Attention-Deficit/Hyperactivity Disorder Symptoms in Offspring of Mothers With Impaired Serotonin Production
Anne Halm√ły, MD; Stefan Johansson, PhD; Ingeborg Winge, PhD; Jeffrey A. McKinney, PhD; Per M. Knappskog, PhD; Jan Haavik, MD, PhD  Arch Gen Psychiatry. 2010;67(10):1033-1043. doi:10.1001/archgenpsychiatry.2010.124

Arch Gen Psychiatry. 2010;67(10):1033-1043. doi:10.1001/archgenpsychiatry.2010.124

Context  Exposure to adverse events during prenatal and postnatal development, as well as serotonin deficiency, have been implicated in disturbances of mood and impulsivity, but the underlying mechanisms are unknown.

Objective  To investigate the long-term effects of an impaired serotonin synthesis on the developing human brain, we studied the effects of nonsynonymous mutations affecting tryptophan hydroxylase (TPH) enzymes responsible for serotonin production in maternal reproductive tissues (TPH1) and the brain (TPH2).

Design  Family-based case-control and functional studies of candidate genes.

Setting  Adult outpatients with attention-deficit/hyperactivity disorder (ADHD), their family members, and random control subjects were recruited across Norway.

Participants  Nine pedigrees with TPH1 and TPH2 mutation carriers were identified among 459 patients with ADHD and 187 controls. The TPH genes were then sequenced in 97 additional family members, and information about psychiatric diagnoses and symptoms was obtained from 606 controls, the 459 patients, and their relatives.

Main Outcome Measures  The effects of maternal vs paternal TPH1 mutations compared in all families.

Results  Nine different TPH1 and TPH2 mutations were found by sequencing in 646 individuals (1.0% and 0.2% allele frequency, respectively). In vitro studies showed that 8 TPH mutants had significantly impaired enzyme function. Family analysis of 38 TPH1 mutation carriers and 41 of their offspring revealed that offspring of mothers carrying TPH1 mutations reported 1.5- to 2.5-times-higher ADHD scores and related symptoms during childhood and as adults than did controls (P < 10–6) or offspring of fathers with the corresponding TPH1 mutations (P < .001).

Conclusions  Impaired maternal serotonin production may have long-term consequences for brain development and increase the risk of ADHD-related symptoms and behavior in offspring. Replication studies are required to form conclusions about the clinical implications of mutations affecting serotonin biosynthesis.

ADD Coach Services Interpretation:

Multiple TPH1 mutations were found. TPH1 is found in the mother's reproductive system and is responsible for sending serotonin to her baby's brain. According to the study, mother's with serotonin production issues had more babies who were eventually dignosed with ADHD than their peers without serotonin production issues. Dads with serotonin production problems also had more children with ADHD, though less than the moms. This indicates the problem may begin with the mom's serotonin production, impacting her child's brain development in vitro, as in the mice.

Furthermore, the mothers with TPH1 problems were more likely to use nicotine, alcohol and drugs. While the data is intriquing, this was a small, initial study. More studies are needed to dicpher the effects of the mother's substance use versus the mother's TPH1 mutation status.


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