Cortisol and other stress hormones in ADHD
- 1. Stress hormones in ADHD
-
2. Cortisol responses to stress and personality traits
- 2.1. High cortisol response: internalizing, low cortisol response: externalizing
- 2.2. Cortisol responses as an expression of stress phenotype
- 2.3. Cortisol stress responses by time course
- 2.4. Cortisol stress responses by gender
- 2.5. Cortisol responses to stress in the unaffected
- 2.6. Interplay between cortisol and dopamine
- 2.7. Interplay between CRH and norepinephrine
- 3. Changes in cortisol levels in ADHD
- 4. ACTH in ADHD
- 5. CRH in ADHD
- 6. α-Amylase in ADHD
- 7. Diagnosis and treatment of ADHD by cortisol / dexamethasone?
- 8. Treatment of ADHD by cortisol / dexamethasone?
1. Stress hormones in ADHD
In ADHD, various stress hormones are altered.
The stress hormones discussed below, cortisol, ACTH, and CRH, are the 3rd, 2nd, and 1st stage stress hormones of the HPA axis. Alpha-amylase is a biomarker of autonomic nervous system activity.
In summary, it must be assumed that although the cortisol response to acute stressors, which is often flattened in ADHD-HI and very often exaggerated in ADHD-I, is a biomarker for a pathological change in the HPA axis, the change in the cortisol response is not the cause of ADHD. Comparable experiences are made in the treatment of depression.1
However, too many studies suffer from the fact that in ADHD, as in depression, the externalizing subtypes (ADHD-HI, atypical depression) and the internalizing subtypes (ADHD-I, melancholic depression) are not recorded separately.
2. Cortisol responses to stress and personality traits
2.1. High cortisol response: internalizing, low cortisol response: externalizing
We have collected quite a few sources showing that high or low cortisol stress responses in healthy individuals correlate with gender and with various general personality traits.
See more at ⇒ Cortisol stress responses and personality traits in healthy individuals In the section ⇒ Stress response patterns in healthy people of the article ⇒ Stress theories and stress phenotypes: a possible explanation of ADHD subtypes.
2.2. Cortisol responses as an expression of stress phenotype
The available research strongly suggests that externalizing or disruptive behaviors, such as aggression, with or without a presence of (comorbid) Oppositional Defiant Disorder (ODD) or a symptomatically more severe Conduct Disorder (CD), are associated with lower basal cortisol levels and a flattened cortisol response to acute stress.
Elevated basal blood cortisol levels in 15-year-old ADHD sufferers (decreasing in the late afternoon) correlated with aggression in boys but not in girls.2 Another study found a correlation of aggression with flattened cortisol responses to acute stress, while basal cortisol levels remained unchanged.3
In contrast, depression or depressive personality traits45 6 as well as anxiety78 correlate with elevated morning (CAR) or serum cortisol levels.
⇒ Cortisol in other disorders
If - as we assume - not only ADHD but also the other mental disorders mentioned here are understood as dimensional disorders, and further ADHD-HI as externalizing stress phenotype and ADHD-I as internalizing stress phenotype, it is reasonable to hypothesize that primarily the stress phenotype could determine the cortisol response to acute stress (or the cortisol response to acute stress could predict the stress phenotype).
This view further leads to the conclusion that dexamethasone testing of the HPA axis for cortisol reactivity could only determine whether an HPA axis disorder is present and whether it results in an externalizing or an internalizing stress phenotype, but not which mental disorder is present within each spectrum.
It is argued that cortisol stress responses are more predictive of comorbidities than ADHD. According to this view, blunted cortisol responses to stress are said to be associated with comorbid DBD (disruptive behavioral disorder), whereas high cortisol responses are associated with comorbid anxiety disorders.910 This is consistent with our view of correlating blunted cortisol stress responses with externalizing and exaggerated cortisol stress responses with internalizing disorders.
Reduced exchange between brain hemispheres appears to be a cause of reduced cortisol stress response (especially in PTSD), as well as alexithymia.11 Further, a coincidence of decreased basal cortisol levels (despite normal cortisol response to ACTH) and alexithymia is reported in some sufferers of chronic stress, from which the authors inferred ACTH-independent mechanisms that decrease cortisol levels.12
2.3. Cortisol stress responses by time course
It is problematic that the individual stress cortisol response maximum differs by up to 20 minutes. In a group of 54 healthy adults, the cortisol maximum in the early group occurred immediately at the end of the 15-minute TSST stressor (cortisol rise from 0.04 to 0.21 ng/ml), whereas in the late group it occurred 20 minutes later (from 0.05 to 0.22 ng/ml). If both groups had been examined immediately after the end of TSST, the late group would have been incorrectly categorized as responding predominantly to stress with a flattened cortisol rise from 0.05 to 0.07.13 In most studies, a cortisol measurement 20 minutes after the end of the TSST is common. The question arises as to whether the early group’s cortisol rise lasts long enough to be cleanly detected when measured after 20 minutes.
Many studies do not take enough cortisol samples at the end of the stress test to account for this.
According to one source, the cortisol levels of ADHD sufferers only deviate (upward) from those of non-affected persons, even in the presence of stress, if relationship-relevant topics were the subject of the stress test (increased sensitivity to relationship topics), but not in the presence of purely cognitive stressors.14 This is not confirmed by most research. To clarify this, a distinction is made below between cognitive and emotional stressors.
2.4. Cortisol stress responses by gender
Cortisol responses to stress also differ by gender.15
2.5. Cortisol responses to stress in the unaffected
- Among 102 non-ADHD-diagnosed five-year-old children, HPA activity was significantly higher in girls than in boys. Emotional stress (story telling away) caused a significant increase in cortisol in all children, and this was even higher in girls than in boys. Increased HPA system activity (basal and stress reactive) correlated significantly with hyperactivity/impulsivity and emotional problems in boys and with positive emotions in girls.16
- Chronic stress decreases the morning cortisol maximum (CAR, typically 30 to 60 min after waking) in healthy young men (mean 22.5 years).17 Even low levels of stress increased baseline levels upon awakening and significantly decreased the CAR maximum (30 min after awakening). Severe stress led to an even significantly higher baseline value with a likewise flattened CAR, which moreover already occurred 16 min after waking.
- The cortisol response to physical stress is dependent on
- The individual cortisol resting concentration and the preload1819
- Of muscle mass. The cortisol response to physical stress is relatively lower with larger muscle mass than with smaller muscle mass.20 According to our assumption, this could simply be due to the lower relative load when one and the same work is performed by more muscle mass.
- The current blood glucose concentration and insulin availability before the start of the load 21
- A metastudy of 29 studies on 2601 subjects found no correlation between externalizing behavior and a (flattened) cortisol stress response, as should exist according to the hypothesis we advocate.23
2.6. Interplay between cortisol and dopamine
Glucocorticoid receptors are located on numerous dopaminergic cells of the midbrain and hypothalamus.24 Cortisol is thought to influence dopamine release in the basal ganglia and in nigrostriatal and mesolimbic pathways.25
Cortisol inhibits tyrosine hydroxylase, an enzyme that limits catecholamine synthesis by serving as a catalyst for the conversion of tyrosine to DOPA. Tyrosine hydroxylase is inhibited by cortisol (as well as by dopamine and norepinephrine themselves (negative feedback).26
This suggests a reciprocal interplay between dopamine and cortisol release.
A retrospective analysis found a correlation between inhaled corticosteroid use in younger children with moderate to severe asthma. This correlation was not found in older children.27
2.7. Interplay between CRH and norepinephrine
The hypothalamus, which releases CRH, is closely connected to the nucleus coeruleus, which produces noradrenaline. CRH activates norepinephrine release, while conversely, at the same time, norepinephrine stimulates CRH production.26
3. Changes in cortisol levels in ADHD
A large number of studies have addressed the question of whether and how the HPA axis responds aberrantly in ADHD. There is now massive evidence that there are sustained changes in the HPA axis in ADHD.
Epidemiological and preclinical studies have shown that HPA axis dysfunction in ADHD may result from excessive cortisol exposure in the fetal and early postnatal period (early childhood stress). Glucocorticoid administration at this stage of life may permanently alter glucocorticoid receptors in the brain, causing dysregulation of HPA axis activity, disturbances in the biosynthesis of neurotransmitters and their receptors, and alterations in intracellular pathways. Glucocorticoids (cortisol) enhance the activity of the dopaminergic system. Decreased expression of glucocorticoids could thereby cause the underactivity of the dopaminergic system.28
A fundamental distinction must be made between basal cortisol levels and cortisol responses (reactions) to acute stress. While the subtypes of ADHD differ by reduced basal cortisol values compared to non-affected persons, but not by deviations among themselves, the cortisol response to acute stress of ADHD-HI/ADHD-C on the one hand and ADHD-I subtype on the other hand differs considerably and systematically from each other and deviates in different directions from the values of non-affected persons.
Basal cortisol levels thus distinguish ADHD sufferers from non-affected individuals, and cortisol responses further distinguish subtypes.
