atypical antipsychotics - narcad ... atypical antipsychotic agents, also known as second-generation

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  • Atypical Antipsychotics

    Age 0-17, Summer 2016

    Collaborative Advancement of

    C A EPrescription Excellence

    How young is too young?

    What if one agent doesn’t work?

    How do we minimize adverse

    drug reactions?

    When should they be used?

    How should they be



  • Atypical antipsychotic agents, also known as second-generation antipsychotics, or SGAs, are only approved for a very small number of specific indications.

    They are being increasingly used off-label and for younger and younger children. They are used disproportionately for males, children in foster care, and those covered by Medicaid.

    Much is still not known about the tolerability, efficacy and long-term safety of these agents, especially in children. There is considerable concern about the side effects/adverse drug reactions (ADRs) of these medications.

    In particular, weight gain and metabolic effects can be significant and long-lasting. Children and adolescents also tend to experience more ADRs than adults taking SGAs.

    Multiple groups have expressed

    concerns over the trends in atypical antipsychotics for


    How young is too young? Age 0-4:

    Avoid use of antipsychotics

    Age 5-17:

    Use with extreme caution

    Pediatric patients 1996 - 2012 Total Second-Generation Antipsychotic (SGA) increase: 600%

    Psychotherapy increase 70%

    2012: SGA use

    Pediatric patients with moderate to

    severe mental health impairment

    2012: SGA use

    Pediatric patients with less severe or no mental

    health impairment

    1996: SGA use

    All pediatric patients

    References: 1-10

    • AACAP: American Academy of Child and Adolescent Psychiatry

    • AAP: American Academy

    • ACF: Administration for Children and Families, Department of Health and Human Services

    • AAFP: American Academy of Family Physicians

    • AHRQ-HEDIS: Agency for Healthcare Research and Quality: Health Plan Employer Data and Information Set

    • CDC: Center for Disease Control and Prevention

    • CMS: Centers for Medicare and Medicaid Services

    2 Pharmacy Management Consultants (managed by OU College of Pharmacy) – Rev. 4/2016

  • 3

    FDA-approved atypical antipsychotics by age: (Age 0-17: First-line treatment in combination with psychosocial interventions)

    Schizophrenia Bipolar Disorder Irritability or Agression due to ASD* Tic Disorder (Tourette’s)

    aripiprazole (Abilify®) 13 - 17 10 - 17 6 - 17 6 - 17

    asenapine (Saphris®) not approved 10 - 17 not approved not approved

    olanzapine (Zyprexa®) 13 - 17 13 - 17 not approved not approved

    paliperidone (Invega®) 12 - 17 not approved not approved not approved

    quetiapine (Seroquel®) 13 - 17 10 - 17 not approved not approved

    risperidone (Risperdal®) 13 - 17 10 - 17 5 - 17 not approved

    ziprasidone (Geodon®) not approved 10 - 17 not approved not approved

    SGAs that are not approved for pediatric use include: brexpiprazole (Rexulti®), cariprazine (Vraylar®), clozapine (Clozaril®), iloperidone (Fanapt®), lurasidone (Latuda®). *ASD: Autism Spectrum Disorder

    Ages 0 - 9 are less likely to: Relevance to SGA prescribing:

    receive psychosocial interventions (PIs) PIs have demonstrated efficacy, with no risk of the ADRs associated with SGA use

    Ages 0 - 9 are more likely to: Relevance to SGA prescribing:

    experience health-related effects of poverty (e.g. obesity, dyslipidemia, cardiovascular disease)

    SGA use creates additive risk of obesity, dyslipidemia, cardiovascular disease

    experience placement in foster care children in foster care receive SGAs 6Xs more often than privately-insured children

    experience ADRs from any medication even when taken correctly, SGA-ADRs lead to hospitalization 2.5Xs more than all other pediatric medications combined

    receive more than one concurrent SGA and/or SGAs combined with other psychotropic medications

    multiple SGA use and additional psychotropic medication use creates additive risk for multiple ADRs

    Younger children have more risk factors than older children:

    “Increasing consensus exists that antipsychotic medication should be the treatment of last resort, after parenting skills training and other behavioral treatments have failed.”

    -Harrison et al, 2012, regarding preschool children

    References: 1-2, 4-5, 7-8, 11-22 Pharmacy Management Consultants (managed by OU College of Pharmacy) – Rev. 4/2016

  • When should an antipsychotic be used?

