iacapap workshop on prescribing for children and adolescents: perspective from low resource country

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WORKSHOP ON PRESCRIBING FOR CHILDREN AND

ADOLESCENTS: PERSPECTIVE FROM LOW RESOURCE

COUNTRY

Devashish Konar Consultant Psychiatrist & Director

Mental Health Care Centre, Kolkata & Burdwan, India20 September 2016, Calgary

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LEARNING OBJECTIVES:• Stimulating people to find ways to cater treatment in

low resource countries.• In countries where Child Psychiatrists are scarce,

simplifying basic concepts of paediatric psychopharmacology to educate other professionals, who need to be involved in the treatment of unreached psychologically ill children.

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FIVE SIMPLE QUESTIONS IN RELATION TO CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

1. As compared to adult, liver is: A. More Active

B. Less Active 2. As compered to adult, elimination (weight adjusted clearance) through kidneys is:

A. Faster B. Slower

3. Research Unit of Pediatric Psychopharmacology (RUPP) has been formed under leadership of: A. Royal College of Psychiatrist, London

B. National Institute of Mental Health C. United States Food and Drug Administration

4. Blood brain barrier in children is: A. Less permeable B. More permeable

5. As compared to adult, metabolic side effects of antipsychotics are: A. More common B. Less common

BEFORE WORKSHOP AFTER WORKSHOP

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ECONOMIC CLASSIFICATIONS OF COUNTRIES OF THE WORLD:

•High resource•Low resource

Developed

Developing

Underdeveloped

First World

Second World

Third World Country

TWO DISTINCT WORLDS

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HIGH RESOURCE

Where there are many child psychiatrists, and a team working with the children.

Burning issue

Are we prescribing more?

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LOW RESOURCE

Where there are very few child psychiatrists, and there is hardly any team working with children.

Burning Issue

Are we able to reach children who need treatment?

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??? TEAM WORK ???IN LOW RESOURCE COUNTRIES

Do we need team work?Is it the same team we are talking about as in high resource countries?Whom to educate?What to educate?

How to make a team?

CASE VIGNETTE

A child of 13 years sleeping excessively, yawning when awake, nagging, clinging, irritable, demanding & destructive. Illness started following a brief febrile illness. Earlier had similar episode 8 months back.

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

(+)(-)

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(-)

HOW DO YOU MANAGE?

Take proper historyPsycho-education about bipolarityStart treatment in a way that mania is not precipitated All medicines to be built up slowFrequent follow up visitsSupport yourself with investigation related to treatmentPlan prolonged follow-up

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FEW DRUGS LICENSED

Historically, pediatric pharmacology in general and pediatric psychopharmacology in particular have received much less research interest and funding than their adult counterparts.

As a consequence, relatively few drugs are licensed for use in child and adolescent populations. (Coghill & Sinita 2014)

There is growing evidence base of increasingly widespread practice of using psychopharmacological treatment in children and adolescents.

(Huline-Dickens 2014)

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CHILDHOOD PSYCHIATRIC ILLNESSES ARE NOT TRIVIAL ONES

Childhood 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.

In fact, a staggering 50% of all adult psychiatric disorders have manifested by age 14, with 75% manifesting by age 24.

Moreover, two thirds of pediatric-onset psychiatric disorders are moderate or severe, and most continue into adulthood.

Such pattern clearly indicate the importance of identifying and appropriately treating psychiatric disorders as early as possible to preserve healthy development and to reduce individual suffering and societal burden.

(Correll et al 2013)

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SHIFT TO COLLABORATIVE CARE

Mental health issues are being recognized more and more at an earlier age.Issue is alarming, at the same time recognizing them early is good for the child. The shortage of clinicians with specialized training is always the main constraint

in case of low resource countries. Medication may become important part of treatment. Judicious evidence based prescribing, slow titration and never, ever,

over-prescribing, should be the mantra to succeed in treating children. Medication is only one piece of treatment plan, but relying on it may be in need if

other trained personnel are not available.

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CONSULTATION SHOULD BE EARLY, TREATMENT JUDICIOUS

One of the most important need in case of child mental health is facilitation of earlier psychiatric consultation.

Too often, referral for psychiatric evaluation is only considered in the context of a significant worsening of clinical status, such as onset of suicidal ideation, or when a patient or family is beginning to lose hope and turn to medications “as a last resort.”