Furthermore, it is striking that in ADHD-I (without hyperactivity/impulsivity) the stress-induced cortisol increase is significantly higher than in non-affected persons, whereas in ADHD-HI (with hyperactivity) as well as in ADHD-C acute stress triggers a significantly lower cortisol response than in non-affected persons.
This may be relevant to treatment because cortisol not only mediates the stress response of the HPA axis but also acts as a feedback loop to calm and deactivate the stress systems (the HPA axis and central nervous system).
We hypothesize that a one-time higher cortisol administration in ADHD-HI could shut down the stress systems again. If the cortisol response that signals the shutdown of stress systems is absent, it would at least be worth considering compensating for this with a one-time cortisol substitution. Since a high cortisol stress response is a healthy response to shut down the HPA axis again, no disadvantages should necessarily result from a one-time intermittent administration. For ADHD-I sufferers, on the other hand, this is unlikely to be useful by its very nature.
Dexamethasone could be recommended for this purpose, as it addresses GR 30 times more strongly than MR. If necessary, a combination with an MR antagonist such as eplerenone could be considered, as it was used in a study for the treatment of back pain.29
Cortisol administration could not only downregulate the HPA axis but also support downregulation of the PFC.
Stress-induced highly elevated norepinephrine inhibits PFC and working memory function via norepinephrine-α1 receptors to shift action control from slow analytic control by the PFC to rapid instinctive control by older brain regions because this is advantageous during fight or flight.
Stress-induced high cortisol release leads to stimulation of these same norepinephrine-α1 receptors in the PFC. The simultaneous addressing of these receptors enhances the effect caused by high norepinephrine levels.30
In healthy individuals, the endocrine stress responses of norepinephrine and cortisol correlate, so that a coincidence of high norepinephrine and high cortisol levels can trigger PFC deactivation.
Cortisol plays a role in ADHD,31 but not in inhibition.32
3.1. Cortisol responses to stress in ADHD altered in a subtype-specific manner
Quite a few studies have looked at the cortisol response of ADHD sufferers to stress by measuring cortisol levels before and after stress exposure.
However, a distinction must be made between ADHD-HI (with hyperactivity) and ADHD-I (without hyperactivity). If this differentiation is omitted, even meta-studies find no difference in the cortisol stress response of ADHD to non-affected individuals.33
Chronic stress exposure decreases the expression of the glucocorticoid receptor (GR), which shuts down the HPA axis after a stress response. A slower decline in cortisol levels to baseline after an acute stressor, i.e., a prolonged time to recovery, was observed34
3.1.1. Responses to cognitive stress in ADHD
- 51 of 68 ADHD-affected children (mean age 8.8 years) showed no increase in cortisol on an unspecified “psychological test as stressor”. It is possible that the Hamburg-Wechsler Intelligence Test (WISC-III) was also used as a stressor. The 17 subjects with cortisol increase under stress had higher IQ, although the report is not clear whether this is the IQ value measured after stress or the IQ value without stress. The pretest cortisol level correlated with IQ. The lower the cortisol level after the test, the lower the IQ of the subjects.35
- 20 Children with ADHD and comorbid oppositional defiant disorder (ODD) and social behavior disorder (CD), thus with high levels of aggression, showed no cortisol increase to a cognitive stressor at age 4 to 6 years as they did 2 years later at age 6 to 8 years. ADHD sufferers whose problem persisted showed a flattened cortisol response.36 This is consistent with the other studies in that ODD and social behavior disorder are typical comorbidities of the hyperactive/impulsive ADHD-HI subtype, for which a decreased/absent cortisol rise is commonly reported.
- Of 48 children exposed to the Korean Hamburg-Wechsler Intelligence Test (KEDI-WISC) as a stressor, 28 showed a drop in cortisol and 15 showed an increase in cortisol levels.37 Children with a cortisol drop made more omission errors and incorrect responses, which is thought to demonstrate impulsivity problems. This suggests the hyperactive-impulsive ADHD-HI subtype. The children with an elevated cortisol stress response made more false responses in the attention test, suggesting attention problems. Non-affected individuals were not compared.
- Of 49 children with ADHD without other comorbidities between 6 and 17 years of age, 33 showed no cortisol increase on the Korean Hamburg-Wechsler Intelligence Test (KEDI-WISC) and the TOVA test as (cognitive) stressors, and 16 showed a cortisol increase.3 The 33 children with a cortisol decrease had an IQ greater than 110, and the 16 children with an increase had an IQ less than 110 (IQ mean: 92.3). A cortisol decrease also correlated with higher aggression scores and lower attention scores in the K-CBCL. Children with cortisol increases tended to have more withdrawn characters and fewer social problems. This also fits the picture of a decreased/absent cortisol response in the hyperactive-impulsive ADHD-HI subtype. Non-affected individuals were not compared.
- 68 of 90 ADHD-affected children did not show increased cortisol responses to stress by the Korean-Wechsler Intelligence Scale for Children-Third Edition (K-WISC-III). Increased cortisol responses to a stressor correlated with increased variance in response time.38 Nonresponders were not compared.
Increased variance in response times could be explained by an impairment in the performance of the PFC, as is particularly pronounced in the ADHD-I subtype.
Prolonged reaction times correlated with ADHD-I.39 - 38 ADHD-affected children showed a significantly higher cortisol increase to the Continuous Performance Test (CPT) as a stressor than 38 unaffected children, regardless of subtype.40 A follow-up study of the same subjects 4 years later showed that the cortisol stress responses of the ADHD-affected subjects had decreased and were now similar to those of the unaffected subjects.41
Rating:
We consider stress testing by means of an intelligence test to be of little use. That people with a higher IQ are less stressed by an IQ test than people with a lower IQ should be the intrinsic purpose of an IQ test. We further assume that children with reduced intelligence are more stressed by cognitive tests and intelligence tests because they expect a negative evaluation, which ultimately means that only the expected social evaluation would trigger stress. On the question of which circumstances trigger cortisolergic stress in the first place, see above.
Further, the ADHD-HI (hyperactive/impulsive) and ADHD-I (non-hyperactive) subtypes are likely to respond differently to different stressors due to their different stress phenotypes. We hypothesize that the more extroverted ADHD-HI type will be less stressed and possibly even more stimulated by social exposure (finishing storytelling and doing mental arithmetic aloud while observing/judging others) than the more introverted ADHD-I type, whose stress response is an inward escape.
This is consistent with van West’s findings.42
3.1.2. Responses to emotional stress in ADHD
- A study of 9 ADHD-HI, 10 ADHD-I, and 14 ADHD-C affected and 33 unaffected (6 to 8 years, mean 6.3 years) using TSST-C also found a significantly decreased cortisol response in ADHD-HI affected and a comparatively higher cortisol response in ADHD-I affected. All subtypes showed lower baseline cortisol levels than unaffecteds. Unaffected individuals did not show a strong cortisol response.43 The latter could indicate test arrangement problems. In addition, the number of subjects per subtype was too small for reliable conclusions.
- A study of 18 ADHD-affected adults and 18 non-affected adults came to no clear conclusion. Only a general tendency towards a reduced cortisol response to acute stress and an increased subjective stress perception in ADHD sufferers was reported.44 This may have been due to the small number of subjects, as well as the lack of separation by subtype.
- A study of young adults without differentiation between ADHD-HI and ADHD-I generally found increased cortisol stress responses in ADHD.45
- A study that used simple sensory items rather than the TSST as stressors to examine high sensitivity in ADHD found no significant differences in cortisol stress response between non-ADHD, ADHD without, and ADHD with high sensitivity.46 It would have been interesting to see if the responses to the TSST would have differed.
3.1.2.1. ADHD-HI, ADHD-C, and comorbid externalizing disorders
- A study of 96 adults with ADHD and 25 unaffected individuals revealed a flattened cortisol response in ADHD-C compared with unaffected individuals, and an increased stress-induced cortisol response in the ADHD-I subtype.47
- Children (6 to 12 years, mean 8.6 years) with the ADHD-HI-ADHD-C were significantly less likely to have the cortisol increase (expected in healthy individuals) to emotional stress (Public Speaking Task, PST and Trier Social Stress Test, TSST) than unaffected individuals, whereas the predominantly inattentive ADHD-I subtype showed a significantly stronger cortisol response than unaffected individuals.48 Only 35% of ADHD-C sufferers showed stress-related elevated cortisol levels, compared with 92% of ADHD-I sufferers and 88% of nonaffected individuals. This study also confirmed a relationship between aggression, externalizing problems, and decreased cortisol stress response.
- ADHD sufferers with high hyperactivity/impulsivity symptoms showed decreased cortisol suppression after dexamethasone testing.49 This may result from a flattened cortisol stress response or lower addressable glucocorticoid receptors.
- When alpha-amylase release (marker of the sympathetic stress system) is low in response to acute stress by the TSST, a concomitant low cortisol response correlates with high levels of aggression; when alpha-amylase release is high in response to acute stress, the cortisol response has no correlation with aggression.50
- Of 202 male adolescents (10 to 17 years, mean 14 years), the 107 who had comorbid social behavior disorder (CD) responded to a psychosocial stressor with significantly greater reduced cortisol stress reactivity compared with the 97 ADHD-HI-only subjects.
