Psychotropic meds for kids and adolescents: WHATS NEW

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Psychotropic medsfor kids and adolescentsWHAT
S NEW?

• Mark D. Edelstein, MD
• Child Adolescent Psychiatrist
• EMQ Children and Family Services
• Victor Community Support Services
• CMHACY - May, 2007

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What we will cover

• Meds in kids Dos Donts
• FDA Approval and Off-Label Use
• Evidence Based Practice
• Foster children foster youth
• Psychiatric Disorders Evidence-based prescribing
  Whats New

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What we will not cover

• Details about medicines
• How they work, doses, side
• effects, etc.
• Details about disorders
• Symptoms, incidence, prognosis, non- medication
  treatments, etc.
• Evidence for benefit of med in adults

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Some Dos Donts

• Fewest number lowest doses that work.
• Good evaluation.
• Discuss findings. Diagnosis is not everything.
• Weigh risks and benefits using meds but also of
  not using meds.
• One part of the plan. Never meds only.

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Some Dos Donts

• Discuss med options.
• Dose Start low, go slow, but get to effective
  dose (kids metabolize meds faster).
• Monitor target symptoms watch for side effects.
  Try to resolve problems (to a point).
• When possible, make one change at a time.
• Consider causes of ineffectiveness wrong med,
  not enough time, dose too low (or high), not
  taking it, med wears off, tolerance, or not a
  med-responsive symptom.

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FDA-Approval

• Pharmaceutical companies research potential
  medicines
• After preclinical testing come 3 phases of
  clinical trials in humans) each must be approved
  by the FDA.
• FDA approves a medicine to be advertised as safe
  and effective for specific medical conditions
  within a specific age group

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Off-Label Prescribing

• Once approved, doctor can prescribe any dose to
  any person for any reason.
• Off-label prescribing prescribing outside age
  parameters diagnosis

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Off-Label Prescribing

• MAY BE NECESSARY
• Pharmaceutical companies done little research on
  meds in kids (except for stimulants)
• Disorders in the real world are not as clear-cut
  as in most research samples
• MAY BE SMART
• additional research and clinical experience may
  show safety and efficacy in different populations
  and for different disorders.

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Evidence Based Practice

• Medicine a long history of EBP, but greater
  emphasis on it since 1990s.
• Research type quality vary
• Best research prospective, randomized,
  placebo-controlled, double-blind
• Rely on research in kids, research in adults,
  clinical experience (e.g., case reports)

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Evidence Based Practice

• Efficacy (efficacious)
• Works in controlled setting
• Effectiveness (effective)
• Works in the real world

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Foster Children Youth

• As with all kids
• Informed consent by adult.
• Developmentally appropriate informed assent by
  the child or youth.

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Foster Children Youth

• Logistical challenges of Court authorization.
• Foster youth sensitive to being involved and
  listened to.
• Public policy influenced by concern but also
• Lack of knowledge
• Lack of data
• Irrational fears
• Poor prescribing practices
• May not appreciate risks of not treating

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Stimulants

• First line option for ADHD
• 3 types
• Methylphenidate (Ritalin, Ritalin-LA, Concerta,
  Metadate, Methylin, etc.)
• Dexmethylphenidate (Focalin, Focalin-XR)
• Amphetamine salts (Adderall, Adderall-XR)
• FDA-approved (MPH to 6, Adderall to 3)
• Efficacy well established 70 have significant
  response (resolved in fewer)

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Stimulants Whats New

• Sudden death? In 2006 FDA review found no
  evidence of increased risk except with structural
  cardiac abnormality.
• Use in preschoolers? Effective but
  hyperactivity, impulsivity and inattention may
  not represent ADHD, and preschoolers may be more
  prone to growth impairment.
• Increasing treatment of ADHD in adults
  (Focalin-XR, Adderall-XR Strattera also
  FDA-approved in adults)

