Differential diagnostics for ADHD

A thorough diagnosis of ADHD always requires a careful differential diagnosis to rule out other disorders with similar symptoms.

The overall prevalence of mental disorders in Germany is quite high at 33.3% within one year (EU: 38.8%).

Important factors that should be considered in the differential diagnosis of ADHD are, for example, acute stress reactions, unrecognized giftedness or underachievement, organic primary disorders such as sleep disorders or post-commotional syndromes or medication side effects.
Mental and psychiatric disorders whose symptoms can resemble ADHD include anxiety disorders, affective disorders, autism spectrum disorders (ASD) and borderline personality disorder (BPD).
The percentages in brackets after the headings indicate the population prevalence, i.e. they are independent of ADHD.

• 1. Differential diagnostics
  • 1.1. Differential diagnosis
  • 1.2. ADHD (ASD, OCD) - homogeneous disorders or purely dimensional grouping?
  • 1.3. Comorbidity: the difference to differential diagnosis
  • 1.4. Prevalence: frequency of mental disorders
• 2. Differential diagnosis for ADHD
  • 2.1. “Healthy” stress reaction to a stressful situation
    • 2.1.1. Acute subjectively threatening stress
    • 2.1.2. (Unrecognized) giftedness (> 120: 8.98 %; > 130: 2.28 %)
      • 2.1.2.1. Stress reaction of unrecognized gifted people as outsiders
      • 2.1.2.2. Similarities between individual typical traits in HB and ADHD
    • 2.1.3. Underachievement (< 80: 8.98 %; < 70: 2.28 %)
  • 2.2. Age-appropriate high activity level
  • 2.3. Primary organic disorders
    • 2.3.1. Consequences of sleep disorders (sleep disorders: children 47.1 %; adults: 0.6 to 7.8 %)
    • 2.3.2. Post-coma syndrome (consequences of a concussion) (11 to 80 %)
    • 2.3.3. Deficiency symptoms (5 to 30 %)
      • 2.3.3.1. Vitamin D3 (30 %)
      • 2.3.3.2. Vitamin B12 (5 to 30 %)
      • 2.3.3.3. Zinc (11 %)
      • 2.3.3.4. Iron (10 %)
      • 2.3.3.5. Other possible deficiency symptoms
    • 2.3.4. Migraine (women: 18 %, men 6 %)
    • 2.3.5. Substance abuse (illegal drugs: 10 %, nicotine: 16.6 to 25.5 %)
    • 2.3.6. Addiction / dependency (alcohol: 5%, gambling: 0.31%)
    • 2.3.7. Thyroid problems (cumulative 7 to 14 % in women, 2.75 to 3.5 % in men)
      • 2.3.7.1. Hyperthyroidism (women 1 - 2 %, men 0.25 - 0.5 %)
      • 2.3.7.2. Underactive thyroid / hypothyroidism (from 60 years approx. 2 %)
      • 2.3.7.3. Hashimoto’s thyroiditis (women 4.5 - 9.5 %, men 0.5 - 1 %)
      • 2.3.7.4. Thyroid hormone resistance (RTH) / thyroid hormone action defect (THAD)
    • 2.3.8. Restless legs syndrome (children 2 %, adults 5 to 10 %)
    • 2.3.9. Prenatal damage due to alcohol, FAS (0.8 to 8.2 %)
    • 2.3.10. Seizure disorders (epilepsy: 0.5 to 1 %)
    • 2.3.11. Hydrocephalus (0.4 - 0.8 %; from 65 years 3 %)
    • 2.3.12. Histamine intolerance, histamine intolerance (1 %, of which 80 % adults)
    • 2.3.13. Prolactinomas (0.02 - 0.05 %)
    • 2.3.14. Phenylketonuria (PKU) (0.0125 %)
    • 2.3.15. Consequences of severe brain infections (cumulative 0.05% to 0.16%)
      • 2.3.15.1. Encephalitis (cumulative 0.03 %)
      • 2.3.15.2. Perinatal hypoxemia (0.001 to 0.009 %)
      • 2.3.15.3. Bacterial infections (cumulative 0.01% in women, 0.12% in men)
    • 2.3.16. Neurofibromatosis type 1 (0.029 %)
    • 2.3.17. Velocardiofacial syndrome (22q11DS) (0.01 to 0.05 %)
    • 2.3.18. Cortisol disorders (cumulative 0.0042 to 0.0048 %)
      • 2.3.18.1. Hypocortisolism (adrenal insufficiency) (0.004 %)
      • 2.3.18.2. Hypercortisolism (Cushing’s syndrome) (0.0002 to 0.0008 %)
    • 2.3.19. Moyamoya (0.0001 % to 0.0009 %)
    • 2.3.20. Hamartoma of the hypothalamus (0.0005 %)
    • 2.3.21. Allergies (with motor restlessness)
    • 2.3.22. Visual and hearing impairment
    • 2.3.23. Lesions of the left cerebral hemisphere / right PFC
    • 2.3.24. Organic brain damage
    • 2.3.25. Status epilepticus during sleep (ESES)
    • 2.3.26. Traumatic or space-occupying cerebral disorders / other psycho-organic syndromes with cerebral damage and/or psycho-mental retardation
    • 2.3.27. Bachmann-Bupp syndrome (BABS)
    • 2.3.28. CAPRIN1 haploinsufficiency
    • 2.3.29. KBG syndrome
    • 2.3.30. Cystic fibrosis
  • 2.4. Side effects of medication
  • 2.5. Mental and psychiatric disorders
    • 2.5.1. Anxiety disorders (annual prevalence: 22.9% (women), 9.7% (men))
      • 2.5.1.1. Panic disorder (3.2 to 3.6 %)
      • 2.5.1.2. Generalized anxiety disorder (1.9 to 31.1 %)
    • 2.5.2. Excretory disorders (enuresis, defecation) (children: 18.5 %)
    • 2.5.3. Affective disorders (10 to 17 %)
      • 2.5.3.1. Depression (10 % (men) 20 % (women))
      • 2.5.3.2. Bipolar disorder (annual prevalence: 3.1 % (women), 2.8 % (men))
        • 2.5.3.2.1. Depressive episode of bipolar disorder
        • 2.5.3.2.2. Manic episode of bipolar disorder
      • 2.5.3.3. Cyclothymia (13 %)
    • 2.5.4. Circumscribed developmental disorders (partial performance disorders) according to ICD-10 (approx. 10 to 15 % (?))
      • 2.5.4.1. Dyspraxia (5 to 6 %)
        • 2.5.4.1.1. Motor dyspraxia / circumscribed developmental disorder of motor functions (UEMF)
        • 2.5.4.1.2. Ideomotor dyspraxia
        • 2.5.4.1.3. Ideational dyspraxia
        • 2.5.4.1.4. Verbal dyspraxia
      • 2.5.4.2. Developmental coordination disorders
      • 2.5.4.3. Partial performance disorders
        • 2.5.4.2.1. Reading and spelling disorder (dyslexia) (5 %)
        • 2.5.4.2.2. Calculation disorder (dyscalculia) (5%)
    • 2.5.5. Post-traumatic stress disorder (PTSD) (5 % (men), 10 % (women))
    • 2.5.6. Tic disorders, Tourette syndrome (1 % to 15 %)
    • 2.5.7. Internet addiction (3.9 %)
    • 2.5.8. Disorder of social behavior / conduct disorder (1.5 % to 5 %)
    • 2.5.9. Emotionally unstable personality / borderline (1 - 5 % (women), 1 % (men))
    • 2.5.10. Obsessive-compulsive disorder (1 to 3 %)
    • 2.5.11. Antisocial personality disorder (0.2 - 3 %)
    • 2.5.12. Narcissism (0.5 to 2.5 %)
    • 2.5.13. Schizophrenic disorder (1 %)
    • 2.5.14. Psychoses (1 %)
    • 2.5.15. Autism spectrum disorder (ASD) (0.9 %)
    • 2.5.16. Fragile X syndrome (0.22% (men) to 0.66% (women))
    • 2.5.17. Pervasive developmental disorders (PDD) (0.06 %)
    • 2.5.18. Wilson Disease (0.0033 %)
    • 2.5.19. Monoamine neurotransmitter disorders
      • 2.5.19.1. Genetically caused BH4 disorders (approx. 0.0002 %)
      • 2.5.19.2. Missing or greatly reduced DAT
    • 2.5.20. Predominantly milieu-related behavioral problems
    • 2.5.21. Oppositional defiant behavior (ODD)

1. Differential diagnostics¶

1.1. Differential diagnosis¶

Differential diagnosis means making sure that the symptoms are not (also) caused by other causes or disorders and therefore require different treatment.

1.2. ADHD (ASD, OCD) - homogeneous disorders or purely dimensional grouping?¶

One study attempted to assign 238 affected individuals who showed different symptoms of ADHD, ASD and OCD or were healthy controls to homogeneous disorder groups based on cortex thickness in 76 cortex regions. This was done using machine learning (weak AI). No homogeneous groups could be formed.¹
This indicates that the individual differences between those affected by a disorder are greater than the similarities.

1.3. Comorbidity: the difference to differential diagnosis¶

While differential diagnosis means checking whether the symptoms that (here:) indicate ADHD might not actually be caused by another problem, i.e. that there is no ADHD, comorbidity means that someone who suffers from one disorder (here: ADHD) is also (additionally) affected by another disorder.

Comorbidity with ADHD therefore means that (here:) ADHD has been clearly identified and other problems exist in addition to ADHD.
Many disorders have very typical comorbidities - including ADHD, so it is always necessary to check these as part of a proper medical history. ⇒ ADHD - comorbidity

Most comorbidities typical of ADHD may have genetic variants in common with ADHD or the common cause of early childhood stress exposure, which meets a gene predisposition specific to the respective (co-)morbidity.
⇒ How ADHD develops: genes + environment

1.4. Prevalence: frequency of mental disorders¶

33.3% of all Germans and 38.8% of all EU citizens suffer from a mental disorder (within 12 months). Men and women are affected in roughly equal numbers, but with different types of disorder. The 18 to 34 age group is most frequently affected.²
Of these 33.3%, 1/3 (i.e. a total of 11.1% of all Germans) suffer from more than one disorder. In these cases, there is an overt comorbidity of several disorders from different diagnostic groups. The comorbidity with regard to different individual diagnoses from the same group is significantly higher again.
Comorbidities increase with age.²

For comparison with the prevalence values (frequency of occurrence) given below:
ADHD has a prevalence of

• Children and young people together 5.29 %
  according to an international long-term meta-analysis of 102 international studies with n = 171,000 subjects³
  • Preschool children: approx. 3 %⁴
  • Young people: approx. 8 %
    • Boys approx. 6 %⁴
    • Girls approx. 2 %⁴
      (We suspect that girls are more likely to go undiagnosed due to the ADHD-I subtype being more common in them)
• Adults:
  • Approx. 1 - 4 %⁴
  • Approx. 3 - 5 %⁵

This would make the lifetime prevalence of ADHD roughly equivalent to that of diabetes.⁶

Friedmann reports that the lifetime prevalence of ADHD in the USA has risen from 7.8% in 2003 to 11% in 2011.⁵
This is not due to an increase in ADHD, but to the fact that ADHD is now better recognized and more reliably diagnosed.

Further information on the prevalence distribution of ADHD:⇒ Frequency of ADHD (prevalence)

2. Differential diagnosis for ADHD¶

The following phenomena should be checked when examining where ADHD-typical symptoms originate from.

2.1. “Healthy” stress reaction to a stressful situation¶

2.1.1. Acute subjectively threatening stress¶

An acute and subjectively threatening stress situation can trigger the entire ADHD symptomatology in otherwise healthy people.
All ADHD symptoms are stress symptoms. Therefore, all symptoms can be triggered by “normal” severe stress, i.e. by a situationally appropriate but strong perception of stress in healthy people.
When the stressful situation ends, the symptoms cease completely in healthy people.
However, if ADHD exists, the stress regulation system is permanently damaged due to genetic causes or a combination of a genetic disposition and too long, too intense (usually early childhood) stress exposure (⇒ Development of ADHD), so that the stress symptoms persist from then on even in the slightest (or no) stressful situations and the stress systems can overreact to minor stressful situations (ADHD-HI) or the stress systems ramp up and shut down again too early (ADHD-I).
⇒ ADHD as a chronic stress regulation disorder.
The first step in a differential diagnosis is therefore to determine whether acute circumstances exist that are so stressful that they can cause the symptoms, for example:

• Bullying⁷
  • Depression
  • Fear
  • Shorter sleep
  • Insomnia
  • Poorer school grades
  • ADHD symptoms
• Separation from caregivers (divorce of parents)
• Separation problems with serious family conflicts⁸
• Death of a close relative
• Loss of the partner
• Subjectively unresolvable stressful situation (loss of control)
• Life change (for children: relocation, for adults: insolvency, contested divorce, etc.)
• Abusive parenting methods (e.g. ignoring the child; playing dead until the child obeys)
• Sexual abuse
• Physical abuse
• Etc.

