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Effect size of different forms of treatment for ADHD


Effect size of different forms of treatment for ADHD

The effect strength of a treatment is the value by which the symptoms improve.

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 affecting many individuals.
A “medium” effect should be perceptible to an attentive observer.
A “large” effect is generally relevant to clinical practice at the level of the individual.

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

Medications (especially stimulants) show the greatest 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) for ADHD are the highest ever found for psychiatric medications 2
Behavioral therapy alone is not as effective as medication alone for 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 between the ages of 7 and 9.34 Medication and behavioral therapy were equally effective for impulsive-aggressive symptoms and emotional disorders.5 A more recent comprehensive meta-study of 190 studies with 26,114 participants with ADHD-HI came to comparable results.6

It has been reported that medication during therapy increases the learning effectiveness of the therapy.7 As we understand it, in many cases they establish the ability to undergo therapy in the first place, as stimulants eliminate the dopamine deficit and thus restore the neurotrophic effect of dopamine required to support the plasticity of the brain. Neurophysiological correlates of learning problems in ADHD

Medication only works 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 values (standard mean difference)9 mentioned in this article are not directly comparable with each other, especially as they were usually 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 varying degrees of effectiveness.
The higher the value, the more effectively the treatment improves ADHD symptoms.

1.1. Effectiveness of medication for ADHD

Effect only while taking the medication.

1.1.1. Comparison by effect size

Positive values are better for effect sizes. Stimulants: 1 to 1.5 Amphetamine drugs: 1.1 to 1.5
  • Total amphetamine drugs
    • Amphetamine medications have an NNT of 1.6 in adults with ADHD10
    • Lisdexamfetamine 1.52 11 (Elvanse)
    • D-Amphetamine unretarded 1.2411 (e.g. Attentin)
    • D-Amphetamine slow-release 1.1311 (not: lisdexamfetamine)
    • Approx. 1.1 AMP total12, approx. 1.02, approx. 0.8 to 1.510
    • 1.07 in European adults (lisdexamfetamine medication; meta-study of 22 studies)13
    • For inattention: 1.5 (lisdexamfetamine medication, but only one examination)12
    • For hyperactivity: approx. 1.2 (total amphetamine medication)12
  • Lisdexamfetamine showed the best effect strength in a meta-study, significantly better than amphetamine salts and methylphenidate.14 Another study came to comparable results for Adderall (amphetamine salts).15
  • In MPH non-responders, lisdexamfetamine and atomoxetine were compared in a randomized double-blind study with n = 200 subjects. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.16
  • Mixed amphetamine salts
    • 1,3411
    • For children: 0.8517
    • For adults: 0.7517
  • Mixed amphetamine salts retarded (e.g. Adderall XR; mixture of dexamphetamine and levoamphetamine in a ratio of 3:1)
  • Amphetamine suspension with extended release
    • For children: 0.8 / 0.5 to 0.8 for up to 13 hours18 Methylphenidate: 0.9 to 1.1
  • MPH total 0.919, approx. 0.82, according to less reliable sources 1.3 to 1.6920
  • Methylphenidate with immediate effect (unretarded)
    • 0.9211,
    • Ritalin, MPH Hexal: 1.0121
    • Equasym: 1.0921
  • Methylphenidate slow-release: 1.0821
    • Concerta: 1.3521
    • Medikinet retard: 0.9521
      • OROS-MPH 0.911
      • MPH-MR 0.8511
      • MPH-LA 0.9511
  • According to symptoms:
    • Inattention on average approx. 0.812
    • Hyperactivity: on average approx. 1.012
  • A meta-study found only a moderate effect strength.14 This is not consistent with general practical experience.
  • D-MPH 0.7611 Mazindol: 1.09

Mazindol, a wakefulness-inducing substance with stimulant properties, showed a high effect size of 1.09 on ADHD core symptoms in adults with ADHD 2

Further studies should be awaited to confirm this. Dasotraline: 0.48

A 6-week RCT with 342 children aged 6-12 years found an effect size of 0.48 at 4 mg/day22 Total non-stimulants (meta-analysis) 0.71

