Dexamethasone for ADHD

1. Hypothesis of dexamethasone shock treatment in ADHD-HI and ADHD-C¶

In many people with ADHD-HI and ADHD-C (with hyperactivity), the cortisol stress response is flattened. We suspect that this leads (in a significant proportion of this group) to too little cortisol being released at the end of a severe stress reaction in order to shut down the HPA axis properly.

Irrespective of this, a considerable number of people with ADHD-HI and ADHD-C also have an elevation of the (more cortisol-affine) mineralocorticoid receptors (MR) or a desensitization of the glucocorticoid receptors (GR), which is why, in the absence of sufficient GR activation, a shutdown of the HPA axis is not successful even with a high cortisol stress response or dexamethasone administration.

This only applies to ADHD-HI and ADHD-C. In ADHD-I (without hyperactivity), reduced GR activity is rare, so that the increased cortisol stress response there ensures sufficient HPA axis resetting. The dexamethasone shock treatment considered here is therefore only suitable for ADHD-HI/ADHD-C and not for people with ADHD-I. In addition, in people with ADHD-HI/and ADHD-C, it can only work in those who show sufficient cortisol suppression by dexamethasone. This is more likely in ADHD-HI/ADHD-C sufferers with lower levels of hyperactivity, so dexamethasone shock treatment may tend to work more for ADHD-HI and ADHD-C sufferers with a less severe symptom picture.

As a result, nonsuppression of the HPA axis is likely to occur more frequently in ADHD-HI, but is not always present.

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Consistent with our hypothesis, studies found that in ADHD only 46.7% (ASD 47.7%) showed suppression to dexamethasone, while of adult controls 100% showed suppression¹ and that cortisol suppression to dexamethasone was particularly reduced in hyperactivity, but not in inattention².
One study found 22.7 % nonsuppression in ADHD (according to DSM-III) with hyperactivity, 29.6 % in major depression and 37.9 % in combined ADHD with hyperactivity and major depression. Controls showed 0% nonsuppression in the dexamethasone test. A meta-analysis found nonsuppression in 45.8% (n = 24) of inpatients with ADHD (according to DSM-III) with hyperactivity and nonsuppression in 31.4% (n = 51) of outpatients with ADHD (according to DSM-III) with hyperactivity³
Among 5 children with minimal cerebral dysfunction (the term for ADHD in the 1980s, when purely inattentive ADHD was still unknown), all showed nonsuppression⁴
One study only found less suppression in ADHD than in controls, but not nonsuppression. by dexamethasone or hydrocortisol.⁵

Among the children with ASD, most of those with good development showed suppression and most of those with poor development showed nonsuppression.⁴⁶
The population prevalence of nonsuppression is 5%.

Dexamethasone corrected inattention and hyperactivity in SHR.^{78 9} and also increased dopamine and noradrenaline by reducing DAT expression, while a GR antagonist reduced it.⁸

BELONGS UNDER CORTISOL STRESS RESPONSE:
One study found that the cortisol stress response to a psychological stress test was negatively correlated with aggression in patients who had maintained their reactivity to stress. The absolute value of the decrease correlated negatively with the attention score on the CBCL for the patients who showed a decrease in cortisol levels after stress. In the patients who showed an increase in their cortisol concentration in response to stress, cortisol may play a protective role against aggression.¹⁰

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More about tests to diagnose ADHD using the dexamethasone test (DST) at ⇒ Endocrine function tests for ADHD In the chapter ⇒ Pharmacological endocrine function tests.

As a study design for researching a treatment option for people with ADHD-HI, we suggest the following approach from a scientific point of view:

1. A DST is performed to determine whether suppression occurs.
Only in this case is dexamethasone shock treatment theoretically even an option.
If suppression occurs, the DST result shows how low the individual cortisol level is in the resting state of the HPA axis.

2. Measurements of the cortisol level every 1 to 3 days (important: always at the same time of day) can determine whether the cortisol level increases again. This would be a sign of activation of the HPA axis.
In the case of a general adrenal insufficiency (e.g. due to insufficient ACTH secretion, which could be triggered by downregulation of the CRH receptors of the pituitary gland), measuring the CRH values could help. However, a CRH deficiency is also conceivable, as can be triggered by prolonged cortisol administration, for example.¹¹

3. If an increase in cortisol levels is detected, a measurement on the following day could be used to check whether the cortisol level decreases again. This would be an indication of a functioning autonomous regulation of the HPA axis restart. In this case, no treatment would be necessary.

4. However, if the cortisol level remains at an elevated level for several days compared to the cortisol level measured at the beginning after dexamethasone administration, the HPA axis could be stimulated to suppression again by a single dose of dexamethasone (at the dosage that was successful with DST).

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Dexamethasone addresses GR 30 times more strongly than MR. If necessary, a combination with an MR antagonist such as eplerenone, as used in a study for the treatment of back pain, would be conceivable.¹²

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5. Follow-up measurements (initially daily) can monitor the frequency at which the HPA axis is activated and remains at this elevated level.

This idea has so far been based solely on theoretical considerations and follows solely from a scientific perspective. It has not yet been tested in practice.
Isolated treatment with dexamethasone should have no greater risks than carrying out dexamethasone tests. Theoretically, the administration of dexamethasone should only replace the amount of cortisol that is released during a healthy stress response of the HPA axis and that causes the HPA axis to shut down again in a healthy state.
While long-term low-dose cortisol administration, as is common in the treatment of inflammatory problems, can lead to downregulation of the corticoid receptors and a reduction in cortisol production by the adrenal cortex, this risk is significantly lower with infrequent shock treatment.
We do not know at what frequency of treatment with dexamethasone risks could arise and must be considered with appropriate medical caution.
As always, the risks must be weighed against the benefits for the people with ADHD.

More on dexamethasone for ADHD at ⇒ Treatment of ADHD with cortisol / dexamethasone? In the article ⇒ Cortisol and other stress hormones in ADHD.

2. Differentiation from long-term treatment with dexamethasone¶

While short-term administration of dexamethasone (as well as short-term administration of cortisol) increases activation and concentration and reduces fatigue, prolonged administration of dexamethasone (within 4 days) leads to negative moods such as anger and sadness.¹³

Administration of 4 mg dexamethasone orally over 4 days to depressed subjects resulted in an improvement in depressive symptoms in 37% of subjects, compared to 8% with placebo.¹⁴ An administration of 3 to 4 mg dexamethasone per day is likely to have a purely peripheral effect in humans. At these doses per kg body weight, dexamethasone did not cross the blood-brain barrier in rats.¹⁵
For the test setup mentioned above, however, a central effect is dispensable, as the last increment of the HPA axis, the adrenal cortex, sits peripherally as a cap on the kidneys.