Autism and Psychopharmacology A Crash Course in Understanding by htt39969

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									Biomedical Interventions:
 Healing the Whole Child
      Susan Schmidt-Lackner, M.D.
     Medical Director, Vista Del Mar
        Child & Family Services
       Assistant Clinical Professor,
    UCLA Neuropsychiatric Institute
            Medical Director,
Early Childhood Partial Hospital Program
          760 Westwood Plaza
      Los Angeles, CA 90024-1759
             (310) 825-0706
      Medical Work-Up of a Child with Autism
A. Family History
     1. 50-fold increase risk of having another child with
        autism (1 in 10 to 1 in 20 as compared with 1 in 500 in the
        general population)
B. Examination
    1. Growth milestone (including head circumference)
    2. General physical examination including observation of skin lesions
         and minor physical stigma
C. Lab tests
    1. Basic: cbc, smac, thyroid, liver function, iron, ferritin, zinc, copper
         (plasma)
    2. Quantitive Immunoglobulins – IgG, IgA, IgM, IgE
    3. IgG subclasses – 1, 2, 3, 4, Ig G- food anti-bodies including
         Antigliadin Antibodies.
    4. Viral Titers
    5. T cell subsets, NK cells
    6. Urine Metabolic analysis / organic acids
    7. Comprehensive digestive stool analysis
 Medical Work-Up of a Child with Autism cont.
D.  Hearing tes
E.  Lead testing in children with pica
F.  Metabolic testing
   1. History of lethargy, cyclic vomiting, early seizures, dysmorphic or
        coarse features, mental retardation
G. Genetic testing (DNA analysis for Fragile X and high resolution
    chromosome studies, 7% carry structural changes not found in parents,
    1% altered portion of chromosome 16)
    1. Family history of fragile X or undiagnosed mental retardation,
    dysmorphic features
H. Imaging study (CT,MRI) not routinely indicated, only if neuro exam
    abnormal; may help identify TSC
     Medical Work-Up of a Child with Autism cont.
I.      If an individual with autism has extreme obsessive-compulsive
        behavior, research blood testing for infection or former infection by
        Group A streptococcus may be done
J.      Targeted Medical Testing for Symptom Complexes
         1. Seizures (clinical or subclinical)
            a. History of regression (significant loss of social and
            communicative function)
            b. Imaging study if the neuro exam is abnormal
          2. Constant ear infections or sick too often for age
            a. Blood test for an immunological profile and other tests
            recommended by your child’s immune specialist.
 Indications of Intestinal Problems in
     Autism Spectrum Disorders
1.     Overt signs and symptoms pertaining to the digestive tract
     •   Abdominal pain, cramping, discomfort
     •   Reflux or excessive burping
     •   Abdominal bloating, especially after meals
     •   Excess gas
     •   Chronic constipation and or history of fecal impaction; hard, dry
         stools
     •   Toe-walking (often indicative of constipation)
     •   Chronic diarrhea or loose stools
     •   Foul smelling stools
     •   Undigested food in stools
     •   Abnormal consistency of stools (i.e “oily” or “foamy” stools)
     •   Abnormal color of stools (I.e. yellow, orange, or pale stools)
     •   Perianal rash
 Indications of Intestinal Problems in
   Autism Spectrum Disorders cont.
2.   Problematic reaction to foods
   •    Gluten and/or casein sensitivity
   •    Food allergies and intolerance (may manifest with dark circles or
        puffiness under eyes, redness of the cheeks or ears, chronic
        postnasal drip, headaches, skin rashes, asthma, environmental
        allergies)
   •    Reactions to phenols and/or salicylates in foods
3.   Past Medical History
   •    Significant history of colic in infancy
   •    Poor immune function with history of frequent infections including
        ear, throat and respiratory infections.
   •    History of fungal infections, such as thrush, diaper rash, or skin
        rashes
   •    History of sensory defensiveness, including sensitivity to sounds,
        lights, tastes, textures and other external stimuli
 Indications of Intestinal Problems in
   Autism Spectrum Disorders cont.
4.   Family History
   •    Maternal history of fungal infections during pregnancy
   •    Family history of celiac disease, Crohn’s disease, ulcerative colitis,
        or other inflammatory bowel conditions
   •    Family history of allergies and/or autoimmune disease
5.   Prescription Drugs
   •    Frequent use of antibiotics in infancy and childhood
   •    History of adverse reactions to antibiotics, including diarrhea,
        thrush, diaper rash, or other abdominal problems.
        Gastrointestinal Abnormalities
                   in ASD
1.   Intestinal Dysbiosis
   •     Imbalance in micro flora (bacteria, yeast, viruses, parasites) in the
         intestinal tract
   •     Alteration in the normal balance of beneficial micro flora and
         harmful organisms begin to overpopulate the digestive tract.
2.   Intestinal Hyperpermeability “Leaky Gut Syndrome”
   •     Increased intestinal permeability resulting from chronic irritation to
         the gut wall
3.   Gluten and Casein Sensitivity
   •     Unable to completely break down of food proteins called gluten and
         casein, resulting in morphine – like reactions due to abnormal
         stimulation of opiate receptors in the brain
4.   Food Allergies and Intolerance
   •     Often caused by damage to intestinal wall and dysfunction of the
         immune system
   •     Food allergies lead to gut inflammation
       Gastrointestinal Abnormalities
                in ASD cont.
5.  Maldigestion and Malabsorption
   • Incomplete breakdown of foods leading to incomplete
      uptake of nutrients
6. Constipation and Diarrhea
7. Sulfation Deficits
   • Sensitivity to phenol containing foods (apples, oranges
      citrus fruits, bananas, grapes, chocolate, food colorings)
   • Deficit in an enzyme known as Phenol Sulfo Transferase
      (PST)
      - involved in process called sulfo conjugation whereby
      the potentially harmful phenols attach to sulfate ions and
      are eliminated from body (Phase II detoxification)
               Nutritional Supplements for
              Treating Gut Issues in Autism
1.   Colostrum – “Nature’s first food”
   •    Secreted by mammary glands of all female mammals in the first few
        days after they give birth
   •    Supplies important immune factors (immunglobulins), antimicrobiol
        peptides, (lactoferrin, lactoperoxidase, etc) and growth factors
        (epidermal growth factor, IGF-I, etc)
   •    Decreased gastrointestinal permeability, viral infections, allergies
2.   Probiotics
   •    Benefical microganisms (“good gut bugs”)
        - Strengthen intestinal tract’s immunological barrier
        - Control overgrowth of harmful bacteria, virus, yeast
        - Control diarrhea and constipation
        - 20-40 billion CFU’s (colony forming units)
             Nutritional Supplements for
          Treating Gut Issues in Autism cont.
3.   Digestive Enzyme Supplementation
   •    Dipeptidyl Peptidase IV (DPP-IV)
   •    Breaks apart proline containing peptides, including caseomorphin and
        gluteomorphin
   •    Opiate-like dietary peptides “exorphins” excessively high in autism
   •    Secondary benefits (22 patients – 12 weeks open label study with
        Enzymaid)
       - Improved socialization, less hyperactivity
       - Adverse reactions: hyperactivity, aggression
4.   Magnesium Sulfate (Epsom Salts)
        - Baths and/or cream (baths can cause dry, irritable skin) strengthen
           intestinal tract’s immunological barrier
        - improved sleep, language
5.   Lauric acid (coconut oil)
   •    Enhances tyrosyl protein sulfotransferase
                 Dietary Interventions
-    Gluten and Casein Sensitivity
    • Incompletely digested gluten (found in wheat and other
        grains) and casein (found in all dairy products)
    • Increased gluteomorphin and caseomorphin
       - Leak into bloodstream through overly permeable
           (“leaky”) gut wall.
           • bind at opiate receptors in brains
-    Signs & Symptoms
    • Diarrhea, foul smelling stools, chronic abdominal pain,
        gas, bloating
-    Diagnosis
    • Urinary Peptide tests measures levels of gluteomorphin
        and caseomorphin excreted through urine
                     Dietary Interventions

