Differential diagnostics in ADHD

A careful diagnosis of ADHD always requires a differential diagnosis for other disorders that may cause the same or similar symptoms.

• 1. Differential diagnostics
  • 1.1. Differential diagnosis
  • 1.2. ADHD (ASD, OCD) - homogeneous disorders or purely dimensional grouping?
  • 1.3. Comorbidity: the difference from differential diagnosis
  • 1.4. Prevalence: frequency of mental disorders
• 2. Differential diagnosis for ADHD
  • 2.1. “Healthy” stress response to 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 unrecognized gifted person as an outsider
      • 2.1.2.2. Similarities of individual typical traits in HB and ADHD
    • 2.1.3. Minor aptitude (< 80: 8.98%; < 70: 2.28%)
  • 2.2. Activity level appropriate to age
  • 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. Postconcussion 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 (illicit drugs: 10%, nicotine: 16.6 to 25.5%)
    • 2.3.6. Addiction / dependence (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. Hypothyroidism / underactive thyroid gland (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 receptor insensitivity
    • 2.3.8. Restless legs syndrome (children 2 %, adults 5 to 10 %)
    • 2.3.9. Prenatal harm from alcohol (0.8% to 8.2%)
    • 2.3.10. Seizure disorders (epilepsy: 0.5 to 1 %)
    • 2.3.11. Hydrocephalus (hydrocephalus) (0.4 - 0.8 %; over 65 years 3 %)
    • 2.3.12. Prolactinomas (0.02 - 0.05 %)
    • 2.3.13. Phenylketunorie (PKU) (0.0125 %)
    • 2.3.14. Consequences of severe brain infections (cumulative 0.05% to 0.16%)
      • 2.3.14.1. Encephalitis (cumulative 0.03%)
      • 2.3.14.2. Perinatal hypoxemia (0.001 to 0.009%)
      • 2.3.14.3. Bacterial infections (cumulative 0.01% in women, 0.12% in men)
    • 2.3.15. Neurofibromatosis type 1 (0.029%)
    • 2.3.16. Velocardiofacial syndrome (22q11DS) (0.01 to 0.05%)
    • 2.3.17. Cortisol disorders (cumulative 0.0042 to 0.0048%)
      • 2.3.17.1. Hypocortisolism (adrenocortical insufficiency) (0.004%)
      • 2.3.17.2. Hypercortisolism (Cushing’s syndrome) (0.0002 to 0.0008%)
    • 2.3.18. Moyamoya (0.0001% to 0.0009%)
    • 2.3.19. Hamartoma of the hypothalamus (0.0005%)
    • 2.3.20. Allergies (with motor restlessness)
    • 2.3.21. Visual, hearing disorders
    • 2.3.22. Lesions of the left cerebral hemisphere
    • 2.3.23. Organic brain damage
    • 2.3.24. Status epilepticus during sleep (ESES)
    • 2.3.25. Traumatic or space-occupying cerebral disorders/other psychoorganic syndromes with cerebral damage and/or psycho-mental retardation
    • 2.3.26. Histamine intolerance, histamine intolerance
    • 2.3.27. Bachmann-Bupp syndrome (BABS)
    • 2.3.28. CAPRIN1 haploinsufficiency
    • 2.3.29. KBG Syndrome
    • 2.3.30. Cystic fibrosis
  • 2.4. Drug side effects
  • 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. Ideatory 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. Dyscalculia (5 %)
    • 2.5.5. Post-traumatic stress disorder (PTSD, PTSD) (5% (men), 10% (women))
    • 2.5.6. Tic disorders, Tourette syndrome (1 to 15 %)
    • 2.5.7. Internet addiction (3.9% (2019) to 7.8% (2020))
    • 2.5.8. Social behavior disorder (1.5 to 5%)
    • 2.5.9. Emotionally unstable personality / borderline (1 - 4 % (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% (males) to 0.66% (females))
    • 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. Genetic BH4 disorders (approx. 0.0002 %)
      • 2.5.19.2. Missing or strongly reduced DAT
    • 2.5.20. Predominantly environment-related behavioral problems

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 consequently 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 picture 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 suggests that the individual differences between those affected by a disorder are greater than the similarities.

1.3. Comorbidity: the difference from differential diagnosis¶

While differential diagnosis means to check whether the symptoms that (here:) point to ADHD might not in fact stem from another problem, i.e. that there is no ADHD, comorbidity means that someone suffering from one disorder (here: ADHD) is at the same time (additionally) affected by another disorder.

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

Most comorbidities typical of ADHD may have gene variants in common with ADHD or the common cause of early childhood stress exposure meeting a gene disposition specific to the particular (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 with roughly the same frequency, but with different types of disorders. The age group most frequently affected is 18 to 34 years.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 open comorbidity of several disorders from different diagnostic groups. The comorbidity with regard to different individual diagnoses from the same group is again significantly higher.
Comorbidities increase with age.²

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

• Children and young people combined 5.29
  according to long-term international meta-analysis of 102 international studies with n = 171,000 subjects³
  • Preschool children: approx. 3⁴
  • Teenagers: approx. 8 %
    • Boys approx. 6 %⁴
    • Girls approx. 2 %⁴
      (We suspect that girls are more likely to be unrecognized because of the ADHD-I subtype that is more common among them)
• Adults:
  • Approx. 1 - 4 %⁴
  • Approx. 3 - 5 %⁵

Thus, the lifetime prevalence of ADHD would be similar to that of diabetes.⁶

Friedmann reports that the lifetime prevalence of ADHD in the U.S. increased from 7.8% in 2003 to 11% in 2011.⁵
This does not result from an increase in ADHD, but that ADHD is now better recognized and more reliably diagnosed.

For further information on the prevalence distribution of ADHD, see:⇒.. Frequency of ADHD (prevalence)

2. Differential diagnosis for ADHD¶

The following phenomena should be checked in an examination of where ADHD-typical symptoms originate.

2.1. “Healthy” stress response to stressful situation¶

2.1.1. Acute subjectively threatening stress¶

An acute and subjectively threatening stress situation can cause 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.
With the end of the stressful situation, the symptomatology ends completely in healthy people.
However, if ADHD exists, the stress regulatory system is permanently damaged due to genetic causes or a coincidence of a genetic disposition and too long, too intense (usually early childhood) stress exposure (⇒ Development of ADHD), so that the stress symptoms henceforth persist even in the slightest (or no) stressful situations and the stress systems may overreact in low stress situations (ADHD-HI) or the stress systems may ramp up and down again too early (ADHD-I).
⇒ ADHD as a chronicized stress regulation disorder.
Therefore, in a differential diagnosis, the first step is to determine whether acute circumstances exist that are so stressful that they can cause the symptoms, for example:

• Bullying⁷
  • Depression
  • Fear
  • Shorter sleep
  • Insomnia
  • Worse school grades
  • ADHD symptoms
• Separation of attachment figures (divorce of parents)
• Separation problems with severe family conflicts⁸
• Death of close person
• Loss of the partner
• Subjectively unsolvable stressful situation (loss of control)
• Life upheaval (for children: relocation, for adults: insolvency, contentious divorce, etc.)
• Abusive parenting methods (e.g., ignoring child; playing dead until child obeys)
• Sexual abuse
• Physical mistreatment
• 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, unrecognized giftedness can give rise to symptoms that are almost identical in nature and composition to ADHD symptoms.

2.1.2.1. Stress reaction unrecognized gifted person as an outsider¶

Highly gifted people have different interests, think “differently”, have different values and react differently. The lower the social competence with which those affected can bridge their being different, the stranger other children find them. This can trigger negative reactions and even bullying. But even without bullying, the “feeling different” and the “not belonging” (this is not only similar but identical to ADHD sufferers) and the lack of friends can increase to such a massive stress that the stress symptoms typical of ADHD can form.
Affected children are then fidgety, disruptive in class, do the class clown (ADHD-HI-like) or shut down internally, daydreaming away (ADHD-I-like).
However, in addition to the possible stress symptoms of bullied outsiders (which may well include unrecognized gifted individuals because of their difference), there are a few similarities between ADHD and giftedness that are not stress-related.

2.1.2.2. Similarities of 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 resemble characteristics that are often observed in ADHD sufferers.
⇒ Giftedness and ADHD

We had suspected 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 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 common high sensitivity.
However, recent data (including from the ADxS.org symptom test, n = 2000, as of July 2020) show no correlation between giftedness and high sensitivity.

