Psychopharmacology in Psychopharmacology in ChildrenChildren

Irving Kuo M.D.Irving Kuo M.D.

Central Arkansas Veterans Central Arkansas Veterans Healthcare SystemHealthcare System

Psychopharmacology requires a Psychopharmacology requires a sense of humor. Sometimes, the sense of humor. Sometimes, the

best use of evidence-based best use of evidence-based medicine is to remember how medicine is to remember how

little evidence we have. little evidence we have.

TA Kramer M.D.TA Kramer M.D.

Psychopharmacology is Psychopharmacology is big business.big business.

Psychiatric Medication Use - Psychiatric Medication Use - AntidepressantsAntidepressants

Antidepressants prescriptions:Antidepressants prescriptions:1988 – 40 million1988 – 40 million1998 – 120 million1998 – 120 million2004 – 150 million2004 – 150 million

Antidepressant revenuesAntidepressant revenues1986 - $263 million1986 - $263 million2004 - $11.2 billion2004 - $11.2 billion

Psychiatric Medication Use - Psychiatric Medication Use - AntipsychoticsAntipsychotics

Revenues:Revenues:

1986 - $263 million1986 - $263 million

2004 - $8.6 billion2004 - $8.6 billion

For last quarter of 2005 – 4/5 drugs that For last quarter of 2005 – 4/5 drugs that Arkansas Medicaid paid most for were Arkansas Medicaid paid most for were for antipsychotic medsfor antipsychotic meds

Psychiatric Medication Use – Psychiatric Medication Use – ADHD MedicationsADHD Medications

2.5 million children and 1.5 million 2.5 million children and 1.5 million adults prescribed these meds (2005)adults prescribed these meds (2005)

$3.5 billion in revenues for 2005$3.5 billion in revenues for 2005

Marked increase in prescription since Marked increase in prescription since 1999 – advent of new formulations1999 – advent of new formulations

Psychiatric Medication Use - Psychiatric Medication Use - DepakoteDepakote

$886 million dollar sales last year$886 million dollar sales last year

Leader in prescriptions for bipolar Leader in prescriptions for bipolar disorderdisorder

The Developing BrainThe Developing Brain

Most brain cells (neurons) are formed Most brain cells (neurons) are formed by the 2by the 2ndnd trimester in the fetus. trimester in the fetus.

Neuronal migration (movement of Neuronal migration (movement of neurons to their correct location) neurons to their correct location) begins within weeks of conception.begins within weeks of conception.

Brain volume is at 95% of adult volume Brain volume is at 95% of adult volume by age 5.by age 5.

The Developing BrainThe Developing Brain

Neurons transmit signals electrically Neurons transmit signals electrically and chemically through synapses.and chemically through synapses.

Neurons ondergo myelinization Neurons ondergo myelinization (insulation) and arborization (branching (insulation) and arborization (branching out) - continue throughout childhood out) - continue throughout childhood and into adolescence/early adulthood.and into adolescence/early adulthood.

Synapse formation continues Synapse formation continues throughout ones lifetimethroughout ones lifetime

The Developing BrainThe Developing Brain

Neurons that are created at birth must Neurons that are created at birth must be the right ones.be the right ones.

Neurons must migrate to the right parts Neurons must migrate to the right parts of the brain – orchestrated traffic.of the brain – orchestrated traffic.

Synapses must form once neurons are Synapses must form once neurons are correctly placed.correctly placed.

The Developing BrainThe Developing Brain

Neurons and their synapses are quite Neurons and their synapses are quite changeable or “plastic” – neuroplasticity.changeable or “plastic” – neuroplasticity.

Neurons kill/prune themselves – Neurons kill/prune themselves – apoptosis.apoptosis.

Up to 90% of neurons made during fetal Up to 90% of neurons made during fetal development undergo apoptosis.development undergo apoptosis.

Apoptitic neurons “fade away” – the body Apoptitic neurons “fade away” – the body removes sick/damaged cells – survival of removes sick/damaged cells – survival of the fittest.the fittest.

The Developing BrainThe Developing Brain

At age 6 – more synapses than at any At age 6 – more synapses than at any other time.other time.

