Attention Deficit (Hyperactivity) Disorder : Genetics, Triggers, and Trajectory
These current summaries concern, respectively, confirmation of the major significance of genetic factors in ADHD; the significance, too, of environmental factors (with foetal alcohol syndrome as an illustration); particular situations, at home, where the ADHD difficulties will be most evident; and the link between childhood-diagnosed ADHD and later anxiety or depression.
M.J.Connor November 2006
In his introduction to a review of evidence in this field, Faraone (2006) describes a consensus that multiple genetic and environmental factors work together to produce observable behavioural symptoms, and that no single risk factor is seen as a necessary and sufficient cause.
The likely influence of genes has long been evident from the frequency of reports that ADHD runs in families so that, for example, there is an enhanced risk for ADHD among the biological relatives of individuals who have been diagnosed with this condition.
It is recognised that environmental reasons could explain at least some of the familial incidence … such as social learning, cultural transmission, or a shared exposure to some toxin … but twin studies and adoption studies have reinforced the strong role played by genes in the development of ADHD.
(Typically, epidemiological data have shown that concordance rates for monozygotic twins is greater than for dizygotic twins; and that biological relatives of children with ADHD are at far greater risk for ADHD themselves than adoptive relatives of such children.)
However, the author is anxious to avoid any belittling of environmental circumstances which may either directly impact upon the individual, or act as a trigger in the case of individuals who have some (genetic) susceptibility to ADHD.
Such factors include exposure to poor parenting strategies or to actual conflict within the family, foetal exposure to maternal smoking or alcohol use, or complications at the pre-natal or peri-natal stages. The emergence of symptoms of ADHD may reflect a particular interaction of genetic and environmental factors at a particular time.
The author continues by describing the improbability that the disorder can be linked to any single gene, and indicates the greater probability that many genes combine to produce the symptoms of ADHD … and a particular combination of gene anomalies may produce a greater susceptibility.
Evidence so far suggests that “susceptibility” genes include some or many of those located on chromosomes 5, 10, 12, 16, and 17.
An earlier review completed by Faraone himself and associates (Faraone et al 2005) concerned the evidence for specific candidate genes for ADHD, and seven genes appeared to be commonly implicated. In particular, and stimulated by research findings that stimulants are effective because of their action in increasing dopamine levels at synapses, an association has been made between ADHD and the operation of those genes concerned with dopamine transmission … notably the D4 receptor gene (DRD4) which is also known to be significant for the operation of frontal-subcortical networks implicated in the aetiology of ADHD.
The dopamine receptor gene 5 (DRD5) and the dopamine transporter gene (DAT1) have also been identified as important for ADHD given the converging evidence (eg Dougherty et al 1999) that one possible cause of ADHD is an excess of activity in the dopamine transporter and corresponding hypo-activity of dopamine synapses.
With regard to the extent to which gene variants can predict response to medication, reference is made to the study of Winsberg and Comings (1999) who examined the effects of 3 genes (DRD2, DRD4, and DAT1) on the responsiveness of a sample of children with ADHD.
The DRD2 and DRD4 gene variants did not predict responsiveness to psycho-stimulant medication (methylphenidate), but anomalies in respect of DAT1 were found to be predictive of (non)-responsiveness to the medication.
One study has been identified which replicated this outcome, but other studies identified have shown conflicting outcomes such that the true effect of the DAT1 variants await further investigation.
Meanwhile, Hamarman et al (2004) studied the DRD4 variant and its association with response to stimulant medication to find that children with this variant, compared to children without any anomaly in the DRD4 gene, required twice the dosage to bring about observable improvements in performance.
Faraone summarises the current situation by arguing that there is no longer any doubt that genes mediate susceptibility to ADHD and that it is a highly heritable disorder. However, the genetic influence is complex and involves the combined action of many genes in interaction with environmental risk factors.
It is further argued that one major implication from such findings is the ability to assert that ADHD is a neurobiological condition and a valid diagnosable disorder
(thus to counter any residual questions over the reality of ADHD and whether it is a term to mask simple non-compliance).
Meanwhile, any parents or others who express concerns about the recommended use of medication among at least some of the children and young people properly assessed and diagnosed with ADHD can be reassured by reference to the evidence for tangible neurological anomalies, and the significance of stimulant medication in enhancing the transmission of the neuro-chemical dopamine.
However, it is recognised that clinical implications cannot currently go beyond this point, and more research evidence is required by which to integrate genetic evidence with intervention (medication) strategies; and it remains necessary to be cautious in prescribing stimulants in maintaining the practice of gradual titration from low to higher dosages while closely monitoring the effects.
ADHD and Foetal Alcohol Syndrome
Pre-natal exposure to maternal alcohol use is one of the environmental hazards mentioned in the previous section, and a brief summary of evidence is provided by Hoffman (2006).
He begins by describing how alcohol has been recognised as a powerful neurotoxin when experienced to a developing child through the placenta.
This awareness has become long term, and reference is made to the early work of Jones and Smith (1973) who discussed foetal alcohol syndrome in terms of a complex range of developmental anomalies.
