Choice of medication for ADHD or ADHD with comorbidity

“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 person with ADHD put all empirical values to the test. Since 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 a person with ADHD.

ADHD medications can be divided into two categories: Stimulants and non-stimulants. Stimulants such as methylphenidate (MPH) and amphetamine medication (AMP) have the advantage of having a high Effect size with low side effects. There is no other class of medication in psychiatry with such a high Effect size.¹²³ 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 persons with ADHD or in 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 size 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 too high a dose, 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.

In the US, medicated children with ADHD most commonly received stimulants only (60%-67%), followed by a combination of stimulants and non-stimulants (13%-15%), a combination of stimulants and antidepressants (6%-9%), and finally non-stimulants only (5%-9%).⁴

When dosing, the often increased sensitivity of people with ADHD to even small differences in dose or to different effects of different preparations of the same active ingredient must be taken into account. This goes so far that even the replacement of a generic drug with a supposedly bioequivalent preparation from another manufacturer can result in considerable differences or even a loss of efficacy. This applies to sustained release and immediate release stimulants as well as non-stimulants. It is not the rule, but, as we know from the ADHD forum of 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.

• 1. Advantages and disadvantages of various ADHD medications
  • 1.1. Stimulants
  • 1.2. Non-stimulants
  • 1.3. Suitability in tabular form
• 2. Choice of medication without specific problem cases
  • 2.1. Order of priority of the choice of medication
    • 2.1.1. Choice of medication for children and adolescents
    • 2.1.2. Choice of medication for adults
  • 2.2. Further factors for the choice of active ingredient
  • 2.3. Trial and error: finding the right active ingredient requires persistence
• 3. Medication selection according to specific problem cases
  • 3.1. Responding
    • 3.1.1. MPH Nonresponder
    • 3.1.2. Amphetamine drug non-responders
  • 3.2. Treatment of specific ADHD symptoms
    • 3.2.1. Inhibition / impulse control
    • 3.2.2. Inattention / ADHD-I
    • 3.2.3. Emotional dysregulation
    • 3.2.4. Rejection Sensitivity
      • 3.2.4.1. Methylphenidate
      • 3.2.4.2. Guanfacine and clonidine
      • 3.2.4.3. MAO-A reuptake inhibitors
      • 3.2.4.4. Imipramine, phenelzine
      • 3.2.4.5. Valproate for borderline
    • 3.2.5. Weak drive
  • 3.3. Avoidance of specific side effects of ADHD medication
  • 3.4. Choice of medication for comorbidities with ADHD
    • 3.4.1. Anxiety disorder comorbid with ADHD
      • 3.4.1.1. Anxiety disorders generally comorbid with ADHD
        • 3.4.1.1.1. Stimulants
        • 3.4.1.1.2. Non-stimulants
        • 3.4.1.1.3. Combination medication
      • 3.4.1.2. Comorbid social phobia in ADHD
    • 3.4.2. Depression comorbid with ADHD
      • 3.4.2.1. Stimulant monotherapy as a first step in comorbid depression and ADHD
      • 3.4.2.2. Atomoxetine as monotherapy
      • 3.4.2.3. Combination medication for comorbid depression and ADHD
        • 3.4.2.3.1. Atomoxetine and fluoxetine
        • 3.4.2.3.2. Atomoxetine and sertraline
        • 3.4.2.3.3. SSRI and MPH for comorbid depression with ADHD
        • 3.4.2.3.4. Escitalopram and MPH for comorbid depression with ADHD
        • 3.4.2.3.5. Fluoxetine and MPH for comorbid depression and ADHD
        • 3.4.2.3.6. Selegiline and lisdexamfetamine for comorbid depression
        • 3.4.2.3.7. Duloxetine and stimulants for comorbid depression
        • 3.4.2.3.8. Venlaflaxine and stimulants for comorbid depression
        • 3.4.2.3.9. MAO inhibitors and stimulants for comorbid depression
        • 3.4.2.3.10. Comorbid depression with specific manifestations
        • 3.4.2.3.10.1. Comorbid depression with concentration and drive disorders
        • 3.4.2.3.10.2. Comorbid depression with severe drive disorder
        • 3.4.2.3.10.3. Comorbid depression with obsessive-compulsive disorder
        • 3.4.2.3.10.4. Comorbid depression with irritability
        • 3.4.2.3.10.5. Comorbid depression with irritability
    • 3.4.3. Bipolar comorbid with ADHD
    • 3.4.4. Mood swings comorbid with ADHD
    • 3.4.5. Borderline comorbid with ADHD
    • 3.4.6. Disruptive Mood Dysregulation Disorder (DMDD) comorbid with ADHD
    • 3.4.7. Aggression comorbid with ADHD
    • 3.4.8. Oppositional defiant behavior comorbid with ADHD
    • 3.4.9. Conduct disorder (CD) comorbid with ADHD
    • 3.4.10. ASD comorbid with ADHD
    • 3.4.11. Comorbid strong irritability / increased sensitivity
    • 3.4.12. Tic disorders comorbid with ADHD
    • 3.4.13. Obsessive-compulsive disorder comorbid with ADHD
    • 3.4.14. Schizophrenia and psychosis comorbid with ADHD
    • 3.4.15. Substance abuse / addiction comorbid with ADHD
    • 3.4.16. Eating disorders comorbid with ADHD
      • 3.4.16.1. Binge eating comorbid with ADHD
      • 3.4.16.2. Bulimia nervosa comorbid with ADHD
      • 3.4.16.3. Anorexia nervosa comorbid with ADHD
    • 3.4.17. Obesity
    • 3.4.18. Chronic pain comorbid with ADHD
    • 3.4.19. Enuresis comorbid with ADHD
    • 3.4.20. Sleep problems and ADHD
      • 3.4.20.1. Melatonin and stimulants
      • 3.4.20.2. Guanfacine (especially in the evening)
      • 3.4.20.3. Amitriptyline
      • 3.4.20.4. Trazodone
    • 3.4.21. Bruxism (teeth grinding) with ADHD
    • 3.4.22. CDS / SCT (cognitive disengagement syndrome, sluggish cognitive tempo)
    • 3.4.23. Histamine intolerance / mast cell activation syndrome
    • 3.4.24. Gluten intolerance
    • 3.4.25. Lactose intolerance
    • 3.4.26. Fructose intolerance
    • 3.4.27. Sorbitol intolerance
    • 3.4.28. Down syndrome
    • 3.4.29. Emotional dysregulation
    • 3.4.30. High blood pressure comorbid with ADHD
    • 3.4.31. Epilepsy comorbid with ADHD
• 4. Choice of medication under further conditions
  • 4.1. Giftedness
  • 4.2. EEG: Alpha, beta and theta values increased
  • 4.3. COMT Met-158-Met
• 5. Different modes of action of ADHD medication
  • 5.1. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT
  • 5.2. Effect of MPH, AMP, ATX on dopamine / noradrenaline per brain region
• 6. Duration of action of various ADHD medications
• 7. Approval status of ADHD medications