Highly gifted as well as ADHD sufferers are attributed from the respective literature:

• Primarily intrinsically motivatable (extrinsically/through external pressure difficult to motivate)
  • Ability to hyperfocus
  • Boredom and concentration problems with uninteresting or monotonous tasks (up to underperforming and excessive error rate)
  • Impatience
  • Tendency to interrupt others
• Rejection of authority (authority is recognized only qua competence, not qua rank)
• For some: difficulty in making decisions (too many options and facts to consider); primarily for people who internalize their stress responses, less so for people who externalize stress
• Smalltalkaversion
• Diplomacy deficit
• Crowd aversion
• High importance of truth, equality, justice
• Often being perceived by others as weird or strange.

These traits (which do not occur in all HBs, of course, but do occur more frequently in HBs) should therefore be examined closely for their cause during diagnosis.

Unrecognized giftedness is not easy to recognize. Not all gifted people have special abilities. Many gifted people even emphatically reject such a classification for themselves because they do not perceive themselves that way. Here it is important to note the difference between giftedness = disposition and ability = implementation of the giftedness. Many highly gifted people need appropriate support in order to develop their abilities. In addition, not all giftedness lies in school-relevant areas. Mathematical geniuses or the variant of the knowledge-thirsty gifted person are easily recognized as gifted by nature.⁹¹⁰¹¹

Highly giftedness is of course not a compelling reason for feeling like an outsider and/or for developing ADHD-like symptoms. Mostly those are affected who cannot compensate their otherness by sufficient social competence.
All of the above-mentioned prevalences are merely a rough guide to make the probability of a possible comorbidity visible. And just as naturally, not every child who has ADHD is highly gifted.

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

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

In the case of an existing intellectual disability, the DSM-V criteria seem to be only partially suitable for ADHD diagnosis. In particular, the main symptoms of the DSM-V in underachievers can also result from the underachievement itself. One study was able to correctly diagnose only 46% of ADHD sufferers among the gifted. 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. Activity level appropriate to age¶

An activity level that is still age-appropriate, especially in younger children, may show an ADHD-like symptom pattern.¹⁴¹¹

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

2.3. Primary organic disorders¶

Sorting by prevalence (frequency of occurrence) in descending order. Prevalence refers to the frequency of the disorder itself, not to the frequency or probability of ADHD in that disorder. Thus, the prevalence of deficiency symptoms is quite high, but the influence of their correction on ADHD symptoms is not resounding.

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 older) in men and 0.8% (15 to 19 years) to 7.8% (60 years and older) in women.¹⁵
Sleep problems in ADHD are extremely common:

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

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

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

With sleep problems and ADHD, it is difficult to separate 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 special priority. In addition, medications for sleep problems must be considered for their potential negative impact on ADHD symptoms, just as medications for ADHD must be evaluated to ensure that they do not exacerbate sleep problems. More on the treatment of sleep problems in ADHD: ⇒ Treatment of sleep problems in ADHD

• Vigilance disorders in sleep-wake regulation impairments¹⁷¹⁸
• Consequences of sleep apnea syndrome¹¹
  “Obstructive sleep apnea syndrome (OSAS) is the most common sleep-related breathing disorder. The prevalence is approximately 4% in men and 2% in women.
  Obstructive sleep apnea (OSA) is even more common and reaches strikingly high numbers, especially when subgroups are considered. For example, patients with diabetes mellitus or arterial hypertension have a prevalence of approximately 36%, obese patients have a prevalence of 50%, and patients with refractory arterial hypertension have a prevalence of 83%. Among these, estimates suggest that 80% of male and 90% of female patients with sleep apnea syndrome are undiagnosed and thus untreated.”¹⁹
  Breathing pauses in children’s sleep can trigger cognitive distress, causing symptoms that resemble ADHD.²⁰
• Chronic lack of sleep¹⁷
• Disturbances of the dream sleep phases cause within a few days:
  • Increased irritability²¹
  • Increased impulsivity²¹
  • Reduced concentration²²
  • Reduced attention²²
  • Working memory disorders²³

Common symptoms of sleep problems and ADHD:²⁴

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

ADHD symptoms atypical of sleep problems:

• Inner restlessness (typical in atypical depression, less so in melancholic depression)
• Impulsivity
• High fluency of speech (logorrhea, polyphrasia)
• Thought chasing, thought circling
• Rapid mood swings
• Dysphoria with inactivity

Symptoms of sleep problems atypical of ADHD:

• Drowsiness
• (Daytime) fatigue

2.3.2. Postconcussion syndrome (consequences of a concussion) (11 to 80 %)¶

Another name: post-concussion syndrome

Prevalence: probably in 1 / 10 patients with mild traumatic brain injury²⁵
Concussion is the mildest form of traumatic brain injury. In the USA, concussion is assumed to have an incidence of 1.15% (3.8 million / 331 million). This would put the incidence of postconcussion syndrome at approximately 0.115%/year.
The prevalence ranges from 11 to 80%.²⁶

In uninjured adolescent athletes, ADHD appears to mimic postcommotion syndrome. ADHD sufferers report more symptoms of postcommotion syndrome than do unaffected individuals.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 concussion.²⁹

2.3.3. Deficiency symptoms (5 to 30 %)¶

2.3.3.1. Vitamin D3 (30 %)¶

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

• At the same time, a vitamin D3 deficiency seems to be very common in ADHD.³² A D3 administration especially in autumn / winter is recommended.

• D3 requires fat for absorption, i.e. an intake requires that the preparations contain fat or a simultaneous food intake. A glass of milk should already suffice for this purpose.

2.3.3.2. Vitamin B12 (5 to 30 %)¶

Prevalence B12 deficiency:³³³¹

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

• At older ages, concentration and attention problems due to B12 deficiency are virtually phenotypic.
• B12 can be supplied more safely by means of injections.
• In the meantime, B12 is also available in tablet form.
• Foods with potentially high levels of B12 (spinel algae), on the other hand, are not reliable enough to dose.

2.3.3.3. Zinc (11 %)¶

Zinc deficiency can exacerbate symptoms of existing ADHD.³⁴

• Prevalence zinc deficiency:
  • Population-wide
    • Europe: 11 %³¹
  • Healthy children from 1 to 3 years:
    • Western Europe: 31.3 %³⁵
  • in children under five (Disease Control Priorities in Developing Countries 2006).
    • East Asia/Pazifik: 7%
    • Eastern Europe and Central Asia: 10
    • Latin America and Caribbean: 33 %
    • Middle East and North Africa: 46 %
    • Sub-Saharan Africa: 50
    • South Asia: 79 %
• Zinc deficiency is manifested, among other things, by a deficiency of T and B lymphocytes
• Zinc deficiency is often accompanied by vitamin A deficiency
• Zinc is involved in the Ada Repair protein. This repairs (demethylates) methylated phosphate linkers in 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 of the paucity of reliable epidemiologic data on the subject, which are also related to several 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 about 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 13th to 15th: 4-8%; mainly storage iron deficiency without iron deficiency anemia

Symptoms of iron deficiency include³⁷

• Fatigue
• Muscle weakness
• decreased physical performance
• Changes in mood and emotional behavior

Iron deficiency affects dopamine metabolism³⁷

• This could be particularly harmful in infants and young adults with alterations in the mesolimbic signaling pathway [30]. Iron is involved in dopaminergic signaling pathways and dopaminergic neurotransmission.
• Iron deficiency in substantia nigra could cause decreased tyrosine hydroxylase activity and thus impaired dopamine synthesis.
• The SERT affects dopaminergic signaling
  • through its modulation of intracerebral iron homeostasis. The SERT-dependent decrease in intracerebral iron concentration affects 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 is usually quite different from ADHD and is hardly permanent.

