Download ADHD Treatment - Dravet Syndrome Foundation

Psychiatric Issues in Dravet
Syndrome: Focusing on
Medications
Sigita Plioplys, M.D.
Head, Pediatric Neuropsychiatry Clinic
Dep. of Child and Adolescent Psychiatry
Ann and Robert H. Lurie Children’s Hospital of
Chicago
Associate Professor
Feinberg School of Medicine, Northwestern
University
Disclosure
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Nothing to disclose
Psychiatric Treatment
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Evidence based treatment integrates best
research evidence with clinical expertise and
patient values
No research studies have been published on:
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Psychopathology in children with Dravet
syndrome
Treatment options
Long term psychiatric outcome
Problems with Psychiatric
Treatment in Dravet Syndrome
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No evidence based data are available to
guide psychiatric treatment in children
with Dravet syndrome
Treatment is guided by the clinical
experience and expertise of a child
psychiatrist
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Shortage of child psychiatrists who have
experience with this disorder
Psychiatric Treatment
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It starts with an accurate identification of
psychiatric problems and associated
impairment
Treatment targets the most impairing
symptom/problem in the context of seizure
presentation and their management
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Seizure control is a priority
Psychiatric Treatment
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Psychiatric problems:
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Psychiatric and cognitive comorbidities
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Multiple emotional and behavioral problems
leading to multiple comorbid diagnoses
Time course association
Cognitive impairment predicts the severity of
psychiatric problems
Impact of seizures and antiepileptic
medications on cognitive and psychiatric
symptoms
Psychiatric Diagnoses
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Psychiatric diagnosis is reached after a
comprehensive clinical assessment:
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Clinical interview with the parents and children
Clinical observation of the patient
Information from the teachers
Review of neurological and psychological testing
Diagnosis is based on the standard DSM-5
criteria
Most Common Psychiatric
Problems and Diagnoses
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Developmental/cognitive
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Inattentiveness, hyperactivity, impulsivity
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Intellectual disability, language and learning
disorders
ADHD
Impairment in executive functioning
Social skills deficits
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Language disorders, ID, ASD, ADHD
Most Common Psychiatric
Problems and Diagnoses
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Aggression
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Learning disorders, ID, ASD, ADHD, ODD,
DBD, mood disorders
Mood problems
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Depression
Anxiety
Psychiatric Treatment
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Medications alone are not as effective as
in combination with other interventions:
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special education, speech, individual, family
therapy, and parent training
Psychiatric Treatment
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Specific pharmacological treatment is not
available for:
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Developmental delay
Social skills deficits
Special education, developmental and
behavioral therapies, social skills training,
ABA
Psychopharmacological
Treatment
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Distractibility, hyperactivity, impulsivity
(ADHD)
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Executive function impairment
Aggression
Mood problems
ADHD Treatment
#1. A stimulant: usually methylphenidate
(Ritalin, Metadate, Concerta, Focalin,
Daytrana)
#2. The other stimulant: usually
amphetamines (Adderall, Vyvance)
#3. Atomoxetine (Strattera)
#4. An alpha agonists: guanfacine (Tenex,
Intunive), clonidine (Catapres)
ADHD Treatment
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FDA-approved product labeling for all
stimulant products states that there is
clinical evidence that stimulants may
lower the convulsive threshold in patients
with prior seizures
The FDA warning recommends that
stimulants should be discontinued in the
presence of seizures
ADHD Treatment
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Methylphenidate (MPH) is the most studied drug
that has shown good short-term efficacy:
 2 controlled studies available, both found
MPH to be safe and effective in children with
well controlled seizures
Controlled trials have noted significant
improvements in ADHD symptoms without an
exacerbation of seizures
No studies to report major interactions between
AEDs and MPH
ADHD Treatment
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Stimulants are effective and safe first-line
medications for ADHD
The selection of a specific stimulant should be
based on the patient’s clinical presentation,
clinician’s experience, and parent’s choices
Adderall XR Warning
FDA - August 2004
Sudden death has been reported in association with
amphetamine treatment at usual doses in children with
structural cardiac abnormalities.