1. Advantages and disadvantages of various ADHD medications¶

1.1. Stimulants¶

• Benefits (common benefits of stimulants)
  • Stimulants are methylphenidate and amphetamine drugs.
    • See under Methylphenidate (MPH) for ADHD
    • See under Amphetamine medication for ADHD
  • Stimulants for ADHD have a special position in psychiatric medication as a whole: no other class of medication has such a high Effect size 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 barely 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 people with ADHD 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 and less effort at every station and in every disco loo
    • Nevertheless possible stimulus for drug use in persons with ADHD with acute or previous amphetamine addiction; then rather test atomoxetine and guanfacine
    • Stimulants reduce the likelihood of developing an addiction,⁵⁶ they certainly do not increase it.⁷⁸
      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.⁹
• Methylphenidate (MPH)
  • Advantages:
    • Particularly good drive boost
    • Immediate release 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 Effect size and slightly lower side effects than MPH, especially in adults
  • Disadvantages:
    • Nonresponder rate approx. 20 %
      • AMP non-responding not congruent with MPH non-responding

1.2. Non-stimulants¶

• Atomoxetine (ATX)
  • Advantages
    • Mirror medication (works (almost) the whole day)
    • No impairment of emotional perception, as there is no dampening effect on the limbic system
  • Disadvantages
    • Difficult to dose
    • Complete effect only after 4 to 8 weeks
    • Sometimes very narrow range between underdosing and overdosing
    • Significantly higher side effects than stimulants
    • Lower Effect size than stimulants
    • Should be dosed out slowly
  • More on atomoxetine at Atomoxetine for ADHD
• Guanfacine
  • Advantages
    • Good effect in comorbid tic disorders
    • Antihypertensive - helpful for high blood pressure
  • Disadvantages
    • Barely has any effect on adults
    • Lower Effect size than stimulants
    • Higher side effects than stimulants
  • More about guanfacine at Guanfacine for ADHD

1.3. Suitability in tabular form¶

Legend:
Sources, unless otherwise stated¹⁰¹¹
— 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

Legend:
Sources, unless otherwise stated¹⁰¹¹
— Unsuitable
(—) Limited suitability, under close supervision
o limited suitability
+ particularly suitable
no entry: no known suitability restriction

** In our opinion, or source information still to be incorporated.
All information without guarantee. Talk to your doctor.

2. Choice of medication without specific problem cases¶

⇒ Medication for ADHD - Overview

• Of the people with ADHD who would be helped by medication, only around 20 to 25% receive medication. Of those not affected, less than 1% receive medication that they do not need.¹⁶
• Before treatment with stimulants, we recommend
  • A cardiovascular examination.¹⁷ to search for cardiovascular abnormalities such as¹⁸
    • Elevated blood pressure
    • Heart murmur
    • Syncope during physical exertion
    • ECG is optional
• Contraindications for stimulants (most of them uncommon in childhood):¹⁸
  • Schizophrenia
  • Severe depression
  • Hyperthyroidism
  • Cardiac arrhythmia
  • Moderate to severe high blood pressure
  • Angina pectoris
  • Glaucoma
  • Monoamine oxidase (MAO) inhibitors
    • Previous hypersensitivity
    • Simultaneous use
    • Use within the last 2 weeks
• Caution is advised for patients with¹⁸
  • Motor tics
  • Known drug addiction
  • History of drug addiction, alcoholism, caffeine addiction
    • But:
      • Stimulants for ADHD can significantly reduce the pressure of addiction
      • Alcohol and MPH at the same time do not mix at all
      • Alcohol and AMP at the same time are not good, but far less bad than alcohol and MPH
    • No caffeine when dosing stimulants - risk of cross-effects
  • Pregnancy
  • Breastfeeding
  • Anorexia nervosa
  • History of suicidal tendencies

2.1. Order of priority of the choice of medication¶

The following mentions are based solely on our opinion from a scientific point of view. Admission restrictions are not taken into account.

2.1.1. Choice of medication for children and adolescents¶

For adults, the most helpful from a scientific point of view is the prioritization of medication*:
* Health insurance licenses may deviate from this

• First choice is methylphenidate¹⁹
• Amphetamine drugs are the second choice²⁰²¹
• 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 MPH²²
  • Approximately 40%²³ to 50% of MPH non-responders respond to atomoxetine, and approximately 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)²⁴
• 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 size with fewer side effects than atomoxetine
• For other possible medications, see the following articles

2.1.2. Choice of medication for adults¶

For adults, the most scientifically helpful* Prioritization of medication is ²⁰²¹
* Health insurance licenses may deviate from this

• Amphetamine drugs are the first choice

  • Since March 2024, Vyvanse has also been indicated as a first-line treatment for adults according to the Takeda information for healthcare professionals, but only for children if MPH was insufficiently effective.²⁵

• Second choice is methylphenidate

• The third choice is atomoxetine. It can be the first choice for SCT or severe ADHD-I.

• In our opinion, the fourth choice is Guanfacine, as the positive effect reports of Guanfacine primarily concern children

  • Guanfacine is off-label for adults
  • Caution in old age due to increased risk of falling with rapid blood pressure reduction

• For other possible medications, see the following articles

• Amphetamine drugs (e.g. lisdexamfetamine (Vyvanse/Vyvanse), amphetamine salts (Adderall))

  • Usually work better in adults and are better tolerated
  • Nonresponders: approx. 20 %
  • Approx. 30% of adults who switch from MPH to Vyvanse switch back again²⁶
    • 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 medication selection:

• Comorbidities
• Metabolization enzyme gene variants that accelerate or slow down degradation
• other medication taken
• Stomach acid
• possible premenstrual worsening of ADHD symptoms
  • women with ADHD should give priority to stimulants, as these can also be taken in higher doses for a short time during the days in question. See below under Side effects of dosing.

More on this at

• Duration of action of medication for ADHD
• Combination medication for ADHD

2.3. Trial and error: finding the right active ingredient requires persistence¶

Psychiatric disorders and other CNS diseases pose particular challenges when it comes to finding a suitable medication.
ADHD still has a special position within the psychiatric disorders², as the responder rates of 70% (MPH) to 80% (AMP) are much higher than for other disorders. The Effect size of ADHD medication is also enormously high compared to other disorders.
Nevertheless, it is not possible to predict which active ingredient will work for a particular person with ADHD. Even within a drug class (MPH), one preparation may have intolerable side effects in one person with ADHD, while the other works excellently - while the next person with ADHD reacts in exactly the opposite way to the two preparations. The different reactions are presumably due to the different efflux and degradation profiles of the active ingredient, which can differ considerably between the individual preparations.
For this reason, persistent and gradual adjustment of medication is also the decisive factor for improving symptoms and quality of life with ADHD. We would like to encourage all people with ADHD to keep at it if the results are not satisfactory and to keep trying 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: Active ingredient, delivery system, dose, duration, and frequency.”²⁷

3. Medication selection according to specific problem cases¶

3.1. Responding¶

According to a meta-analysis, children with ADHD showed the best symptom improvement with:²⁸

• Dextroamphetamine: 35.5 %
• Methylphenidate: 26.2 %
• equally well with both active ingredients: 38.3 %

3.1.1. MPH Nonresponder¶

• Adults: AMP, then atomoxetine, then guanfacine, then bupropion.
• Children: AMP, then guanfacine, then atomoxetine, then bupropion.

