Using Evidence-Based Medicine to Choose Effective Biomedical Treatments for Autism and ADHD

1. Using Evidence-Based Medicine to Choose Effective Biomedical Treatments for Autism and ADHD Dan Rossignol, MD FAAFP International Child Development Resource Center 321-259-7111 www.icdrc.org Autism One Conference 2009 May 24, 2009

2. Autism Spectrum Asperger Syndrome ADHD PDD-NOS Autism Psychologically / Behaviorally defined Stereotypical behaviors Social interaction Communication Underlying pathophysiology ???

3. Inflammation: GI, Brain Toxins Oxidative Stress / Mito Dysfunction Impaired Glutathione / Sulphation

4. Active Treatment Maintenance IV Chelation IVIG Chelation Anti-inflammatories HBOT Supplements GFCF diet Methyl B12 Antioxidants

5. Modified CGI – ParentalAutism Research Institute

6. Levels of Evidence • Level I: Evidence obtained from at least one properly designed randomized controlled trial. • Level II-1: Evidence obtained from well-designed controlled trials without randomization. • Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. • Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. • Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

7. This study presents the results of a 30-week double-blind, placebo-controlled trial exploring the effectiveness of ascorbic acid (8g/70kg/day) as a supplemental pharmacological treatment for autistic children in residential treatment. Significant group by phase interactions were found for total scores and also sensory motor scores indicating a reduction in symptom severity associated with the ascorbic acid treatment. Dolske et al., 1993 Prh Neuro-Psychopharmacol 17:765-74

8. Objective: Determine the effect of a moderate dose multivitamin/mineral supplement on children with autistic spectrum disorder. Design: Randomized, double-blind, placebo-controlled 3-month study. Twenty (20) children with autistic spectrum disorder, ages 3-8 years. RESULTS: A Global Impressions parental questionnaire found that the supplement group reported statistically significant improvements in sleep and gastrointestinal problems compared to the placebo group. Adams and Holloway, 2004 J Alt Comp Med 10(6): 1033-9

9. In an open-label trial, 40 autistic children were treated with 75 mcg/kg methylcobalamin (2 times/wk) and 400 mcg folinic acid (bid) for 3 mo. The 3-mo intervention resulted in significant increases in cysteine, cysteinylglycine, and glutathione concentrations (P < 0.001). Measures of autistic behavior were assessed by a trained study nurse before and after treatment using the Vineland Adaptive Behavior Scales. Although significant improvement was observed after treatment, the scores remained significantly below standard normal scores. James et al., 2009 Am J Clin Nutr 89(1):425-30

10. Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Ramaekers et al., 2007 Neuropediatrics 38(6): 276-81

11. Serum zinc correlated at r = -0.45 (p = 0.004) with parent-teacher-rated inattention, even after controlling for gender, age, income, and diagnostic subtype. These findings add to accumulating evidence for a possible role of zinc in ADHD, even for middle-class Americans, and, for the first time, suggest a special relationship to inattentive symptoms. They do not establish either that zinc deficiency causes ADHD nor that ADHD should be treated with zinc. Arnold et al., 2005 J Child Adolesc Psychopharmacol 15(4):628-36

12. Yorbik et al., 2004 J Trace Elem Exp Med 17(2):101-107

13. Bilici et al., 2004 Prog Neuropsychopharmacol Biol Psychiatry 28(1):181-90

14. The Mg-B6 regimen improved PDD symptoms in 23/33 children (p < 0.0001) with no adverse effects: social interactions (23/33), communication (24/33), stereotyped restricted behavior (18/33), and abnormal/delayed functioning (17/33); 15/33 children were improved in the first three groups of symptoms. When the Mg-B6 treatment was stopped, PDD symptoms reappeared in a few weeks. Mousain-Bosc et al., 2006 Magnes Res 19(1):53-62