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Stimulants Whats New

• Dexmethylphenidate (Focalin, Focalin-XR) the
  d-enantiomer of Methylphenidate
• Methylphenidate Transdermal System Daytrana
  patch lasts 9 hours (if leave on)
• Lisdexamfetamine dimesylate (Vyvnase)
  FDA-approved dextroamphetamine linked to lysine
  inactive if snorted or injected

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Atomoxetine (Strattera)

• Norepinephrine Reuptake Inhibitor
• FDA-approved in children (6 and older),
  adolescents adults.
• 5 randomized controlled trials show efficacy in
  children and adolescents.
• Head-to-head studies favor stimulants.
• Takes weeks to start working.
• Long-lasting and non-abusable.

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Other meds for ADHD

• Not FDA-approved for ADHD less evidence
• Bupropion (Wellbutrin-SR, Wellbutrin-XL)
• Guanfacine (Tenex) Clonidine (Catapres)
• Some studies show benefit
• Expect approval for XR form of Guanfacine.
• Modafinil (Provigil for narcolepsy)
• Multi-center 2006 study showed efficacy but
  potential for skin reaction needs more study.
• Tricyclic antidepressants

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Bipolar Disorder

• 3 categories of mood stabilizers
• Lithium
• Anticonvulsants (valproic acid/divalproex
  oxcarbazepine, lamotrigine, et al.)
• Atypical antipsychotics (risperidone, olanzapine,
  quetiapine, et al.)
• Very few rigorous studies in pediatric
  population, especially for bipolar depression
  maintenance therapy.

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Acute mania Mixed Episodes

• Efficacious in children adolescents
• Lithium (most studied)
• Probably efficacious
• Divalproex (Depakote)
• Lamotrigine (Lamictal)
• Atypical antipsychotics
• Inconclusive, no or negative evidence
• Carbamazepine (Tegretol), oxcarbazepine
  (Trileptal), topiramate (Topamax), gabapentin
  (Neurontin)

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More on Bipolar Disorder

• About 50 of pediatric patients Bipolar Disorder
  fail to respond to monotherapy.
• One controlled trial showed Depakote Quetiapine
  superior to Depakote placebo in adolescents.
• Open trials suggest efficacy of Lithium combined
  with an antipsychotic or anticonvulsant.

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Bipolar Depression Maintenance

• Bipolar Depression
• No good evidence
• Lithium, Lamictal, SSRIs may help
• Maintenance
• No good evidence
• In 2005 a panel of experts from the Child
  Adolescent Bipolar Foundation recommended
  continuing same meds that worked acutely for
  12-24 months.

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Depression Children

• High placebo response makes research difficult
  (also true in adolescents).
• No solid evidence of benefit from antidepressants
  for depression.
• Compared to adolescents, children have 3 times
  rate of activation/agitation from SSRIs.
• Omega-3 fatty acids appear safe but mixed
  results in adults one small, controlled
  double-blind study in children suggested benefit
  (Nemets et al., 2006)

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Depression TADS

• TADS Treatment for Adolescents with Depression
  Study (Data collected 2000-2003)
• Randomized, double blind multi-center study of
  439 adolescents with Major Depressive Disorder
• Improvement rates
• Fluoxetine CBT 71
• Fluoxetine alone 60
• CBT alone 43 - not statistically
  significant vs. placebo
• Placebo 35
• Even in combined group, only 37 remission.

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Depression SSRIs in Adolescents

• Fluoxetine (Prozac) the only FDA-approved
  antidepressant for depression in adolescents
• Do other SSRIs work?
• Paxil shown in 4 studies to be no more effective
  than placebo in adolescent MDD except perhaps
  helpful in older adolescents.
• Multi-center placebo-controlled trial
  (Konijnenberg et al. , 2006) showed no benefit of
  Lexapro vs. placebo for 6-11 year olds but
  significant improvement in global functioning in
  12-17 year olds.