3.1.2. Amphetamine drug non-responders¶

• Adults: MPH, then atomoxetine, then guanfacine, then bupropion.
• Children: MPH, then guanfacine, then atomoxetine, then bupropion.

3.2. Treatment of specific ADHD symptoms¶

3.2.1. Inhibition / impulse control¶

The ADHD symptom of a lack of inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen).²⁹ A lack of inhibition of emotion regulation is caused noradrenergically by the hippocampus.²⁹
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 strong impulsivity is a prominent symptom of the person with ADHD, it would be negligent to dose stimulants unseen to such a high level that this is adequately eliminated, as this would 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
  • E.g:
    • (Es)Citalopram 2-4 mg / day
    • Imipramine 10 mg / day

3.2.2. Inattention / ADHD-I¶

In a small placebo-controlled study, selegiline only improved inattention, but not hyperactivity/impulsivity.³⁰

Amphetamine drugs probably have a more activating effect than methylphenidate. Therefore, amphetamine medications are more useful for ADHD-I than methylphenidate.
It is also reported that people with ADHD-I are more likely to be nonresponders to MPH.
While MPH has a more inhibitory effect and is therefore particularly suitable for the treatment of ADHD-HI (with hyperactivity (children) / inner tension (adults)), D-amphetamine has a more activating / drive-increasing effect and is therefore said to be better suited for the treatment of ADHD-I (without hyperactivity (children) / inner restlessness (adults))³¹ On this side, however, a number of people with ADHD-HI are known to be significantly better helped by amphetamine medication than MPH.

In persons with ADHD-I subtype, a significant proportion of whom are said to be MPH nonresponders³², D-amphetamine may therefore be an efficient alternative to MPH.

3.2.3. Emotional dysregulation¶

Emotional dysregulation in ADHD can be treated with stimulants or atomoxetine.³³

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 a significantly lower Effect size 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. For people with ADHD who are capable of finely graduated dosing, this will often be the optimal approach.

3.2.4. Rejection Sensitivity¶

3.2.4.1. Methylphenidate¶

Many people with ADHD reported that stimulants had a significant and direct influence on their rejection sensitivity. In this context, 90% reported a positive and RS-reducing influence of MPH, 10% reported a rather increasing influence.

Methylphenidate significantly reduces the feeling of mistrust in people with ADHD.³⁴

3.2.4.2. Guanfacine and clonidine¶

According to a single report by an American doctor (Dodson), a combination of the alpha-2-adrenoreceptor agonists guanfacine and clonidine is particularly effective for rejection sensitivity. He reports that at a dosage of between 0.5 and 7 mg guanfacine and between 0.1 mg and 0.5 mg clonidine, one in three people with ADHD loses their rejection sensitivity symptoms. He also reported that the effect on quality of life of this treatment was greater than that of treatment with stimulants.³⁵

Dodson also reports from a Harvard University study that increasing the dosage for guanfacine up to 4 mg and for clonidine up to 7-8 mg resulted in a 40 % higher response, although this dosage was above the recommended limits. This also results in increased side effects.

Guanfacine is more effective as an ADHD medication compared to atomoxetine.

Alpha-2 adrenoreceptors (adrenoceptors) are activated by the neurotransmitters adrenaline and noradrenaline. They are therefore responsible for the effects mediated by adrenaline and noradrenaline.³⁶
Agonists increase the effect of the receptors. As a result, guanfacine and clonidine have a noradrenergic effect and reduce the adrenergic effect.

3.2.4.3. MAO-A reuptake inhibitors¶

Dodson³⁵ goes on to describe successes with MAO-A reuptake inhibitors, in particular with Parnate (tranylcypromine), which has been the usual treatment for rejection sensitivity to date. MAO-A reuptake inhibitors have also been used successfully in relation to ADHD symptoms.

3.2.4.4. Imipramine, phenelzine¶

Imipramine and phenelzine are each said to be more suitable (than valproate) for combating rejection sensitivity, depending on the nature of the other symptoms.³⁷.

Imipramine is a conceivable complementary medication to stimulants for ADHD. However, the mutual enhancement of the effects of imipramine and methylphenidate should be taken into account.

3.2.4.5. Valproate for borderline¶

Valproate (250 mg to 500 mg) moderately improved symptoms of irritability, anger, anxiety, rejection sensitivity and impulsivity in 50% of people with ADHD. The results varied greatly from person with ADHD to person with ADHD.³⁸

3.2.5. Weak drive¶

• Amphetamine drugs
• For AMP non-responding: MPH

Supplementary:

• Bupropion

While MPH has a more inhibitory effect and is therefore particularly suitable for the treatment of ADHD-HI (with hyperactivity (children) / inner tension (adults).), D-amphetamine has a more activating / drive-increasing effect and is therefore more suitable for the treatment of ADHD-I (without hyperactivity (children) / inner restlessness (adults).)³¹
However, we are aware of a number of people with ADHD-HI who are significantly better helped by amphetamine medication than MPH.

Bupropion can have a supportive effect in the case of a lack of drive. Conversely, bupropion can lead to decompensation in ADHD-HI and ADHD-C.

3.3. Avoidance of specific side effects of ADHD medication¶

See under Dosing of medication for ADHD

3.4. Choice of medication for comorbidities with ADHD¶

3.4.1. Anxiety disorder comorbid with ADHD¶

3.4.1.1. Anxiety disorders generally comorbid with ADHD¶

3.4.1.1.1. Stimulants¶

Some physicians have reservations about stimulant treatment in children with ADHD and comorbid anxiety disorder, as “anxiety and nervousness” is cited as a common side effect by major drug information databases such as Micromedex, Lexicomp and UptoDate.³⁹.

However, most people with ADHD also benefit from stimulant treatment in terms of comorbid anxiety symptoms.³⁹
A meta-analysis of k = 23 studies on n = 2,959 children with ADHD found a significant reduction in anxiety symptoms with stimulant use compared to placebo.⁴⁰
Immediate release methylphenidate derivatives reduced anxiety more than placebo. Sustained-release MPH and amphetamine derivatives did not influence the risk.
In a minority of people with ADHD, stimulants can exacerbate anxiety, although this is more common with amphetamine medications than with methylphenidate. High doses, especially above the recommended maximum daily doses, increase the risk. ⁴⁰ Anxiety disorders can be exacerbated by stimulants, as anxiety and moods are regulated by the dopaminergic activity of the ventromedial prefrontal cortex in conjunction with the limbic system.⁴¹
We are aware of reports from the forum of depression or anxiety symptoms as a side effect of amphetamine medication. Although such reports are rather rare, they should be taken seriously. In these cases, the first step is to consider changing the active ingredient.