2.1.2. (Unrecognized) giftedness (> 120: 8.98 %; > 130: 2.28 %)¶

Prevalence of giftedness: IQ 120 and above: 8.98%, IQ 130 and above: 2.28%

Giftedness is not a disorder. Nevertheless, symptoms can arise from unrecognized giftedness that are almost identical in nature and composition to ADHD symptoms.

2.1.2.1. Stress reaction of unrecognized gifted people as outsiders¶

Gifted children have different interests, think “differently”, have different values and react differently. The lower the social competence with which those affected can bridge their differences, the stranger other children find them. This can trigger negative reactions and even bullying. But even without bullying, the “feeling different” and “not belonging” (which is not only similar, but identical to ADHD sufferers) and the lack of friends can increase stress to such an extent that the stress symptoms typical of ADHD can develop.
Affected children are then fidgety, disrupt lessons, act out in class (ADHD-HI-like) or switch off internally and daydream (ADHD-I-like).
In addition to the possible stress symptoms of bullied outsiders (which may well include unrecognized gifted people due to their difference), there are other similarities between ADHD and giftedness that are not caused by stress.

2.1.2.2. Similarities between individual typical traits in HB and ADHD¶

Giftedness not only causes faster thinking, but often correlates with typical traits (“character traits”). Many of these traits are similar to characteristics that are often observed in ADHD sufferers.
⇒ Giftedness and ADHD

We had assumed that the impressive correspondence between the positive characteristics of ADHD described in the ADHD literature and the typical character traits of gifted people described in the gifted literature resulted from the fact that ADHD almost always correlates with giftedness and giftedness very often correlates with high sensitivity. We assumed that these are character traits that do not result from ADHD or giftedness itself, but that they have their actual root in the shared high sensitivity.
However, more recent data (also from the ADxS.org symptom test, n = 2000, as of July 2020) show no correlation between giftedness and high sensitivity.

Both gifted people and those with ADHD are ascribed this trait in the relevant specialist literature:

• Primarily intrinsically motivated (extrinsically difficult to motivate through external pressure)
  • Ability to hyperfocus
  • Boredom and concentration problems with uninteresting or monotonous tasks (up to underperformance and excessive error rate)
  • Impatience
  • Tendency to interrupt others
• Rejection of authority (authority is only recognized on the basis of competence, not rank)
• For some: difficulty in making decisions (too many options and facts to consider); mainly in people who internalize their stress reactions, less in people who externalize stress
• Smalltalk version
• Diplomacy deficit
• Aversion to crowds
• High importance of truth, equality, justice
• Often being perceived as weird or strange by others.

These traits (which of course do not occur in every case of HB, but are common in HBs) should therefore be examined closely for their cause during diagnosis.

Unrecognized giftedness is not easy to spot. Not all gifted people have special abilities. Many gifted people even emphatically reject such a classification for themselves because they do not perceive themselves in this way. It is important to note the difference between giftedness = disposition and ability = realization of giftedness. Many gifted people need suitable support in order to develop their abilities. In addition, not all giftedness lies in areas relevant to school. Mathematical geniuses or the variant of the gifted person with a thirst for knowledge are naturally easily recognized as gifted.⁹¹⁰¹¹

Of course, giftedness is not a compelling reason to feel like an outsider and/or to develop ADHD-like symptoms. It usually affects those who are unable to compensate for their difference with sufficient social skills.
All the prevalence rates mentioned are merely a rough guide to make the probability of possible comorbidity visible. And, of course, not every child with ADHD is gifted.

2.1.3. Underachievement (< 80: 8.98 %; < 70: 2.28 %)¶

Giftedness and its consequences for learning-performance behavior and reactive behavioral disorders (when over/underchallenged) can act like ADHD. ADHD occurs more frequently with giftedness.¹¹
Prevalence of giftedness: IQ 80 and below: 8.98%, IQ 70 and below: 2.28%

In the case of an existing intellectual disability, the DSM-V criteria only appear to be suitable for ADHD diagnosis to a limited extent. In particular, the main symptoms of the DSM-V in underachievers can also result from the underachievement itself. One study was only able to correctly diagnose 46% of ADHD sufferers using the DSM-V. Additional criteria - which the authors do not mention - are said to have increased the diagnostic accuracy of ADHD among the gifted to 82%.¹²

One study found that the Verbal Fluency Task showed lower phonological and semantic fluency in underachievers than in ADHD sufferers and lower semantic fluency than in dyslexics.¹³

2.2. Age-appropriate high activity level¶

A still age-appropriate high level of activity, especially in younger children, can show ADHD-like symptoms.¹⁴¹¹

A (very) high level of activity in (very) young children can be age-related. This declines as the brain develops (which fits the description of ADHD as a developmental delay of the brain if the activity level is significantly above the usual age-appropriate level). Some children also simply need more time than others in certain developmental phases. This is not a disorder, but an individual characteristic that everyone has. Warm attention and patient encouragement, combined with plenty of opportunity to act out the urge to move are the most sensible ways to respond.

2.3. Primary organic disorders¶

Sorted by prevalence (frequency of occurrence) in descending order. The prevalence indicates the frequency of the disorder itself, not the frequency or probability of ADHD in this disorder. For example, the prevalence of deficiency symptoms is quite high, but the influence of their elimination on ADHD symptoms is not significant.

2.3.1. Consequences of sleep disorders (sleep disorders: children 47.1 %; adults: 0.6 to 7.8 %)¶

The annual prevalence of sleep disorders in Germany in 2008 was 0.6 % (15 to 19 years) to 6.6 % (60 years and over) for men and 0.8 % (15 to 19 years) to 7.8 % (60 years and over) for women.¹⁵
Sleep problems with ADHD are extremely common:

• 70 - 80 % of children with ADHD suffer from sleep problems
• 20 - 30 % of adults with ADHD suffer from sleep problems

A Chinese study of 23,791 schoolchildren found that 68.7% of children with ADHD had poor sleep quality, compared to 47.1% of children without ADHD¹⁶

See also: ⇒ ADHD - comorbidity, there on sleep problems

When it comes to sleep problems and ADHD, it is difficult to distinguish between cause and effect. ADHD very often causes sleep disorders and sleep disorders often cause ADHD-like symptoms.

In the case of an ADHD diagnosis, comorbid sleep disorders should always be treated with particular priority. In addition, when taking medication for sleep problems, their possible negative effect on ADHD symptoms must be taken into account, just as medication for ADHD must be checked to ensure that it does not exacerbate sleep problems. More on the treatment of sleep problems with ADHD: ⇒ Treatment of sleep problems with ADHD

• Vigilance disorders with impaired sleep-wake regulation¹⁷¹⁸
• Consequences of sleep apnea syndrome¹¹
  “Obstructive sleep apnoea syndrome (OSAS) is the most common sleep-related breathing disorder. The prevalence is around 4% in men and around 2% in women.
  Obstructive sleep apnea (OSA) is even more common and reaches strikingly high figures, particularly when subgroups are considered. For example, there is a prevalence of around 36% in patients with diabetes mellitus or arterial hypertension, a prevalence of 50% in obese patients and a prevalence of 83% in patients with refractory arterial hypertension. It is estimated that 80 % of male and 90 % of female patients with sleep apnoea syndrome are undiagnosed and therefore untreated.”¹⁹
  Breathing interruptions in children’s sleep can trigger cognitive stress, causing symptoms that resemble ADHD.²⁰
• Chronic lack of sleep¹⁷
• Disturbances in the dream sleep phases occur within a few days:
  • Increased irritability²¹
  • Increased impulsivity²¹
  • Reduced concentration²²
  • Reduced attention²²
  • Disorders of the working memory²³

Common symptoms of sleep problems and ADHD:²⁴

• Motor hyperactivity, physical restlessness
• Concentration problems
• Attention problems

ADHD symptoms that are atypical for sleep problems:

• Inner restlessness (typical in atypical depression, less so in melancholic depression)
• Impulsiveness
• High flow of speech (logorrhea, polyphrasia)
• Chasing thoughts, circling thoughts
• Rapid mood swings
• Dysphoria with inactivity

Symptoms of sleep problems that are atypical for ADHD:

• Drowsiness
• (Day) tiredness

2.3.2. Post-coma syndrome (consequences of a concussion) (11 to 80 %)¶

Another name: post-concussion syndrome

Prevalence: probably in 1 / 10 patients with mild traumatic brain injury²⁵
A concussion is the mildest form of traumatic brain injury. In the USA, an incidence of 1.15 % is assumed for concussion (3.8 million / 331 million). This would put the incidence of postconcussion syndrome at around 0.115% per year.
The prevalence is between 11 and 80 %.²⁶

In uninjured adolescent athletes, ADHD appears to mimic post-commotional syndrome. ADHD sufferers report more symptoms of postconcussion syndrome than non-sufferers.²⁷ Another study reports prolonged times to recovery from concussion in ADHD.²⁸
One study found no clustering of ADHD in 12-/13-year-old athletes with a concussion.²⁹

2.3.3. Deficiency symptoms (5 to 30 %)¶

2.3.3.1. Vitamin D3 (30 %)¶

Prevalence of D3 deficiency:³⁰³¹
* 30.2 % inadequately supplied
* 38.4 % sufficiently supplied
* 31.4 % in need of improvement or oversupplied

• A vitamin D3 deficiency also appears to be very common in ADHD.³² D3 supplementation is recommended, especially in the fall/winter.

• D3 requires fat for absorption, i.e. ingestion requires that the preparations contain fat or that food is consumed at the same time. A glass of milk should suffice for this.

2.3.3.2. Vitamin B12 (5 to 30 %)¶

Prevalence of B12 deficiency:³³³¹

• Young adults 5 to 10 %
• Older adults 10 to 30 %

• At an older age, concentration and attention problems due to B12 deficiency are almost phenotypical.
• B12 can be administered more safely by means of injections.
• In the meantime, B12 is also available in tablet form.
• Foods with a potentially high B12 content (spinel algae), on the other hand, cannot be dosed reliably enough.

2.3.3.3. Zinc (11 %)¶

Zinc deficiency can exacerbate symptoms of existing ADHD.³⁴

• Prevalence of zinc deficiency:
  • Population-wide
    • Europe: 11 %³¹
  • Healthy children from 1 to 3 years:
    • Western Europe: 31.3 %³⁵
  • in children under five years of age (Disease Control Priorities in Developing Countries 2006).
    • East Asia/Pacific: 7 %
    • Eastern Europe and Central Asia: 10%
    • Latin America and the Caribbean: 33 %
    • Middle East and North Africa: 46 %
    • Sub-Saharan Africa: 50 %
    • South Asia: 79 %
• Zinc deficiency manifests itself in a lack of T and B lymphocytes, among other things
• Zinc deficiency often goes hand in hand with vitamin A deficiency
• Zinc is involved in the Ada repair protein. This repairs (demethylates) methylated phosphate linkers in the DNA by transferring the methyl group to the cysteinate-S³⁶

2.3.3.4. Iron (10 %)¶

The prevalence of iron deficiency is difficult to determine because there is little reliable epidemiologic data on the subject, and it is also related to various related pathologic entities such as anemia, iron deficiency anemia, and isolated iron deficiency without anemia.

• Worldwide: 50 %³⁷
  • for women: 37% (42% and 25% for children)
    • non-pregnant women: 33 %
    • pregnant women: 40 %
    • In around 50% of cases, this is due to severe iron deficiency.
  • large differences depending on age, gender and world region
• Europe: 5-10 %³⁸
  • Women of childbearing age: approx. 20 %
  • Other risk groups: Infants and young children
  • Adolescents from 13 to 15: 4-8 %; mainly storage iron deficiency without iron deficiency anemia

Symptoms of iron deficiency are³⁷

• Tiredness
• Muscle weakness
• reduced physical performance
• Changes in mood and emotional behavior

Iron deficiency affects the dopamine metabolism³⁷

• This could be particularly harmful in infants and young adults with changes in the mesolimbic signaling pathway [30]. Iron is involved in dopaminergic signaling pathways and dopaminergic neurotransmission.
• Iron deficiency in the substantia nigra could result in reduced tyrosine hydroxylase activity and thus impaired dopamine synthesis.
• The SERT influences dopaminergic signaling
  • through its modulation of intracerebral iron homeostasis. The SERT-dependent decrease in intracerebral iron concentration influences dopaminergic and noradrenergic neurotransmission because iron is required for the conversion of phenylalanine to L-tyrosine and L-tyrosine to L-dopa and thus co-regulates dopamine synthesis.
  • by the (reversible) decrease in the density of dopaminergic D2 receptors and presynaptic DAT, which ensure presynaptic reuptake.

2.3.3.5. Other possible deficiency symptoms¶

• Vitamin B6
• Magnesium
• Iodine

2.3.4. Migraine (women: 18 %, men 6 %)¶

Prevalence women 18 %, men 6 %
The overall symptom picture usually differs significantly from ADHD and is hardly permanent.