15. Pyridoxine treatment was associated with a significant increase in verbal IQ scores. Net gain in verbal IQ scores in the pyridoxine group as relative to the placebo group showed a signif-icant difference (5.2, 95% CI 0.2 to 10.3). After controlling for sex, age, body weight, interval between IQ tests, and baseline verbal IQ scores using ANCOVA, the adjusted net gain in verbal IQ scores in the pyridoxine group compared with the placebo group still showed a significant difference (6.8, 95% CI 5.0 to 8.5; p=0.01). Kuriyama et al., 2002 Dev Med Child Neurol 44(4):284-6

16. Konofal et al., 2004 Arch Pediatr Adolesc Med 158(12):1113-5

17. Infants are at high risk for iron deficiency and iron-deficiency anemia. This review summarizes evidence of long-term effects of iron deficiency in infancy. Follow-up studies from preschool age to adolescence report poorer cognitive, motor, and social-emotional function, as well as persisting neurophysiologic differences. Research in animal models points to mechanisms for such long-lasting effects. Potential mechanisms relate to effects of iron deficiency during brain development on neurometabolism, myelination, and neurotransmitter function. Lozoff et al., 2006 Nutr Rev 64(5 Pt 2):S34-43

18. Twenty-three nonanemic children (aged 5-8 years) with serum ferritin levels <30 ng/mL who met DSM-IV criteria for ADHD were randomized (3:1 ratio) to either oral iron (ferrous sulfate, 80 mg/day, n = 18) or placebo (n = 5) for 12 weeks. Iron supplementation (80 mg/day) appeared to improve ADHD symptoms in children with low serum ferritin levels. Iron therapy was well tolerated and effectiveness is comparable to stimulants. Konofal et al., 2008 Pediatr Neurol 38(1):20-6

19. Seventy-seven percent had restless sleep at baseline, which improved significantly with iron therapy, suggesting a relationship between sleep disturbance and iron deficiency in children with autism spectrum disorder. 69% of preschoolers and 35% of school-aged children had insufficient dietary iron intake. Children with autism spectrum disorder require ongoing screening for iron deficiency. Dosman et al., 2007 Pediatr Neurol 36(3):152-8

20. The aim of this randomized, double-blind, placebo-controlled trial was to investigate the influence of administered Pycnogenol or placebo on the level of reduced (GSH) and oxidized (GSSG) glutathione in children suffering from ADHD. One month of Pycnogenol administration (1 mg/kg/day) caused a significant decrease in GSSG and a highly significant increase in GSH levels as well as improvement of GSH/GSSG ratio in comparison to a group of patients taking a placebo. Dvorakova et al., 2006 Redox Rep 11(4):163-72

21. We have found significantly increased damage to DNA in ADHD children when compared to controls. 8-oxoG was significantly lower after 1 month of Pyc administration in comparison to the beginning state and to placebo group. Improvement of DNA damage and TAS after Pyc administration is associated with the improvement of attention in ADHD children. In conclusion, Pycnogenol administration reduces oxidative damage to DNA, normalizes TAS and improves attention of ADHD children. Chovanova et al., 2006 Free Radic Res 40(9):1003-10

22. Sixty-one children were supplemented with 1 mg/kg/day Pycnogenol or placebo over a period of 4 weeks in a randomised, placebo-controlled, double-blind study. Results show that 1-month Pycnogenol administration caused a significant reduction of hyperactivity, improves attention and visual-motoric coordination and concentration of children with ADHD. In the placebo group no positive effects were found. One month after termination of Pycnogenol administration a relapse of symptoms was noted. Trebaticka et al., 2006 Eur Child Adolesc Psychiatry 15(6):329-35

23. Values of free and total carnitine (p < 0.001), and pyruvate (p = 0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children. Filipek et al., 2004 J Autism Dev Disord 34(6):615-23

24. Compared with the Rett syndrome controls, treatment with L-carnitine led to significant improvements in sleep efficiency (P=0.027), especially in the subjects with a baseline sleep efficiency less than 90%, energy level (P<0.005) and communication skills (P=0.004). In addition, before and after comparisons of the treatment group showed improvements in expressive speech (P=0.011). Ellaway et al., 2001 Brain and Develop 23:S85-89