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

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

If, in addition to ADHD, aggressive and oppositional defiant behavior and low self-esteem are also present, the likelihood of substance abuse is significantly increased, whereas adolescent ADHD sufferers without these additional symptoms were not found to abuse substances more frequently.⁴⁵⁴⁶

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

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

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

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

Alcohol:⁴³

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

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

In Germany, the prevalence for gambling addiction is 0.31%, and the prevalence for problem gambling 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 addiction and not addiction the cause of ADHD. This was shown at least for smoking, cannabis and probably also alcohol.⁵⁰

With elevated gene risk scores for ADHD (polygenic risc scores, PRS), one study also found a 20% increased probability of addiction. There were no differences in the intensity of addiction (use, abuse, dependence) or the type of addictive substances (alcohol, cannabis, other illicit drugs). Conversely, 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 severe addicts compared to 2.5% in the control group.⁵²
More significantly, 53% of the severely addicted had a socially disordered behavior in childhood or adolescence (up to 15 years of age) as measured by the SKID-II (control subjects at 2.5%).⁵³ Earlier social behavior disorder (OR = 35.1) compared to childhood hyperkinetic behavior (OR = 5.7) was by far the greater risk factor for severe addiction.⁵⁴
This suggests to us that addiction plays a role predominantly in ADHD-HI and less in ADHD-I.
Regarding the preference of addictive substances, there is an indication of a more frequent use of cannabis products among people with (former) hyperkinetic behavior. For opiates, cocaine, amphetamines, sedatives and hallucinogens there seems to be no significant difference.⁵⁵
A co-occurrence of hyperkinetic and socially dysfunctional behavior is associated with an early first use of illicit drugs, but statistically only an earlier and increased use of nicotine could be demonstrated.⁵⁶
Long-term abuse of dopaminergic drugs (cocaine, amphetamines) leads to long-term downregulation of the dopamine level. Withdrawal symptoms then correspond to ADHD symptomatology. ⁵⁷ Against this background, the question arises whether ADHD drugs (stimulants), which are known to have no intoxicating effect, might not be helpful in the withdrawal of dopaminergic drugs.
ADHD sufferers with comorbid cocaine addiction showed significant reductions in addictive behaviors when treated with stimulants.⁵⁸

Common symptoms of addiction/substance abuse and ADHD:²⁴

• Impulsivity
• (inner) restlessness, motor hyperactivity
• Concentration problems
• High fluency of speech (logorrhea, polyphrasia)

ADHD symptoms atypical of addiction/substance abuse:

• Thought chasing, thought circling
• Attention problems
• Dysphoria with inactivity
• Mood swings

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

• Substance Abuse:
  • Excessive consumption of a substance, even if serious consequences are present
• 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 guideline of the Arbeitsgemeinschaft ADHS der Kinder- und Jugendärzte e.V., 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 may include:⁶¹

• Nervousness
• Aggression
• Irritability
• Increased feeling of anxiety up to fearfulness
• (extreme) jumpiness
• Difficulty to relax
• Sleep disorders

Other symptoms not typical of ADHD may include:⁶¹

• • Sweating
    • Palpitations
    • Atrial fibrillation
    • (strong) trembling
    • Diarrhea
    • Strong weight loss
    • Fatigue
    • Weakness
    • Additional occurring psychosis

2.3.7.2. Hypothyroidism / underactive thyroid gland (from 60 years approx. 2 %)¶

From the age of 60, about 2% of the population is affected by hypothyroidism.¹⁷

ADHD-like symptoms may result from hypothyroidism⁶²
Hypothyroidism becomes more common with age (usually a consequence of Hashimoto’s autoimmune thyroiditis).

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

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

Hashimoto’s (Struma lymphomatosa Hashimoto) is an autoimmune disorder that causes hypothyroidism⁶²
The prevalence of Hashimoto’s in Germany is about 5 to 10 %. Prevalence and incidence increase with age. Women in the 3rd-5th decade of life are affected about 10 to 20 times more often than men.⁶³

ADHD-like symptoms may include:⁶¹

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

Other symptoms not typical of ADHD may include:⁶¹

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

It is reported that adrenal insufficiency (an attenuated production of cortisol by the adrenal gland) often leads to thyroid insufficiency. Treatment of the thyroid 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, a collapse of the adrenal gland can be the result, which further reduces cortisol production, which is why the adrenal gland should be considered and treated before thyroxine treatment.⁶⁴

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 result from pituitary insufficiency due to CRH receptor downregulation. To differentiate this from adrenal insufficiency, see ⇒ Hypocortisolism (adrenocortical insufficiency) In this article.
However, adrenal collapse due to thyroxine therapy is not reported as typical in ADHD.

2.3.7.4. Thyroid hormone receptor insensitivity¶

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 females than in males. Since ADHD is further associated with thyroid hormone receptor insensitivity, a role of thyroid hormones in the development and manifestation of ADHD in women and girls should be further investigated.⁶⁵

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

Prevalence:⁶⁶

• Children 2 %
• Adults 5 - 10

Restless Legs correlates with ADHD symptoms.¹⁷¹⁸
Intense sugar consumption - especially in people who do not tolerate sugar well - can cause twitching in the limbs (especially the legs), which can act similarly to a mild form of restless legs and can be a hindrance to falling asleep.

A lower frequency of D4.7R is suspected in restless legs, whereas this gene variant is more frequent in ADHD.⁶⁷

In restless legs, treatment with L-dopa is often helpful in the short term but may be detrimental in the long term.
Further, treatment with D4 agonists is discussed⁶⁷

2.3.9. Prenatal harm from alcohol (0.8% to 8.2%)¶

Other names: Fetal Alcohol Syndrome, Embryofetal Alcohol Syndrome, alcohol effects, FAE, FAS, alcohol embryopathy
Prevalence: 0.8 to 8.2% of all births, with approximately 10% of all cases developing full symptomatology.⁶⁸

Around 15 to 30% of all mothers continue to drink alcohol during pregnancy.⁶⁸ The risk to unborn children is considerable.
This problem is also considered a possible cause of ADHD.⁶⁹ The risk of ADHD among FAE/FAS sufferers is said to be increased 10-fold.⁷⁰ One study found 70% of adopted children with Fetal Alcohol Spectrum Disorder later developed ADHD.⁷¹

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

The prevalence of epilepsy is 0.5% to 1%.⁷²

Source¹¹

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

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

Prevalence: 0.4 - 0.8%, > 65 years: approx. 3%⁷³

Children with hydrocephalus are at nearly three times the risk for ADHD.⁷⁴
In old age, hydrocephalus often occurs comorbid with Alzheimer’s disease and vascular dementia.

2.3.12. Prolactinomas (0.02 - 0.05 %)¶

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

Prolactinomas are prolactin-secreting (benign) tumors
⇒ ADHD- Neurotransmitter - Messenger substances

2.3.13. Phenylketunorie (PKU) (0.0125 %)¶

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

Phenylketonuria sufferers often show symptoms of ADHD, although the subtypes with hyperactivity seem to predominate.^7576777879

Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations of the phenylalanine hydroxylase gene). PKU results in a significant excess of phenylalanine (hyperphenylalaninemia). Since phenylalanine and tyrosine pass through the blood-brain barrier through the same transporters, and these transporters have a higher affinity for phenylalanine, when there is excess phenylalanine in the blood, too little tyrosine enters the brain. Tyrosine is a precursor for dopamine, which further gives rise to norepinephrine and epinephrine. Therefore, an excess of phenylalanine in the blood leads to a lack of dopamine, norepinephrine, and epinephrine in the brain.⁸⁰ In addition, phenylalanine excess causes changes in cerebral myelin and protein synthesis, as well as reduced levels of serotonin in the brain.⁸¹ ADHD and phenylketonuria thus have the common feature of a dopamine deficiency.⁷⁷⁸²

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

Sources⁸⁸³¹⁸

2.3.14.1. Encephalitis (cumulative 0.03%)¶

Prevalence:⁸⁴
Autoimmune encephalitis 13.7/100,000 (0.0137%)
infectious encephalitides 11.6/100,000 (0.0116%)
viral encephalitis 8.3/100,000 (0.0083%)

Brain infection with inflammatory change due to invading microorganisms.
Encephalitis destroys the cells in the substantia nigra that make dopamine.
Those affected by the encephalitis epidemic of 1914 to 1917 showed typical symptoms of ADHD as it progressed. Children developed hyperactive motor skills, adults Parkinson’s symptoms.
The symptoms are consequences of the dopamine deficiency characteristic of ADHD. These symptoms could be reproduced in animal experiments as a consequence of disturbed dopamine production.⁸⁵

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

2.3.14.2. 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 major causes of early childhood brain damage (FKHS).
Led to the death of dopamine-producing cells in the substantia nigra in animal experiments, resulting in a decrease in dopamine levels of up to 70%.⁸⁶
Hypoxemia is associated with adenosine excess. Adenosine inhibits dopamine.

