Treatments of Autism Justified in Scientific Publication

Atomoxetine

Atomexetine is an antidepressant, mainly used for treating attention deficit hyperactivedisorder (ADHD) in 2005 has been tried out on individual patients since then.

Arnold LE, Aman MG, Cook AM, Witwer AN, Hall KL, Thompson S, Ramadan Y. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry. 2006 Oct;45(10):1196-205.

Niederhofer H, Damodharan SK, Joji R, Corfield A. Atomoxetine treating patients with Autistic disorder. Autism. 2006 Nov;10(6):647-9.

Olanzapine (an antipsychotic, aimed against anxiety)

Antipsychotics

Posey DJ, Stigler KA, Erickson CA, McDougle CJ. Antipsychotics in the treatment of autism.  J Clin Invest. 2008 Jan;118(1):6-14.  They are frequently used to treat irritability and associated behaviours including aggression and self injury. They may also be efficacious for hyperactivity and stereotyped behavior.

Hollander E, Wasserman S, Swanson EN, Chaplin W, Schapiro ML, Zagursky K, Novotny S. A double-blind placebo-controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder. J Child Adolesc Psychopharmacol. 2006 Oct;16(5):541-8. Basically showing that they could alleviate some symptoms.

Selective serotonin reuptake inhibitors (also see SSRI in Serotonin)

These were considered because of the high levels of serotonin uptake that is seen in cells of autistics (again the reason is unclear).

Kolevzon A, Mathewson KA, Hollander E. Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry. 2006 Mar;67(3):407-14. (a review including the use of fluoxetine, the commonest in the UK.  Their meta-analysis, as many do, showed the current work warranted further randomised studies, and they also highlighted the side effects that workers had seen).

Fatemi SH, Realmuto GM, Khan L, Thuras P. Fluoxetine in treatment of adolescent patients with autism: a longitudinal open trial. J Autism Dev Disord. 1998 Aug;28(4):303-7. Improvement from baseline was seen in four subscales: irritability (21%), lethargy (37%), stereotype (27%), and inappropriate speech (21%).  Hyperactivity subscale improved by 14% but did not attain statistical significance. Fluoxetine appears to have important behavioral effects in treatment of clinic-referred autistic children.

Melatonin (also see hormones)

Garstang J, Wallis M. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev. 2006 Sep;32(5):585-9. (Although the study was small owing to recruitment difficulties, it still provides evidence of effectiveness of melatonin in children with sleep difficulties and ASD, which we predict a larger study would confirm)

Giannotti F, Cortesi F, Cerquiglini A, Bernabei P. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord. 2006 Aug;36(6):741-52  (During treatment sleep patterns of all children improved. After discontinuation 16 children returned to pre-treatment score, readministration of melatonin was again effective. Treatment gains were maintained at 12 and 24-month follow-ups. No adverse side effects were reported. In conclusion, controlled-release melatonin may provide an effective and well-tolerated treatment for autistic children with chronic sleep disorders.)

Gupta R, Hutchins J. Melatonin: a panacea for desperate parents? (Hype or truth). Arch Dis Child. 2005 Sep;90(9):986-7.

Guanfacine

Posey DJ, McDougle CJ.  Guanfacine and guanfacine extended release: treatment for ADHD and related disorders.

CNS Drug Rev. 2007 Winter;13(4):465-74 (Small placebo-controlled trials support the use of guanfacine for the treatment of ADHD. There is more limited research on the use of guanfacine in treating hyperactivity occurring in children diagnosed with PDD)

Handen BL, Sahl R, Hardan AY. Guanfacine in Children with Autism and/or Intellectual Disabilities.  J Dev Behav Pediatr. 2008 Jun 12. Guanfacine, an alpha2-adrenergic receptor agonist, has shown some promise as an alternative to psychostimulants.  Significant benefits were observed on the Hyperactivity subscale of the parent and teacher Aberrant Behavior Checklist (ABC) and Global Improvement Ratings. No gains were noted on other ABC subscales. Five of the 11 subjects (45%) were judged to be responders based on a 50% decrease in the ABC Hyperactivity subscale score between the placebo and guanfacine conditions. Several side effects were reported, including drowsiness and irritability.