2.3.5. Substance abuse (illegal drugs: 10 %, nicotine: 16.6 to 25.5 %)¶

Among adults with ADHD, the prevalence of substance abuse is 33.5%.³⁹ The risk of substance abuse among adults with ADHD in the USA is 1.7 to 7.9 times higher.⁴⁰

If, in addition to ADHD, aggressive and oppositional defiant behavior and low self-esteem are also present, the probability of substance abuse is significantly increased, while no more frequent substance abuse was found in adolescent ADHD sufferers without these additional symptoms.⁴⁵⁴⁶

In our estimation, substance abuse is much more likely to be a consequence of ADHD than the cause of a full ADHD symptom picture. In rarer cases, it is comorbid. Treatment with stimulants very often eliminates the addictive tendency in ADHD. Modern dosage forms of stimulant medications are hardly suitable for abuse as a drug (e.g. Elvanse: prodrug of amphetamine bound to lysine, which is only very slowly converted to the active ingredient in the intestine).

In the Continuous Performance Test, ADHD sufferers showed more responses to correct timing compared to substance misuse sufferers.⁴⁷

2.3.6. Addiction / dependency (alcohol: 5%, gambling: 0.31%)¶

Prevalence: Found in 24.9% of adults with ADHD.¹⁴

Alcohol:⁴³

• Dependence
  • Men 4.8 %
  • Women 2 %
• Abuse
  • Men 4.6 %
  • Women 1.5 %

In Berlin, 5.0% of respondents aged 15 to 64 met the criteria for alcohol dependence according to DSM-IV (men: 6.4%, women: 3.5%).⁴⁸

In Germany, the prevalence of gambling addiction is 0.31% and the prevalence of problematic gambling behavior is 0.56%.⁴⁹

In the case of comorbidity of ADHD and addiction, there is an increased probability that ADHD is the causal cause of the addiction and not addiction the cause of ADHD. This was shown at least for smoking, cannabis and probably also alcohol.⁵⁰

One study found that increased polygenic risk scores (PRS) for ADHD also increased the likelihood of addiction by 20%. There were no differences with regard to the intensity of the addiction (use, abuse, dependence) or the type of addictive substance (alcohol, cannabis, other illegal drugs). Conversely, the ADHD-PRS explained only 0.2% of the probability of addiction compared to other risk factors.⁵¹

One study showed an ADHD prevalence of 16.7% in severely addicted people compared to 2.5% in the control group.⁵²
Even more significant was the fact that 53% of severe addicts had socially disturbed behavior in childhood or adolescence (up to 15 years), as measured by the SKID-II (control subjects with 2.5%).⁵³ An earlier disorder of social behavior (OR = 35.1) compared to childhood hyperkinetic behavior (OR = 5.7) is by far the greater risk factor for severe addiction.⁵⁴
This indicates to us that addiction plays a role predominantly in ADHD-HI and less in ADHD-I.
The preference for addictive substances indicates a more frequent use of cannabis products among people with (former) hyperkinetic behavior. There appears to be no significant difference for opiates, cocaine, amphetamines, sedatives and hallucinogens.⁵⁵
Although a joint occurrence of hyperkinetic and socially disturbed behavior is associated with an early first use of illegal drugs, statistically only an earlier and increased use of nicotine could be proven.⁵⁶
Long-term abuse of dopaminergic drugs (cocaine, amphetamines) leads to prolonged downregulation of dopamine levels. Withdrawal symptoms then correspond to ADHD symptoms. ⁵⁷ Against this background, the question arises as to whether ADHD medications (stimulants), which are known to have no intoxicating effect, could be helpful in the withdrawal of dopaminergic drugs.
ADHD sufferers with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants.⁵⁸

Common symptoms of addiction / substance abuse and ADHD:²⁴

• Impulsiveness
• (Inner) restlessness, motor hyperactivity
• Concentration problems
• High flow of speech (logorrhea, polyphrasia)

ADHD symptoms that are atypical for addiction / substance abuse:

• Chasing thoughts, circling thoughts
• Attention problems
• Dysphoria with inactivity
• Mood swings

Symptoms of addiction / substance abuse that are atypical for ADHD:

• Substance abuse:
  • Excessive consumption of a substance, even if there are serious consequences
• Addiction / dependence:
  • Excessive consumption to the point of dependence on the drug
  • Very difficult to stop

2.3.7. Thyroid problems (cumulative 7 to 14 % in women, 2.75 to 3.5 % in men)¶

See also the guidelines of the ADHD Working Group of Pediatricians and Adolescent Doctors, as of 2014.¹¹

2.3.7.1. Hyperthyroidism (women 1 - 2 %, men 0.25 - 0.5 %)¶

Prevalence: 1-2 % in women, 0.25 - 0.5 % in men⁵⁹⁶⁰¹⁷

ADHD-like symptoms can be:⁶¹

• Nervousness
• Aggression
• Irritability
• Increased anxiety up to and including fearfulness
• (Extreme) jumpiness
• Difficulty to relax
• Sleep disorders
• Hyperactivity⁶²

Other symptoms that are not typical of ADHD can include⁶¹

• Sweating
• Palpitations
• Atrial fibrillation
• (Severe) tremor
• Diarrhea
• Severe weight loss
• Tiredness
• Weakness
• Additionally occurring psychosis
• High blood pressure⁶²
• Oily skin⁶²
• Hyperventilation⁶²
• Cravings⁶²
• TSH low, fT3 high, fT4 high

2.3.7.2. Underactive thyroid / hypothyroidism (from 60 years approx. 2 %)¶

From the age of 60, around 2% of the population are affected by hypothyroidism.¹⁷

ADHD-like symptoms can result from hypothyroidism⁶³
Hypothyroidism becomes more common with increasing age (usually the result of Hashimoto’s autoimmune thyroiditis).

Hypothyroidism often develops slowly, which is why symptoms are difficult to recognize.

Healthy 4-year-old children with thyroid-stimulating hormone levels in the upper normal range have a higher risk of ADHD than children with low free thyroxine levels. Thyroid disorders are more common in women than in men. As there is a possible association with thyroid hormone receptor insensitivity in ADHD (see below), the role of thyroid hormones in the development and manifestation of ADHD in women and girls should be investigated in more detail.⁶⁴

Symptoms of an underactive thyroid can include⁶²

• Constipation
• Weight gain
• Blemished skin
• Freeze
• Lack of drive
• Weepiness
• Increased need for sleep
• Low blood pressure
• Difficult breathing
• Loss of appetite
• TSH high, fT3 low, fT4 low

Hyperthyroidism does not preclude treatment with methylphenidate, but requires particular caution, especially strict monitoring of thyroid levels, pulse and blood pressure.

2.3.7.3. Hashimoto’s thyroiditis (women 4.5 - 9.5 %, men 0.5 - 1 %)¶

Hashimoto’s (Hashimoto’s lymphomatous goiter) is an autoimmune disorder that causes hypothyroidism⁶³
The prevalence of Hashimoto’s in Germany is around 5 to 10 %. Prevalence and incidence increase with age. Women in the 3rd-5th decade of life are affected around 10 to 20 times more frequently than men.⁶⁵

ADHD-like symptoms can be:⁶¹

• Depressive moods
  • Apathy
  • Rapid exhaustion
  • Concentration disorders.

Other symptoms that are not typical of ADHD can include⁶¹

• Tiredness
  • In extreme cases: delusions / suicidal thoughts
  • Weight gain
  • Slowed heartbeat
  • Slowed reflexes
  • Decreased libido.

It is reported that adrenal insufficiency (reduced cortisol production by the adrenal gland) often leads to thyroid insufficiency. Treatment of the thyroid gland with thyroxine then increases the cortisol demand on the adrenal gland. However, if the adrenal gland is already so weakened that the increased cortisol production completely overwhelms it, this can result in a collapse of the adrenal gland, which reduces cortisol production even further, which is why the adrenal gland should be considered and treated before thyroxine treatment.⁶⁶

An attenuated cortisol stress response is often present in ADHD-HI. *⇒ Cortisol and other stress hormones in ADHD *This could be a sign of mild adrenal insufficiency. However, this is often likely to be caused by pituitary weakness due to CRH receptor downregulation. To differentiate from adrenal insufficiency, see ⇒ Hypocortisolism (adrenal cortical insufficiency) In this article.
However, a collapse of the adrenal gland due to therapy with thyroxine is not typically reported in ADHD.

2.3.7.4. Thyroid hormone resistance (RTH) / thyroid hormone action defect (THAD)¶

The β-thyroid receptors (TRβ) in the pituitary gland control the down-regulation of thyroid-stimulating hormone (TSH), which leads to reduced production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

Thyroid hormone resistance (RTH) / thyroid hormone action deficiency (THAD) is an overall rare, hereditary syndrome, but the most common syndrome with reduced sensitivity to thyroid hormones.⁶⁷
Mutations in the β gene of the thyroid receptor (Thrb, formerly just called RTH) can impair the receptors’ ability to bind T3⁶⁸
There is an imbalance between

• the resistance of tissues that predominantly express thyroid hormone receptor β isoforms 1 and 2 and
• overstimulation of tissues that mainly express the thyroid hormone receptor α isoform
  In functional receptors, the mutant receptors form homo- and heterodimers that lack the ability to act on genomic response elements. The result of this dominant negative effect is that TSH is not downregulated (thyroid hormone resistance (RTH)).

THRB mutation thyroid hormone resistance has the following typical symptoms:

• normal⁶⁹⁷⁰ or elevated levels of triiodothyronine/free thyroxine and non-suppressed thyroid-stimulating hormone⁶⁷⁷⁰
• Sinus tachycardia⁶⁷⁷¹ at rest⁷⁰
• Short stature⁷⁰
• Osteoporosis⁷⁰
• Hearing loss
• Goitre⁷¹⁶⁹ or goitre (enlargement of the thyroid gland)⁶⁷
• ADHD⁶⁷⁶⁹
  • in 70 % of children with thyroid hormone resistance⁷²
  • entire spectrum of ADHD symptoms
  • Foggy Brain⁶⁹
  • suggests that mechanisms downstream of the TRβ receptor may be responsible for the manifestation of behavioral phenotypes in both disorders

THRA mutation thyroid hormone resistance has the following typical symptoms:⁶⁷

• mental retardation of varying degrees
• Short stature with reduced subischial leg length
• chronic constipation
• Bradycardia

2.3.8. Restless legs syndrome (children 2 %, adults 5 to 10 %)¶

Prevalence:⁷³

• Children 2 %
• Adults 5 - 10 %

Restless legs correlates with ADHD symptoms.¹⁷¹⁸
Intensive sugar consumption can cause twitching in the limbs (especially in the legs) - especially in people who do not tolerate sugar well - which is similar to a mild form of restless legs and can make it difficult to fall asleep.

A lower frequency of D4.7R is suspected in restless legs, while this gene variant is more common in ADHD.⁷⁴

In restless legs, treatment with L-dopa is often helpful in the short term, but can be detrimental in the long term.
Treatment with D4 agonists is also being discussed⁷⁴

2.3.9. Prenatal damage due to alcohol, FAS (0.8 to 8.2 %)¶

Other names: Fetal alcohol syndrome, embryofetal alcohol syndrome, alcohol effects, FAE, FAS, FASD, alcohol embryopathy

Prevalence: 0.8 to 8.2 % of all births, with around 10 % of all cases developing full symptoms.⁷⁶ Long-term studies of children with FAS (fetal alcohol syndrome) found ADHD in 47.2 %⁷⁷, 67.6 %⁷⁸ or 70 %⁷⁹.

Around 15 to 30% of all mothers continue to drink alcohol during pregnancy.⁷⁶ The risk to the unborn child is considerable.
This problem is also considered a possible cause of ADHD.⁸⁰ The risk of ADHD among FAE/FAS sufferers was 10 times higher.⁸¹

2.3.10. Seizure disorders (epilepsy: 0.5 to 1 %)¶

The prevalence of epilepsy is 0.5 to 1 %.⁸³

Source¹¹

• Pyknolepsy¹⁷
• Seizure disorder with absences or complex partial seizures¹⁷¹⁸
• Epilepsy-related seizures (absences)⁸

2.3.11. Hydrocephalus (0.4 - 0.8 %; from 65 years 3 %)¶

Prevalence: 0.4 - 0.8 %, > 65 years: approx. 3 %⁸⁴

Children with hydrocephalus have an almost threefold risk of ADHD.⁸⁵
In old age, hydrocephalus often occurs comorbidly with Alzheimer’s disease and vascular dementia.