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Other Antidepressants in Adolescents

• Bupropion (Wellbutrin-SR, Wellbutrin-XL)
  probably 2nd line agent (after SSRIs)
• Venlafaxine (Effexor-XR) open label trial in
  showed effectiveness (but activating withdrawal
  symptoms)
• Others TCAs, mirtazepine (Remeron), lithium
  augmentation (inhibitors
• Omega-3 fatty acids appear safe but mixed
  results in adults promising small controlled
  double-blind study in children (Nemets et al.,
  2006)

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Do Antidepressants Increase Suicide Risk?

• 2004 FDA meta-analysis confirmed controversial
  British 2003 meta-analysis of increased
  suicidality (4 vs. 2 with placebo) except
  fluoxetine
• No completed suicides in the studies
• 2004 Black Box Warning recommendation for
  follow-up visits weekly x 4, every other week x
  2, and at 12 weeks.
• Concern about risk of depressed adolescents not
  getting treatment.

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Do Antidepressants Increase Suicide Risk?

• 2004 placebo-controlled study by Eli Lilly (maker
  of Prozac) suicidality and self-harm in
  pediatric population same for fluoxetine
  placebo.
• 2004 Valuck et al. review of over 24,000
  adolescents treated with antidepressants for MDD
  suggested antidepressants did not contribute to
  increased risk in suicide.
• 2004 FDA reassessment of its data paroxetine
  venlafaxine linked with increased suicidality but
  others showed little or no effect.

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Do Antidepressants Increase Suicide Risk?

• 11/06 FDA reviewed 372 randomized
  placebo-controlled trials involving almost
  100,000 adults.
• Risk of suicidality clearly age-related
• 65 and over striking and statistically
  significant protective effect
• 31-64 modest protective effective
• 25-30 neutral effective on suicidal thoughts and
  behavior.
• 19-24 increased risk of suicidal thoughts and
  behavior, though not statistically significant.

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TADS revisited

• Adolescents felt to be dangerous to themselves
  were excluded from the study.
• Still, 29 had suicidal ideation at the start and
  21 had some form of suicidal behavior.
• This decreased substantially over 12 weeks for
  all treatment groups (less than 10 had suicidal
  ideation after 12 weeks) but decreased most in
  the fluoxetine CBT group.
• 18 incidents of new or worsening suicidal
  ideation and 5 of suicidal behavior (no completed
  suicides) most occurred over a month after
  initiating treatment.
• Risk of suicidal behavior did not differ among
  groups
• Risk of suicidal ideation higher (3.7) in the
  fluoxetine-only and placebo groups (CBT
  protective?) but not statistically significant.

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Do Antidepressants Increase Suicide Risk?

• 2006 Simon et al. reviewed 5000 treatment
• episodes of pediatric patients with
  antidepressants.

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Do Antidepressants ReduceSuicide Risk?

• From 2003 to 2004
• 20 decline in antidepressant prescriptions
  written for youth under age 20
• 18 increase in suicides in this age
• Gibbons et al.(2006) from 1996-98, areas of the
  country that had highest rate of SSRI
  prescriptions had lowest rates of suicide rates
  in children and young adolescents
• May be very important to distinguish between
  suicidal ideation and suicidal behavior (duh)

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Antidepressants Suicide Risk

• Possible increased risk of suicidal ideation
  (and behavior?) in young people from
  (particular?) antidepressants (therapy
  protective?)
• Probable reduction in suicides with effective
• treatment (best medicine therapy)
• Solution for MDD in adolescents (as in any
  similar situation in the medical field)
• Diagnose and Treat
• Educate and Monitor

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Schizophrenia

• Antipsychotics efficacious in adults evidence
  less but still good in pediatric population
• Atypical (2nd generation) antipsychotics
• Risperidone (Risperdal)
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Clozapine (Clozaril)
• Aripiprazole (Abilify)
• Ziprasidone (Geodon)
• Also used as mood stabilizers, for agitation
  aggression, and tics

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CATIE (Phase I)

• About the same somewhat effectiveness
• Olanzapine a little more efficacious but also
  more side effects. Ziprasidone the opposite.
  Risperdal good balance.
• High rates of discontinuation of all meds
• Due to inefficacy or side effects.
• Perphenazine as effective as the atypicals
• No greater incidence of EPS.

