed consent after discussing possible side effects and need for monitoring. Discuss black box warnings. Use the lowest possible dose. There should be frequent contact with the patient and the family. After a period of stabilization (6-12 months), evaluate the need for continued medications. Most psychiatric disorders are chronic or recurrent and so they need close follow-up after drug discontinuation. The lack of FDA approval for pediatric use of many medications imposes restrictions but also allows for the careful introduction of innovative treatment; discuss this with patient and family. Familiarize yourself well with the medicine you write and also with other drugs including OTC medication that the child may be taking for other conditions.

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Cobert J. (2013) Tarascon Pediatric Psychiatrica, Jones & Bartlett Learning, Burlington MA, P. 226-229

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CONCLUSIONAnd then to add to it, we seriously need to have our own research agenda. Research even though may seem a luxury in developing economies, there is a definite role of it for having country specific, culture specific and need based models of delivery. Copying western models blindly may neither serve the purpose nor address the problem adequately. 54

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workshop on child and adolescent psychopharmacology

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