Improving Medication Prescribing for Arkansas Children Through Off-label Education IMPACT Off-label...

Improving Medication Prescribing for Arkansas Children Through Off-label Education

IMPACT Off-label Education

Update on Depression and Anxiety in Children and Adolescents

UAMS College of PharmacyEvidence-based Prescription Drug Program

UAMS College of MedicineDivision of Child and Adolescent Psychiatry

Goals

Review anxiety and depression prevalence and recommendations

Discuss recently completed clinical trials and consensus national treatment guidelines

Review FDA advisory on “suicidality” Examine treatment patterns in Arkansas

Medicaid Provide points of access to useful resources

Anxiety in Children

Anxiety in Children

Fear and worry can be normal, but excessive anxiety causes impairment

Prevalence in children is reported between 6% and 20%

Anxiety can be recognized at young ages, and may recur or persist to adulthood

Association with poor problem-solving, low self-esteem, negative self perceptions

Source: AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007

Anxiety in Children

Anxiety in children predicts: Adult anxiety Major depression Suicide attempts Psychiatric hospitalization

Source: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007

Anxiety in Children

Includes, generalized anxiety, separation anxiety, social phobia (and selective mutism), obsessive compulsive disorder, specific phobias, panic disorder, PTSD

Separate guidelines for OCD and PTSD in children are available by the AACAP

Anxiety can be a family phenomenon


Anxiety in Children

Screening tools for children exist A positive screen is not a diagnosis – but

an indication for more formal assessment Consider overlap or overlay of physical ills Comorbid conditions should be evaluated

and effectively treated Early assessment and intervention may

improve long-term outlook


Anxiety in Children - Treatments

Treatment Guideline considerations: Multiple treatment modalities Severity of impairment Psychotherapy – especially Cognitive

Behavioral Therapy (CBT) Pharmacotherapy with SSRIs

Short-term helpful, long-term unknown

Pharmacotherapy with other agentsSource: AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007


Psychotherapy (CBT) is consensus first-line approach56% remission vs. 34% remission on wait-list

control SSRI are helpful, but no comparisons

Sertraline and fluoxetine have supportive trialsFluvoxamine more useful if no baseline depressionParoxetine useful, but not recommended due to

safety concerns/”suicidality” association Combined CBT with sertraline trial is

recently published – NIMH CAMS trialSource: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007


TCAs – Imipramine has mixed data. Risks (esp. CV) limit use – no longer supported

Benzodiazepines – not supported alone in children or adolescents. Avoid with history of substance use

SNRIs – limited information on venlafaxine ER

Buspirone – no published dataSources: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007. AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007

Anxiety in ChildrenMajor Points: Screen, evaluate and intervene early Refer for evaluation and psychotherapy SRI role – likely second-line or adjunct:

Fluoxetine, fluvoxamine, sertraline supported Paroxetine good anxiety data, but suicide warnings in

teens Some ER venlafaxine support, though less than SSRIs

New study from NIMH on CBT vs. sertraline vs. combination

Depression in Children


Prevalence estimated at 2.5% of children, 8.3% of adolescents

Anxiety is often associated Suicidal thoughts are reported by 40 to

80% of depressed youth; attempts may be as high as 35%

Depression marks significant risks for recurrence, substance abuse, teen pregnancy…

Source: PhysiciansMedGuide The Use of Medication in Treating Childhood and Adolescent Depression: Information for Physicians, 2007


Younger Children Somatic complaints Psychomotor

agitation Mood-congruent

hallucinations School refusal Anxiety related

issues

Older Children Esteem issues,

boredom, apathy Substance use Change in weight,

eating, sleep Excess

sleep/depressed affect

Aggression/antisocial behavior

Source: GLAD-PC Toolkit available at www.GLAD-PC.org

Depression in ChildrenRecent Trial Information

TADS Study Results:

Source: TADS Team Treatment for Adolescents with Depression Study (TADS) – Long-term Effectiveness and Safety Outcomes. Arch Gen Psychiatry. 2007; 64(10) 1132-1144

