Choice of medication for ADHD

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

Choosing the most effective medication for ADHD and its optimal dosage is a challenge. Although there are many guidelines, the individual characteristics of each sufferer can put all empirical values to the test

• 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. Emotional impairment
  • 2.3. Inhibition / impulse control control
  • 2.4. Anxiety disorder comorbid
  • 2.5. Tic disorders comorbid
  • 2.6. ASA comorbid
• 3. Different modes of action of ADHD medication
  • 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

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
    • Cause: 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
      • But not congruent with AMP nonresponders
• Amphetamine drugs (AMP)
  • Advantages
    • More mood-equalizing than MPH
  • Disadvantages
    • Nonresponder rate approx. 20
      • But not congruent with MPH nonresponders

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. Emotional impairment¶

• Reduce stimulants
• Atomoxetine or guanfacine
• Combination medication
  • Adults: stimulants and atomoxetine
  • Children: Stimulants and guanfacine or Stimulants and guanfacine

2.3. 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 primarily 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

2.4. Anxiety disorder comorbid¶

Atomoxetine may help reduce comorbid anxiety symptoms in children and adolescents.²

2.5. Tic disorders comorbid¶

• Guanfacin³
• Atomoxetine³

2.6. ASA comorbid¶

• MPH: worse effect on hyperactivity in intellectual impairment⁴
• Atomoxetine: worse effect on ADHD symptoms with the same level of tolerability⁴
• Guanfacine: same effect on hyperactivity in intellectual impairment, with poorer tolerance⁴

3. Different modes of action of ADHD medication¶

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.⁵

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,⁵ modified.

	PFC	striatum	nucleus accumbens
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

Note: the NET binds dopamine slightly better than norepinephrine, the DAT binds dopamine much better than norepinephrine.