The more severe the ADHD symptoms were, the lower the basal cortisol level was. In contrast, social behavior disorder was associated with increased basal cortisol levels and decreased cortisol stress response. Impaired cortisol reactivity might reflect fearlessness and be associated with poor emotion regulation and inhibition of aggressive and antisocial behavior.51 Regrettably, no nonaffected individuals were included as controls. - 7-12 years (mean: 10 years) old children with oppositional defiant disorder (ODD) have decreased patterns of activity of the autonomic nervous system or HPA axis. fifteen children with ODD, 31 children with ODD and AD, and 23 ADHD-only children were compared with 26 unaffected children. The cortisol response to competition-induced stress (nonrelational stress) was significantly decreased in ODD children with or without ADHD-HI and was equally normal in those with only ADHD and unaffected. Pulse rate was significantly decreased in ODD affected with and without stress. ODD, ODD/ADHD-HI, and ADHD-HI sufferers all equally had significantly lower skin conductance values under stress.52 Because MPH medication was not suspended for the study, the results are likely to be biased. That 17 of the 23 ADHD-HI-only children received MPH may explain the normalization of the stress-induced cortisol response.
- Oppositional defiant behavior in ADHD correlated with aberrant cortisol responses to acute stress.53
- ADHD-affected children showed a flattened cortisol response to the TSST, the more they showed psychopathic traits (callous unemotional traits = CU traits) such as lack of empathy, coldness of feeling, etc.54
- 22 Children with DBD (disruptive behavior disorder) showed both decreasing and increasing cortisol responses to stress, with those with decreasing cortisol responses exhibiting more severe symptoms than those with increasing cortisol responses.55
- Disorder of social behavior (CD) correlates with a flattened cortisol stress response.56
Because externalizing disorders correlate with ADHD-HI (with hyperactivity), we consider a tendency toward flattened cortisol stress responses in ADHD-HI and ADHD-C a plausible possibility.
3.1.2.2. ADHD-I and comorbid internalizing disorders
- A study of 96 adults with ADHD and 25 unaffected individuals revealed a higher stress-induced cortisol response in the ADHD-I subtype than in unaffected individuals, and a flattened cortisol response in ADHD-C.47
- ADHD-I sufferers of the pure inattentive subtype exhibited an exaggerated cortisol response to acute stress.57
- A study of 20 ADHD-I sufferers and 19 unaffected (8 to 13 years, mean 10.3 years) using TSST-C58 revealed that the 7 ADHD-I sufferers with severe inattention symptoms showed a significantly reduced cortisol response to the stressor, unlike the 13 ADHD-I sufferers with moderate symptoms and the 19 unaffected.
A similar study found a greater decreased cortisol response in ADHD sufferers with severe inattention symptoms than in sufferers with less severe inattention symptoms.59
These results contradict our analysis that ADHD-I is characterized by an exaggerated cortisol stress response. - One study found a severely flattened cortisol stress response to the TSST in boys with marked inattention. Girls with marked inattention also showed a flattened cortisol stress response during and after the TSST, with elevated levels before the TSST. Basal cortisol levels were unchanged.60 The study further mentions that flattened cortisol stress responses are common in chronic stress.
The children were categorized as ADHD-I according to inattention scores alone, not according to the absence of hyperactivity/impulsivity. This could explain the results if they were subjects showing strong hyperactivity/impulsivity scores at the same time. Comorbid externalizing or internalizing disorders did not affect the results. - In healthy adults, lower Novelty Seeking (which is more consistent with the ADHD-I subtype) correlated with increased cortisol responses to the TSST (as typically exhibited by the ADHD-I), but not with ACTH levels.61
- This is equally true for higher risk aversion (which is also more consistent with the ADHD-I subtype).62
- Anxiety, depression, subjective stress perception, impulsivity, and a higher ADHD symptom total score correlated with elevated cortisol responses to acute stress (which is surprising in relation to impulsivity) in a study of adults.63
3.1.3. Reactions to physical stress
- Of 170 ADHD-affected elementary school-aged children, venipuncture as a stressor resulted in a cortisol increase in those with comorbid anxiety problems, whereas those with comorbid DBD and oppositional defiant disorder had a decreased cortisol response. ADHD-HI subtypes did not elicit different cortisol responses.64
- Of 62 ADHD-affected children, the ADHD-HI type showed an identical cortisol level before venipuncture as nonaffected individuals, whereas the ADHD-I subtype showed an elevated cortisol level even before venipuncture compared with nonaffected individuals. Since basal cortisol levels are lower in both ADHD-I and ADHD-HI affected individuals compared with nonaffected individuals, this could be an anxiety response in anticipation of the stressor.65 The same pattern was shown with respect to alpha-amylase as a representative of the autonomic nervous system.
- In the same 62 ADHD-affected children, the ADHD-HI subtype showed a decrease in cortisol levels 10 minutes after venipuncture, whereas it increased slightly in the 40 unaffected and increased more in the ADHD-I affected.65 The same pattern was seen with respect to alpha-amylase as a representative of the autonomic nervous system.
- Children with ADHD tended to show increased cortisol stress responses to venipuncture at the first screening in the home setting and significantly lower basal cortisol levels and significantly blunted cortisol stress responses at the second screening in the clinic setting compared with unaffected individuals.66
- Children with ADHD showed a lower cortisol increase in response to a dentist visit as a stressor than those not affected. The cortisol increase was particularly low in children with high hyperactivity/impulsivity scores.67
3.2. Basal cortisol levels reduced in ADHD
Results on basal cortisol levels in ADHD show majority decreased levels.
3.2.1. Decreased basal cortisol levels: 12 studies
Several studies found that basal (steady, underlying) cortisol levels are generally decreased in ADHD, with cortisol level decreases being even more pronounced in ADHD-HI and in ADHD-C than in the ADHD-I subtype.2868
Decreased basal hair cortisol levels in 4-year-old children over several months are a good predictor of an increase in ADHD symptoms in boys (but not girls) the following year.69 Similar findings are described by Pauli-Pott et al.70 Another study found that hair cortisol levels in children correlate between parental psychopathology and major depression and ADHD in children.71 One study found a correlation between low hair cortisol levels and low working memory scores and low intelligence performance only in boys but not in girls. In boys, hair cortisol fully explained the associations of ADHD inattention symptoms with working memory and intelligence performance.72
Several other studies found decreased morning blood cortisol levels in ADHD.73677475
Significantly lower cortisol levels were found at 8 a.m. in 128 Chinese children between 6 and 12 years of age with ADHD.76
The salivary cortisol level of 5 to 9-year-old boys immediately after waking up around 06:30 was on average 0.4 ng/ml lower than that of non-affected individuals. However, the individual range of cortisol levels in people is much wider than the statistical difference (unaffected 0.7 to 10.5 ng/ml; ADHD affected 1.3 to 8.1 ng/ml).77
248 Adolescents with ADHD showed lower basal cortisol levels and higher perceived stress, although basal cortisol levels and perceived stress were not correlated.78
Low basal stress levels (basal = not stress-induced) are interpreted as an adaptation reaction of the HPA axis (stress axis) to chronic stress experience. Not only ADHD-affected children, but also their mothers showed reduced cortisol levels at 9 a.m. compared to non-affected individuals.
3.2.2. Unchanged basal cortisol levels: 5 studies
In ADHD-I sufferers, one study found no changes in daily cortisol levels.59
Among 109 adults with ADHD, 64% were found to have a normal morning cortisol awakening response (with no significant differences between subtypes), compared with 84% in unaffected controls.79
Three other studies also found no change in basal cortisol levels in ADHD compared with nonaffected individuals.805349
3.2.3. Elevated basal cortisol levels: 3 studies
In contrast, ADHD sufferers with high inattention symptoms showed an elevated cortisol awakening response (CAR), and this was predominantly due to comorbid anxiety or depressive disorders.49
In healthy adults, lower Novelty Seeking (which is more consistent with the ADHD-I subtype) correlated with elevated baseline cortisol levels but not with elevated ACTH levels.81
One study found consistently elevated basal cortisol levels.82
Several studies show that decreased basal cortisol levels are not an exclusive feature of ADHD. They also correlate with (comorbidly present) social behavior disorders.838485
However, the measure of aggression does not yield different basal cortisol levels.3
Elevated blood cortisol levels in 15-year-old ADHD sufferers (decrease in late afternoon) correlated with aggressiveness in boys but not in girls.2
