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Hearing little voices: Psychopharmacological treatment of severe behavioural disturbance in children

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Title: Hearing little voices: Psychopharmacological treatment of severe behavioural disturbance in children


1
Hearing little voices Psychopharmacological
treatment of severe behavioural disturbance in
children
  • Tamison Doey MD FRCPC
  • Head, Division of Child Psychiatry, Windsor
  • Adjunct professor, Schulich School of Medicine
    and Dentistry
  • Chief of psychiatry, Hotel Dieu Grace Hospital
    Windsor ON
  • drtamison_at_yohoo.com
  • OACRS October 20 2008

2
Industry affiliationsAstraZenecaBiovailGlaxoSm
ithKlineJanssen PharmaceuticalsLillyShire
3
Objectives
  • Review pharmacological options in disruptive
    behaviour disorders in children
  • Review the history of the use of atypical
    neuroleptics (ATNs) for this indication in
    Canada and the world
  • Discuss concerns that have arisen and future
    directions for research and study

4
Disruptive behaviour
  • What is it?
  • What are we treating?

5
  • lagging skills Ross Greene
  • Language difficulties
  • Poor social skills/reading cues
  • Cognitive inflexibility
  • Anxiety
  • Environmental sensitivity
  • All of the above

6
  • Psychiatric diagnosis
  • ADHD
  • ODD-oppositional defiant disorder
  • Mood disorders
  • Anxiety disorders
  • Intermittent explosive disorder
  • Psychotic disorders

7
Why is a diagnosis important?
  • Guide treatment
  • Anticipate future changes/needs
  • Non-clinical reasons

8
What medications are used?
  • Atypical neuroleptics/antipsychotics (ATNs)
  • Mood stabilizers (lithium, divalproic acid,
    carbamazepine)
  • SSRIs (selective serotonin reuptake inhibitors)

9
Atypical antipsychotics
  • Less likely to cause movement disorders than
    typical agents (example haloperidol)
  • More likely to cause weight gain

10
Clozapine
  • First introduced 70s
  • Taken off the market due to fatal agranulocytosis
  • Reintroduced in 1991 ( deMaio 1972)

11
Clozapine in guidelines
  • Treatment resistant schizophrenia CPA, Royal
    Australia and New Zealand, Royal College of
    Thailand, etc.
  • Azorin AJP 2001
  • Neurological intolerence (TD PD )
  • Suicidality, agression (CPA guidelines)
  • Bipolar disorder, adjunct
  • Sachs Expert Consensus 2000
  • Yathum CANMET guidelines

12
Clozapine-Drawbacks
  • Higher risk of agranulocytosis? Not confirmed by
    Gerbino-Rosen JAACAP June 2006
  • Hyperglycemia, seizures, sinus tachycardia, ECG
    changes, sedation, hypersalivation, weight gain

13
Risperidone
  • Introduced in Canada in 1994
  • Guidelines ATN widely mentioned in treatment
    guidelines for adults with schizophrenia, bipolar
    mood disorders, behavioural problems in dementia,
    mental retardation and behavioural/psychiatric
    emergencies

14
Side effects
  • weight gain, metabolic abnormalities
  • EPS high doses and TD
  • sedation
  • elevated Prolactin
  • leukocytopenia
  • hepatic side effects

15
Olanzapine
  • Introduced in Canada July 1996
  • Use schizophrenia, mood disorders, emergency
    treatment of agitation and behaviour

16
Olanzapine side effects
  • EPS
  • weight gain
  • Sedation
  • DM (7 FDA MedWatch reports adolescents with new
    onset DM, 2 exacerbations 1996-2001,?denominator)
  • Case reports of new onset DM in children, Selma
    and Scott, Domon

17
Quetiapine
  • Introduced in Canada 1997
  • Use schizophrenia, mood disorders
  • Particularly helpful in patients with Parkinsons
    disease or who are neuroleptic sensitive ( LBD)

18
Quetiapine side effects
  • Weight gain in adolescents
  • cataracts in beagles Stip and Boisjoly 1999
  • Tachycardia
  • sedation

19
Ziprasidone
  • Less weight gain
  • Concern about cardiac rhythm disturbances
  • AUGMENT THIS SLIDE

20
Other atypicals
  • aripiprazole
  • Amisulpride

21
Treatment of aggressionSchur et al JAACP Feb 2003
  • Lesch Nyhan model, dopamine implicated Lloyd NEJM
    1981
  • Clozapine case studies showing reduced
    aggression in youth with BP, schiz, psychosis NOS
  • Open label trial of olanzapine in children,
    adolescents and adults Potenza 1999

