Using Evidence-Based Medicine to Choose Effective

Biomedical Treatments for Autism and ADHD

Dan Rossignol, MD FAAFPInternational Child Development Resource Center

321-259-7111 www.icdrc.orgAutism One Conference 2009

May 24, 2009

ADHD AspergerSyndrome

PDD-NOS Autism

Autism Spectrum

Underlying pathophysiology

Psychologically / Behaviorally defined

Communication Stereotypicalbehaviors

Socialinteraction

???

Toxins

ImpairedGlutathione /Sulphation

OxidativeStress / MitoDysfunction

Inflammation:GI, Brain

ActiveTreatment Maintenance

Chelation

Anti-inflammatories

Antioxidants

HBOT

Supplements

Methyl B12

IVIG

GFCF diet

IV Chelation

Modified CGI – ParentalModified CGI – ParentalAutism Research InstituteAutism Research Institute

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

Dolske et al., 1993 Prh Neuro-Psychopharmacol 17:765-74

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.

Adams and Holloway, 2004 J Alt Comp Med 10(6): 1033-9

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.

James et al., 2009 Am J Clin Nutr 89(1):425-30

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.

Ramaekers et al., 2007 Neuropediatrics 38(6): 276-81

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.

Arnold et al., 2005 J Child Adolesc Psychopharmacol 15(4):628-36

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.

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

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

Mousain-Bosc et al., 2006 Magnes Res 19(1):53-62

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.

Kuriyama et al., 2002 Dev Med Child Neurol 44(4):284-6

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).

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

Lozoff et al., 2006 Nutr Rev 64(5 Pt 2):S34-43

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.

Konofal et al., 2008 Pediatr Neurol 38(1):20-6

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.

Dosman et al., 2007 Pediatr Neurol 36(3):152-8

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.

Dvorakova et al., 2006 Redox Rep 11(4):163-72

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.

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

Trebaticka et al., 2006 Eur Child Adolesc Psychiatry 15(6):329-35

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.

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

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

Van Oudhesden et al., 2002 Prostaglandins Leukot Essent Fatty Acids 67(1):33-8

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.

Torrioli et al., 2008 Am J Med Genet A 146(7):803-12

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.

Chez et al., 2002 J Child Neurol 17(11):833-7

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).

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

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

Schultz et al., 2006 Int Breastfeed J 1:16

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.

Richardson, et al., 2005 Pediatrics 115(5):1360-6

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.

Sinn et al., 2008 Prostaglandins Leukot Essent Fatty Acids 78(4-5):311-26

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

Meguid et al., 2008 Clin Biochem 41(13):1044-8

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.

Amminger et al., 2008 Biol Psychiatry 61(4):551-3

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 EPA700 mg/day DHA

Schreck et al., 2004 Res Dev Disabil 25(1):57-66

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.

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

Andersen et al., 2007 J Child Neurol 23(5):482-5

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.

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

Hirayama et al., 2006 AgroFood industry hi-tech 17(5):16-19

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).

Akhondzadeh et al., 2008 Child Psychiatry Hum Dev 39(3):237-45

p < 0.001

800mg/day

Danfors et al., 2005 J Clin Psychopharmacol 25(5):485-9

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.

McDougle et al., 1996 Arch Gen Psychiatry 53(11):993-1000

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.

5-HTP StayAsleep

Low Serotonin

OCD

Self-stimulatory

Behavior

Melatonin

Frustration

Anxiety

TP

Brudnak et al., 2002 Med Hypotheses 58(5):422-8

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.

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

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 Psychiatry 20(2):165-70

Doses: AntioxidantsDoses: Antioxidants Vitamin C: 100 mg/kg/dayVitamin C: 100 mg/kg/day CoEnzyme Q 10: 5-10 mg/kg/dayCoEnzyme Q 10: 5-10 mg/kg/day Acetyl-L-Carnitine: 50-100 mg/kg/dayAcetyl-L-Carnitine: 50-100 mg/kg/day L-Carnosine: 200-400 mg twice a dayL-Carnosine: 200-400 mg twice a day Pycnogenol: 1 mg/kg/day (often higher)Pycnogenol: 1 mg/kg/day (often higher) MB12 injections: 75 mcg/kg every 1-3 daysMB12 injections: 75 mcg/kg every 1-3 days Folinic acid 400 mcg twice a dayFolinic acid 400 mcg twice a day Omega-3’s: DHA and EPA ~800 mg/day eachOmega-3’s: DHA and EPA ~800 mg/day each Zinc 20-150 mg/dayZinc 20-150 mg/day Melatonin: 1-6 mg 30 mins before bedtimeMelatonin: 1-6 mg 30 mins before bedtime

McCann et al., 2007 Lancet 370(9598):1560-7

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.