TherapyImprovement/Response Rate

Week 12 Week 18 Week 36

CBT+Fluoxetine

71% 85% 86%

Fluoxetine 61% 69% 81%

CBT 43% 65% 81%

Placebo 35%


TADS Study Suicide Event Screening Results

Source: TADS Team Treatment for Adolescents with Depression Study (TADS) – Long-term Effectiveness and Safety Outcomes. Arch Gen Psychiatry. 2007; 64(10) 1132-1144

TreatmentPositive Suicide Event Screening

Baseline Week 12 Week 36

CBT+Fluoxetine

42/106 8/90 2/79

Fluoxetine 28/107 18/97 10/73

CBT 27/107 5/91 3/76Fluoxetine differed significantly from both other treatments at weeks 12 and 36


TORDIA trial – resistant depression/poor treatment response in adolescents

Entering subjects had prior SSRI treatment +/- CBT, high rate of suicidal thoughts

Tested changing medication vs. changing medication with CBT

Postulated changing to an SNRI after an SSRI may increase response rate

Source: Brent, et. al. Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-ResistantDepression. JAMA. 2008;299(8):901-913


Initially treated with at least 40mg fluoxetine (or equivalent)

Switched to SSRI, SSRI+CBT, SNRI, or SNRI+CBT

SNRI was venlafaxine ER Initial SSRIs were fluoxetine or paroxetine After FDA warnings, paroxetine was

dropped, and citalopram was substituted.



Best responses occurred with switch from SSRI to either arm with CBT

ER venlafaxine was no better than a change from one SSRI to another

CBT showed site variations, but robust and durable improvement

ER venlafaxine had higher rates of cardiovascular and other side effects.


Depression in Children - Treatments

Fluoxetine plus CBT has best evidence of success. Consistent benefits and FDA approved down to age 8 (7 for OCD)

Non-responders to SSRI alone, may benefit from addition of CBT with change in SSRI

Most medication trials have serious flaws/ limitations

Several psychotherapy approaches may helpSources: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007.

Brent, et. al. Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-ResistantDepression. JAMA. 2008;299(8):901-913

Depression in ChildrenMajor Points: Screen, evaluate and intervene early Refer for evaluation and psychotherapy SRI role – likely first-line in combination:

Fluoxetine was the only approved agent, still a good starting point

Monitoring is key Shorter half-life agents seem problematic

Watch for more from NIMH: Antidepressant Safety in Kids (ASK) Treatment of Adolescent Suicide Attempters (TASA)

FDA “Suicidality” Warnings, Antidepressants, and Young

People

FDA and “Suicidality”

“Suicidality” links thoughts of suicide and suicide attempts

60% of completed suicides are thought to be in patients with depression

FDA warning based on 23 studies of nine medications, none with a completed suicide

Monitoring for thoughts, plans and attempts is important with any treatment

Source: PhysiciansMedGuide The Use of Medication in Treating Childhood and Adolescent Depression: Information for Physicians, 2007

FDA and “Suicidality” Timeline

June 2003 – FDA issues warnings specific to paroxetine and increased rate of suicide reports

December 2003 – EU/UK agencies advise not to use most SSRI/SNRIs in patients under 18

October 2004 – FDA “black box” warning relating to children and adolescents on all agents

December 2006 – FDA warning extended to young adults

Selective Reuptake Inhibitors

Uses are anxiety and depression Reasonable evidence, some very recent Recent controversy – “suicidality” link

FDA statements in 2003 and 2004Subsequent drop in youth SSRI use of 22% from

2003 to 2005 reported2003 to 2004 suicide rate increases

10-14 YO females – 56 to 94 or .95/100K (+75%) 15-19 YO females – 265 to 365 or 3.52/100K (+32%) 15-19 YO males – 1,222 to 1,345 or 12.65/100K (+9%)

Sources: Gibbons, et al. Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents. Am J Psychiatry 2007; 164:1356–1363. CDC Suicide Trends among Youths and Young Adults aged 10 to 24 years – United States,1990 to 2004. MMWR. 2007 56(35);905-908.