As children grow older – the brain prunes As children grow older – the brain prunes away half of all synaptic connections.away half of all synaptic connections.

Hopefully, the body chooses well which Hopefully, the body chooses well which synapses to keep and which ones to synapses to keep and which ones to destroy.destroy.

New synapses form and are pruned New synapses form and are pruned throughout adulthood at a much slower throughout adulthood at a much slower raterate

Children are not small adults in Children are not small adults in how their body handles drugs.how their body handles drugs.

As little evidence as there is for As little evidence as there is for psychopharmacology in adults, psychopharmacology in adults, there’s much less for children.there’s much less for children.

Antidepressants - SSRIsAntidepressants - SSRIs

Prozac (fluoxetine)Prozac (fluoxetine)

Paxil (paroxetine)Paxil (paroxetine)

Zoloft (sertraline)Zoloft (sertraline)

Luvox (fluvoxamine)Luvox (fluvoxamine)

Celexa (citalopram)Celexa (citalopram)

Lexapro (escitalopram)Lexapro (escitalopram)

Antidepressants - SSRIsAntidepressants - SSRIs

Selective serotonin reuptake Selective serotonin reuptake inhibitors – increase serotonin inhibitors – increase serotonin available in synapseavailable in synapse

Takes 2-4 weeks to begin to workTakes 2-4 weeks to begin to work

Used for depression and anxiety Used for depression and anxiety disorders (OCD, panic disorder, disorders (OCD, panic disorder, PTSD, social phobia)PTSD, social phobia)

Used for eating disorders, especially Used for eating disorders, especially bulimia nervosabulimia nervosa

Antidepressants – SSRIsAntidepressants – SSRIsHow well do they work?How well do they work?

In ideal studies – 2/3 patients In ideal studies – 2/3 patients respondedresponded

Response vs. remissionResponse vs. remission

In more “real world” studies – 30% In more “real world” studies – 30% remission rate in adultsremission rate in adults

Only Prozac is approved by FDA for Only Prozac is approved by FDA for depression in childrendepression in children

Prozac, Luvox and Zoloft FDA-Prozac, Luvox and Zoloft FDA-approved for OCDapproved for OCD

Antidepressants – SSRIsAntidepressants – SSRIsHow well do they work?How well do they work?

Research indicate mixed results in Research indicate mixed results in children – some studies show a modest children – some studies show a modest improvement in depressive symptoms, improvement in depressive symptoms, others show no difference when others show no difference when compared to placebo (sugar pill)compared to placebo (sugar pill)

British study in 2004 – pooled available British study in 2004 – pooled available studies and indicated little to no studies and indicated little to no improvement in children compared to improvement in children compared to placeboplacebo

Antidepressants – SSRIsAntidepressants – SSRIsPharmocokinetic DifferencesPharmocokinetic Differences

Paxil cleared in children ages 6-17 Paxil cleared in children ages 6-17 faster than in adults, although once a faster than in adults, although once a day dosing is still recommended.day dosing is still recommended.

Prozac serum levels were almost twice Prozac serum levels were almost twice as high in children than as high in children than adolescents/adults with same dose – adolescents/adults with same dose – decrease dose for kidsdecrease dose for kids

Antidepressants – SSRIAntidepressants – SSRIAdverse eventsAdverse events

Behavioral activation in children – Behavioral activation in children – anxiety, restlessness or agitationanxiety, restlessness or agitation

Possible switch to mania if patient is Possible switch to mania if patient is really bipolarreally bipolar

Amotivational syndrome Amotivational syndrome

Possible bleeding complications – easy Possible bleeding complications – easy bruisabilitybruisability

Antidepressants and Suicide Antidepressants and Suicide in Childrenin Children

In 2004, the FDA looked at 24 clinical In 2004, the FDA looked at 24 clinical trial involving 4,400 children and trial involving 4,400 children and adolescents taking antidepressants adolescents taking antidepressants for depression and anxiety disorders.for depression and anxiety disorders.

Children taking active meds – 4% Children taking active meds – 4% developed suicidal thoughts/behaviorsdeveloped suicidal thoughts/behaviors

Children taking placebo – 2%Children taking placebo – 2%

No children in studies committed No children in studies committed suicide.suicide.