-     Treatment Approach
    •    Casein elimination (3 week trial; watch for prepared foods)
    •    Gluten elimination (3 month trial)
        - Wheat
        - Oats
        - Barley
        - Rye
        - Semolina
        - Spelt
        - Triticale
        - Kamut
    •    Reduce Sugar
          Poor Nutritional Profile

•   Vision Abnormality
•   Unhealthy Skin condition
•   Extreme tiredness or lack of energy
•   Lethargy
•   Failure to Thrive
•   Frequent illness due to poor immune support
•   Dental Caries/ Gingivitis
    Nutritional Status of Autistic Children

•    Low Vitamin B6 levels and poor B6-binding combined with low or
     low-normal amounts of intracellular magnesium
•    Low intracellular zinc
•    Low blood levels of Vitamin A
•    Low biotin B1, B3, B5 function (microbiological assays)
•    Low urinary Vitamin C
•    Low red blood cell (RBC) membrane levels of Eicsapentaenoic Acid
     (EPA is a derivative of OMEGA–3 fatty acid)
•    Low levels of taurine (vital to nerve cells)
•    Elevated casomorphine and gliadomorphine levels (opioid peptides)
•    Elevated IgG antibodies to milk
•    Low serum selenium (50% of subjects)
•    Low Folate
•    High Copper
•    Low Iron
            Immune Dysregulation Autism