Mirtizapine

Coskun M, Mukaddes NM. Mirtazapine treatment in a subject with autistic disorder and fetishism. J Child Adolesc Psychopharmacol. 2008 Apr;18(2):206-9. (this is basically in the treatment for sexual fetishism)

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Anti-infective Agents

The aim being to change the number and type of bacteria and yeast present in the gut:  See site concerning gut flora.  Notably see the section concerning probiotics (i.e. taking in low pathogenicity bacteria and yeasts in the diet) as the section goes into the use of these in other inflammatory conditions of the gut. 

Anti-fungals: aimed at stopping the overgrowth of yeasts in the gut flora. E.g. fluconazole.  No useful scientific data available.

Anti-bacterials aimed at the anaerobes: e.g. metronidazole.  No useful scientific data although this has been stated at conferences with Finegold.

Vancomycin (active against all Gram-positive bacteria).  Shown to have a notable activity in improving autism.  See Sandler.  The reason for this is currently uncertain and the drug is only available by medical prescription. The drug is very expensive and effect appears to go after it is stopped.

Monolaurin, a small chain fatty acid type antibiotic that is given orally.  There is no scientific published evidence that it is of any advantage but many individual parents claiming its activity.  Available over the internet.

Acyclovir (an inhibitor of the ability of herpes viruses to infect cells) .  Now there is suggestions  that this has no significant value.

Serotonin (see above).

Explanation is complex: partly because we simply don’t know why in a large proportion of autistic cases there is an change in serotonin distribution in the blood. See serotonin

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Immunotherapy (Pioglitazone, Transfer Factor, Phosphodiesterase inhibitor, Steroids/ACTH, Thalidomide, Pentosan, Gamma-globulin)

The aim being to decrease the inflammation seen in the gut wall and to some degree in the brain.  As a result several drugs have been tested but with only minor reports for some. 

Sperner-Unterweger B. Immunological aetiology of major psychiatric disorders: evidence and therapeutic implications.

Drugs. 2005;65(11):1493-520. Review.  (a wide review)

Gupta S.  Immunological treatments for autism. J Autism Dev Disord. 2000 Oct;30(5):475-9.  review e.g. Steroids.  The idea is to decrease the immune response to external factors and to internal autoimmunes. 

Pioglitazone

In fact this is a drug used in diabetes that for some reason appeared to have some advantage in Alzheimer’s disease, in which a specific form of damage takes place in the brain. 

Boris M, Kaiser CC, Goldblatt A, Elice MW, Edelson SM, Adams JB, Feinstein DL. Effect of pioglitazone treatment on symptoms in autistic children. J Neuroinflammation. 2007 Jan 5;4:3 (small numbers, anti-inflammatory effect in brain etc).  Feinstein DL Therapeutic potential of peroxisome proliferator-activated receptor agonists for neurological disease.  Diabetes Technol Ther. 2003;5(1):67-73.  They did work in vitro on cell cultures looking at the PPAR activation, which can have additional effects upon cellular physiology, including anti-proliferative and anti-inflammatory. These effects are observed in many cell types, including brain glial cells and blood lymphocytes, cells whose activation contributes to the initiation and progression of damage occurring in neurological diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS). In view of the need for development of additional therapeutic options, several recent studies have tested the possibility that PPAR agonists would be neuroprotective in these diseases.  Notably the effect is probably also seen in autism.  (don’t forget other PPARs like rosiglitazone and others e.g. Pershadsingh HA. Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis? Expert Opin Investig Drugs. 2004 Mar;13(3):215-28.  The reasons behind it all are to do with decreasing the action of microglia and astrocytes: Storer PD, Xu J, Chavis J, Drew PD. Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis. J Neuroimmunol. 2005 Apr;161(1-2):113-22. and that may make sense when you see this paper:  Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304

Gamma globulin

This was tried out in the idea of the transfer factor being simply a gamma globulin and the reports from elsewhere being that there would be some advantage.  See immunology.

Transfer Factor

This is a fairly non-specific affair in which a compound (protein, chemical but not a cell) can be transferred from the blood of a well animal and cause the alleviation of disease in humans.  Because it is not a specific serum-derived injection it cannot be a pharmaceutical as such and very difficult to demonstrate as safe.  However, simply finding it as being effective in any way would be an insight into the pathology of the disease: see Fudenberg.   

