Effect size of different forms of ADHD treatment

To our knowledge, this is the most complete overall representation of the Effect size of ADHD treatment methods.
It is used to compare the effectiveness of the various forms of ADHD treatment in order to be able to select the most appropriate treatment for each case - after also taking into account the possible side effects.

The Effect size of a treatment is the value by which the symptoms improve.

The magnitude of the Effect sizes found is described using standard criteria.¹
One measure of Effect size is SMD (standardized mean difference, Cohen’s d; sometimes also Hedges g, a slightly modified form of Cohen’s d):
0.20 to 0.49: A “small” effect (also called “purely statistical”).²³ Usually difficult to observe in an individual, but can be very important for public health if it is a general exposure affecting many individuals.
0.50 to 0.79: from 0.80. A “medium” / “moderate” effect (also called “subtle”).²³ Should be perceptible to an attentive observer. From 0.5 clinical benefit.
0.80 and more: A “large” / “strong” effect (also called “obvious”)²³ represents a clearly noticeable improvement.
The average Effect size of psychotropic drugs overall is 0.49 (SMD).⁴ The average Effect size of antidepressants on depression is 0.30.⁵ Large Effect sizes (from 0.8) are less common in medicine.⁶

Medication (especially stimulants) has the greatest effect in the treatment of ADHD.
ADHD medications have a special position within psychiatric medications. Compared to the usual Effect size of psychiatric medications, the Effect size of stimulants for ADHD is exceptionally high at 1.1 to 1.5 (AMP) and approx. 0.9 to 1.1 (MPH).⁷⁸ These are the highest Effect sizes found for psychiatric medications⁹
Behavioral therapy alone is nowhere near as effective as medication alone, with an Effect size of 0.5 (see below).
A combination of medication and intensive behavioral interventions did not perform significantly better than medication alone in the MTA study of n = 579 children between the ages of 7 and 9.¹⁰¹¹ For impulsive-aggressive symptoms and emotional disorders, medication and behavioral therapy were equally effective.¹² A more recent comprehensive meta-analysis of k = 190 studies with n = 26,114 participants with ADHD-HI came to comparable results.¹³

It has been reported that medication during psychotherapy increases the learning effectiveness of psychotherapy.¹⁴ 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, which is necessary for the ability to learn and supports the plasticity of the brain. ⇒ Neurophysiological correlates of learning problems in ADHD

Medication only works for ADHD for as long as it is given. Psychotherapy, environmental intervention and psychoeducation, on the other hand, have a long-term effect and continue to work beyond their specific application.

The Effect sizes mentioned in this article¹⁵¹⁶ generally refer to SMD values (Standard mean difference)¹⁷. SMD is a value that makes different studies comparable with each other. However, it always depends on what is being compared, as SMD represents a comparative value, so that a treatment method has a completely different SMD compared to placebo than compared to a “standard treatment” or compared to another treatment method. Nevertheless, the data as a whole gives an impression of the comparison of efficacy between the different drugs and forms of treatment.

When assessing studies on Effect sizes, a distinction must be made between unblinded and blinded evaluations.¹⁸ Unblinded evaluators are biased and overestimate treatment effects.¹⁹ In parent ratings, knowledge of the intervention increases parental tolerance of ADHD and/or their ability to cope with the negative effects rather than reducing symptoms.²⁰ Even more so, parental involvement leads to a bias (“the effort must have been worth it”), which is why parent ratings should be viewed with particular caution. Therapist ratings (especially in industry-financed studies) also have an increased BIAS risk. Teacher ratings are much more neutral in comparison.

Effect sizes in the headings indicate the range of studies / meta-study results, with the lowest and highest values omitted to limit bias due to outliers. Furthermore, values are only given in the headings if a sufficient number of studies or meta-analyses allow a reliable statement to be made.

• 1. Effectiveness of the treatment methods
  • 1.1. Comparison by Effect size (SMD)
    • 1.1.1. Drug treatment according to Effect size (0.61 to 0.68)
      • 1.1.1.1. Stimulants: 0.8 to 1.5
        • 1.1.1.1.1. Amphetamine drugs: 1.1 to 1.5
        • 1.1.1.1.2. Methylphenidate: 0.9 to 1.1
        • 1.1.1.1.3. Mazindol
      • 1.1.1.2. Total non-stimulants: 0.52 to 0.71
        • 1.1.1.2.1. Guanfacine : 0.67 to 0.76 for children and adolescents
        • 1.1.1.2.2. Atomoxetine: 0.63 children, 0.45 adults
        • 1.1.1.2.3. Modafinil: 0.62 to 0.76 KiJu
        • 1.1.1.2.4. Viloxazine: 0.45 to 0.63
        • 1.1.1.2.5. Bupropion: 0.32 to 0.46
        • 1.1.1.2.6. Clonidine: 0.38
        • 1.1.1.2.7. Centanafadine
        • 1.1.1.2.8. Dasotraline
        • 1.1.1.2.9. Cannabinoids, Sativex
        • 1.1.1.2.10. SGA (second generation of antipsychotics) for hyperactivity in ASD
        • 1.1.1.2.11. Desipramine
        • 1.1.1.2.12. Tipepidine
        • 1.1.1.2.13. Nortriptyline
        • 1.1.1.2.14. Venlaflaxine
        • 1.1.1.2.15. Selegelin
        • 1.1.1.2.16. Edivoxetine
        • 1.1.1.2.17. Reboxetine
        • 1.1.1.2.18. Vortioxetine
        • 1.1.1.2.19. Duloxetine
      • 1.1.1.3. Combination medication
        • 1.1.1.3.1. Combination therapy guanfacine with stimulants: plus 0.36 g compared to stimulants alone
      • 1.1.1.4. Vitamins, minerals, natural preparations
        • 1.1.1.4.1. Probiotics: 0.25
        • 1.1.1.4.2. Omega-3/-6 / PUFA supplementation: 0.11 to 0.17
        • 1.1.1.4.3. Zinc
        • 1.1.1.4.4. Acetyl-L-carnitine
        • 1.1.1.4.5. Phosphate dilyserine
        • 1.1.1.4.6. Iron
        • 1.1.1.4.7. St. John’s wort
        • 1.1.1.4.8. Saffron
        • 1.1.1.4.9. Wheat protein
        • 1.1.1.4.10. Antioxidants
        • 1.1.1.4.11. Micronutrients
    • 1.1.2. Effectiveness of non-drug therapies for ADHD according to Effect size
      • 1.1.2.1. Sports (endurance training): approx. 0.8 (0.62 to 1.96)
        • 1.1.2.1.1. Reviews on the Effect size of sports on ADHD
        • 1.1.2.1.2. Meta-analyses of the Effect size of sports on ADHD
        • 1.1.2.1.3. Individual studies on the Effect size of sports on ADHD
        • 1.1.2.1.4. Effect size of sports on other disorders
      • 1.1.2.2. Cognitive behavioral therapy: 0.5 (0.3 to 0.85)
      • 1.1.2.3. Mindfulness-based behavioral therapy (MBCT)
      • 1.1.2.4. Neurofeedback: 0.29 to 1.2
      • 1.1.2.5. Parent training: 0.31 to 0.68
      • 1.1.2.6. Repetitive transcranial magnetic stimulation (rTMS) 0.54
      • 1.1.2.7. Cognitive self-regulation training: 0.54
      • 1.1.2.8. Behavioral training: 0.54
      • 1.1.2.9. Food diets: 0.51
      • 1.1.2.10. Cognitive training: 0.22 to 0.45
      • 1.1.2.11. Total psychological behavioral interventions: 0.35 for children and adolescents
      • 1.1.2.12. Social skills training: 0.26 to 0.31
      • 1.1.2.13. Transcranial direct current stimulation (tDCS): 0.23
      • 1.1.2.14. Teacher training
      • 1.1.2.15. Virtual reality interventions
      • 1.1.2.16. Online interventions
      • 1.1.2.17. Working memory training
      • 1.1.2.18. Digital interventions
      • 1.1.2.19. Digital therapy games
      • 1.1.2.20. School interventions
      • 1.1.2.21. Acupuncture
      • 1.1.2.22. Age difference within school classes
      • 1.1.2.23. Weighted blankets in relation to anxiety symptoms
  • 1.2. Comparison after risk reduction
    • 1.2.1. Reducing the risk of psychiatric hospitalization
    • 1.2.2. Risk reduction of non-psychiatric hospitalization
    • 1.2.3. Risk reduction of suicidal behavior
    • 1.2.4. Risk reduction of incapacity for work
  • 1.3. Comparison according to odds ratio (OR)
    • 1.3.1. Drug interventions
    • 1.3.2. Minerals / vitamins / amino acids / herbal remedies
    • 1.3.3. Non-drug interventions
  • 1.4. Multimodal therapy
• 2. Efficacy latency of the treatment forms
• 3. Effectiveness of the forms of treatment
  • 3.1. Medication
  • 3.2. Psychotherapy
• 4. Duration of effectiveness of the treatment forms
  • 4.1. Early medication
  • 4.2. Short-term medication
  • 4.3. Long-term medication
  • 4.4. Multimodal treatment: non-drug therapy and medication
• 5. Compatibility
• 6. Comparative values: Effect size for other disorders
  • 6.1. Effect size of medication for depression
  • 6.1.1. Classic antidepressants: 0.30
  • 6.1.2. Psilocybin treatment embedded in psychotherapy (PAP): 0.78 to 1.5
  • 6.1.3. Electroconvulsive therapy
  • 6.2. Effect size of psychotherapy for depression 0.34
  • 6.3. Effect size of medication for ASA
  • 6.4. NNT for other disorders