Canada
2004 - Pulled Adderall XR
2005 – back on market – no evidence for increased
cardiac risk
FDA Stimulant Warnings
Amphetamine and Methylphenidate
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Sudden death reported in patients with
structural cardiac abnormalities or other serious
heart problems.
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Careful family and personal history needed, further
cardiac evaluation only if indicated
No routine pre-tx cardiac eval indicated unless known
disorder or cardiac symptoms
Hypertension (primarily concern in adults)
Hallucinations
Aggression and hostility
Stimulants and Drug
Abuse
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No evidence for stimulant-induced
increase in drug abuse
Successful ADHD treatment reduces drug
abuse in adolescence
Stimulant intake must be supervised and
monitored by parents
ADHD Treatment
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Stimulant with a shorter duration (6-8
hours vs 10-12 hours) of action may help
to prevent potential delay in sleep onset
and disruption of sleep pattern.
Significantly decreased weight may affect
AED’s serum levels. Weight needs to be
monitored at each appointment.
ADHD Treatment: Growth
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Studies inconsistent re height
Monitor height and weight
Adjust foods and mealtimes
Catch-up growth when off medication
Temporary height deficits may be related
to ADHD
Some studies – ADHD kids bigger than
average pre-medication
ADHD Treatment:
Atomoxetine
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The second-line of treatment:
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May affect liver function due to the
polypharmacy with AEDs
No interactions with any of the AEDs have
been reported
On direct comparison, ATX is less effective
than Adderall XR and MPH
Some non-responders to stimulants
respond to ATX
Guanfacine (Tenex) and
Clonidine (Catapress)
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The third-line of treatment:
 Guanfacine is less sedating than clonidine
 Clonidine produces more:
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rebound and withdrawal
blood pressure reduction
shorter acting - must use four times per day
transdermal Patch (5 days)
Psychiatric Treatment
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Unproven ADHD treatments
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Treatment of food allergies
Caffeine
Megavitamins
Biofeedback
Eye-tracking therapies
Chiropractic manipulations
BrainGym and other “brain training” programs
Aggression
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Irritability
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Defiance
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Communication problems, anxiety, impulsivity
Self-injurious behaviors
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Rule medication side effects
Sensory issues, boredom, negative attention seeking
Aggression towards others
Usually caused by multiple factors
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Functional behavioral analysis
Psychiatric Treatment
Aggression
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Treatment targets potential triggers:
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Impulsivity, hyperactivity – treatment as in
ADHD
Anxiety, depression – SSRIs, mood stabilizers
No clear triggers or resistant to the above
mentioned treatments - atypical neuroleptics
Aggression/tantrums/selfinjury
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SSRIs
Atypical antipsychotics
Typical antipsychotics
Traditional mood stabilizers
Alpha agonists
Glutamatergic agents
Selective Serotonine
Reuptake Inhibitors (SSRIs)
Increase serotonin levels in the brain:
 Fluoxetine (Prozac)
 Sertraline (Zoloft)
 Escitalopram (Lexapro)
 Citalopram (Celexa)
 Fluvoxamine (Luvox)
 Paroxetine (Paxil)
SSRIs
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Most common side effects:
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Nausea, headaches (short duration)
Extremely rare side effects:
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Bleeding, jitteriness, agitation, sleep
disturbance
FDA Black Box warning about increased
suicidal thinking – in selected population.
SSRIs
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Extremely rare side effects:
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Cardiovascular side effects, with a reported
incidence of less than 0.0003%
SSRIs inhibit cardiac and vascular sodium,
calcium and potassium channels and prolong
QT intervals.
