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The tests compiled here could be suitable for diagnosing ADHD subtypes and identifying appropriate treatment methods. In practice, there is no use of these tests in relation to ADHD so far.
Since the HPA axis is hyperactivated or hypoactivated not only in depression and ADHD, but also in other mental disorders, the above-mentioned tests can only be used to a limited extent to determine which mental disorder is present. Within an identified mental disorder, however, they are very helpful for differentiation from other disorders and for finding a suitable medication.
Measurement of cortisol level (ACTH, too, if necessary) 8 to 9 a.m. or 3 to 4 p.m. to determine basal level
Administration: Dexamethasone 23 hrs p.m
Action: selective on glucocorticoid receptors (GR).
Effect on GR 30 times stronger than on mineralocorticoid receptors (MR).
GRs shut down the HPA axis (unlike MR, which does the “day-to-day” business)
Dexamethasone hardly crosses the blood-brain barrier; therefore, hardly any effect on hypothalamus, strong effect on pituitary gland
Measurement of cortisol level at the same time of day (8 to 9 a.m. or 3 to 4 p.m.) on the following day, midnight after dexamethasone administration if necessary
08:00, 16:00, 23:00 Following day: measurement of cortisol in blood plasma
Due to impaired negative feedback of the HPA axis or desensitization of glucocorticoid receptors at the pituitary gland (here: in melancholic depression)7 the cortisol level decreases only insufficiently after dexamethasone administration (nonsuppression) and remains above 5 µg/dl8
The dexamethasone-only suppression test (DST) is the precursor of the DEX/CRH test that is primarily used today. The DST can also detect hypercortisolism of the HPA axis.9 However, the DST proved to be too insensitive and not specific enough for the diagnosis of depression and was therefore replaced by the dexamethasone/CRH test.10
The probability of distinguishing a depressed subject from healthy control subjects by measuring an elevated cortisol level on dexamethasone administration of > 5 µg/dl cortisol ranges from 25% to 64%.111213
In sufferers with psychotic depression, as much as 95% nonsupressors have been identified.14 Since psychotic depression, in our opinion, can be understood as a “particularly severe melancholic depression” and also correlates with an excessive cortisol stress response, which should actually cause a suppression of the HPA axis, this illustrates that in melancholic / psychotic depression there is likely to be a downregulation or otherwise lack of response of the glucocorticoid receptors.
Females are more likely to show a positive test response than males.1516 This may support our view that an increased cortisol response of the HPA axis to acute stressors reflects an internalizing stress phenotype, as women more often have an internalizing stress response than men.
However, the finding that the HPA axis normalizes after recovery in men but not in women17 suggests that the relationships are more complex.
That stimulants such as caffeine or nicotine tend to increase ACTH and cortisol levels1816 (especially when used as intoxicants rather than drugs, as nicotine is in tobacco) is also not surprising from the perspective of ADHD, which is treated primarily with stimulants.
The fact that increased or non-decreased ACTH and cortisol levels are not found in all depressed patients191620 is justified by depression medicine as follows
The number of depressive episodes (the fewer episodes, the less increase)
The DEX/CRH test is a combination of the CRH test and the simple DST.2324 It has replaced the pure dexamethasone test (DST) and is used to predict the success of therapy, to identify remitted depression patients at risk of relapse and family members not yet ill who are at risk of developing the disease.10
Administration: 1st stage: dexamethasone 11 pm evening, 2nd stage: CRH after cortisol measurement at 3 to 4 pm
Effect: see dexamethasone test
Stage: Measurement: Cortisol at 15:00 to 16:00 on the following day
Suspicion of melancholic (internalizing) depression8
Desensitization of glucocorticoid receptors on the pituitary gland (here: in melancholic depression)7
Note: normal supression in ADHD-I, despite cortisol stress response elevated as in melancholic depression25 Therefore, probably no desensitization of GR / overexpression of MR at pituitary in ADHD-I
Step: Injection 100 µg human CRH
Stage: Measurement CRH and ACTH in blood plasma every 15 minutes
Not healthy reaction:
Possibly markedly increased ACTH response to CRH administration compared to healthy subjects and high blood cortisol levels26
Sarubin explains one possible explanation27:
GR have a very high binding affinity for artificial glucocorticoids such as dexamethasone and cause the negative feedback at the pituitary gland in healthy subjects. However, the cited study refers to the hippocampus.27
Dexamethasone leads to decreased ACTH secretion in depressed patients only in the short term, as the brain attempts to compensate by increased secretion of CRH-synergistic hormones such as vasopressin2829 .