Stimulants can therefore be used in children with ADHD and comorbid anxiety disorder. Even if anxiety occurs, discontinuation of stimulants is rarely necessary.³⁹

An analysis of the proteins addressed by Vyvanse showed indications that Vyvanse could also have a positive effect in the treatment of anxiety.⁴²

3.4.1.1.2. Non-stimulants¶

Atomoxetine can help to reduce comorbid anxiety symptoms in children and adolescents.^43444546
Positive effects of atomoxetine on comorbid anxiety disorders have been reported.⁴⁷ Atomoxetine is said to have an Effect size of 0.5 in relation to anxiety.²³
The improvement in anxiety symptoms with atomoxetine was slightly greater than with MPH⁴⁸

3.4.1.1.3. Combination medication¶

One study examined 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.⁴⁹

Beneficial experiences in ADHD and mild to moderate comorbid anxiety disorder were reported by:

• Stimulants plus venlafaxine 18.75 to 150 mg / day⁵⁰
• Stimulants plus duloxetine 30 mg / day⁵⁰
• Stimulants plus fluoxetine 10 to 20 mg / day⁵⁰

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 person with ADHD who did not respond to atomoxetine, reacted to MPH with dysphoria and could not tolerate augmenting clonidine. This was achieved with high tolerability.⁵¹

3.4.1.2. Comorbid social phobia in ADHD¶

Positive effects of atomoxetine on comorbid social anxiety have been reported.⁴⁷

3.4.2. Depression comorbid with ADHD¶

As stimulants have a drive-increasing effect, this can release an existing suicidal tendency that was not previously acted out due to existing depression. Stimulants should therefore only be used with particular caution in cases of (even concealed) severe depression.

Dysthymia / dysphoria in the sense of long-term (for years) mild depression (moodiness, especially when inactive) is only rarely a comorbid depression, but regularly an intrinsic ADHD symptom. In the case of dysthymia / dysphoria, ADHD-oriented medication with activating agents (bupropion, amphetamine medication) is indicated according to this view.
In the case of comorbid mild to moderate depression and, in our opinion, severe depression with suicidal tendencies ruled out, the ADHD should be treated first. Given 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.

• Comorbid depression is often a consequence of untreated ADHD. Previously undiagnosed ADHD is found in around a third of all treatment-resistant depression.
• ADHD medications work much faster (15 minutes to 1 hour) than antidepressants (to 2 weeks or more), although proper fine-tuning to ADHD stimulants can often take months
• MPH has no steady state, lisdexamfetamine has a steady state of 3 days
• Stimulants have significantly fewer side effects than antidepressants
• Stimulants do not have to be dosed out, but can be discontinued immediately. Consequences: preparations and active ingredients can be changed immediately
• Stimulants only have withdrawal side effects in very rare exceptional cases, while ADs have much more frequent withdrawal side effects, which can become very severe in some cases (especially with venlafaxine, up to the point of hospitalization)
• Stimulants have a much greater Effect size (MPH 0.9 to 1.1, lisdexamfetamine up to 1.5, both in relation to ADHD) than antidepressants (on average 0.3, with venlafaxine having the best value of 0.49 for depression).

3.4.2.1. Stimulant monotherapy as a first step in comorbid depression and ADHD¶

In persons with ADHD 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%.⁵²

Unlike MPH, amphetamine medications are suitable for the co-treatment of comorbid dysphoria or depression.⁵³⁵⁴ . In forums, a number of people with ADHD report a significant antidepressant effect of amphetamine medication, which they do not know from MPH.⁵⁵. In our experience, lisdexamfetamine (Vyvanse) also shows greater improvement in depressive symptoms as part of ADHD treatment than methylphenidate.
An analysis of the proteins addressed by Vyvanse showed indications that Vyvanse could also have a positive effect in the treatment of depression.⁴²

Moderate or severe depression can be exacerbated by stimulants, as anxiety and moods are regulated by the dopaminergic activity of the ventromedial prefrontal cortex in conjunction with the limbic system.⁴¹
We are aware of reports from the forum of depression or anxiety symptoms as a side effect of amphetamine medication. Although such reports are rather rare, they should be taken seriously. In these cases, the first step is to consider changing the active ingredient.

3.4.2.2. Atomoxetine as monotherapy¶

Whether atomoxetine is effective for depression is controversial. While the majority of voices deny this^{1856 57} , one study found an improvement in depression symptoms with atomoxetine that corresponded to that of paroxetine and venlaflaxine.⁵⁸

3.4.2.3. Combination medication for comorbid depression and ADHD¶

3.4.2.3.1. Atomoxetine and fluoxetine¶

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 area of symptoms of comorbid depression with combination therapy 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.⁴⁶

3.4.2.3.2. Atomoxetine and sertraline¶

One study found evidence of an effect of atomoxetine together with sertraline in HTTLPR (SERT) genotype s/s compared to sertraline monotherapy ⁵⁹

3.4.2.3.3. 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 vilazodone⁶⁰

3.4.2.3.4. Escitalopram and MPH for comorbid depression with ADHD¶

One study found no increased risk of augmenting escitalopram to MPH in ADHD, except in the presence of additional comorbid TIC disorders.⁶¹

3.4.2.3.5. Fluoxetine and MPH for comorbid depression and ADHD¶

Positive experiences have been reported with stimulants plus fluoxetine 10 to 20 mg / day for comorbid mild to moderate depression⁵⁰

A study of people with ADHD 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.⁶² 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.⁶¹
Combined administration of MPH and fluoxetine reduced anxiety and depression-like behaviors in rats significantly more than either drug alone.⁶³

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.⁶⁴ However, healthy animals and no ADHD model animals were tested.

3.4.2.3.6. Selegiline and lisdexamfetamine for comorbid depression¶

One study reports successful co-medication of selegiline and lisdexamfetamine (Vyvanse) for ADHD and comorbid depression.⁶⁵ Another study on the co-medication of stimulants and MAO inhibitors in depression found no problems arising from this⁶⁶
Thus, a combination medication of selegiline with stimulants can also be considered for ADHD.

3.4.2.3.7. Duloxetine and stimulants for comorbid depression¶

Positive experiences have been reported with stimulants plus duloxetine 30 mg/day for mild to moderate depression⁵⁰

3.4.2.3.8. Venlaflaxine and stimulants for comorbid depression¶

Positive experiences have been reported with stimulants plus venlafaxine 18.75 to 150mg/day for mild to moderate depression⁵⁰

We are aware of many reports of massive discontinuation symptoms with venlaflaxine. In some cases, discontinuation was not successful at all or took six months, with massive side effects. Against this background, venlaflaxine should be considered as one of the last remaining antidepressants.

3.4.2.3.9. 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,⁶⁶ contrary to the frequently assumed problem of blood pressure crises.

