Lecture psychiatric disorders 10: ADHD

Question 1

Which 3 words would you choose to describe ADHD symptoms (and are also DSM criteria)?

Answer 1

• Inattention
• Hyperactivity
• Impulsivity

Question 2

Fill in prevalence percentages:

• …% - …% of children aged 6-16 years are diagnosed with ADHD.
• …% of all ADHD patients are boys.
• In …% - …%, symptoms will persist into adulthood.

Answer 2

• 2-5% of children aged 6-16 years are diagnosed with ADHD.
• 80% of all ADHD patients are boys.
• In 30% - 50%, symptoms will persist into adulthood

Question 3

What’s the difference between boys and girls with ADHD?

Answer 3

• Boys → externalized symptoms (running and impulsivity), more physically aggressive.
• Girls → interalized symptoms (inattentiveness and low self-esteem), more verbally aggressive.

Question 4

Which brain structures could be impaired in people with ADHD? Think of these brain structures and pair them with the typical ADHD symptoms.

Answer 4

• Prefrontal cortex → less inhibitory control and thus more impulsive.
• Cerebellum and caudate nucleus → motor hyperactivity
• Corpus callosum → less communication between hemispheres

Question 5

These brain regions that have been discovered to be (thought to be) impaired in ADHD are found with neuroimaging. What is a disadvantage of these imaging studies?

Answer 5

Most studies are underpowered, where they used less than 20 subject per group. This makes statistics harder, which can cause differences to show up that are not really there.

Question 6

The fact that most brain imaging studies for ADHD are underpowered, resulted in the generation of a meta-analysis of structural imaging findins in ADHD. What brain regions were found to be most frequently assesed as different in ADHD?

Answer 6

Cerebellum, corpus callosum, caudate nucleus and frontal regions.

Question 7

The fact that most brain imaging studies for ADHD are underpowered, resulted in the generation of a meta-analysis of structural imaging findins in ADHD.

What’s the problem with this meta-analysis?

Answer 7

That there were differences between studies in experimental design.

Question 8

What’s the difference between a meta- and mega-analysis?

Answer 8

• Meta-analysis → combining results of independent studies with different experimental designs.
• Mega-analysis → very large study with more than 1000 subjects, summarizing results of independent studies with the same experimental designs (e.g. using the same MRI data analysis)

Question 9

A mega-analysis was performed where they looked at the size of different brain areas in children, adolescent and adult patients with ADHD.

What brain regions were identified for being different in ADHD patients and also name which brain regions were newly identified (i.e. not known previously to play a role in ADHD)?

Answer 9

• Nucleus accumbens → previously not found
• Amygdale → previously not found
• Caudate nucleus → was already known to change in ADHD patients
• Hippocampus → previously not found
• Intracranial volume → was already known

Question 10

What’s interesting about identification of the nucleus accumbens (NAc) and amygdala as a brain regions that might play a role in ADHD?

Answer 10

• The NAc plays a role in the reward system of the brain and it might explain why ADHD patients are more likely to take risks.
• The amygdale is important for emotional regulation, it might explain why ADHD patients have difficulty with emotional regulation.

Question 11

A mega-analysis was performed where they looked at the size of different brain areas in children, adolescent and adult patients with ADHD.

What did they find?

Answer 11

That for the whole group of ADHD patients (children, adolescents and adults) significant small changes in brain regions size were found. They saw in all patients, that there was a small significant decrease in brain size.

However, these changes were not significant for adults. It seems like the decrease in brain region size is restored in adults.

Question 12

The identification of the reduction in amygdala size in ADHD patients might be important in ADHD diagnosis. Why is this?

Answer 12

Because emotional regulation problems often present in patients with ADHD, but this has not yet been included into the official DSM criteria.

Question 13

How does this mega-analysis contribute to ADHD diagnosis?

Answer 13

Their finding confirm that:

• patients with ADHD have altered brains. An altered brain is seen as an disorder, so ADHD is a disorder of the brain.
• This helps reduces the stigma that ADHD is just a label for difficult children and caused by incompetent parenting.
• Better understanding of ADHD

Question 14

The publishing of this mega-analysis caused criticism from other scientists. What were these criticisms, what was the reply of the author of the mega-analysis and what are the future goals of the authors?

Answer 14

• Criticism: only small effects are measured, it’s only on group level, it’s heterogeneous and stigmatizing.
• Reply of author: there were no claims made about causality, only claims about association of these effects to ADHD. So to make a claim about causality, we do need longitudinal studies.
• Future goals: to develop a growth curve of the brain (similar to body weight) to understand if/when children are at risk for developing ADHD.

Question 15

From twin and adoption studies, there have been several behavioral traits and psychiatric disease found that have moderate/high heritability.

What is the heritability of major depression disorder (MDD), ADHD and autism, bipolar disorder and schizophrenia?

Answer 15

• MDD → 40-50%
• ADHD → 75%
• Autism, bipolar disorder and schizophrenia → 80%

Question 16

So ADHD can be explained in part by the 75% heritability. Some weak associations have been found in two genes that can only account for about 3% of the variation in ADHD. What genes have been found?