Lucarelli, 1995 Panminerva Med 37(3):137-41

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.

Hadjivassiliou et al., 2002 J Neurol Neurosurg Psychiatry 72(5):560-3

Sun et al., 1999 Autism 3(1):67-83

O’Banion et al., 1978 J Autism Child Schizophr 8(3):325-37

The effect of particular foods on levels of hyperactivity, uncontrolled laughter, and disruptive behaviors was studied in an 8-year-old autistic boy. The floor of the child's room was taped off into 6 equal-sized rectangles to measure general activity level. Frequency data were recorded on screaming, biting, scratching, and object throwing. During an initial 4-day period the child was fed a normal American diet. A 6-day fasting period followed, during which time only spring water was allowed. The third phase lasted 18 days and involved the presentation of individual foods. During the final phase the child was given only foods that had not provoked a reaction in the third phase. Results showed that foods such as wheat, corn, tomatoes, sugar, mushrooms, and dairy products were instrumental in producing behavioral disorders with this child.

Whiteley at al., 1999 Autism 3(1):45-65

The introduction of a gluten-free diet to children with autism and associated spectrum disorders (n 5 22) was monitored over a 5 month period using a battery of parental and teacher interview/questionnaire sessions, observation reports, psychometric tests and urinary profiling. Results suggested that participants on a gluten-free diet showed an improvement on a number of behavioural measures.

Knivsberg et al., 2002 Nutr Neurosci 5(4):251-61

The aim of this single blind study was to evaluate effect of gluten and casein-free diet for children with autistic syndromes and urinary peptide abnormalities. A randomly selected diet and control group with 10 children in each group participated. Observations and tests were done before and after a period of 1 year. The development for the group of children on diet was significantly better than for the controls.

Elder et al., 2006 J Autism Dev Disord 36(3):413-20

This study tested the efficacy of a gluten-free and casein-free (GFCF) diet in treating autism using a randomized, double blind repeated measures crossover design. The sample included 15 children aged 2-16 years with autism spectrum disorder. Data on autistic symptoms and urinary peptide levels were collected in the subjects' homes over the 12 weeks that they were on the diet. Group data indicated no statistically significant findings even though several parents reported improvement in their children.

Millward et al., 2008 Cochrane Database Syst Rev(2): CD003498

MAIN RESULTS: Two small RCTs were identified (n = 35). No meta-analysis was possible. There were only three significant treatment effects in favour of the diet intervention: overall autistic traits, mean difference (MD) = -5.60 (95% CI -9.02 to -2.18), z = 3.21, p=0.001 (Knivsberg 2002) ; social isolation, MD = -3.20 (95% CI -5.20 to 1.20), z = 3.14, p = 0.002) and overall ability to communicate and interact, MD = 1.70 (95% CI 0.50 to 2.90), z = 2.77, p = 0.006) (Knivsberg 2003).

Hediger et al., 2008 J Autism Dev Disord 38(5):848-56

Bone development, casein-free diet use, supplements, and medications were assessed for 75 boys with autism or autism spectrum disorder, ages 4-8 years. The 12% of the boys on casein-free diets had an overall % deviation of -18.9 +/- 3.7%, nearly twice that of boys on minimally restricted or unrestricted diets (-10.5 +/- 1.3%, p < .04), although even for boys on minimally restricted or unrestricted diets the % deviation was highly significant (p < .001).

Curl et al., 2003 Environ Health Perspect 111:377-82

We assessed organophosphorus (OP) pesticide exposure from diet. The median total dimethyl metabolite concentration was approximately 6 times higher for children with conventional diets than for children with organic diets (0.17 and 0.03 micro mol/L; p = 0.0003). The dose estimates suggest that consumption of organic fruits, vegetables, and juice can reduce children's exposure levels from above to below the U.S. Environmental Protection Agency's current guidelines.

Lu et al., 2006 Environ Health Perspect 114:260-3

Evangeliou et al., 2003 J Child Neurol 18(2):113-8

A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale.