Clinical Clues to Immune           Evidenced Immune Dysregulation
  Dysregulation                    • Increased IgE
• Allergic shiners                 • Autoimmunity markers
• Eczema                           • Abnormal natural killer cell
• Hives                              function
• Rhinitis, Asthma                 • IgA deficiency
• Fungal skin infection            • Lymphopenia
• Oral thrush                      • T cell abnormalities
• Mollascum contagiosum            • TH1 to TH2 shift –
• Warts                              •increased autoimmunity & allergy
• Frequent illness or infections     •chronic viral and fungal infections
• Excessive ear infections
       Immune Boosters / Supporters

•   Juice Plus
•   Zinc
•   Beta Glucan
•   Vitamin C
•   Vitamin E
•   Selenium
•   Coenzyme Q10
•   Glutathione
•   N-acetylcysteine
•   Antioxidants
            Sleep Disorders
•   Insomnia
    1. Periodic night wake ups
    2. Restlessness
    3. Nightmares
    4. Early morning awakening
           Dietary Supplements
•   Magnesium
•   Melatonin
•   Taurine
•   GABA
•   L-tryptophan
         Juice-Plus Research Studies
(866) 313-8177 Tami Hulcher, Health Educator
                         Step 1 - Composition
•   Analysis to prove that Juice-Plus + provides nutritional essence of
    fresh raw fruits and vegetables
•   Juice-Plus+ contains the Vitamin C of 4 oranges, the betacarotene
    of 3 carrots, and more Vitamins E than several servings of broccoli
    and spinach, micronutrients, phytochemicals and antioxidants found
    in fresh raw fruits and vegetables
                           Step 2 Bioavailability
•   Plasma level of antioxidants increased after only 28 days
•   Plasma levels of antioxidants were maintained for the duration of
    the study
                              Juice Plus –
•   T-Cell proliferation
•   Natural killer cell cytotoxicity
•   Increased IL-2/IL- 6 production
•   Increase IL-2/IL – 6 receptors
•   Increased CD4cells
                   Bottom line: Decreased infection
                   Safe Supplements
•    Vitamin B6 50 mg under 5 yrs/day (biologically activated 50-100 mg
     over 5 yrs/day form, pyridoxol 5 phosphate
    - Magnesium glycinate form most absorbable (200-400mg/day)
•    Zinc, picolinate form most absorbable (20-50mg/day)
•    Calcium – one gram daily divided into several doses
•    Selenium doses up to 150-200mcg daily for older children; 75-150
     mcg under 5 (high doses can be toxic)
•    Vitamin A (beta-carotene, 2500-5000 IU/day (may be as cod liver
     oil)
•    Vitamin C, up to 1000mg/day to tolerance, better given 3 or 4x/day
     (Does not stay in body very long)
•    Vitamins E – 200mg/day for under 5yrs. 400mg/day for over 5yrs.
•    Essential fatty acids (OMEGA 3), 750mg EPA/day 250-500mg,
     DHA/day, GLA 50-100mg/day
                         L-Carnosine
•   A naturally occurring dipeptide that consists of Alanine and Histidine
•   Benefits
        - Receptive language
        - Auditory processing
        - Socialization
        - Expressive language
•   Dosage
   -    400mg twice/daily
•   Side effects
   -    Irritability
   -    Hyperactivity
   -    Insomnia
Chez et al 2002
•   31 children, 8 week double blind placebo study, mean age=7.45
   -    Placebo n=17, no significant change on outcome measures
   -    N=14 statistically significant improvements (GARS, EOWVT, CARS)
   -    May enhance frontal lobe function and metal ion transfer of zinc and
        copper in the entorhinal cortex
Omega-3 Fatty Acids in Bipolar Disorder
            Study Design

• Double-blind placebo-controlled 4-month trial
   – N = 30 bipolar outpatients
   – All subjects had mania/hypomania with past 1 year
• Randomized to 9.6 g/day Omega-3 vs. placebo (olive oil)
• Concomitant meds left unchanged
   – N = 8 entered study on no other drug therapy
• Main outcome measures
   – recurrence or lack of response
                   Omega-3 Fatty Acids
                     Usage Guide
• Fish oil preferred to flaxseed oil at this time
• Usual dosage range 1.5-10g/d (3-5 g/d typical) omega-3 fatty acids (EPA
  or EPA + DHA) EPA >>DHA
• Read labels carefully. Brands differ widely in omega-3 content
• Twice daily schedule optimal
• Food increases omega-3 absorption
• Highest content of EPA desirable
• Antioxidants (e.g. Vitamins C & E, etc) may prevent in vivo degradation
  of omega-3s
• If GI upset: divide dose, ginger root, daikon rash
• Caution: anticoagulants or high-dose NSAID
                     Something Fishy

A. Autism may be caused by inserting a G-alpha protein defect
   (partussis toxin found in the DPT vaccine, into genetically at-risk
   children).
        1. Toxin separates the G-alpha protein from retinoid
        receptors.
        2. Family history of at least one parent with a pre-existing G-
   alpha protein defect (night blindness,
        pseudohypoparathyroidism or adenoma of thyroid or
        pituitary gland).
                      Something Fishy cont.

