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“Treating ADHD is easy. Treating ADHD well is very difficult.”
Choosing the most individually effective medication for ADHD and its optimal dosage is a challenge. There are a number of points of reference for orientation. Often enough, however, the individual characteristics of each affected person put all empirical values to the test. As ADHD is a syndrome and there is therefore no “one ADHD”, ADHD symptoms can arise from a large number of different causes. Consequently, there is no single treatment. If necessary, a variety of different options must be tried out for an affected person.
ADHD medications can be divided into two categories: Stimulants and non-stimulants. Stimulants such as methylphenidate (MPH) and amphetamine medication (AMP) have the advantage that they have a high potency with few side effects. There is no other class of medication in psychiatry with such a strong effect.12 They take effect from the first day of use and can be discontinued at any time without withdrawal symptoms. However, stimulants can impair emotional perception in some particularly sensitive patients or in the case of overdose and are BtM. Non-stimulants such as atomoxetine and guanfacine, on the other hand, have a longer duration of action, have advantages in terms of emotional dysregulation and have no dampening effect on emotional perception, but their effect strength is lower and the side effects are significantly higher. They are also more difficult to dose than stimulants due to their long duration of action and long half-life.
Furthermore, specific problem cases and comorbidities must be taken into account when choosing medication. For example, AMP, atomoxetine or guanfacine can be used in patients who do not respond to various MPH preparations. If stimulants cause an impairment of emotional perception despite avoiding excessive doses, they can be replaced by atomoxetine or guanfacine or lower doses can be combined with these. A combination medication of stimulants and atomoxetine can improve drive and at the same time reduce emotional dysregulation. Certain medications have particular benefits for tic disorders, anxiety disorders, substance abuse and other comorbidities.
The modes of action of the various medications differ in terms of their binding affinity to transporters and their effects on dopamine and noradrenaline in different regions of the brain. It is important to customize the right medication to achieve the best possible effect with minimal side effects.
When dosing, ADHD sufferers are often more sensitive to even small differences in dose or to different effects of different preparations of the same active ingredient. This goes so far that even the replacement of a generic drug with a supposedly bioequivalent preparation from another manufacturer can lead to considerable differences or even a loss of efficacy. This applies to retarded and unretarded stimulants as well as non-stimulants. It is not the rule, but, as we know from the ADHD forum at ADxS.org, it is far more common than previously assumed. More on this under Dosing of medication for ADHD.
Information without guarantee. Talk to your doctor.
Stimulants for ADHD have a special position in the entire field of psychiatric medication: no other class of medication has such a high effect strength with such low side effects 1
It is advisable to compare the package inserts for aspirin or antidepressants and methylphenidate
Stimulants have been used as ADHD medications for many decades, longer than almost any other class of medication
Stimulants work from the first day of use
Stimulants can be discontinued at any time without the risk of withdrawal symptoms (in contrast to antidepressants, some of which can cause dependence and massive side effects from overdosing)
Disadvantages (common disadvantages of stimulants
Impairment of emotional perception in approx. 20% of those affected due to the dampening effect of stimulants on the limbic system
Causes: Hypersensitivity or overdose
In this case, consider combination medication of atomoxetine and MPH or AMP (at a lower dosage in each case compared to monotherapy)
BtM mandatory, because theoretical possibility of abuse
No risk of abuse if taken correctly (oral dose of medication)
There are better “spinning” things for less money at every station and in every disco loo
Nevertheless possible stimulus for drug use in patients with acute or previous amphetamine addiction; in this case, test atomoxetine and guanfacine instead
Stimulants reduce the likelihood of developing an addiction,34 they certainly do not increase it.56
Treating ADHD with stimulants as early as possible reduced the risk of developing addiction in adulthood. For every year that stimulant treatment began later, the risk of developing addiction in adulthood increased 1.46-fold.7
Methylphenidate (MPH)
Advantages:
Particularly good drive boost
Unretarded short duration of action (2.5 - 3 hours)