It may not be clear exactly how the toxicity operates, nor the amount of alcohol that is needed to induce the full symptoms; but it is argued that, in addition to those children diagnosed with the syndrome, there is a subgroup of children with a history of prenatal exposure who may not demonstrate the complete syndrome but still show neuro-developmental disorders which can be attributed to alcohol.
The children concerned often show a range of cognitive and behavioural needs.
These can include learning disabilities (particularly in mathematics), receptive or expressive language weaknesses, and deficits in working memory. Behavioural or social deficits may exist, reflected in mood or anxiety disorders.
Observable behaviours symptomatic of ADHD are said to be among the most common problems for these children …. and Hoffman refers to recent survey data from a referral centre indicating that over 40% of the cases diagnosed with foetal alcohol syndrome could also be diagnosed with ADHD.
17% had a learning disorder, and 16% met the criteria for oppositional defiant disorder … both of which are commonly comorbid with ADHD.
It is reported that little evidence exists about the use of stimulant medication among children with joint symptoms of foetal alcohol syndrome and ADHD, but one small scale study found that methylphenidate did have a positive effect in reducing hyperactivity (as measured by the appropriate section in the Connors’ Parental Rating Scales) but had no impact upon measures of (in)attention.
Hoffman cites his own experience (as Professor of Clinical Paediatrics at the School of Biomedical Science, University at Buffalo, New York; and Medical Director of the Centre for Children and Families, Buffalo, New York ), and that of a number of colleagues who are experienced in the treatment of children with foetal alcohol syndrome, to the effect that medications used typically with ADHD are beneficial for these children but that side effects are common.
The practice has been to use a long-acting stimulant but beginning with a low dose and modifying the dosage quite rapidly according to observed results; and the advice is that the usual medications can be used, but with caution among those children with the more complex permutations of needs.
Meanwhile, medication would best be used as part of a multi-modal approach; and liaison with the school staff is seen as important in order that there can be a monitoring of learning needs and progress.
“Trigger” Occasions at Home
The study by Whalen et al (2006) sampled the day to day interactions between mothers and their children with ADHD to assess how the effects of ADHD (and the impact upon the mothers) might differ according to the demands of a given situation.
They had recognised that challenging behaviours tend to wax and wane in the course of a day, and their goal was to identify where and when the symptoms of ADHD would be most significant.
“ Getting Ready”, as in having the children organised for, and en route to, their school in the morning, or in managing any shift from one activity to another, was frequently reported to be difficult for the children and the mothers.
Existing evidence has shown that the situations particularly problematic at school for children with ADHD are those where the task difficulty is high, when the setting is relatively noisy and when peer cooperation is required, and where direct supervision may not be immediately available but where there is a reliance upon the children to manage their own behaviour according to the (shifting) demands.
However, hitherto, there has not been a recognition of those precise circumstances at home which give rise to the most difficulty.
The authors describe how the use of digital technology has now made it more possible to gain insight into daily experiences at home.
A personal palm-top recording device can be available to the parents throughout the day and to be programmed to emit a warning beep at selected intervals, at which point the parent makes a note of activities, feelings, and context.
(An initial study had demonstrated that mothers of children with ADHD, compared with mothers of control children with no known developmental difficulties, experienced more anger towards their children, and tended more frequently to report feeling ineffective as parents and as being limited in their activities by their children.)
The participants in this current study were 27 children (18 boys and 9 girls) with ADHD (mean age 10+) and their mothers, and 25 children without ADHD (15 boys and 10 girls in the same age-range) and their mothers.
All the target group children were receiving long-acting stimulants with positive response reported by the mothers.
The electronic monitoring was scheduled for 7 consecutive days during non-school time, with the mothers asked to record at the selected times what was actually happening, where, and what they and the children were doing; and to rate their own feelings/mood and those of the children.
The two groups differed most conspicuously in regard to the reports of events and feelings when the children should be getting ready for some activity or transition, especially if time was an issue. The mothers of the target children expressed higher rates of impatience or anger or frustration, or feelings of disappointment and discouragement about their children at such times.
Reports also indicated that the children with ADHD were less likely than their peers to be concentrating or to be in a good mood, but more likely to be talking too much and too loudly.
No such disparity was observed at other times (including what might have been predicted to be challenging times such as having the children do their homework or their share of the chores).
Meanwhile, the general quality of the mother-child interactions was noted for the frequency of disagreements, as described by both the mothers and the children, during the getting-ready times.
Mothers in the other group reported no real differences in their mood during the getting-ready times relative to other occasions or activities.
The authors concluded that the getting-ready periods pose special challenges for the children with ADHD and their mothers, and it was their view that the critical element about such occasions was the feeling of urgency over time … such as an anxiety about being late for school or missing the school transport.
The particular significance attached to the issue of getting ready for school, which, by definition, is a matter for a relatively early part of each morning, was thought possibly to result from the lack of peak effectiveness of the medication given.
However, the authors held that this might be so, but that stimulants hardly normalize behaviour, and that their impact does vary during the day. The important point was that, despite typical use of medication, situational and temporal factors appear to be significant for adjustment and for family harmony !
