Serotonin changes in ASD

Serotonin in autism

It is remarkable that 5-hydroxytryptamine (serotonin, 5HT) is found in excess in the blood of ASD children as a relatively reliable element in them although in around 60%.

The rise in serotonin is found to be in the platelets throughout the lifespan of the autistic person. In other words this effect is taking place many years after any specific damage has taken place in the brain.

It is unlikely that the platelet serotonaemia is caused by the brain, and indeed that the platelet carriage of serotonin affects the brain because the blood brain barrier is almost impenetrable to 5-HT. As a result we must consider that an original effect is causing both effects separately.

Serotonin in the blood

It appears that

The serotonin in the platelets is produced outside them through increased activity of tryptophan hydroxylase and pumped into the cells through 5HT transporter e.g. 5HT injected into the blood of an ASD patient causes and increase in platelet 5HT to a much greater degree than in controls.
Decreased 5HT release from platelets through 5HT2A receptor and decreased metabolism by monoamine oxidase (MAOA).
Serotonin that is soluble in the plasma is cleared from the blood rapidly probably by the lung tissue.
Certain genotypes for MAOA alter the platelet levels of 5HT in autism.
It is not clear currently that specific genotypes are necessarily ASD.

Serotonin in the brain

Normally 5HT production decreases from the level as a baby, but in an autistic child it increases to 1.5 times adult level.
Serotonin levels (not production) are found to be relatively high in the brain frontal cortex of ASD although this open to argument.

Genetics of serotonin

Serotonin transporter protein.

Serotonin and treatment?

This simply is unclear at the moment. Many reports of improvements with drugs acting against 5HT have come along with others that suggest the opposite.

Risperidone: acts alters 5HT activity and penetrates the brain.
Fluoxetine: as a selective serotonin reuptake inhibitor tended to increase the level of 5HT in the brain.

Production of 5HT from tryptophan

Serotonin: The biochemistry in autism (this one of the most reliable factors in autism biochemistry and so the literature is large and goes back until the 1970s. I have not increased all the literature here but ones that appear to be of value in allowing a reader to get a good idea as to where things have got to. There is large amounts of literature quoted in the articles of Janusonis, and Harnilovic, which are recent.

Anderson GM, Horne W C., et al. The Hyperserotonemia of Autism. Annals of the New York Academy of Sciences 600 (1), 331–340. Volume 600 The Neuropharmacology of Serotonin Page 331-340, October 1990

Singh VK, Singh EA, Warren RP. Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental retardation. Biol Psychiatry. 1997 Mar 15;41(6):753-5. (Not useful on PubMed).

Burgess NK, Sweeten TL, McMahon WM, Fujinami RS. Hyperserotoninemia and altered immunity in autism. J Autism Dev Disord. 2006 Jul;36(5):697-704. Review (just puts the point forward that 5HT is known to alter immunity but no data showing cause and effect in autism)

Anderson GM, Gutknecht L, Cohen DJ, Brailly-Tabard S, Cohen JH, Ferrari P, Roubertoux PL, Tordjman S. Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia. Mol Psychiatry. 2002;7(8):831-6. (but they were not the cause of the autism!)

Hranilovic D, Bujas-Petkovic Z, Vragovic R, Vuk T, Hock K, Jernej B. Hyperserotonemia in adults with autistic disorder.J Autism Dev Disord. 2007 Nov;37(10):1934-40. (shows that the high serotonin factor is one of the most commonly reliable ones found in autism, and that currently there is no specific reason for it)

Janusonis S. Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities. Theor Biol Med Model. 2005 Jul 19;2:27. (they try to show how the build up of platelet serotonin takes place statistically and whether it is predictable…their data tries hard but does not come up with perfect results)

McNamara IM, Borella AW, Bialowas LA, Whitaker-Azmitia PM. Further studies in the developmental hyperserotonemia model (DHS) of autism: Social, permutation and peptide changes. Brain Res. 2007 (the model is that high serotonin in the blood and low in the brain – as is found in autism – would cause embryological brain to be exposed to high serotonin and they showed in rats that this effect caused a change in the developing animal’s psychology)

Croonenberghs J, Verkerk R, Scharpe S, Deboutte D, Maes M. Serotonergic disturbances in autistic disorder: L-5-hydroxytryptophan administration to autistic youngsters increases the blood concentrations of serotonin in patients but not in controls. Life Sci. 2005 Mar 25;76(19):2171-83

Croonenberghs J, Wauters A, Deboutte D, Verkerk R, Scharpe S, Maes M. Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test. Neuro Endocrinol Lett. 2007 Aug;28(4):449-55. (this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children.) This is actually quite important, showing specifically poor response in a manner that would suggest the lack of 5-HTP modification or some other factor.

Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol. 1999 Mar;45(3):287-95. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children.

Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol. 1992 Jul;34(7):593-603. 156 autistic children aged two to 12 years 6 months, compared with matched mentally retarded and normal controls. Very significant group and age effects were found for dopamine (DA), Homovanillinic acid (HVA), 3methoxy-tryptamine (3MT), norepinephrine and epinephrine (NE + E) and serotonin (5HT). High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The DA, HVA, 3MT, NE + E, 5HT and its metabolite 5HIAA levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol)

Israngkun PP, Newman HA, Patel ST, Duruibe VA, Abou-Issa H. Potential biochemical markers for infantile autism. Neurochem Pathol. 1986 Aug;5(1):51-70. (raised epinephrine, norepinephrine, serotonin in blood)

Toda Y, Mori K, Hashimoto T, Miyazaki M, Nozaki S, Watanabe Y, Kuroda Y, Kagami S. Administration of secretin for autism alters dopamine metabolism in the central nervous system. Brain Dev. 2006 Mar;28(2):99-103. (a complex study in which they gave 12 autistic children some i.v. secretin and looked for improvements in biopterin, 5HIAA, and homovanillinic acid –taken as signs of irritation, serotonin turnover and dopamine turnover- these were found in 7 but all of those with raised biopterin results initially)

Warren RP, Singh VK. Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiology. 1996;34(2):72-5.

Hranilović D, Novak R, Babić M, Novokmet M, Bujas-Petković Z, Jernej B. Hyperserotonemia in autism: the potential role of 5HT-related gene variants. Coll Antropol. 2008 Jan;32 Suppl 1:75-80

Huang CH, Santangelo SL.Autism and serotonin transporter gene polymorphisms: A systematic review and meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2008 Feb 19. [Epub ahead of print]. Also have a look at Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley

JL, Han Q, Jiang L, Li C, Folstein SE, Blakely RD. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005 Aug;77(2):265-79.

Tsujino N, Nakatani Y, Seki Y, Nakasato A, Nakamura M, Sugawara M, Arita H. Abnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism. Neurosci Res. 2007 Feb;57(2):289-95. Epub 2006 Dec 6.

Serotonin in the brain

The idea is that in autism there is a change in the production of serotonin and that this may be concerning the genetics is unclear in that some of the patients without any of the serotonin transporter polymorphisms seem to have the same effect (poor data). However, in brain neurochemistry this is an interesting finding. It is clear that changes take place during development and that this is also different in autistic children from controls.

Chugani DC. Serotonin in autism and pediatric epilepsies. Ment Retard Dev Disabil Res Rev. 2004;10(2):112-6. Review. (this suggests that there are problems that associate brain changes with other epilepsies. An argument is made that cortical malformation leads to abnormalities of thalamocortical connectivity, and that serotonin plays a critical role in this process. Finally, a role for altered metabolism of the serotonin precursur, tryptophan, in both epilepsy and autism is discussed. )

Nabi R, Serajee FJ, Chugani DC, Zhong H, Huq AH. Association of tryptophan 2,3 dioxygenase gene polymorphism with autism. Am J Med Genet B Neuropsychiatr Genet. 2004 Feb 15;125B(1):63-8. (Haplotype analysis also demonstrated significant difference in the transmission of TDO2 haplotypes to autistic subjects (P = 0.0027). Our results suggest the presence of a susceptibility mutation in the TDO2 or a nearby gene, but may also represent a chance finding.)

