Psychopharmacology in Children

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Psychopharmacology in Children

• Irving Kuo M.D.
• Central Arkansas Veterans Healthcare System

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Psychopharmacology requires a sense of humor.
Sometimes, the best use of evidence-based
medicine is to remember how little evidence we
have. TA Kramer M.D.
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Psychopharmacology is big business.
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Psychiatric Medication Use - Antidepressants

• Antidepressants prescriptions
• 1988 40 million
• 1998 120 million
• 2004 150 million
• Antidepressant revenues
• 1986 - 263 million
• 2004 - 11.2 billion

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Psychiatric Medication Use - Antipsychotics

• Revenues
• 1986 - 263 million
• 2004 - 8.6 billion
• For last quarter of 2005 4/5 drugs that
  Arkansas Medicaid paid most for were for
  antipsychotic meds

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Psychiatric Medication Use ADHD Medications

• 2.5 million children and 1.5 million adults
  prescribed these meds (2005)
• 3.5 billion in revenues for 2005
• Marked increase in prescription since 1999
  advent of new formulations

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Psychiatric Medication Use - Depakote

• 886 million dollar sales last year
• Leader in prescriptions for bipolar disorder

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The Developing Brain

• Most brain cells (neurons) are formed by the 2nd
  trimester in the fetus.
• Neuronal migration (movement of neurons to their
  correct location) begins within weeks of
  conception.
• Brain volume is at 95 of adult volume by age 5.

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The Developing Brain

• Neurons transmit signals electrically and
  chemically through synapses.
• Neurons ondergo myelinization (insulation) and
  arborization (branching out) - continue
  throughout childhood and into adolescence/early
  adulthood.
• Synapse formation continues throughout ones
  lifetime

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The Developing Brain

• Neurons that are created at birth must be the
  right ones.
• Neurons must migrate to the right parts of the
  brain orchestrated traffic.
• Synapses must form once neurons are correctly
  placed.

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The Developing Brain

• Neurons and their synapses are quite changeable
  or plastic neuroplasticity.
• Neurons kill/prune themselves apoptosis.
• Up to 90 of neurons made during fetal
  development undergo apoptosis.
• Apoptitic neurons fade away the body removes
  sick/damaged cells survival of the fittest.

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The Developing Brain

• At age 6 more synapses than at any other time.
• As children grow older the brain prunes away
  half of all synaptic connections.
• Hopefully, the body chooses well which synapses
  to keep and which ones to destroy.
• New synapses form and are pruned throughout
  adulthood at a much slower rate

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Children are not small adults in how their body
handles drugs.
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As little evidence as there is for
psychopharmacology in adults, theres much less
for children.
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Antidepressants - SSRIs

• Prozac (fluoxetine)
• Paxil (paroxetine)
• Zoloft (sertraline)
• Luvox (fluvoxamine)
• Celexa (citalopram)
• Lexapro (escitalopram)

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Antidepressants - SSRIs

• Selective serotonin reuptake inhibitors
  increase serotonin available in synapse
• Takes 2-4 weeks to begin to work
• Used for depression and anxiety disorders (OCD,
  panic disorder, PTSD, social phobia)
• Used for eating disorders, especially bulimia
  nervosa

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Antidepressants SSRIsHow well do they work?

• In ideal studies 2/3 patients responded
• Response vs. remission
• In more real world studies 30 remission rate
  in adults
• Only Prozac is approved by FDA for depression in
  children
• Prozac, Luvox and Zoloft FDA-approved for OCD

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Antidepressants SSRIsHow well do they work?

• Research indicate mixed results in children
  some studies show a modest improvement in
  depressive symptoms, others show no difference
  when compared to placebo (sugar pill)
• British study in 2004 pooled available studies
  and indicated little to no improvement in
  children compared to placebo

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Antidepressants SSRIsPharmocokinetic
Differences

• Paxil cleared in children ages 6-17 faster than
  in adults, although once a day dosing is still
  recommended.
• Prozac serum levels were almost twice as high in
  children than adolescents/adults with same dose
  decrease dose for kids

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Antidepressants SSRIAdverse events

• Behavioral activation in children anxiety,
  restlessness or agitation
• Possible switch to mania if patient is really
  bipolar
• Amotivational syndrome
• Possible bleeding complications easy
  bruisability

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Antidepressants and Suicide in Children

• In 2004, the FDA looked at 24 clinical trial
  involving 4,400 children and adolescents taking
  antidepressants for depression and anxiety
  disorders.
• Children taking active meds 4 developed
  suicidal thoughts/behaviors
• Children taking placebo 2
• No children in studies committed suicide.

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Antidepressants and Suicide in Children

• This led to the FDA black box warning on
  package inserts about a possible link between
  antidepressants and onset of suicide behavior.
• Possible explanations
• - behavioral activation
• - manic switch
• - patient getting better in terms of energy
  but not mood

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Antidepressants and Suicide in Children
Conclusions?