Antidepressants and Suicide Antidepressants and Suicide in Childrenin Children

This led to the FDA “black box” This led to the FDA “black box” warning on package inserts about a warning on package inserts about a possible link between antidepressants possible link between antidepressants and onset of suicide behavior.and onset of suicide behavior.Possible explanations:Possible explanations:

- behavioral activation- behavioral activation- manic switch- manic switch- patient getting better in terms of - patient getting better in terms of

energy but not moodenergy but not mood

Antidepressants and Suicide Antidepressants and Suicide in Children – Conclusions?in Children – Conclusions?

Antidepressants do help some children Antidepressants do help some children – the actual suicide rate in – the actual suicide rate in children/adolescents has decreased children/adolescents has decreased since the advent of SSRIs.since the advent of SSRIs.Close monitoring is a must for those on Close monitoring is a must for those on antidepressants – especially initially.antidepressants – especially initially.Medications should be only a part of a Medications should be only a part of a comprehensive treatment plan.comprehensive treatment plan.

Atypical AntipsychoticsAtypical Antipsychotics

Clozaril (clozapine) – not much in kidsClozaril (clozapine) – not much in kids

Risperdal (risperidone)Risperdal (risperidone)

Zyprexa (olanzapine)Zyprexa (olanzapine)

Seroquel (quetiapine)Seroquel (quetiapine)

Geodon (ziprasidone)Geodon (ziprasidone)

Abilify (aripiprazole)Abilify (aripiprazole)

Atypical Antipsychotics – Atypical Antipsychotics – Indications/UsesIndications/Uses

PsychosisPsychosis

Disorganized behaviorDisorganized behavior

Bipolar disorderBipolar disorder

TicsTics

More controversial but increasing:More controversial but increasing: ADHDADHD Conduct disorderConduct disorder Pretty much any behavior we don’t likePretty much any behavior we don’t like

Atypical Antipsychotics – Atypical Antipsychotics – Indications/UsesIndications/Uses

Recent Vanderbilt University study – Recent Vanderbilt University study – 5-fold increase in antipsychotic use in 5-fold increase in antipsychotic use in children for ADHDchildren for ADHD

Feeling among prescribers that Feeling among prescribers that atypicals are safer than the old atypicals are safer than the old generation antipsychoticsgeneration antipsychotics

Don’t have the neurologic side effects Don’t have the neurologic side effects of typical agents (or less frequent)of typical agents (or less frequent)

Atypical Antipsychotics – Atypical Antipsychotics – Mechanism of ActionMechanism of Action

Block dopamine receptors – Block dopamine receptors – antipsychotic actionantipsychotic action

Block serotonin receptors – prevent Block serotonin receptors – prevent extrapyramidal side effects, reduce extrapyramidal side effects, reduce negative symtoms of schizophrenianegative symtoms of schizophrenia

Pharmacokinetics have not been Pharmacokinetics have not been studied in children very much – seems studied in children very much – seems to be similar to adultsto be similar to adults

Atypical Antipsychotics – Atypical Antipsychotics – Adverse EffectsAdverse Effects

Extrapyramidal effectsExtrapyramidal effects

- acute dystonic reaction- acute dystonic reaction

- akathesia (restlessness)- akathesia (restlessness)

- Parkinson-like symptoms- Parkinson-like symptoms

Tardive dyskinesiaTardive dyskinesia

These are less common in the These are less common in the atypical antipsychotics but still atypical antipsychotics but still possiblepossible

Atypical Antipsychotics –Atypical Antipsychotics –Adverse EffectsAdverse Effects

Weight gain/obesityWeight gain/obesity

Increase blood sugar (diabetes)Increase blood sugar (diabetes)

Increase lipids (cholesterol/triglyceride Increase lipids (cholesterol/triglyceride levels)levels)

SedationSedation

Increase prolactin levels – amenorrhea, Increase prolactin levels – amenorrhea, galactorrhea, breast enlargement galactorrhea, breast enlargement (males)(males)

Cardiovascular - arrhythmiasCardiovascular - arrhythmias

Atypical Antipsychotics – Atypical Antipsychotics – Conclusions?Conclusions?