B. Natural vitamin A may reconnect the retinoid receptors critical for vision
   sensory perception, language processing and attention.
        1. Improvement in language, vision attention and social
        interaction in some children.
        2. Doses:        under 2 years old       1250 IU Vitamin A
                         2-5 years old           2500 IU
                         5-10 years old          3750 IU
                         over 10 years old       5000 IU
C. Caution
        1. Hypervitaminosis A
        2. Elevation of lipids
                Nutritional Pharmacology for
                        Specific Issues
A. Hyperactivity
        1. GABA (500-1000 mg tid)
        2. Taurine (500-1000 mg tid)
        3. EFA (1000-2000 mg gd)
        4. TMG (125 mg bid and work dose up slowly)
B. Inattention
        1. Tyroxine (500 mg bid)
        2. EFA (up to 2000 mg gd)
        3. CoQ10 (25-50 mg bid)
        4. TMG (125-250 mg bid)
        5. Pycnogenol (French pine bark extract, 1mg/kg)

C. Self-Abusive Behaviors
        1. Taurine (up to 10,000 mg total daily)
        2. GABA (up to 10,000 mg total daily)
          Nutritional Pharmacology for
              Specific Issues cont.
D. Poor sleep
       1. Melatonin 1-3 mg hs
       2. Taurine (1000-4000 mg hs)
       3. GABA (1000-5000 mg hs)
       4. Magnesium glycinate (up to 400mg)
E. Tantrums, Transitions, “Melt downs”
       1. Taurine (1000-2000 mg, prn)
       2. GABA (500-1000 mg, prn)
F. Diarrhea
       1. Colostrum
       2. Probiotics
              Nutritional Pharmacology for
                  Specific Issues cont.
G. Infections
        1. Colostrum
        2. Zinc (up to 60 mg/day)
        3. Selenium (up to 200 mg/day)
        4. Echinacea +/-
        5. EFA
H. Constipation
        1. Fiber (Basic Green, Ciracel)
        2. Xprep (prune concentrate)
        3. Senna
        4. Miralax (Rx) 1/2 or 1 tablespoon
        daily as needed
        5. Mg Citrate
        6. Vitamin C
        7. Smooth move Tea ( Traditional Medicinals)
        8. Juice Plus
  Medications treat symptoms
• Medications used to treat autism were
  developed primarily to treat some other
  disorders and then tried on autistic children or
  adults because of overlap in certain
  symptoms
• Target symptoms
  – Over activity, short attention span, impulsivity,
    distractibility
  – Stereotyped motor movements
  – Self-injurious behaviors (SIB)
  – Aggression
  – Social withdrawal
  – Anxiety
  – Sleep disturbance
• When are medications started?
  – Treat specific symptoms with behavioral
    approaches first
  – Meds must be used in combination with
    behavioral treatments and educational
    approaches
  – Severe symptoms
    • Hyperactivity
    • Self-injurious behavior
    • Aggression
• Child’s age and use of medications
  – Children under 3 should not be on meds
  – 3-5 years old
    • over activity/impulsivity/distractibility
       – stimulants
       – Clonidine/Tenex

    • Repetitive behavior, perseveration, social relatedness,
      aggression, language
       – Serotonin substrate reuptake inhibitors (SSRI)
– Prepuberty
  • Over activity/impulsivity/distractibility
     – stimulants
     – Clonidine/Tenex
  • Repetitive behaviors, perseveration, social relatedness,
    aggression, language
     – SSRI
  • Episodic outbursts, aggression, moodiness, language
     – Lithium
     – anticonvulsants
  • Aggression, SIB, perseveration, social relatedness
     – Atypical antipsychotics
– Adolescence
  • 1/2 of all patients have dramatic aggravation of
    symptoms such as SIB, aggression, restlessness,
    hyperactivity with the onset of puberty (year before or
    after)
• Criteria for using psychoactive
  medications
  – Is there any behavior that is such a problem that
    the child is frequently injuring himself or others?
    (Aggression, SIB)

  – Have behavioral approaches been tried with little
    or marginal success?
     • Behavioral methods should be tried first to see how
       much of the severity of the behavior problem can be
       reduced without meds
– Are the target behaviors present in more than one
  setting?
   • If the target behavior is a reaction to a particular setting (only
     at home or school), the setting may need to be changed

– Do the target behaviors interfere with the child’s ability
  to learn? (Hyperactivity, distractibility, short attention
  span, perseveration, repetitive behaviors)