1. Effectiveness of the treatment methods¶

The different treatment options have varying degrees of effectiveness.
Depending on the question, a lower or higher SMD is “better”.
We have normalized the SMD of the studies in this review so that a higher value always represents greater efficacy in terms of treating ADHD symptoms.

1.1. Comparison by Effect size (SMD)¶

SMD (standardized mean difference, Cohen’s d) is one of the measures in which Effect size can be measured: small = 0.20, medium = 0.50, large = 0.80.
SMD 0.2: NNT = 8.93²¹
SMD 0.3: the value of the average person in the experimental group is greater than the value of 62% of the people in the control group²²
SMD 0.5: 69% greater than in the control group; NNT = 3.62²¹
SMD 0.6: at 73 % larger
SMD 0.75: at 77 % larger
SMD 0.8: NNT = 2.34²¹
SMD 1.0: around 70 % probability of a treatment benefit²³
SMD 2.0: almost 90 % probability of a treatment benefit²³

SMD is calculated as the mean value of the active substance group minus the mean value of the comparison group, whereby the result is divided by the pooled standard deviation of the groups. SMD is therefore a measure of effect size that reflects mean differences between two groups with the same group sizes and the same group variances. The effect is measured in comparison to a comparative measure (usually placebo). Therefore, SMD does not measure the overall improvement, but by how much the improvement was greater than the competitor (usually placebo). Unless we state otherwise, we mean the Effect size after SMD compared to placebo,

1.1.1. Drug treatment according to Effect size (0.61 to 0.68)¶

Reviews
A meta-meta-analysis (Umbrella study) found an Effect size for

• pharmacological treatment of ADHD from
  • 0.67 (parent rating)
  • 0.68 (teacher rating) and for
• psychological interventions from
  • 0.42 (parent rating) and
  • 0.25 (teacher rating).²⁴

METASTUDIES

• Children and young people
  • 0.61 Meta-analysis (k = 49 studies, n = 7,685 children and adolescents) of all ADHD medications in relation to ADHD symptoms overall²⁵
  • Meta-analysis (k = 63 RPCCT, n = 11,788 children and adolescents) (10 medications, especially frequently MPH and ATX, mean duration 7.9 weeks) found an overall effectiveness of ADHD medications of
  • 0.74 (treatment provider rating; indications of BIAS bias, especially in industry-funded studies)
  • 0.63 (parent rating)
  • 0.75 (teacher rating)
    Stimulants were more effective than non-stimulants and showed 32% fewer treatment discontinuations than placebo (OR = 0.68).²⁶
• Adults
  • 0.45 Meta-analysis (k = 44 studies, n = 9,952 adults) on all medications for ADHD overall²⁷

1.1.1.1. Stimulants: 0.8 to 1.5¶

• Regardless of age
• Effect size of stimulants was reported to be 0.44 stronger than non-stimulants (expert rating).²⁷
• A meta-analysis of k = 15 RCTs with n = 4,648 children and/or adolescents aged 6 to 17 years with ADHD found an Effect size of;²⁸
  • 0.83 for stimulants
  • 0.58 for non-stimulants
• for children and adolescents
  • 0.88 on ADHD symptoms overall (meta-analysis, k = 12, n = 1,620)²⁵

1.1.1.1.1. Amphetamine drugs: 1.1 to 1.5¶

• Amphetamine medication regardless of age

  • Amphetamine drugs in total:
    • 1,1²⁹
    • 1,0⁹
    • 0.8 to 1.5³⁰
    • 0.90 in the expert assessment³¹ as an update of an earlier meta-analysis with 0.72 at that time³²
  • According to symptoms:
    • For inattention: 1.5 (lisdexamfetamine medication, but only one examination)²⁹
    • For hyperactivity: approx. 1.2 (total amphetamine medication)²⁹
  • By active ingredient
    • Lisdexamfetamine (Vyvanse) 1.06 to 1.52
      • 1.34, 1.46 and 1.53 (3 studies on children)²⁵
      • 1,52³³
      • 1,28³⁴
      • 1,06³¹
      • 0.89³⁵ In a randomized double-blind study with n = 200 subjects, lisdexamfetamine and atomoxetine were compared in MPH nonresponders. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment. In terms of learning and school, lisdexamfetamine was 0.19 SMD better than atomoxetine.³⁶
    • D-Amphetamine immediate release
      • 1.24³³ (e.g. Attentin)
    • D-Amphetamine sustained release
      • 1.13³³ (not: lisdexamfetamine)
    • Mixed amphetamine salts immediate release
      • 1.34³³ 0.64³⁵
      • 0,80³¹
      • In a meta-analysis from the time before lisdexamfetamine was available, Adderall showed the best Effect size, significantly better than methylphenidate.³⁷
    • Mixed amphetamine salts sustained release (e.g. Adderall XR; mixture of dexamphetamine and levoamphetamine in a ratio of 3:1)
      • 0,77³³

• Children and young people:

  • Amphetamine drugs in total:
    • 1.16 (meta-analysis, k = 5, n = 757 children)²⁵ Lisdexamfetamine performed significantly better with 1.34, 1.46 and 1.53 (3 studies) than mixed amphetamine salts with 0.76 and 0.77.
    • 1,02³⁸
    • 0.84 in the physician rating; k = 3, n = 813³⁹
    • 0.57 in the parent rating; k = 7, n = 1,247³⁹
    • 0.55 in the teacher rating; k = 5, n = 745³⁹
  • Lisdexamfetamine
    • 1.34, 1.46 and 1.53 (3 studies)²⁵
  • Mixed amphetamine salts (Adderall):
    • 0,85⁴⁰
    • 0.9 to 1.2 Adderall XR⁴¹
  • Amphetamine suspension with extended release
    • 0.8 / 0.5 to 0.8 for up to 13 hours⁴²

