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Effect size of different forms of treatment for ADHD


Effect size of different forms of treatment for ADHD

The effect size of a treatment is the value by which the symptomatology improves.

The magnitude of the effect sizes found is described using standard criteria:1
SMD (standardized mean difference): small = 0.20, medium = 0.50, large = 0.80
Correlation coefficient: small = 0.10, medium = 0.24, large = 0.37.

A “small” effect is usually difficult to observe in an individual, but can be very important for public health if it is a general exposure that affects many individuals.
A “medium” effect should be perceptible to a careful observer.
A “large” effect is generally relevant to clinical practice at the individual level.

Synonyms are:
“Moderate” and “medium
“Strong” and “big

Medications (especially stimulants) show the highest effect in the treatment of ADHD. The effect sizes of AMP (approx. 1.0 to 1.5) and MPH (approx. 0.8 to 1.1) on ADHD are the highest ever found for psychiatric medications 2
Behavioral therapy alone is not as effective as medication alone over many years.
A combination of medication and intensive behavioral therapy did not perform significantly better than medication alone in the MTA study of n = 579 children aged 7 to 9 years.34 For impulsive-aggressive symptomatology and emotional disturbance, medication and behavior therapy were equally effective.5 A more recent comprehensive metastudy of 190 studies involving 26,114 participants with ADHD-HI found similar results.6

Medications during therapy have been reported to increase the learning efficacy of therapy.7 It is our understanding that in many cases they establish the capacity for therapy in the first place, because stimulants eliminate the dopamine deficit and thus restore the neurotrophic effect of dopamine required for learning capacity to support brain plasticity. Neurophysiological correlates of learning problems in ADHD

Medication is only effective for ADHD for as long as it is given. Therapy, environmental intervention and psychoeducation, on the other hand, have a long-term effect. Therapies have an effect beyond their specific application.

The effect sizes8 and SMD (standard mean difference) values9 mentioned in this article are not directly comparable with each other, especially since they were mostly determined using different methods. Nevertheless, the data provide an approximate picture for comparing effectiveness.

1. Effectiveness intensity of the treatment methods

The different treatment options have different efficacy.
The higher the value, the more effectively the treatment improves ADHD symptoms.

1.1. Effectiveness of medication in ADHD

Effect only while taking medication.

1.1.1. Comparison by effect size

For effect size, positive values are better. Stimulants: 1 to 1.5 Amphetamine drugs: 1.1 to 1.5
  • Amphetamine drugs total
    • Approx. 1.1 AMP total10, approx. 1.02
    • 1.07 in European adults (lisdexamfetamine drugs; metastudy of 22 studies)11
    • For inattention: 1.5 (lisdexamfetamine medication, but only one examination)10
    • For hyperactivity: approx. 1.2 (total amphetamine drugs)10
  • Lisdexamfetamine showed the best effect size in a metastudy, significantly better than amphetamine salts and methylphenidate.12 Another study came to comparable results for Adderall (amphetamine salts).13
  • In MPH nonresponders, lisdexamfetamine and atomoxetine were compared in a randomized double-blind trial with n = 200 subjects. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.14
  • Adderall XR
    (mixture of dexamphetamine and levoamphetamine in the ratio 3:1)
    • For children: 0.8515
    • For adults: 0.7515
  • Amphetamine suspension with prolonged release
    • For children: 0.8 / 0.5 to 0.8 for up to 13 hours16 Mazindol: 1.09

Mazindol, an awakening substance with stimulant properties, showed a high effect size of 1.09 on ADHD core symptoms in adults with ADHD 2 Methylphenidate: 0.9 to 1.1
  • 0.9 MPH total17, approx. 0.82, according to less reliable source 1.3 to 1.6918
  • Methylphenidate with immediate effect (unretarded)
    • Ritalin, MPH Hexal: 1.0119
    • Equasym: 1.0919
  • Methylphenidate sustained release: 1.0819
    • Concerta: 1.3519
    • Medikinet retard: 0.9519
      The better tolerability/efficacy of Concerta compared to Medikinet reported in the studies is consistent with our experience.
  • According to symptoms:
    • Inattention on average approx. 0.810
    • Hyperactivity: on average approx. 1.010
  • One metastudy found only a moderate effect size.12 This is not consistent with general experience in practice. Dasotraline: 0.48

A 6-week RCT of 342 children aged 6-12 years found an effect size of 0.48 at 4 mg/day20 Total non-stimulants (meta-analysis) 0.71