Effective in treatment of psychosis, tics, Effective in treatment of psychosis, tics, and behavioral problems where nothing and behavioral problems where nothing else helps (i.e. developmental disorders)else helps (i.e. developmental disorders)Increasing use in ADHD and conduct Increasing use in ADHD and conduct disorders without basis in literaturedisorders without basis in literatureSide-effects are not trivial – weight gain, Side-effects are not trivial – weight gain, metabolic – in a population where obesity metabolic – in a population where obesity is an increasing problemis an increasing problemNeurological side-effects still possible – Neurological side-effects still possible – who know what are the long-term CNS who know what are the long-term CNS impact on kidsimpact on kids

ADHD Medications – ADHD Medications – stimulantsstimulants

Ritalin, Concerta (methylphenidate)Ritalin, Concerta (methylphenidate)

Dexedrine (dextroamphetamine)Dexedrine (dextroamphetamine)

Adderall (mixed amphetamine salts)Adderall (mixed amphetamine salts)

ADHD Medications – stimulantsADHD Medications – stimulantsMechanism of ActionMechanism of Action

Effect dopamine (DA) and Effect dopamine (DA) and norepiniphrine (NE) in the frontal lobes norepiniphrine (NE) in the frontal lobes and other parts of the brainand other parts of the brain

Increase release of DA and NE in Increase release of DA and NE in neuronsneurons

Block reuptake of DA and NEBlock reuptake of DA and NE

Basically increase DA concentration in Basically increase DA concentration in synapsessynapses

ADHD Medications – ADHD Medications – stimulantsstimulants

Numerous studies point to significant Numerous studies point to significant efficacy over placebo in treatment of efficacy over placebo in treatment of ADHD – in children and now in adultsADHD – in children and now in adults

Rate of prescriptions for children is Rate of prescriptions for children is actually leveling off, but increasing for actually leveling off, but increasing for adults (adult ADHD) – 140% increase adults (adult ADHD) – 140% increase from 2004 to 2005from 2004 to 2005

ADHD Medications – stimulantsADHD Medications – stimulantsPharmacokineticsPharmacokinetics

Immediate release stimulants are Immediate release stimulants are rapidly absorbed by the gut – this can rapidly absorbed by the gut – this can be increased by foodbe increased by foodImmediate release stimulants begin to Immediate release stimulants begin to act 30 minutes after ingestion and act 30 minutes after ingestion and effect last 3-5 hourseffect last 3-5 hoursRecent introduction of long-acting Recent introduction of long-acting stimulants with delayed delivery stimulants with delayed delivery system – once a day dosingsystem – once a day dosing

ADHD Medications – stimulantsADHD Medications – stimulantsAdverse EventsAdverse Events

Sleep problemsSleep problems

Decreased appetiteDecreased appetite

JitterinessJitteriness

HeadacheHeadache

Cardiovascular effectsCardiovascular effects

ADHD Medications – stimulantsADHD Medications – stimulantsCardiovascular effectsCardiovascular effects

February 9, 2006 – FDA voted to have February 9, 2006 – FDA voted to have “black box” warnings added to labeling “black box” warnings added to labeling of stimulants warning about the of stimulants warning about the cardiovascular risks of stimulantscardiovascular risks of stimulants

Sudden heart failure seen in childrenSudden heart failure seen in children

Concern that adults with preexisting Concern that adults with preexisting cardiac problems could be at increased cardiac problems could be at increased risk when taking stimulantsrisk when taking stimulants

ADHD Medications – stimulantsADHD Medications – stimulantsCardiovascular effectsCardiovascular effects

Increase heart rate and blood pressureIncrease heart rate and blood pressure

Committee feeling that stimulant Committee feeling that stimulant prescribing needed to be “slowed prescribing needed to be “slowed down.”down.”

Fear surrounding increased utilization Fear surrounding increased utilization in adultsin adults

ADHD Medications – StimulantsADHD Medications – StimulantsConclusions?Conclusions?