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

• Meningitis: meningitis
  • Prevalence: 0.5 / 100,000 (0.0005 %)⁸⁷
• Brain abscesses: 0.3-1.3 /100,000 per year (0.0003% to 0.0013%)
  • Local infection of the brain tissue. Starts as focal encephalitis (cerebral phlegmon, “cerebritis”). As it progresses, slowly 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)

2.3.15. Neurofibromatosis type 1 (0.029%)¶

Other names: Von Recklinghausen disease, Recklinghausen’s disease, neurofibromatosis Recklinghausen, peripheral neurofibromatosis
Prevalence of about 1:3500 (0.029%) 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 -affected individuals (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 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%), central nervous system gliomas (3.1%).⁸⁸

Diagnostic criteria - at least 2 of the following symptoms:⁸⁹

• Six or more café-au-lait spots (CAL) > 5 mm in diameter prepubertally and > 15 mm postpubertally.
• Freckling in axilla or inguinal region.
• Two or more neurofibromas of any type or a 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 wedge bone 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 tissues such as leukocytes.

2.3.16. 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)⁹⁰

The prevalence of velocardiofacial syndrome is 1 - 5 / 10,000 (0.01 to 0.05 %)⁹¹

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

2.3.17.1. Hypocortisolism (adrenocortical insufficiency) (0.004%)¶

Sources:⁹²⁹³

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

Since basal cortisol levels are slightly reduced in ADHD (in ADHD-HI as in ADHD-I), ADHD could be described as very mild adrenal insufficiency (adrenal weakness).

2.3.17.2. 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%)⁹⁴

• 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 cause for ectopic ACTH production
• ACTH-independent form (20 % of cases)
  Overproduction of glucocorticoids (cortisol) and mineralocorticoids by adrenal cortex
  • Adrenocortical adenoma (pure cortisol overproduction)
  • Adrenocortical carcinoma (increased production of cortisol and androgens)
  • Nodular hyperplasia of the adrenal cortex

2.3.18. 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 %)⁹⁵
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 leading to relative anemia (stroke and transient ischemic attack) in the brain. Many small compensatory vessels form as bypasses.
Moyamoya may present with symptoms confusable to ADHD.⁹⁶

2.3.19. Hamartoma of the hypothalamus (0.0005%)¶

Prevalence: 1 / 200,000 (0.0005 %)⁹⁷

A hamartoma is a tumor-like, benign tissue change due to defectively differentiated or scattered germinal tissue. A hypothalamic hamartoma can produce a variety of hormones and cause premature puberty, obesity, and epilepsy in addition to ADHD symptoms, conduct disorder, oppositional defiant behavior, antisocial behavior, tantrums, intellectual regression, and cognitive impairment. 60% of those affected by a hypothalamic hamartoma develop externalizing disorders (especially in boys and in epilepsy), and 30% develop internalizing disorders.⁹⁸⁹⁹ MPH can significantly improve ADHD caused by a hypothalamic hamartoma, as can treatment with a gonadotropin-releasing hormone (GnRH) analog.¹⁰⁰ In severe cases, stereotactic laser surgery could be helpful.¹⁰¹

2.3.20. Allergies (with motor restlessness)¶

Source¹⁷

2.3.21. Visual, hearing disorders¶

Sources¹¹¹⁷

2.3.22. Lesions of the left cerebral hemisphere¶

• Attention selection impairs¹⁰²
  • 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:¹⁰³

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

The OFC normally has inhibitory functions. These take place via efferents to:¹⁰³

• Hypothalamus
• Basal Ganglia
• other neocortical areas, including in the PFC

2.3.23. Organic brain damage¶

Source¹⁷

2.3.24. Status epilepticus during sleep (ESES)¶

Other names: Bioelectric status epilepticus during sleep, CSWS, CSWS syndrome, ESES syndrome, Epileptic encephalopathy with continuous spike-wave discharges in slow-wave sleep
Prevalence: unknown. Orphan disorder (rare).¹⁰⁴

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.¹⁰⁵

ESES is associated with ADHD-like symptoms. In one study, treatment with ACTH showed a 67% mean reduction in ADHD symptoms.¹⁰⁶ Another study by the same authors found similar improvements with ACTH in ADHD and in stuttering.¹⁰⁷

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

Source¹¹

2.3.26. Histamine intolerance, histamine intolerance¶

The main physical symptoms of histamine intolerance are:^108109110

• Psychological symptoms
  • Depression
  • depressive moods
  • Winter depression
  • Mood swings
  • Exhaustion states
  • increased sensitivity (acoustic, visual, tactile, temperature, emotional, etc.)
  • Sleep disturbances, wakefulness
  • Tension, restlessness, agitation, arousal, nervousness, over-excitedness

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

• Muscle tension

• Hormone 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 wind, flatulence
  • Recurrent cystitis
  • Nausea, nausea
  • Vomiting, vomitus
• Cardiovascular system
  • Palpitations (synonyms: rapid pulse, tachycardia), up to panic attacks
  • Low blood pressure, sudden drop in blood pressure (hypotension, drop in blood pressure)]
  • Extra heartbeats (extra beats, extrasystoles)
  • Cardiac arrhythmias, cardiac strokes, arrhythmias, cardiac problems
  • Palpitations, palpitation
• Skin, mucous membranes, respiratory tract
  • Stuffy or runny nose (synonyms: blocked nose, runny nose, runny nose, rhinorrhea, nonallergic rhinitis, runny nose, nasal obstruction)
  • Sneezing, sneezing irritation
  • Airway constriction (synonyms: Bronchoconstriction, bronchoconstriction, bronchial constriction, and bronchial obstruction): e.g., shortness of breath (breathlessness, dyspnea), asthma, bronchospasm
  • Blush, red face, flush
  • Itching, pruritus, scratching
  • Erythema, skin redness
  • Hives, urticaria, urticaria, urticarial exanthema
  • Edema, water retention, swelling of the eyelids
  • Conjunctivitis, inflammation of the conjunctiva of the eye, inflammation of the eye

2.3.27. Bachmann-Bupp syndrome (BABS)¶

Bachmann-Bupp syndrome (BABS) is characterized by:¹¹¹

• 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 clumps during the first weeks of life
• Seizures at the beginning of later childhood (rare)
• Conductive hearing loss (rare)

Abnormal metabolites of polyamine metabolism (including elevated N-acetylputrescine levels) is suggestive of BABS.
Diagnosis by molecular genetic testing for heterozygous pathogenic de novo variant 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 critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in various cell types.
CAPRIN1 loss-of-function variants were associated with the following symptoms:¹¹²

• Speech Impairment/Language Delay (100%)
• mental disability (83%)
• ADHD (82 %)
• ASA (67 %)
• Breathing 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 KBG affected individuals, 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
• Dwarfism
• Skeletal anomalies
• global developmental delay
• Seizures
• mental disability

2.3.30. Cystic fibrosis¶

Cystic fibrosis is associated with increased ADHD symptoms.¹¹³

Cystic fibrosis correlates with mutations of the CFTR gene¹¹⁴, which has been found to be a win gene candidate for ADHD.¹¹⁵

2.4. Drug side effects¶

Significant effects usually only with continuous therapy.

Examples:

• Anticonvulsants
  e.g.:
  • Valproate¹¹
  • Phenobarbital⁵⁹¹¹⁶
• Beta-mimetics¹¹
• Drug-induced Hypovitaminosis of the B vitamins
  Vitamin B-12 deficiency causes ADHD-like symptoms
• Neuroleptics^17117118
• Benzodiazepines^17117118
  Benzodiazepines reduce the activity of the locus coeruleus and thus reduce the transport of norepinephrine to other parts of the brain.¹¹⁹ The disturbance of the norepinephrine production of the locus coeruleus is at the same time typical for ADHD.
• Antihistamines^17117118
• Antiepileptic drugs¹¹⁷¹¹⁸
• Isoniazid¹⁷¹¹⁸
• Bronchiospasmolytics¹¹⁷¹¹⁸
• Isoniazid¹¹⁷¹¹⁸
• Selective serotonin reuptake inhibitors (SSRIs)
  SSRIs (namely citalopram and escitalopram) are suspected to increase the action of dopamine reuptake transporters.¹²⁰. Overactive dopamine reuptake transporters are a possible cause to bring about the dopamine deficiency (especially in the striatum) that triggers ADHD symptoms by reuptaking the presynaptically released dopamine even before it has had a chance to produce its communication effect at the postsynapse. ⇒ ADHD - Neurotransmitter - 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 years: 7.85%.¹²¹
Anxiety disorders co-morbidly exist in 25% of ADHD sufferers,¹²² 16.7% of ADHD affected children and 27.2% of ADHD affected adults.¹⁴ Other sources cite 15% to 35%¹²³ and 35.6% in adults in England in 2007.¹²⁴