The implication drawn was that, as part of multi-modal intervention, efforts could be directed towards helping parents and children to recognise these situational and time triggers, and seek to prevent significant difficulties from arising (which would also reduce the risk of angry reactions interfering with stable and positive parent-child interactions) … perhaps with some emphasis upon helping the children to set targets for themselves and to monitor their own behaviours.
ADHD and Anxiety and Mood Disorders
It has been argued by Bagwell et al (2006) that there has been much evidence concerning the comorbidity of ADHD with conduct disorder or oppositional defiance, but relatively little about the link with anxiety or mod disorder. Further, what evidence there is shows some inconsistency in the perceived degree of risk that ADHD holds for these other disorders.
The review by these current authors indicates that most existing data concern the outcomes in late adolescence or early adulthood.
One such study (Mannuzza et al 1991) suggested low rates of anxiety or depression among individuals of 18+ years of age who had been diagnosed with ADHD in childhood. However, another study (Fischer et al 2002) indicated significantly enhanced rates of depression among their sample of 20 year olds with a history of ADHD.
One study of anxiety or mood disorder in mid-adolescence (Biederman et al 1996) was identified, and the findings here showed a significantly higher (and prolonged) incidence of depression and anxiety disorder at age 14+ among individuals with a diagnosis of ADHD than among a control group.
Reasons for discrepancies were speculated to include different ages at follow-up, different diagnostic criteria for ADHD, the presence or absence of comorbid difficulties, and variations in assessment procedures among the older individuals.
The research by the present authors was stimulated by the perceived need for more data by which to gain a greater understanding of any association between ADHD and these other disorders.
One hypothesis was that enhanced risk for anxiety or depression is a function of the persistent impairment in day to day routines or interactions, including social skill weaknesses and the associated peer rejection that may continue into adolescence, or long term academic difficulties with associated loss of self esteem and self confidence.
Alternatively, it has been hypothesised that the association between ADHD and anxiety/mood disorder is mediated through comorbid oppositional defiance or conduct disorder.
This combination of problems, with particular relevance in the overt behavioural symptoms, may lead to greater psychological sequelae.
The target sample consisted of 142 adolescents (aged between 13 and 18) who had been diagnosed with ADHD in childhood at some point between the ages of 5 and 12 years.
All the target sample, and controls, were subject to a structured interview by which to assess adjustment in a number of domains. Parents were also interviewed.
Additionally, the presence of anxiety or depressive states was assessed via the NIMH Diagnostic Interview Schedule; and the Child Behaviour Checklist was used with parents and teachers to assess for internalising and externalising problems.
The outcomes suggested that, as a whole group, children diagnosed with ADHD are not at significantly higher risk for anxiety and depression than non-ADHD counterparts.
However, there was evidence that the ADHD children who had more externalising behaviours or social problems were likely to have anxiety or depressive disorders in adolescence … ie a subgroup of children diagnosed with ADHD are at risk for subsequent specific disorders.
Differences between these current results and the Biederman findings were attributed to differences in the populations served in the two centres involved.
It was acknowledged that the current results may underestimate the longer term risk for these additional problems given that entry into the adult world, with associated problems about gaining and maintaining employment and about (financial) self sufficiency, might be associated with more significant emotional consequences than what is already observable during mid-adolescence.
Further research is needed to learn if the rates of anxiety and depression in the adolescents with ADHD will rise substantially compared to the control group.
The current findings do, in any event, support existing evidence that a combination of ADHD and externalising problems, such as oppositional defiance and conduct disorder, is associated with a much greater probability of later anxiety and/or depression.
Boys with ADHD who are also aggressive are found to be subject most commonly to peer rejection, and this combination is linked to an increasing trajectory of increasing internalising problems as adolescence proceeds.
One implication for mental health professionals would be the potential usefulness of observing peer problems experienced by children with ADHD as a marker for later anxiety.
The authors acknowledge some weaknesses in their study, such as a reliance upon categorical information about anxiety or mood disorder rather than an awareness of the nature or degree of such difficulties. For example, some of the ADHD sample may have been experiencing certain anxiety or mood symptoms below the diagnostic threshold but still enough to impact upon day to day functioning.
There is also reference to some question over the generalisability of the findings which were based upon clinic-referred individuals, with the possibility that this sample have a higher rate of existing comorbidities than non-referred individuals.
Few girls were included, raising the question whether there may prove to be a gender effect when it comes to ADHD linked with other disorders.
However, the authors were able to emphasize in their conclusion the importance of assessing for externalising symptoms and difficulties with peer relationships when determining the level of need among individuals referred because of (suspected) ADHD given that these two issues have a clear association with later internalising symptoms such as stress or anxiety or depression.
A further practical implication is for the inclusion of social skills work within an intervention package for those individuals who are already experiencing, or who seem likely to experience, peer interaction difficulties or actual rejection, thus to avert a source of further psychological stress.
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M.J.Connor November 2006
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© Mike Connor 2006.
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