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

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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

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Industry affiliationsAstraZenecaBiovailGlaxoSm
ithKlineJanssen PharmaceuticalsLillyShire
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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

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Disruptive behaviour

• What is it?
• What are we treating?

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

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

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Why is a diagnosis important?

• Guide treatment
• Anticipate future changes/needs
• Non-clinical reasons

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What medications are used?

• Atypical neuroleptics/antipsychotics (ATNs)
• Mood stabilizers (lithium, divalproic acid,
  carbamazepine)
• SSRIs (selective serotonin reuptake inhibitors)

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Atypical antipsychotics

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

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Clozapine

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

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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

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Clozapine-Drawbacks

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

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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

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Side effects

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

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Olanzapine

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

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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

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Quetiapine

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

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Quetiapine side effects

• Weight gain in adolescents
• cataracts in beagles Stip and Boisjoly 1999
• Tachycardia
• sedation

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Ziprasidone

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

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Other atypicals

• aripiprazole
• Amisulpride

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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

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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

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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

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Guidelines aggression

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

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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

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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

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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

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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

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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

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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

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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

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• What about other diagnoses/treatments?

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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

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ADHD cont

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

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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

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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

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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

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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)

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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

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Guidelines depression

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

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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

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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

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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)

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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

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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)

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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

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SSRIs Risk\Benefit Issues
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Anxiety disorders

• CBT
• Exposure therapy with response prevention
• Behavioural therapy
• SSRIs
• No evidence that benzodiazepines are effective,
  may cause dis-inhibition

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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

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ATNs what are the issues?
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• 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

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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.

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• 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

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• 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

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• 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?

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• 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?

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• 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

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• 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

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

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

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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

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Use of antypicals

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

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

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Other symptoms mentioned included aggression,
psychosis, tics
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12 of prescriptions in the lt9 age group
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Other tests included CBC, TSH, renal function
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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

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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)

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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

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Current limitations

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

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Covert op medicine

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

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Eminence based medicine

• Ex Tim Willens and combining stimulants and
  atomoxetine

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Questions?