Performance anxiety is particularly common.¹²⁵

Common symptoms of anxiety disorders and ADHD:²⁴

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

ADHD symptoms atypical of anxiety disorders:

• High fluency of speech (logorrhea, polyphrasia)
• Thought chasing, thought circling
• Impulsivity (atypical for ADHD-I)

Symptoms of anxiety disorders atypical of ADHD:

• Fatigue
• Muscle tension

Anxiety in ADHD may partially reduce impulsivity and response inhibition deficits, exacerbate working memory deficits, and appears to be qualitatively different from pure anxiety. Comorbid anxiety in ADHD appears to have divergent expressions:¹²³¹²⁶

• 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 panic disorder: 3.2% to 3.6%¹²⁷

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

Prevalence of generalized anxiety disorder: 1.9% to 31.1%¹²⁷

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 17¹²⁸
under 18 years: Girls 2.54%, boys 1.10%.¹²⁹

Affective disorders are described in 27.9% of ADHD affected children and in 57.9% of ADHD affected adults¹⁴. Further, a prevalence of 37.1% for mood instability and 29.9% for depression in adults in England in 2007 is cited.¹³⁰

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

12% to 50% of children with ADHD also have depression, which is 5 times more common than children without ADHD.¹²³ A study of young adult depression sufferers reported a lifetime ADHD prevalence of 25.9%,¹³¹ which is also about five times.
The lifetime prevalence of major depression is 15%¹³²; women are affected twice as often as men, i.e., women 20%, men 10%.

In children with ADHD, emotional dysregulation occurs before comorbid onset depression.¹³³¹³⁴ This is not surprising, since emotional dysregulation is an original ADHD symptom, whereas depression can occur as a comorbid disorder. Nevertheless, the degree of emotional dysregulation in children with ADHD seems to moderate the likelihood of later depression.¹³⁵

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 incorrect here.
See ⇒ Depression and dysphoria in ADHD In this chapter.

Common symptoms of depression and ADHD:²⁴

• Inner restlessness (typical in atypical depression, less so in melancholic depression)
• Concentration problems
• Attention problems¹³⁶
• Memory problems¹³⁶
• Sleep problems
• Daytime sleepiness (typical in atypical depression, atypical in melancholic depression, possible in ADHD)
• Negative self-image¹²⁵

ADHD symptoms atypical of depression:

• Rapid mood swings
• Dysphoria only during inactivity
• High fluency of speech (logorrhea, polyphrasia)
• Thought chasing, thought circling
• Impulsivity (atypical of ADHD-I, atypical of melancholic depression)

Symptoms of depression atypical of 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)
• Decreased interest in activities (in ADHD, more likely withdrawal due to increased sensitivity or social phobia)
• Suicidal thoughts

In ADHD sufferers, depression typically occurs years after the onset of ADHD symptoms.¹³⁷ In this case, it is essential to treat the underlying ADHD, which is often the cause of the depression, in addition to the existing depression. Otherwise, the depression would merely be a secondary symptom of ADHD.^138137126
About 34% of all treatment-resistant depression is due to previously undiagnosed 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 alternation between depressive and manic symptoms. The changes can occur at different speeds. A change to a full-blown manic episode does not always occur.

ADHD is more common than average in people with bipolar, but the comorbidity with ADHD is arguably weaker than in relation to other mental disorders.¹²³

In a reaction test study, both ADHD and bipolar sufferers showed significantly increased variability of infrequent slow responses than controls, while bipolar sufferers showed significantly increased speed and variability of typical responses in the flanker task compared to ADHD sufferers and controls.¹³⁹

2.5.3.2.1. Depressive episode of bipolar disorder¶

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

See above under Depression as well as 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 problems¹³⁶²⁴
• Memory problems¹³⁶²⁴
• Sleep problems²⁴
• Daytime sleepiness (typical in atypical depression, atypical in melancholic depression, possible in ADHD)²⁴
• Rapid mood swings^{140 24}
• Thought chasing, thought circling^{140 24}
• Impulsivity (atypical for ADHD-I)¹⁴⁰²⁴
• Problems to relax (ADHD-HI, Bipolar in manic phase)¹⁴⁰
• Regulation of one’s own arousal.Inner restlessness, restlessness¹⁴⁰

ADHD symptoms atypical of manic episodes:

• Dysphoria only during inactivity

Symptoms of Bipolar that are atypical of ADHD:

• Alternation between depressive and manic phases

In ADHD, mood swings tend to be triggered (reactive) and pass quickly with distraction, whereas bipolar manic episodes tend to be more continuous and long-lasting.¹⁴¹

2.5.3.3. Cyclothymia (13 %)¶

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

Zyclothymia has been found in 75% of all bipolar sufferers and is significantly increased in ADHD and depression.¹⁴²

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

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

2.5.4.1. Dyspraxia (5 to 6 %)¶

Prevalence 5 to 6¹⁴³¹⁴⁴

Dyspraxia is also called the “clumsy child syndrome” or “clumsy child syndrome”.
Dyspraxia is a developmental disorder that lasts throughout life.
Dyspraxia is very often comorbid with ADHD or ASD.
Children with dyspraxia do not show abnormalities 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 slowdown
• Balance problems
  • Impaired gait
  • Difficulty getting dressed while standing
• Clumsiness in complex movements requiring balance and dexterity¹⁴⁵
  • Catch ball
  • Bounce
  • Jump
  • Climbing
  • Bike
  • Swimming
  • Couple dance
• Impaired automation of fine motor and gross motor activities
  • Impaired handwriting
    • Difficulty in guiding the pen with the correct pressure
    • Problems to keep boundaries of the sheet.
    • Writing on the computer goes much better
  • Problems tying shoelaces or bows
  • Problems closing buttons
  • Difficulty eating with knife and fork
  • Problems cutting out a figure cleanly
  • Frequent dropping of things
  • Problems with careful handling of glasses or dishes
  • Difficulty pouring into glasses
  • Problems with crafting or wrapping gifts
• Difficulty in acquiring new motor skills
• Impaired eye-hand coordination
• Frequent confusion of right and left
• Problems with the order of the clothes when dressing
• Rapid fatigue during physical activity
  • Sports
  • Hiking
  • Physical play
• Easy distractibility during tasks
  • Too much information on one sheet confuse
  • Improved task performance with larger line spacing, larger font size

No problems with:

• Hyperactivity.

2.5.4.1.2. Ideomotor dyspraxia¶

Problems with:¹⁴⁶

• Execution of the own plan of action
• Fill actions completely
• Writing difficulties
• Action difficulties
• Execution of understood instructions impaired
• Order is easily confused
• Impairment of imaginative or creative play

No problems with:

• Describe sequences of movements
• Recognize mistakes of others
• Read
• Talk

2.5.4.1.3. Ideatory dyspraxia¶

Difficulty planning and describing motor actions, but they do not have motor limitations.¹⁴⁶

Problems with:

• Form series (associated with weakness of memory)
• Describe sequences of actions
• Read words
• Work fast
• 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.¹⁴⁷

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

• Problems of planning the speech movements
• Difficulty pronouncing the right words at the right time in the right order.
• Frequent coughing or swallowing during food intake
  • Sequence of sucking, swallowing and breathing difficult
  • High saliva production when changing food from porridge to solid meals
• Language development significantly delayed
  • Significantly later start to speak
  • Initially only a few “babbling” sounds
  • Later often vowel language without consonants (“Oaaaa”, “Eeea”).
• Often problems with gross motor skills at the same time (see motor dyspraxia)
  • Stumble
  • Bump into each other, many 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 seem 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. decreased muscle tone
3. increased muscle tone
4. Inability to perform a uniform movement or to combine individual movement elements into an overall movement
5. Inability to form written symbols
6. Difficulties in visual perception associated with the development of the eye muscles

Affected individuals with developmental coordination disorder are said to have 50% ADHD as well.