Disadvantages:
Nonresponder rate approx. 30 %
MPH non-responding not congruent with AMP non-responding
Amphetamine medication (AMP)
Advantages
More mood-balancing than MPH
Slightly better potency and slightly lower side effects than MPH, especially in adults
Disadvantages:
Nonresponder rate approx. 20 %
AMP non-responding not congruent with MPH non-responding
Legend:
Sources, unless otherwise stated89 — Unsuitable (—) Limited suitability, under close supervision
o limited suitability
+ particularly suitable
no entry: no known suitability restriction
** In our opinion or sources to be included
General physical contraindications
General physical contraindications
LDX /D-AMP
ATX
MPH
Guanfacine
Bupropion
Comments
Hypersensitivity to the active substance or any of the other ingredients
—
—
—
—
—
Glaucoma
—
— (narrow-angle glaucoma)
—
Hyperthyroidism or thyrotoxicosis
—
—
Pheochromocytoma
—
—
Stomach not acidic enough / too alkaline, pH value above 5.5
—
Tumor in the central nervous system
—
severe liver cirrhosis
—
Histamine intolerance
—
—
—
—
—
Viloxazine appears to be the only ADHD medication that does not increase histamine
Cardiovascular problems
Cardiovascular problems:
LDX /D-AMP
ATX
MPH
Guanfacine
Bupropion
Comments
Symptomatic cardiovascular disease
—
—
Advanced arteriosclerosis
—
Moderate to severe hypertension
—
—**
+**
Serious cardiovascular or cerebrovascular disease in which a clinically significant increase in blood pressure or heart rate could worsen the condition, e.g.: severe hypertension, heart failure, arterial occlusive disease, angina pectoris, haemodynamically relevant congenital heart defect, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias, diseases caused by altered ion channel function
(—)**
—
(—)**
+**
Cerebrovascular diseases (e.g. cerebral aneurysms, vascular abnormalities, vasculitis or stroke)
—
Moderate to severe hypotension
suitable
suitable
suitable
o
Addiction problems
Addiction problems:
LDX /D-AMP
ATX
MPH
Guanfacine
Bupropion
Comments
Alcohol addiction, acute
o**
o**
o**
o**
o**
Amphetamine addiction, acute
—**
—**
Amphetamine addiction, long ago
(—)**
(—)**
THC addiction
o**
o**
a planned withdrawal, which may be accompanied by an increased tendency to convulsions
—
Alcohol consumption when ingested (quantities consumed)
Hospital stays reduced in ADHD + psychosis/schizophrenia due to stimulants with continued antipsychotic medication**
psychopathic / borderline personality disorders
—
Epilepsy tendency
to be used with caution
—
Tourette
—
++**
Arousal states
—
Anorexia nervosa/anorectic disorders
—**
—
—
Bulimia
—
Taking other medication
Taking other medications
LDX /D-AMP
ATX
MPH
Guanfacine
Bupropion
Comments
Use of monoamine oxidase inhibitors within the last 14 days
—
—
—
—
Taking sedative medication
—
Taking antihypertensive medication
(—)**
(—)**
(—)**
+ (dose adjustment if necessary)
Taking other medicines containing bupropion
—
H2 receptor blockers or antacids
—
Maternity
Maternity
LDX /D-AMP
ATX
MPH
Guanfacine
Bupropion
Comments
Women of childbearing age who do not use contraceptives
—
Pregnancy
— (especially first trimester)
—
(—)
—
—
Breastfeeding
—
—
(—)
—
—
Ability to drive
Ability to drive
LDX /D-AMP
ATX
MPH
Guanfacine
Bupropion
Comments
Ability to drive / drive safe machinery
o Warn patients of possible impairment due to drowsiness and visual disturbances until it is certain that these side effects will not occur in the person concerned or will disappear with continued use
o Warn patients of possible impairment due to drowsiness, somnolence and dizziness until it is certain that these side effects will not occur in the person concerned or will disappear with continued use
o Warn patients of possible impairment due to drowsiness, dizziness and visual disturbances until it is certain that these side effects will not occur in the person concerned or will disappear with continued use o Warn patients of possible impairment due to drowsiness, somnolence and dizziness until it is certain that these side effects will not occur in the person concerned or will disappear with continued use, Dizziness, dizziness and dizziness until it has been established that these side effects do not occur in the patient or disappear with long-term use
o Moderate to strongly varying influence on the ability to drive or operate machinery due to dizziness and drowsiness (primarily at the start of use) and Fainting spells
o Ability to drive given, provided no serious side effects such as dizziness occur
Taking other medication
Taking other medications with an effect on:
LDX /D-AMP
ATX
MPH
Guanfacine
Bupropion
Comments
CYP3A4/5
—
OCT-1
—
MATE1
—
Drugs that can prolong the QT interval
—
—
CES1
—
CYP2D6
—
—
—
Legend:
Sources, unless otherwise stated89 — Unsuitable (—) Limited suitability, under close supervision
o limited suitability
+ particularly suitable
no entry: no known suitability restriction
** In our opinion or sources to be included.
All information without guarantee. Talk to your doctor.