22
Treatment of aggression cont.
  • DBPC study 20 children with conduct disorder 10
    weeks treated with risperidone Findling 2000
  • Responders to risperidone for disruptive
    behaviour (335/527) (MR and N IQ) DB
    discontinuation Time to recurrence significantly
    longer with risperidone Reyes 2005
  • Open label clozapine reduced administration of
    emergency medication/seclusion and increased the
    likelihood of discharge over three months in 20
    treatment resistant children with schizophrenia.
    Kranzler 2005

23
Guidelines ATNs in aggression
  • ATNs mainstay of treatment in emergency
    settings Behavioral management of medically ill
    children Cummings 2004
  • TRAAY (Treatment recommendations for the use odf
    atypical antipsychotics in aggressive youth)
    2002-3 substantial efficacy in the treatment of
    aggression in selected pediatric
    populationsless EPS cites lack of definitive
    data open label/case reports non-peer reviewed,
    side effects in trials for disorders, not just
    aggression

24
Guidelines aggression
  • Patel 2005 JCAP growing use, concern regarding
    side effects, no head to head trials vs behaviour
    management, efficacy vs effectiveness

25
Externalizing behaviours in MR
  • 2 Case reports olanzapine resulted in a decrease
    in aggression and SIB in children with MR, autism
    Horrigan 1997
  • Mixed aged DB cross over trial of risperidone in
    aberrant behaviour (aggression, SIB) in DD (5
    children, 6 adolescents, 9adults) demonstrated
    efficacy Zarcone 2003
  • Open label trial of risperidone 34 children with
    MR and behavioural symptoms showed efficacy
    Holford 2000

26
Externalizing behaviours in MR cont.
  • CT 13 children 4 weeks treated with risperidone
    Van Bellinghen and DeTroch 2001
  • CT 38 adolescents treated with risperidone
    Buitelaar 2001
  • RCT 118 children treated with risperidone Aman
    2000-2, 48 week follow up Findling 2000
  • RCT 110 children treated with risperidone Turgay
    2000

27
Externalizing behaviours in autism
  • Case series with risperidone include Demb 1996,
    Fisman and Steele 1996, Harden 1996
  • Open label trials with risperidone include Malone
    1999, Findling 1997, Horrigan 1997, McDougle
    1997, Nicolson 1998, Perry 1997

28
Externalizing behaviours in autism cont.
  • In a six week open label comparison of olanzapine
    and haloperidol, both groups had symptom
    reduction(CGI and CPRS) Malone 1999
  • Quetiapine ineffective and poorly tolerated in an
    open label trial of 6 boys Martin 1999

29
Externalizing behaviours in autism cont.
  • Open label trial 36 children with aggression
    and/or SIB treated with risperidone for 8 weeks
    26 responders treated with double blind
    discontinuation Troost 2005

30
Externalizing behaviours in autism cont.
  • Large multisite controlled trial with risperidone
    McDougle et al demonstrated
  • short term improvement in tantrums, aggression,
    SIB 2002
  • sustained for 6 months, recurrence of symptoms
    upon discontinuation 2005
  • decline in stereotypies, behaviour and special
    interests, but not social skills 2005
  • more improvement on Vineland than expected
    Williams 2006

31
Guidelines autism and MR
  • International consensus handbook 1998 aggression
    SIB
  • AACAP practice parameters list a number of
    medications including neuroleptics that may
    prove beneficial
  • Brylewski Cochrane review 2001 concluded
    risperidone was effective in adults but very
    many adults with LD and challenging behaviours
    with no discernable mental illness are being
    treated with these powerful drugs which pose
    ethical issues
  • Antochi 2003 may be usedcaution

32
  • What about other diagnoses/treatments?