The risk of ADHD is also increased in children 4 to 5 years of age with developmental coordination disorder. However, the DSM-5 scale seems to apply less frequently here.¹⁴⁸

2.5.4.3. Partial performance disorders¶

The comorbidity of ADHD and learning disorders is reported between 10% and 90%.¹²³
Learning disorders are reported to correlate with ADHD-I more often than with ADHD-HI.¹⁴⁹ Writing disorders are reported to be twice as common as reading, math, or spelling disorders in ADHD sufferers.¹⁵⁰

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

Present in 17.6% of children with ADHD.¹⁴
Dyslexia is reported to be more common in ADHD-I than in ADHD-HI.¹⁵¹

2.5.4.2.2. Dyscalculia (5 %)¶

Dyscalculia is reported to be more common in ADHD-I than in ADHD-HI.¹⁵¹

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

Prevalence: 10% of all adult women and 5% of all adult men experience post-traumatic stress disorder.¹⁷¹⁸
60% of all men and 50% of all women have at least one potentially traumatizing experience in their lives.¹⁵²
Of these, suffer from PTSD:

• Rape victims: 49 %¹⁵³
• Severe beating or physical assault: 31.9%¹⁵³
• Victims of crime: 25%¹⁵³
• Sexual assault without rape: 23.7%¹⁵³
• Serious accident (car or train): 16,8 %¹⁵³
• Shooting or stabbing: 15.4%¹⁵³
• Sudden death of a near or dear one: 14.3%¹⁵³
• Childhood life-threatening illness: 10.9%¹⁵³
• Victims of potentially traumatic experiences without crime: 9.4%¹⁵³
• Witnesses to a murder or violent assault: 7.3%¹⁵³
• Natural disaster: 3.9¹⁵³

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,¹⁵⁴ which is also not typical for ADHD). In ADHD, on the other hand, the sleep disturbances usually persist throughout life.

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

Source¹¹

Prevalence: 1% in primary school age (varying severity), 15% in elementary school age (incl. mild and transient forms).¹⁵⁵
Tic disorders are present in 9.5% of ADHD affected children.¹⁴
31%¹⁵⁶ to 55%¹⁵⁷ of children with tic disorders also exhibit ADHD.

2.5.7. Internet addiction (3.9% (2019) to 7.8% (2020))¶

Prevalence: among students in Germany 3.9% (2019) to 7.8% (2020, corona lockdown year) ¹⁵⁸
Internet addiction was distinguished by one study into two subtypes: one subtype that correlated with impulsivity and ADHD-HI and another subtype that correlated with compulsivity.¹⁵⁹

2.5.8. Social behavior disorder (1.5 to 5%)¶

Other names: Conduct Disorder
Source¹¹

Prevalence: in primary school age about 1.5%, in adolescents about 5%.¹⁶⁰
Oppositional defiant disorder is reported to be present in 46.9% of ADHD-affected children, and social behavior disorders in another 18.5%.¹⁴
Comorbidity between ADHD-HI and social behavior disorder is reported to be 15% to 85% of cases, depending on study design and direction of association, 4.7 times more common overall than in unaffected individuals.¹⁶¹
Oppositional defiant behavior and other social disorders are considered by individual professionals as a subtype of ADHD (Rage type). We rather suspect it to be a disorder of its own, which has a high comorbidity to ADHD.

Differentiation from ADHD: Aggression in (purely) ADHD sufferers is reactive, defensive motive, no intention to harm.¹⁰²¹⁶² Aggression in ADHD sufferers often arises from a misjudgement of situations, after which they (supposedly rightly) defend themselves. ADHD sufferers thus show a reactive and not a proactive aggressiveness.¹⁶³

2.5.9. Emotionally unstable personality / borderline (1 - 4 % (women), 1 % (men))¶

Prevalence Borderline: 1% - 3%¹⁶⁴ to 5%¹⁶⁵¹⁶⁶ Prevalence increases to 11% in psychiatric patients and up to 50% in inpatients.¹⁶⁷

75% of borderline victims are women.

Borderline is often found to be comorbid with ADHD in addition to symptom similarity to ADHD.¹⁶⁸¹⁶⁹ One study addresses the question whether one of the disorders (ADHD or Borderline) can change to one of the other disorders over time. Seemingly, ADHD is more likely to be considered an antecedent disorder and Borderline a subsequent disorder in adulthood. A major environmental difference reported in Borderline was the increased number of traumatic childhood experiences.¹⁷⁰ This, as well as the different genetic disposition described below, argue against a regular developmental sequence between the two disorders. Nevertheless, we know individual cases in which we consider a development of ADHD to a later Borderline or a later addition of Borderline to be a plausible explanation of the symptom picture.

Since Borderline is associated with a genetic disposition on the MAO-A gene, which is at the same time associated with aggression and behavioral disorders, Borderline is likely to co-occur primarily with ADHD-HI and rarely with ADHD-I.
ADHD resembles a personality disorder in its course (early onset, persistent behavior patterns, and possible persistence into adulthood).¹⁷¹
There are voices that consider ADHD-HI (with hyperactivity) and Borderline as a continuum varied by symptom intensity. Hallowell reports an ADHD-HI type with Borderline overtones.¹⁷² We also see a striking relationship to the point of strong confusability in layman’s terms, but assume that the aggressiveness added in Borderline is mediated by genes not typical of ADHD. As the correlating gene variants show, ADHD is characterized by a deficit of dopamine and norepinephrine in the dlPFC and striatum, whereas Borderline tends to have normal levels of dopamine in the PFC and an excess of dopamine in the striatum (see below).

Borderline and ADHD have very similar symptomatology, which is easily confused, and a high comorbidity. About 50% of borderline sufferers also have ADHD.
The “inner pressure” described in borderline (which can lead to self-injurious behavior) is also known in ADHD.

Differentiation of the symptomatology of ADHD and borderline:¹⁷³

The previous assumption that ADHD and borderline differ by the time of onset (ADHD earlier, borderline later) has since been questioned.¹⁶⁹

Common symptoms of borderline and ADHD:

• Impulsivity^{24174 175 176}
  • Much stronger in ADHD-HI than in borderline
  • High impulsivity in borderline is thought to indicate ADHD-HI comorbidity.
  • Different view: high aggressive impulsivity an endophenotype of BPD.¹⁷⁷ We think this is more likely because DAT 9R, the gene suspected 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 increased action impulsivity only in ADHD¹⁷⁸
  • Addiction problems¹⁷⁴
• Affective lability (ADHD-HI) / affective instability (borderline)¹⁷⁴

  • In ADHD-HI sufferers (with hyperactivity) and borderline sufferers, behavioral and affect regulation are similarly disturbed.

  • Rapid mood swings²⁴

  • Emotional dysregulation is even more pronounced in borderline than in ADHD. ADHD sufferers have a better use of adaptive cognitive emotional strategies than borderline sufferers.¹⁷⁹ All emotions are perceived significantly more intensely (and with more distressing intensity) than in non-affected individuals.¹⁶⁶

  • In Borderline, behavioral dysregulation also does not occur in neutral life circumstances, but only in stressful moments.¹⁷⁵

• Attention Deficit Disorder
  • In ADHD often when arousal is too low (lack of activation / stimulation)¹⁷⁴
  • In BPS more often during a rise in tension as a dissociative phenomenon¹⁷¹
• Dissatisfaction
• Dysphoria with inactivity
• Boredom (ADHD-HI) / Dysphoria, Boredom, Emptiness (Borderline)
• Self-esteem issues / grievability / rejection sensitivity¹⁷⁴
  • Especially Rejection Sensitivity (RS) ⇒ Rejection Sensitivity: sickliness/sensitivity to rejection and criticism as a specific ADHD symptom
    • RS has so far been confirmed to us by most ADHD sufferers 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, which decline much more slowly than in non-affected individuals.¹⁶⁶
• Conflictual relationships (ADHD-HI) / instability in relationships (borderline)¹⁷⁴
• Social weakness, impaired social behavior
• Sleep problems common
  • Borderline often shows a prolonged REM phase and nightmares (on average every 2nd night).¹⁵⁴ Nightmares are atypical for ADHD.
  • Difficulty falling asleep, shortened sleep duration, low sleep efficiency with subjectively less restful sleep are common in Borderline,¹⁵⁴ as well as ADHD.
  • Difficulty falling asleep in borderline is said to improve well with clonidine.¹⁵⁴ Probably guanfacine could also be helpful.
• Inner restlessness, restlessness²⁴
  • Required voltage reduction
    • In ADHD-HI (more often men): sports, sex¹⁷⁴
    • In BPD (more often women): Dissociation, freezing, self-harm,¹⁷⁴ sex

ADHD symptoms atypical of Borderline:

• Concentration problems²⁴
• Attention problems²⁴
• Cognitive impairments¹⁷⁸
• Hyperactivity
• Dysphoria with inactivity
• High fluency of speech (logorrhea, polyphrasia)²⁴
• Thought chasing, thought circling²⁴
• Executive function disorders
  • Disorganized
• One study found increased self-reported impulsivity in ADHD and borderline, but increased action impulsivity only in ADHD¹⁷⁸
• Slowing of reaction time,¹⁸⁰ although other studies have also found shortened reaction times in ADHD