– Be aware of side effects
   • Risk/benefits
   • Robust response
• Collecting baseline behavioral data before
  a medication trial
  – Define target behaviors
  – Document how often and how long child exhibits
    problem behavior
    • Antecedents/behavior/consequences
  – Teacher rating scales (Connors)
  – PDD Behavior Inventory (Ira Cohen)
  – Blind trials
    • One significant caregiver (teacher, friend, relative)
• Baseline assessment prior to initiation of
  medication
  – Complete medical history, physical, neurological
    exam
  – Urinalysis
  – Serum electrolyte levels of (Na+, K+, Cl- , Ca++,
    PO4, CO2, BUN)
  – Liver function testing (SGOT, SGPT, alkaline
    phosphatase, LDH, bilirubin)
– Thyroid function tests (thyroxine T4,
  triodthyronine resin reuptake [T3RU], TSH)

– Renal function tests (serum creatinine, BUN)
  • Especially with LiCO3


– Electrocardiogram
  • Especially with TCAs, LiCO3, Clonidine
  Tricyclic Antidepressants (TCA)
 II     M edication       M ost like      Possible       Side effects/
          (trade          benefits        benefits        problem s
       nam e/generic)

TCA   Tofranil           increased      decreased     very rare cardiac
      (im ipram ine)     attention      anxiety,      com plications,
                                        inhibits      m ay lower seizure
                                        enuresis      threshold, rare
                                                      sudden pediatric
                                                      death
      Norpram in
      (desipram ine)

      Anafranil          decreased      decreased     m ay lower seizure
      (clom ipram ine)   com pulsive,   SIB,          threshold
                         repetitive,    decreased
                         behavior       aggression,
                                        im proved
                                        social
                                        relatedness
• Tricyclic Antidepressants (block reuptake
  of serotonin and norepinephrine)
  – PR interval - less than or equal to 210
    milliseconds
  – QRS interval - widening to no more than 30%
    over baseline
  – QT interval - less than 450 millisec
  – HR - max 130 beats/min
  – Systolic BP max of 130mm Hg
  – Diastolic BP max of 85mm Hg
• Other side effects of TCA
  – Drowsiness, EEG changes, seizures,
    incoordination, anxiety, insomnia, nightmares,
    confusion 20 to anticholinergic toxicity, delusions,
    worsening of psychosis
  – Blood dyscrasias
  – Anticholinergic side effects: dry mouth, blurred
    vision, constipation
• Clomipramine HCl (TCA)
  – More potent inhibitory effects on neuronal reuptake
    of serotonin as compared to norepinephrine
• SSRI (Selective Serotonin Reuptake
  Inhibitors)
  – Chemically unrelated to TCAs
    • Little effect on NE reuptake mechanisms
    • Differing specificity in the serotonin receptors whose
      reuptake they inhibit which explains their efficacy in
      treating disorders other than depression and the fact
      that they have somewhat different side effect profile
  – Less severe side effects than TCA
    • No risk of overdose or fatality
– Side effects are symptoms of administration of
  exogenous serotonin
  • Headache, nausea, vomiting, diarrhea, nervousness,
    sleep disturbance, and sexual dysfunction
– Low doses
• Trazodone
  – Chemically unrelated to tricyclic, tetracyclic and
    other antidepressants
  – It is a SSRI but unlike SSRIs in that its
    metabolites have significant effects on other
    neurotransmitters and their receptors
  – Side effects
     • Drowsiness, dizziness, lightheadness, dry mouth,
       nausea, vomiting
     • Priapism 1:15,000 (painful erection)
      Serotonin Substrate Reuptake
            Inhibitors (SSRI)
II   Medication      Most likely     Possible       Side effects/
     (trade name/    benefits        benefits       problems
     generic)

SSRI Prozac          decreased       decreased       very rare
     (fluoxetine)    compulsive,     anxiety, panic, cardiac
     Celexa          repetitive      depression,     complications
     (citalopram)    behaviors,      decreased
     Paxil           decreased       aggression,
     (paroxitene)    perseveration   improved
     Zoloft                          social
     (sertraline)                    relatedness,
     Luvox                           language
     (fluvoxamine)
     Lexapro                         increased
     Cescitalopram   Helps child     daytime        occasional
     Desyrel         sleep through   calmness,      nausea
     (trazodone)     night           decreased
                                     aggression
  Research with Serotonergic Agents
• Fluvoxamine
  – McDougle, et. al. (1996)
    •   30 adults, mean age 30, mean dose 276 mg/d
    •   Double blind, placebo-controlled study
    •   Responders 8/15 (53%) active vs. 0/15 placebo
    •   0/15 children responders in attempt at study
        replications
• Sertraline
  – McDougle, et. al. (1998)
    • Open-label study in adults
    • Responders
       – 15/22 (68%) of AD
       – 9/14 (64%) of PDD-NOS
       – 0/15 (0%) of Asp Syndrome