33
Treatment of ADHD
  • Well established treatment with stimulants,
    supported by 300 short term, randomized
    controlled trials
  • Some longer term trials
  • No evidence of long term detriment aside from
    minor decrease in final height (1 cm)
  • Demonstrate behavioural improvement, decreased
    risk for substance abuse
  • No long term changes in academic, legal,
    vocational or other changes

34
ADHD cont
  • Non-stimulant medication indicated for ADHD
    atomoxetine
  • Other, off label medications
  • Tricyclic antidepressants, clonidine

35
Data and Guidelines ADHD
  • Risperidone appeared more effective than
    methylphenidate for symptoms of ADHD in 45
    patients with moderate MR Correia 2005
  • Brown 2005, Wolraich 2005 (adolescents) ATN not
    mentioned
  • Lilienfeld 2005 unsupported treatments no
    compelling evidence of their efficacy quotes
    Cooper TennCare study

36
Bipolar mood disorder
  • Standard medications
  • Lithium
  • Anticonvulsants divalproic acid, carbamazepine
  • All have been shown to have non-specific effects
    on aggression and impulsivity
  • Significant side-effects, require blood monitoring

37
Bipolar disorder
  • Open label treatment of 23 youth for 8 weeks with
    olanzapine for mania resulted in significant
    improvement of YMRS Frazier 2001
  • Quetiapine divalproex in adolescents with
    mania, (reduction in YMRS) with more rapid
    response, and higher rates of response and
    remission with quetiapine in 50 youth DelBello
    2006
  • Quetiapine divalproex vs divalproex alone
    greater reduction in YMRS, higher response rate,
    also higher sedation rate DelBello 2002

38
Guidelines bipolar disorder
  • Guidelines for treatment in bipolar children and
    adolescents Kafantaris 1995 points out that
    lithium alone improves psychotic symptoms in
    adults (Goodnick and Meltzer) and youth (Varanka,
    Horowitz) and mentions the increased risk of TD
    in patients with mood disorders
  • Expert concensus guidelines 2000 Sachs et al,
    recommended ATN in bipolar disorder with
    psychosis (adults and youth)

39
Guidelines bipolar disorder cont.
  • Danielyn, Kowatch in Pediatric Drugs 2005 noted
    increased use of ATN but few controlled studies
  • CANMAT guidelines 2005 quotes the DelBello study
    and also indicates that atypicals may be
    effective as monotherapy based on
  • Fraziers retrospective chart review, risperidone
    1999
  • Soutellos case reports olanzapine treatment of
    mania in youth 1999
  • Fraziers prospective open-label study 2001

40
Guidelines depression
  • CBT
  • SSRIs
  • Psychotic depression ATNs (with SSRIs) AACAP
    guidelines 2001

41
SSRIs
  • Act by modifying the function of the serotonin,
    norepinephrine and dopamine systems.
  • Onset of action 2-4 weeks after initiation of
    therapy
  • Efficacy (response) 60
  • Increases to 90 if several agents tried
  • Patient may respond to some and not others

42
SSRIs cont
  • Response remission if meds
    continued-50at 6 months, 66 at two years
  • Relapse within 1 year
  • 50 off meds
  • 10-20 on meds

43
Side effects
  • Mild, common, transient change in sleep,
    headache, digestive symptoms
  • Sexual side effects
  • Activation, anxiety
  • Mania
  • Suicide-related effects (thoughts, gestures) 4
    (placebo 2)

44
Treatment of Adolescent Depression Study (TADS)
  • 439 patients aged 12-17
  • Intensity of symptoms resembled real life
    patients
  • 12 week treatment
  • 4 groups
  • Fluoxetine
  • CBT
  • Both
  • Placebo

45
TADS study
  • CBT plus fluoxetine gtgt fluoxetine gtCBTgt placebo
  • Suicidality was common at start, improved with
    symptom relief
  • Adverse effects including disinhibition were more
    common with fluoxetine and this was offset with
    CBT(study too small, self harm too rare to
    comment)

46
TADS cont.
  • 60.6 response rate of fluoxetine, alone,
    consistent with previous trials
  • low response rate of CBT alone a surprise (43 vs
    60
  • placebo rate lower 37

47
SSRIs Risk\Benefit Issues
48
Anxiety disorders
  • CBT
  • Exposure therapy with response prevention
  • Behavioural therapy
  • SSRIs
  • No evidence that benzodiazepines are effective,
    may cause dis-inhibition

49
Atypicals and anxiety adults
  • Adding Risperidone vs placebo to SSRI therapy
    significantly lowered HAM-A Brawman-Mintzer 2005
  • SSRI plus risperidone vs haldol in OCD both
    reduced YBOCS, risperidone reduced depression Li
    2005
  • Patients with PTSD, adjunctive risperidone vs
    placebo improved CAPS, CAPS-D. HAM-A and PANSS-P
    Bartzokis 2005
  • Risperidone superior to placebo as adjunctive
    therapy to SSRis in treatment resistant OCD
    McDougal 2000

50
ATNs what are the issues?
51
  • The majority of clinical practice is supported
    by few controlled studies and is primarily
    justified by the adult literature, case reports
    or clinical lore.
  • McClellen and Werry JAACAP 2003

52
Prescribing patterns USA
  • Cooper reviewed prescribing patterns of ATNs for
    children in the US in 1995-2002. Nearly 6 million
    visits, 1/3 non mental health prescribers, 53
    for behavioural symptoms of affective disorders.
    8/1000 in 1995 to 39/1000 in 2002. Off label
    increased more than on label.