25. To determine safety and the efficacy of carnitine treatment in children with attention-deficit hyperactivity disorder (ADHD). In 13/24 boys receiving carnitine, home behavior improved as assessed with the CBCL total score (P < 0.02). In 13/24 boys, school behavior improved as assessed with the Conners teacher-rating score (P < 0.05). In the majority of boys no side effects were seen. Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD. Van Oudhesden et al., 2002 Prostaglandins Leukot Essent Fatty Acids 67(1):33-8

26. We observed a stronger reduction of hyperactivity and improvement of social behavior in patients treated with LAC, compared with the placebo group, as determined by the Conners' Global Index Parents and the Vineland Adaptive Behavior Scale. Our results show that LAC (20-50 mg/kg/day) represents a safe alternative to the use of stimulant drugs for the treatment of ADHD in FXS children. Torrioli et al., 2008 Am J Med Genet A 146(7):803-12

27. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Chez et al., 2002 J Child Neurol 17(11):833-7

28. Wu et al., 2006 Neuroscience Letters 400:146-9

29. Stevens et al., 1996 Physiol Behav 59(4-5):915-20

30. Absence of breastfeeding when compared to breastfeeding for more than six months was significantly associated with an increase in the odds of having autistic disorder when all cases were considered (OR 2.48, 95% CI 1.42, 4.35). The results of this preliminary study indicate that children who were not breastfed or were fed infant formula without docosahexaenoic acid/arachidonic acid supplementation were significantly more likely to have autistic disorder. Schultz et al., 2006 Int Breastfeed J 1:16

31. A randomized, controlled trial of dietary supplementation with omega-3 and omega-6 fatty acids, compared with placebo, was conducted with 117 children with DCD (5-12 years of age). Significant improvements for active treatment versus placebo were found in reading, spelling, and behavior over 3 months of treatment in parallel groups. After the crossover, similar changes were seen in the placebo-active group. Richardson, et al., 2005 Pediatrics 115(5):1360-6

32. After 15 weeks there were improvements in a test of the ability to switch and control attention (Creature Counting) in the PUFA groups compared to placebo (N=129, p=0.002). This improvement was also observed in the placebo group after taking PUFA from weeks 16 to 30 (N=104). Total of 167 children in study. EPA 93 mg, DHA 29 mg, GLA 10 mg Sinn et al., 2008 Prostaglandins Leukot Essent Fatty Acids 78(4-5):311-26

33. 30 autistic children (18 males and 12 females) aged 3-11 years and 30 healthy children as control group were included in this study. After taking Efalex, 66% of autistic children showed clinical and biochemical improvement, linolenic acid and docosahexaenoic acid showed the highest levels after Efalex supplementation. CONCLUSION: PUFA supplementation may play an important role in ameliorating the autistic behavior. Increased eye contact, language, concentration, and motor skills in 2/3. Meguid et al., 2008 Clin Biochem 41(13):1044-8

34. We observed an advantage of omega-3 fatty acids compared with placebo for hyperactivity and stereotypy, each with a large effect size. Repeated-measures ANOVA indicated a trend toward superiority of omega-3 fatty acids over placebo for hyperactivity. No clinically relevant adverse effects were elicited in either group. 840 mg/day EPA 700 mg/day DHA Amminger et al., 2008 Biol Psychiatry61(4):551-3

36. Results suggested that fewer hours of sleep per night predicted overall autism scores and social skills deficits. Similarly, stereotypic behavior was predicted by fewer hours of sleep per night and screaming during the night. Increased sensitivity to environmental stimuli in the bedroom and screaming at night predicted communication problems. Finally, sensitivity to environmental stimuli in the bedroom also predicted fewer developmental sequence disturbances. Schreck et al., 2004 Res Dev Disabil 25(1):57-66