Chugani DC. Role of altered brain serotonin mechanisms in autism. Mol Psychiatry. 2002;7 Suppl 2:S16-7. Review. (a lot of this is basically theory but may be of significance)

Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, Chugani HT. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol. 1997 Oct;42(4):666-9. (Using alpha-[11C]methyl-L-tryptophan as a tracer for serotonin synthesis with positron emission tomography, we now report unilateral alterations of serotonin synthesis in the dentatothalamocortical pathway in autistic boys. They did this using siblings or non-autistics as controls)

Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children Ann Neurol. 1999 Mar;45(3):287-95. (For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity.)

Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol. 1992 Jul;34(7):593-603. (Very significant group and age effects were found for DA, HVA, 3MT, NE + E and 5HT. High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The dopamine, homovanillic acid, methyltryptamine, norepinephrine + epinephrine, 5HT and 5-hydroxyiminoacetic acid levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol, compared with non-medicated autistic children.

Serotonin associated genes

This is important in that the reasons why the serotonin has built up and has specific pharmacokinetics when injected must surely be to do with the way in which it is produced and moved inside cells.

Ramoz N, Reichert JG, Corwin TE, Smith CJ, Silverman JM, Hollander E, Buxbaum JD. Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism. Biol Psychiatry. 2006 Jul 15;60(2):186-91. Epub 2006 Apr 17.

Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP. Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. The International Molecular Genetic Study of Autism Consortium. Am J Med Genet. 1999 Oct 15;88(5):492-6.

Coutinho AM, Oliveira G, Morgadinho T, Fesel C, Macedo TR, Bento C, Marques C, Ataíde A, Miguel T, Borges L, Vicente AM. Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism Mol Psychiatry. 2004 Mar;9(3):264-71

Coutinho AM, Sousa I, Martins M, Correia C, Morgadinho T, Bento C, Marques C, Ataíde A, Miguel TS, Moore JH, Oliveira G, Vicente AM. Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels Hum Genet. 2007 Apr;121(2):243-56. Epub 2007 Jan 3. (these are two proteins that are linked in manufacture by cells).

Cross S, Kim SJ, Weiss LA, Delahanty RJ, Sutcliffe JS, Leventhal BL, Cook EH Jr, Veenstra-Vanderweele J Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism. Neuropsychopharmacology. 2008 Jan;33(2):353-60. Epub 2007 Apr 4 (Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT.)

Wassink TH, Hazlett HC, Epping EA, Arndt S, Dager SR, Schellenberg GD, Dawson G, Piven J. Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiatry. 2007 Jun;64(6):709-17. (The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism)

Brune CW, Kim SJ, Salt J, Leventhal BL, Lord C, Cook EH Jr 5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism.Am J Psychiatry. 2006 Dec;163(12):2148-56 (this is a locus of the serotonin transporter protein gene)

Treatments concerning serotonin

It should be realised that there is a wide range of drugs that are active against serotonin. They work in migraine, in allergy, and in various psychological and psychotic conditions. Nobody is claiming that they actually have jumped forward and pointed at them as helping in autism, despite many having been: Also see treatments

Scott LJ, Dhillon S. Risperidone: a review of its use in the treatment of irritability associated with autistic disorder in children and adolescents. Paediatr Drugs. 2007;9(5):343-54. (goes through the mechanism of action of risperidone and its pharmacokinetics. Does not claim activity in autism).

Shea S, Turgay A, Carroll A, Schulz M, Orlik H, Smith I, Dunbar F Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics. 2004 Nov;114(5):e634-41. Epub 2004 Oct 18 Comment in:

Pediatrics. 2005 May;115(5):1447-8; author reply 1448. (they felt that there was no sign of problems in the children receiving the drug)

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. (the most commonly used example is fluoxetine – Prozac – but little advantage is seen compared with side effects of the drugs. These were clearly not a major treatments and further research was required)

Hollander E, Phillips A, Chaplin W, Zagursky K, Novotny S, Wasserman S, Iyengar R. A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology. 2005 Mar;30(3):582-9.

Moore ML, Eichner SF, Jones JR. Treating functional impairment of autism with selective serotonin-reuptake inhibitors. Ann Pharmacother. 2004 Sep;38(9):1515-9. Epub 2004 Aug 3. Review.

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