• Fluoxetine
  – Cook et. al. (1992)
       – Open label
          • 15/23 subjects with autism improved on CGI (mean age
            15.9 years)
– DeLong, et. al., (1998)
  • open-label
     –22/37 children between ages 2 and 7
      improved
     –21 subjects with a family history of major
      affective disorder
        • 18 had positive response
                  Stimulants (enhance dopamine
                       neurotransmission)
        Medication                 Most likely          Possible     Side effects/ problems
    (Trade name generic)            benefits            benefits


Short acting agents
Ritalin (methylphenidate)
                               Less hyperactivity,    Decreased    Abdominal pain, lower
Dexedrine
(Dextroamphetamine)            increased attention,   aggression   seizure threshold,
Focalin (dexmethylphenidate)   decrease impulsivity                decreased appetite, nausea,
Cylert (pemoline)                                                  irritability, mood ability,
Adderall (sulfate salts of                                         weepiness, tachycaridia,
dextroamphetamine and                                              blood pressure changes,
amphetamine)                                                       tics increased, stereotypies,
                                                                   psychosis, rebound

Long acting agents             Once daily dosing                   Less appetite suppression,
Dexedrine spansules            Less rebound                        Insomnia
Concerta
                               Consistent delivery                 Sever liver toxicity
Fooalin XR
Adderall XR                                                        Severe local allergic
Mitadate CD                                                        reaction
Ritalin LA
Daytrana Patch
(Methylphenidate transdermal
system
• Behavioral rebound
  – About 5 hrs after last dose
  – Excitability, talkativeness, overactivity, insomnia,
    stomach aches, mild nausea

• Stimulants should be used with great
  caution in presence of family history of
  tics or Tourette disorder
    Research with Stimulants
• Campbell et. al. (1976)
  – Found that amphetamine worsened negativism in
    8 of 11 autistic children, 5 of 7 who had
    hyperactivity showed reduction of that symptom
  – Need controlled studies of stimulants
               Strattera (Atomoxetine)
•    Highly selective Norepinephrine reuptake inhibitor
•    Non-stimulant
•    Should not be used in patients with glaucoma
•    Some children experience a loss of weight when starting treatment with
     Strattera
•    Should be used with caution in patients with hypertension, hypotension,
     tachycardia or cardiovascular disease
•    In children and adolescents the most common adverse events in clinical
     trials were
    - Decreased appetite
    - Nausea
    - Vomiting
    - Dyspepsia
    - Dizziness
    - Mood swings
•    No significant difference in insomnia vs. placebo
•    Not contraindicated in patients with tics or anxiety
• Fenfluramine (sympathomimetic amine
  with antiserotonergic properties)
  – Less hyperactivity, better attention, improved
    language, decreased stereotypies
  – Double blind placebo controlled study of 28
    autistic children (Campbell et. al. 1988)
    • Not statistically superior to placebo
    • Retarding effects on discrimination learning
    • Neural toxicity
  – No individual child had strong positive response
• Anxiolytics
  – Benzodiazepines (generally disinhibiting)
  – Buspar (buspirone)
    • Not pharmacologically related to benzodiazepines or
      barbiturates
    • Antiserotonergic
    • 5HT1a receptor agonist with an alpha2 -adrenergic
      antagonist metabolite
    • Side effects
       –   Dizziness (12%)
       –   Drowsiness (10%)
       –   Nausea (8%)
       –   Headache (6%)
       –   Insomnia (3%)
       –   Lightheadness (3%)
       –   Disinhibition
     Research with Buspirone
• Realmuto et. al.
  – 15 autistic children, 5 mg tid to 10 mg bid
    Buspirone
     • Decreased anxiety
     • Decreased aggression
     • Of the 9 responders, 7 were on concomitant
       psychoactive medication
• Trexan (naltrexone)
  – Long-acting, potent, opiate antagonist
     • Potentially useful in a subgroup of autistic children who have elevated
       endorphin (opioid peptides) levels
         – Insensitivity to pain may be due to increased endorphin level
         – Less hyperactivity, negative behavior, fewer stereotypies, decreased
           aggression, self-injurious behavior