Total non-stimulants (meta-analysis) 0.7121 Guanfacine: 0.76

Guanfacine: 0.7622
In one study, guanfacine alone (at least 50% symptom reduction in 68% of subjects) was shown to be inferior to methylphenidate alone (at least 50% symptom reduction in 81% of subjects). However, a combination medication of MPH and guanfacine was most successful (symptom reduction of at least 50% in 91% of sufferers).23 Atomoxetine: 0.68
  • Atomoxetine 0.6815 Modafinil: 0.65
  • Modafinil 0.6521
  • In contrast, another metastudy found no symptom improvement with modafinil. However, this study also differed significantly from real-world experience with respect to MPH.12 Viloxazine: 0.46 to 0.63

The effect size of viloxazine was found to be between 0.46 to 0.63 in different studies.2

1.1.2. Comparison according to SMD

A large metastudy evaluating 133 studies with a total of 10,068 children and 8,131 adults determined the following efficacy values (in SMD; lower values are better):

  • Amphetamine drugs: -1.02 (from -1.19 to -0.85)24
  • Methylphenidate: -0.8 (from -0.93 to -0.62)24
  • Atomoxetine: -0.56 (from -0.66 to -0.45)24
  • Modafinil: -0.56 (from -0.66 to -0.45)24

In adults alone, the following efficacy values were found (in SMD, lower values are better)

  • Amphetamine drugs: -0.79 (from -0.99 to -0.58)24 which is consistent with other publications2526
  • Methylphenidate: -0.49 (from -0.64 to -0.35)24
  • Bupropion: -0.46 (from -0.85 to -0.07, i.e., a very wide range of variation)24
  • Atomoxetine: -0.45 (from -0.58 to -0.32)24
  • Modafinil: 0.16 (from -0.28 to 0.59)24
    • The positive value for modafinil means a worse effect than placebo in adults.

1.1.3. Compatibility

The compatibility was also analyzed.
Positive values mean: worse tolerated than placebo.

  • Amphetamine drugs
    • In children (2.30 odds ratio [OR], 95% CI 1.36 to 3.89)24
    • In adults (3.26, 1.54 to 6.92)24
  • Guanfacine in children and adults (2.64, 1.20 to 5.81)24
  • Atomoxetine (2.33, 1.28 to 4.25)24
  • Methylphenidate (2.39, 1.40 to 4.08)24
  • Modafinil (4.01, 1.42 to 11.33)24

1.2. Effectiveness of non-drug therapies for ADHD (effect size)

Efficacy expressed in effect size. Positive values are better.

1.2.1. Sports (endurance training): approx. 0.8 to 1

By effect size (higher values are better):

  • 0.93 according to a meta-review of 5 studies with a total of 144 subjects27 Unfortunately, no comparison was made on the effect size of medication.
  • An aerobic group exercise program produced improvements in participants with various disorders compared to the passive control group in terms of28
    • Global symptom severity: 0.77
    • Depression; 0.68
    • Anxiety: 0.87
    • Sleep quality: 0.88

According to SMD (lower values are better):

  • -0.65 SMD (mean). One meta-study found moderate effect sizes of endurance training in children with ADHD. Data in SMD, (more negative is stronger)29
    • Attention (-0.84)
    • Anxiety symptoms (-0.66)
    • Executive functions (-0.58)
    • Social disorders (-0.59)
    • Hyperactivity (-0.56)
    • Impulsivity (-0.56)
  • -0.62 (SMD) A Cochrane meta-analysis of 35 studies on the effect of exercise training on depression found an SMD (more negative is stronger) of -0.62 (35 studies with 1356 participants comparing endurance training against controls) and a long-term effect of -0.33. However, when only the studies with a high blinding were evaluated, the SMD dropped to barely relevant -0.18. However, when only the studies with high blinding were evaluated, the SMD decreased to a barely relevant -0.18. The comparative studies on the effect size of psychotherapy (7 studies, n = 189) or medication (4 studies, n = 300) each found an identical SMD of endurance training.30

1.2.2. Behavioral therapy: 0.69 to 1

  • Without concurrent medication:
    • 1,031
    • 0.69 according to a meta-review of 3 studies with a total of 107 subjects27 Unfortunately, no comparison was made on the effect size of medication.
    • A large metastudy of 190 studies involving 26,114 participants with ADHD-HI found that stimulants were more effective than behavior therapy, cognitive training, or non-stimulants. Stimulants in combination with behavioral therapy appeared to be most effective.6
  • With concomitant medication: 1.731
  • Effect remains largely after end of therapy
  • Duration until onset of action very long