Lawrence HS, Borkowsky W. Transfer factor--current status and future prospects. Biotherapy. 1996;9(1-3):1-5.

Fudenberg HH, Fudenberg HH. Transfer factor: past, present and future. Annu Rev Pharmacol Toxicol. 1989;29:475-516. Review.

Fudenberg HH.. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy. 1996;9(1-3):143-7. (They found that a high proportion of the children improved dramatically and the effect went away when the treatment was stopped) (I’m quite surprised that it got the OK for the research on what was clearly such a baseline piece of study! It is mentioned in Phillis Kidd’s review: Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99. and review: Sperner-Unterweger B. Immunological aetiology of major psychiatric disorders: evidence and therapeutic implications. Drugs. 2005;65(11):1493-520.

Immunoglobulins: see under immunology above

Schneider CK, Melmed RD, Barstow LE, Enriquez FJ, Ranger-Moore J, Ostrem JA. Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study. J Autism Dev Disord. 2006 Nov;36(8):1053-64. (They carried out twelve male subjects diagnosed with AD were evaluated using a GI severity index (GSI) while receiving daily dosing with encapsulated human immunoglobulin. Following eight weeks of treatment, 50% of the subjects met prespecified criteria for response in GI signs and symptoms and showed significant behavioral improvement as assessed by the Autism Behavior Checklist) However this was not a controlled trial and the data was not present for stopping the drug.

A phosphodiesterase inhibitor, which acts against the action of TNF-alpha.

Plioplys G.  Intravenous immunoglobulin treatment of children with autism.  J Child Neurol 1998;13:79-82.

Pentoxifylline: A selective phosphdiesterase inhibitor that acts against allergies partly by inhibiting TNF-alpha.  It also increases the blood flow to the brain by allowing an increase in the deformability of the red cell membranes.  This must be one of the many drugs that are now useful for use in the treatment of inflammatory bowel disease..showing that many further ones have not yet been considered in autism.

Steroids and ACTH

Geier MR, Geier DA. The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity. Med Hypotheses. 2005;64(5):946-54.  (This is the hepothesis that if you can do something about the immunity against the mercury of the vaccines etc then improvement may be seen)

Matarazzo EB.  Treatment of late onset autism as a consequence of probable autommune processes related to chronic bacterial infection.  World J Biol Psychiatry. 2002 Jul;3(3):162-6. Adrenocorticotrophic hormone (ACTH), prescribed in the first months of the disease, cured one case. The other patient, who was two years old when autistic symptoms appeared and was treated only six years later, showed a partial but definitive improvement with the immunosuppressive treatment.

Spironolactone

This is an inhibitor of aldosterone, a steroid hormone produced by the adrenal gland, and its job is to modify the sodium and potassium levels in the blood by altering the absorption by the kidney tubeules.  It does claim potent immune modifying properties that might make it an excellent medical intervention in autism (hence the hypothesis below)

Bradstreet JJ, Smith S, Granpeesheh D, El-Dahr JM, Rossignol D.Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders. Med Hypotheses. 2007;68(5):979-87. Epub 2006 Dec 5 (they also tried it out on a single patient, who appeared to improve)

Thalidomide 

I can find no data on its use in autism but it would seem reasonable to have tried.  The drug, apart from awful effect on the foetus, and it effect in calming and inducing sleep, was noticed in Africa to have an amazing effect on erythema nodosum leprosum.  This took place in people treated for leprosy in which the dead bacteria in the skin were destroyed by the body’s immune system and released cytokines that damaged the skin at the same time.  It was very serious and so thalidomide, which made a dramatic effect, is now the standard treatment for ENL.  The mechanism by which it worked was by inhibiting the production of TNF-alpha, neutrophil phagocytosis, monocyte chemotaxis and angiogenesis (and probably plenty more).  There are other (not licensed) derivatives of thalidomide that do all these things without the psychological side effects.  For data on its use in inflammatory bowel disease see ‘gut flora’.

Pentosan polysulphate. 

Acts against cytokines by interacting with heparan binding sites on cell surfaces.  Given orally the attempt is to decrease the inflammatory nature of the gut without steroids. No published data.

Gamma-globulins from other people:  this is taken as a serum fragment from a normal person and injected into the autistic one. See inflammation.

