This document summarizes a workshop on prescribing psychotropic medications for children and adolescents in low resource countries. The workshop covered key differences in pediatric pharmacokinetics and pharmacodynamics compared to adults. It emphasized starting with low doses and slow titration given the active liver and rapid metabolism in children. General principles of monitoring, education, and avoiding polypharmacy were discussed. Challenges in low resource settings where few specialists are available were highlighted, along with the need for collaborative care models involving training of other professionals.
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Iacapap workshop on PRESCRIBING FOR CHILDREN AND ADOLESCENTS: PERSPECTIVE FROM LOW RESOURCE COUNTRY
1. WORKSHOP ON
PRESCRIBING FOR CHILDREN AND ADOLESCENTS:
PERSPECTIVE FROM LOW RESOURCE COUNTRY
Devashish Konar Consultant Psychiatrist & Director
Mental Health Care Centre, Kolkata & Burdwan, India
120 September 2016, Calgary
2. 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.
2
3. 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
3
BEFORE WORKSHOP AFTER WORKSHOP
4. ECONOMIC CLASSIFICATIONS OF COUNTRIES OF THE WORLD:
•High resource
•Low resource
Developed
Developing
Underdeveloped
4
First World
Second World
Third World Country
TWO DISTINCT WORLDS
5. HIGH RESOURCE
Where there are many child psychiatrists,
and a team working with the children.
Burning issue
5
Are we prescribing more?
6. LOW RESOURCE
Where there are very few child psychiatrists, and
there is hardly any team working with children.
Burning Issue
6
Are we able to reach children who need treatment?
7. ??? 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?
7
8. 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
(+)
(-)
8
(-)
9. HOW DO YOU MANAGE?
Take proper history
Psycho-education about bipolarity
Start treatment in a way that mania is not precipitated
All medicines to be built up slow
Frequent follow up visits
Support yourself with investigation related to treatment
Plan prolonged follow-up
9
10. 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)
10
11. 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)
11
12. 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.
12
13. 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. 13
14. 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. 14
15. 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.
15
16. 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)
16
17. 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.
17
18. GENERAL PRINCIPLES OF PRESCRIBING FOR CHILDREN
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.
18
19. AWARENESS AMONGST TEACHERS ABOUT SIDE EFFECTS OF
MEDICATION
Minor side effects like sedation
Dystonia
Seizure
19
20. GENERAL PRINCIPLES OF PRESCRIBING FOR CHILDREN
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.
20
21. 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.
21
22. 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)
22
23. 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)
23
24. 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.
24
25. 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)
25
26. 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.
26
27. 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)
27
28. 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)
28
29. 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)
29
30. 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)
30
31. 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)
31
32. 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)
32
33. 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)
33
34. SPECIFIC ISSUES RELATED TO PEDIATRIC PHARMACOLOGY
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)
34
35. SPECIFIC ISSUES RELATED TO PEDIATRIC PHARMACOLOGY
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)
35
36. SPECIFIC ISSUES RELATED TO PEDIATRIC PHARMACOLOGY
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.
36
37. SPECIFIC ISSUES RELATED TO PEDIATRIC PHARMACOLOGY
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.
37
38. SPECIFIC ISSUES RELATED TO PEDIATRIC PHARMACOLOGY
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.
38
39. 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.39
40. 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.
40
41. 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
41
BEFORE WORKSHOP AFTER WORKSHOP
42. ANSWER SHEET
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
42
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