3.3. Decrease in cortisol levels without stress induction in ADHD?
A fairly small study concluded that a steeper drop in cortisol levels from 06:30 to 09:00 was typical in ADHD. In 19 ADHD sufferers, the 66% drop in cortisol levels was significantly steeper than the 56% drop in 40 non-affected individuals.86
Another study also reported abnormal cortisol level changes throughout the day that correlated with levels of hyperactivity.87
3.4. GR variant influences cortisol action and ADHD risk
See here ⇒ Gene variants of the GR In the article ⇒ Cortisol and other stress hormones in AD(H)S
4. ACTH in ADHD
-
No differences in basal ACTH levels were found between 128 ADHD-affected and 30 unaffected children. ADHD subtypes also did not differ.73
-
In healthy adults, lower Novelty Seeking (which is more consistent with the ADHD-I subtype) correlated with increased cortisol responses to the TSST (as is very common in the ADHD-I subtype), but not with altered ACTH levels.81
-
This is equally true for higher risk aversion (which also correlates with ADHD-I subtype).62
-
In one study, sexually abused girls were found to have decreased basal ACTH levels and decreased ACTH responses to CRH stimulation, whereas the cortisol response was unremarkable.88
-
Early childhood stress causes permanent changes in the HPA axis, as evidenced by altered basal and stress-induced cortisol levels. Children with internalizing problems often showed elevated cortisol stress responses, whereas adults who suffered early childhood psychological stress often showed decreased basal cortisol levels and increased ACTH responses to acute stress.89
-
Early experiences of stress can result in disruptions of the ACTH receptor systems that prevent extinction of the fear experience, causing long-term stress. This could be ameliorated by ACTH administration.90 In our opinion, the alteration of ACTH receptor systems could possibly be a consequence of a downregulation/upregulation response. ⇒ Downregulation/upregulation
-
Rats separated from their mothers early or poorly cared for showed91
- Elevated ACTH levels basal
- Elevated ACTH levels on acute stress
- More than doubled CRH levels on inflammation
- Reduced density of CRH receptors in the anterior pituitary lobe
- Alterations in extrahypothalamic CRH systems
- Increase of 59% in the number of CRH receptor binding sites in raphe nuclei
- Increase in immunoreactive CRH concentrations in the parabrachial nucleus by 86%
- Behavioral problems such as92
- Increased anxiety
- Anhedonia
- Increased alcohol preference
- Sleep disorders
- Cognitive impairments
- Increased sensitivity to pain
-
In borderline sufferers without comorbid PTSD, the DST showed an increased ACTH response; in borderline sufferers with comorbid PTSD, the DST showed a significantly attenuated ACTH response.93
5. CRH in ADHD
- Young monkeys raised under early attachment stress had elevated CRH and decreased epinephrine levels at 4 years of age.9495
-
Cortisol initially mediates stress symptoms after its release. Further, a high cortisol level has the effect of shutting down the HPA axis and norepinephrine again.
However, since GR cortisol receptors are less sensitive after prolonged stress due to downregulation, they do not perceive this signal. The shutdown of the stress systems fails to occur.96 As a result, CRH levels remain permanently elevated and permanently trigger CRH-mediated symptoms. This mechanism has already been outlined for depression.9798 - Prolonged stress caused chronic demethylation of the CRH gene in adult mice.99
6. α-Amylase in ADHD
The alpha-amylase level represents the activity of the primarily adrenergic controlled autonomic nervous system. Alpha-amylase reacts very strongly to a psychosocial stressor, but does not correlate with other so-called stress markers such as cortisol, noradrenaline or heart rate. Alpha-amylase is thus suitable for detecting physical changes caused by stress.100101102103 In contrast, concentration tasks (Stroop test) as a stressor do not increase the alpha-amylase level.104
- In ADHD, basal alpha-amylase levels are usually decreased, with the α-amylase level decrease being even more pronounced in ADHD-HI subtype/ADHD-C than in ADHD-I subtype. This pattern is consistent with decreased basal cortisol levels (a representative of the HPA axis).65
- Of 62 ADHD-affected children, the ADHD-HI type showed an iden-reduction in ADHD-HI subtype/ADHD-C even more marked than in ADHD-I subtype before venipuncture. This pattern is consistent with decreased basal cortisol levels (a representative of the HPA axis).65ty Disorder. Psychoneuroendocrinology. 2018 Apr;90:174-181. doi: 10.1016/j.psyneuen.2018.02.026.](https://www.ncbi.nlm.nih.gov/pubmed/29501948))) The same pattern was seen with respect to cortisol as a representative of the HPA axis.
- In the same 62 ADHD-affected children, the ADHD-HI subtype showed a decrease in α-amylase level 10 minutes after venipuncture, whereas it increased slightly in the 40 unaffected and increased more in the ADHD-I affected.65 The same pattern was seen with respect to cortisol as a representative of the HPA axis.
Alpha-amylase is an enzyme in the intestine responsible for breaking down carbohydrates into sugars. There could be a connection here between stress and eating problems or obesity.
6.1. Correlation between alpha-amylase and cortisol
An examination of the time course of the response of alpha-amylase, representing the autonomic nervous system, and cortisol, representing the HPA axis, to a TSST as a stressor indicates mutual dependencies of the two stress hormones:105
- An alpha-amylase rise was followed moderately frequently by a cortisol rise 14 minutes later.
- A rise in cortisol was followed slightly frequently by a fall in alpha-amylase 14 minutes later.
- An alpha-amylase increase was followed moderately frequently by a cortisol decrease 42 minutes later.
7. Diagnosis and treatment of ADHD by cortisol / dexamethasone?
Dexamethasone is a (man-made) glucocorticoid that binds to the glucocorticoid receptors of the pituitary gland in healthy volunteers, thereby inhibiting the ACTH precursor protein POMC. As a result, the release of ACTH from the anterior pituitary is reduced. Since ACTH normally stimulates cortisol release, a healthy response to administration of dexamethasone would be to decrease cortisol levels - called suppression.
Nonsuppression (a lack of cortisol reduction by dexamethasone) suggests a maladjustment of the HPA axis, in the form of a lack of response of the glucocorticoid receptors that mediate HPA axis shutdown. We suspect such HPA axis misalignments as a possible cause of ADHD, and we believe that the lack of HPA axis shutoff is typical of ADHD-HI.
Whether there is a problem of HPA axis shutdown in the form of cortisol nonsupression can be determined using the dexamethasone/CRH test, an evolution of the previously used dexamethasone-only test.
For the procedure and evaluation of the dexamethasone test, see ⇒ Dexamethasone/CRH test and ⇒ Dexamethasone test in the chapter ⇒ Pharmacologic endocrine function tests.
In melancholic depression, which like ADHD-I is very often characterized by an exaggerated cortisol response, but probably also frequently in atypical depression, which is characterized by a flattened cortisol stress response, the dexamethasone test to dexamethasone administration shows insufficient negative feedback from the HPA axis and therefore insufficient cortisol suppression.
We hypothesize that in ADHD-I (unlike melancholic depression), the exaggerated cortisol response leads to frequent shutdown of the HPA axis. This may be a misconception, or may reveal a difference between melancholic depression and ADHD-I.
In support of the hypothesized difference between depression and ADHD-I, a large study (n = 2307) found decreased cortisol suppression to dexamethasone in hyperactivity/impulsivity (ADHD-HI), whereas inattention (ADHD-I) showed no correlation with nonsupression.106 This is consistent with the results of a smaller study that found nonsupression in only a portion of ADHD sufferers and found that nonsuppression correlated with higher levels of hyperactivity.107 Another small study, but involving only 9 ADHD-affected children, found suppression in ADHD.108 Another smaller study found nonsuppression in 22.7% of ADHD-HI sufferers (with hyperactivity), a 4-fold increase over the 5.7% in healthy individuals.109
However, an argument against general nonsupression is that in rats that serve as animal models of ADHD-HI (with Hperactivity) (Spontaneous hypertensive rat), dexamethasone shows a reduction in ADHD-HI symptoms.110111 SHR genetically have excessive mineralocorticoid receptor (MR) expression and normal glucocorticoid receptor (GR) expression.112
These results suggest that in ADHD-I, glucocorticoid receptors are not desensitized.
The results further suggest that in ADHD-HI, in addition to the reduced cortisol response, which by its nature results in insufficient downshifting of the HPA axis, there is also (relative) overactivity of the MR or desensitization of the GR. The nonsupression of the HPA axis observed in hyperactivity when dexamethasone is administered proves that nonsuppression exists even in the presence of a short-term high cortisol level, i.e., a deficient shutdown of the HPA axis.
In summary, we interpret this as follows:
- Melancholic / psychotic depression:
l High cortisol stress response- Nevertheless no shutdown of the HPA axis
- → Desensitization of the GR or overactivity of the MR
-
ADHD-I
HSHigh cortisol stress response- Shutdown of the HPA axis
- → no desensitization of the GR or overactivity of the MR
- Atypical depression
typeLow cortisol stress response- No shutdown of the HPA axis
- Not only for lack of sufficient cortisol stress response
- Also with artificial glucocorticoid administration (dexamethasone)
ch→ more frequent desensitization of GR (more likely) or hyperactivity of MR (less likely because dexamethasone addresses GR 30 times more than MR and yet nonsupression occurs)
- No shutdown of the HPA axis
-
ADHD-HI
HSLow cortisol stress response- More often no shutdown of the HPA axis
- Not only for lack of sufficient cortisol stress response
- Also with artificial glucocorticoid administration (dexamethasone)
ch→ more frequent desensitization of GR (more likely) or hyperactivity of MR (less likely because dexamethasone addresses GR 30 times more than MR and yet nonsupression occurs)
- More often no shutdown of the HPA axis
8. Treatment of ADHD by cortisol / dexamethasone?
8.1. Dexamethasone as a drug for ADHD
Another strong indication that the HPA axis, and cortisol in particular, plays a central role in ADHD is provided by a study according to which dexamethasone (as a drug) in SHR rats (considered an animal model for ADHD-HI (with hyperactivity)) was able to significantly reduce their ADHD-HI symptoms.113
However, it must be taken into account that ADHD-HI can be caused by a variety of different gene constellations and that the SHR only represent a single gene constellation, so that the result cannot be readily generalized to every ADHD-HI.