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Thyroid hormones

This is suggesting that the thyroid releasing hormone changes and autoimmunity against thyroid factors may be involved.  No good data concerning treatment using thyroid hormones.

Cook EH. Autism: review of neurochemical investigation. Synapse 1990;6:292-308. Showed a high rate of abnormal response to TRH challenge

Adams JB, Holloway CE, George F, Quig D.  Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biol Trace Elem Res. 2006 Jun;110(3):193-209. One study by Adams et al found that many children with autism have unusually low levels of iodine in their hair, which possibly suggests a low level in their body and need for more.

Román GC. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. J Neurol Sci. 2007 Nov 15;262(1-2):15-26. Epub 2007 Jul 24. (they have tried giving a thyroid hormone decrease to animals for a short period during pregnancy.  This caused neurological illness in the offspring.  The association between autoimmunity in autism is seen above (see Singh-K) and how immunity against the thyroid has been seen.

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Nutrient Therapy.  Also see folate, B12, tetrahyrobiopterin, fatty acids

One reason why this can be at least tried easily by parents is that commonly it does not involve pharmaceuticals and because vitamins are easily available from local pharmacies or on the internet.  However filled with good ideas, the data for many of the claims is missing.

Isaacson et al., “Autism: A Retrospective Outcome Study of Nutrient Therapy,” Journal of Applied Nutrition, vol. 48, No. 4, 1996. 

Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99.

Johnson S. Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease? Med Hypotheses. 2001 May;56(5):641-5  (Johnson goes into why there may be significance in diet)

Raiten DJ, Massaro T  Perspectives on the nutritional ecology of autistic children.  Autism Dev Disord. 1986 Jun;16(2):133-43.  (this is an interesting article in that it showed no nutritional inadequacy in autistic children, and only being less than controls with vitamin A, C and fats.  It does mean that vitamin treatment may not be fully rational unless there is specific biochemistry that is pushing it forward)

Rimland B. Controversies in the treatment of autistic children: vitamin and drug therapy. J Child Neurol. 1988;3 Suppl:S68-72.

Vitamins of various kinds as mixtures

Adams JB, Holloway C.Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. J Altern Complement Med. 2004 Dec;10(6):1033-9.  (see fatty acids above)

Lonsdale D, Shamberger RJ, Audhya T. Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Neuro Endocrinol Lett. 2002 Aug;23(4):303-8. Thiamine tetrahydrofurfuryl disulfide appears to have a beneficial clinical effect on some autistic children, since 8 of the 10 children improved clinically. We obtained evidence of an association of this increasingly occurring disease with presence of urinary SH-reactive metals, arsenic in particular.

Niacin and B6:  Kleijnen J, Knipschild P.  Niacin and vitamin B6 in mental functioning: a review of controlled trials in humans.Biol Psychiatry. 1991 May 1;29(9):931-41 ‘(Fifty-three controlled trials of the effects of niacin, vitamin B6, and multivitamins on mental functions are reviewed. The results are interpreted with emphasis on the methodological quality of the trials. It turns out that virtually all trials show serious short-comings: in the number of participants, the presentation of baseline characteristics and outcomes, and the description of changes in concomitant treatments. Only in autistic children are some positive results are found with very high dosages of vitamin B6 combined with magnesium, but further evidence is needed before more definitive conclusions can be drawn.’)

Rimland B, Callaway E, Dreyfus P. The effect of high doses of vitamin B6 on autistic children: a double-blind crossover study. Am J Psychiatry. 1978 Apr;135(4):472-5. (they felt there was an advantage)

Vitamin D3:  No useful scientific data available.

High dose Vitamin A (very high doses for short period suggested to clear the body of measles virus).   No scientific data available in terms of treatment.  There is an hypothesis that autism is associated with a G-protein modification, which is brought back to normal using Vit A see Megson-M.  in 2000.

Activated B6.  (see the literature on magnesium and activated B6)

This is considered because pyridoxal (B6) seems to be in high concentrations and this suggests that it is not being turned into pyrodoxal-5-phosphate (activated B6) in the body adequately.

Adams JB, George F, Audhya T. Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. J Altern Complement Med. 2006 Jan-Feb;12(1):59-63. (indicating that the body has difficulty in changing the B6 to the phosphated form).  Adams also has tried to show an advantage (or not) clinically in cases with autism that were taking the activated B6

Coleman M, Steinberg G, Tippett J, Bhagavan HN, Coursin DB, Gross M, Lewis C, DeVeau L. A preliminary study of the effect of pyridoxine administration in a subgroup of hyperkinetic children: a double-blind crossover comparison with methylphenidate.