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1st vs. 2nd Generation

• May see increased use of 1st generation meds
• Perphenazine (Trilafon), Haloperidol (Haldol),
  Chlorpromazine (Thorazine), etc.
• Why?
• CATIE
• Less cost
• Concerns about Metabolic Syndrome with atypicals
  (next slide)
• A problem?
• CATIE is one study
• Greater risk of certain side effects (tardive
  dyskinesia, NMS, others?)

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Metabolic Syndrome

• Combination of increased
• Waist circumference
• Blood pressure
• Blood sugar
• Triglycerides and lipids
• High cardiovascular risk (heart attack, stroke)
• Greatest risk from Clozaril Olanzapine
• Moderate risk from Risperdal Seroquel
• Minimal to no risk from Abilify Geodon.
• Family history monitoring

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Forms of Atypical Antipsychotics
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Paliperidone (Invega)

• Brand new from Janssen
• The main active metabolite of risperidone
  (Risperdal)
• Risperdal is off-patent
• Slow release (OROS) system once daily dosing
• FDA approved for adults with schizophrenia

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Clozapine

• Clearly established in adults as the most
  efficacious antipsychotic (and effective mood
  stabilizer), though with significant side
  effects.
• Studies now suggest this also applies to children
  and adolescents.
• Shaw et al. (2006) in children adolescents
  with onset of schizophrenia before age 13,
  clozapine worked faster and better than
  Olanzapine also caused more side effects.

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PTSD

• As of 8/05, no double-blind randomized placebo-
  controlled trials of meds for PTSD in children.
• CBT most important treatment.
• Hyperarousal may be best target symptom for meds
  (vs. re-experience avoidance/numbing)
• 1st line SSRIs (some SSRIs have FDA approval
  for PTSD in adults). Favorable response reported
  in children and adolescents.
• Other options buspirone cyproheptadine or
  trazodone for insomnia clonidine, guanfacine
  propranolol.
• Less evidence for benzodiazepines, TCAs,
  bupropion, antipsychotics, anticonvulsants

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Other Anxiety Disorders

• OCD, Separation Anxiety, GAD, Social Anxiety
  Disorder
• CBT most important treatment
• For OCD, Fluvoxamine, Zoloft, and Clomipramine
  are FDA-approved in pediatric patients (probably
  all SSRIs can be helpful)

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Affective/Impulsive Aggression

• Seen in some Oppositional Defiant Disorder, etc.
• 2006 meta-analysis of suggests improvement in
  pediatric population with Lithium, typical
  antipsychotics, Risperdal, and possibly others.
• Mixed results for valproic acid.

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Autism

• Risperdal FDA-approved in 2006 for aggression,
  self-injury, tantrums, and mood lability in
  children (age 5-16) with autistic disorders.
• 2005 review of studies reported moderate benefit
  for Risperdal and Olanzapine.
• No effect on core symptoms of autism.

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Eating Disorders

• Anorexia nervosa
• No meds indicated except cautious treatment of
  co-occurring MDD or OCD
• Bulimia
• CBT is first line treatment
• SSRIs clearly can be effective
• Fluoxetine is FDA-approved for adults

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Alcohol Opioid Dependence

• Little to no research in adolescents
• Alcohol dependence in adults
• Naltrexone acamprosate each increase duration
  of abstinence in about 15 of individuals.
• Opioid dependence in adults
• Methadone significantly reduces amount of opioid
  used
• Naltrexolne decreases craving and blocks the
  high from opioids