Symptoms of borderline that are atypical of ADHD:

• Self-harming / self-injurious behavior
  Impulsive behavior in response to intense negative feelings (“negative urgency”)¹⁷⁸ is one of the most distinctive symptoms that characterizes Borderline¹⁸¹
  • E.g. scratching (nevertheless not every self-injurious behavior is borderline)
    • Self-injury reduces subjective stress levels and objective amygdala activity, which are very high after a stress test, in borderline sufferers (by increasing connectivity in frontal-limbic brain regions that dampen amygdala activity), whereas it further increases (lower) stress levels and objective amygdala activity in unaffected individuals.¹⁶⁶
• Think black and white
  • Shades of gray, a both/and, mediating positions are difficult to perceive and hard to bear.
  • In discussions, sufferers tend to take extreme positions. For interlocutors, this can feel like the person is sliding off a bar of soap - either left or right, but unable to take a middle both/and or mediating position.
• Identity Disorders
• Dissociation
• Abandonment fears²⁴
  • Feel lonely, even when among people¹⁶⁶. We suspect that this is much more pronounced in Borderline than in ADHD.
• Unstable relationships, unstable self-image²⁴
• Suicidal thoughts²⁴
• Paranoid symptoms²⁴
• Strong sense of guilt and shame

In comorbid ADHD + Borderline in particular are said to be more pronounced:¹⁶⁹

• Impulsivity (as in ADHD alone)
• Symptoms of regulation of traits and emotions (than in Borderline alone)

In children and adolescents, certain character traits increase the risk of borderline personality disorder later in life:¹⁶⁷

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

Borderline sufferers differ from sufferers of other personality disorders primarily by a pronounced histrionic as well as by more frequent narcissistic, bipolar / cyclothyme or aggressive expression. There is greater lability in relation to anger and anxiety, as well as greater oscillation of occurrence between depression and anxiety. The level of intensity of emotion perception is surprisingly not higher. In contrast, obsessive-compulsive, schizoid, and anxious-avoidant expressions are less frequent. These results are independent of gender.¹⁸²

Dopaminergic substances (stimulants) can provoke impulsive and aggressive behavior in borderline.¹⁷⁷ This indicates an excess of dopamine in borderline, which is different from the dopamine deficit in ADHD.
This is consistent with research findings that Borderline correlates with DAT1 gene variants 9/9 and 9/10, which cause lower DAT expression in the striatum, so higher dopamine levels in the striatum should be expected due to lower dopamine depletion by DAT.¹⁸³

The 9-repeat variant of the DAT1 gene causes an excess of dopamine in the synaptic cleft, because the dopamine transporters then insufficiently reuptake the dopamine presynaptically. DAT 9R is associated with affective disorders and borderline.¹⁸⁴
Borderline correlates more often with¹⁸³

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

The risk for borderline increases for carriers of the gene variant combinations¹⁸³

• 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 clearance and therefore decreased dopamine levels in the striatum. This now explains why stimulants that increase dopamine and norepinephrine levels in the PFC and striatum work well in ADHD, whereas they can be counterproductive in borderline.

5 HTTPLR and 5-HT2c are two other canditate data genes in Borderline.¹⁸⁵

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 thought to correlate with deviation in μ-opioid receptors compared with unaffected individuals.¹⁸⁶

Antipsychotics produce significant but small improvement in cognitive perceptual symptoms, mood lability, and global functioning in BPD. The effect is more pronounced with respect to anger/rage. They have no significant effect on behavioral impulsivity, depression, and anxiety.¹⁸⁷

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

Source¹¹

Prevalence: lifetime prevalence of 1 to 3%,¹⁸⁸¹⁸⁹ 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%.¹²⁹

Olfactory disorders (disorders of the sense of smell) are common in ASD and OCD, but not in ADHD.¹⁹⁰

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

Source¹⁹¹

• High impulsivity
• Strong Novelty Seeking / Sensation Seeking
• Self-centeredness / egocentricity
• Lack of empathy towards others
  • Not being able to feel how others feel

Subgroups of antisocial personality disorder:

• Impulsive type
  • Frequent comorbidity to ADHD-HI / ADHD-C
  • Emotionally highly sensitive / hyperreactive
  • Increased excitability
  • High impulsivity
  • Reactive aggression - as an immediate reaction to triggers
  • Low stress tolerance
• Psychopathic type
  • Rare comorbidity to ADHD-HI / ADHD-C
  • Emotionally insensitive / hyporeactive
  • Active aggression - purposeful, instrumental violence
  • No increased arousal when frustrated
  • No reduced stress tolerance

Differentiation from ADHD: Aggression in (purely) ADHD sufferers is reactive, defensive motive, no intention to harm ^{102 162} Aggression in ADHD sufferers often arises from a misjudgement of situations, after which they defend themselves (supposedly rightly). We see in this a connection to Rejection Sensitivity as an overshooting sensitivity to supposed or actual rejection / offending. ADHD sufferers thus show a reactive and not a proactive aggressiveness.¹⁶³

Common symptoms of antisocial personality disorder and ADHD:²⁴

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

ADHD symptoms atypical of antisocial personality disorder:

• Inner restlessness (typical in atypical depression, less so in melancholic depression)
• Concentration problems
• Attention problems
• Dysphoria with inactivity
• High fluency of speech (logorrhea, polyphrasia)
• Thought chasing, thought circling

Symptoms of antisocial personality disorder atypical of ADHD:

• Criminal behavior
• Deception of others
• Disregard for self 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. Similar are:

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

2.5.13. Schizophrenic disorder (1%)¶

Lifetime prevalence is approximately 1%.⁶⁰
Girls under 18 years: Prevalence 0.76%, boys 0.48%.¹²⁹

Schizophrenia is highly heritable (like ADHD about 80%)¹⁹² and usually develops after adolescence. However, it is usually preceded by childhood precursors that do not resemble schizophrenia itself but seem to genetically indicate schizophrenia.¹⁹³

The negative symptoms of schizophrenia are based on dopamine deficiency. They are similar to ADHD symptoms.
Positive symptoms, on the other hand, are due to excessive subcortical presynaptic dopamine transmission (dopamine hypothesis). This is reduced by antipsychotic dopamine D2 receptor antagonists, but in schizophrenia D2/D3 receptors seem to be only very slightly increased and DAT not altered at all, so that other medication approaches might be more reasonable.¹⁹⁴
The excessive subcortical dopamine drive is likely due to alterations in cortical function, particularly the reduction in cortical NMDA receptor-mediated glutamate signaling, which impairs cortical dopamine and GABA function. These cortical changes likely cause the cognitive impairments and negative symptoms of schizophrenia.¹⁹²

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

COMT rs4680, which is implicated in schizophrenia (as one of 50 or more candidate genes), enhances the degradation of dopamine and norepinephrine by forming a more active and thermally stable COMT enzyme.¹⁹⁵ This causes higher schizotypal symptoms.
This can be reconciled with the recent dopamine hypothesis, according to which the positive symptoms of schizophrenia are not caused by a generally increased level of dopamine 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 lack of dopamine in the ventral tegmentum.¹⁹⁵

Schizophrenia and attention:

• Sensitivity to sensory stimulation increased¹⁰²
• High sensitivity causes sensory overload¹⁰²
• Attentional selection for individual events disturbed¹⁰²
• Concentration/maintenance of concentration on relevant aspects of a task disturbed.¹⁰²

Symptoms of schizophrenia atypical of ADHD:

• Drawings are non-spatial, no three-dimensional representation
• Irony / sarcasm are not understood
• Olfactory disturbances.¹⁹⁰

2.5.14. Psychoses (1 %)¶

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

Sources⁹¹⁰¹¹

Prevalence ASA: approx. 0.9%¹⁹⁶
About 42%¹⁹⁷ to 50%¹⁹⁸ of all ASD sufferers also have ADHD.
ADHD and autism probably have common neurological/genetic roots.¹⁹⁹ One review concluded that ADHD and ASD may be a continuum.²⁰⁰