Biol Psychiatry. 1979 Oct;14(5):741-51. (The children had had low whole blood serotonin levels – which is a bit odd in itself - and a history of previous responsiveness to methylphenidate. The results of the double-blind clinical evaluation showed trends suggesting that both pyridoxine and methylphenidate were more effective than placebo in suppressing the symptoms of hyperkinesis. Pyridoxine elevated whole-blood serotonin levels, methylphenidate did not. Clinical and laboratory evidence indicated that the pyridoxine effects persisted after the 3-week period when the vitamin had been given in this experimental design.  Inadequate statistics were put with the data)

Taurine: 

Gaull GE. Taurine in pediatric nutrition: review and update. Pediatrics. 1989 Mar;83(3):433-42. Review

No evidence of significance in autism. Moreno-Fuenmayor H, Borjas L, Arrieta A, Valera V, Socorro-Candanoza L. Plasma excitatory amino acids in autism. Invest Clin. 1996 Jun;37(2):113-28. (they showed no particular oddity for the levels of taurine in the  blood of autistic children but eleven children had increased aspartic acid and eight children had high levels of glutamate; seven of these children had a concomitant increment of taurine.)

Terahydrobiopterin: clinical advantage but complex study: see below.  Folate: no advantage found: see below

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Gut enzymes as part of the diet. 

The suggestion is that the inflammation that appears to take place in the upper bowel may give rise to a lack of disaccharidases and other similar enzymes that are generally present in the gut wall.   The problem with the theorising is that there is no clinical study published that assesses the value of giving oral enzymes (generally derived gut and pancreas of cattle at slaughter).

Horvath K et al, Gastrointestinal abnormalities in children with autistic disorder,” J. Pediatrics 135;no. 5 (1999) 559-563.

Horvath K and Perman JA  “Autistic disorder and gastrointestinal disease,” Curr. Opinion in Pediatrics, 14 (2002) 583.

Kushak R and Buie T “Disaccharidase deficiencies in patients with autistic spectrum disorders,” presented at DAN! New Orleans Jan 2004.

Kushak R, Winter W, Farber N, Buie T.  Gastrointestinal symptoms and intestinal disaccharidase activities in children with autism.  J Pediatri Gastroenterol Nutr.  2005;41:508.

Gluten-free, casein-free diets (and some with low sugars and low additives)

This follows the suggestion that opioid peptides present in diet penetrate into the brain and cause a change in its activity.  The data is varying according to the researcher but there does appear to be some evidence that it has some ability.  Claims by parents that the return of even minute amounts of the food to the diet by mistake may cause a clear  affect on the autism is interesting (simply because there is a tendency for neurones to produce more receptors when there is a lack of stimulating compound), but there is no scientific data currently.  Also see naltrexone.

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Carnitine   

A simple compound that is involved in the it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids (or fats) for the generation of metabolic energy.  The carnitines exert a substantial antioxidant action, thereby providing a protective effect against lipoperoxidation of phospholipid membranes and against oxidative stress induced at the myocardial and endothelial cell level. 

Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ. Relative carnitine deficiency in autism. J Autism Dev Disord. 2004;34:615-623. A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. 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.  There does not appear to be clinical evaluation of giving carnitine as a therapeutic measure currently.

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Glutathione

Used as an antioxidant supply of SH (may use other liver herbs with it).  The problem is that it should not be given as an oral drug in that it will not reach most tissues in the body.  Because of this it seems extremely difficult to carry out studies concerning the treatment using glutathione.

The formation of glutathione, in order to act as an antioxidant..  Large amounts of work (involving Aw-T) has been to see the changes in gut wall oxidation and glutathione in inflammatory bowel diseases.

Aw TY. Intestinal glutathione: determinant of mucosal peroxide transport, metabolism, and oxidative susceptibility. Toxicol Appl Pharmacol. 2005 May 1;204(3):320-8. (summarizes our current understanding of the determinants of intestinal absorption and metabolism of peroxidized lipids. Supporting the pivotal role that glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) play in mucosal transport and metab