Effective in treating ADHD – both in Effective in treating ADHD – both in children and adultschildren and adults

Side-effects are not trivialSide-effects are not trivial

Monitoring of BP and heart rate as well Monitoring of BP and heart rate as well as baseline and follow-up EKGsas baseline and follow-up EKGs

Mood StabilizersMood Stabilizers

LithiumLithium

Depakote (sodium valproate)Depakote (sodium valproate)

Tegretol (carbamazepine)Tegretol (carbamazepine)

Topomax (topirimate)Topomax (topirimate)

Lamictal (lamotrigine)Lamictal (lamotrigine)

Mood Stabilizers – Depakote Mood Stabilizers – Depakote Indications/UsesIndications/Uses

Anticonvulsant – adults and children > Anticonvulsant – adults and children > 10yo10yo

Bipolar disorderBipolar disorder

Migraine headaches – adultsMigraine headaches – adults

Behavioral problems in adults and kids Behavioral problems in adults and kids secondary to brain damagesecondary to brain damage

PTSDPTSD

Mood Stabilizers - DepakoteMood Stabilizers - Depakote

Most frequently prescribed medication Most frequently prescribed medication used for bipolar disorderused for bipolar disorder

Increasing pediatric use for mood and Increasing pediatric use for mood and behavioral control – impulsive and behavioral control – impulsive and aggressive behaviorsaggressive behaviors

Increase GABA in brain – inhibitory Increase GABA in brain – inhibitory effectseffects

Mood Stabilizers – DepakoteMood Stabilizers – DepakotePharmacokineticsPharmacokinetics

After absorption (slowed by food), After absorption (slowed by food), reaches peak blood level in 3 hours reaches peak blood level in 3 hours

Half life in children – 7 hoursHalf life in children – 7 hours

Half life in adults – 13 hoursHalf life in adults – 13 hours

Liver metabolism – kids under 10 yo Liver metabolism – kids under 10 yo have 50% greater clearance than in have 50% greater clearance than in adolescents/adultsadolescents/adults

Multiple drug-drug interactionsMultiple drug-drug interactions

Mood Stabilizers – DepakoteMood Stabilizers – DepakoteAdverse EventsAdverse Events

GI effects – nausea, vomiting, GI effects – nausea, vomiting, indigestion – can improve with foodindigestion – can improve with foodWeight gain/increased appetiteWeight gain/increased appetiteNeurological – tremor, sedation, Neurological – tremor, sedation, cognitive slowing, ataxia – may be cognitive slowing, ataxia – may be dose relateddose relatedDecrease platelets in blood – increase Decrease platelets in blood – increase bleedingbleedingAcute pancreatitis – rareAcute pancreatitis – rareHair lossHair loss

Mood Stabilizers – DepakoteMood Stabilizers – DepakoteLiver toxicityLiver toxicity

Fatal liver failure seen – 29/1,000,000 Fatal liver failure seen – 29/1,000,000 patients between 1987-1993patients between 1987-1993

Highest risk at age 2 or youngerHighest risk at age 2 or younger

High risk in children with mental High risk in children with mental retardation, receiving other retardation, receiving other anticonvulsants, or are anticonvulsants, or are developmentally delayeddevelopmentally delayed

Not indicated in children < 10 yoNot indicated in children < 10 yo

Mood Stabilizers – DepakoteMood Stabilizers – DepakoteConclusions?Conclusions?

Lots of experience with kids since it was Lots of experience with kids since it was used as a seizure med in the pediatric used as a seizure med in the pediatric populationpopulationEffective in adult bipolar disorderEffective in adult bipolar disorderUsed off-label in kids – can be effective for Used off-label in kids – can be effective for aggressive/impulsive behaviorsaggressive/impulsive behaviorsMultiple side effects – tough med to takeMultiple side effects – tough med to takeNot for kids under 10 yo because of Not for kids under 10 yo because of potential fatal liver problemspotential fatal liver problems

Psych Meds in KidsPsych Meds in KidsConclusions?Conclusions?

Very little supportive evidence for Very little supportive evidence for efficacy (except stimulants in ADHD)efficacy (except stimulants in ADHD)Many known side-effectsMany known side-effectsUnknown effects – long term on the Unknown effects – long term on the developing brain and bodydeveloping brain and bodyOverused? – recent study of child Overused? – recent study of child psychiatrists show that 9/10 of their psychiatrists show that 9/10 of their patients are on medspatients are on medsNeed much more than meds to help Need much more than meds to help kidskids