• Adults:

  • 0.79³⁸ which is consistent with other publications⁴³⁴⁴ Amphetamine medications have an NNT of 1.6 in adults with ADHD.³⁰
  • Lisdexamfetamine:
    • 1.07 in European adults (lisdexamfetamine medication; meta-analysis of 22 studies)⁴⁵
    • 0,97⁴⁶
    • 0,5⁴⁷

• Mixed amphetamine salts:

  • 0.76, 0.77 (2 studies)²⁵
  • 0.75 independent of age⁴⁰

• On Emotional Dysregulation approx. 0.41 (stimulants and ATX), compared to 0.8 on ADHD symptoms overall⁴⁸

1.1.1.1.2. Methylphenidate: 0.9 to 1.1¶

• Methylphenidate independent of age

  • MPH as a whole:
    • 0,9⁴⁹
    • Approx. 0.8⁹, 0.73²⁹
    • 0,75³⁴
    • 0,5³⁵
    • According to less reliable source 1.3 to 1.69⁵⁰
  • According to symptoms:
    • Inattention
      • Approx. 0.8²⁹
      • 0.42 Sustained attention (metastudy, k = 29, n = 956)⁵¹
    • Hyperactivity: on average approx. 1.0²⁹
    • Reading speed 0.47 (meta-analysis)⁵²
    • Inhibition 0.40 (k = 25, n = 775)⁵¹ * Methylphenidate with immediate release (unretarded)
    • Working memory 0.24 (k = 13, n = 559)⁵¹
    • Emotional dysregulation: 0.34⁵³
  • Methylphenidate with immediate effect (immediate release)
    • 0,92³³
    • Ritalin, MPH Hexal: 1.01⁵⁴
  • Methylphenidate sustained release: 1.08⁵⁴
    • Concerta: 1.35⁵⁴
    • Medikinet retard: 0.95⁵⁴
    • Equasym: 1.09⁵⁴

• MPH in children and adolescents:

  • MPH in general
    • 0.87 in the teacher rating (meta-analysis of k = 5 studies, n = 668)⁵⁵
    • 0,78³⁸
    • 0.77 in the teacher rating (meta-analysis of k = 19 studies, n = 1,698)⁵⁵
    • 0,74⁵⁶
    • 0.26 on executive memory compared to placebo (meta-analysis of k = 36 studies⁵⁷
    • 0.60 on non-executive memory vs. placebo (meta-analysis of k = 36 studies⁵⁷
    • 0.24 on reaction time compared to placebo (meta-analysis of k = 36 studies⁵⁷
    • 0.62 on reaction time variability vs. placebo (meta-analysis of k = 36 studies⁵⁷
    • 0.41 on response inhibition vs. placebo (meta-analysis of k = 36 studies⁵⁷
  • Concerta:
    • Children and young people: 1.0⁴¹
  • Equasym retard:
    • Children and adolescents: 0.6 to 1.8⁴¹
  • MPH immediate release
    • Inattention
      • 0.96 in the parent rating meta-study, k = 7)⁵⁸
      • 0.98 in the teacher rating meta-study, k = 7)⁵⁸
    • Hyperactivity/impulsivity
      • 1.12 in the parent rating metastudy, k = 7)⁵⁸
      • In the teacher rating
        • 1.25 (meta-analysis, k = 7)⁵⁸
        • 0.29 on hyperactivity/impulsivity in the teacher rating (meta-analysis, k = 3 RCTs)⁵⁹
  • Methylphenidate sustained release:
    * Children and young people:
    * 0.9 to 1.0⁴¹
    * 0.30 on hyperactivity/impulsivity in parent ratings (meta-analysis of k = 3 RCTs)⁵⁹
    * OROS-MPH 0.9³³
    * 0.35 on inattention in the parent rating (meta-analysis of k = 3 RCTs)⁵⁹
    * MPH-MR 0.85³³
    • Ritalin LA:
      • MPH-LA 0.95³³
      • Children and young people: 1.0⁴¹
      • Adults: 0.49³⁸, 0.34⁴⁷
    • D-MPH: 0.76³³

Adults:

• 0.49 for total MPH (total means: without differentiation between immediate release and sustained release)⁶⁰
• 0.58 for immediate release MPH, found a meta-study of k = 18 RCTs in n = 2,045 adults⁶¹
  • Dose level
    • 0.58 at an average dose of 57.4 mg/day
    • Each increase of 10 mg/dose resulted in an increase in Effect size of 0.12
  • Dosage regime
    • 0.40 solid doses
    • 0.53 Variable dosage
• OROS-MPH
  • 0,51⁶²
• Rertarded MPH compared to placebo⁶³
  • ADHD symptoms overall
    • 0.37 Self-assessment; k = 16, n = 3799
    • 0.42 Physician assessment; k = 18, n = 4183
    • 0.31 Peers and family members; k = 3, n = 1005
  • Quality of life
    • 0.15 Self-assessment; k = 6, n = 1888
  • Reduction in days missed from work 0.15; k = 1, n = 409
• Emotional dysregulation:
  • 0.41 (stimulants and ATX), compared to 0.8 on ADHD symptoms overall⁴⁸
  • 0.34 for MPH (without differentiation between immediate release and sustained release)⁶⁰

Meta-analyses comparing MPH with atomoxetine:
In comparison with atomoxetine, MPH proved barely superior in all its medication forms (0.07⁶⁴ to 0.09⁶⁵⁶⁶ .). With regard to inattention, MPH was minimally superior overall (0.13⁶⁴.).
However, OROS-MPH proved to be 0.31⁶⁶ to 0.32⁶⁵ more effective than atomoxetine.
The responder rate for MPH was 14% higher.⁶⁴

Meta-analyses comparing MPH with neurofeedback:
According to a meta-analysis of k = 18 RCTs with 778 participants, methylphenidate proved to be superior to neurofeedback with an Effect size of:⁶⁷

• 0.59 on ADHD core symptoms
• 0.96 on inattention
• 0.47 on inhibition
  with a 40 % higher treatment discontinuation rate under MPH.

1.1.1.1.3. Mazindol¶

Mazindol, an alerting substance with stimulant properties, showed a high Effect size of 1.09 on ADHD core symptoms in adults with ADHD ⁹

Further studies should be awaited to confirm this.

1.1.1.2. Total non-stimulants: 0.52 to 0.71¶

Total non-stimulants

• Regardless of age
  • 0,71⁶⁸
• for children and adolescents
  • 0.52 than according to a meta-analysis of Effect size on ADHD symptoms overall (k = 37, n = 6,065)²⁵

Effect size of stimulants was reported to be 0.44 stronger than non-stimulants (expert rating).²⁷

1.1.1.2.1. Guanfacine : 0.67 to 0.76 for children and adolescents¶

Guanfacine as monotherapy has an Effect size of 0.57 to 0.76.