Answer 16

DAT (dopamine transporter) gene and the DRD4 (dopamine receptor D4) gene

Question 17

So ADHD can be explained in part by the 75% heritability. Some weak associations have been found in two genes that can only account for about 3% of the variation in ADHD.

What does this suggest?

Answer 17

That there are many unidentified common variants with small effects. And that gene-environment or gene-gene interactions, rare variants or a combination of these factors play a prominent role in the genetic cause of ADHD.

Question 18

Are there non-genetic factors that are associated with ADHD?

Answer 18

Yes, since only 75% of ADHD variability can be explained by genetics/heritability, 25% should be explained by non-genetic factors.

This is indeed the case, only some non-genetic factors are only found in association with ADHD and some are probably causal.

Question 19

Some non-genetic risk factors have been identified.

Name pre- and perinatal risk factors that are most likely a causal risk factor, but not yet have been proven to be causal risk factor.

Answer 19

Maternal smoking, alcohol and substance misuse, maternal stress and low birth weight and prematurity.

Question 20

Some non-genetic risk factors have been identified.

Name environmental risk factors that are most likely a causal risk factor, but not yet have been proven as a causal risk factor.

Answer 20

Certain pesticides, PCB and lead

Question 21

Some non-genetic risk factors have been identified.

Name dietary risk factors that correlate as a risk factor, but not yet have been proven as a risk factor.

Answer 21

Nutrional deficiencies in certain elements (zinc, magnesium, polyunsaturated fatty acids), nutritional surpluses (sugar, artificial food colourings), low/high IgG foods.

Question 22

Some non-genetic risk factors have been identified.

Name psychosocial adversity risk factors that correlate as a risk factor, but not yet have been proven as a risk factor.

Answer 22

Family adversity and low income and conflict/parent-child hostility.

Question 23

What is the only risk factor that is proven as a risk factor and is most likely to be a causal risk factor?

Answer 23

Severe early deprivation (seperated by parents, emotional neglect etc.)

Question 24

(I don’t think you need to know all these non-genetic risk factors for ADHD).

But what do these non-genetic risk factors tell us about ADHD?

Answer 24

That on top of all the genetic risk factors that contribute to the development of ADHD, there are also many non-genetic risk factors that influence this development. And that together shape the probability, severity and the symptoms of ADHD development.

Question 25

What system in the brain is dysfunctioning in ADHD?

Answer 25

The dopamine neurotransmitter system, where it is in a hypodopaminergic condition (significantly reduced levels op dopamine in the brain)

Question 26

Name two drugs that act on the dopamine NT system and explain how they do this.

Answer 26

Methylphenidate and (dex)amphetamine, they block reuptake of dopamine by inhibiting dopamine transporters (DAT). This increases the dopamine (DA) concentration.

Note: claiming that ADHD is purely a dopamine disorder, is too symplistic.

Question 27

What kind of study is the Multimodel Treatmnt Study of Children with ADHD (MTA)?

Answer 27

A very large longitudinal study in child psychiatry. 579 children, aged 7-9, divided randomly into 4 treatment groups, are included in this study.
They wanted to know whether these treatments are effective, if they are effective compared to behavioural therapy and if there are side effects.

Question 28

What treatments are used in the Multimodel Treatment Study of Children with ADHD (MTA)?

Answer 28

1. Standard community care (treatments by community providers) often with prescribed medication (this treatment is not part of the National Institute for Mental Health (NIMH)) → control group
2. Intensive behavioral therapy without medication (BT)
3. Intensive carefully tailored medical treatment with accompanying counseling for child and parents (MED)
4. Combination of medication and behavioral therapy (COMB)

Question 29

What were the results of the Multimodel Treatment Study of Children with ADHD (MTA)?

Answer 29

• All 4 groups showed sizable reduction in symptoms over time
• For most ADHD symptoms, children in COMB and MED showed significantly greater improvement than those given intensive BT and community care.
• The control group used the same medications as the MED group, only the fact that the MED group got carefully tailored medical treatment, caused the MED group to be superior in effectiveness compared to the control group.
• COMB and MED group did not differ significantly on any direct comparisons for core ADHD symptoms.
• COMB proved superior for non-ADHD symptoms and positive functioning outcomes.

Question 30

After 8 years a follow-up of the Multimodel Treatment Study of Children with ADHD (MTA) was performed. What were the results?

Answer 30

• There was symptom improvement that was largely maintained after treatment.
• In nearly every analysis, the 4 groups did not differ significantly on repeated measures or newly analyzed variables.

Question 31

What can be concluded based on the first Multimodel Treatment Study of Children with ADHD (MTA) and the follow-up of this study?

Answer 31

That these treatments work on short-term, but in regard to long-term effectiveness; all 4 treatments are ‘equally’ effective. And since these treatments (except the control) are very expensive, the question comes up if it’s beneficial to use expensive treatments if long-term the less expensive options are equally effective.