2. Choice of medication without specific problem cases¶
Of those affected who would benefit from medication, only around 20 to 25% receive medication. Of those not affected, less than 1% receive medication that they do not need.11
Before treatment with stimulants, we recommend
A cardiovascular examination.12 to search for cardiovascular abnormalities such as13
Elevated blood pressure
Heart murmur
Syncope during physical exertion
ECG is optional
Contraindications for stimulants (most of them uncommon in childhood):13
The third choice is atomoxetine. It may be the first choice for comorbid SCT or severe ADHD-I.
In children with ADHD, 8.4% switched from an initial MPH medication to atomoxetine, 31.3% from an initial ATX medication to MPH17
About 50% of MPH non-responders respond to atomoxetine, and about 75% of MPH responders also respond to atomoxetine. Atomoxetine can be co-administered with MPH during the switching phase without undue concern for adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is required)18
In our opinion, the fourth choice is guanfacine (especially for generic hypertension or hypertension caused by MPH or AMP or for comorbid tics), which statistically has a significantly better effect strength with fewer side effects than atomoxetine
For other possible medications, see the following articles
Usually work better in adults and are better tolerated
Nonresponders: approx. 20 %
Approx. 30% of adults who switch from MPH to Elvanse switch back again19
Dosing too quickly in too high increments increases the discontinuation rate due to side effects or overdosing
Methylphenidate:
If not effective: test several other MPH preparations
Different MPH preparations can have very different effects
Differences in effectiveness are more individual than typical for the preparation
Nonresponders: approx. 30 %
Dosing too quickly in too high increments increases the discontinuation rate due to side effects or overdosing
2.2. Further factors for the choice of active ingredient¶
Further consideration should be given to the choice of active ingredient:
Comorbidities
Metabolization enzyme gene variants that accelerate or slow down degradation
other medication taken
Stomach acid
possible premenstrual worsening of ADHD symptoms
affected women should primarily use stimulants, as these can also be dosed higher in the short term during the days in question. See below under Side effects of dosing.
2.3. Trial and error: finding the right active ingredient requires patience¶
Psychiatric disorders and other CNS diseases pose particular challenges when it comes to finding a suitable medication. ADHD still has a special position within psychiatric disorders2, as the responder rates of 70% (MPH) to 80% (AMP) are far higher than for other disorders. The effect strength of ADHD medication is also extremely high compared to other disorders.
Nevertheless, it is not possible to predict which active ingredient will work for a particular ADHD sufferer. Even within a drug class (MPH), one drug may have intolerable side effects in one person while the other works excellently - while the next person reacts in exactly the opposite way to the two drugs. The different reactions are presumably due to the different onset and degradation profiles of the active substance, which can vary considerably between the individual preparations.
This is why patient and gradual adjustment of medication is the decisive factor for improving symptoms and quality of life in ADHD. We would like to encourage all those affected to “keep at it” if the results are not satisfactory and to keep trying out new preparations and active ingredients together with their doctor.
“In controlled trials, the drug is selected before the subjects are recruited and the dosage is determined by a protocol. In clinical practice, the dosage is determined by the individual response of the subjects. In fact, there is no identified parameter that predicts the molecule, dose, timing of administration and frequency of administration at which an individual will derive optimal benefit from the medication. … In clinical practice, stimulant class medications are adapted to the needs and responses of the individual patient in at least five ways: Agent, delivery system, dose, duration, and frequency.”20
3. Medication selection according to specific problem cases¶
The ADHD symptom of a lack of inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen).22 A lack of inhibition of emotion regulation is caused noradrenergically by the hippocampus.22
Therefore, the former may be more amenable to dopaminergic treatment, while emotion regulation and affect control may be more amenable to noradrenergic treatment.
Impulsiveness is also serotonergically mediated
If severe impulsivity is a prominent symptom of the affected person, it would be negligent to dose stimulants so high that this is adequately eliminated, as this would result in an overdose with regard to the other symptoms. If impulsivity is prominent, treatment with low-dose SSRIs may be helpful.
