Choice of medication for ADHD

“Treating ADHD is easy. Treating ADHD well is very difficult.”

Choosing the most effective medication for ADHD and dosing it optimally is a challenge. There are, to be sure, quite a few points of reference for orientation. Often enough, however, the individual characteristics of each sufferer put all empirical values to the test. Since there is no such thing as “one ADHD”, but rather ADHD symptoms can arise from a large number of different causes, a large number of different options must be tried out for each affected person if necessary.

• 1. Advantages and disadvantages of different ADHD medications
  • 1.1. Stimulants
  • 1.2. Nonstimulants
• 2. Drug selection according to specific problem cases
  • 2.1. MPH Nonresponder
  • 2.2. Amphetamine medication nonresponder
  • 2.3. Emotional impairment due to stimulants
  • 2.4. Inhibition / impulse control control
  • 2.5. Inattention
  • 2.6. Anxiety disorder comorbid
  • 2.7. Tic disorders comorbid
  • 2.8. ASA comorbid
  • 2.9. Stimulant weight loss
  • 2.10. Depression comorbid
  • 2.11. Aggression comorbid
• 3. Different modes of action of ADHD medications
  • 3.1. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT
  • 3.2. Effect of MPH, AMP, ATX on dopamine / norepinephrine per brain region
• 4. Duration of action of various ADHD drugs

1. Advantages and disadvantages of different ADHD medications¶

1.1. Stimulants¶

• Benefits (common benefits of stimulants)
• Disadvantages (common disadvantages of stimulants
  • Impairment of emotional sensation in approximately 20% of affected individuals due to the depressant effect of stimulants on the limbic system
    • Causes: Hypersensitivity or overdose
    • In this case, consider combination medication of 50% atomoxetine and 50% MPH or AMP (each compared to monotherapy)
• Methylphenidate (MPH)
  • Advantages:
    • Particularly good drive increase
    • Unretarded short duration of action (2.5 - 3 hours)
  • Disadvantages:
    • Nonresponder rate approx. 30
      • MPH nonresponding not congruent with AMP nonresponding
• Amphetamine drugs (AMP)
  • Advantages
    • More mood-equalizing than MPH
  • Disadvantages:
    • Nonresponder rate approx. 20
      • AMP nonresponding not congruent with MPH nonresponding

1.2. Nonstimulants¶

• Atomoxetine (ATX)
  • Advantages
    • Mirror drug
    • No impairment of emotional sensation, as no dampening effect on the limbic system
  • Disadvantages
    • Difficult to dose
    • Sometimes very narrow range between under- and overdosing
    • Considerably higher side effects than stimulants
    • Lower effect strength than stimulants
• Guanfacin
  • Advantages
    • Good effect in comorbid tic disorders
    • Antihypertensive - helpful in case of high blood pressure
  • Disadvantages
    • Has little effect on adults
    • Higher side effects than stimulants
    • Lower effect strength than stimulants

2. Drug selection according to specific problem cases¶

The following is the beginning of a collection and is still quite incomplete.

2.1. MPH Nonresponder¶

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

2.2. Amphetamine medication nonresponder¶

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

2.3. Emotional impairment due to stimulants¶

• Reduce stimulants
  • Stimulants inhibit the limbic system.
    In sensitive sufferers, this can be too strong and cause an emotional flattening (“zombies”). This is not a normal reaction.
    Here, it should first be ensured that this does not result from an overdose. Therefore, the stimulants should be dosed down first, and if necessary, much more finely than the standard doses of the drugs provide. The next options should be considered only after it has been ensured that a dosage reduction that just misses the emotional impairment does not sufficiently improve ADHD symptoms.
• Atomoxetine or guanfacine instead of stimulants
  • Nonstimulants
    • Do not inhibit the limbic system
    • Do not improve drive
• Combination medication (advantage: drive from stimulants remains, emotional dysregulation is improved throughout the day)
  • Adults: stimulants and atomoxetine
  • Children: stimulants and guanfacine or stimulants and atomoxetine

2.4. Inhibition / impulse control control¶

The ADHD symptom of lack of inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen)¹

• Lack of inhibition of emotion regulation is noradrenergically caused by the hippocampus.¹
• Thus, the former is likely to be more amenable to dopaminergic treatment, whereas emotion regulation and affect control are likely to be more amenable to noradrenergic treatment.