CRH injection leads to an interaction of increased vasopressin concentration with the injected CRH. This not only cancels the partial ACTH suppression at the pituitary gland, but on the contrary leads to increased ACTH release in depressed subjects.3031
Cortisol and ACTH levels decreased by dexamethasone were not raised by subsequent single administration of either CRH or vasopressin in another study. Only subsequent joint administration of CRH and vasopressin increased the cortisol and ACTH levels reduced by dexamethasone again.30
Details of the DEX/CRH test
The combined DEX/CRH test can distinguish32 (melancholic) depressed from healthy subjects with a certainty of 80 to 90%3334 and is the standard neuroendocrinological test for depressed patients worldwide.3536
However, the combined DEX/CRH test can only be used diagnostically if the expected cortisol response of the disorder to be tested is known. The cortisol responses of severe melancholic (or psychotic) depression on the one hand and (atypical depression or) bipolar disorder on the other hand differ in the remitted as well as in the non-remitted state.37
This is consistent with our other presentations in this paper, which suggest that the cortisol responses of mental disorders are merely a reflection of HPA axis dysfunction, but are not directly related in their expression to any particular disorder.
The DEX/CRH test should allow conclusions to be drawn about the relationship between mineralocorticoid receptors (MR) and glucocorticoids (GR). Administration of the MR antagonist spironolactone increases basal and mean cortisol levels38394041 and the cortisol response to the DEX/CRH test.42
The effect of MR antagonists on the HPA axis, although clearly measurable, is small, suggesting that mineralocortoid receptors modulate but do not regulate HPA axis activity.38
A high cortisol response (cortisol nonsupression) to the DEX/CRH test-as is common in melancholic depression and then about 10 times higher than in healthy individuals43 -is likely to indicate a low number of MR relative to GR, and a low cortisol response (supression) is likely to indicate a high number of MR relative to GR.
Administration: ACTH(1-24) (Synacthen, an artificial ACTH made of 24 amino acids instead of the 35 in natural ACTH)
Effect: stimulation of the adrenal cortex
Measurement: cortisol, aldosterone if necessary, 1 hour after ACTH injection (ACTH short test)
Cortisol increase of more than 15 ng/ml44 or of ≥ 180-200 μg/l (500-550 nmol/l) after ACTH stimulation or doubling or more after ACTH stimulation45
Test quality: stable reliability (± 12 %)
Progesterone increase less than 2.5 ng/ml
Not healthy reaction:
No / lower cortisol increase
Suspicion of adrenal insufficiency (= weakness) (NNRI),
Primary NNRI, adrenal gland itself is impaired in hormone production
Secondary NNRI caused by pituitary gland
Tertiary NNRI caused by hypothalamus
To find out which of these problems exists: Do ACTH long tests. The background to this is that after a prolonged ACTH deficit, the adrenal cortex does not immediately produce cortisol again after the first ACTH administration, but must first slowly ramp up cortisol production again.
Reappearance of cortisol increase after several days of ACTH(1-24) administration (ACTH long test)
Suspicion of secondary NNRI
Failure to increase cortisol after several days of ACTH/1-24) administration (ACTH long test)
Suspicion of primary NNRI
Suspicion of depression
Lack of aldosterone increase
Suspected deficient addressing of mineralocorticoid receptors
Progesterone increase by more than 2.5 ng/ml to max. 15 ng/m and cortisol increase less than 15 ng/ml
Suspicion of heterozygous 21-hydroxylase deficiency44
17-alpha-hydroxyprogesterone increases to over 15 ng/ml to 100ng//ml
Suspected non-classical or late-onset AGS/21-hydroxylase deficiency due to CYP21A2 gene defect
One large study (n = 2307) found reduced cortisol suppression to dexamethasone in hyperactivity/impulsivity (ADHD-HI), whereas inattention (ADHD-I) showed no correlation with nonsuppression.25 This is consistent with the results of a smaller study that found nonsuppression in only a portion of ADHD sufferers and found that nonsuppression correlated with higher levels of hyperactivity.52 In contrast, another small study, but involving only 9 ADHD-affected children, found suppression in ADHD.53 Another study found nonsuppression in 22.7% of ADHD-HI sufferers (with hyperactivity), which is 4-fold higher than the 5.7% in healthy individuals.54
In SHR rats, which serve as animal models of ADHD-HI (with hyperactivity), dexamethasone causes a reduction in ADHD-HI symptoms.5556SHR genetically have excessive expression of mineralocorticoid receptors (MR) and normal expression of glucocorticoid receptors (GR).57
Dexamethasone acts selectively as a GR agonist, i.e., MR are addressed 30 times more weakly than GR.58 Whether prednisone is also a selective GR agonist is debatable. There are voices for it58 as against it59
The results suggest that HPA axis nonsuppression is more common in ADHD-HI but may not always be present.
For an account of possible treatment for ADHD-HI sufferers in whom the dexamethasone suppression test (DST) shows suppression, that is, in whom there is a reduction in cortisol levels on dexamethasone, see ⇒ Dexamethasone in ADHD.