It is important for providers to inform patients and families that waiting for symptoms to become more severe may decrease the probability of response or remission of symptoms. (Stroeh and Trivedi 2012)

So, on the one hand they need to be educated to come early for assessment, and on the other hand, you need to restrict yourself in prescribing medication unnecessarily or at the drop of hat.

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REACHING THE UNREACHED IS THE REAL CHALLENGE

Children and adolescents with psychiatric illness in low resource countries is a grossly under-cared section of population.

By rough estimates, ten percent of children & adolescents have a diagnosable mental health disorder.

Very few have access to specialist services. The treatment gap is huge.

Service delivery model has to be innovative.

With limited trained child psychiatrists, training other general psychiatrists and even pediatricians and family physicians may be more important than in high resource countries.

Sensitization about diagnostic clarity, proper drug selection, some minimal counselling and psycho-education skills and identifying adverse effects are the minimum targets that we need to foray into.

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SELECTIVE AND USEFUL KNOWLEDGE

Transmitting information in this collaborative model has to be specifically very restricted and simple.

Generalist and other specialist have to be acquainted with restricted number of medicines.

In case of antipsychotics possible drugs are risperidone, aripiprazole and quetiapine; in case of antidepressants, fluoxetine, sertraline and escitalopram; in mood-stabilizers, lithium and divalproex and among drugs for ADHD, methylphenidate and atomoxetine.

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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, introduced legislation has given FDA the authority 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. (Vitiello 2006)

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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.

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.

Off-label use has to have a scientific basis, you must take consent and the rationale for use has to be documented.

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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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AWARENESS AMONGST TEACHERS ABOUT SIDE EFFECTS OF MEDICATION

Minor side effects like sedationDystoniaSeizure

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Children 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.

Knowledge of essential differences between child and adult psycho-pharmacology should always guide a prescribing physician.

Long term deleterious effects have to be kept in mind.

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PHARMACODYNAMICS

Most psychotropics act through neurotransmitters, such as dopamine, serotonin, and norepinephrine, whose receptors undergo major changes during development. (Rho & Storey, 2001)

Receptor density tends to peak in preschool years and then gradually declines towards adult levels in late adolescence. (Chugani et al, 2001)

The impact of these developmental changes on drug activity and possible implications for efficacy and safety are still not well understood.

However, differences between children and adults in efficacy and safety have been observed thus suggesting that development can significantly influence the effects of these medications.

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PHARMACODYNAMICS

Clearly the developmental stage influences the response to a number of psychotropic medicines.

Tricyclic antidepressants, though proven effective in adult depression, have no demonstrable antidepressant effect in children (Hazell et al, 1995)

Amphetamine-like stimulants are more likely to induce euphoria in adults than in children.

Antipsychotics tend to cause stronger metabolic effects in youth than in adults (Correll et al, 2009)

Serotonergic antidepressants were found to increase the risk for suicidal ideation and attempts in children, adolescents, and young adults, but not in the middle-aged or the elderly.

(Hammad et al, 2006; Stone et al, 2009)

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PHARMACODYNAMICS

This is evident also in the lower tolerability and efficacy of methylphenidate in children with ADHD between 3 and 5 years of age as compared with older children. (Greenhill et al, 2006)

When brain development is abnormal, such as in autism, the effects of medication can be impacted, as shown by the lack of benefit from selective serotonin reuptake inhibitors for compulsive and repetitive behaviors in autism. (King et al, 2009)

Thus, information derived from data from adolescents may not be applicable to children who are younger or suffer from pervasive disorders of development.

This underscores the need for research directly in the patient populations likely to be treated with these medications. (Vitiello B. 2014)

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PHARMACOKINETICS

Right from absorption to excretion there are many differences between adults and children and they must be kept in mind while prescribing for children.

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ABSORPTION:

Although the extent of drug absorption for most medication is similar in children and adults, the rate of absorption may be faster in children and peak levels are reached earlier.

Absorption is also dependent on the form in which it is administered i.e. liquid versus tablet, and levels peak faster for liquid preparations.

(Santosh P.J. 2009) Ionized drugs (many of them weak acids) may be less well absorbed from

a child’s less acidic stomach. (Taylor E. 2015)

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METABOLISM:

The normal rate of hepatic metabolism is high in children until the time of puberty.

The result is that most medications are aggressively metabolized in the liver and rapidly excreted.

Because what ultimately matters is how much of the drug enters the bloodstream, treatment of pre-pubertal children may require dose that approach or equal those for adults.

The use of seemingly high doses for young children may seem counterintuitive to many parents, and thus it will be helpful for clinicians to explain the role of increased rate of drug metabolism.