1.2.3. Neurofeedback: 0.8 (0.39 to 1.2)

  • 0,63233
  • 0.49 to 0.68 after only 30 sessions18
  • 0.61 according to a meta-review of 6 studies with a total of 203 subjects27 Unfortunately, no comparison was made on the effect size of medication.
  • To attention: 0.8 to 1.2
    • 0,831
    • After 40 sessions: 1.231
  • On impulsivity: 0.68
    • After 20 sessions: 0.731
    • Cannot be improved further by increasing the number of meetings
  • On hyperactivity: 0.39
    • Cannot be improved further by increasing the number of meetings
  • Neurofeedback is not as effective as MPH34
    • MPH showed a symptom improvement of 46.9% (SMD 2.03) in one study, whereas neurofeedback produced a symptom improvement of 26.7% (SMD 0.89).35
  • Effect usually remains completely after the end of therapy

1.2.4. Parent training 0.65

A single study of a particular training for parents of children with ADHD found an improvement in problematic behavior of 0.6 to 0.7. Because the data collection was done through self-report questionnaires by parents, a substantial bias toward elevated scores is likely to be expected.36

1.2.5. Cognitive training 0.45

  • 0.45 according to a meta-survey of 4 studies with a total of 159 subjects.27 Unfortunately, no comparison was made on the effect size of medication.

1.2.6. Elimination diet: 0.45 (0.12 to 0.8)

  • 0,2937
    Effect only during error-free diet compliance
  • 0.51 to 0.838

There is evidence that an elimination diet only works for certain affected individuals (“subgroup”).39

1.2.7. Elimination of food supplements / colorants: 0.2 (0.08 to 0.44)

  • 0.08 to 0.11 (teacher and observer rating)38
  • 0.12 to 0.2537
  • 0.21 to 0.283 (if smaller, lower-quality studies are also added)40
  • 0.21 to 0.44 in parent rating38
  • Effect only during error-free diet compliance

1.2.8. PUFA supplementation: 0.16

  • 0.16 to 0.17 in parent and teacher rating38

1.2.7. Mindfulness-Based Behavior Therapy (MBCT)

ADHD sufferers who were additionally treated with MBCT (Mindfullness based cognitive therapy, a mindfulness-based behavioral therapy) showed a significantly greater reduction in ADHD symptoms [M difference = -3.44 (-5.75, -1.11), p = 0.004, d = 0.41]. This effect was maintained until the 6-month follow-up. Of those additionally treated with MBCT, 27% showed a 30% reduction in ADHD-HI symptoms (p = 0.001), compared with only 4% of those not additionally treated with MBCT.41
The effect largely persisted after the end of therapy.

1.2.8. Multimodal therapy

In the Multimodal Treatment Study of Children with ADHD (MTA study) in the late 1990s, 579 children ages 7 to 10 were treated for 14 months with medication, cognitive behavioral therapy, or both.
Teachers and parents rated the symptom reduction with regard to the core symptoms of ADHD better in the group of children treated with medication only than in the group of children treated with behavior therapy only. The children who received medication and behavioral therapy still did a tiny bit better than the children treated with medication only. When not only the core symptoms but all symptoms were considered, the children treated with medication and cognitive behavioral therapy clearly did best. In contrast, the effect of behavioral therapy alone was lower than treatment with medication alone.4

2. Effectiveness latency of the treatment forms

By efficacy latency, we mean how long it takes for a treatment to produce an effect.

  • Medication
    • Stimulants: immediately effective, fully effective immediately when optimally adjusted
    • Norepinephrine reuptake inhibitors: 2-3 weeks of flare-up phase
    • Atomoxetine: several weeks to 6 months of tarnish phase
  • Therapy
    • Behavioral therapy: several months for first steps, 3 years for adequate treatment effect
    • Neurofeedback: several months for first steps, 6 to 15 months for adequate treatment effect

3. Effectiveness object of the treatment forms

By efficacy object, we mean what symptoms each treatment modifies.