2.3.12. Histamine intolerance, histamine intolerance (1 %, of which 80 % adults)¶

The prevalence of histamine intolerance is given as 1%. However, 80% of those affected are said to be adults.⁸⁶
The main physical symptoms of histamine intolerance are⁸⁷⁸⁸⁸⁹

• Psychological symptoms
  • Depression
  • depressive moods
  • Winter depression
  • Mood swings
  • States of exhaustion
  • increased sensitivity (acoustic, visual, tactile, temperature, emotional, etc.)
  • Sleep disorders, wakefulness
  • Tension, restlessness, agitation, arousal, nervousness, overexcitement

• Nervous system
  • Headache, cluster headache
  • Migraine
  • Dizziness (vertigo), seasickness, motion sickness

• Muscle tension

• Endocrine system
  • Menstrual cramps: Period pain, menstrual pain, dysmenorrhea
  • Increased PMS symptoms
• Digestive tract, gastrointestinal tract
  • Diarrhea (diarrhea, soft stools, diarrhea), indigestion
  • Abdominal cramps, stomach pain
  • Flatulence, meteorism, bloating, intestinal winds, flatulence
  • Recurrent cystitis
  • Nausea, nausea
  • Vomiting, vomitus
• Cardiovascular system
  • Palpitations (synonyms: rapid heartbeat, tachycardia), up to and including panic attacks
  • Low blood pressure, sudden drop in blood pressure (hypotension, drop in blood pressure)]
  • Additional heartbeats (extra beats, extrasystoles)
  • Cardiac arrhythmia, heart stumbling, arrhythmias, heart problems
  • Palpitations, palpitations
• Skin, mucous membranes, respiratory tract
  • Stuffy or runny nose (synonyms: blocked nose, runny nose, runny nose, rhinorrhea, non-allergic rhinitis, runny nose, nasal obstruction)
  • Sneezing, sneezing irritation
  • Narrowing of the airways (synonyms: Bronchoconstriction, bronchoconstriction, bronchial constriction and bronchial obstruction): e.g. shortness of breath (breathlessness, dyspnea), asthma, bronchospasm
  • Flushing, red face, flush
  • Itching, pruritus, scratching
  • Erythema, reddening of the skin
  • Hives, hives, urticaria, urticaria, urticarial exanthema
  • Edema, water retention, swelling of the eyelids
  • Conjunctivitis, inflammation of the conjunctiva of the eye, eye inflammation

2.3.13. Prolactinomas (0.02 - 0.05 %)¶

Prevalence: 30 to 50 / 100000 (0.02 to 0.05 %)

Prolactinomas are prolactin-secreting (benign) tumors
⇒ ADHD neurotransmitters - messenger substances

2.3.14. Phenylketonuria (PKU) (0.0125 %)¶

Other names; Følling’s disease, Fölling’s disease, phenylpyruvic acid oligophrenia, oligophrenia phenylpyruvica, hyperphenylalaninemia
Prevalence; 1 / 8,000 (0.0125 %)

People with phenylketonuria often show symptoms of ADHD, although the subtypes with hyperactivity seem to predominate.^9091929394

Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations in the phenylalanine hydroxylase gene.) PKU leads to a significant excess of phenylalanine (hyperphenylalaninemia). As phenylalanine and tyrosine pass through the blood-brain barrier via the same transporters, and these transporters have a higher affinity for phenylalanine, too little tyrosine reaches the brain if there is an excess of phenylalanine in the blood. Tyrosine is a precursor for dopamine, from which noradrenaline and adrenaline are further produced. Excess phenylalanine in the blood therefore leads to a lack of dopamine, noradrenaline and adrenaline in the brain.⁹⁵In addition, excess phenylalanine causes changes in cerebral myelin and protein synthesis as well as reduced levels of serotonin in the brain.⁹⁶ ADHD and phenylketonuria therefore have a dopamine deficiency in common ^{92 9798}

Treatment with sapropterin improved ADHD symptoms in a pharma-funded study in phenylketunorie.⁹⁹ A study suggests that treatment with BH4, which is helpful for PKU, should also be used for ADHD⁹⁸

2.3.15. Consequences of severe brain infections (cumulative 0.05% to 0.16%)¶

Sources⁸¹⁰⁰¹⁸

2.3.15.1. Encephalitis (cumulative 0.03 %)¶

Prevalence:¹⁰¹
Autoimmune encephalitis 13.7/100,000 (0.0137 %)
infectious encephalitis 11.6/100,000 (0.0116 %)
viral encephalitis 8.3/100,000 (0.0083 %)

Brain infection with inflammatory changes caused by invading microorganisms.
Encephalitis destroys the cells in the substantia nigra that produce dopamine.
Those affected by the encephalitis epidemic of 1914 to 1917 showed typical symptoms of ADHD as the disease progressed. Children developed hyperactive motor skills, adults Parkinson’s symptoms.
The symptoms are the result of the dopamine deficiency that characterizes ADHD. These symptoms have been reproduced in animal experiments as a result of impaired dopamine production.¹⁰²

See also Viral infections as a cause of ADHD in the article Age-independent physical stress as an environmental cause of ADHD in the chapter Development.

2.3.15.2. Perinatal hypoxemia (0.001 to 0.009 %)¶

Prevalence: 1 to 9 / 100,000 (0.001 to 0.009 %)((Hypoxic-ischemic encephalopathy (HIE), Orpha.net))

Oxygen deprivation during birth is one of the main causes of early childhood brain damage (ECBD).
In animal experiments, led to the death of dopamine-producing cells in the substantia nigra and thus to a decrease in dopamine levels of up to 70 %.¹⁰³
Hypoxemia is associated with excess adenosine. Adenosine inhibits dopamine.

2.3.15.3. Bacterial infections (cumulative 0.01% in women, 0.12% in men)¶

• Meningitis: inflammation of the meninges
  • Prevalence: 0.5 / 100,000 (0.0005 %)¹⁰⁴
• Brain abscesses: 0.3-1.3 /100,000 per year (0.0003% to 0.0013%)
  • Local infection of the brain tissue. Begins as focal encephalitis (cerebral phlegmon, “cerebritis”). Gradually develops into a collection of pus with a connective tissue capsule
• Syphilis (prevalence 11.5 / 100,000 (0.115 %) in men, 0.9/100,000 (0.009 %) in women)

2.3.16. Neurofibromatosis type 1 (0.029 %)¶

Other names: Von Recklinghausen’s disease, Recklinghausen’s disease, neurofibromatosis Recklinghausen, peripheral neurofibromatosis
With a prevalence of around 1:3500 (0.029 %), it is one of the most common hereditary neurological diseases. Neurofibromatosis type 1 shows malformations of the skin and the central nervous system. Neurofibromatoses are nerve tumors.

Among 128 neurofibromatosis type 1 patients (53.1 % girls), 28.9 % (37/128) were found to have ADHD, including 20 ADHD-C, 15 ADHD-I and 2 ADHD-HI.
Other comorbidities of neurofibromatosis type 1 were macrocephaly (head circumference more than 2 SDs above the age average, 37.5 %), headache (18.6 %), cognitive impairment (7.8 %), motor deficits (6.2 %) and epilepsy (4.68 %). MRI revealed T2-weighted hyperintensities in the basal ganglia and/or cerebellum (70.5 %), optic nerve gliomas (25.8 %), plexiform neurofibromas (9.3 %), Chiari malformation type 1 (6.7 %), arachnoid cysts (5 %), gliomas of the central nervous system (3.1 %).¹⁰⁵

Diagnostic criteria - at least 2 of the following symptoms:¹⁰⁶

• Six or more café-au-lait spots (CAL) > 5 mm in diameter prepubertal and > 15 mm postpubertal.
• Freckling in the armpit or groin region.
• Two or more neurofibromas of any type or one plexiform neurofibroma (PNF)
• Glioma of the visual pathway
• Two or more iris nodules identified by slit lamp examination or two or more choroidal abnormalities (CAs) detected as irregular bright nodules by optical coherence tomography (OCT) or near infrared imaging (NIR imaging).
• Specific bony lesions such as sphenoid dysplasia, anterolateral bowing of the tibia or pseudarthrosis of the long tubular bones.
• A heterozygous pathogenic (= disease-causing) NF1 variant with an allele frequency of 50 % in normal tissue such as leukocytes.

2.3.17. Velocardiofacial syndrome (22q11DS) (0.01 to 0.05 %)¶

Other names: CATCH 22, Cayler cardiofacial syndrome, Di George syndrome, DiGeorge sequence, microdeletion 22q11.2, monosomy 22q11, Sedlackova syndrome, Sphrintzen syndrome, syndrome of conotruncal anomaly with facial dysmorphia, Takao syndrome

22q11.2 deletion syndrome (DS)¹⁰⁷

The prevalence of velocardiofacial syndrome is 1 - 5 / 10,000 (0.01 to 0.05 %)¹⁰⁸

2.3.18. Cortisol disorders (cumulative 0.0042 to 0.0048 %)¶

2.3.18.1. Hypocortisolism (adrenal insufficiency) (0.004 %)¶

Sources:¹⁰⁹¹¹⁰

Addison’s disease: Prevalence: 4/100,000 (0.004 %).
Weaker forms are much more common.

Since the basal cortisol level is slightly reduced in ADHD (in ADHD-HI as in ADHD-I), ADHD could be described as very weak adrenal insufficiency (adrenal insufficiency).

2.3.18.2. Hypercortisolism (Cushing’s syndrome) (0.0002 to 0.0008 %)¶

Prevalence: 8/1,000,000 in men (0.0008%), 2/1,000,000 in women (0.0002%)¹¹¹

• ACTH-dependent form (80% of cases)
  • Micro- or macroadenoma of the anterior pituitary gland produces ACTH (= Cushing’s disease)
  • (mostly malignant) tumors outside the pituitary gland (often bronchial carcinomas) as the cause of ectopic ACTH production
• ACTH-independent form (20% of cases)
  Overproduction of glucocorticoids (cortisol) and mineralocorticoids by the adrenal cortex
  • Adrenal cortical adenoma (pure cortisol overproduction)
  • Adrenal carcinoma (increased cortisol and androgen production)
  • Nodular hyperplasia of the adrenal cortex

2.3.19. Moyamoya (0.0001 % to 0.0009 %)¶

Moyamoya is particularly common in Japan.
Prevalence
Worldwide: 1 / 1,000,000 to 9 / 1,000,000 (0.0001 % to 0.0009 %)¹¹²
Japan: 1 / 30,000 to 1 / 9,500 (0.0033 % to 0.0105 %)
Incidence Japan: 1 / 280,000 to 1 / 89,000

Moyamoya is a narrowing or occlusion of cerebral arteries that leads to relative anemia (stroke and transient ischemic attack) in the brain. Many small compensatory vessels form as bypass circuits.
Moyamoya can be accompanied by symptoms that can be confused with ADHD.¹¹³

2.3.20. Hamartoma of the hypothalamus (0.0005 %)¶

Prevalence: 1 / 200,000 (0.0005 %)¹¹⁴

A hamartoma is a tumor-like, benign tissue change due to incorrectly differentiated or dispersed germinal tissue. A hypothalamic hamartoma can produce a variety of hormones and cause ADHD symptoms, conduct disorder, oppositional defiant disorder, antisocial behavior, tantrums, intellectual regression, cognitive disorders, premature puberty, obesity and epilepsy. 60 % of those affected by a hypothalamic hamartoma develop externalizing disorders (especially in boys and in epilepsy), 30 % develop internalizing disorders.¹¹⁵¹¹⁶ MPH can significantly improve ADHD caused by a hypothalamic hamartoma, as can treatment with a gonadotropin-releasing hormone (GnRH) analog.¹¹⁷ In severe cases, stereotactic laser surgery may be helpful.¹¹⁸

2.3.21. Allergies (with motor restlessness)¶

Source¹⁷

2.3.22. Visual and hearing impairment¶

Sources¹¹¹⁷

2.3.23. Lesions of the left cerebral hemisphere / right PFC¶

• Attention selection impairs¹¹⁹
  • E.g. in situations that require quick decisions between relevant and irrelevant stimuli
  • Frequently increased number of errors in choice-response tasks or extended response times

Lesions of the OFC have been known since the case of Phineas Gage (Harlow 1848) and are associated with specific symptoms:¹²⁰

• often dramatic changes in personality
• impulsive
  • often reckless, risky behavior
  • frequent conflicts with the law
  • disinhibited in terms of instinctive behaviors
  • Problems with drive control
• irritable
• quarrelsome
• Tendency to crude humor
• Disregard for social and moral principles
• severe attention deficit disorder
  • strong distractibility due to external or internal stimuli

The OFC normally has inhibitory functions. These take place via efferents to:¹²⁰

• Hypothalamus
• Basal ganglia
• other neocortical areas, e.g. in the PFC

Patients with lesions of the right frontal cortex often show ADHD-like behavior.¹²¹

2.3.24. Organic brain damage¶

Source¹⁷

2.3.25. Status epilepticus during sleep (ESES)¶

Other names: Bioelectric status epilepticus during sleep, CSWS, CSWS syndrome, ESES syndrome, Epileptic encephalopathy with continuous spike-wave discharges during slow-wave sleep
Prevalence: unknown. Orphane disorder (rare).¹²²

Epilepsy with continuous spike-wave discharges during sleep (CSWS) is a rare epileptic encephalopathy in children. It is characterized by seizures, electroencephalographic patterns of status epilepticus during sleep (ESES) and cognitive developmental regression.¹²³

ESES is associated with ADHD-like symptoms. In one study, treatment with ACTH reduced ADHD symptoms by an average of 67%.¹²⁴ Another study by the same authors found similar improvements with ACTH in ADHD and stuttering.¹²⁵

2.3.26. Traumatic or space-occupying cerebral disorders / other psycho-organic syndromes with cerebral damage and/or psycho-mental retardation¶

Source¹¹

2.3.27. Bachmann-Bupp syndrome (BABS)¶

Bachmann-Bupp syndrome (BABS) is characterized by¹²⁶

• pronounced alopecia
• global developmental delay in the moderate to severe range
• Hypotension
• non-specific dysmorphic features
• Behavioral problems
  • ASS
  • ADHD
• Feeding problems
• Hair
  • usually present at birth
  • can be sparse
  • may have unexpected color
  • falls out in large clusters in the first weeks of life
• Seizures at the beginning of later childhood (rare)
• Conductive hearing loss (rare)

Abnormal metabolites of polyamine metabolism (including elevated levels of N-acetylputrescine) indicates BABS.
Diagnosis by molecular genetic testing for heterozygous pathogenic de novo variants of the ODC1 gene.