Attention / HyperactivityAttention / Hyperactivity

Eliminate food coloring, additives, dyesEliminate food coloring, additives, dyes Methyl B12 shots 75 mcg/kg every 2-3 daysMethyl B12 shots 75 mcg/kg every 2-3 days Pycnogenol 1 mg/kg/dayPycnogenol 1 mg/kg/day Acetyl-L-Carnitine 50-100 mg/kg/dayAcetyl-L-Carnitine 50-100 mg/kg/day Zinc sulfate 150 mg/day (40 mg elemental zinc)Zinc sulfate 150 mg/day (40 mg elemental zinc) Omega-3 fatty acids (~800 mg each DHA + EPA)Omega-3 fatty acids (~800 mg each DHA + EPA) Iron (if deficient)Iron (if deficient) Phosphytidylserine 200 mg/dayPhosphytidylserine 200 mg/day GABA: calming, 250-500 mg 3x/day, as neededGABA: calming, 250-500 mg 3x/day, as needed

InsomniaInsomnia

MelatoninMelatonin 5-HTP 25-50 mg 1 hr before bedtime5-HTP 25-50 mg 1 hr before bedtime GABA 250-750 mg 3x/day, as neededGABA 250-750 mg 3x/day, as needed Omega-3 fatty acidsOmega-3 fatty acids Acetyl-L-CarnitineAcetyl-L-Carnitine ClonidineClonidine

Speech

• Omega-3 fatty acids• MB12 injections• L-Carnosine• DMG 125 mg/year of life• Acetyl-L-Carnitine• Tetrahydrobiopterin (BH4) 1 mg/kg/day• Piracetam 800 mg/day

Social Interaction

• Acetyl-L-Carnitine

• Vitamin B6

• Oxytocin

• Omega-3 fatty acids

• Vitamin A

• Galantamine

Eye Contact

Coordination

• Pycnogenol

• Omega-3’s

• Tryptophan deficiency

• GI-related

Toe-walking

Self-stimulatory Behavior

Consider

• Low Serotonin

• PANDAS

• Clostridia

Treatment

• 5-HTP or TP• Omega-3 fatty

acids• Vitamin C (~100

mg/kg/day)• Azithromycin or

PCN

Seizures

Taurine Vitamin B6 Magnesium Omega-3 fatty acids GABA DMG L-Carnosine

Summary: Where to start?

Sleep / Melatonin / 5-HTP Multivitamin Omega-3 fatty acids Anti-oxidants Methyl B12 (SC injections) Diet, at least organic and eliminate food

colorings and preservatives, GFCF Digestive enzymes / probiotics

CONCLUSION: Children with autism who received hyperbaric treatment at 1.3 atm and 24% oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air.

Rossignol et al., 2009 BMC Pediatr 9:21

Stefanatos et al., 1995 J Am Acad Child Adolesc Psychiatry 34(8):1107-11

The authors describe a child whose language and behavior regressed at 22 months and in whom pervasive developmental disorder was later diagnosed. At 6 years, he displayed a profound receptive-expressive aphasia accompanied by behavioral disturbances characterized by hyperactivity, impaired social interactions, tantrums, gestural stereotypies, and echolalia. Corticosteroid treatment resulted in amelioration of language abilities and behavior.

Bradstreet et al., 2007 Med Hypotheses 68(5):979-87

Boris et al., 2007 J Neuroinflammation 4:3

A total of 25 children (average age 7.9 +/- 0.7 year old) were enrolled. Safety was assessed by measurements of metabolic profiles and blood pressure. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.

Acute nicotine treatment has been found to reduce symptoms of attention deficit/hyperactivity disorder in adults. Acute and chronic nicotine treatment significantly attenuated the rise in hit reaction time standard error over session blocks on the Conners Continuous Performance Test. Acute nicotine significantly reduced severity of clinical symptoms on the Clinical Global Impressions scale. Nicotine caused a significant decrease in self-report of depressive mood as measured by the Profile of Mood States test.

Levin et al., 2001 Exp Clin Psychopharmacol 9(1):83-90

Chez et al., 2003 Journal of Pediatric Neurology 1(2):83-88

Forty-three patients (35 males, 8 females, average age 6.8 yrs., range 2.1-10.3 yrs), with diagnoses of Autistic Spectrum Disorders enrolled in a randomized six-week, double blind, placebo-controlled trial of donepezil hydrochloride, with an additional six weeks of open-label treatment. Expressive and receptive speech gains, as well as decreases in severity of overall autistic behavior, were documented after 6-weeks for the treatment group. These improvements were statistically significant when compared to placebo, and were clinically meaningful as assessed over time.

When parent and teacher scores were combined, mean scores were slightly lower during treatment with galantamine than during treatment with placebo for irritability classified by ratings of the aberrant behaviour checklist (galantamine 11.5 (7.6) v placebo 15.1 (5.4), P=0.039), hyperactivity (17.2 (12.8) v 21.7 (15.4), P=0.038), inadequate eye contact (placebo 7.6 (3.2) v 8.4 (5.2), P=0.049), and inappropriate speech 4.7 (3.1) v 6.2 (2.4), P=0.045).