3.1. Medication

  • Stimulants:
    • Attention
    • Hyperactivity
    • Impulsivity (MPH more than amphetamine medication)
    • Internal pressure
    • Emotional dysregulation
      • Mood swings / affect stability
      • Aggression/fearfulness
      • Dysphoria (predominantly amphetamine medications, but MPH less so)
  • Non-stimulants:
    • Impulsivity
      e.g. low doses of SSRIs
    • Emotional regulation
    • Attention
  • Norepinephrine reuptake inhibitors:
    • Impulsivity
    • Depression
    • Mood swings / affect stability
    • Hyperactivity

3.2. Therapy

  • Behavioral therapy:
    • Cognitive VT:
      Self-esteem, social behavior, stress reduction
      To a certain extent also change in stress processing including hormonal and immunological physical changes42
    • Mindfulness-based VT:
      Attention, empathy, stress reduction
  • Mindfulness Training:
    Alteration of stress perception; alteration of stress processing in the CNS, impulsivity
    Improved perception of pleasant aspects causes immediate changes in the dopaminergic focusing and reinforcement system. Perceptions of the nature of an individual’s spatial environment and (permanently) a high social rank have the same effect.43
    However, whether these changes (with the exception of social rank) have a lasting influence, which is a prerequisite for therapeutic use, or only activation occurs during perception in each case is unclear.
  • Neurofeedback:
    Attention; impulsivity; hyperactivity, relaxation, sleep
  • Environment Interventions:
    Elimination of stressors through elimination of stressors and greater understanding of the environment
  • Psychoeducation:
    Elimination of stressors and better ability to regulate due to greater understanding of the affected person
    Self-esteem enhancement through the feeling of coming home, meeting and exchanging with other affected people

4. Efficacy duration of the treatment forms

4.1. Early medication

There is an indication that methylphenidate treatment at 2 mg/kg/day in very young rats caused a permanent reduction of dopamine transporters in the striatum (which would correspond to a permanent curative effect), whereas methylphenidate administration in slightly older animals (“after puberty”) no longer did so.44 These results could not be reproduced so far.

In the treatment of humans, no permanent reduction of DAT in the striatum is known, even in children before puberty with MPH. Either an application in humans is required at even much earlier ages or the - compared to the postulated maximum dose of 1 mg / kg / day in children - significantly increased dosage (here 2 mg / kg) causes as yet unexplored effects.

Despite the immense importance of this issue, no other studies on this subject are known to confirm the results. At a dosage of even two times 5 mg / kg / day in rats from the 7th day until the 35th day after birth, short-term reductions in the number of DAT were observed, but these were no longer found on the 135th day of life.45
What part the massively increased dosage plays in this is an open question.
Structural changes in brain structures were not found immediately after the end of treatment on day 35, nor on day 135.45 Considering the extreme dosage, this also proves a low hazard of MPH.

4.2. Short term medication

The improvements with drug treatment end (at least with stimulants) immediately with the end of drug administration, with other drugs with a mirror effect at the latest after approx. 14 days.
Learning effects with neurofeedback and behavioral therapy are better with medication administration.
The efficacy of non-drug therapy is long-lasting; however, sufficiently long and intensive therapy (6 months to 3 years) is required.
With neurofeedback, persistence of treatment effects was noted as late as 6 months after the end of treatment746 Kühle observed that treatment effects persisted years later in some cases and not in others.

4.3. Long term medication

There is evidence that longer-term medication may cause post-maturation of those brain structures that are affected by developmental delay in ADHD.

In ADHD, dysfunctional executive functions are associated with a decreased amount of brain matter in the cortex.47 In children with ADHD, brain matter growth in the cortex is significantly reduced, with the greatest delays in the PFC and ACC.47
Adult ADHD sufferers treated with stimulants have a significantly larger brain mass in the relevant brain regions than adult ADHD sufferers not treated with stimulants.48 This may indicate that treatment with stimulants can catch up or compensate for the developmental delay.47
In ADHD sufferers who still showed full ADHD symptoms as adults, no post maturation (i.e. growth) of the brain mass in the relevant brain regions was detectable.49

4.4. Multimodal treatment: non-drug therapy and medication

There is evidence that dopaminergic ADHD medications-in particular, D-amphetamine medications in the study (levodopa, also mentioned, is not suitable as an ADHD medication)-can increase neuroplasticity and thus increase the success of psychotherapy.50

In our opinion, psychotherapeutic measures are significantly less effective in ADHD patients who are not medicated, since the learning and receptive ability is massively reduced by ADHD itself. In our opinion, the establishment of a learning and receptive ability through medication is therefore clearly recommended for successful psychotherapy and is in the interest of reducing and discontinuing medication as soon as possible after successful psychotherapeutic treatment.

Apart from this, psychotherapy makes little sense if the patient does not even know what the state feels like that he is supposed to achieve through therapy. This feeling can only be conveyed to the patient after a longer period (1 year or more) of properly adjusted medication.
This is particularly true for ADHD sufferers, since motivation is altered in ADHD in the direction of significantly increased intrinsic control. ADHD implies precisely that compliance with extrinsic requests is massively impeded.

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