2.3.28. CAPRIN1 haploinsufficiency¶

Haploinsufficiency of the CAPRIN1 gene is an autosomal dominant disorder associated with loss-of-function variants in cell cycle-associated protein 1 (CAPRIN1).
The CAPRIN1 protein regulates the transport and translation of neuronal mRNAs that are crucial for synaptic plasticity, as well as mRNAs encoding proteins that are important for cell proliferation and migration in different cell types.
CAPRIN1 variants with loss of function were associated with the following symptoms:¹²⁷

• Speech impediment/speech delay (100 %)
• mental disability (83 %)
• ADHD (82 %)
• ASS (67 %)
• Respiratory problems (50 %)
• Anomalies of the limbs and skeleton (50%)
• Developmental delays (42%)
• Feeding problems (33 %)
• Seizures (33 %)
• Eye problems (33 %)

2.3.29. KBG syndrome¶

KBG is a rare monegenetic syndrome. Genetic variants in ankyrin repeat domain 11 (ANKRD11) and deletions in 16q24.3 can cause KBG syndrome. In a group of 25 patients with KBG, 24% were diagnosed with ADHD((Guo L, Park J, Yi E, Marchi, Hsieh, Kibalnyk, Moreno-Sáez, Biskup, Puk, Beger, Li Q, Wang K, Voronova, Krawitz, Lyon (2022): KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients. Eur J Hum Genet. 2022 Aug 15. doi: 10.1038/s41431-022-01171-1. Epub ahead of print. PMID: 35970914. n = 25
KBG goes hand in hand with:

• Macrodontia
• pronounced craniofacial features
• Short stature
• Skeletal anomalies
• global developmental delay
• Seizures
• mental disability

2.3.30. Cystic fibrosis¶

Cystic fibrosis is associated with increased ADHD symptoms.¹²⁸ The reported prevalence rates of ADHD in pwCF ranged from 5.26% to 21.9%.¹²⁹

Cystic fibrosis correlates with mutations in the CFTR gene¹³⁰, which has been identified as a gene candidate for ADHD.¹³¹

2.4. Side effects of medication¶

Significant effects usually only with long-term therapy.

Examples:

• Anticonvulsants
  e.g.:
  • Valproate¹¹
  • Phenobarbital⁵⁹¹³²
• Beta-mimetics¹¹
• Drug-induced Hypovitaminosis of the B vitamins
  Vitamin B-12 deficiency causes ADHD-like symptoms
• Neuroleptics^17133134
• Benzodiazepines^17133134
  Benzodiazepines reduce the activity of the locus coeruleus and thus reduce the transport of noradrenaline to other parts of the brain.¹³⁵ The disruption of noradrenaline production in the locus coeruleus is also typical of ADHD.
• Antihistamines^17133134
• Antiepileptic drugs¹³³¹³⁴
• Isoniazid¹⁷¹³⁴
• Bronchiospasmolytics¹³³¹³⁴
• Isoniazid¹³³¹³⁴
• Selective serotonin reuptake inhibitors (SSRIs)
  SSRIs (namely citalopram and escitalopram) are suspected of increasing the effect of dopamine reuptake transporters.¹³⁶. Overactive dopamine reuptake transporters are a possible cause of the dopamine deficiency that triggers ADHD symptoms (especially in the striatum) by reabsorbing the presynaptically released dopamine before it has had a chance to exert its communication effect at the postsynapse. ⇒ ADHD - Neurotransmitters - Messenger substances

2.5. Mental and psychiatric disorders¶

2.5.1. Anxiety disorders (annual prevalence: 22.9% (women), 9.7% (men))¶

Prevalence: 22.9% of all women, 9.7% of all men within one year.²¹¹
Prevalence in girls under 18: 7.85%.¹³⁷
Anxiety disorders are comorbid in 25% of ADHD sufferers,¹³⁸ 16.7% of children with ADHD and 27.2% of adults with ADHD.¹⁴ Other sources cite 15% to 35%¹³⁹ and 35.6% of adults in England in 2007.¹⁴⁰

Performance anxiety is particularly common.¹⁴¹

Common symptoms of anxiety disorders and ADHD:²⁴

• Inner restlessness
• Concentration problems
• Attention reduced
• Mood swings
• Sleep problems

ADHD symptoms that are atypical for anxiety disorders:

• High flow of speech (logorrhea, polyphrasia)
• Chasing thoughts, circling thoughts
• Impulsivity (atypical for ADHD-I)
• Impaired executive function¹⁴²

Symptoms of anxiety disorders that are atypical for ADHD:

• Fatigue
• Muscle tension

Anxiety in ADHD may partially reduce impulsivity and response inhibition deficits, exacerbate working memory deficits, and appear to be qualitatively different from pure anxiety. Comorbid anxiety in ADHD appears to have different forms of expression:¹³⁹¹⁴³

• Seem increased
  • Negative affect
  • Mood disorders
  • Disruptive social behavior
  • Attention problems
  • School phobia
• Seem reduced
  • Anxious / phobic behavior
  • Social competence

2.5.1.1. Panic disorder (3.2 to 3.6 %)¶

Prevalence of panic disorder: 3.2% to 3.6%¹⁴⁴

2.5.1.2. Generalized anxiety disorder (1.9 to 31.1 %)¶

Prevalence of generalized anxiety disorder: 1.9% to 31.1%¹⁴⁴

2.5.2. Excretory disorders (enuresis, defecation) (children: 18.5 %)¶

18.5% of children with ADHD are affected.¹⁴

2.5.3. Affective disorders (10 to 17 %)¶

Prevalence:
Lifetime: 10 % to 17 %¹⁴⁵
under the age of 18: Girls 2.54 %, boys 1.10 %.¹⁴⁶

Affective disorders are described in 27.9% of children with ADHD and 57.9% of adults with ADHD¹⁴. Furthermore, a prevalence of 37.1 % for mood instability and 29.9 % for depression in adults in England in 2007 is cited.¹⁴⁷

2.5.3.1. Depression (10 % (men) 20 % (women))¶

Depression must be distinguished from mere dysphoria with inactivity, which is a typical symptom of ADHD and does not constitute depression. Treatment with antidepressants would be inappropriate here.
Detailed information on this can be found at ⇒ Depression and dysphoria in ADHD In this chapter.

12% to 50% of children with ADHD also suffer from depression, which is five times more common than in children without ADHD.¹³⁹ A study of young adults with depression reports a lifetime prevalence of ADHD of 25.9%,¹⁴⁸ which is also around five times higher.
The lifetime prevalence of major depression is 15 %¹⁴⁹; women are affected twice as often as men, i.e. women 20 %, men 10 %.

In children with ADHD, emotional dysregulation occurs before comorbid depression.¹⁵⁰¹⁵¹ This is not surprising, as emotional dysregulation is an original ADHD symptom, while depression can occur as a comorbid disorder. Nevertheless, the degree of emotional dysregulation in children with ADHD appears to moderate the likelihood of later depression.¹⁵²

Common symptoms of depression and ADHD:²⁴

• Inner restlessness (typical in atypical depression, less so in melancholic depression)
• Concentration problems
• Attention problems¹⁵³
• Memory problems¹⁵³
• Sleep problems
• Daytime sleepiness (typical in atypical depression, atypical in melancholic depression, possible in ADHD)
• Negative self-image¹⁴¹

ADHD symptoms that are atypical for depression:

• Rapid mood swings
• Dysphoria only during inactivity
• High flow of speech (logorrhea, polyphrasia)
• Chasing thoughts, circling thoughts
• Impulsivity (atypical for ADHD-I, atypical for melancholic depression)
• Problems with cognitive control¹⁵⁴

Symptoms of depression that are atypical for ADHD:

• Permanent depressive mood (even with things that are actually interesting)
• Low mood in the morning (melancholic depression)
• Low mood in the evening (atypical depression)
• Weight loss (in ADHD at most as a side effect of stimulants)
• Reduced interest in activities (in ADHD more likely withdrawal due to increased sensitivity or social phobia)
• Suicidal thoughts
• Low desire for rewards¹⁵⁴

In ADHD sufferers, depression typically occurs years after the onset of ADHD symptoms.¹⁵⁵ In this case, in addition to the existing depression, the underlying ADHD, which is often the cause of the depression, must also be treated. Otherwise, the depression would merely be treating a secondary symptom of ADHD.^156155143
Around 34% of all treatment-resistant depression is caused by previously unrecognized ADHD.

2.5.3.2. Bipolar disorder (annual prevalence: 3.1 % (women), 2.8 % (men))¶

Prevalence: 3.1 % of all women, 2.8 % of all men within one year²

Bipolar disorder is characterized in particular by an alternation between depressive and manic symptoms. The changes can occur at different speeds. There is not always a change to a full-blown manic episode.

ADHD occurs more frequently than average in people with bipolar disorder, although the co-morbidity with ADHD is probably weaker than in relation to other mental disorders.¹³⁹ The prevalence of ADHD in people with bipolar disorder differs according to the age at which the bipolar disorder first occurs¹⁵⁷

• Childhood: 80 to 95% have comorbid ADHD
• Youth: approx. 50 % have comorbid ADHD
• Adulthood: approx. 25 % have comorbid ADHD

In a reaction test study, both ADHD and bipolar sufferers showed a significantly increased variability of slower reactions than controls, while bipolar sufferers showed a significantly increased speed and variability of typical reactions in the flanker task compared to ADHD sufferers and controls.¹⁵⁸

2.5.3.2.1. Depressive episode of bipolar disorder¶

The common and different symptoms of depressive episodes of bipolar disorder and ADHD correspond to those of depression and ADHD.

See above under depression and at ⇒ Depression and dysphoria in ADHD In the section⇒ In-depth description of individual ADHD symptoms in the chapter⇒ Symptoms.

2.5.3.2.2. Manic episode of bipolar disorder¶

Common symptoms of manic episode of bipolar disorder and ADHD:

• Concentration problems²⁴
• Attention problems¹⁵³²⁴
• Memory problems¹⁵³²⁴
• Sleep problems²⁴
• Daytime sleepiness (typical in atypical depression, atypical in melancholic depression, possible in ADHD)²⁴
• Rapid mood swings^{159 24}
• Chasing thoughts, circling thoughts^{159 24}
• Impulsivity (atypical for ADHD-I)¹⁵⁹²⁴
• Problems relaxing (ADHD-HI, bipolar in manic phase)¹⁵⁹
• Regulation of own arousal, inner restlessness, restlessness¹⁵⁹
• Hypersexuality¹⁵⁷

ADHD symptoms that are atypical for manic episodes:

• Dysphoria only during inactivity

Symptoms of bipolar that are atypical for ADHD:

• Alternation between depressive and manic phases

In ADHD, mood swings tend to be triggered (reactive) and disappear quickly when distracted, whereas bipolar manic phases tend to be more continuous and long-lasting.¹⁶⁰

2.5.3.3. Cyclothymia (13 %)¶

Cyclothymia (cyclothymia) is a rapid change of moods without reaching the intensity of the symptoms of bipolar disorder. Cyclothymia has a prevalence of 13% in the general population.

Cyclothymia has been found in 75% of all bipolar patients and is significantly higher in ADHD and depression.¹⁶¹

2.5.4. Circumscribed developmental disorders (partial performance disorders) according to ICD-10 (approx. 10 to 15 % (?))¶

Partial performance disorders are said to be a common comorbidity (especially in the ADHD-I subtype without hyperactivity).
Dyspraxia, on the other hand, is a purely motor development disorder that tends to be confused with ADHD-HI (without inattention).

2.5.4.1. Dyspraxia (5 to 6 %)¶

Prevalence 5 to 6 %¹⁶²¹⁶³

Dyspraxia is also known as “clumsy child syndrome” or “clumsy child syndrome”.
Dyspraxia is a developmental disorder that lasts a lifetime.
Dyspraxia is very often comorbid with ADHD or ASD.
Children with dyspraxia show no deviations in intelligence.

There are different forms of dyspraxia.