Niederhofer et al., 2002 BMJ 325:1422

OBJECTIVE: To review the efficacy and safety of naltrexone in pediatric patients with autistic disorder (AD). Naltrexone has been used most commonly at doses ranging from 0.5 to 2 mg/kg/day and found to be predominantly effective in decreasing self-injurious behavior. Naltrexone may also attenuate hyperactivity, agitation, irritability, temper tantrums, social withdrawal, and stereotyped behaviors. Patients may also exhibit improved attention and eye contact. Transient sedation was the most commonly reported adverse event.

Elchaar et al., 2006 Ann Pharmacother 40(6):1086-95

Subjects were included in the study if they had inattention, impulsivity, and hyperactivity that was excessive for their developmental level. Subjects had not tolerated or responded to other psychopharmacologic treatments (neuroleptics, methylphenidate, or desipramine). Teacher ratings on the Aberrant Behavior Checklist irritability, stereotypy, hyperactivity, and inappropriate speech factors were lower during treatment with clonidine than during treatment with placebo.

Jaselskis et al., 1992 J Clin Psychopharmacol12(5):322-7

Open-label add-on therapy was offered to 151 patients with prior diagnoses of autism or Pervasive Developmental Disorder Not Otherwise Specified over a 21-month period. Results showed significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree.

Chez et al., 2007 J Child Neurol 22(5):574-9

METHODS: Oxytocin and placebo challenges were administered to 15 adult subjects diagnosed with autism or Asperger's disorder, and comprehension of affective speech (happy, indifferent, angry, and sad) in neutral content sentences was tested. RESULTS: All subjects showed improvements in affective speech comprehension from pre- to post-infusion.

Hollander et al., 2007 Biol Psychiatry 61(4):498-503

Kaplan et al., 1998 Child Psychiatry Hum Dev 29(1):65-76

A double-blind crossover design was used to assess the efficacy of wearing ambient lenses to reduce the behavioral symptoms of autism. Eighteen autistic individuals, ranging in age from 7 to 18 years, participated in the study. Behavior, attention, and orientation were evaluated at 1 1/2 months, 2 months, 3 months, and 4 months. Compared to the placebo condition, the results showed a decrease in behavior problems at the 1 1/2 and 2 month assessment periods and a slight loss of these benefits at the 3 and 4 month assessment periods.

According to parents' and teachers' ratings, children of the neurofeedback training group improved more than children who had participated in a group therapy program, particularly in attention and cognition related domains. CONCLUSION: There is a specific training effect of neurofeedback of slow cortical potentials due to enhanced cortical control. However, non-specific factors, such as parental support, may also contribute to the positive behavioural effects induced by the neurofeedback training.

Drechsler et al., 2007 Behav Brain Funct 3:35

Altunc et al., 2007 Mayo Clin Proc 82(1):69-75

A total of 326 articles were identified, 91 of which were retrieved for detailed evaluation. Sixteen trials that assessed 9 different conditions were included in the study. With the exception of attention-deficit/hyperactivity disorder and acute childhood diarrhea (each tested in 3 trials), no condition was assessed in more than 2 double-blind randomized clinical trials. The evidence for attention-deficit/hyperactivity disorder and acute childhood diarrhea is mixed, showing both positive and negative results for their respective main outcome measures.

Gold et al., 2006 Cochrane Database Syst Rev (2):CD004381

Three small studies were included (total n = 24). These examined the short-term effect of brief music therapy interventions (daily sessions over one week) for autistic children. Music therapy was superior to "placebo" therapy with respect to verbal and gestural communicative skills (verbal: 2 RCTs, n = 20, SMD 0.36 CI 0.15 to 0.57; gestural: 2 RCTs, n = 20, SMD 0.50 CI 0.22 to 0.79). Effects on behavioural problems were not significant. The findings indicate that music therapy may help children with autistic spectrum disorder to improve their communicative skills.

Escalona et al., 2001 J Autism Dev Disord 31(5):513-6

Twenty children with autism, ages 3 to 6 years, were randomly assigned to massage therapy and reading attention control groups. Parents in the massage therapy group were trained by a massage therapist to massage their children for 15 minutes prior to bedtime every night for 1 month. Results suggested that the children in the massage group exhibited less stereotypic behavior and showed more on-task and social relatedness behavior during play observations at school, and they experienced fewer sleep problems at home.