W
The dopamine D1 transporter in the PFC, which is damaged in schizophrenia, can be reactivated by cortisol in animal models, which restores dopamine levels to normal.114
Dexamethasone has so far only been studied for its basic efficacy in rats. There are no studies on its use in humans or the effects of long-term use, which may have side effects (e.g., on the immune system), with regard to ADHD.
On the other hand, balancing the cortisol level that is too low in ADHD and especially in ADHD-HI - as long as only the existing deficit is balanced - could show a positive influence in other ways as well.
We developed the idea of dexamethasone shock treatment as a hypothesis: ⇒ Dexamethasone for ADHD
8.2. Cortisol as a drug for emotional stabilization in ADHD?
In one study, administration of 20 mg to 40 mg of cortisol significantly reduced feelings of sadness, activity, alertness to acute stress, and improved relaxation. In addition, fatigue was reduced.115
Cortisol (along with other mechanisms) influences attention, vigilance, and memory.116 The hippocampus, which is responsible for memory storage and retrieval processes, has the greatest cortisol receptor density in the brain.116
An administration of 10 mg cortisol before learning vocabulary significantly worsened memory retrieval performance. Whether this occurred only in men or also in women, who might be protected against this by their sex hormones, is an open question.117 ADHD-I sufferers respond to acute stress with increased cortisol release. Memory recall is also impaired in these individuals after stress - but only in males.117
L
While existing medications for ADHD (stimulants, atomoxetine, guanfacine) primarily improve attention and hyperactivity problems, we do not believe these are as effective in reducing internal tension. According to our hypothesis, infrequent high-dose cortisol administration should be able to reassure the HPA axis. In contrast, prolonged or regular administration is detrimental because it may cause effects similar to chronic severe stress.
Nnig,
Because of the significant disadvantages of corticoids acting on mineralocorticoid receptors, only corticoids that selectively address glucocorticoid receptors should be considered (such as dexamethasone, which addresses GR to MR in a 30:1 ratio).
8.3. Mode of action of dexamethasone
Dexamethasone is a selective glucocorticoid receptor (GR) agonist and thus acts like an increase in cortisol levels.113
The cortisol receptor agonist dexamethasone promotes PACAP mRNA transcription, cell proliferation, and DA synthesis, whereas a cortisol receptor antagonist inhibits this.118
Cortisol acts on the β-adrenoceptor -cAMP/protein kinase A (PKA) signaling pathway to facilitate the synthesis and release of norepinephrine, which binds postsynaptically to ɑ1-adrenoceptor and β-adrenoceptor. A β-adrenoceptor directly coupled to adenylate cyclase (AC) can stimulate cAMP production and trigger certain responses that can be regulated by ɑ1-adrenoceptor. Glucocorticoid receptors, together with the ɑ1-adrenoceptor, have an influence on the β-adrenoceptor-cAMP system.119 and may activate the NE system by activating the NE neuronal group in the brainstem. GR may also regulate transcription.
Activated GR bound to the glucocorticoid response element (GRE) affects gene expression as well as transcription factors, such as NF-kB, AP-1, CREB, etc., which in turn affect the combination of cAMP and PKA regulatory subtypes that model DA neuron production and survival and regulate DA activity and secretion.120
8.4. Dexamethasone in ADHD-HI, GR antagonists in ADHD-I?
The studies that established efficacy of dexamethasone as an ADHD medication did so using SHR rats, which are considered a typical model of ADHD-HI (with hyperactivity).
This raises the theoretical question of whether, just as the GR agonist dexamethasone might function as an active agent in ADHD-HI, a GR antagonist might possibly be effective in ADHD-I.
This should not be the case.
A GR antagonist would prevent the HPA axis from shutting down. However, the reswitching of the HPA axis after a stress response is, first, usually a healthy response and, second, is probably not impaired in ADHD-I.
Studies of dexamethasone testing in ADHD show that problems with HPA axis shutdown correlate with measures of hyperactivity, but not with inattention.
For more on this, see Medications for ADHD, here *⇒ Dexamethasone for ADHD.*ß
In our opinion, the problems of ADHD-I do not arise at the level of the HPA axis but at the level of excessive PFC addressing due to too much norepinephrine, which causes a shutdown of the PFC and triggers the thought blocks and decision-making difficulties typical in ADHD-I.
Büchs (2009): Einfluss von Mirtazapin auf die Hypothalamus-Hypophysen-Nebennierenrindenachse bei depressiven Patienten; Dissertation, Seite 126 ↥
Poustka, Maras, Hohm, Fellinger, Holtmann, Banaschewski, Lewicka, Schmidt, Esser, Laucht (2010): Negative association between plasma cortisol levels and aggression in a high-risk community sample of adolescents. J Neural Transm 117:621–627, n = 245 ↥ ↥
Yang, Shin, Noh, Stein (2007): Cortisol is inversely correlated with aggression for those boys with attention deficit hyperactivity disorder who retain their reactivity to stress. Psychiatry Res. Sep 30; 153( 1):55-60 ↥ ↥ ↥
Mannie, Harmer, Cowen (2007): Increased waking salivary cortisol levels in young people at familial risk of depression. Am J Psychiatry 164:617–621 ↥
Moore B (2002): Cortisol, stress and depression. Br J Psychiatry 181:348–353 mwNw ↥
Piwowarska, Wrzosek, Radziwon-Zaleska, Ryszewska-Pokrasniewicz, Skalski, Matsumoto, Biernacka-Bazyluk, Szelenberger, Pachecka (2009): Serum cortisol concentration in patients with major depression after treatment with clomipramine. Pharmacol Rep 2(61):604–611 ↥
(Vreeburg, Zitman, van Pelt, DeRijk, Verhagen, van Dyck, Hoogendijk, Smit, Penninx (2010): Salivary cortisol levels in persons with and without different anxiety disorders. Psychosom Med 72:340–347 ↥
Greaves-Lord, Ferdinand, Oldehinkel, Sondeijker, Ormel, Verhulst (2007): Higher cortisol awakening response in young adolescents with persistent anxiety problems. Acta Psychiatr Scand 116:137–144 ↥
Corominas, Ramos-Quiroga, Ferrer, Saez-Francas, Palomar, Bosch, Casas (2012): Cortisol responses in children and adults with attention deficit hyperactivity disorder (ADHD): a possible marker of inhibition deficits, ADHD Atten Def Hyp Disord (2012) 4:63–75. DOI 10.1007/s12402-012-0075-59, Seite 70 ↥
Fairchild (2012): Hypothalamic-pituitary-adrenocortical axis function in attention-deficit hyperactivity disorder. Curr Top Behav Neurosci. 2012;9:93-111. doi: 10.1007/7854_2010_101. ↥
Henry (1997): Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding. Acta Physiol Scand Suppl. 1997;640:10-25. PMID: 9401599. REVIEW ↥
Mason, Giller, Kosten, Yehuda (1990), zitiert nach Henry (1997): Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding. Acta Physiol Scand Suppl. 1997;640:10-25. PMID: 9401599. REVIEW ↥
Lopez-Duran, Mayer, Abelson (2014): Modeling neuroendocrine stress reactivity in salivary cortisol: adjusting for peak latency variability. Stress. 2014 Jul;17(4):285-95. doi: 10.3109/10253890.2014.915517. ↥
Vuksanovic: Traumatische Erfahrungen, Stress und ADHS. Was können wir von der Neuroendokrinologie lernen? ↥
Daoust, Kotelnikova, Kryski, Sheikh, Singh, Hayden (2018). Child sex moderates the relationship between cortisol stress reactivity and symptoms over time. Comprehensive Psychiatry, 87, 161–170. doi:10.1016/j.comppsych.2018.10.009 ↥