2.5.4.1.1. Motor dyspraxia / circumscribed developmental disorder of motor functions (UEMF)¶

Problems with:

• Motor deceleration
• Balance problems
  • Impaired gait
  • Difficulty getting dressed while standing
• Clumsiness in complex movements that require balance and dexterity¹⁶⁴
  • Catch ball
  • Bounce
  • Jump
  • Climb
  • Cycling
  • Swim
  • Couple dance
• Impaired automation of fine motor and gross motor activities
  • Impaired handwriting
    • Difficulty guiding the pen with the correct pressure
    • Problems adhering to the boundaries of the sheet.
    • Writing on the computer goes much better
  • Problems tying shoelaces or bows
  • Problems closing buttons
  • Difficulty eating with a knife and fork
  • Problems cutting out a figure cleanly
  • Frequent dropping of things
  • Problems with careful handling of glasses or crockery
  • Difficulties when pouring into glasses
  • Problems with crafting or wrapping gifts
• Difficulty in acquiring new motor skills
• Impaired eye-hand coordination
• Frequent confusion between right and left
• Problems with the order of the garments when putting them on
• Rapid fatigue during physical activity
  • Sport
  • Hiking
  • Physically active play
• Easily distracted during tasks
  • Too much information on one sheet can be confusing
  • Improved task performance with larger line spacing, larger font

No problems with:

• Hyperactivity.

2.5.4.1.2. Ideomotor dyspraxia¶

Problems with:¹⁶⁵

• Execution of your own action plan
• Complete actions in full
• Writing difficulties
• Action difficulties
• Execution of understood instructions impaired
• Order is easily mixed up
• Impairment of imaginative or creative play

No problems with:

• Describe movement sequences
• Recognize the mistakes of others
• Read
• Talk

2.5.4.1.3. Ideational dyspraxia¶

Difficulties in planning and describing motor actions, but they have no motor impairment.¹⁶⁵

Problems with:

• Forming series (associated with memory loss)
• Describe sequences of actions
• Read words
• Work quickly
• Keep order

No problems with:

• Imitate individual movement sequences
• Write words

2.5.4.1.4. Verbal dyspraxia¶

Approximately 30% of children with dyspraxia also have a verbal developmental delay = verbal dyspraxia.¹⁶⁶

Verbal dyspraxia is a disorder in the planning of speech motor skills. The speech organs are not impaired (tongue, vocal cords).

• Problems with planning speech movements
• Difficulty pronouncing the right words at the right time in the right order.
• Frequent coughing or choking when eating
  • Sequence of sucking, swallowing and breathing made more difficult
  • High saliva production when switching from porridge to solid meals
• Language development significantly delayed
  • Significantly later start to speak
  • Only a few “babbling sounds” at the beginning
  • Later often vowel language without consonants (“Oaaaa”, “Eeea”).
• Often also problems with gross motor skills (see motor dyspraxia)
  • Stumble
  • Bump into each other, lots of bruises
  • Learning difficulties
    • Read
    • Spell

The risk factors for the development of dyspraxia are still unclear. As with ADHD, environmental influences during pregnancy and birth appear to increase the risk.

2.5.4.2. Developmental coordination disorders¶

The extent to which the concept of developmental coordination disorders differs from that of circumscribed developmental disorders of motor functions and developmental coordination disorder (DCD) is unclear.

There are said to be different subtypes with six main symptom groups:

1. general instability / slight tremor
2. reduced muscle tone
3. increased muscle tone
4. Inability to perform a smooth movement or to combine individual movement elements into an overall movement
5. Inability to form written symbols
6. Difficulties with visual perception associated with the development of the eye muscles

50% of those affected by developmental coordination disorders are also said to have ADHD.

The risk of ADHD is also increased in children aged 4 to 5 years with developmental coordination disorder. However, the DSM-5 scale appears to be less effective here.¹⁶⁷

2.5.4.3. Partial performance disorders¶

The comorbidity of ADHD and learning disorders is reported to be between 10 % and 90 %.¹³⁹
Learning disorders are said to correlate more frequently with ADHD-I than with ADHD-HI.¹⁶⁸ In ADHD sufferers, writing disorders are said to be twice as common as reading, arithmetic or spelling disorders.¹⁶⁹

2.5.4.2.1. Reading and spelling disorder (dyslexia) (5 %)¶

Present in 17.6% of children with ADHD.¹⁴
Dyslexia is said to occur more frequently in ADHD-I than in ADHD-HI.¹⁷⁰

2.5.4.2.2. Calculation disorder (dyscalculia) (5%)¶

Dyscalculia is said to occur more frequently in ADHD-I than in ADHD-HI.¹⁷⁰

2.5.5. Post-traumatic stress disorder (PTSD) (5 % (men), 10 % (women))¶

Prevalence: 10% of all adult women and 5% of all adult men suffer from post-traumatic stress disorder.¹⁷¹⁸
60% of all men and 50% of all women have at least one potentially traumatizing experience in their lives.¹⁷¹
Of these suffer from PTSD:

• Rape victims: 49 %¹⁷²
• Severe beatings or physical assaults: 31.9 %¹⁷²
• Victims of crime: 25 %¹⁷²
• Sexual assault without rape: 23.7%¹⁷²
• Serious accident (car or train): 16,8 %¹⁷²
• Shooting or stabbing: 15.4 %¹⁷²
• Sudden death of a close relative or loved one: 14.3 %¹⁷²
• Childhood life-threatening illness: 10.9%¹⁷²
• Victims of potentially traumatic experiences without crime: 9.4 %¹⁷²
• Witnesses of a murder or violent attack: 7.3 %¹⁷²
• Natural disaster: 3.9 %¹⁷²

Sleep problems are common in both ADHD and PTSD. In PTSD, these often arise in the first 2 weeks after the traumatizing event and are often characterized by persistent nightmares,¹⁷³ which is also not typical for ADHD. In ADHD, on the other hand, the sleep disorders usually persist for life.

The “Posttraumatic Stress Disorder” subscale of the Child Behavior Checklist (PTSD-CBCL) is good at distinguishing PTSD from ADHD.¹⁷⁴

While ADHD is associated with reduced dopamine and noradrenaline levels, excessive noradrenaline release is suspected in PTSDLevy F (2009): Dopamine vs noradrenaline: inverted-U effects and ADHD theories. Aust N Z J Psychiatry. 2009 Feb;43(2):101-8. doi: 10.1080/00048670802607238. PMID: 19153917. REVIEW)) Since noradrenaline (like dopamine) acts in the form of an inverted-U curve¹⁷⁵, this could explain why ADHD medications (which increase dopamine and noradrenaline) do not bring about any improvement in some sufferers

2.5.6. Tic disorders, Tourette syndrome (1 % to 15 %)¶

Source¹¹

Prevalence: 1% in primary school age (varying degrees of severity), 15% in primary school age (including mild and transient forms).¹⁷⁶
Tic disorders are present in 9.5% of children with ADHD.¹⁴
31%¹⁷⁷ to 55%¹⁷⁸ of children with tic disorders also have ADHD.

2.5.7. Internet addiction (3.9 %)¶

Prevalence: among students in Germany 3.9% (2019) to 7.8% (2020, corona lockdown year)¹⁷⁹
Internet addiction was differentiated into two subtypes by one study: one subtype that correlated with impulsivity and ADHD-HI and another subtype that correlated with compulsivity.¹⁸⁰

2.5.8. Disorder of social behavior / conduct disorder (1.5 % to 5 %)¶

Source¹¹

Common symptoms:¹⁸¹

• Aggressive behavior
• Lies
• Stealing
• Arson
• Running away from home and school

Conduct Disorder is usually accompanied by comorbid disorders. These are common:¹⁸¹

• ADHD
  • Problems with cognitive control¹⁵⁴
• Oppositional defiant disorder (ODD)
  • high striving for rewards¹⁵⁴
• Depression (especially in adolescents)
  • low desire for rewards¹⁵⁴
• Anxiety disorder (especially in adolescents)

Prevalence: in primary school children approx. 1.5%, in adolescents approx. 5%.¹⁸²
Oppositional defiant disorder is said to be present in 46.9% of children with ADHD, and social behavior disorders in a further 18.5%.¹⁴
Comorbidity between ADHD-HI and social behavior disorder is reported in 15 to 85% of cases, depending on the study design and direction of the correlation, i.e. 4.7 times more frequently overall than in those not affected.¹⁸³
Oppositional defiant behavior and other social disorders are considered by some experts to be a subtype of ADHD (rage type). We suspect that this is more of a separate disorder that has a high degree of comorbidity with ADHD.

Differentiation from ADHD: Aggression in (pure) ADHD sufferers is reactive, defense motive, no intention to harm.¹¹⁹¹⁸⁴ Aggression in ADHD sufferers often arises from a misjudgement of situations, after which they (supposedly rightly) defend themselves. ADHD sufferers therefore show reactive and not proactive aggression.¹⁸⁵

2.5.9. Emotionally unstable personality / borderline (1 - 5 % (women), 1 % (men))¶

Borderline prevalence: 0.7 % - 2.7 %¹⁸⁶, 1 % - 3 %¹⁸⁷, 5 %¹⁸⁸¹⁸⁹ In psychiatric patients, the prevalence increases to 11 %¹⁹⁰ to 12 %¹⁸⁶, in hospitalized patients to 22 %¹⁸⁶ to 50 %.¹⁹⁰

ADHD increases the risk of a BPD diagnosis to 33.7%¹⁹¹. More on this at Borderline PS / Emotionally unstable PS In the article Psychiatric comorbidities in ADHD.
However, we are seeing a high number of borderline diagnoses that ultimately turn out to be ADHD, which is fully treatable with stimulants. In view of the high similarity of symptoms and the only slowly developing awareness of how far-reaching symptoms and consequences ADHD can have, this is not surprising from our point of view.

75% of borderline sufferers are women.

In the case of borderline, a comorbid occurrence of ADHD is often found in addition to a symptom similarity to ADHD.^186192193 One study addresses the question of whether one of the disorders (ADHD or borderline) can develop into one of the other disorders over time. Apparently, ADHD is more likely to be a preceding disorder and borderline is more likely to be a subsequent disorder in adulthood. The increased number of traumatic childhood experiences in borderline was reported as a significant difference in environmental influences. This, as well as the different genetic disposition described below, argues against a regular developmental sequence between the two disorders. Nevertheless, we are aware of individual cases in which we consider a development from ADHD to a later borderline or a later addition of borderline to be a plausible explanation for the symptom pattern.¹⁹⁴

Since borderline is associated with a genetic disposition on the MAO-A gene, which is also associated with aggression and behavioral disorders, borderline is likely to occur mainly with ADHD-HI and hardly ever together with ADHD-I.
ADHD resembles a personality disorder in its course (early onset, persistent behavioral patterns and possible continuation into adulthood).¹⁹⁵
There are those who view ADHD-HI (with hyperactivity) and borderline as a continuum that varies in symptom intensity. One study found that ADHD and borderline are less distinguishable on the basis of individual symptoms, but differ primarily in the intensity of the borderline symptoms.¹⁹⁶ Hallowell reports on an ADHD-HI type with borderline overtones.¹⁹⁷ We also see a conspicuous relationship, to the point of a strong confusability for laypersons, but assume that the aggressiveness associated with borderline is mediated by genes that are not typical for ADHD. As the correlating gene variants show, ADHD is characterized by a deficit of dopamine and noradrenaline in the dlPFC and striatum, while borderline patients tend to have a normal dopamine level in the PFC and an excess of dopamine in the striatum (see below).

Borderline and ADHD have very similar symptoms, which are easily confused, and a high level of comorbidity. Around 50% of borderline sufferers also suffer from ADHD.
The “inner pressure” described in Borderline (which can lead to self-harming behavior) is also known in ADHD.