Impulsivity

• Impulsivity is also serotonergically mediated
• If strong impulsivity is a prominent ADHD symptom, it would be negligent to use stimulants at such high doses that this is adequately eliminated, since this would result in an overdose with regard to the other symptoms
• Serotonin reuptake inhibitor
  • Significantly lower doses than when used as antidepressants
  • E.g.:
    • (Es)Citalopram 2-4 mg / day
    • Imipramine 10 mg / day

2.5. Inattention¶

In a small placebo-controlled trial, selegiline improved only inattention but not hyperactivity/impulsivity.²

2.6. Anxiety disorder comorbid¶

Atomoxetine may help reduce comorbid anxiety symptoms in children and adolescents.³

2.7. Tic disorders comorbid¶

• Guanfacin⁴
• Atomoxetine⁴
• Selegiline⁵

2.8. ASA comorbid¶

• MPH: worse effect on hyperactivity in intellectual impairment⁶
• Atomoxetine: worse effect on ADHD symptoms with the same level of tolerability⁶
• Guanfacine: same effect on hyperactivity in intellectual impairment, with poorer tolerance⁶

2.9. Stimulant weight loss¶

Stimulants and desipramine are often associated with the side effect of decreased appetite and consequent weight loss.
Nortryptiline is reported to be associated with weight gain as a side effect⁷

Augmenting administration of low doses of antipsychotics could help prevent stimulant-induced weight loss.
While MPH was often associated with appetite deficiency, thioridazine showed an increase in appetite as a side effect.⁸ Atypical antipsychotics are reported to show an even stronger effect toward appetite increase and metabolic syndrome.⁹

Combination treatment with antipsychotics and psychostimulants is being used more and more frequently. ¹⁰ Improved efficacy compared to stimulant monotherapy has also been reported in isolated cases.⁹ One registry study found that 3.9% of ADHD children and adolescents receiving stimulants were comedicated with atypical antipsychotics.¹¹

This opens up the option of using combination medication to counteract excessive weight loss with stimulants.

2.10. Depression comorbid¶

In ADHD with mild comorbid depression, monotherapy with stimulants should be given first.
In about one-third of all treatment-resistant depression, previously undiagnosed ADHD is found.
Given the rapid effectiveness of stimulants, it should be observed whether the elimination of the ADHD problem eliminates the stressor driving the depression. This is quite often the case.
A study of comedication of stimulants and MAO inhibitors in depression found no problems arising in the process,¹² contrary to the commonly assumed problem of hypertensive crises.
Another study reported successful comedication of selegiline and lisdexamfetamine (Vyvanse) for ADHD and comorbid depression¹³
Thus, combination medication of selegiline with stimulants may also be considered for ADHD.

2.11. Aggression comorbid¶

Several atypical antipsychotics, particularly risperidone, effectively ameliorated 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 children¹⁴

Combination treatment with (low-dose) antipsychotics and psychostimulants may be helpful, especially in cases of comorbid aggression, when monotherapy with stimulants and a combination of stimulants with behavioral interventions have not been sufficient to treat aggression.¹⁰ Several expert panels concluded that when aggression comorbid to ADHD (not: aggression following from stimulants) is not sufficiently ameliorated by stimulant prescription, concomitant use of atypical antipsychotics is indicated, with cautious dosing.¹⁵¹⁶

For comedication of antipsychotics and psychostimulants, see also weight loss above.

3. Different modes of action of ADHD medications¶

3.1. 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 inhibition of the activity of the respective transporters.¹⁷

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

3.2. Effect of MPH, AMP, ATX on dopamine / norepinephrine per brain region¶

The drugs methylphenidate (MPH), d-amphetamine (AMP), and atomoxetine (ATX) differentially alter extracellular dopamine (DA) and norepinephrine (NE) in different brain regions. Table based on Madras,¹⁷ modified.

	PFC	striatum	nucleus accumbens	cortex occipital	hypothalamus lateral	hippocampus dorsal	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 slightly better than norepinephrine, the DAT binds dopamine much better than norepinephrine.
Nevertheless, atomoxetine increases dopamine only in the PFC and not everywhere it binds to the NET, so there appears to be a specific mechanism of action here.

4. Duration of action of various ADHD drugs¶

See also Medication duration in ADHD