Hatzinger, Brand, Perren, von Wyl, von Klitzing, Holsboer-Trachsler (2007): Hypothalamic-pituitary-adrenocortical (HPA) activity in kindergarten children: importance of gender and associations with behavioral/emotional difficulties. J Psychiatr Res., 41(10):861-70 ↥
Duan, Yuan, Zhang, Qin, Zhang, Buchanan, Wu (2013): Chronic stress exposure decreases the cortisol awakening response in healthy young men. Stress. 2013 Nov;16(6):630-7. doi: 10.3109/10253890.2013.840579. ↥
Galbo (1983). Hormonal and metabolic adaptation to exercise: Disputats. Thieme Medical Publishers. ↥
Porta, Emsenhuber, Petek, Purstner, Vogel, Schwaberger, Salwitsch, Korstako (1993): Detection and evaluation of persisting stress-induced hormonal disturbances by a post stress provocation test in humans; Life Sciences, Volume 53, Issue 21, 1993, Pages 1583-1589; https://doi.org/10.1016/0024-3205(93)90181-2 ↥
Few, Cashmore, Turton (1980): Adrenocortical response to one-leg and two-leg exercise on a bicycle ergometer; European Journal of Applied Physiology and Occupational Physiology; August 1980, Volume 44, Issue 2, pp 167–174 ↥
Brechtel (1998): Das parasympathikotone Übertrainingssyndrom – Ein Modell zur Maladaption an Streß – Diagnostik und Pathophysiologie. Dissertation. Seite 198 ↥
Brechtel (1998): Das parasympathikotone Übertrainingssyndrom – Ein Modell zur Maladaption an Streß – Diagnostik und Pathophysiologie. Dissertation. Seite 198, mit weiteren Nachweisen ↥ ↥
Alink, van Ijzendoorn, Bakermans-Kranenburg, Mesman, Juffer, Koot (2008): Cortisol and externalizing behavior in children and adolescents: mixed meta-analytic evidence for the inverse relation of basal cortisol and cortisol reactivity with externalizing behavior. Dev Psychobiol. 2008 Jul;50(5):427-50. doi: 10.1002/dev.20300. ↥
Härfstrand, Fuxe, Cintra, Agnati, Zini, Wikstrom, Okret (1986): Glucocorticoid receptor immunoreactivity in monoaminergic neurons of rat brain. Proceedings of the National Academy of Sciences of the USA, 83, 24: 9779-9783. ↥
Fuxe, Agnati, Jannsson, von-Euler, Tanganelli (1990): Regulation of endocrine function by the nicotinic cholinergic receptor. Ciba-Foundation-Symposium, pp. 127-130. ↥
Bieger (2011): Neurostressguide, Seite 11 ↥ ↥
Xie L, Gelfand, Mathew, Atem, Delclos, Messiah (2022): Association of Corticosteroid Use and Attention Deficit/Hyperactivity Disorder in Asthmatic Children Varies by Age. J Asthma. 2022 Jun 13:1-13. doi: 10.1080/02770903.2022.2089995. PMID: 35696551. ↥
Budziszewska, Basta-Kaim, Kubera, Lasoń (2010); [Immunological and endocrinological pattern in ADHD etiopathogenesis]. Przeglad Lekarski [01 Jan 2010, 67(11):1200-1204], PMID:21442976 ↥ ↥
Ibrahim, Xie, Strong, Tonello, Berta, Zhang (2018): Mineralocorticoid Antagonist Improves Glucocorticoid Receptor Signaling and Dexamethasone Analgesia in an Animal Model of Low Back Pain. Front Cell Neurosci. 2018;12:453. doi:10.3389/fncel.2018.00453 ↥
Shansky, Lipps (2013): Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex. Front. Hum. Neurosci. 7, 123. http://dx.doi.org/10.3389/fnhum.2013.00123 ↥
Scassellati, Bonvicini, Faraone, Gennarelli (2012). Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses. J Am Acad Child Adolesc Psychiatry. 2012 Oct;51(10):1003-1019.e20. doi: 10.1016/j.jaac.2012.08.015. PMID: 23021477. ↥
Corominas, Ramos-Quiroga, Ferrer, Sáez-Francàs, Palomar G, Bosch, Casas (2012): Cortisol responses in children and adults with attention deficit hyperactivity disorder (ADHD): a possible marker of inhibition deficits. Atten Defic Hyperact Disord. 2012 Jun;4(2):63-75. doi: 10.1007/s12402-012-0075-5. PMID: 22576746. ↥
Kamradt, Momany, Nikolas (2017): A meta-analytic review of the association between cortisol reactivity in response to a stressor and attention-deficit hyperactivity disorder. Atten Defic Hyperact Disord. 2018 Jun;10(2):99-111. doi: 10.1007/s12402-017-0238-5. ↥
van der Knaap, Oldehinkel, Verhulst, van Oort, Riese (2015): Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study. Psychoneuroendocrinology. 2015 Aug;58:46-50. doi: 10.1016/j.psyneuen.2015.04.012. PMID: 25951242. ↥
Shin, Lee (2007): Blunted hypothalamo-pituitary-adrenal axis reactivity is associated with the poor intelligence; Performance in children with attention-deficit/hyperactivity disorder. Neuropediatrics., 38(6):298-303 ↥
King, Barkley, Barrett (1998) Attention-Deficit Hyperactivity Disorder and the Stress Response. Biol Psychiatry 73 , 44:72-74; n = 20 ↥
Hong, Shin, Lee, Oh, Noh (2003) Hypothalamic-pituitary-adrenal reactivity in boys with attention deficit hyperactivity disorder. Yonsei Med J., 44(4):608-14. ↥
Lee, Shin, Stein (2010): Increased cortisol after stress is associated with variability in response time in ADHD children. Yonsei Med J 51:206–211 ↥
Ünsel-Bolat, Ercan, Bolat, Süren, Bacanlı, Yazıcı, Rohde (2019): Comparisons between sluggish cognitive tempo and ADHD-restrictive inattentive presentation phenotypes in a clinical ADHD sample. Atten Defic Hyperact Disord. 2019 Mar 25. doi: 10.1007/s12402-019-00301-y. n = 155 ↥
Palma, Fernandes, Muszkat, Calil (2012): The response to stress in Brazilian children and adolescents with attention deficit hyperactivity disorder. Psychiatry Res. 2012 Aug 15;198(3):477-81. doi: 10.1016/j.psychres.2011.10.016. n = 76 ↥
Palma, Natale, Calil (2015): A four-year follow-up controlled study of stress response and symptom persistence in Brazilian children and adolescents with attention deficit disorder and hyperactivity (ADHD). Psychiatry Res. 2015 Dec 15;230(2):227-32. doi: 10.1016/j.psychres.2015.08.044. n = 59 ↥
van West, Claes, Deboutte (2009): Differences in hypothalamic-pituitary-adrenal axis functioning among children with ADHD predominantly inattentive and combined types. Eur Child Adolesc Psychiatry. 2009 Mar 18. ↥
Maldonado, Trianes, Cortes, Moreno, Escobar (2009): Salivary cortisol response to a psychosocial Stressor on children diagnosed with attention-deficit/hyperactivity disorder: differences between diagnostic subtypes. Span J Psychol. 2009 Nov;12(2):707-14. n = 33 ↥
Lackschewitz, Hüther, Kröner-Herwig (2008): Physiological and psychological stress responses in adults with attentiondeficit/hyperactivity disorder (ADHD). Psychoneuroendocrinology; 33:612–624, n = 36 ↥
Raz, Leykin (2015): Psychological and cortisol reactivity to experimentally induced stress in adults with ADHD. Psychoneuroendocrinology. 2015 Oct;60:7-17. doi: 10.1016/j.psyneuen.2015.05.008. n = 49 ↥
Lane, Reynolds, Thacker (2010): Sensory Over-Responsivity and ADHD: Differentiating Using Electrodermal Responses, Cortisol, and Anxiety. Front Integr Neurosci. 2010 Mar 29;4:8. doi: 10.3389/fnint.2010.00008. eCollection 2010. ↥
Corominas-Roso, Palomar, Ferrer, Real, Nogueira, Corrales, Casas, Ramos-Quiroga (2015): Cortisol Response to Stress in Adults with Attention Deficit Hyperactivity Disorder.Int J Neuropsychopharmacol. 2015 Mar 17;18(9). pii: pyv027. doi: 10.1093/ijnp/pyv027, n = 121 ↥ ↥
West, Glaes, Deboutte (2009): Differences in hypothalamic-pituitary-adrenal axis functioning among children with ADHD predominantly inattentive and combined types. Eur Child Adolesc Psychiatry. 2009 Mar 18. ↥
Vogel, Bijlenga, Verduijn, Bron, Beekman, Kooij, Penninx (2018): Attention-deficit/hyperactivity disorder symptoms and stress-related biomarkers. Psychoneuroendocrinology. 2017 May;79:31-39. doi: 10.1016/j.psyneuen.2017.02.009. ↥ ↥ ↥
Gordis, Granger, Susman, Trickett (2006): Asymmetry between salivary cortisol and alpha-amylase reactivity to stress: relation to aggressive behavior in adolescents. Psychoneuroendocrinology. 2006 Sep;31(8):976-87.. n = 67 ↥