Total non-stimulants (meta-analysis) 0.7123 Guanfacine: 0.78 (monotherapy; in combination with MPH better than MPH alone)
  • Clonidine 0.811
  • Guanfacine: 0.7624
  • One study found an improved effect of guanfacine + MPH compared to guanfacine or MPH alone:25
    • Guanfacine alone (symptom reduction of at least 50% in 68% of patients)
    • Methylphenidate alone (symptom reduction of at least 50% in 81% of those affected)
    • Combination medication of MPH and guanfacine (symptom reduction of at least 50% in 91% of patients) Atomoxetine: 0.66
  • Atomoxetine 0.6817
  • Atomoxetine 0.6311
  • Atomoxetine has an NNT of 5 with regard to attention problems in ADHD10 Modafinil: 0.59
  • Modafinil 0.6517
  • Modafinil 0.5211
  • Another meta-study, on the other hand, did not find any improvement in symptoms with modafinil. However, this study also deviated considerably from practical experience with MPH.14 Viloxazine: 0.46 to 0.63

The effect size of viloxazine was determined to be between 0.46 and 0.63 in various studies.2 Bupropion: 0.22
  • Bupropion 0.2211 Clonidine: 0.03
  • Clonidine 0.0311

1.1.2. Comparison according to SMD

A comprehensive meta-study, which analyzed 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)26
  • Methylphenidate: -0.8 (from -0.93 to -0.62)26; -0.74 in children and adolescents27
  • Atomoxetine: -0.56 (from -0.66 to -0.45)26
  • Modafinil: -0.56 (from -0.66 to -0.45)26

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)26 which is in line with other publications2829
  • Methylphenidate: -0.49 (from -0.64 to -0.35)26
  • Bupropion: -0.46 (from -0.85 to -0.07, i.e. a very wide fluctuation range)26
  • Atomoxetine: -0.45 (from -0.58 to -0.32)26
  • Modafinil: 0.16 (from -0.28 to 0.59)26
    • The positive value for modafinil means a worse effect than placebo in adults.

1.1.3. Compatibility

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)26
    • For adults (3.26, 1.54 to 6.92)26
  • Guanfacine in children and adults (2.64, 1.20 to 5.81)26
  • Atomoxetine (2.33, 1.28 to 4.25)26
  • Methylphenidate (2.39, 1.40 to 4.08)26
  • Modafinil (4.01, 1.42 to 11.33)26

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

Effectiveness indicated in effect size. Positive values are better.

1.2.1. Multimodal therapy 1.7

In the “Multimodal Treatment Study of Children with ADHD” (MTA study) at the end of the 1990s, 579 children aged 7 to 10 were treated for 14 months with medication, cognitive behavioral therapy or both.
Teachers and parents rated the reduction in symptoms with regard to the core symptoms of ADHD better in the group of children treated only with medication than in the group of children treated only with behavioral therapy. The children who received medication and behavioral therapy performed even slightly better than the children treated with medication alone. When not only the core symptoms but all symptoms were considered, the children treated with medication and cognitive behavioral therapy clearly performed best. In contrast, the effect of behavioral therapy alone was lower than treatment with medication alone.4

  • 1.7 for behavioral therapy with concomitant medication: 1.730

1.2.2. Behavioral therapy: 0.85 (0.69 to 1.0)

  • Without concomitant medication:
    • 1,030
    • 0.69 according to a meta-analysis of 3 studies with a total of 107 subjects31 Unfortunately, no comparison was made on the effect strength of medication.
    • A large meta-study of 190 studies involving 26,114 participants with ADHD-HI found that stimulants were more effective than behavioral therapy, cognitive training, or non-stimulants. Stimulants in combination with behavioral therapy appeared to be the most effective.6
  • With concomitant medication: 1.730
  • Effect largely persists after the end of therapy
  • Very long time to take effect

1.2.3. Sport (endurance training): approx. 0.8 (0.77 to 0.93)

By effect size (higher values are better):

  • 0.93 according to a meta-analysis of 5 studies with a total of 144 subjects31 Unfortunately, no comparison was made on the effect strength of medication.
  • An aerobics group exercise program brought about improvements in participants with various disorders compared to the passive control group in terms of32
    • Global symptom severity: 0.77
    • Depression; 0.68
    • Anxiety: 0.87
    • Sleep quality: 0.88
  • A review analyzed 37 meta-studies with 106 studies and found Hedges g:33
    • Inattention: 0.92
    • Impulse control: 0.82
    • Cognitive flexibility: 0.52

The evidence for the effectiveness of exercise on emotional, social and working memory performance was weak, and on hyperactivity and behavioral function was not significant.