Differentiation of the symptoms of ADHD and borderline:¹⁹⁸

The previous assumption that ADHD and borderline differ in the time of onset (ADHD earlier, borderline later) is now being questioned.¹⁹³

The BPFSC-11 appears to be well able to differentiate between borderline and ADHD.¹⁹⁹

Common symptoms of borderline and ADHD:

• Impulsiveness^{24200 201 202}
  • Significantly stronger in ADHD-HI/ADHD-C than in Borderline
  • High impulsivity in borderline is thought to indicate ADHD-HI comorbidity.
  • Other view: high aggressive impulsivity an endophenotype of BPD.²⁰³ We think this is more likely because DAT 9R, the gene suspected of being responsible for aggressive-impulsive behavior in borderline, is not associated with ADHD. (see below).
  • One study found increased self-reported impulsivity in ADHD and borderline, but only increased action impulsivity in ADHD²⁰⁴
  • Borderline: Impulsiveness only in relation to negative affects, ADHD: Impulsiveness also in relation to positive affects²⁰⁵
  • Borderline: Impulsivity only under stress; ADHD: independent of stress²⁰⁶
  • Addiction problems²⁰⁰
• Affective lability (ADHD-HI) / affective instability (borderline)²⁰⁰
  • In ADHD-HI sufferers (with hyperactivity) and borderline sufferers, behavior and affect regulation are similarly disturbed.
  • Rapid mood swings²⁴
  • Emotional dysregulation is even more pronounced in borderline than in ADHD. ADHD sufferers make better use of adaptive cognitive emotional strategies than borderline sufferers.²⁰⁷ All emotions are perceived considerably more intensely (and with more stressful intensity) than in non-affected persons.¹⁸⁹
  • Borderline behavioral dysregulation also does not occur in neutral life circumstances, but only in stressful moments.²⁰¹
• Attention deficit disorders
  • In ADHD often with too little arousal (lack of activation / stimulation)²⁰⁰
  • More frequent in BPD with a rise in tension as a dissociative phenomenon¹⁹⁵
  • Borderline: no attention problems with boring things, ADHD: attention problems especially with boring things²⁰⁵
• Dissatisfaction
• Dysphoria with inactivity
• Boredom (ADHD-HI) / Dysphoria, boredom, emptiness (borderline)
• Self-esteem issues / offendedness / rejection sensitivity²⁰⁰
  • Especially Rejection Sensitivity (RS) ⇒ Rejection sensitivity: offendedness / sensitivity to rejection and criticism as a specific ADHD symptom
    • RS has so far been confirmed by most of the ADHD sufferers we have interviewed
    • Whereby this sickliness is a core symptom in borderline, i.e. much stronger than in ADHD
      • Often extreme jealousy (borderline)
• Excitability, outbursts of anger
• Stress intolerance
  • Stressors lead to significantly higher stress levels in borderline patients, which decrease much more slowly than in those not affected.¹⁸⁹
• Conflictual relationships (ADHD-HI) / instability in relationships (borderline)²⁰⁰
• Social weakness, impaired social behavior
• Sleep problems common
  • Borderline often shows a prolonged REM phase and nightmares (on average every 2nd night).¹⁷³ Nightmares are atypical for ADHD.
  • Difficulty falling asleep, shortened sleep duration, low sleep efficiency with subjectively less restful sleep are common in Borderline,¹⁷³ as well as in ADHD.
  • Difficulty falling asleep in borderline patients is said to improve well with clonidine.¹⁷³ Guanfacine could probably also be helpful.
• Inner restlessness, restlessness²⁴
  • Required voltage reduction
    • For ADHD-HI (more often men): sport, sex²⁰⁰
    • In BPD (more often women): Dissociation, freezing, self-harm,²⁰⁰ sex

ADHD symptoms that are atypical for borderline:

• Concentration problems²⁴²⁰⁶
• Attention problems²⁴²⁰⁶
  • Attention problems with boring things²⁰⁵
• Distractibility²⁰⁶
• Hyperfocus²⁰⁶
• Motivation problems²⁰⁶
• Cognitive impairments²⁰⁴
• Hyperactivity²⁰⁶
• Dysphoria with inactivity
• High flow of speech (logorrhea, polyphrasia)²⁴
• Chasing thoughts, circling thoughts²⁴
• Disorders of the executive functions
  • Disorganization²⁰⁶
• One study found increased self-reported impulsivity in ADHD and borderline, but only increased action impulsivity in ADHD²⁰⁴
• Slowing of reaction time²⁰⁸ although other studies have also found shorter reaction times in ADHD

Symptoms of Borderline that are atypical for ADHD:

• Self-harming / self-injurious behavior
  Impulsive behavior in response to intense negative feelings (“negative urgency”)²⁰⁴ is one of the most distinctive symptoms that characterize Borderline²⁰⁹
  • E.g. scratching (however, not all self-harming behavior is borderline)
    • Self-injury reduces the very high subjective stress load and objective amygdala activity in borderline sufferers after a stress test (by increasing connectivity in frontal-limbic brain regions that dampen amygdala activity), while it further increases the (lower) stress load and objective amygdala activity in non-affected persons.¹⁸⁹
    • Self-injuries that are unintentional or serve more as self-stimulation are therefore not indicative of borderline, but rather of ADHD
• Thinking black and white
  • Shades of gray, both-and, mediating positions are difficult to perceive and hard to bear.
  • In discussions, those affected tend to take extreme positions. It can feel to the other party as if the person is always slipping off a bar of soap, falling into one extreme or the other, but not being able to take a middle ground or mediating position.
• Identity disorders
• Dissociation
• Unstable self-image²⁴
• Fear of abandonment²⁴²⁰⁶
  • Feeling lonely, even when among people.¹⁸⁹ We suspect that this is much more pronounced in borderline than the feeling of not belonging in ADHD
• Unstable relationships²⁴²⁰⁶
  • Exaggeration at the beginning²⁰⁶
  • Devaluation at the end²⁰⁶
• Suicidal thoughts²⁴
• Paranoid symptoms²⁴
• Strong sense of guilt and shame
• Pervasive feeling of inner emptiness²⁰⁶

Comorbid ADHD + Borderline should be particularly pronounced:¹⁹³

• Impulsivity (as with ADHD alone)
• Symptoms of regulation of traits and emotions (as in borderline alone)

In children and adolescents, certain character traits increase the risk of a later borderline personality disorder:¹⁹⁰

• Affective instability
• Negative affectivity
• Negative emotionality
• Inappropriate anger
• Poor emotional control
• Impulsiveness
• Aggression

Borderline sufferers differ from sufferers of other personality disorders primarily in their pronounced histrionic and more frequent narcissistic, bipolar/cyclothymic or aggressive characteristics. There is greater instability in relation to anger and anxiety and a greater oscillation of occurrence between depression and anxiety. Surprisingly, the level of intensity of emotion perception is not higher. Obsessive-compulsive, schizoid and anxious-avoidant manifestations, on the other hand, are rarer. These results are independent of gender.²¹⁰

Dopaminergic substances (stimulants) can provoke impulsive and aggressive behavior in borderline patients.²⁰³ This indicates an excess of dopamine in borderline, which differs from the dopamine deficit in ADHD.
This is consistent with the results of studies according to which borderline correlates with the DAT1 gene variants 9/9 and 9/10, which cause lower DAT expression in the striatum, so that a higher dopamine level in the striatum can be expected due to the lower dopamine degradation caused by DAT.²¹¹
ADHD treatment with stimulants is also possible in cases of comorbid borderline disorder²⁰⁵

The 9-repeat variant of the DAT1 gene causes an excess of dopamine in the synaptic cleft because the dopamine transporters then only reabsorb the dopamine insufficiently presynaptically. DAT 9R is associated with affective disorders and borderline personality disorder.²¹²
Borderline correlates more frequently with²¹¹

• DAT1 9/9 (OR = 2.67)
• DAT1 9/10 (OR = 3.67)
• HTR1A G/G (OR = 2.03)

The risk of borderline increases for carriers of the gene variant combinations²¹¹

• DAT1 9/10 and HTR1A G, G (OR = 6.64)
• DAT1 9/9 and C/G (OR = 5.42).

ADHD is not associated with DAT1 9R, but with DAT1 10/10, which causes increased DAT expression in the striatum, which is associated with increased dopamine removal and therefore decreased dopamine levels in the striatum. This now explains why stimulants that increase dopamine and noradrenaline levels in the PFC and striatum work well in ADHD, while they can be counterproductive in borderline.

5 HTTPLR and 5-HT2c are two other candit data genes in Borderline.²¹³

Borderline sufferers may have more regional μ-opioid receptors in some brain regions and fewer regional μ-opioid receptors in other brain regions. Emotional dysregulation (sadness) is said to correlate with the deviation of μ-opioid receptors compared to non-affected people.²¹⁴

In BPD, antipsychotics bring about significant but small improvements in cognitive symptoms, mood instability and global functions. The effect on anger/rage is more pronounced. They have no significant effect on behavioral impulsivity, depression and anxiety.²¹⁵

A study of n = 17,532 patients with BPD found with different forms of treatment:²¹⁶

• the risk of psychiatric rehospitalization
  • increased by
    • Benzodiazepines (HR = 1.38)
    • Antipsychotics (HR = 1.19)
    • Antidepressants (HR = 1.18)
  • unchanged by
    • Mood stabilizers
  • reduced by
    • ADHD medication (HR = 0.88)
    • Clozapine (HR = 0.54)
    • Lisdexamphetamine (HR = 0.79)
    • Bupropion (HR = 0.84)
    • Methylphenidate (HR = 0.90)
• the risk of hospitalization or death
  • increased by
    • Benzodiazepines (HR = 1.37)
    • Antipsychotics (HR = 1.21)
    • Antidepressants (HR = 1.17)
  • unchanged by
    • Mood stabilizers
  • reduced by
  • ADHD medication (HR = 0.86)

2.5.10. Obsessive-compulsive disorder (1 to 3 %)¶

Source¹¹

Prevalence: Lifetime prevalence of 1 to 3 %,²¹⁷²¹⁸ according to other sources 4.2 % of all women, 3.5 % of all men within one year.²
Girls under 18 years: Prevalence 0.96%, boys 0.63%.¹⁴⁶

Olfactory disorders (disorders of the sense of smell) are common in ASD and OCD, but not in ADHD.²¹⁹

2.5.11. Antisocial personality disorder (0.2 - 3 %)¶

Source²²⁰

• High impulsiveness
• Strong novelty seeking / sensation seeking
• Self-centeredness / egocentrism
• Lack of empathy towards others
  • Not being able to feel how others feel

Subgroups of antisocial personality disorder:

• Impulsive type
  • Frequent comorbidity with ADHD-HI / ADHD-C
  • Emotionally highly sensitive / hyper-reactive
  • Increased excitability
  • High impulsiveness
  • Reactive aggression - as an immediate reaction to triggers
  • Low stress tolerance
• Psychopathic type
  • Rare comorbidity with ADHD-HI / ADHD-C
  • Emotionally insensitive / hyporeactive
  • Active aggression - purposeful, instrumental violence
  • No increased arousal in case of frustration
  • No reduced stress tolerance

Differentiation from ADHD: aggression in (pure) ADHD sufferers is reactive, defense motive, no intention to harm ^{119 184} Aggression in ADHD sufferers often arises from a misjudgment of situations, after which they (supposedly rightly) defend themselves. We see a connection between this and rejection sensitivity as an excessive sensitivity to perceived or actual rejection/offensiveness. ADHD sufferers therefore show a reactive and not a proactive aggressiveness.¹⁸⁵

Common symptoms of antisocial personality disorder and ADHD:²⁴

• Impulsivity (atypical for ADHD-I)
• Rapid mood swings

ADHD symptoms that are atypical for antisocial personality disorder:

• Inner restlessness (typical in atypical depression, less so in melancholic depression)
• Concentration problems
• Attention problems
• Dysphoria with inactivity
• High flow of speech (logorrhea, polyphrasia)
• Chasing thoughts, circling thoughts

Symptoms of antisocial personality disorder that are atypical of ADHD:

• Criminal behavior
• Deception of others
• Disregard for oneself and others
• Lack of remorse

2.5.12. Narcissism (0.5 to 2.5 %)¶

Prevalence 0.5 % to 2.5 %.

Narcissism and ADHD share some possible symptoms. They are similar:

• Depressive symptoms
  • Feeling of inner emptiness
  • Dejection
• Unspecific fears
• Relationships with other people strained or disturbed
  • Devaluation of others to emphasize own value (only narcissism)
• Emotional problems
  • With narcissism, as with ADHD, increased problems perceiving and living one’s own feelings and needs
• Disturbance of self-esteem
  • With narcissism, as with ADHD, increased sickliness. ⇒ Rejection sensitivity: offendedness / sensitivity to rejection and criticism as a specific ADHD symptom

2.5.13. Schizophrenic disorder (1 %)¶

The lifetime prevalence is around 1%.⁶⁰
Girls under 18 years: Prevalence 0.76%, boys 0.48%.¹⁴⁶

Schizophrenia is highly hereditary (like ADHD approx. 80 %)²²¹ and usually only develops after adolescence. However, it is usually preceded by precursors from childhood that do not resemble schizophrenia itself, but appear to genetically indicate schizophrenia.²²²

The negative symptoms of schizophrenia are based on a lack of dopamine. They are similar to ADHD symptoms.
The positive symptoms, on the other hand, are based on excessive subcortical presynaptic dopamine transmission (dopamine hypothesis). Although this is reduced by antipsychotic dopamine D2 receptor antagonists, in schizophrenia D2/D3 receptors appear to be only very slightly increased and DAT not altered at all, so that other medication approaches may be more appropriate.²²³
The excessive subcortical dopamine drive is likely due to changes in cortical function, specifically the reduction in cortical NMDA receptor-mediated glutamate signaling, which impairs cortical dopamine and GABA function. These cortical changes are thought to cause the cognitive impairments and negative symptoms of schizophrenia.²²¹

Schizophrenia is also thought to be caused by a combination of genetic factors and environmental influences. Emotional trauma, social stress and hallucinogenic drugs have been identified as environmental influences for schizophrenia.
⇒ Genes + early childhood stress as a cause of other mental disorders

The COMT rs4680 involved in schizophrenia (as one of 50 or more candidate genes) enhances the degradation of dopamine and noradrenaline by forming a more active and thermally stable COMT enzyme.²²⁴ This causes higher schizotypal symptoms.
This can be reconciled with the newer dopamine hypothesis, according to which the positive symptoms of schizophrenia are not caused by a generally increased dopamine level in the frontal cortex (and in the nucleus accumbens, a part of the striatum), but by an increased activity (firing rate) of the mesolimbic system, which in turn is caused or influenced by a dopamine deficiency in the ventral tegmentum.²²⁴