• Optimal dose 1mg/kg/day
• Research studies with naltrexone
     • Campbell - 1993
     • 41 hospitalized patients 8-week double-blind study naltrexone vs.
       placebo
         – Only significant finding was modest decrease in hyperactivity
         – Main side effect is mild sedation
     • Low dose Naltrexone
         – Language, mood improved
         – 1.3-4.5mg transdermal cream
• Clonidine (Catapres)
  – Clonidine patch (transdermal)
  – Centrally active antihypertensive
    • Alpha2 Noradrenergic receptor agonist acts
      preferentially and on presynaptic Alpha2 neurons to
      inhibit endogenous release of NE in brain
    • Side effects
       – Hypotension, depression, sedation
       – Must wean over 4-7 days to avoid hypotensive reaction and
         other withdrawal symptomatology such as nervousness,
         agitation, headache
           • 4-5 microgram/kg/day (.05 mg four times/day)
           • Short ½ life in kids (4-6 hrs)
           • May improve sleep disturbance, attention, impulsivity,
             hyperactivity, aggression
• Guanfacine HCl (Tenex)
  –Less sedating and hypotensive effects than
   clonidine
  –Twice daily dosage (.5-1 mg bid)
       Research with Clonidine
• Jaselskis, Cook, Fletcher, Leventhal (1992)
   – 8 autistic boys previously treated with
     methylphenidate,neuroleptic,desipramine without
     effect
   – Modest decrease in hyperactivity and irritability
   – Patients may develop tolerance to therapeutic effects
     and see increase in irritability
• LiCO3
  – Highly soluble salt, 95% excreted by kidneys
    • Decrease episodic anger outbursts, aggression,
      moodiness
    • Low therapeutic index, toxicity related to serum levels
    • LiCO3 toxicity
       – Diarrhea, vomiting, ataxia, tremor, muscular weakness and
         twitches, drowsiness, sedation, slurred speech, acne
    • Severe and life-threatening toxic effects
       – Cardiac arrhythmias and severe CNS difficulties such as impaired
         consciousness, confusion, stupor, seizures, coma and death
    • Delong (1994) 1/3 autistics have family history of bipolar
      illness. Developmental Medicine and Child Neurology, vol
      36, pages 674-688
                  Anticonvulsants

            Most likely      Possible
            benefits         benefits   Side effects/problems

Tegretol    Less           Improved     Dizziness, drowsiness,
            hyperactivity, language     nausea, vomiting,
            fewer                       unsteadiness, occasional
            behavioral                  effects on liver function
            outbursts,                  and rarely, bone marrow
            improved                    blood dyscrasias
            sleep
Depakote                                behavior disinhibition

Neurontin

Lamictal    Mood stability              Steven Johnson’s
                                        syndrome
• Neuroleptic medications (antipsychotic meds)
  – D2 Receptor Blockers
  – Try after other medications have failed
  – Severe agitation, aggression or SIB
– Major side effects
  • Extrapyramidal symptoms
     – Acute Dystonic Reactions
        • Most common with high potency, low dose antipsychotics
        • Muscular hypertonicity
        • Tonic contractions (spasms) of the neck (torticollis), mouth,
          tongue
        • Oculogyric crisis (eyes rolling upward and remaining in that
          position)
        • Opisthonos (spasm in spine and extremities)
– Parkinsonism
– Tremor, cogwheel rigidity, drooling, masked facies
– Akathisia (motor restlessness)
• Neuroleptic Malignant Syndrome
  – Life-threatening
  – Most frequently within 2 weeks after initiation of
    therapy
  – Severe muscular rigidity, altered consciousness,
    stupor, catatonia, myoglobinemea
  – Increased CPK levels
• Tardive Dyskinesia
  – Develops after 3 months of treatment
  – Choreoathetoid movements (characteristic
    slithering movements of the neck, body, or
    extremities)
  – Involuntary tic and grunts (form of respiratory tic)
  – Preexisting motor stereotypies should be
    carefully noted by the doctor giving neuroleptic
    medication before starting a new drug so that any
    later dyskinetic side effects can be distinguished
    from preexisting stereotyped motor movements
        Traditional Neuroleptics
 Medication          Most              Possible              Side
(trade name/         likely             benefit        effects/problems
   generic)         benefits

Haldol           less withdrawal,   possibly           lower seizure
(Haloperidol)    fewer              increased          threshold, weight
.5-3mg/d         stereotypies,      teachability due   gain, sedation,
                 less               to improved        EPS, endocrine
                 hyperactivity,     attention, less    effects
                 agitation,         withdrawal
                 aggression, SIB

Mellaril                                               weight gain,
(thioridazine)                                         insomnia or
.5mg/kg/day                                            somnolence
-3mg/kg/day
       Research Studies with
           Haloperidol
• Campbell et. al. (1978)
  – Double blind, placebo controlled study
  – 40 children, mean age 4.5
  – Mean dose 1.65 mg/day
  – decreased stereotypies, repetitive behavior,
    increased attention
• Anderson (1984)
  – Double blind, placebo controlled study
  – 40 children, mean age 4.6
  – Improved learning
  – Direct attentional effect
  – Not due to decrease in maladaptive behaviors
• Campbell et al (1997)
  – Withdrawal (WD) and Tardive (TD) Dyskinesias
    • 118 children treated between 1979 and 1994
    • 6 month haloperidol/4 week placebo cycles
    • 34% of subjects developed dyskinesias
       – 86 episodes (12 TD, 74 WD); higher than expected
    • Putative risk factors
       – female gender
       – perinatal complications
       – dose and cumulative drug exposure
• “Atypical” Antipsychotic Drugs
  – Differ from traditional antipsychotic drugs in that
    in addition to being dopamine receptor (D2)
    blockers, they are significant serotonin receptors
    (S2) blockers
  – High affinity for alpha1 and alpha2 adrenergic H1
    histaminergic receptors
  – New to market, long term safety unknown
 Atypical Neuroleptic Medications Most Often Used With
                    Autistic Children
 Medication (Trade       Most likely benefits          Possible benefits             Side effects/problems
  name/generic)
Risperidone            Decreased impulsivity,     Improved social relatedness   Runny nose, marked weight gain,
(Risperdal)            perseveration,                                           fatty liver, increased prolactin,
                       aggression, SIB                                          occasionally energizes children
1-6mg/day