A number of large studies of patients without
known pre-existing heart disease have
reported no EKG changes related to SSRI use
SSRIs
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There are a number of potential drugdrug interactions between the various
individual SSRIs and antiepileptic
medications
Most of these arise due to SSRI ability to
inhibit liver enzymes (P450 cytochromes)
and slow down the metabolism of the
antiepileptics potentially resulting in
increased levels
Atypical Neuroleptics
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Increase dopamine, serotonin, and
histamine levels in the brain
“Off label” use for aggression, irritability,
tics, mood disorders, and psychosis
Metabolic and neurological complications
with chronic use
Atypical Antipsychotics
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Currently have the strongest evidence base of
any pharmacologic treatment of irritability,
aggression, rigid preoccupations in ASDs
FDA approval for:
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Risperidone: irritability and associated
dysfunctional behaviors associated with autistic
disorder in 5-16 year olds
Aripiprazole: irritability associated with autistic
disorder in 6-17 year olds
Atypical Antipsychotics
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The RUPP study showed significant
positive responses for stereotypical and
repetitive behaviors vs placebo
Considered as second line agents for
treatment refractory ASD cases prior to
the recent Citalopram study
Atypical Neuroleptics
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Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Aripiprazole (Abilify)
Ziprasidone (Geodon)
Paliperidone (Invega)
Atypical Neuroleptics
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Most common side effects:
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Weight gain and increased body mass index
Increased lipids (cholesterol)
Increased blood glucose and risk for type II
diabetes
Sedation
Drooling
Atypical Neuroleptics
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Extremely rare side effects:
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Abnormal muscle movements (Dystonia)
Parkinson –like symptoms
Discharges from the breasts in boys and girls
Increased seizures
Neuroleptic-malignant syndrome (high fever,
kidney failure, destruction of muscles)
Hypothyroidism
Atypical Neuroleptics
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Extremely rare side effects:
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Changes in heart rhythm (prolongation of qT)
that may cause ventricular arrhythmias
Physical activation (akathesia - increased
need to move)
Pediatric Clinical Use Tidbits
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Akathisia risk appears equal to adult rates
Dyskinesias are frequently reversible
Tardive dyskinesia risk appears ~1/2 that of
adults (annualized incidence rate of 0.04%)
Cases of neuroleptic malignant syndrome have
been reported with SGAs
Case reports of new onset diabetes
Tidbits - continued
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Hyperprolactinemia is dose-dependant, reduces over
time and resolves when medication is stopped
Only Olanzapine has been associated with sig increase
in glucose, insulin, lipids and LFTs in RCTs
Relative Risk of Side
Effects
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Weight Gain
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Prolactin Elevation
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OLZ>Ris
QTP>HAL>
ARP>ZIP
PAL>RIS>HAL>OLZ>ZIP>QTP>CLZ>ARP
Sedation
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OLZ>RIS>QTP>ZIP>ARP
Typical Antipsychotics
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Multiple RCTs beginning in the 1960’s
demonstrated benefit, especially with
Haloperidol, in alleviating
aggression/tantrums/self-injury in ASDs
However, there were high rates of acute
dystonic reactions, drug-induced and withdrawal
dyskinesias, and increased risk for seizures
leading to using atypicals once these drugs
became available
Typicals are now generally reserved for
individuals with severe, treatment-resistant
symptoms
Glutamatergic Agents
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Amantadine (NMDA antagonist)– single
small DBPC trial showed improvement in
hyperactivity and inappropriate speech
domains of the ABC-CV
Memantine (NMDA antagonist) and Dcycloserine (NMDA partial-agonist) have
shown positive results in small, open trials
Traditional Mood
Stabilizers
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Lithium
Valproate
Carbamazepine
Take Home Message
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Evidence based data on safe and effective
pharmacological treatment options for psychiatric
problems in children with Dravet syndrome are
not available
Treatment studies are desperately needed to
identify safe and effective medications for this
patient population
Currently, pharmacological treatment decision
depends only on the experience and expertise of a
treating psychiatrist's and parental values