Serotonin reuptake inhibitors
Significantly lower doses than when used as antidepressants
Emotional dysregulation in ADHD can be treated with stimulants or atomoxetine.24
In our experience, atomoxetine and guanfacine have an advantage over stimulants in the treatment of emotional dysregulation. Atomoxetine and guanfacine work throughout the day. The socially very impairing symptom of rejection sensitivity in particular, which can put a lot of strain on social relationships and partnerships, especially outside the effective period of stimulants, can be significantly improved by non-stimulants that work throughout the day.
On the other hand, these medications have the disadvantages of being more difficult to dose (level medications), which can take weeks, as well as having a significantly lower effect on the other ADHD symptoms with higher side effects. In particular, the control of drive and motivation that can be achieved with stimulants cannot be achieved with non-stimulants. A combination of (lower doses of) non-stimulants and stimulants is therefore recommended. This is often the optimal approach for patients who are capable of finely graduated dosing.
3.3. Avoidance of specific side effects of ADHD medication¶
Atomoxetine can help to reduce comorbid anxiety symptoms in children and adolescents.25262728
Positive effects of atomoxetine on comorbid anxiety disorders have been reported29
One study investigated the combination treatment of atomoxetine with SNRIs and SSRIs in adults with ADHD and comorbid generalized anxiety disorder. In all subjects, SNRIs or SRIs alone failed to improve anxiety symptoms. A combination treatment of SNRI or SSRI with atomoxetine showed significant improvements in anxiety symptoms compared to the previous monotherapy with SNRI/SSRI.30
MPH can also help with anxiety symptoms, although the improvement in anxiety symptoms was slightly greater with atomoxetine.31 An individual case report noted a good long-term effect of a combination medication of vortioxetine (10 mg/day) and MPH on stimulant-induced anxiety and ADHD symptoms in a 15-year-old ADHD sufferer who did not respond to atomoxetine, reacted to MPH with dysphoria and could not tolerate augmenting clonidine. This was achieved with high tolerability.32
An analysis of the proteins addressed by Elvanse showed indications that Elvanse could also have a positive effect in the treatment of anxiety.33
3.4.2.1. Stimulant monotherapy as a first step in comorbid depression and ADHD¶
In the case of ADHD with mild comorbid depression, monotherapy with stimulants should be used first. Stimulants work much faster and, above all, have no withdrawal side effects, which can be massive with antidepressants. In view of the rapid effectiveness of stimulants, it can then be observed whether the elimination of the ADHD problem eliminates the stressor driving the depression. This is quite often the case.
In around a third of all treatment-resistant depression cases, previously undiagnosed ADHD is found.
In ADHD sufferers with comorbid depression, the risk of depression was found to be 20% lower during the period of ADHD medication than during the unmedicated period. The 3-year long-term risk of depression was reduced by 43%.34
An analysis of the proteins addressed by Elvanse showed indications that Elvanse could also have a positive effect in the treatment of depression.33
Our experience is that Elvanse shows greater improvement in depressive symptoms as part of ADHD treatment than methylphenidate.
3.4.2.2. Atomoxetine for comorbid depression and ADHD¶
Whether atomoxetine has an effect on depression is controversial. There are voices against it133536 as well as for it. In one study, the improvement in depression symptoms corresponded to that of paroxetine and venlaflaxine.37
A double-blind placebo-controlled study investigated combination treatment with atomoxetine and fluoxetine (an SSRI) compared to monotherapy with atomoxetine in children and adolescents with ADHD and comorbid symptoms of depression or anxiety. The study found no relevant improvements in ADHD symptoms with the combination treatment. There were small improvements in the symptoms of comorbid depression with combination treatment compared to monotherapy with atomoxetine, with the latter already improving depression and anxiety symptoms in addition to ADHD symptoms. The combination treatment did not show any increased side effects. Blood pressure was slightly higher with combination therapy than with monotherapy.28
One study found evidence of an effect of atomoxetine together with sertraline in HTTLPR (SERT) genotype s/s compared to sertraline monotherapy 38
3.4.2.3. SSRI and MPH for comorbid depression with ADHD¶
One study problematizes that SSRIs (e.g. fluoxetine) increase a moderate addiction-related gene regulation of MPH in the striatum of rats and could thus increase dependence on methylphenidate. This is less pronounced with vilazodone39
3.4.2.4. Escitalopram and MPH for comorbid depression with ADHD¶
One study found no increased risk of augmenting escitalopram with MPH in ADHD, except in the presence of additional comorbid TIC disorders.40
3.4.2.5. Fluoxetine and MPH for comorbid depression and ADHD¶
A study of ADHD sufferers with comorbid depression, who did not show sufficient improvement in ADHD symptoms with MPH alone, found significant improvements in ADHD symptoms in almost all subjects with augmenting fluoxetine. In 40% of the test subjects, an additional dose of less than 20 mg fluoxetine was sufficient. There were no increased side effects.41 Another study found no increased side effects for fluoxetine with MPH medication for ADHD and a significantly lower risk compared to escitalopram for comorbid TIC disorders.40
Combined administration of MPH and fluoxetine reduced anxiety and depression-like behaviors in rats significantly more than either drug alone.42
Fluoxetine is said to be the only SSRI with a drive-enhancing effect. As a monotherapy, it does not appear to be suitable for the treatment of ADHD. ⇒ Fluoxetine for ADHD
Co-administration of MPH and fluoxetine to juvenile rats resulted in increased sensitivity to reward stimuli (which should be positive in ADHD) and increased anxiety and stress sensitivity (which would be detrimental in ADHD) in adult animals.43 However, healthy animals and no ADHD model animals were tested.