Olanzapine (Zyprexa)   No increase in prolactin                                 Weight gain
6-10mg/day
Quetiapine             No EPS                     Less weight gain, less        Ocular assessments
(Seroquel)             No increase in prolactin   histaminergic                 No casual relationships have been
                                                                                established with lens changes in
75-300mg/day
                                                                                humans, but development of
                                                                                cataracts in dog studies
Ziprasidone            No weight gain             Healthier alternative         Potentially dangerous, 1/4000
(Geodon) 2001                                                                   change in heart rhythm (prolonged
                                                                                QT interval) carbamazepine can
20mg-40 mg                                                                      reduce effectiveness, sleepiness,
Twice/day                                                                       nausea, rash, cough/runny nose
Aripiprazole           Decreased impulsivity,     Improved cognition and        Agitation, orthostatic, hypotension,
(Abilify)              perseveration,             social relatedness            headache, anxiety, nausea,
                       aggression, SIB                                          vomiting, akathisia
2.5-30 mg/day
                 Atypical Antipsychotics
Brand Name       Zyprexa                   Risperdal          Seroquel          Geodon
Generic Name     Olanzapine                Risperidone        Quetiapine        Ziprasidone
Dosing           -once daily dosing        -either twice or   Either twice or   -twice daily
                 -Without regard to food   once daily         three times daily -taken with
                 -zydis can be taken       -without regard                      meals
                 with or without water     to food
Sedation         Moderate                  High               Low/moderate      Low
Weight gain      Moderate/high             High               Low/moderate      Low/moderate
Dose-related     Low                       Very low/low       Moderate          low
extrapyramidal
side effects
QTC              No                        Yes                No                Yes
prolongation
Anti-            Moderate                  Very low/low       Low               Low
Cholinergic
Side effects
Seizures         Moderate                  Moderate           Moderate          Low/moderate
Research with Risperidone in Autism

• 11 studies in children and adolescents
  – n=3-20, all open-label
• McDougle et. al. (1997)
  – 18 children and adolescents, mean age 10.2
  – 12 week open-label study, mean dose 1.8mg/day
  – Improvements in repetitive behaviors,
    aggression, impulsivity
• RUPP Study: Research in Pediatric
  Psychopharmacology
  – “Autism RUPPs”
    •   Indiana University - C. McDougle, M.D.
    •   Ohio State University - M. Aman, Ph.D.
    •   Kennedy Krieger Institute - E. Tierney, M.D.
    •   Yale University - F. Volkmar, M.D.
    •   UCLA - J. McCracken, M.D.
• Design
  – Randomized, double-blind, placebo-controlled,
    parallel groups
  – Eight week double-blind phase; risperidone or
    placebo (Study I)
  – four month open follow-up option
  – Eight week double-blind discontinuation for six
    month risperidone completers (Study II)
• Inclusion Criteria
  – Males and females, ages 5-21
  – DSM-IV Autistic Disorder (ADI-R)
  – Inpatients or outpatients
  – Medication free for 2 weeks
  – Anticonvulsants permitted if dosage stable >2
    wks and seizure free > 6 mos.
  – ABC Irritability or RFRLRS > 1.5 SD of age
    norms and CGI > 4
• Exclusion Criteria
  – Mental age < 3 (Leiter R)
  – Prior risperidone treatment (>2mg, >2 wk)
  – PDD-NOS, Asperger’s, Rett’s, CDD, COS, SA
  – Significant medical conditions, including
    pregnancy
  – Weight <20kg
 Psychopharmacology Practice
• Aman et. al. (1995)
  – 838 subjects with autism
  – Project TEACH, North Carolina
  – 30.5% on psychotropics/50% if seizure
    medications
  – Age, housing away from family, MR
• Patzer et. al. (July-December 1997)
  – 125 individuals screened/109 included
     • age mean 13.9 range 4-43
          – males 83%
          – FSIQ 85-114   51%
     • Excluded: IQ < 70, no PDD diagnosis
  – Psychotropic Medication Use
     •   SSRIs 27%
     •   Stimulants 20%
     •   Atypical neuroleptics 17%
     •   Any psychotropic 55%
     •   2 or more psychotropics 53%
     •   Lifetime prevalence 53%

								
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