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

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Atypical Antipsychotics

• Clozaril (clozapine) not much in kids
• Risperdal (risperidone)
• Zyprexa (olanzapine)
• Seroquel (quetiapine)
• Geodon (ziprasidone)
• Abilify (aripiprazole)

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Atypical Antipsychotics Indications/Uses

• Psychosis
• Disorganized behavior
• Bipolar disorder
• Tics
• More controversial but increasing
• ADHD
• Conduct disorder
• Pretty much any behavior we dont like

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Atypical Antipsychotics Indications/Uses

• Recent Vanderbilt University study 5-fold
  increase in antipsychotic use in children for
  ADHD
• Feeling among prescribers that atypicals are
  safer than the old generation antipsychotics
• Dont have the neurologic side effects of typical
  agents (or less frequent)

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Atypical Antipsychotics Mechanism of Action

• Block dopamine receptors antipsychotic action
• Block serotonin receptors prevent
  extrapyramidal side effects, reduce negative
  symtoms of schizophrenia
• Pharmacokinetics have not been studied in
  children very much seems to be similar to adults

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Atypical Antipsychotics Adverse Effects

• Extrapyramidal effects
• - acute dystonic reaction
• - akathesia (restlessness)
• - Parkinson-like symptoms
• Tardive dyskinesia
• These are less common in the atypical
  antipsychotics but still possible

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Atypical Antipsychotics Adverse Effects

• Weight gain/obesity
• Increase blood sugar (diabetes)
• Increase lipids (cholesterol/triglyceride levels)
• Sedation
• Increase prolactin levels amenorrhea,
  galactorrhea, breast enlargement (males)
• Cardiovascular - arrhythmias

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Atypical Antipsychotics Conclusions?

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

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ADHD Medications stimulants

• Ritalin, Concerta (methylphenidate)
• Dexedrine (dextroamphetamine)
• Adderall (mixed amphetamine salts)

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ADHD Medications stimulantsMechanism of Action

• Effect dopamine (DA) and norepiniphrine (NE) in
  the frontal lobes and other parts of the brain
• Increase release of DA and NE in neurons
• Block reuptake of DA and NE
• Basically increase DA concentration in synapses

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ADHD Medications stimulants

• Numerous studies point to significant efficacy
  over placebo in treatment of ADHD in children
  and now in adults
• Rate of prescriptions for children is actually
  leveling off, but increasing for adults (adult
  ADHD) 140 increase from 2004 to 2005

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ADHD Medications stimulantsPharmacokinetics

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

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ADHD Medications stimulantsAdverse Events

• Sleep problems
• Decreased appetite
• Jitteriness
• Headache
• Cardiovascular effects

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ADHD Medications stimulantsCardiovascular
effects

• February 9, 2006 FDA voted to have black box
  warnings added to labeling of stimulants warning
  about the cardiovascular risks of stimulants
• Sudden heart failure seen in children
• Concern that adults with preexisting cardiac
  problems could be at increased risk when taking
  stimulants

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ADHD Medications stimulantsCardiovascular
effects

• Increase heart rate and blood pressure
• Committee feeling that stimulant prescribing
  needed to be slowed down.
• Fear surrounding increased utilization in adults

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ADHD Medications StimulantsConclusions?

• Effective in treating ADHD both in children and
  adults
• Side-effects are not trivial
• Monitoring of BP and heart rate as well as
  baseline and follow-up EKGs

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Mood Stabilizers

• Lithium
• Depakote (sodium valproate)
• Tegretol (carbamazepine)
• Topomax (topirimate)
• Lamictal (lamotrigine)

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Mood Stabilizers Depakote Indications/Uses

• Anticonvulsant adults and children gt 10yo
• Bipolar disorder
• Migraine headaches adults
• Behavioral problems in adults and kids secondary
  to brain damage
• PTSD

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Mood Stabilizers - Depakote

• Most frequently prescribed medication used for
  bipolar disorder
• Increasing pediatric use for mood and behavioral
  control impulsive and aggressive behaviors
• Increase GABA in brain inhibitory effects

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Mood Stabilizers DepakotePharmacokinetics

• After absorption (slowed by food), reaches peak
  blood level in 3 hours
• Half life in children 7 hours
• Half life in adults 13 hours
• Liver metabolism kids under 10 yo have 50
  greater clearance than in adolescents/adults
• Multiple drug-drug interactions

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Mood Stabilizers DepakoteAdverse Events

• GI effects nausea, vomiting, indigestion can
  improve with food
• Weight gain/increased appetite
• Neurological tremor, sedation, cognitive
  slowing, ataxia may be dose related
• Decrease platelets in blood increase bleeding
• Acute pancreatitis rare
• Hair loss

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Mood Stabilizers DepakoteLiver toxicity

• Fatal liver failure seen 29/1,000,000 patients
  between 1987-1993
• Highest risk at age 2 or younger
• High risk in children with mental retardation,
  receiving other anticonvulsants, or are
  developmentally delayed
• Not indicated in children lt 10 yo

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Mood Stabilizers DepakoteConclusions?

• Lots of experience with kids since it was used as
  a seizure med in the pediatric population
• Effective in adult bipolar disorder
• Used off-label in kids can be effective for
  aggressive/impulsive behaviors
• Multiple side effects tough med to take
• Not for kids under 10 yo because of potential
  fatal liver problems

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Psych Meds in KidsConclusions?

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