• Children and young people:
  • 0,8³³
  • 0,76⁶⁹
  • 0.67 (meta-analysis)³⁸
  • 0.60 (approx.) by guafancin XR on ADHD total symptoms (meta-analysis, k = 6)²⁵

α-2 agonists (guanfacine and clonidine) in children and adolescents

• 0.59 on ADHD total symptoms (meta-analysis, k = 12, n = 2,276 children and adolescents) with α-2 agonist monotherapy (k = 9, n = 1,550):⁷⁰
  • 0.56 on hyperactivity/impulsivity (k = 9, n = 1 550)
  • 0.57 on inattention (k = 9, n = 1 550)
  • 0.44 on ODD symptoms (k = 9, n = 1 550)
  • fewer discontinuations of monotherapy due to ineffectiveness than with placebo
• 0.52 (approx.) on overall ADHD symptoms (meta-analysis, k = 11, n = 1,885 children and adolescents)²⁵

1.1.1.2.2. Atomoxetine: 0.63 children, 0.45 adults¶

• Atomoxetine independent of age:

  • 0.68 (meta-analysis)³⁴
  • Atomoxetine 0.68 (meta-analysis)⁴⁰

• Children and young people:

  • 0.7 (meta-analysis)⁴¹
  • 0.64 ADHD total symptoms (meta-analysis, k = 25 DBRCTs, n = 3,928)⁷¹
  • 0.63 (meta-analysis)³³
  • 0.56 (meta-analysis)³⁸
  • Individual symptoms
    • 0.67 Hyperactivity/impulsivity (meta-analysis, k = 25 DBRCTs, n = 3,928)⁷¹
    • 0.59 Inattention (meta-analysis, k = 25 DBRCTs, n = 3,928)⁷¹
    • 0.33 Oppositional defiant behavior (meta-analysis, k = 25 DBRCTs, n = 3,928)⁷¹
    • 0.25 to 0.48 Quality of life (meta-analysis, k = 25 DBRCTs, n = 3,928)⁷¹
  • Comparison with MPH
    • 0.09 worse than MPH IR (meta-analysis, k = 11; n = 2,772)⁷²
    • 0.23 worse than MPH overall (meta-analysis, k = 7; n = 1,611)²⁵
    • 0.31 worse than MPH OROS (meta-analysis, k = 11; n = 2,772)⁷²

• Adults:

  • 0,46⁶²
  • 0,45³⁸
  • 0.40 in the practitioner rating (meta-analysis, k = 12, n = 3,375)⁷³
  • 0.33 in the patient rating (meta-analysis, k = 12, n = 3,375)⁷³
  • 0,24⁴⁷

• Emotional dysregulation

  • 0.41 (stimulants and ATX), compared to 0.8 on ADHD symptoms overall⁴⁸

• Atomoxetine has an NNT of 5 with regard to attention problems in ADHD³⁰

Noradrenaline reuptake inhibitors (atomoxetine and viloxazine) showed an Effect size of 0.55 on ADHD symptoms in general (meta-analysis, k = 28, n = 1,925).²⁵

2.57 times as many treatment discontinuations as with placebo (meta-analysis, k = 12, n = 3,375).⁷³

1.1.1.2.3. Modafinil: 0.62 to 0.76 KiJu¶

• Modafinil independent of age:
  • 0,65⁴⁰
  • 0.08 (individual study){Stuhec, Lukić, Locatelli (2018): Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis. Ann Pharmacother. 2018 Aug 17:1060028018795703. doi: 10.1177/1060028018795703. n = 701}}
• Children and young people:
  • 0.71 to 0.77 compared to placebo (meta-analysis, k = 5 RCT)⁷⁴
  • 0.76 (meta-analysis, k = 4; n = 667)²⁵ with 3 of the 4 studies reporting an Effect size of 0.42 to 0.54.
  • 0,62³⁸
  • 0.52 (meta-analysis)³³
• Adults:
  • Minus 0.16 (deterioration; meta-analysis)³⁸

1.1.1.2.4. Viloxazine: 0.45 to 0.63¶

• 0.46 to 0.63 were determined.⁹
• 0.45 (meta-analysis)⁷⁵

1.1.1.2.5. Bupropion: 0.32 to 0.46¶

METASTUDY:

• Bupropion independent of age:
  • 0,32³⁴
  • 0,22³³
  • 0.33 (meta-analysis)⁷⁵
  • The medications that showed a significant reduction on the ADHD rating scale compared to placebo were bupropion (SMD: 0.33; 95%CrI: 0.60,-0.059), dasotraline (SMD: 0.49; 95%CrI: 0.82,-0.16), venlafaxine (SMD: 0.71; 95%CrI: 1.3,-0.15), viloxazine (SMD: 0.45; 95%CrI: 0.77,-0.12). Other medications (centanafadine, duloxetine, edivoxetine, reboxetine, tipepidine, vortioxetine) were no better than placebo in reducing ADHD symptom severity. No significant difference in efficacy was found for any of the medications compared to methylphenidate. There were significantly more treatment-related adverse events with duloxetine (OR:15; 95%CrI:1.8130) than with methylphenidate.
• Children and young people:
  • 0,96³⁸
• Adults:
  • 0,46³⁸

1.1.1.2.6. Clonidine: 0.38¶

• Regardless of age:
  • 0.03 (meta-analysis)³³
• Children and young people:
  • 0.71 (meta-analysis)³⁸
  • 0.38 (approx.) on ADHD total symptoms (meta-analysis, k = 5)²⁵
• In children with ADHD and comorbid tics or Tourette’s syndrome
  • 0.40 in the parent evaluation (study with n = 68 participants)⁷⁶

For studies on alpha-2 agonists in general (guanfacine and clonidine), see Guanfacine monotherapy and Guanfacine combination medication with stimulants.

1.1.1.2.7. Centanafadine¶

Manufacturer’s specification 0.6.⁴⁷
No significant effect (meta-analysis)⁷⁵

Further independent studies are needed here.

1.1.1.2.8. Dasotraline¶

0.48 (6-week RCT with n = 342 children aged 6-12 years) at 4 mg/day. 2 mg/day was almost ineffective^{77 47}

• 0.49 (meta-analysis)⁷⁵

• 0.35 on ADHD total symptoms (meta-analysis, k = 8, in children and adults)⁷⁸
• 0.33 on inattention (meta-analysis, k = 8, in children and adults)⁷⁸
• 0.27 on hyperactivity/impulsivity (meta-analysis, k = 8, in children and adults)⁷⁸

1.1.1.2.9. Cannabinoids, Sativex¶

There is only one small RCT on THC with n = 30 subjects. This found an Effect size of 0.2 compared to placebo for cognitive performance.⁷⁹⁸⁰

1.1.1.2.10. SGA (second generation of antipsychotics) for hyperactivity in ASD¶

A meta-analysis (k = 13, n = 712) investigated the Effect size of the second generation of antipsychotics on the ADHD symptom of hyperactivity in children with ASD:⁸¹

• 0.66 Stimulants
• 0.59 SGA

1.1.1.2.11. Desipramine¶

Desipramine improved the core symptoms of ADHD in children and adolescents⁷⁶

• 1.42 in the parent rating (k = 2, n = 99)
• 0.97 in the teacher rating (k = 2, n = 89)
• Improvement in physician rating (k = 2, n = 103, no information in SMD)

• 0.90 in the parent rating in children with ADHD and comorbid tics or Tourette syndrome (study with n = 68 participants)

Desipramine is no longer on the market in most countries due to its broad-spectrum effect and the resulting high level of side effects.

1.1.1.2.12. Tipepidine¶

• 0.38 in children and adolescents according to a single study (n = 51)²⁵
• No significant effect compared to placebo (meta-analysis)⁷⁵

1.1.1.2.13. Nortriptyline¶

Improvement in core symptoms of ADHD in children and adolescents in physician ratings. Not specified in SMD⁷⁶

1.1.1.2.14. Venlaflaxine¶

0.71 (meta-analysis)⁷⁵

This value is in no way consistent with the experiences from the ADxS forum and from the ADHD specialists known to us.
In our experience, we would assume that venlaflaxine has little or no effect on ADHD symptoms.
In view of the sometimes serious side effects (we know several people with ADHD who suffered massive side effects from dosing and some for whom dosing was so severe that dosing failed or required hospitalization), we are very skeptical about venlaflaxine.