3.4.2.6. Selegiline and lisdexamfetamine for comorbid depression¶
One study reports successful co-medication of selegiline and lisdexamfetamine (Elvanse) for ADHD and comorbid depression.44 Another study on the co-medication of stimulants and MAO inhibitors in depression found no problems arising from this45
A combination medication of selegiline with stimulants can therefore also be considered for ADHD.
2.4.2.7. MAO inhibitors and stimulants for comorbid depression¶
A study on the co-medication of stimulants and MAO inhibitors in depression found no problems arising from this,45 contrary to the frequently assumed problem of blood pressure crises.
MPH together with a mood stabilizer does not increase the risk of manic changes or psychotic symptoms. If stimulants are ineffective or poorly tolerated, atomoxetine appears to be an option.26
An analysis of the proteins addressed by Elvanse showed indications that Elvanse could also have a positive effect in the treatment of bipolar disorder.33
Several atypical antipsychotics, particularly risperidone, were effective in improving aggression. Some studies showed - contrary to FDA warnings that stimulants could worsen aggression - that stimulants, like antipsychotics, were effective in improving aggression, especially in hyperactive children46
Combination treatment with (low-dose) antipsychotics and psychostimulants can be particularly helpful for comorbid aggression if monotherapy with stimulants and a combination of stimulants with behavioral therapy interventions were not sufficient to treat aggression.47 Various expert committees came to the conclusion that if aggression comorbid with ADHD (not: aggression resulting from stimulants) is not sufficiently improved by the prescription of stimulants, the simultaneous use of atypical antipsychotics is indicated, with cautious dosing.4849
For co-medication with antipsychotics and psychostimulants, see also above under weight loss.
3.4.5. Oppositional defiant behavior comorbid with ADHD¶
Atomoxetine is helpful for comorbid oppositional defiant behavior.26
Antidepressants such as imipramine, desipramine, SSRIs
Lithium
One study found 67,595 children and adolescents who started medication with methylphenidate between 2005 and 2013 who received a combination therapy of MPH and antipsychotics. Among them was a combination with
Risperidone (72 %)
Pipamperon (15 %)
Tiapride (8 %)
A quarter of the users of a combination therapy of MPH and antipsychotics were prescribed these only once.
The use of combinations of MPH with risperidone and tiapride was frequently suitable (> 72%), whereas the use of the combination MPH-pipamperone was only rarely suitable (< 15%).51
Combination treatment with risperidone and MPH proved helpful in comorbid ODD and ADHD52, as well as in comorbid conduct disorder (CD).53
3.4.7. Disruptive Mood Dysregulation Disorder (DMDD) comorbid with ADHD¶
DMDD is characterized by persistent strong irritability and high impulsivity. ADHD often occurs comorbidly.