3.4.2.3.10. Comorbid depression with specific manifestations¶

3.4.2.3.10.1. Comorbid depression with concentration and drive disorders¶

Experience has shown that it is helpful for comorbid depression with concentration and drive disorders:

• Nortriptyline⁶⁷
• Milnacipran 25 to 100 mg⁶⁷

3.4.2.3.10.2. Comorbid depression with severe drive disorder¶

Experience has shown that it is helpful for comorbid depression with pronounced drive disorders:

• Bupropion 150 to 300 mg⁶⁷

3.4.2.3.10.3. Comorbid depression with obsessive-compulsive disorder¶

Experience has shown that it is helpful in cases of comorbid depression with an obsessive-compulsive personality structure:

• Sertraline 50 to 100 mg⁶⁷

3.4.2.3.10.4. Comorbid depression with irritability¶

Experience has shown that it is helpful for comorbid irritable depression:

• Moclobemide 75 to 100 mg⁶⁷

3.4.2.3.10.5. Comorbid depression with irritability¶

Experience has shown that it is helpful for comorbid depression with strong irritability:

• Amisulpride 25 to 100 mg / day⁵⁰⁶⁷

3.4.3. Bipolar comorbid with ADHD¶

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.⁴⁴

Stimulants can be used safely in children and adolescents comorbid with bipolar Disorder if the manic/hypomanic symptoms are effectively treated with a mood stabilizer.³⁹

A meta-analysis of k = 5 studies with n = 1,653 data sets found no increase in Young Mania Rating Scale scores for stimulant bipolar compared to placebo in patients who were in a euthymic or depressed state (SMD -0.17). The study results were highly heterogeneous and a qualitative synthesis of the studies showed a limited risk of drug-induced manic symptoms.⁶⁸

It is said to be helpful in cases of Bipolar Disorder and strong fluctuations in affect:

• Lamotrigine⁶⁷
  • carbamazepine or valproate if necessary

In comorbid bipolar Disorder with irritable depression, good experiences were reported by
- Aripiprazole 5 to 15 mg day⁵⁰
- Lamotrigine (important: dose slowly)⁵⁰

An analysis of the proteins addressed by Vyvanse showed indications that Vyvanse could also have a positive effect in the treatment of bipolar Disorder.⁴²

3.4.4. Mood swings comorbid with ADHD¶

Strong and frequent mood swings are said to be helpful:

• Venlaflaxine retard 18.75 to 150 mg⁶⁷
  Carbamazepine (CBZ), valproate (VPA) and lamotrigine (LTG)

3.4.5. Borderline comorbid with ADHD¶

A comparative effectiveness study of N = 22,601 people with Emotionally Unstable Personality Disorder with comorbid ADHD showed that ADHD medications were the only medication group that significantly reduced the risk of suicidality.⁶⁹

Should be helpful for comorbid borderline:

• Venlaflaxine retard 37.5 to 75 mg⁶⁷
• Venlaflaxine retard 18.75 to 150 mg⁵⁰

Valproate (250 mg to 500 mg) moderately improved symptoms of irritability, anger, anxiety, rejection sensitivity and impulsivity in 50% of people with ADHD. The results varied greatly from person with ADHD to person with ADHD.³⁸

3.4.6. 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.⁷⁰

3.4.7. Aggression comorbid with ADHD¶

Several atypical antipsychotics, particularly risperidone, were effective in improving aggression. Some studies showed (contrary to the FDA’s warning that stimulants could worsen aggression) that stimulants, like antipsychotics, were effective in improving aggression, especially in hyperactive children⁷¹

Stimulants that improve ADHD often also improve aggression and disruptive behavior from comorbid oppositional defiant disorder, conduct disorder, mood regulation disorder, or ASD.³⁹ In a study using rapid titration of MPH in n = 155 boys aged 6 to 12 years with ADHD and comorbid CD, 2/3 of subjects showed remission of aggression symptoms (R-MOAS score <18) after an average of 75 days of stimulant treatment.

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.⁷² Various expert panels have come to the conclusion that if aggression comorbid with ADHD (not: aggression resulting from stimulants) is not sufficiently improved by the prescription of stimulants, the concomitant use of atypical antipsychotics is indicated, with cautious dosing.⁷³⁷⁴

For co-medication with antipsychotics and psychostimulants, see also above under weight loss.

Bipolar disorders, intermittent explosive disorders and early-onset psychosis without comorbid ADHD are more likely to show treatment-induced mania, psychosis or their explosive behavior may become more aggressive on stimulants. Stimulants are therefore only helpful in reducing aggression in existing ADHD.³⁹

3.4.8. Oppositional defiant behavior comorbid with ADHD¶

A meta-analysis of k = 28 studies found that stimulants showed similarly good improvements on aggressive behaviors in ADHD as on the core ADHD symptoms themselves. For aggressive behaviors without comorbid ADHD, the effect of stimulants was slightly worse.⁷⁵ MPH⁷⁶⁷⁷ was just as helpful as AMP²³.

Atomoxetine is said to be helpful for comorbid oppositional defiant behavior.⁴⁴⁷⁸ However, one study only found an Effect size of 0.39 on Oppositional Defiant Behavior, with higher doses being more helpful than for ADHD without comorbidity⁷⁹, two studies found no efficacy ⁸⁰²³

Combination treatment with risperidone and MPH proved helpful for comorbid ODD and ADHD⁸¹, as well as for comorbid conduct disorder (CD).⁸²

Effect size of different drugs on ODD compared to placebo:⁸³

• 0.85 Stimulants (k = 6, n = 545)
• 0.43 Guanfacine (k = 2, n = 678)
• 0.33 Atomoxetine (k = 15, n = 1,907)
• 0.27 Clonidine (k = 3, n = 283)

3.4.9. Conduct disorder (CD) comorbid with ADHD¶

Atomoxetine is said to be helpful for comorbid conduct disorder.⁴⁴⁸⁴

Conduct disorder is also often treated with:⁸⁴

• Antipsychotics
• 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%).⁸⁵

3.4.10. ASD comorbid with ADHD¶

Medication for autism spectrum disorder and comorbid ADHD:

• There are frequent reports of increased sensitivity to medication in general, including ADHD medication, or a reduced dose requirement. In some cases, the doses required are extremely low³⁹
• Stimulants
  • Children with ASD and comorbid ADHD reported (% of patients):⁸⁶
    • Restlessness:
      • 47.4 % improved (especially in children diagnosed later)
      • 28.1 % worsened (especially due to sustained release MPH)
    • Concentration
      • 56.1 % improved
      • 15.8 deteriorated
    • Sleep
      • 8.8 % improved
      • 17.5 % deteriorated
    • Language
      • 86 % unchanged
      • 12.25 % deteriorated
      • 1.75 % improved
    • Other behavioral changes
      • 50.9 % unchanged
      • 45.6 % negative changes
      • 3.5 % positive changes
• MPH:
  • Poorer effect on hyperactivity with intellectual impairment⁸⁷
  • Poorer effect and worse level of side effects than with ADHD without ASA⁸⁸
  • Dose MPH low (e.g. 0.3 mg/kg/day) with low target doses (e.g. 0.5 mg/kg/day) under careful monitoring⁸⁹
  • More sensitive side effect reactions to stimulants possible, especially loss of appetite and insomnia⁸⁹
• Vyvanse
  • Choice of medication if MPH does not work or shows inappropriate side effects. Here too, use a low dose and expect a lower target dose⁸⁹
• Atomoxetine:
  • Poorer effect on ADHD symptoms with the same level of tolerability⁸⁷⁸⁸
• Guanfacin:
  • Same effect on hyperactivity with intellectual impairment, with poorer tolerance⁸⁷
  • Same effect on hyperactivity in ASD as in TD⁸⁸
• Amitriptyline:
  • At a dosage of about 1 mg/kg/day with cautious use is effective for⁸⁸
    • Sleep, anxiety, impulsivity and ADHD, repetitive behavior and enuresis
• Aripiprazole (off label) 2.5 mg (starting dose) to 10 mg⁶⁷

For autistic traits (subclinical ASD)

• Fluoxetine 10 to 20 mg⁶⁷
• Fluoxetine 5 to 20 mg⁵⁰
• Aripiprazole 2.5 to 7.5 mg⁵⁰

Pure ASA medication:
In the USA, only risperidone and aripiprazole are approved by the FDA for ASA treatment⁸⁸

• 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.¹⁸
• Citalopram and fluoxetine (SSRI):
  • Poor tolerance and lack of effectiveness for repetitive behaviors⁸⁸
• Oxytocin:
  • Showed no effectiveness⁸⁸
• Amitriptyline and loxapine:
  • Promising⁸⁸
• Loxapine:
  • In a dosage of 5 to 10 mg daily in PET similar to atypical antipsychotic, possibly without weight side effects⁸⁸

Memantine has been shown to be helpful for both ASD and ADHD. More on this under Memantine for ADHD.