Northover, Thapar, Langley, Fairchild, van Goozena (2016): Cortisol levels at baseline and under stress in adolescent males with attention-deficit hyperactivity disorder, with or without comorbid conduct disorder; Psychiatry Res. 2016 Aug 30; 242: 130–136; doi: 10.1016/j.psychres.2016.05.052; PMCID: PMC4986851 ↥
Snoek, Van Goozen, Matthys, Buitelaar, van Engeland (2004).Stress responsivity in children with externalizing behavior disorders. Dev Psychopathd 16(2): 389-406. ↥
Christiansen, Oades, Psychogiou, Hauffa, Sonuga-Barke (2010): Does the cortisol response to stress mediate the link between expressed emotion and oppositional behavior in Attention-Deficit/Hyperactivity-Disorder (ADHD)? Behav Brain Funct 6:45 ↥ ↥
Stadler, Kroeger, Weyers, Grasmann, Horschinek, Freitag, Clement (2011): Cortisol reactivity in boys with attention-deficit/hyperactivity disorder and disruptive behavior problems: the impact of callous unemotional traits. Psychiatry Res 187:204–209, n = 36 ↥
Van de Wiel, Van Goozen, Matthys, Snoek, Van Engeland (2004): Cortisol and treatment effect in children with disruptive behavior disorders: A preliminary study. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 1011–1018. n = 22 ↥
Fairchild, van Goozen, Stollery, Brown, Gardiner, Herbert, Goodyer (2008): Cortisol diurnal rhythm and stress reactivity in male adolescents with early-onset or adolescence-onset conduct disorder. Biol Psychiatry. 2008 Oct 1;64(7):599-606. doi: 10.1016/j.biopsych.2008.05.022 ↥
Abelson, Curtis, Cameron (1996): Hypothalamic-pituitary-adrenal axis activity in panic disorder: Effects of alprazolam on 24 h secretion of adrenocorticotropin and cortisol, Journal of Psychiatric Research, Volume 30, Issue 2, March–April 1996, Pages 79-93, zitiert nach Park, Jung, Park, Yang, Kim (2018): Melatonin inhibits attention-deficit/hyperactivity disorder caused by atopic dermatitis-induced psychological stress in an NC/Nga atopic-like mouse model. Sci Rep. 2018 Oct 8;8(1):14981. doi: 10.1038/s41598-018-33317-x. ↥
Randazzo, Dockray, Susman (2008): The stress response in adolescents with inattentive type ADHD symptoms; Child Psychiatry Hum Dev. 2008 Mar;39(1):27-38. ↥
Pesonen, Kajantie, Heinonen, Pyhala, Lahti, Jones, Matthews, Eriksson, Strandberg, Raikkonen (2012): Sex-specific associations between sleep problems and hypothalamic–pituitary–adrenocortical axis activity in children. Psychoneuroendocrinology 37:238–248 ↥ ↥
Pesonen, Kajantie, Jones, Pyhälä, Lahti, Heinonen, Eriksson, Strandberg, Räikkönen (2011): Symptoms of attention deficit hyperactivity disorder in children are associated with cortisol responses to psychosocial stress but not with daily cortisol levels, Journal of Psychiatric Research, Volume 45, Issue 11, 2011, Pages 1471-1476, ISSN 0022-3956, https://doi.org/10.1016/j.jpsychires.2011.07.002. ↥
Tyrka, Wier, Anderson, Wilkinson, Price, Carpenter (2007): Temperament and response to the Trier Social Stress Test; Published in final edited form as: Acta Psychiatr Scand. 2007 May; 115(5): 395–402; doi: 10.1111/j.1600-0447.2006.00941.x; PMCID: PMC4469468; NIHMSID: NIHMS698884 ↥
Tyrka, Wier, Price, Rikhye, Ross, Anderson, Wilkinson, Carpenter (2008): Cortisol and ACTH Responses to the Dex/CRH Test: Influence of Temperament; Horm Behav. 2008 Apr; 53(4): 518–525; doi: 10.1016/j.yhbeh.2007.12.004; PMCID: PMC2637444; NIHMSID: NIHMS45728 ↥ ↥
Hirvikoski, Lindholm, Nordenström, Nordström, Lajic (2009): High self-perceived stress and many stressors, but normal diurnal cortisol rhythm, in adults with ADHD (attention-deficit/hyperactivity disorder). Horm Behav 55:418–424, n = 56 ↥
Hastings, Fortier, Utendale, Simard, Robaey (2009): Adrenocortical Functioning in Boys with Attention-Deficit/Hyperactivity Disorder: Examining Subtypes of ADHD and Associated Comorbid Conditions. J Abnorm Child Psychol 37:565-578 ↥
Angeli, Korpa, Johnson, Apostolakou, Papassotiriou, Chrousos, Pervanidou (2018):Salivary cortisol and alpha-amylase diurnal profiles and stress reactivity in children with Attention Deficit Hyperactivity Disorder. Psychoneuroendocrinology. 2018 Apr;90:174-181. doi: 10.1016/j.psyneuen.2018.02.026. ↥ ↥ ↥ ↥ ↥
McCarthy, Hanrahan, Scott, Zemblidge, Kleiber, Zimmerman (2011): Salivary cortisol responsivity to an intravenous catheter insertion in children with attention-deficit/hyperactivity disorder. J Pediatr Psychol. 2011 Sep;36(8):902-10. doi: 10.1093/jpepsy/jsr012. n = 29 AD(H)S-Betroffene und 339 Kontrollprobanden ↥
Blomqvist, Holmberg, Lindblad, Fernell, Ek, Dahllöf (2007): Salivary cortisol levels and dental anxiety in children with attention deficit hyperactivity disorder. European Journal of Oral Sciences, 115 (1), S. 1–6 ↥ ↥
Angeli, Korpa, Johnson, Apostolakou, Papassotiriou, Chrousos, Pervanidou (2018):Salivary cortisol and alpha-amylase diurnal profiles and stress reactivity in children with Attention Deficit Hyperactivity Disorder. Psychoneuroendocrinology. 2018 Apr;90:174-181. doi: 10.1016/j.psyneuen.2018.02.026. n = 102 ↥
Schloß, Ruhl, Müller, Becker, Skoluda, Nater, Pauli-Pott (2018): Low hair cortisol concentration and emerging attention-deficit/hyperactivity symptoms in preschool age. Dev Psychobiol. 2018 Mar 23. doi: 10.1002/dev.21627., n = 125 ↥
Pauli-Pott, Schloß, Ruhl, Skoluda, Nater, Becker (2017):. Hair cortisol concentration in preschoolers with attention-deficit/hyperactivity symptoms-Roles of gender and family adversity. Psychoneuroendocrinology. 2017 Dec;86:25-33. doi: 10.1016/j.psyneuen.2017.09.002. PMID: 28910602. ↥
Ferro, Gonzalez (2020): Hair cortisol concentration mediates the association between parent and child psychopathology. Psychoneuroendocrinology. 2020 Apr;114:104613. doi: 10.1016/j.psyneuen.2020.104613. Epub 2020 Feb 7. PMID: 32088544. ↥
Mann, Schloß, Cosan, Becker, Skoluda, Nater, Pauli-Pott (2021): Hair cortisol concentration and neurocognitive functions in preschool children at risk of developing attention deficit hyperactivity disorder. Psychoneuroendocrinology. 2021 Jun 12;131:105322. doi: 10.1016/j.psyneuen.2021.105322. Epub ahead of print. PMID: 34175557. n = 122 ↥
Ma, Chen, Chen, Liu, Wang (2011): The function of hypothalamus-pituitary-adrenal axis in children with ADHD. Brain Res. 2011 Jan 12;1368:159-162. doi: 10.1016/j.brainres.2010.10.045. n = 158 ↥ ↥
Shin, Lee (2007): Blunted hypothalamo-pituitary-adrenal axis reactivity is associated with the poor intelligence performance in children with attention-deficit/hyperactivity disorder. Neuropediatrics, 38 (6), S. 298–303 ↥
Kariyawasam, Zaw, Handley (2002): Reduced salivary cortisol in children with comorbid attention deficit hyperactivity disorder and oppositional defiant disorder. Neuro Endocrinol Lett 23: 45–48 ↥
Chen, Chen, Liu, Lin, Wei, Chen (2009): [Function of the hypothalamus-pituitary-adrenal axis in children with attention deficit hyperactivity disorder].[Article in Chinese].Zhongguo Dang Dai Er Ke Za Zhi. 2009 Dec;11(12):992-5. ↥
Vuksanovic (2013): Die Aktivität der Hpothalamus-Hypophysen-Nebennierenrinden-Achse bei Aufmerksamkeits-Defizit und Hyperaktivitäts-Störung, Dissertation, Seite 64 ↥
Isaksson, Nilsson, Lindblad (2015): The Pressure-Activation-Stress scale in relation to ADHD and cortisol. Eur Child Adolesc Psychiatry. 2015 Feb;24(2):153-61. doi: 10.1007/s00787-014-0544-9. n = 248 ↥
Ramos-Quiroga, Corominas-Roso, Palomar, Ferrerd, Valero, Corrales, Richarte, Casas (2016): Cortisol awakening response in adults with attention deficit hyperactivity disorder: Subtype differences and association with the emotional lability; European Neuropsychopharmacology, Volume 26, Issue 7, July 2016, Pages 1140-1149, https://doi.org/10.1016/j.euroneuro.2016.03.014 ↥