“Suicidality” Warning Impact

Gibbons commercially available data show:no prescribing gain or drop between 2003 and 200422% prescribing drop between 2004 and 2005

Olfson reported on pharmacy claims data:Rapid annualized increases in SSRI use in children prior

to paroxetine warnings (May 2002 to June 2003)Significant drop (mostly due to paroxetine) seen after

paroxetine warning (June 2003 to October 2004)Stable/no significant drop after black box warning

(October 2004 through Dec 2005)

Sources: Gibbons, et al. Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents. Am J Psychiatry 2007; 164:1356–1363.

Olfson, et. al. Effects of Food and Drug Administration Warnings on Antidepressant Use in a National Sample, Arch Gen Psychiatry 2008;65(1): 94-101.

“Suicidality” in Practice

Screening does not increase risks or cause suicidal thoughts

Failing to screen may lead to missing vital information

“Suicidality” in Practice

When starting Tx, FDA recommends weekly assessment for first four weekstwice weekly assessment for four weeks,then (minimally) at the end of 12 weeks

Practically, this can be individualized

Formal assessment tools available Suicide risk and assessment plan

should be documented

Anxiety and Depression Treatment Trends in Arkansas

Medicaid

Treatment Pattern Trends

Arkansas Medicaid claims data are robust (half of all children in the state)

We include only continuously enrolled Medicaid and ARKids recipients which corrects for variations in total enrollment over time.

Prevalence can be grouped by recipient age:Preschool – one year to age sixPrimary School – six years to age 12Adolescent – 12 years to age 18

Recent Initial Treatment Trends

777 newly diagnosed/ treated Medicaid recipients under 18 from April – Oct 2008

Treatment patterns identified by CPT codes and pharmacy claims paid

No severity indicator, but all had no treatment in prior six months

68%

12%

20%

Counseling Only CombinedMedication Only

Persistence Of Treatment

Same 777 newly diagnosed/treated children

Question: How many received more than two claims for either intervention?

Answer: About 70% -

Possibly better persistence with counseling

Counseling Visits

Pre

scriptio

ns

Disp

en

sed

None 1-23 or more

None122

406

1-2 89 23 43

3 or More 68 9 27

Preschool Prevalence Trends

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

Newer Antidepressants ADHD MedicationsTri/ Tetracyclics Atypical Antipsychotics

Source: Arkansas Medicaid claims data, EBRx analysis

Grade School Prevalence Trends

0%

2%

4%

6%

8%

10%

12%



Adolescent Prevalence Trends

0%1%2%3%4%5%6%7%8%9%

10%



Newer Antidepressant Use Patterns

Four Groups of SSRI/SNRI medications FDA approved – fluoxetine* Supported with some evidence:

Anxiety – sertraline, fluvoxamine Depression – citalopram, ER venlafaxine

No adequate/supportive trials Buproprion, duloxetine, escitalopram*, mirtazepine,

nefazodone

Negative information – paroxetine

* During the periods reviewed. Escitalopram was FDA approved in March 09, but at this time, studies are not yet available.

Pattern of Medication Treatment in Arkansas

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Approved Supported Negative No Support

What we know now

Some decrease in prevalence of medication use after FDA warnings – but now stable

Almost half of Arkansas children treated with medication did not receive an evidence-supported SSRI/SNRI

Still need more data on children and adolescents receiving counseling alone or combined with SSRI