3.4.11. Comorbid strong irritability / increased sensitivity¶

Experience has shown that it is helpful in cases of comorbid severe irritability:

• Aripiprazole (off-label) starting dose 2.5 mg, up to 10 mg⁶⁷

One study reports a reduction in sensory over-responsivity (SOR due to high-dose vitamin B6 (100 mg / day)).⁹⁰
100 mg / day is the maximum safe dose. In view of the serious side effects, it is advisable not to take it without medical supervision.
At the same time, it should be borne in mind that B6 intoxication can lead to neuropathies, which can be associated with impaired sensory sensitivity.⁹¹

3.4.12. Tic disorders comorbid with ADHD¶

Tourette’s has an estimated prevalence of 0.52% and is four times more common in boys than in girls. Every second adolescent with Tourette’s suffers from ADHD⁹²

In children and adolescents with ADHD and tic disorders or Tourette’s, stimulants can be an effective treatment. As a rule, tics or Tourette’s are not aggravated by them, even if there are individual cases where this is not the case.⁹³³⁹

As dextroamphetamine in high doses can (initially) worsen tics in some children, methylphenidate should be preferred.³⁹ As always, a slow and small-step dosage is recommended, even if this requires more persistence.
According to a Cochrane review, MPH such as dextroamphetamine are effective for ADHD-affected children and adolescents with tics. MPH also improved tics. However, dose increases were restricted due to concerns about an increased risk of tics.⁹³ Krause reports that monotherapy with stimulants can initially worsen comorbid tics. However, this usually disappears within about 4 weeks. In addition, a slow up-dosing and a low dosage can be helpful.¹⁴ In the case of severe ADHD and a history of tic exacerbation with stimulants, it is possible that the stimulant will not exacerbate the tics when administered again.⁹⁴

Stimulants used to be discouraged for adolescents with Tourette’s or chronic tic disorders,⁹⁵ as case reports from the 1970s reported tics in children treated for ADHD with a stimulant (especially motor tics, e.g. eye blinking, nose scrunching, lip licking).⁹⁵
However, a meta-analysis of k = 22 studies with n = 2,385 children with ADHD found no causation of tics by stimulants compared to placebo in adolescents without pre-existing tic disorders.⁹⁴

Positive effects on tics/Tourette’s have been described for the following other medications:

• Guanfacin⁹⁶⁹⁷
• Atomoxetine⁹⁶¹⁵
• Selegiline
  • One study found 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.⁹⁸
  • Another study of 24 children with ADHD and comorbid Tourette’s found only minor improvements in ADHD symptoms with a high dropout rate among participants⁹⁹
• Clonidine
  • Worked better than methylphenidate with halperidol in children with ADHD and comorbid tic disorders.¹⁰⁰

An analysis of the proteins addressed by Vyvanse showed indications that Vyvanse could also have a positive effect in the treatment of tic disorders.⁴²

Barkley reports in a lecture on the advantages of a combination of stimulants and guanfacine (which is helpful for comorbid tics) to counteract the dampening of the limbic system caused by stimulants and the associated reduced perception of emotions.¹⁰¹

Antipsychotics appear to have a higher Effect size for tic disorders without ADHD.⁹⁷

3.4.13. Obsessive-compulsive disorder comorbid with ADHD¶

Atomoxetine showed positive effects on compulsive behaviors.¹⁰²
A report on 2 children with Compulsions and AD(H)D (ages 9 and 10) suggested a positive effect of a combination of behavior therapy, sertraline, and guanfacine.¹⁰³
Positive experiences have been reported with sertraline 50 to 100 mg/day for comorbid obsessive-compulsive disorder.⁵⁰

3.4.14. Schizophrenia and psychosis 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.¹⁰⁴
A Swedish cohort study found a very small increase in the risk of psychosis of 4% in adolescents without a history of psychosis (average age 17 years) in the 12 weeks after starting MPH treatment compared to the 12 weeks before starting treatment.¹⁰⁵

A risk factor for stimulant-induced psychosis, on the other hand, are:³⁹

• Schizophrenia
• bipolar disorders
• other psychiatric disorders with psychotic features in childhood

Stimulant-induced psychotic symptoms disappear after discontinuation of the stimulant in 92% of patients without the need for antipsychotic treatment.¹⁰⁶

Experience has shown that it is helpful for comorbid psychotic symptoms:

• Quetiapine, amisulpride, also below the usual dosage⁶⁷
• Quetiapine, aripiprazole, amisulpride⁵⁰ People with ADHD are said to develop extrapyramidal symptoms quickly.

3.4.15. Substance abuse / addiction comorbid with ADHD¶

According to the updated European consensus on the diagnosis and treatment of ADHD in adults from 2018⁵⁶, stimulants do not increase the risk of addiction in ADHD,¹⁰⁷ but significantly reduce it during use. The use of addictive substances was around 35% lower during medication with stimulants than during the unmedicated period.¹⁰⁸ A meta-analysis of k = 6 studies with n = 1014 subjects showed a significantly reduced risk of later addiction for participants medicated with stimulants (here: MPH).¹⁰⁹ The risk of later addiction, whether to alcohol or other substances, is 1.9 times lower.¹¹⁰.
Methylphenidate is now considered a treatment option for addiction disorders.¹¹¹ A case report gives an example of the effect of lisdexamfetamine on a former addict.¹¹²
Previous substance abuse is therefore not normally a contraindication for stimulants¹¹³
In acute comorbid amphetamine substance abuse, atomoxetine is advantageous due to the lower risk of abuse⁴⁴

Lisdexamfetamine (Vyvanse) produces the same D-amp levels as when taken orally, even when taken intranasally (snorting)¹¹⁴ or intravenously (injecting)¹¹⁵ 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.¹¹⁶

In the case of acute THC or alcohol substance abuse without acute amphetamine addiction, we consider the risk of a person with ADHD attempting to abuse prescribed stimulants as a drug to be very low.

When withdrawing from dopaminergic drugs (including alcohol), the administration of stimulants can help to reduce withdrawal symptoms and prevent relapse.