53
  • Cooper examined patterns in TennCare from
    1996-2001 23/10,000 in 1996 to 45/10,000 in
    2001.
  • Use for ADHD and affective disorders increased
    use for psychosis, Tourettes, autism and MR
    stable

54
  • Staller prescribing patterns of CPs in NY 74
    of patients on meds, 50 on two or more, 77 of
    those on antipsychotics did not have psychosis
    2005

55
  • Similar changes in adult prescribing 4.6 million
    in 1998 to 8.6 million in 2002, visits for ATN
    tripled, TN declined, with substantial increase
    in non-psychiatrists, not psychiatrists
  • (could argue the same about SSRIs)
  • Good thing or a bad thing?

56
  • We have to ask
  • How are we using these medications?
  • What are we monitoring?
  • Before we can ask
  • How should we be using these medications?
  • What should we be monitoring?

57
  • Survey of Atypical Antipsychotic Use by Canadian
    Child Psychiatrists in Patients under 18 Years
  • Authors
  • Tamison Doey MD Resident Department of Psychiatry
    Schulich School of Medicine and Dentistry
    University of Western Ontario
  • Kenneth Handelman MD FRCPC adjunct Professor,
    division of Child and Adolescent Psychiatry,
    Schulich School of Medicine and Dentistry
    University of Western Ontario
  • Margaret Steele, MD, FRCPC, MEd Chairman,
    Division of Child and Adolescent Psychiatry,
    Schulich School of Medicine and Dentistry, UWO

58
  • Ethics approval from the REB of the UWO
  • Approval from both professional organizations
  • Surveyed members of the CACAP and the division of
    developmental pediatrics of the CPS

59
  • Canadian Academy of Child and Adolescent
    Psychiatrists (CACAP)
  • 361 members
  • 349 in Canada
  • 342 eligible members
  • 178 questionnaires returned
  • Rate of return 52

60
  • Division of developmental pediatrics of the
    Canadian Pediatric Society (CPS)
  • 97 members
  • 12 returned questionnaires
  • Rate of return of 12.4

61
Instrument and methods of distribution
  • 2 page questionnaire regarding the clinicians
    use of atypical antipsychotics and monitoring
    practices
  • CACAP questionnaires mailed and returned by mail,
    fax or email
  • CPS-DP questionnaires sent and returned by email

62
Use of antypicals
  • CPs 95
  • DPs 88.9
  • No significant difference
  • Results combined for the remainder of the analysis

63
  • Risperidone 66
  • Olanzapine 17
  • Quetiapine 17
  • Clozapine lt1

64
(No Transcript)
65
Other symptoms mentioned included aggression,
psychosis, tics
66
12 of prescriptions in the lt9 age group
67
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68
Other tests included CBC, TSH, renal function
69
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70
Conclusions
  • Medications are widely used by CPs and DPs
  • 18 of patients are children under 9
  • Many indications
  • Monitoring is frequently done
  • No general consensus as to types and frequency of
    monitoring

71
Limitations
  • Retrospective generalization about practice
  • Respondents may not be representative of the
    profession as a whole
  • Non prescribers may be less likely to respond
  • Nevertheless, results are consistent with data
    obtained with other methodology (prescription
    data review)

72
Evidence based medicine
  • Randomized controlled research designs
  • Adequate sample sizes
  • Defined study populations
  • Replication
  • Definable treatments
  • In child psychiatry, diagnostic co-morbidity the
    rule in child psychiatry
  • ?effectiveness
  • McClellan and Werry JAACAP Dec 2003

73
Current limitations
  • Dearth of research
  • Ethical limitations
  • Lack of long term studies
  • Funding limitations
  • Off-label Double bind

74
Covert op medicine
  • Extrapolation from experience with adult
    patients we know we shouldnt
  • ?dose ex acetominophen
  • ?risks agitation, suicidality
  • ?efficacy ex TCAs

75
Eminence based medicine
  • Ex Tim Willens and combining stimulants and
    atomoxetine

76
Questions?
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