1.1.1.2.15. Selegelin¶

No improvement over placebo in terms of improvement in ADHD symptoms (meta-analysis, k = 2).⁸²

1.1.1.2.16. Edivoxetine¶

No significant effect compared to placebo (meta-analysis)⁷⁵

1.1.1.2.17. Reboxetine¶

No significant effect compared to placebo (meta-analysis)⁷⁵

1.1.1.2.18. Vortioxetine¶

No significant effect compared to placebo (meta-analysis)⁷⁵

1.1.1.2.19. Duloxetine¶

No significant effect compared to placebo (meta-analysis)⁷⁵
Significantly more treatment-related adverse events than with methylphenidate.⁷⁵

1.1.1.3. Combination medication¶

1.1.1.3.1. Combination therapy guanfacine with stimulants: plus 0.36 g compared to stimulants alone¶

A combination of MPH with guanfacine works better than MPH alone.

For augmenting additional treatment with α-2 agonists (k = 3, n = 726), there was an additional effect of (meta-analysis):⁷⁰
- 0.36 on overall ADHD symptoms
- 0.33 on hyperactivity/impulsivity
- 0.34 on inattention

A meta-analysis determined the overall Effect size of taking alpha-2 agonists (guanfacine, clonidine) in addition to stimulants in children and adolescents on ADHD symptoms²⁵

• 0.36 as additional effect size of alpha-2 agonists compared to stimulants alone (k = 5, n = 724)
• 0.64 and 0.34 were determined by the two studies for guanfacine XR (both statistically significant)
• 0.34, 0.30 and 0.16 were determined by the three studies for clonidine (only one of which was statistically significant).

One study found an improved effect of guanfacine plus MPH compared to guanfacine or MPH alone:⁸³

• Guanfacine alone: a reduction in symptoms of at least 50% in 68% of people with ADHD
• Methylphenidate alone: symptom reduction of at least 50% in 81% of people with ADHD
• Combination medication of MPH and guanfacine: symptom reduction of at least 50% in 91% of persons with ADHD)

1.1.1.4. Vitamins, minerals, natural preparations¶

1.1.1.4.1. Probiotics: 0.25¶

Probiotics improved ADHD compared to placebo:⁸⁴
0.25 Total ADHD symptoms
0.14 Inattention
0.08 Hyperactivity/impulsivity

1.1.1.4.2. Omega-3/-6 / PUFA supplementation: 0.11 to 0.17¶

There is no evidence that PUFAs (omega-3 and omega-6 fatty acids) are effective for ADHD.
Even in parent ratings, which are subject to a bias due to knowledge of the administration, the effects were below the minimum value of 0.2 that is meaningful for treatment⁸⁵

METASTUDY:

• 0.16 to 0.17 in the parent and teacher rating ⁸⁶
• Minus 0.08 in the parent rating meta-analysis of k = 16 studies with n = 1,116 participants. The effect on hyperactivity/impulsivity (0.08) was slightly better than that on inattention (minus 0.01).⁸⁷
• 0.16 on ADHD core symptoms Meta-analysis with k = 22 studies and n = 1,789 participants by omega-3 fatty acids⁸⁸
• 0.35 when limited to studies with a duration of at least 4 months compared to placebo.⁸⁸ Neither a high dosage of EPA nor a high EPA/DHA ratio improved ADHD symptoms.
• 0.06 to 0.17 on ADHD symptoms, meta-analysis of k = 31 studies with n = 1,755 patients:⁸⁹
  • ADHD core symptoms
    • 0.17 in the parent rating (k = 23)
    • 0.06 in the teacher rating (k = 10)
  • Behavioral difficulties
    • 0.02 in the parent rating (k = 7)
    • 0.04 in the teacher rating (k = 5)
  • Quality of life: no relevant effect (SMD = 0.01)

• 0.11 on ADHD symptoms. Meta-analysis of k = 7 studies with n = 719 children and adolescents²⁵

1.1.1.4.3. Zinc¶

A meta-analysis of k = 6 RCTs with n = 489 children found an Effect size on:⁹⁰

• 0.62 ADHD core symptoms
• 0.93 Hyperactivity (not statistically significant)
• 0.21 Inattention (not statistically significant)

An individual study (Bilici, 2004) reports an Effect size of 1.61 for children and adolescents. Unfortunately, such values are in no way consistent with empirical experience.²⁵

1.1.1.4.4. Acetyl-L-carnitine¶

A meta-analysis found two studies on this, one of which found a deterioration of 0.06 and the other an improvement of 0.21 in children and adolescents.
Overall, there is no detectable effect on ADHD symptoms.²⁵

1.1.1.4.5. Phosphate dilyserine¶

There is only one study on the effect of phosphate dilyserin on ADHD, which found an Effect size of 0.85 on ADHD symptoms in children and adolescents.²⁵

1.1.1.4.6. Iron¶

One study found an Effect size of 0.15 on ADHD symptoms in children and adolescents.²⁵

1.1.1.4.7. St. John’s wort¶

In this regard, a single study found a 0.22 worsening of ADHD symptoms in children and adolescents.²⁵

1.1.1.4.8. Saffron¶

A single study found an Effect size of 0.97 on ADHD symptoms in children and adolescents.²⁵
Another study (Baziar 2019) reported that saffron has a similar effect to methylphenidate.

1.1.1.4.9. Wheat protein¶

A single study found an Effect size of 1.07 on ADHD symptoms in children and adolescents.²⁵

1.1.1.4.10. Antioxidants¶

A meta-analysis found two studies on this, one of which found a deterioration of 0.14 and the other an improvement of 0.38 in children and adolescents.
Overall, there is no detectable effect on ADHD symptoms.²⁵

1.1.1.4.11. Micronutrients¶

0.49 on general functioning (meta-analysis, k = 16, n = 1,719)⁹¹

1.1.2. Effectiveness of non-drug therapies for ADHD according to Effect size¶

Effect indicated in Effect size (SMD). Higher values are better.

A meta-meta-analysis found an Effect size for pharmacological treatment of ADHD of 0.67 (parent rating) and 0.68 (teacher rating) and for psychological interventions of 0.42 (parent rating) and 0.25 (teacher rating).⁹²

A review of inter- and intra-individual psychological treatments for ADHD found that psychoeducation and parent training, school-based interventions, reinforcement strategies and neurofeedback consistently showed small to moderate Effect sizes in reducing hyperactivity/impulsivity in children. Emotional self-regulation, social skills and cognitive training, on the other hand, showed unsatisfactory results. A combination with medication brought about considerably greater improvements.⁹³
A meta-analysis of k = 32 published RCTs of behavioral interventions (all interventions aimed at increasing desirable and decreasing undesirable behaviors, i.e. classical contingency management, behavioral therapy (mainly by mediators such as parents or teachers) and cognitive behavioral therapy (such as verbal self-instruction, problem-solving strategies or social skills training) in children aged 3 to 18 years, found¹⁸

• unblinded
  • Improvements in the quality of education:
    • 0.68 Positive parenting behavior
    • 0.57 Negative parenting behavior
  • 0.37 Parental self-concept
  • 0.35 ADHD of the child
  • 0.26 Behavioral problems
  • 0.47 Social skills
  • 0.28 School performance
• blinded, only some results remained statistically significant:
  • 0.63 Positive parenting behavior
  • 0.43 Negative parenting behavior
  • 0.31 Behavioral problems