Depression and Anxiety in Children and Adolescents

Take Home Points

Depression and Anxiety in Children and Adolescents

Anxiety and depression are common in children and adolescents

Earlier awareness/intervention may prevent negative events

Screening tools are available, easy to use, and facilitate recognition

Practice guidelines and recent evidence should inform treatment decisions

Anxiety Recommendations

Counseling can help define diagnosis and is a first-line treatment

Limited SSRI/SNRI supportFluoxetine appears to be best supportedSertraline with CBT for anxietyFluvoxamine (only if no depression present)Maybe ER venlafaxine, but CV effects are limitingParoxetine good for anxiety, but specific suicide

risk Other pharmacotherapy not supported

Depression Recommendations

Counseling can help define diagnosis and is a first-line treatment

Frequent suicidality screening CBT plus fluoxetine – best practice Fluoxetine alone caries suicidality risk Other SSRI/SNRI agents with published

dataCitalopramVenlafaxine ER – higher side effects than SSRIs

Other pharmacotherapy not supported

SSRI/SNRI Adverse Effects

Serious Adverse Effects

Serotonin Syndrome Akathisia Hypomania Discontinuation

syndromes

Common Adverse Effects

GI effects (dry mouth, constipation, diarrhea)

Sleep disturbance Irritability Disinhibition Agitation/jitteriness Headache

Recommendations

CBT is a first-line approach with or without medication

Foster a relationship with a psychologist to refer and communicate about your patients

Identify and use screening tools Remember fluoxetine dosing:

Younger children - 10mg daily, cautious titrationOlder children - 10mg initially with titration to

20mg after 2 weeksLimited experience above 20mg

Recommendations

Use GLAD-PC materials for depression or other screening tools for anxiety

If treating with SSRIs, establish, document and monitor a safety/suicidal thoughts plan

ParentsMedGuide.org has useful information on pharmacologic treatment for obtaining informed consent


If this was helpful to you: Make time for AFMC to bring you more

materials/resources AFMC will have tool-kit items and other

free resources Web-based curricula/resource pages

available at: COP.UAMS.EDU/OffLabel

Hows and Whys of the Project

Project Funding

Attorney General Consumer Prescriber Education Grant Program

Settlement paid for off-label promotion of Neurontin(gabapentin)

Arkansas received $370,000 of this grant.

Focus: SSRI and SNRI medication use in children and adolescents


The concept: Use techniques and tools of the industry Provide up-to-date evidence-based information on off-

label medication uses in children Report our results

Pharmaceutical representative discussion of uses not FDA approved is prohibited by federal law

Physician-to-physician communication is not restricted, but usually only available with corporate sponsorship

Off-label Uses:

Finding information on appropriate, safe and helpful off-label uses is a challenge

Sometimes, national meetings have reasonably authoritative presentations

Usually manufacturers have more information, but they don’t always share

Pediatric medication trials have special challenges, so there is much off-label use

Why SSRI/SNRIs?

Mental health medications stand out for off-label uses in children

2006 Medicaid data analysis revealed high use of SSRIs/SNRIs in children

General interest, need and utility:Current controversy/new dataLow industry noise level – only a few brand

playersStable category for analysis of our program

IMPACT Off-label EducationDrug

CategoryChildren Treated

Prescriber Count

PrescriptionCount

Paid Amounts

SSRIs/SNRIs

12,297 1,465 56,395 $3,533,620

Tri/Tetra 6,486 989 23,607 $273,276

Newer Antipsycho

tic11,974 945 69,229

$19,672,764

Older Antipsycho

tic327 132 1,654 $48,921

Newer Sleep Aids

972 353 2,555 $231,427Source: Arkansas Medicaid MIS, Calendar Year 2006, Children under age 18 years.

Our Information Sources

American Academy of Child and Adolescent Psychiatry

American Psychiatric Association American Psychological Association Agency for Healthcare Research and Quality Centers for Disease Control NIMH funded Treatment for Adolescents with

Depression Study (TADS) GLAD-PC project Other recent peer-reviewed reports

Thank you for your interest

Screening/Monitoring Tools

Anxiety (for 8 yo and up) Multidimensional Anxiety Scale for Children Screen for Child Anxiety Related Emotional

DisordersDepression Columbia Depression Scale Beck Depression Inventory Children’s Depression Rating Scale –

Revised Reynold’s Adolescent Depression Scale

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