Posted by Phillipa on October 13, 2010, at 20:09:35
Looks like some headway in adhd in children if Mom is deficient in Serotonin. Phillipa
From Medscape Medical News
Maternal Serotonin Deficiency During Pregnancy May Increase Children's ADHD Risk
Jacquelyn K. Beals, PhDAuthors and Disclosures
October 12, 2010 Researchers in Norway have found that decreased maternal serotonin synthesis during gestation may increase a child's risk for attention-deficit/hyperactivity disorder (ADHD) and related behavioral problems. The study focused on impaired serotonin production resulting from variants of TPH1 and TPH2 genes that encode 2 enzymes that catalyze conversion of tryptophan to 5-hydroxytryptophan in serotonin biosynthesis."Our work was inspired from animal studies, where it has clearly been shown that maternal TPH1 has an effect on embryonic development and that this is related to levels of free serotonin," said senior author Jan Haavik, MD, PhD, from the Department of Biomedicine, University of Bergen, and Division of Psychiatry, Haukeland University Hospital, Bergen, Norway, via email to Medscape Medical News.
"However, this is more difficult to study in humans, where the role of local serotonin production in ovaries and other tissues is incompletely studied," Dr. Haavik explained.
TPH1 and TPH2 differ slightly in structure and function. TPH1 is present in the pineal gland, the striatum, and hippocampus, as well as in female reproductive tissues and other organs. TPH2 catalyzes most of the brain's production of serotonin.
The report notes that impaired serotonin function and TPH1 or TPH2 variants have been detected in a variety of psychiatric conditions among them, anxiety, autism, depression, schizophrenia, and ADHD but evidence for serotonin pathway abnormalities in ADHD has been inconclusive.
Dr. Haavik's motivation for the study grew from his frustration with the slow progress in psychiatric knowledge. As he observed: "Not a single 'candidate gene' for ADHD has been robustly replicated across studies, and virtually nothing is known about the function of the handful of genetic markers recently found to be associated with either schizophrenia, bipolar disorder, or autism."
The new study, published in the October issue of the Archives of General Psychiatry, enrolled adults diagnosed with ADHD, following Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. DNA was obtained from saliva or blood samples of participants; exons and intron-exon regions of TPH1 and TPH2 were sequenced in 457/459 adults with ADHD and 187/179 control individuals, respectively.
Patients found to have TPH1 mutations then recruited family members, with a guideline of 3 or more participants per family; the resulting TPH1 analyses assessed DNA samples from 86 members of 7 families.
The initial case/control screening identified 5 new (and 1 known) TPH1 missense mutations, as well as 1 new nonsense mutation. Missense mutations usually affect only 1 amino acid, leading to mutant proteins whose functions may be normal or impaired; nonsense mutations do not encode functional proteins. For TPH2, 1 new and 1 known missense mutation were identified.
TPH1 mutations were present in 1.8% of ADHD cases and 2.1% of control individuals; no TPH2 mutations were found in control participants. In the general Norwegian population, coding variants of TPH1 have been reported in 1% of the population, and coding variants of TPH2 in .2%.
No association was identified between TPH1 mutations and ADHD diagnosis. All participants completed the Wender Utah Rating Scale, the ADHD Self-Report Rating Scale, and the Mood Disorder Questionnaire. Those having TPH1 variants scored slightly higher than control individuals on symptoms of childhood (P = .03) and adult (P = .07) ADHD. However, when ADHD-diagnosed individuals were excluded from the analysis, the effect of a single TPH1 variant was nonsignificant.
Comparing adult children of mothers with TPH1 variants with adult children of fathers with TPH1 variants revealed striking contrasts between these 2 groups: Children of TPH1-variant mothers were 1.5 to 2.5 times more likely to have ADHD or bipolar disorder symptoms than children with TPH1-variant fathers or the control population. Analysis of variance found that these 3 groups differed significantly in their current ADHD symptoms (P = 5 × 10−5), childhood ADHD symptoms (P = 3.7 × 10−7), and bipolar disorder symptoms (P = 6.2 × 10−7).
"Although we report a correlation between inactivating mutations of TPH1 in mothers and offspring symptoms and behavior, we don't consider this as definite proof of such a relationship," cautions Dr. Haavik. "Rather...we emphasize that the findings should be replicated in other independent samples."
The maternal effects were evident in all families involved and for all TPH1 mutations. Use of illegal drugs indicating impulsive behavior also differed significantly between participants whose mothers vs their fathers had TPH1 mutations: 47.4% of the former group had used illegal drugs compared with 11.8% of the latter (P = .03).
The authors propose that "the effect of serotonin deficiency depends on the maternal TPH1 status, independent of the patient's own genotype." However, given the relatively small size of the study, they urge the importance of replication studies in larger samples to verify their results.
"Serotonin per se cannot be supplemented, but...if the finding gets replicated, then ultimately [it] might lead to the recommendation that pregnant mutation carriers are supplemented with [5-hydroxytryptophan] (which is freely available, eg, in the Netherlands and is licensed as a food additive, so probably not even large trials are needed)," commented Andreas Reif, MD, from the Department of Psychiatry and Psychotherapy, Julius Maximilians University, Würzburg, Germany, by email to Medscape Medical News.
"[M]utation screening for such rare variants will not take place in the near future, limiting this application," said Dr. Reif. However, he considered the study important for "really introducing a new line of research maternal genetic variation to increase the offspring's risk towards psychiatric disorder...it points towards new mechanisms of disease which are worthwhile to pursue further."
"The main purpose of our work has been to suggest a new approach to study the biology of mental disorders," noted Dr. Haavik, "and to specifically address the possibility that maternally produced serotonin has long-term effects on offspring behavior.... At this stage," he added, "we are reluctant to suggest specific pharmacological interventions, except to warn against the use of medications that lower serotonin levels during pregnancy."
Dr. Haavik and Dr. Reif have disclosed no relevant financial relationships.
Arch Gen Psychiat. 2010;67:1033-1043.
poster:Phillipa
thread:965667
URL: http://www.dr-bob.org/babble/20101009/msgs/965667.html