3.4.16. Eating disorders comorbid with ADHD¶

3.4.16.1. Binge eating comorbid with ADHD¶

An analysis of the proteins addressed by Vyvanse showed indications that Vyvanse could also have a positive effect in the treatment of binge eating.⁴²
In the USA, Vyvanse is approved for the treatment of binge eating in adults. At 50 to 70 mg daily for 11 weeks, it reduced the severity and frequency of binge eating episodes³⁹

Lisdexamfetamine has not been systematically studied in children and adolescents with BED, but a retrospective review (N = 25; 12-19 years) suggests some benefit in self-reported binge eating symptoms.30 There are currently no specific recommendations for the use of lisdexamfetamine in children and adolescents with BED in the guidelines for the treatment of eating disorders due to a lack of robust data. Based on clinical practice, lisdexamfetamine may be considered in adolescents with moderate to severe BED and concurrent ADHD without a clinically significant cardiac history in conjunction with other supportive ED treatment (e.g., cognitive behavioral therapy).3,31

3.4.16.2. Bulimia nervosa comorbid with ADHD¶

A meta-analysis reported that almost all studies reported a positive effect of stimulants on eating behavior in bulimia nervosa.¹¹⁷ However, there are safety concerns due to a lack of data on their use in children and adolescents with bulimia nervosa.³⁹
Stimulants have been reported in children and adolescents with bulimia nervosa:

• cardiovascular complications related to dehydration and electrolyte imbalances as a result of purging
• self-induced vomiting and abuse of laxatives
• orthostatic tachycardia and increased blood pressure when taking stimulants

Treatment with stimulants for ADHD symptoms in comorbid bulimia is conceivable if:³⁹

• Purging behavior is low/very rare
• Laboratory values and hydration status are stable.

3.4.16.3. Anorexia nervosa comorbid with ADHD¶

Stimulants should be avoided in children and adolescents with anorexia nervosa. There are various risks:¹¹⁸

• additional appetite suppression
• additional weight loss
• Exacerbation of restrictive eating behavior
• Increase in cardiovascular risks including cardiomyopathy (e.g. hypertrophy) in severely malnourished children

If anorexia has subsided, treatment of ADHD symptoms with stimulants can be considered with increased monitoring of appetite, weight and eating behavior.³⁹

3.4.17. Obesity¶

Stimulants are known to reduce appetite.
Atomoxetine is approved by the FDA for the treatment of obesity.¹⁰²

3.4.18. Chronic pain comorbid with ADHD¶

Chronic pain is a common comorbidity in ADHD
Stimulants such as atomoxetine¹¹⁹ can also reduce chronic pain in people with ADHD.

3.4.19. Enuresis comorbid with ADHD¶

Duloxetine alleviates comorbid enuresis (bedwetting) and stimulant-induced dysphoria in ADHD. A single case report noted relief of comorbid enuresis (bedwetting), stimulant-induced dysphoria and improvement in cognitive ability in an adolescent with ADHD.¹²⁰
Atomoxetine increased the number of dry nights by half.¹²¹

3.4.20. Sleep problems and ADHD¶

People with ADHD often suffer from sleep problems. Stimulants can improve sleep problems (many people with ADHD report that they have significantly improved sleep since taking stimulants). For some people with ADHD (we estimate around 5 to 10%), small doses (14/ to 1/3 of a single daily dose) of immediate release 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

For the treatment of sleep problems with ADHD, see the detailed article Sleep problems with ADHD - treatment

3.4.20.1. Melatonin and stimulants¶

A Swedish cohort study found that two-thirds of the boys and half of the girls who received melatonin also received ADHD medication¹²², suggesting a high effectiveness of melatonin for ADHD-related sleep problems.
More on melatonin as a medication for treating sleep problems in ADHD at Melatonin for ADHD

3.4.20.2. Guanfacine (especially in the evening)¶

One person with ADHD reported good experiences with taking Guanfacine about 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.

3.4.20.3. Amitriptyline¶

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.⁸⁸

As with all serotonergic antidepressants, discontinuation side effects must be taken into account and tapering is recommended.

3.4.20.4. Trazodone¶

Experience has shown that it is helpful for comorbid sleep disorders, especially comorbid anxiety disorders and depression:

• Trazodone; starting dose 25 mg, rarely over 100 mg⁵⁰⁶⁷

3.4.21. Bruxism (teeth grinding) with ADHD¶

A case study reports a positive effect of buspirone on bruxism caused by atomoxetine.¹²³
ADHD medication can increase bruxism.

3.4.22. CDS / SCT (cognitive disengagement syndrome, sluggish cognitive tempo)¶

In one study, atomoxetine significantly improved 7 of 9 symptoms of the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) in CDS / SCT. The symptom improvement in SCT was completely independent of ADHD symptoms.¹²⁴

SCT people with ADHD are also particularly frequent MPH non-responders. In contrast, the ADHD-HI and ADHD-I subtypes do not differ in the MPH response rate.¹²⁵

3.4.23. Histamine intolerance / mast cell activation syndrome¶

One of the few non-histamine increasing ADHD medications mentioned is:

• Viloxazine
  • Viloxazine appears to exert a weak competitive inhibition at the histamine receptors H1 and H2 (< 25 %).¹²⁶

Most common ADHD medications, on the other hand, appear to increase histamine. On the one hand, the active ingredients themselves increase histamine. In addition, co-formulants can have a histamine-increasing effect:

• Atomoxetine¹²⁷¹²⁸
  • ATX increases extracellular histamine in the PFC
  • Winkler reports that with regard to the co-formulants among the ATX preparations, agakalin is said to be less detrimental in histamine intolerance than Strattera¹²⁹
• Methylphenidate¹²⁸
  • the histamine increase does not appear to be due to diamine oxidase inhibition
  • MPH induced diamine oxidase, which increases histamine degradation¹³⁰
  • Winkler reports that with regard to the co-formulants among the MPH preparations, Medikinet immediate release and Kinecteen are said to be less detrimental for histamine intolerance than Ritalin immediate release, Medikinet retard, Medikinet adult, Ritalin LA, Ritalin adult and Concerta¹²⁹
• Amphetamine¹³¹¹³²
  • the histamine increase does not appear to be due to diamine oxidase inhibition
  • Lisdexamfetamine induced a strong upregulation of DAO mRNA levels in Caco-2 cells, which increases histamine degradation¹³⁰
  • Winkler reports that with regard to the co-formulants among the AMP preparations, Attentin is said to be less detrimental to histamine intolerance than Vyvanse¹²⁹
• Modafinil¹³³
• Nicotine
• Caffeine

A list of other medications that increase histamine levels can be found at Histaminintioleranz.ch: List of medications.

A person with ADHD with histamine intolerance reported that she could not tolerate AMP and sustained release MPH at all, but could tolerate immediate release MPH in small doses.
Another person with ADHD reported that she was able to control her histamine intolerance reactions caused by ADHD medication by taking cetirizine in the morning.