According to a meta-analysis, different forms of therapy improved various symptoms in ADHD (SMD: standard mean difference; higher is better: up to 0.5 low to medium, up to 1 medium to high, from 1 high)⁹⁴

• Depression
  • Cognitive behavioral therapy (medium to large Effect size)
    • 0.52 SMD in follow-up in group comparison
    • 0.74 SMD in follow-up subjectively for affected person
  • Neurofeedback
    • Ineffective in group comparison
    • Subjectively slightly more effective than cognitive behavioral therapy
  • DBT
    • Ineffective in group comparison
    • Subjectively moderately effective, worse than cognitive behavioral therapy
  • MBSR
    • Ineffective in group comparison
    • Subjectively moderately effective, even worse than DBT
• Anxiety symptoms
  • Cognitive behavioral therapy (medium to larger Effect size)
    • 0.73 SMD in follow-up in group comparison
    • 0.74 SMD in follow-up subjectively for affected person
  • Neurofeedback
    • Ineffective in group comparison
    • Subjectively more effective in the long term than cognitive behavioral therapy
  • MBSR
    • Ineffective in group comparison
    • Subjectively moderately effective, ineffective in the long term
  • DBT
    • Completely ineffective
• Self-worth
  • Cognitive behavioral therapy (medium to large Effect size)
    • Ineffective in group comparison
    • 1,404 SMD in follow-up subjectively for affected person
  • Neurofeedback
    • Ineffective in group comparison
    • Subjectively more effective in the long term than cognitive behavioral therapy
  • MBSR
    • Ineffective in group comparison
    • Subjectively moderately effective, ineffective in the long term
  • DBT
    • Completely ineffective
• Quality of life
  • Cognitive behavioral therapy (medium to large Effect size)
    • Ineffective to slightly effective in group comparison
    • 0.57 SMD in follow-up subjectively for affected person
  • MBSR
    • Subjectively very good in the short term
  • DBT
    • Very good in the short term compared to the group, ineffective in the long term
    • Subjectively moderately effective in the short term, weakly effective in the long term
• Emotional dysregulation
  • Cognitive behavioral therapy (medium to large Effect size)
    • 0.64 SMD in follow-up in group comparison
    • 0.73 SMD in follow-up subjectively for affected person
  • MBSR
    • Weakly effective in the short term compared to the group, not known in the long term
    • Subjectively very effective in the short term, not known in the long term

1.1.2.1. Sports (endurance training): approx. 0.8 (0.62 to 1.96)¶

In addition to Effect size, adherence to therapy should also be taken into account. People with ADHD should therefore do the sport that they enjoy the most.⁹⁵ Sports only help if they are actually practiced. In addition, anything that is fun increases quality of life.

1.1.2.1.1. Reviews on the Effect size of sports on ADHD¶

A review analyzed 37 meta-analyses of 106 studies and found Hedges g⁹⁶

• Inattention: 0.92
• Impulse control: 0.82
• Cognitive flexibility: 0.52
• Emotional symptoms: weak evidence
• Social symptoms: weak evidence
• Working memory: weak evidence
• Hyperactivity: not significant
• Behavioral functions: not significant

1.1.2.1.2. Meta-analyses of the Effect size of sports on ADHD¶

• Overall ADHD symptoms

  • 0.93 (meta-analysis of k = 5 studies with n = 144 subjects)⁹⁷ Unfortunately, there was no comparison of the Effect size of medication
  • 0.83 ADHD core symptoms through closed skills training (meta-analysis of k = 22 RCTs on children and adolescents with ADHD)⁹⁸
  • 0.65 for endurance training in children with ADHD (meta-analysis, k = 8, n = 249)⁹⁹
  • 0.39 ADHD core symptoms through long-term sports (meta-analysis of k = 22 RCTs on children and adolescents with ADHD)⁹⁸