37. Melke et al., 2008 Molecular Psych 13:90-98

38. 107 children (2-18 years of age) with a confirmed diagnosis of autism spectrum disorders who received melatonin were identified. After initiation of melatonin, parents of 27 children (25%) no longer reported sleep concerns at follow-up visits. Parents of 64 children (60%) reported improved sleep, although continued to have concerns regarding sleep. Parents of 14 children (13%) continued to report sleep problems as a major concern. Andersen et al., 2007 J Child Neurol 23(5):482-5

39. Garstang and Wallis, 2006 Child Care Health Dev 32(5):585-9

40. 200 mg/day After the intervention, (1) AD/HD symptoms were significantly improved (p<0.01). Significant improvement was observed both in the inattention and hyperactivity and impulsiveness (p<0.01 and p<0.05 respectively) (3) visual perception was also significantly improved (p<0.001). A tendency towards an improvement was observed in (2) LD and (5) CPT (9 only error) (p<0.10). However, no significant difference was observed with regard to visual and auditory short-term memory (4). Hirayama et al., 2006 AgroFood industry hi-tech 17(5):16-19

41. 800 mg/day p < 0.001 Akhondzadeh et al., 2008 Child Psychiatry Hum Dev 39(3):237-45

42. Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal tetrahydrobiopterin. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. Danfors et al., 2005 J Clin Psychopharmacol 25(5):485-9

43. Study was short-term tryptophan depletion in a double-blind, placebo-controlled, randomized crossover design. Tryptophan depletion led to a significant increase in behaviors such as whirling, flapping, pacing, banging and hitting self, rocking, and toe walking (p < 0.05). In addition, patients were significantly less calm and happy and more anxious. McDougle et al., 1996 Arch Gen Psychiatry 53(11):993-1000

44. Stay Asleep TP 5-HTP Low Serotonin OCD Anxiety Self- stimulatory Behavior Frustration Melatonin

45. The diets were supplemented with a novel dietary enzyme formulation, ENZYMAID, for a period of 12 weeks. Progress was tracked according to the Symptom Outcome Survey (SOS) (1) form method of symptom charting and presented in a table for further analysis. The novel enzyme formula, ENZYMAID, beneficially and safely affected all 13 of the parameters measured. Improvements ranged from 50-90%, depending on the parameter measured. Brudnak et al., 2002 Med Hypotheses 58(5):422-8

46. http://news.scotsman.com/ViewArticle.aspx?articleid=2807937

47. Children receiving cholesterol treatment display fewer autistic behaviours, infections, and symptoms of irritability and hyperactivity, with improvements in physical growth, sleep and social interactions. Other behaviours shown to improve with cholesterol supplementation include aggressive behaviours, self-injury, temper outbursts and trichotillomania. Aneja and Tierney, 2008 Int Rev Psychiatry20(2):165-70

48. Doses: Antioxidants Vitamin C: 100 mg/kg/day CoEnzyme Q 10: 5-10 mg/kg/day Acetyl-L-Carnitine: 50-100 mg/kg/day L-Carnosine: 200-400 mg twice a day Pycnogenol: 1 mg/kg/day (often higher) MB12 injections: 75 mcg/kg every 1-3 days Folinic acid 400 mcg twice a day Omega-3’s: DHA and EPA ~800 mg/day each Zinc 20-150 mg/day Melatonin: 1-6 mg 30 mins before bedtime

49. We undertook a randomised, double-blinded, placebo-controlled, crossover trial to test whether intake of artificial food colour and additives (AFCA) affected childhood behaviour. Artificial colours or a sodium benzoate preservative (or both) in the diet result in increased hyperactivity in 3-year-old and 8/9-year-old children in the general population. McCann et al., 2007 Lancet 370(9598):1560-7

50. The aim of the present study has been to verify the efficacy of a cow's milk free diet (or other foods which gave a positive result after a skin test) in 36 autistic patients. We noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet. Our results lead us to hypothesise a relationship between food allergy and infantile autism as has already been suggested for other disturbances of the central nervous system. Lucarelli, 1995 Panminerva Med 37(3):137-41