• Profound developmental disorder
  Prevalence: approx. 0.6 %¹⁹⁶
• Autism⁵⁹
  Prevalence: approx. 0.3 %¹⁹⁶
• Asperger’s
  Prevalence: approx. 0.084 %¹⁹⁶
• Disintegrative disorder⁵⁹
  Prevalence: 0.008% (One affected person in 12500 people)¹⁹⁶
• Rett syndrome⁵⁹
  Prevalence: 0.006% (One affected person in 10000 to 17000 people)²⁰¹¹⁹⁶
  Concerns only girls
  Rett syndrome symptoms²⁰¹
  • Stereotypies of the hands (washing movements)
  • Partial autistic behavior
  • Dementia
  • Reduced head growth
  • Epileptic seizures (later stage)
  • Spasticity (later stage)
  • Apraxias
  • Muscle atrophy
  • Movement disorders in the area of the thorax
  • Social behavior and play development strongly inhibited
  • Social interest continues

Differential diagnosis to ADHD:

Children with ASD had 15 or more of the 30 symptoms (mean: 22 = 73%) of the Checklist for Autism Spectrum Disorder symptoms, whereas 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 common among children with ASD.²⁰²
ADHD-affected children showed elevated scores on the Social Responsiveness Scale (SRS), but these did not approach the scores of ASD-affected children.²⁰³

In favor of ASS:²⁰⁴

• Inattention more likely due to too much detail orientation in ASD (vs. overlooking details in ADHD)
• Concentration breaks down when routines are disrupted in ASD (vs. lack of routines and jumping quickly between different things in ADHD)
• The unexpected is seen as an unpleasant irritation and disruption of one’s own structure (rather than as a welcome change in ADHD)
• Routines due to own need for structure (versus tedious habit of routines to not lose structure too much in ADHD)
• High difficulty in social situations due to internal uncertainty about how to behave properly (vs. ticking off due to careless behaviors in ADHD)
• Difficulty grasping social rules of play (versus difficulty adhering to well-grasped social rules of play in ADHD)
• High attention to detail blows up time frames for activities (vs. project cancellations 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 keep order due to other priorities in ADHD)
• Deviation from the plan leads to irritation (versus frequent deviations from the plan due to own spontaneity and impulsiveness)
• Reduced flexibility (versus more mildly impaired flexibility in ADHD)
• Concentration can be maintained on longer and repetitive tasks (vs. difficulty maintaining concentration on monotonous boring tasks in ADHD)
• Motor restlessness tends to occur in agitated situations to relieve (versus motor restlessness in calm situations to stimulate in ADHD)
• Motor restlessness more likely to be from aversion to something = running away (vs. from interest in something = running towards in ADHD)
• Loose conversations or small talk unpopular, as own thought structures are thwarted; sometimes compensation by strict conversation (not present in ADHD)
• Lack of sense of 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 non-stimulating room is a rather pleasant idea (very unpleasant in ADHD-HI / ADHD-C; both possible in ADHD-I)

In ASD, the intracortical pathway (facilitation) appears unimpaired, whereas in ASD with comorbid ADHD, the intracortical pathway appears impaired. This could represent a biomarker to distinguish ASD from ADHD.²⁰⁵

ASD as well as ADHD showed slower orienting responses to relatively unexpected spatial target stimuli compared with controls, which was associated with higher amplitudes of pupil dilation in ASD. ADHD showed shorter cue-evoked pupil dilation latencies than ASA and controls.²⁰⁷

Several studies addressed differences between ASD and ADHD:

• Lower verbal comprehension in ASD than in ADHD²⁰⁸
• Lower vocabulary in ASD²⁰⁸
• Lower comprehension in ASD²⁰⁸
• Worse image concepts in ASD²⁰⁸
• Worse image completion with ASS²⁰⁸
• Slower processing speed with ASD²⁰⁸
• Lower social judgment in ASD²⁰⁸
• Poorer response to name call at 24 months of age in ASD²⁰⁹
• Higher shifting with ASS²¹⁰
• Poorer emotional self-regulation in ASD²¹⁰
• ASD, like dyslexia, shows deficits in global motion processing, unlike ADHD. ASD and dyslexia show significantly lower flicker fusion frequency than healthy controls or ADHD subjects.²¹¹

ADHD compared to ASD:

• Poorer working memory typical for ADHD, less so for ASD²⁰⁸²¹⁰
• Planning and organization problems (largely determined by working memory) typical of ADHD, less so of ASD²¹⁰
• Inhibition problems typical of ADHD, less so in ASD²¹⁰
• Fewer points in the Digit Span for ADHD than for ASD²⁰⁸
• Worse graphomotor processing in ADHD²⁰⁸

ADHD like 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 had significantly lower volumes of the left postcentral gyrus, but only children, not adolescents.²¹²
One review compared catecholaminergic and cholinergic neuromodulation in ASD and ADHD. The authors concluded:²¹³

• Stimulants may be a viable treatment option for a (possibly genetically defined) ASD subgroup
• a disturbance of the cerebellum is much more frequent in ASD than in ADHD
  • in both cases, this could open up a norepinephrine- or acetylcholine-driven 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 may predict efficacy of targeted treatment of an underlying deficit using dopamine, norepinephrine, or acetylcholine, in ADHD as in ASA

ASD is characterized by high aggression and risk-taking behavior. In addition, ASD is disproportionately involved in child abuse.²¹⁴ Aggression and high-risk behavior are also hallmarks of the ADHD-HI subtype.

One review article found blood norepinephrine levels approximately doubled in ADHD and approximately halved in ASA, compared to unaffected individuals. In contrast, serotonin blood levels were increased fourfold in ASA and decreased more than fourfold in ADHD.²¹⁵

2.5.16. Fragile X syndrome (0.22% (males) to 0.66% (females))¶

Prevalence: 1/150 (0.66%) women, 1/456 (0.22%) men in the U.S²¹⁶
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, and repetitive and stereotyped interests and behaviors. There are often comorbidities to decreased intelligence, ADHD, aggression, and obsessive-compulsive disorder.²¹⁷

2.5.18. Wilson Disease (0.0033%)¶

Wilson Disease (prevalence: 1 in 30,000 people, 0.0033%) is associated with excessive copper levels.
Affected individuals with Wilson Disease show symptoms confusable with ADHD²¹⁸
Wilson Disease is associated with an ATP7B gene defect and shows an excess of copper.
Although dopamine-β-hydroxylase, which converts dopamine to norepinephrine, 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).²¹⁹

Symptoms of severe dopamine deficiency may include:²²⁰

• Parkinson’s
• Dystonia
• Chorea
• oculogyric crises/gaze spasm
• Ptosis/eyelid muscle weakness
• Dysphagia
• myoclonic epilepsy
• Epileptic encephalopathy
• Progressive cognitive dysfunction
• Microcephaly
• Pyramid web sign

Symptoms of severe serotonin deficiency may include:²²⁰

• Temperature problems
• Sweating
• Dystonia

To detect deficiencies of precursors and specific metabolic defects, the measurement of pterins (especially biopterin and neopterin) in urine is helpful:

*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
  • Prolactin increased in blood
  • Galactorrhea
• Strong dopamine excess
  • Prolactin in blood decreased

2.5.19.1. Genetic 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%)²²¹
  • 46 % of all BH4 disorders
• 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency
  • Prevalence: 1 / 500,000 to 1/ 1,000,000 (0.0001 % to 0.0002 %) ²²²
  • 54 % of all BH4 disorders

appear to co-occur with ADHD and other mental health disorders such as anxiety, depression, aggression, or oppositional defiant behavior.²²³

See also Tyrosine hydroxylase In the article Dopamine formation.

2.5.19.2. Missing or strongly reduced DAT¶

There are (rarely) people without or with very much reduced DAT. However, these show other symptoms that are not typical for ADHD (e.g. early Parkinson’s dystonia) and are therefore rarely misdiagnosed with ADHD and rather with cerebral palsy. Many affected individuals die as teenagers.²²⁴ Excess extracellular dopamine leads to decreased production of dopamine (and thus decreased storage of dopamine in vesicles) and downregulation or desensitization of dopamine receptors through activation of presynaptic D2 autoreceptors, resulting in phasic dopamine deficiency and dopamine action deficiency.²¹⁹

2.5.20. Predominantly environment-related behavioral problems¶

Predominantly milieu-related behavioral problems means, for example, lack of attention and stimulation, physical and/or mental abuse, media abuse, intra-family conflicts and sibling conflicts¹¹
According to our understanding, this description corresponds to the environmental causes of most mental disorders such as ADHD, depression, anxiety disorders, borderline, etc., which can all 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 environment-related behavioral disorders are therefore unsuitable to define a separate disorder pattern.
⇒ How ADHD develops: genes or genes + environment
⇒ Genes + early childhood stress as a cause of other mental disorders