One study found a positive effect of a combination therapy of aripiprazole and methylphenidate in children with comorbid DMDD and ADHD. Increased side effects were not found.54
A comparative effectiveness study of N = 22,601 sufferers of Emotionally Unstable Personality Disorder with comorbid ADHD showed that ADHD medication was the only medication group that significantly reduced the risk of suicidality.55
At a dosage of about 1 mg/kg/day with cautious use is effective for57
Sleep, anxiety, impulsivity and ADHD, repetitive behavior and enuresis
Pure ASA medication:
In the USA, only risperidone and aripiprazole are approved by the FDA for ASA treatment57
Risperidone
Hyperactivity/impulsivity in autism or mental retardation can be improved by stimulants such as risperidone. Risperidone is not generally approved for the treatment of ADHD, but could be considered for comorbid autism. Due to the potential for increased side effects, cautious dosing is required for these symptom combinations.13
Citalopram and fluoxetine (SSRI):
Poor tolerance and lack of effectiveness for repetitive behaviors57
Worked better than methylphenidate with halperidol in children with ADHD and comorbid tic disorders.60
An analysis of the proteins addressed by Elvanse showed indications that Elvanse could also have a positive effect in the treatment of tic disorders.33
Barkley reports in a lecture on the advantages of a combination of stimulants and guanfacine (which is helpful for comorbid tics) in order to counteract the dampening of the limbic system caused by stimulants and the associated reduced perception of emotions.61
One study found a good improvement in ADHD symptoms with selegiline in children with ADHD and comorbid tic disorder over a test period of more than 6 months. Only 2 of the 29 subjects reported an exacerbation of tics. The side effects were minor.59 Another study of 24 children with ADHD and comorbid Tourette’s found only minor improvements in ADHD symptoms with a high dropout rate among participants62
3.4.11. Obsessive-compulsive disorder comorbid with ADHD¶
Atomoxetine showed positive effects on compulsive behaviors.63
A report on 2 children with obsessive-compulsive disorder and AD(H)D (9 and 10 years old) indicated a positive effect of a combination of behavioral therapy, sertraline and guanfacine.64
3.4.12. Substance abuse / addiction comorbid with ADHD¶
According to the updated European consensus on the diagnosis and treatment of ADHD in adults from 201835 and other sources (decrease of around 35% in the period medicated with stimulants compared to the unmedicated period65 A case report reports the effect of lisdexamfetamine on a former addict as an example.66
Previous substance abuse is therefore not normally a contraindication for stimulants67
In acute comorbid amphetamine substance abuse, atomoxetine is advantageous due to the lower risk of abuse26
Lisdexamfetamine (Elvanse) has the same effect on D-amp levels as when taken orally, even when taken intranasally (snorting)68 or intravenously (injecting)69 as prescribed. The effect was approximately the same, with slightly increased side effects. There was no intoxicating effect. This shows that the risk of abuse of lisdexamfetamine is very low.
One study compared the abuse potential of single oral doses of lisdexamfetamine (LDX) 50, 100 (equivalent to 40 mg d-amp) and 150 mg, 40 mg d-amphetamine and 200 mg diethylpropion in 36 subjects with previous stimulant abuse. When susceptibility to abuse was measured using the Drug Rating Questionnaire-Subject Liking Scale, lisdexamfetamine at 50 mg and 100 mg showed no significant increase compared to placebo (2.1), but a significant increase at 150 mg (6.1). D-amphetamine and diethylpropion showed significantly increased values of 4.0 and 4.5 respectively. The subjects preferred 40 mg D-amp to 100 mg LDX, while 150 mg LDX and 40 mg D-amp were on a par.70
In the case of acute THC or alcohol substance abuse without acute amphetamine addiction, we consider the risk of an affected person attempting to abuse prescribed stimulants as a drug to be very low.
Duloxetine alleviates comorbid enuresis (bedwetting) and stimulant-induced dysphoria in ADHD.
A single case report noted relief of comorbid enuresis, stimulant-induced dysphoria and improvement in cognitive abilities in an adolescent with ADHD.72
People with ADHD often suffer from sleep problems. Stimulants can improve sleep problems (many sufferers report that they have significantly improved sleep since taking stimulants). For some sufferers (we estimate around 5 to 10 %), small doses (14/ to 1/3 of a single daily dose) of untreated MPH can also improve sleep.
However, stimulants can also cause sleep problems. In most cases, these are single-dose side effects that disappear within the first few weeks. Sometimes it is a consequence of taking the medication too late or taking it for too long due to slower metabolism. For the latter, see Effect and duration of action of ADHD medication
A Swedish cohort study found that two-thirds of the boys and half of the girls who received melatonin also received ADHD medication73, suggesting a high efficacy of melatonin for ADHD-related sleep problems.