Question 32

What could be a suggestion based on the first study of the Multimodel Treatment Study of Children with ADHD (MTA) and the follow-up?

Answer 32

To temporarily discontinue the medication after 1 or 2 years of treatment, to determine whether benefits of the medication are lost. So if the symptoms come back after discontinuation of the treatment, then the treatment is still useful to continue. But it can also be that the brain has developed/matured enough, that the symptoms have gone away. So then you don’t need the medication anymore.

Question 33

Now we want to know whether ADHD medication has any effects on brain abnormalities, or in other words: if ADHD medication causes any brain normalization of brain areas that are smaller in ADHD patients.

On what two levels can we determine this and what is used to determine this?

Answer 33

• Structural → gray matter volume (i.e. brain region size) by MRI.
• Functional → connection between brain areas with inhibition and attention tasks by fMRI.

Question 34

Now we want to know whether ADHD medication has any effects on brain abnormalities, or in other words: if ADHD medication causes any brain normalization of brain areas that are smaller in ADHD patients.

What was found when measuring structural brain region size of the grey matter?

Answer 34

That the most prominent and replicable structural abnormalities in ADHD are in the basal ganglia. They also see that medications that act on the dopamine system, normalize structural abnormalities, like in the basal ganglia. However, aging is also associated with normalization of structural abnormalities.

Question 35

What contradiction was found between the study that looked at abnormalities in grey matter brain regions and the mega-analysis discussed before?

Answer 35

The mega-analysis did not find the same results and so couldn’t replicate these results. They found that: ‘psychostimulant medication did not influence brain area volumes’.

Question 36

What explanation was given by the authors of the mega-analysis in regard to the contradictory results of the study that looked at grey matter brain region sizes?

Answer 36

• That their study (non-randomised, cross-sectional) is not optimal to test for medication effects, so some caution is needed to interpret their result.
• They also state that they used another technique than other previous meta-analyses, and that their technique could be too local to be picked these observed normalizing effects.

Question 37

Now we want to know whether ADHD medication has any effects on brain abnormalities, or in other words: if ADHD medication causes any brain normalization of brain areas that are smaller in ADHD patients.

What two brain areas were investigated? And what was found when measuring these functional brain areas?

Answer 37

• They looked into two brain areas that connect the frontal lobe with the basal ganglia, that are important for attention.
• They found that these networks were impaired in patients with ADHD.
• They also found that medication improved this impairment and caused normalization. This was also found for advancing age.

Question 38

So we now know that medication is effective in ADHD patients and that it doesn’t cause any brain damage. But we still don’t know anything about side effects. Why would we even consider that there might be side effects for these medications?

Answer 38

Because methylphenidate and amphetamine closely resemble respectively cocaine and speed. So would administration of these drugs increase the chances of later-life substance abuse/dependence?

Question 39

What was found in a meta-analysis of 2003 in regard to the question whether ADHD medication causes an increased chance of later-life substance abuse?

Answer 39

They found that medication in childhood was associated with a reduced risk of drug and alcohol abuse in later-life.

Question 40

What was found in a 2008 study in regard to the question whether ADHD medication causes an increased chance of later-life substance abuse?

Answer 40

Their findings revealed that there was no evidence that medication increases or decreases the risk for subsequent substance use disorders in children and adolescent with ADHD when they reach young adulthood.

Question 41

Before 2008, there were almost no studies that tried to replicate the results about increased or decreased chances of substance abuse later in life due to childhood ADHD medication. But from 2008 on, more studies were published that looked into this effect. What was mostly found?

Answer 41

That a few studies did find beneficial effects of stimulant medication, meaning that the use of stimulatn medication in young ADHD patients reduced their risk for substance abuse later in life.

Note: these are preliminary results.

Question 42

What was the most important finding in the study that got published in 2017 that looked into the probable beneficial effect of stimulant medication in regard to substance abuse?

Answer 42

That well-monitored stimulant treatment may reduce the risk for alcohol and substance use in adolescent ADHD.

Question 43

Why is it so relevant to find a association between well-monitored stimulation medication and the reduced risk for alcohol and substance use in adolescent ADHD?

Answer 43

Because ADHD as a condition in itself increases the probability of substance use disorders later on in life (co-morbidity), due to problems with impulse control.

Question 44

There is one side effect of stimulant medication that hasn’t been discussed yet. Name this side effect.

Answer 44

Stimulant medication affects growth, medication causes an average growth reduction of 2.0 cm and 2.7 kg.

Question 45

What is neurodiversity?

Answer 45

A diversity among human brains in regard to sociability, learning, attention, mood and other important mental functions.

Question 46

What are the negative and positive aspects of ADHD?

Answer 46

• Negative → overly active, low concentration, low impulse control, easily distracted
• Positive → spontaneous, creative, divergent mind, vital, high-energy, fast-thinking

Question 47

What is the Niche construction?

Answer 47

Success in life depends on modifying your surrounding environment to fit the needs of your unique brain. So knowing strenghts and weaknesses of your condition can help with this.

Question 48

What would be the Niche construction for ADHD?

Answer 48