Schulz, Halperin, Newcorn, Sharma, Gabriel (1997): Plasma cortisol and aggression in boys with ADHD; J Am Acad Child Adolesc Psychiatry. 1997 May;36(5):605-9., n = 50 ↥
Tyrka, Wier, Anderson, Wilkinson, Price, Carpenter (2007): Temperament and response to the Trier Social Stress Test; Acta Psychiatr Scand. 2007 May; 115(5): 395–402; doi: 10.1111/j.1600-0447.2006.00941.x; PMCID: PMC4469468; NIHMSID: NIHMS698884 ↥ ↥
Berens A, LeMoult J, Kircanski K, Gotlib IH (2022): ADHD symptoms and diurnal cortisol in adolescents: The importance of comorbidities. Psychoneuroendocrinology. 2022 Nov 26;148:105990. doi: 10.1016/j.psyneuen.2022.105990. PMID: 36462296. n = 138 ↥
Freitag, Hänig, Palmason, Meyer, Wüst, Seitz (2009): Cortisol awakening response in healthy children and children with ADHD: Impact of comorbid disorders and psychosocial risk factors. Psychoneuroendocrinology, 34 (7), S. 1019–28. ↥
Snoek, Van Goozen, Matthys, Buitelaar, van Engeland (2004): Stress responsivity in children with externalizing behavior disorders. Dev Psychopathol. 2004;16(2):389-406. doi:10.1017/s0954579404044578 ↥
Hastings, Fortier, Utendale, Simard, Robaey (2009): Adrenocortical functioning in boys with AttentionDeficit/Hyperactivity Disorder: Examining subtypes of ADHD and associated comorbid conditions. Journal of Abnormal Child Psychology, 37, S. 565–578. ↥
Vuksanovic (2013): Die Aktivität der Hpothalamus-Hypophysen-Nebennierenrinden-Achse bei Aufmerksamkeits-Defizit und Hyperaktivitäts-Störung, Dissertation, Seite 64; kleine Probandenzahl: n = 19 ↥
Kaneko, Hoshino, Hashimoto, Okano, Kumashiro (1993): Hypothalamic-pituitary-adrenal axis function in children with attention-deficit hyperactivity disorder. J Autism Dev Disord 23:59–65 ↥
De Bellis, Chrousos, Dorn, Burke, Helmers, Kling, Trickett, Putman (1994): Hypothalamic–pituitary–adrenal axis dysregulation in sexually abused girls. J. Clin. Endocrinol. Metab. 78, 249–255, n = 26 ↥
Tarullo, Gunnar (2006): Child maltreatment and the developing HPA axis. Horm. Behav. 50: 632-639 ↥
Massey, Lerner, Holmes, Scott, Hernan, (2016):ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures; Front Neurol. 2016; 7: 65. doi: 10.3389/fneur.2016.00065; PMCID: PMC4852169 ↥
Ladd, Owens, Nemeroff (1996): Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 1996; 137: 1212–18. ↥
Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 48 ↥
Rinne, de Kloet, Wouters, Goekoop, DeRijk (2002): RH, van den Brink W. Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse. Biol Psychiatry 2002; 52: 1102–12. ↥
Coplan, Andrews, Rosenblum, Owens, Friedman, Gorman, Nemeroff (1996): Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the patho-physiology of mood and anxiety disorders. Proc Natl Acad Sci 1996; 93: 1619–23. ↥
Coplan, Smith, Altemus, Scharf, Owens, Nemeroff, Gorman, Rosenblum (2001): Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentration in adult primates. Biol Psychiatry 2001; 50: 200–4. ↥
Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seiten 120, 151 ↥
Holsboer (2001): Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord. 2001 Jan;62(1-2):77-91. ↥
Miller, Ancoli-Israel, Bower, Capuron, Irwin (2008): Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer; J Clin Oncol. 2008 Feb 20; 26(6): 971–982. doi: 10.1200/JCO.2007.10.7805, PMCID: PMC2770012, NIHMSID: NIHMS147295 ↥
Elliott, Gili, Limor, Neufeld-Cohen (2010): Resilience to social stress coincides with functional DANN methylation of the CRF gene in adult mice. Nat Neurosci 2010; 13: 1351–53. ↥
Nater, La Marca, Florin, Koller, Ehlert (2003): The relationship between salivary alpha-amylase and plasma catecholamines. Journal of Psychophysiology. ↥
Nater, Rohleder, Gaab, Berger, Jud, Kirschbaum, Ehlert (2003). Alpha-Amylase im Speichel als biologischer Indikator einer psychosozialen Stressreaktion. Verhaltenstherapie, 13 (Suppl. 1), 42. ↥
Nater, Rohleder, Gaab, Berger, Jud, Kirschbaum, Ehlert (2003): Alpha-Amylase in saliva as a useful indicator of autonomic stress reaction. Psychosomatic Medicine, 65 (1), 28. ↥
Nater, Rohleder, Gaab, Berger, Jud, Kirschbaum, Ehlert (2005): Reactivity of human salivary alpha-amylase in a psychosocial stress paradigm. Journal of Psychophysiology. ↥
Reinhardt (2007): Endokrinologische Veränderungen (Cortisol und Amylase) im Speichel bei akutem und chronischem Stress während einer stationären Psychotherapie; Dissertation; Seite 83; n = 75 ↥
Engert, Vogel, Efanov, Duchesne, Corbo, Ali, Pruessner (2011): Investigation into the cross-correlation of salivary cortisol and alpha-amylase responses to psychological stress; Psychoneuroendocrinology (2011) 36, 1294—1302; n = 50 ↥
Vogel, Bijlenga, Verduijn, Bron, Beekman, Kooij, Penninx (2017): Attention-deficit/hyperactivity disorder symptoms and stress-related biomarkers. Psychoneuroendocrinology. 2017 May;79:31-39. doi: 10.1016/j.psyneuen.2017.02.009. n = 2307 ↥
Kaneko, Hoshino, Hashimoto, Okano, Kumashiro (1993): Hypothalamic-pituitary-adrenal axis function in children with attention-deficit hyperactivity disorder; Journal of Autism and Developmental Disorders; March 1993, Volume 23, Issue 1, pp 59–65 ↥
Gispen-de Wied, Jansen, Wynne, Matthys, van der Gaag, Thijssen, van Engeland (1998): Differential effects of hydrocortisone and dexamethasone on cortisol suppression in a child psychiatric population. Psychoneuroendocrinology. 1998 Apr;23(3):295-306. ↥
Steingard, Biederman, Keenan, Moore (1990): Comorbidity in the interpretation of dexamethasone suppression test results in children: a review and report. Biol Psychiatry. 1990 Aug 1;28(3):193-202. ↥
Chen, Zheng, Xie, Huang, Ke, Zheng, Lu, Hu (2017): Glucocorticoids/glucocorticoid receptors effect on dopaminergic neurotransmitters in ADHD rats. Brain Res Bull. 2017 May;131:214-220. doi: 10.1016/j.brainresbull.2017.04.013. ↥
Lu, Zhang, Hong, Wang, Huang, Zheng, Chen (2018): [Effect of glucocorticoid receptor function on the behavior of rats with attention deficit hyperactivity disorder] [Article in Chinese]; Zhongguo Dang Dai Er Ke Za Zhi. 2018 Oct;20(10):848-853. ↥
Brocca, Pietranera, de Kloet, De Nicola (2018): Mineralocorticoid Receptors, Neuroinflammation and Hypertensive Encephalopathy. Cell Mol Neurobiol. 2018 Aug 16. doi: 10.1007/s10571-018-0610-9. ↥
Chen, Zheng, Xie, Huang, Ke, Zheng, Lu, Hu (2017): Glucocorticoids/glucocorticoid receptors effect on dopaminergic neurotransmitters in ADHD rats; Brain Research Bulletin; Volume 131, May 2017, Pages 214-220 ↥ ↥
Roozendaal, Williams, McGaugh (1999): Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: Involvement of the basolateral amygdala. Eur J Neurosci, 11:1317-1323 ↥
Reuter (2002); Impact of Cortisol on Emotions under Stress and Nonstress Conditions: A Pharmacopsychological Approach. Neuropsychobiology 2002;46:41-48, n = 100 ↥
Kirschbaum (2001): Das Stresshormon Cortisol – Ein Bindeglied zwischen Psyche und Soma? in: Jahrbuch der Heinrich-Heine-Universität Düsseldorf, 2001, 150-156 ↥ ↥
Kirschbaum (2001): Das Stresshormon Cortisol – Ein Bindeglied zwischen Psyche und Soma? in: Jahrbuch der Heinrich-Heine-Universität Düsseldorf, 2001, 150-156, mwNw ↥ ↥
McArthur, McHale, Dalley, Buckingham, Gillies (2005): Altered mesencephalic dopaminergic populations in adulthood as a consequence of brief perinatal glucocorticoid exposure. Journal of Neuroendocrinology 17(8):475-82 · September 2005 ↥
Kassel, Herrlich (2002): Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects. Mol Cell Endocrinol. 2007 Sep 15;275(1-2):13-29. ↥
Yang, Tsao, Li, Wu, Hsu, Cheng (2007): Changes of dopamine content and cell proliferation by dexamethsone via pituitary adenylate cyclae-activating polypeptide in PC12 cell. Neurosci Lett, 426(1):45-48. ↥