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 Nothing to disclose
Psychiatric Treatment Evidence based treatment integrates best research evidence with clinical expertise and patient values No research studies have been published on: Psychopathology in children with Dravet syndrome Treatment options Long term psychiatric outcome
Problems with Psychiatric Treatment in Dravet Syndrome 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 Shortage of child psychiatrists who have experience with this disorder
Psychiatric Treatment 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 Seizure control is a priority
Psychiatric Treatment Psychiatric problems: Multiple emotional and behavioral problems leading to multiple comorbid diagnoses Psychiatric and cognitive comorbidities Time course association Cognitive impairment predicts the severity of psychiatric problems Impact of seizures and antiepileptic medications on cognitive and psychiatric symptoms
Psychiatric Diagnoses Psychiatric diagnosis is reached after a comprehensive clinical assessment: 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 Developmental/cognitive Intellectual disability, language and learning disorders Inattentiveness, hyperactivity, impulsivity ADHD Impairment in executive functioning Social skills deficits Language disorders, ID, ASD, ADHD
Most Common Psychiatric Problems and Diagnoses Aggression Learning disorders, ID, ASD, ADHD, ODD, DBD, mood disorders Mood problems Depression Anxiety
Psychiatric Treatment Medications alone are not as effective as in combination with other interventions: special education, speech, individual, family therapy, and parent training
Psychiatric Treatment Specific pharmacological treatment is not available for: Developmental delay Social skills deficits Special education, developmental and behavioral therapies, social skills training, ABA
Psychopharmacological Treatment Distractibility, hyperactivity, impulsivity (ADHD) 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 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 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 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 Sudden death reported in patients with structural cardiac abnormalities or other serious heart problems. 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 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 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 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 The second-line of treatment: 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) The third-line of treatment: Guanfacine is less sedating than clonidine Clonidine produces more: rebound and withdrawal blood pressure reduction shorter acting - must use four times per day transdermal Patch (5 days)
Psychiatric Treatment Unproven ADHD treatments Treatment of food allergies Caffeine Megavitamins Biofeedback Eye-tracking therapies Chiropractic manipulations BrainGym and other brain training programs
Aggression Irritability Rule medication side effects Defiance Communication problems, anxiety, impulsivity Self-injurious behaviors Sensory issues, boredom, negative attention seeking Aggression towards others Usually caused by multiple factors Functional behavioral analysis
Psychiatric Treatment Aggression Treatment targets potential triggers: 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 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 Most common side effects: Nausea, headaches (short duration) Extremely rare side effects: Bleeding, jitteriness, agitation, sleep disturbance FDA Black Box warning about increased suicidal thinking in selected population.
SSRIs Extremely rare side effects: 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 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 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 Currently have the strongest evidence base of any pharmacologic treatment of irritability, aggression, rigid preoccupations in ASDs FDA approval for: 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 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 Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Aripiprazole (Abilify) Ziprasidone (Geodon) Paliperidone (Invega)
Atypical Neuroleptics Most common side effects: Weight gain and increased body mass index Increased lipids (cholesterol) Increased blood glucose and risk for type II diabetes Sedation Drooling
Atypical Neuroleptics Extremely rare side effects: 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 Extremely rare side effects: Changes in heart rhythm (prolongation of qt) that may cause ventricular arrhythmias Physical activation (akathesia - increased need to move)
Pediatric Clinical Use - Tidbits 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 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 Weight Gain OLZ>Ris QTP>HAL> ARP>ZIP Prolactin Elevation Effects PAL>RIS>HAL>OLZ>ZIP>QTP>CLZ>ARP Sedation OLZ>RIS>QTP>ZIP>ARP
Typical Antipsychotics 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 Amantadine (NMDA antagonist) single small DBPC trial showed improvement in hyperactivity and inappropriate speech domains of the ABC-CV Memantine (NMDA antagonist) and D- cycloserine (NMDA partial-agonist) have shown positive results in small, open trials
Traditional Mood Stabilizers Lithium Valproate Carbamazepine
Take Home Message 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