• Individual ADHD symptoms

  • Impulse control
    • 1.98 through Open Skills Training (meta-analysis, k = 15, n = 578; recommended: 12 weeks, at least 2 x / week medium or high intensity)¹⁰⁰
    • 1.94 by open-ended skills activities (meta-analysis of k = 44 studies from 1983 to 2022 with n = 1,757 children and adolescents compared to controlled alternatives (e.g. waiting list, no intervention, watching video or sedentary attention control))⁹⁵
    • 1.3 through continuous sports (meta-analysis, k = 11, n = 346 children with ADHD/ASS)¹⁰¹
    • 1.0 through closed skills training (meta-analysis, k = 15, n = 578; recommended: 12 weeks, at least 2 x / week medium or high intensity)¹⁰⁰
    • 0.83 Inhibition by aerobic sports (meta-analysis of k = 9 RCTs (mean PEDro score: 7.78) on children with ADHD from 6 to 12 years)¹⁰² 60 to 90 minutes duration, moderate intensity and 6 to 12 minimum duration favored inhibition and cognitive flexibility
    • 0.78 (meta-analysis, k = 11 studies with n = 713 children)¹⁰³ Open training twice a week for 60 minutes or longer showed the best effect Inhibition in children with ADHD
    • 0.76 (meta-analysis of k = 15 studies with n = 664 children and adolescents from 6 to 18 years)¹⁰⁴
    • 0.676 (meta-analysis of k = 23 studies with n = 535)¹⁰⁵
    • 0.56 (meta-analysis, k = 8, n = 249)⁹⁹
    • 0.50 (meta-analysis of k = 24 with n = 914 children and adolescents with ADHD)¹⁰⁶
  • Hyperactivity
    • 1.60 by closed-skill activities dominated by aerobic exercise (meta-analysis of k = 44 studies from 1983 to 2022 with n = 1,757 children and adolescents compared to controlled alternatives (e.g. waitlist, no intervention, watching video or sedentary attention control))⁹⁵
    • 0.56 (meta-analysis, k = 8, n = 249)⁹⁹
    • 0.676 (meta-analysis of k = 23 studies with n = 535)¹⁰⁵
    • 0.06 (meta-analysis of k = 15 RCT with n = 734 subjects)¹⁰⁷
  • Cognitive flexibility
    • 1.44 by multi-component physical exercise (meta-analysis of k = 44 studies from 1983 to 2022 with n = 1,757 children and adolescents compared to controlled alternatives (e.g. waiting list, no intervention, watching a video or sedentary attention control))⁹⁵
    • 1.33 through closed skills training (meta-analysis, k = 15, n = 578; recommended: 12 weeks, at least 2 x / week medium or high intensity)¹⁰⁰
    • 0.97 through Open Skills Training (meta-analysis, k = 15, n = 578; recommended: 12 weeks, at least 2 x / week medium or high intensity)¹⁰⁰
    • 0.85 through continuous sports (meta-analysis, k = 11, n = 346 children with ADHD/ASS)¹⁰¹
    • 0.78 (meta-analysis of k = 15 studies with n = 664 children and adolescents from 6 to 18 years)¹⁰⁴
    • 0.65 cognitive flexibility through aerobic sports (meta-analysis of k = 9 RCTs (mean PEDro score: 7.78) on children with ADHD from 6 to 12 years)¹⁰² 60 to 90 minutes duration, moderate intensity and 6 to 12 minimum duration favored inhibition and cognitive flexibility
    • 0.45 (meta-analysis of k = 24 with n = 914 children and adolescents with ADHD)¹⁰⁶
  • Executive functions
    • 1.96 through open-ended skills activities that require participants to respond in a dynamically changing and externally controlled environment (meta-analysis of k = 44 studies from 1983 to 2022 with n = 1,757 children and adolescents compared to controlled alternatives (e.g., waitlist, no intervention, watching video, or sedentary attention control))⁹⁵
    • 1.22 (meta-analysis of k = 15 RCT with n = 734 subjects)¹⁰⁷
    • 1.15 by all types of physical activity (meta-analysis of k = 44 studies from 1983 to 2022 with n = 1,757 children and adolescents compared to controlled alternatives (e.g. waiting list, no intervention, watching a video or sedentary attention control))⁹⁵
    • 0.90 through continuous sports (meta-analysis, k = 11, n = 346 children with ADHD/ASS)¹⁰¹
    • 0.68 Executive functions through continuous sports (meta-analysis of k = 22 RCTs on children and adolescents with ADHD)⁹⁸
    • 0.61 (meta-analysis of k = 15 studies with n = 664 children and adolescents from 6 to 18 years)¹⁰⁴
    • 0.58 (meta-analysis, k = 8, n = 249)⁹⁹
  • Working memory
    • 1.21 by closed-skill activities dominated by aerobic exercise (meta-analysis of k = 44 studies from 1983 to 2022 with n = 1,757 children and adolescents compared to controlled alternatives (e.g. waiting list, no intervention, watching video or sedentary attention control))⁹⁵
    • 0.85 through closed skills training (meta-analysis, k = 15, n = 578; recommended: 12 weeks, at least 2 x / week medium or high intensity)¹⁰⁰
    • 0.50 (meta-analysis of k = 24 with n = 914 children and adolescents with ADHD)¹⁰⁶
    • 0.48 aerobic sports (meta-analysis of k = 9 RCTs (mean PEDro score: 7.78) on children with ADHD aged 6 to 12 years)¹⁰² 60 to 90 minutes duration, moderate intensity and 6 to 12 minimum duration promoted inhibition and cognitive flexibility
    • 0.28 on working memory (not statistically significant) through continuous sports (meta-analysis, k = 11, n = 346 children with ADHD/ASS)¹⁰¹
  • Gross motor skills
    • 0.80 through continuous sports (meta-analysis, k = 11, n = 346 children with ADHD/ASS)¹⁰¹
    • 0.67 (meta-analysis of k = 15 RCT with n = 734 subjects)¹⁰⁷
  • Fine motor skills
    • 0.30 (not statistically significant) through continuous sports (meta-analysis, k = 11, n = 346 children with ADHD/ASS)¹⁰¹
  • Inattention
    • 1.51 by closed-skill activities dominated by aerobic exercise (meta-analysis of k = 44 studies from 1983 to 2022 with n = 1,757 children and adolescents compared to controlled alternatives (e.g. waitlist, no intervention, watching video or sedentary attention control))⁹⁵
    • 0.84 (meta-analysis, k = 8, n = 249)⁹⁹
    • 0.604 to 0.715 (meta-analysis of k = 23 studies with n = 535)¹⁰⁵
    • 0.60 (meta-analysis of k = 15 RCT with n = 734 subjects)¹⁰⁷
    • 0.48 (meta-analysis of k = 10 RCT with n = 474 children aged 6 to 12)¹⁰⁸
      • Effect size was moderated by the type, frequency and duration of physical activity, not by the physical activity setting or the timing of the individual intervention.
    • 0.32 through long-term sports (meta-analysis of k = 22 RCTs on children and adolescents with ADHD)⁹⁸
    • 0.29 (not statistically significant) (meta-analysis of k = 32 RCTs (5 of which related to ADHD) with n = 1,255 children and adolescents). In contrast, the meta-analysis found a significant effect for ASD (0.50), depression (0.68) and obesity (0.58)¹⁰⁹
  • Anxiety symptoms
    • 0.66 (meta-analysis, k = 8, n = 249)⁹⁹
  • Social disorders
    • 0.59 (meta-analysis, k = 8, n = 249)⁹⁹
  • Emotional problems
    • 0.416 (meta-analysis of k = 23 studies with n = 535)¹⁰⁵
  • Behavioral problems
    • 0.347 (meta-analysis of k = 23 studies with n = 535)¹⁰⁵
  • Social problems:
    • 0.27 (not statistically significant) (meta-analysis of k = 15 RCT with n = 734 subjects)¹⁰⁷
  • Aggressive behavior:
    • 0.24 (not statistically significant) (meta-analysis of k = 15 RCT with n = 734 subjects)¹⁰⁷

1.1.2.1.3. Individual studies on the Effect size of sports on ADHD¶

• An aerobic group sports program brought about improvements in participants with various disorders compared to the passive control group in terms of¹¹⁰
  • Global ADHD symptom severity: 0.77
  • Depression; 0.68
  • Anxiety: 0.87
  • Sleep quality: 0.88

1.1.2.1.4. Effect size of sports on other disorders¶

• Depression:
  • 0.72 (not statistically significant) (meta-analysis of k = 15 RCT with n = 734 subjects)¹⁰⁷
  • 0.68 (meta-analysis of k = 32 RCTs (5 of which related to ADHD) with n = 1,255 children and adolescents)¹⁰⁹
  • 0.62 Cochrane meta-analysis (k = 35 studies with n = 1,356 subjects)¹¹¹
    • Long-term effect: 0.33
    • 0.18 when limited to the studies with high blinding. The comparative studies on the Effect size of psychotherapy (k = 7 studies, n = 189) or medication (k = 4 studies, n = 300) each found an identical SMD of endurance training
• Obesity
  • 0.58 (meta-analysis of k = 32 RCTs with n = 1,255 children and adolescents)¹⁰⁹

1.1.2.2. Cognitive behavioral therapy: 0.5 (0.3 to 0.85)¶

Cognitive Behavioral Therapy (CBT)

• Effect largely persists after the end of therapy
• Very long time to take effect

Studies:

• Effect on externally observed ADHD symptoms in adults

  • CBT compared to supportive therapy
    • 0,56¹¹²
  • MBCT compared to waiting list
    • 0,85¹¹³
  • CBT compared to waiting list
    • 1,68¹¹⁴
  • CBT compared to continued medication alone
    • 0,60¹¹⁵¹¹⁶

• Effect on self-observed ADHD symptoms in adults

  • CBT compared to supportive therapy: 0.16¹¹⁷ with reference to 2 studies. Only one of these dealt with CBT¹¹², the second study examined DBT/skill training and also reported a good result¹¹⁸.
  • CBT compared to waiting list: 0.84¹¹⁷ with reference to 5 studies. However, only studies on MBCT^{119113 120} , internet-based CBT¹²¹ and brief therapy¹²² were included
  • 1,0¹¹⁶

• CBT without concomitant medication:
  • 0,34¹²³
  • 0,3⁷

METASTUDY:

• 0.70 according to a meta-analysis of k = 3 studies with a total of n = 107 subjects¹²⁴
• 0.79 compared to waiting lists in k = 4 studies with n = 160 subjects¹²⁵
• 0.43 compared to active control groups (e.g. psychoeducation, progressive muscle relaxation, encouragement) in k = 3 studies with n = 191 subjects¹²⁶

A meta-analysis found an effect of behavioral therapy on inattention in adults with ADHD of¹²⁷

• against waiting list or therapy as usual
  • in the external observation rating
    • 1.18 (0.44, 0.92, 0.95, 2.41; k = 4 studies with n = 124 adults)
  • in the self-assessment rating
    • 0.93 (0.18, 0.28, 0.68, 0.82, 0.92, 1.18, 1.22, 1.35, 1.71; k = 9 studies with n = 215 adults)
• against active controls (psychoeducation, neurofeedback, clinical management, cognitive training)
  • in the external observation rating
    • below 0.0 = slightly negative SMD = slight worsening (k = 4 studies with n = 229 adults, compared to psychoeducation, MPH or placebo)
    • 0.5 in k = 2 studies with a total of n = 49 adults, of which only one was statistically significant
  • in the self-assessment rating
    • below 0.0 = slightly negative SMD = slight deterioration (k = 8 studies with n = 298 adults)
    • 0.4 in k = 3 studies with n = 91 adults, of which only 1 was statistically significant

A large meta-analysis of k = 190 studies with n = 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 most effective.¹²⁸ See below under Effectiveness by OR.