3.4.24. Gluten intolerance¶

Co-ingredients in medicines may contain gluten.
Winkler reports that the co-formulants Medikinet immediate release, Medikinet retard, Medikinet adult, Ritalin LA, Ritalin adult, Concerta, Kinecteen, Vyvanse, Attentin, Strattera and Agakalin are safe, while Ritalin immediate release is problematic in the case of gluten intolerance¹²⁹

3.4.25. Lactose intolerance¶

Co-ingredients in medicines may contain lactose.
Winkler reports that with regard to the co-formulants Medikinet retard, Medikinet adult, Ritalin LA, Ritalin adult, Vyvanse, Attentin, Strattera and Agakalin are harmless, while Ritalin unretarded, Medikinet unretarded, Concerta and Kinecteen are problematic in the case of lactose intolerance¹²⁹

3.4.26. Fructose intolerance¶

Co-ingredients in medicines may contain fructose.
Winkler reports that with regard to the co-formulants Ritalin immediate release, Medikinet immediate release, Vyvanse, Strattera and Agakalin are safe, while Medikinet retard, Medikinet adult, Ritalin LA, Ritalin adult, Concerta, Kinecteen and Attentin are problematic in the case of fructose intolerance¹²⁹

3.4.27. Sorbitol intolerance¶

Co-ingredients in medicines may contain sorbitol.
Winkler reports that with regard to the co-formulants Ritalin immediate release, Medikinet immediate release, Medikinet retard, Medikinet adult, Ritalin LA, Ritalin adult, Concerta, Kinecteen, Vyvanse, Strattera and Agakalin are safe, while Attentin is problematic in the case of sorbitol intolerance¹²⁹

3.4.28. Down syndrome¶

Down syndrome is associated with a significantly increased prevalence of ADHD.
A study of n = 21 Down’s people with ADHD reported a guanfacine responder rate of 48 %. 43 % reported side effects, mostly daytime sleepiness (33 %) and constipation (10 %).¹³⁴

3.4.29. Emotional dysregulation¶

Atomoxetine is particularly suitable for emotional instability¹¹³

Experience has shown that stimulants (e.g. methylphenidate) not only improve attention and reduce hyperactivity and impulsivity, but also improve emotional self-regulation, which may be at least partly a consequence of reduced impulsivity ^{135 136 137138}
One study found no improvement in the ability to regulate emotions with stimulants.¹³⁹

Our impression is that stimulants can provide sufficient improvement in cases of moderate emotional dysregulation. If the effect of stimulants is not sufficient, atomoxetine (or guanfacine) is helpful, which has a better effect on emotional dysregulation, but covers the typical ADHD symptoms less well.
In case of doubt, a combination medication of atomoxetine (or guanfacine) with stimulants (each at a correspondingly lower dose) is helpful, as ATX as an all-day medication can then help to improve social life even outside the effective times of the stimulants (family life in the evening), while the stimulants improve drive and attention control during the day. We suspect that these combination medications will establish themselves as standard treatments in the future, even if this requires even more persistent and sensitive dosing.

3.4.30. High blood pressure comorbid with ADHD¶

Treatment with α-2 agonists (clonidine, guanfacine) may be indicated for high blood pressure.
Clonidine-IR has an even stronger hypotensive (blood pressure-lowering) and bradycardic (pulse-lowering) effect than clonidine-XR and guanfacine-XR¹⁴⁰
Guanfacine-XR prolonged the QTc.¹⁴⁰

MPH is less effective at increasing blood pressure than atomoxetine:

• Atomoxetine caused an average increase in heart rate of 6.4 beats, Concerta 3 beats and placebo 0.3 beats.¹⁴¹
• Systolic blood pressure increased on average by 3.7 with atomoxetine, by 2.4 with Concerta and by 1.3 with placebo.¹⁴¹
• Diastolic blood pressure increased on average by 3.8 with atomoxetine, by 3.1 with Concerta and by 0.4 with placebo.¹⁴¹

3.4.31. Epilepsy comorbid with ADHD¶

Methylphenidate appears to be the best option for treating ADHD in epilepsy and has a low risk of worsening seizures.¹⁴²¹⁴³ In addition to MPH, the administration of AMP or atomoxetine is also possible with a low risk.¹⁴⁴
The tendency to convulsions should be well treated before stimulants are administered.³⁹

Epilepsy medications themselves can worsen or improve the symptoms of ADHD.
A worsening of ADHD symptoms has been reported for the following epilepsy medications:³⁹

• Valproate (high evidence of a deterioration in attention)¹⁴⁵¹⁴⁶
• Phenobarbital
• Phenytoin
• Topiramate
• Zonisamide
• Perampanel
• Ethosuximide

Improvement in ADHD symptoms has been reported for the following epilepsy medications:³⁹

• Lacosamide
• Carbamazepine
• Lamotrigine

Whether ADHD symptoms are improved or worsened is an open question:³⁹

• Levetiracetam¹⁴⁵

4. Choice of medication under further conditions¶

4.1. Giftedness¶

Highly gifted people are said to respond better to amphetamine medication than to MPH.¹⁴⁷
Giftedness is not a comorbidity.

4.2. EEG: Alpha, beta and theta values increased¶

• Atomoxetine unsuitable

One study examined the EEG structure of atomoxetine responders and non-responders. According to the study, atomoxetine works better in those who have increased alpha and delta power in the frontal and temporal areas and in whom there are no deviations in the beta and theta bands. Atomoxetine non-responders, on the other hand, exhibit reduced absolute power in all EEG frequencies or increased alpha and simultaneously increased beta power. Atomoxetine caused a long-term normalization of the excessive alpha and delta values, while these remained unchanged in non-responders. Atomoxetine appeared unsuitable in the case of simultaneously elevated alpha, beta and theta values.¹⁴⁸
With increased alpha and delta power frontally and temporally and unchanged power in the beta and theta bands, atomoxetine should not be unsuitable. This does not indicate whether amphetamine drugs, MPH and guanfacine are not preferable due to their higher Effect size.

4.3. COMT Met-158-Met¶

In the presence of a COMT Met-158-met polymorphism, amphetamine drugs are said to be unsuitable.
In carriers of the COMT Val-158-Met gene polymorphism, amphetamine increased the efficiency of prefrontal cortex function in subjects with presumably low dopamine levels in the PFC. In contrast, in carriers of the COMT Met-158-Met polymorphism, amphetamine had no effect on cortical efficiency at low to moderate working memory load and caused deterioration at high working memory load. Individuals with the Met-158-Met polymorphism appear to be at increased risk for an adverse response to amphetamine.¹⁴⁹

5. Different modes of action of ADHD medication¶

5.1. 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.¹⁵⁰

Binding affinity: stronger with smaller number (KD = Ki)	DAT	NET	SERT
MPH	34 - 200	339	> 10,000
d-AMP (Vyvanse, 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

5.2. Effect of MPH, AMP, ATX on dopamine / noradrenaline per brain region¶

The active ingredients methylphenidate (MPH), d-amphetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different regions of the brain. Table based on Madras,¹⁵⁰ 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 there appears to be a special mechanism of action here.

6. Duration of action of various ADHD medications¶

In our experience, the actual duration of action is generally shorter than stated. This is particularly clear with Vyvanse.

See under Duration of action of medication for ADHD

7. Approval status of ADHD medications¶

This section has been moved to a separate post: Approval status of ADHD medications