According to SMD (lower values are better):

  • -0.65 SMD (mean). A meta-study found moderate effect sizes of endurance training in children with ADHD. Data in SMD, (more negative is stronger)34
    • Attention (-0.84)
    • Anxiety symptoms (-0.66)
    • Executive functions (-0.58)
    • Social disorders (-0.59)
    • Hyperactivity (-0.56)
    • Impulsiveness (-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, if only the studies with a high degree of blinding were evaluated, the SMD fell to a barely relevant -0.18. The comparative studies on the effect strength of psychotherapy (7 studies, n = 189) or medication (4 studies, n = 300) each found an identical SMD for endurance training.35

1.2.4. Neurofeedback: 0.8 (0.39 to 1.2)

  • 0,63637
  • 0.49 to 0.68 after only 30 sessions20
  • 0.61 according to a meta-analysis of 6 studies with a total of 203 subjects31 Unfortunately, no comparison was made on the effect strength of medication.
  • On attention: 0.8 to 1.2
    • 0,830
    • After 40 sessions: 1.230
  • On impulsivity: 0.68
    • After 20 sessions: 0.730
    • Cannot be further improved by increasing the number of sessions
  • For hyperactivity: 0.39
    • Cannot be further improved by increasing the number of sessions
  • Neurofeedback is not as effective as MPH38
    • In one study, MPH showed a symptom improvement of 46.9 % (SMD 2.03), while neurofeedback led to a symptom improvement of 26.7 % (SMD 0.89).39
  • Effect usually remains complete after the end of therapy

1.2.5. Parent training 0.59 (0.31 to 0.86)

A single study of a specific training course for parents of children with ADHD found an improvement in the problematic behavior of children from

  • 0.86 for parent training in the group40
  • 0.6 to 0.7.41 As the data was collected using parental questionnaires, a considerable bias towards higher values can be expected.
  • 0.42 to 0.5342
  • 0.40 for ADHD43
  • 0.36 for externalizing symptoms43
  • 0.31, n = 4 studies44 although at the same time antidepressants were attributed an effect size of 0.85, stimulants an effect size of 0.35 and multimodal treatment an effect size of 0.28, which raises questions regarding the robustness of the data.

1.2.6. Cognitive self-regulation training 0.54

  • Out-of-school 0.58, n = 5 studies44. However, an effect size of 0.85 was attributed to antidepressants, an effect size of 0.35 to stimulants and an effect size of 0.28 to multimodal treatment, which raises questions about the robustness of the data.
  • School-based 0.49, n = 2 studies44 although at the same time antidepressants were attributed an effect size of 0.85, stimulants an effect size of 0.35 and multimodal treatment an effect size of 0.28, which raises questions regarding the robustness of the data.

1.2.7. Behavioral training 0.54

  • Out-of-school 0.29, n = 1 study44 although at the same time antidepressants were attributed an effect size of 0.85, stimulants an effect size of 0.35 and multimodal treatment an effect size of 0.28, which raises questions about the robustness of the data.
  • School-based 0.50, n = 3 studies44 although at the same time antidepressants were attributed an effect size of 0.85, stimulants an effect size of 0.35 and multimodal treatment an effect size of 0.28, which raises questions regarding the robustness of the data.

1.2.8. Elimination diet: 0.54 (0.29 to 0.8)

Effect only during faultless dietary compliance

  • 0,2945
  • 0.51 to 0.846
  • 0,2945
    There are indications that an elimination diet is only effective in certain patients (“subgroup”).47

1.2.9. Cognitive training 0.45

  • 0.45 after a meta-analysis of 4 studies with a total of 159 test subjects.31 Unfortunately, there was no comparison of the effect strength of medication.
  • SMD = 0.21648
  • One review found only limited to minor symptom improvement with computer-assisted cognitive training49

1.2.10. Social skills training 0.31

  • Social skills training 0.31, n = 3 studies44 although an effect size of 0.85 was attributed to antidepressants, an effect size of 0.35 to stimulants and an effect size of 0.28 to multimodal treatment, which raises questions about the robustness of the data.

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

  • 0.08 to 0.11 (teacher and observer rating)46
  • 0.12 to 0.2545
  • 0.21 to 0.283 (with the addition of smaller, less high-quality studies)50
  • 0.21 to 0.44 in the parent rating46
  • Effect only during faultless dietary compliance

1.2.12. PUFA supplementation: 0.16

  • 0.16 to 0.17 in the parent and teacher rating46

1.2.13. Mindfulness-based behavioral therapy (MBCT)

ADHD sufferers who were additionally treated with MBCT (mindfulness-based cognitive 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 up to the 6-month follow-up. Of those additionally treated with MBCT, 27% showed a 30% reduction in ADHD-HI symptoms (p = 0.001), compared to only 4% of ADHD sufferers not additionally treated with MBCT.51
The effect largely persisted even after the end of therapy.