Schizophrenia and attention:

• Increased sensitivity to sensory stimulation¹¹⁹
• High sensitivity causes sensory overload¹¹⁹
• Attention selection for individual events disturbed¹¹⁹
• Concentration / maintaining concentration on relevant aspects of a task is disturbed.¹¹⁹

Symptoms of schizophrenia that are atypical for ADHD:

• Drawings are non-spatial, no three-dimensional representation
• Irony / sarcasm are not understood
• Olfactory disorders.²¹⁹

2.5.14. Psychoses (1 %)¶

2.5.15. Autism spectrum disorder (ASD) (0.9 %)¶

Sources⁹¹⁰¹¹

Prevalence of ASA: approx. 0.9 %²²⁵
How many people with ASD also show ADHD symptoms is an open question. A meta-analysis of 23 articles found results ranging from 2.6% to 95.5% for ASD without intellectual impairment.²²⁶ Some sources assume that around 42%²²⁷ to 50%²²⁸²⁰⁵ of all ASD sufferers also have ADHD.
One review came to the conclusion that ADHD and ASD could be a continuum.²²⁹
ADHD and autism probably have common neurological/genetic roots.²³⁰

• Profound developmental disorder
  Prevalence: approx. 0.6 %²²⁵
• Autism⁵⁹
  Prevalence: approx. 0.3 %²²⁵
• Asperger’s
  Prevalence: approx. 0.084 %²²⁵
• Disintegrative disorder⁵⁹
  Prevalence: 0.008 % (one affected person in 12500 people)²²⁵
• Rett syndrome⁵⁹
  Prevalence: 0.006 % (one affected person in 10000 to 17000 people)²³¹²²⁵
  Affects girls only
  Symptoms of Rett syndrome²³¹
  • Stereotypes of the hands (washing movements)
  • Partially autistic behavior
  • Dementia
  • Reduced head growth
  • Epileptic seizures (later stage)
  • Spasticity (later stage)
  • Apraxia
  • Muscle atrophy
  • Movement disorders in the area of the thorax
  • Social behavior and play development severely inhibited
  • Social interest continues to exist
• Both ASD and ADHD show a downregulation of neuroligin genes, which was even more pronounced in ASD.²³²

Differential diagnosis of ADHD:

Children with ASD had 15 or more of the 30 symptoms (average: 22 = 73%) of the Checklist for Autism Spectrum Disorder symptoms, while children with ADHD had an average of 4 symptoms (13.3%), none of which had 15 or more. ADHD symptoms, on the other hand, were widespread among children with ASD.²³³
Children with ADHD showed higher scores on the Social Responsiveness Scale (SRS), but these did not come close to the scores of children with ASD.²³⁴

The case for ASS:²³⁵

• Inattention rather due to too much detail orientation in ASD (compared to overlooking details in ADHD)²⁰⁵
• Concentration breaks down when routines are disrupted in ASD (compared to lack of routines and rapid jumping between different things in ADHD)
• The unexpected is seen as an unpleasant irritation and disruption of their own structure (rather than a welcome change in ADHD)
• Routines due to own need for structure (as opposed to laborious habituation of routines in order not to lose too much structure with ADHD)
• Great difficulty in social situations due to inner insecurity about how to behave correctly (compared to offending others through thoughtless behavior in ADHD)
• Difficulty grasping social rules (compared to difficulty adhering to the well-understood social rules in ADHD)
• High attention to detail exceeds the time frame for activities (compared to project abandonment due to change of interest in ADHD)
• Needs order for own inner structure, tends to find things in disorder (compared to not being able to maintain order due to other priorities with ADHD)
• Deviation from the plan leads to irritation (compared to frequent deviations from the plan due to own spontaneity and impulsiveness)
• Reduced flexibility (compared to less impaired flexibility in ADHD)
• Concentration can be maintained during longer and repetitive tasks (compared to difficulties in maintaining concentration during monotonous, boring tasks in ADHD)
• Motor restlessness tends to occur in agitated situations to react (compared to motor restlessness in calm situations to stimulate ADHD)
• Motor restlessness rather out of aversion to something = running away (as opposed to out of interest in something = running towards something in ADHD)
• Loose conversations or small talk are unpopular, as own thought structures are thwarted; sometimes compensation through strict conversation (this is not present in ADHD; in our opinion, this is already present in ADHD, but weaker)
• Lack of feeling for the situation and mood (present in ADHD)
• Interrupting others rarely (like ADHD-I, different from ADHD-HI / ADHD-C)
• Having to wait in a rather dark, completely unstimulating room is a rather pleasant idea (very unpleasant with ADHD-HI / ADHD-C; both possible with ADHD-I)

In ASD, the intracortical pathway (facilitation) appears to be unimpaired, whereas in ASD with comorbid ADHD, the intracortical pathway appears to be impaired. This could be a biomarker to differentiate between ASD and ADHD.²³⁶

Both ASD and ADHD showed slower orienting responses to relatively unexpected spatial target stimuli compared to controls, which was associated with higher pupil dilation amplitudes in ASD. ADHD showed shorter cue-evoked pupil dilation latencies than ASD and controls.²³⁸

Several studies have looked at differences between ASD and ADHD.

ASD symptoms that are atypical for ADHD:

• Less verbal comprehension with ASD than with ADHD²³⁹
• Lower vocabulary with ASD²³⁹
• Less comprehension with ASD²³⁹
• Poorer image concepts with ASD²³⁹
• Poorer image completion with ASS²³⁹
• Slower processing speed with ASD²³⁹
• Lower social judgment with ASD²³⁹
• Poorer response to name calling at the age of 24 months with ASD²⁴⁰
• Higher shifting with ASS²⁴¹
• Poorer emotional self-regulation with ASD²⁴¹
• ASD, like dyslexia, shows deficits in global motion processing, unlike ADHD. ASD and dyslexia show a significantly lower flicker fusion frequency than healthy controls or ADHD subjects.²⁴²
• Self-soothing through repetitive behavior and routines²⁰⁶

ADHD symptoms that are atypical for ASD:

• Poorer working memory typical for ADHD, less so for ASD²³⁹²⁴¹
• Attention regulation problems²⁰⁶
• Planning and organization problems (which are largely determined by working memory) typical for ADHD, less so for ASD²⁴¹
• Inhibition problems typical for ADHD, less so for ASD²⁴¹
• Fewer points in the Digit Span for ADHD than for ASD²³⁹
• Poorer graphomotor processing in ADHD²³⁹
• Novelty seeking typical for ADHD, not for ASD²⁰⁶
• Hyperactivity²⁰⁶
• An above-average number of glances into the eyes of the other person, even compared to non-affected people²⁴³

Both ADHD and ASD show structural abnormalities in the PFC, cerebellum and basal ganglia. Affected individuals with comorbid ASD and ADHD showed no significant differences in the volumes of the PFC, cerebellum or basal ganglia. However, they showed significantly lower volumes of the left postcentral gyrus, but only children, not adolescents.²⁴⁴
One review compared catecholaminergic and cholinergic neuromodulation in ASD and ADHD. The authors came to the following conclusion:²⁴⁵

• Stimulants could be a viable treatment option for a (possibly genetically defined) ASA subgroup
• a disorder of the cerebellum is much more common in ASD than in ADHD
  • in both cases, this could open up a noradrenaline- or acetylcholine-controlled treatment option
• a deficit of the cortical salience network is considerable in subgroups of ASD such as ADHD
  • Biomarkers such as eye blink rate or pupillometric data can predict efficacy of targeted treatment of an underlying deficit using dopamine, noradrenaline or acetylcholine, in ADHD as in ASD

ASD is characterized by high levels of aggression and risk-taking behaviour. In addition, ASD is more frequently involved in child abuse than average.²⁴⁶ Aggression and high-risk behavior are also characteristics of the ADHD-HI subtype.

A review article found approximately doubled noradrenaline levels in the blood of people with ADHD and approximately halved noradrenaline levels in the blood of people with ASD compared to those not affected. Serotonin blood levels, on the other hand, were four times higher in those with ASD and more than four times lower in those with ADHD.²⁴⁷

2.5.16. Fragile X syndrome (0.22% (men) to 0.66% (women))¶

Prevalence: 1/150 (0.66%) women, 1/456 (0.22%) men in the USA²⁴⁸
Source¹¹¹⁷

2.5.17. Pervasive developmental disorders (PDD) (0.06 %)¶

Prevalence: 60/100,000 (0.06 %)

PDD is characterized by severe deficits in social behavior and communication, as well as repetitive and stereotypical interests and behaviors. There are often comorbidities with reduced intelligence, ADHD, aggression and obsessive-compulsive disorder.²⁴⁹

2.5.18. Wilson Disease (0.0033 %)¶

Wilson’s disease (prevalence: 1 in 30,000 people, 0.0033%) is associated with excessive copper levels.
People affected by Wilson’s disease show symptoms that can be confused with ADHD²⁵⁰
Wilson disease is associated with an ATP7B gene defect and shows an excess of copper.
Although dopamine β-hydroxylase, which converts dopamine to noradrenaline, is dependent on copper for this, it does not appear to be involved in Wilson’s disease.

2.5.19. Monoamine neurotransmitter disorders¶

Monoamine neurotransmitter disorders are genetic defects in transporters or deficiencies in precursors, cofactors or degradation enzymes of monoamines (e.g. dopamine).²⁵¹

Symptoms of a severe dopamine deficiency can include²⁵²

• Parkinson’s disease
• Dystonia
• Chorea
• oculogyric crises/gazing spasm
• Ptosis/eyelid muscle weakness
• Swallowing disorders
• myoclonic epilepsy
• Epileptic encephalopathy
• Progressive cognitive dysfunction
• Microcephaly
• Pyramid sign

Symptoms of a severe serotonin deficiency can include²⁵²

• Temperature problems
• Sweating
• Dystonia

The measurement of pterins (especially biopterin and neopterin) in urine is helpful in detecting deficiencies in precursors and specific metabolic defects:

*GTP cyclohydrolase 1 deficiency (GCH 1)

• 6-Pyruvoyl tetrahydropterin synthase deficiency
• Dihydropteridine reductase deficiency
• Sepiapterin reductase deficiency
• Aromatic L-amino acid decarboxylase deficiency
  • 3-ortho-methyldopa increased
  • Vanillic acid increased
• Dopamine transporter deficiency syndrome (DTDS)
  • HVA to creatine ratio in urine increased
• Severe dopamine deficiency
  • Increased prolactin in the blood
  • Galactorrhea
• Strong excess of dopamine
  • Reduced prolactin in the blood

2.5.19.1. Genetically caused BH4 disorders (approx. 0.0002 %)¶

Genetic disorders of tetrahydrobiopterin synthesis (BH4, an important enzyme for dopamine synthesis) such as

• autosomal recessive (AR) guanosine triphosphate cyclohydrolase deficiency (GTPCH deficiency)
  • Prevalence less than 1 / 1,000,000 (less than 0.0001 %)²⁵³
  • 46 % of all BH4 disorders
• 6-Pyruvoyl tetrahydropterin synthase deficiency (PTPS)
  • Prevalence: 1 / 500,000 to 1 / 1,000,000 (0.0001 % to 0.0002 %) ²⁵⁴
  • 54 % of all BH4 disorders

seem to contribute to ADHD and other mental disorders such as anxiety, depression, aggression or oppositional defiant behavior.²⁵⁵

See also Tyrosine hydroxylase In the article Dopamine formation.

2.5.19.2. Missing or greatly reduced DAT¶

There are (rarely) people with no or very severely reduced DAT. However, they show other symptoms that are not typical of ADHD (e.g. Parkinson’s dystonia in early childhood) and are therefore rarely misdiagnosed with ADHD and are more likely to be misdiagnosed with cerebral palsy. Many of those affected die as teenagers.²⁵⁶ An excess of extracellular dopamine leads to reduced production of dopamine (and thus reduced storage of dopamine in the vesicles) through activation of presynaptic D2 autoreceptors, as well as downregulation or desensitization of dopamine receptors, resulting in a lack of phasic dopamine and a dopamine effect deficiency.²⁵¹

2.5.20. Predominantly milieu-related behavioral problems¶

Predominantly milieu-related behavioral problems means, for example, lack of attention and stimulation, physical and/or emotional abuse, media abuse, intrafamilial conflicts and sibling conflicts¹¹
In our understanding, this description corresponds to the environmental causes of most mental disorders such as ADHD, depression, anxiety disorders, borderline etc., all of which can arise when environmental causes, usually stressful experiences in the first 6 years of life, permanently manifest an existing genetic disposition by means of epigenetic change. Predominantly milieu-related behavioral abnormalities are therefore unsuitable for defining a separate disorder.
⇒ How ADHD develops: genes or genes + environment
⇒ Genes + early childhood stress as a cause of other mental disorders

2.5.21. Oppositional defiant behavior (ODD)¶

ADHD is characterized in particular by problems with cognitive control, whereas oppositional defiant disorder (ODD) is characterized by a high desire for reward.¹⁵⁴