More on melatonin as a medication for treating sleep problems in ADHD at Melatonin for ADHD
One sufferer reported good experiences with taking Guanfacine approx. 5 hours before going to bed. Tiredness is a common side effect of Guanfacine, Guanfacine is a level medication and works almost the whole day, so there should still be a positive effect on the ADHD symptoms the next day.
Amitryptiline at a dosage of about 1 mg/kg/day when used cautiously showed improvement in sleep, anxiety, impulsivity and ADHD, repetitive behavior and enuresis.57
As with all serotonergic antidepressants, discontinuation side effects must be taken into account and tapering is recommended.
In one study, atomoxetine significantly improved 7 out of 9 symptoms of the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) in SCT. The symptom improvement in SCT was completely independent of the ADHD symptoms.75
SCT sufferers are also particularly frequent MPH non-responders. In contrast, the ADHD-HI and ADHD-I subtypes do not differ in the MPH response rate.76
An ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but was able to tolerate low doses of sustained-release MPH.
3.4.22. Schizophrenia and psychoses comorbid with ADHD¶
Taking stimulants or atomoxetine reduced the risk of psychosis-related hospitalization by 2/3 (HR = 0.36) in the 12 months following the introduction of these drugs when taken in combination with antipsychotics.84
Down syndrome is associated with a significantly increased prevalence of ADHD.
A study of n = 21 Down’s patients with ADHD reported a guanfacine responder rate of 48%. 43 % reported side effects, mostly daytime sleepiness (33 %) and constipation (10 %).85
Atomoxetine is particularly suitable for emotional instability.67 This is consistent with our impression if stimulants alone are not sufficiently effective. This also applies to a combination medication of atomoxetine with stimulants (in correspondingly lower doses).
Guanfacine can also be helpful here.
4.1. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT¶
The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP) and atomoxetine (ATX) bind with different affinities to dopamine transporters (DAT), noradrenaline transporters (NET) and serotonin transporters (SERT). The binding causes an inhibition of the activity of the respective transporters.86
Binding affinity: stronger with smaller number (KD = Ki)
DAT
NET
SERT
MPH
34 - 200
339
> 10,000
d-AMP (Elvanse, Attentin)
34 - 41
23.3 - 38.9
3,830 - 11,000
l-AMP
138
30.1
57,000
ATX
1451 - 1600
2.6 - 5
48 - 77
4.2. Effect of MPH, AMP, ATX on dopamine / noradrenaline per brain region¶
The active substances methylphenidate (MPH), d-amphetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different brain regions. Table based on Madras,86 modified.
PFC
Striatum
Nucleus accumbens
Occipital cortex
Lateral hypothalamus
Dorsal hippocampus
Cerebellum
MPH
DA + NE (+)
DA + NE +/- 0
DA + NE +/- 0
AMP
DA + NE +
DA + NE +/- 0
DA + NE +/- 0
ATX
DA + NE +
DA +/- 0 NE +/- 0
DA +/- 0 NE +/- 0
DA +/- 0 NE + (rat)
DA +/- 0 NE + (rat)
DA +/- 0 NE + (rat)
DA +/- 0 NE + (rat)
Note: the NET binds dopamine in the PFC slightly better than noradrenaline, the DAT binds dopamine much better than noradrenaline.
However, atomoxetine only increases dopamine in the PFC and not everywhere where it binds to the NET, so that there appears to be a special mechanism of action here.
5. Duration of action of various ADHD medications¶
In France, methylphenidate is approved for children and can be prescribed to adults if they were given methylphenidate as a child. In view of the fact that it has been known for decades that ADHD persists in around 2/3 of those affected in adulthood, this is extremely surprising and very regrettable for those affected who had the misfortune not to be diagnosed and treated as a child.
Initial prescription to adults appears to be possible in the context of off-label use88
Overall, the diagnosis and treatment of ADHD in France appears to be decades out of date.
6.3. Approval status of ADHD medications in the USA¶
As of January 2023, the following ADHD medications are approved in the USA:89
Active substance
Authorization
Dexmepthyl phenidate unretarded
Focalin®
Dexmepthylhenidate slow-release
Focalin® XR
Methylphenidate unretarded
Methylin®, Ritalin®, Metadate CD®
Methylphenidate Half-Day Retard
Metadate® ER, Methylin® ER, QuilliChew ER™, Quillivant XR®, Ritalin LA®