2. Efficacy latency of the treatment forms

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

  • Medication
    • Stimulants: immediate effect, fully effective immediately when optimally adjusted
    • Noradrenaline reuptake inhibitors: 2-3 weeks flooding phase
    • Atomoxetine: several weeks to 6 months flooding 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 of the forms of treatment

By effectiveness, we mean which symptoms the individual forms of treatment change.

3.1. Medication

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

3.2. Therapy

  • Behavioral therapy:
    • Cognitive VT:
      Self-esteem, social behavior, stress reduction
      To a certain extent, changes in stress processing, including hormonal and immunological physical changes52
    • Mindfulness-based VT:
      Attention, empathy, stress reduction
  • Mindfulness training:
    Change in stress perception; change in stress processing in the CNS, impulsivity
    An improved perception of pleasant aspects causes direct changes in the dopaminergic focusing and reinforcement system. Perceptions of the nature of an individual’s spatial environment and (permanently) a high social status have the same effect.53
    However, it is unclear whether these changes (with the exception of social rank) have a lasting influence, which is a prerequisite for therapeutic use, or whether they are only activated during perception.
  • Neurofeedback:
    Attention; impulsivity; hyperactivity, relaxation, sleep
  • Environmental interventions:
    Elimination of stressors through elimination of stressors and greater understanding of the environment
  • Psychoeducation:
    Elimination of stressors and improved ability to regulate through greater understanding of the affected person
    Increased self-esteem through the feeling of coming home, meeting and exchanging ideas with other affected people

4. Duration of effectiveness of the treatment forms

4.1. Early medication

There is an indication that methylphenidate treatment with 2 mg / kg / day in very young rats caused a permanent reduction in dopamine transporters in the striatum (which would correspond to a permanent healing effect), while methylphenidate administration in somewhat older animals (“after puberty”) no longer had this effect.54 These results have not yet been reproduced.

When treating humans with MPH, no permanent reduction of DAT in the striatum is known, even in children before puberty. Either it is necessary to use it at a much earlier age in humans or the significantly higher dosage (in this case 2 mg / kg) compared to the maximum dose of 1 mg / kg / day postulated for children has as yet unexplored effects.

Despite the immense importance of this question, no further studies are known to confirm the results. With a dosage of even two times 5 mg / kg / day in rats from the 7th day to the 35th day after birth, short-term reductions in the DAT count were observed, but these were no longer found on the 135th day of life.55
It remains to be seen what part the massively increased dosage plays in this.
There were no structural changes in the brain structures either immediately after the end of treatment on day 35 or on day 135.55 In view of the extreme dosage, this also proves that MPH is not very dangerous.

4.2. Short-term medication

The improvements with drug treatment end (at least with stimulants) immediately when the medication is stopped, with other drugs with a mirror effect after approx. 14 days at the latest.
The learning effects of neurofeedback and behavioral therapy are better with medication.
The effectiveness of non-drug therapy is long-lasting; however, sufficiently long and intensive therapy (6 months to 3 years) is required.
With neurofeedback, a continuation of treatment successes was observed 6 months after the end of treatment756 Kühle observed that treatment successes persisted years later in some cases, but not in others.

4.3. Long-term medication

There are indications that longer-term medication could bring about a subsequent maturation of those brain structures that are affected by a developmental delay in ADHD.

In ADHD, the dysfunctional executive functions are associated with a reduced amount of brain matter in the cortex.57 In children with ADHD, the growth of brain matter in the cortex is significantly reduced, with the greatest delays in the PFC and ACC.57
Adults with ADHD who are treated with stimulants have a significantly larger brain mass in the relevant brain regions than adults with ADHD who are not treated with stimulants.58 This could indicate that treatment with stimulants can make up for or compensate for the developmental delay.57
In ADHD sufferers who still showed the full ADHD symptoms as adults, no post-maturation (i.e. growth) of the brain mass in the relevant brain regions was recognizable.59

4.4. Multimodal treatment: non-drug therapy and medication

There is evidence that dopaminergic ADHD medications - in this study particularly D-amphetamine medications (levodopa, which was also mentioned, is not suitable as an ADHD medication) - can increase neuroplasticity and thus increase the success of psychotherapy.60

We are convinced that psychotherapeutic measures are significantly less effective for ADHD sufferers who are not medicated, as the ability to learn and absorb is massively reduced by ADHD itself. In our opinion, 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 that, psychotherapy makes little sense if the patient does not even know what the condition they are supposed to achieve through therapy feels like. 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, as their motivation is altered in the direction of significantly increased intrinsic control. After all, ADHD makes it extremely difficult to follow extrinsic prompts.

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