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METABOLISM:

During the entry into puberty, the rate of hepatic metabolism significantly slows.For this reason, youngsters who have been on a maintenance dose of psychiatric

medication and tolerating it well may begin to show increasing side effects when this change in metabolic rate occurs and more of the drug begins to escape the liver and enter circulation.

Dosage adjustments may then be required, to minimize side effects. (Preston et al. 2015)

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DISTRIBUTION:

Children differ from adults in the proportions of extracellular water volume and body fat.

The proportion of extracellular water decreases substantially from birth through early adolescence.

Younger children have a relatively larger distribution volume for water-soluble drugs.

They therefore require a relatively higher dose to achieve a comparable plasma concentration.

(Johnson M.R. et al 2015)

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BLOOD - BRAIN BARRIER:

The blood-brain barrier tends to be more permeable in children than in adults. The greater permeability of the blood-brain barrier in children may mean a

greater than predicted effect. (Taylor E. 2015)

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EXCRETION:

The main route of drug elimination is through the kidneys. Absolute clearance is usually lower in children than in adults, but weight-

adjusted clearance is greater. Because of the faster elimination, the drug plasma half-life can be shorter in

children than in adults. A shorter elimination half-life means that plasma steady-state is reached

sooner during repeated administration, and that elimination is faster so that withdrawal symptoms upon discontinuation are more likely.

In these cases, a more frequent dosing is needed to maintain consistent therapeutic levels and prevent withdrawal symptoms between doses. (Vitiello 2014)

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CLINICAL GUIDELINES

At 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. Therapeutic level for :

Lithium 0.6-1.2 mEq/L. Carbamazepine 8-12 ng/ml Valproic Acid 50-125 µg/ml.

(Cobert 2013)

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PREVENTIVE MEASURES TO AVOID DRUG INTERACTION

Obtain a detailed medication history including OTC drugs and compounds from alternative approaches than modern medicine.

Young patients constitute high risk group.

So, use drugs with minimum interaction potential.

Avoid poly-pharmacy, whenever possible.

Educate patient and family, include written instruction, when appropriate.

Keep detailed, up-dated references on important potential drug interactions. (Konar 2005)

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SPECIFIC ISSUES RELATED TO PEDIATRIC PHARMACOLOGY

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.

(Bostic & Rho 2006)

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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 parents / grand parents / guardian into the working alliance paradigms of goal identification, tasks consolidation, and therapeutic bond establishment.

(Joshi 2006)

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Children’s concept about medications is to be acknowledged and respected.

They may be concerned about physical properties of the medication itself like form or size.

Then there 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.

(Joshi 2006)

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Comorbidity 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 trends toward poly-pharmacy as in adults.

Here you have to be more cautious because children have more propensity for seizure and EPS.

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Adverse events are more likely when multiple drugs are used, and interactions can be unpredictable.

Combining drugs from the same pharmacological class is rarely indicated, except when cross-tapering while switching drugs.

Combining drugs can be rational when their pharmacological actions are complementary, although the side effect burden is usually higher.

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Polypharmacy requires pharmacological expertise and should usually be supervised by a specialist.

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 low resource countries 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 low resource countries, when advising battery of investigation.

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SOME SPECIAL PRECAUTIONS First we should be committed to try to diagnose the condition to the best of our

understanding and ability before we prescribe.

We must remember, pharmacotherapy is only a part of treatment plan.Consideration must be given to all aspect of child’s life like psychosocial,

educational and family interventions. 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.

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CONCLUSION

There is great concern today that children are being over treated with medication, especially in the US. (Rapoport 2013)

By contrast, many countries make so little use of medication that it seems probable that children who could benefit do not receive it.

Under-treatment is perhaps a bigger problem globally than overmedication.

With limited availability of professionals, the low resource countries should focus on services delivery to reach to the widest population.

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FIVE SIMPLE QUESTIONS IN RELATION TO CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

1. As compared to adult, liver is: A. More Active

B. Less Active 2. As compered to adult, elimination (weight adjusted clearance) through kidneys is:

A. Faster B. Slower





BEFORE WORKSHOP AFTER WORKSHOP

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ANSWER SHEET1. As compared to adult, liver is:

A. More Active B. Less Active 2. As compered to adult, elimination (weight adjusted clearance) through kidneys is:

A. Faster B. Slower





43THANKS

iacapap workshop on prescribing for children and adolescents: perspective from low resource country

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