    1st and 2nd line: • Bipolar disorder • Schizophrenia • Tic disorder • Irritability or aggression due to autism

    spectrum disorder (ASD)

    3rd line: • Non-ASD aggression • Conduct disorder • Oppositional defiant disorder

    Use an SGA in combination with psychosocial interventions:

    These three disorders make up more than 75 percent of all pediatric SGA prescriptions. These disorders are most often symptomatic of another underlying disorder. Treatment of the underlying disorder usually removes the need for use of an SGA. (See Resources, pg. 20-21)

    Most recent studies: • Aripiprazole (monotherapy): may help with additional ASD symptoms (lethargy, social withdrawal,

    stereotypy, inappropriate speech, compulsions) • Risperidone (monotherapy): may help with Attention Deficit Hyperactivity Disorder (ADHD) that is not

    responsive to stimulants • Oklahoma children covered by SoonerCare (Oklahoma Medicaid): only 6.3 percent had an appropriate

    diagnosis while receiving an SGA in 2014

    41% 37%


    67% of claims showed

    quality-of-care concerns

    Too young 17%

    Side effects

    7% Taken

    too long


    Wrong dose


    Wrong treatment

    Too many drugs

    Poor monitoring

    41% 53%


    Second Generation Antipsychotic Drug Use Among Medicaid-enrolled Children: Quality-of-Care Concerns (Office of the Inspector General, March 2015)

    This report also showed:

    - Multiple concerns present in 49% of claims

    - Only 8% of SGAs were prescribed for medically- accepted indications and correct age

    References: 1-2, 19-28, 38

    4 Pharmacy Management Consultants (managed by OU College of Pharmacy) – Rev. 4/2016

  • 5 References: 1, 4, 6, 8, 29-33

    What if one antipsychotic doesn’t work?

    • Allow adequate trial length (4-6 weeks)

    • Assess comorbid conditions and medication adherence

    • Re-evaluate initial diagnosis

    • Redefine targeted symptoms

    • Substitute with alternate SGA

    Avoid combining SGAs.

    Combining two or more SGAs should only be considered after:

    • failed addition of a mood stabilizer, AND

    • failed trials of three individual SGAs

    □ Adequate trial length

    □ In combination with PI (Psychosocial Interventions) With at least 80 percent adherence

    □ One of the three trials was clozapine

    SGAs are a very diverse class of medications, with mutliple pharmacological mechanisms of action and varying receptor site activity. The choice of agent is often determined by its side effect profile. Adding multiple agents rarely results in additive efficacy, but nearly always results in additive side effects and decreased adherence.

    In particular, obesity, diabetes, dyslipidemia and hypertension are likely to increase when multiple agents are used. These risk factors increase the likelihood of morbidity and/or mortality due to cardiovascular disease later in life.

    Olanzapine and clozapine are considered to have the highest potential for causing weight gain, glucose changes, diabetes and dyslipidemia. As such, even more extreme care should be exercised before using these agents in combination with another SGA.

    Addition of, or substitution with, a mood stabilizer is preferred over combining multiple SGAs. (See Resources, pg. 20-21)

    “There’s a general consensus that great caution should be exercised with

    antipsychotic drugs.” -Mark Olfson, M.D., MPH, Professor of Clinical Psychiatry, Columbia University, Co-director AHRQ

    Center for Education and Research on Mental Health Therapeutics

    Pharmacy Management Consultants (managed by OU College of Pharmacy) – Rev. 4/2016

  • How do we minimize ADRs?

    Emergency care: SGA-ADRs Neuroleptic Malignant Syndrome

    NMS is a rare but potentially fatal ADR. It is characterized by high fever, sweating, unstable blood pressure, stupor, muscle rigidity and autonomic dysfunction. Patients who experience NMS should not be re-challenged with the same medication.

    SGAs v. First-generation antipsychotics (FGAs)

    Although they have similar efficacy, SGAs have a much higher risk of metabolic and weight-related ADRs. While FGAs have a higher risk of movement disorders, SGA movement risk is still present. Movement disorders are the most common ADR (47.7 percent) for children requiring emergency care related to an SGA-ADR.

    SGAs v. Stimulants SGAs are 3.8Xs more likely to require emergency care.

    SGAs v. Antidepressants SGAs are 2.7Xs more likely to require emergency care.

    • Use an SGA only when recommended

    • Use the lowest effective dose for the shortest time possibl


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