A meta-analysis of k = 17 RCTs with n = 1,075 participants found an effect of cognitive interventions of:¹²⁹

• 0.39 on attention symptoms
  • Working memory training: no significant effect on attention symptoms
  • multiple cognitive training: 0.51 on attention symptoms
• 0.32 on executive functional behavior
  • Working memory training: no significant effect on executive functioning behavior
  • multiple cognitive training: 0.5 on executive functional behavior
• multiple cognitive training: 0.31 on hyperactivity/impulsivity

Overall, only treatment frequency had a significant effect on ADHD symptoms and executive behaviors.¹²⁹

1.1.2.3. Mindfulness-based behavioral therapy (MBCT)¶

People with ADHD who were treated with MBCT (mindfulness-based cognitive therapy) in addition to standard treatment 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 the people with ADHD who were additionally treated with MBCT, 27% showed a 30% reduction in ADHD-HI symptoms (p = 0.001), compared to only 4% of the people with ADHD who were not additionally treated with MBCT.¹³⁰
The effect largely persisted even after the end of therapy.

1.1.2.4. Neurofeedback: 0.29 to 1.2¶

Studies without limitation to blinded observation:

• 0.49 to 0.68 after only 30 sessions⁵⁰
• 0,6¹³¹¹³²

• 0,7¹³³
• 1,2¹³⁴
• 1,2¹³⁵
• 1,2¹³⁶

METASTUDIES

• 0.49 (parent rating); k = 5, n = 246¹³⁷
• 0.35 ADHD total symptoms meta-analysis with k = 13 studies on n = 520 subjects, unblinded:¹³⁸ Further results in relation to individual symptoms:
  • 0.36 Inattention
  • 0.26 Hyperactivity/impulsivity

Studies with limitation to blinded observation according to Sonuga-Barke et al (2013):¹³⁹

• 0,4¹³¹
• 0,4¹³³
• 0,3¹³⁶
• 0,1¹⁴⁰

METASTUDY:

• (also) unblinded studies:
  • 0,59¹³⁹
  • 0.61 after a meta-analysis of k = 6 studies with a total of n = 203 subjects¹⁴¹ Unfortunately, there was no comparison of the Effect size of medication.
• Meta-analyses with only blinded studies
  • 0.30 (teacher rating, k = 5, n = 246)¹³⁷
  • 0,29¹³⁹
  • 0.30 Impulse control (not statistically significant; k = 13, n = 520)¹⁴²
  • 0.13 Attention (not statistically significant; k = 13, n = 520)¹⁴²

Children and young people:

• 0.44 on ADHD symptoms (statistically significant, meta-analysis, n = 12, n = 945)²⁵

According to symptoms:

• On attention: 0.8 to 1.2
  • 0.64 directly after treatment compared to untreated controls (MPH in contrast 1.08)¹⁴³
  • 0.80 at follow-up after 2 to 12 months (MPH in contrast 1.06)¹⁴³
  • 0,8¹⁴⁴
  • 0.48 for inattention in EEG-NF compared to waiting list/TAU (k = 5; n = 279)¹⁴⁵
  • 0.46 (parent rating); k = 5, n = 246¹³⁷
  • After 40 sessions: 1.2¹⁴⁶

• on hyperactivity/impulsivity: 0.5 to 0.61
  • 0.50 directly after treatment compared to untreated controls¹⁴³
  • 0.61 at follow-up after 2 to 12 months¹⁴³
  • 0.39 after 20 sessions; cannot be further improved by increasing the number of sessions¹⁴⁶
  • 0.03 for hyperactivity/impulsivity in EEG-NF compared to waiting list/TAU (k = 5; n = 279)¹⁴⁵
  • 0.34 (parent rating); k = 5, n = 246¹³⁷

• On impulsivity: 0.68
  • After 20 sessions: 0.7¹⁴⁶
  • Cannot be further improved by increasing the number of sessions

In comparison:

• Neurofeedback is not as effective as MPH¹⁴⁷
  • 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).¹⁴⁸
• Effect usually remains complete after the end of therapy

1.1.2.5. Parent training: 0.31 to 0.68¶

The results relate to the improvement of the children’s problematic behavior through parent training.
Parent training courses include, for example²⁵

• Educational and behavioral strategy programs for parents of preschool children
• Psychoeducation for families
• New Forest Parenting Package for parents of preschool children

METASTUDY:

• 0.86 for parent training in the group¹⁴⁹
• 0.68 in relation to ADHD (k = 11, n = 603 children from 33 to 144 months)¹⁵⁰
• 0.61 in relation to the ADHD of preschool children¹⁵¹
• 0.42 to 0.53¹⁵²
• 0.40 for ADHD¹⁵³
• 0.31 in relation to children’s ADHD symptoms (k = 11 RCT, n = 1,078)²⁵
• 0.31, k = 4 studies¹⁵⁴ although at the same time an Effect size of 0.85 was attributed to antidepressants, 0.35 to stimulants and 0.28 to multimodal treatment, which deviates so far from other findings that it raises questions about the robustness of the data.

Improvement of certain symptoms:

• externalizing behaviour of the child (e.g. breaking rules, oppositional behaviour or aggression):
  • 0.36 for externalizing symptoms¹⁵³
  • 0.32; not statistically significant (k = 3, n = 190)¹⁵⁵
• internalizing behaviour of the child (e.g. withdrawal or anxiety):
  • 0.48, statistically significant (k = 2, n = 142)¹⁵⁵
• 0.59 on comorbid behavioral problems¹⁵⁰
• 0.93 on parental self-esteem¹⁵⁰

1.1.2.6. Repetitive transcranial magnetic stimulation (rTMS) 0.54¶

Improvement in cognitive function: 0.54 compared to controls¹⁵⁶

A meta-analysis of k = 6 RCTs with n = 169 participants showed the Effect size for rTMS compared to sham treatment:¹⁵⁷ (although there was no statistical significance for superiority of treatment of the right PFC)

• on overall ADHD symptoms
  • 0.49 Treatment of right PFC
  • 0.24 Total group (treatment of left or right PFC)
  • 0.01 Treatment of left PFC
• on individual symptoms
  • 0.76 Inattention
  • 0.43 Impulsiveness
  • 0.0 Hyperactivity
  • 0.0 Depression

1.1.2.7. Cognitive self-regulation training: 0.54¶

• Out-of-school 0.58, n = 5 studies¹⁵⁸ although at the same time an Effect size of 0.85 was attributed to antidepressants, 0.35 to stimulants and 0.28 to multimodal treatment. These figures are in no way consistent with the clinical evidence, which raises questions regarding the reliability of the data.
• School-based 0.49, n = 2 studies¹⁵⁸ although an Effect size of 0.85 was attributed to antidepressants, 0.35 to stimulants and 0.28 to multimodal treatment. These figures are in no way consistent with the clinical evidence, which raises questions regarding the reliability of the data.

1.1.2.8. Behavioral training: 0.54¶

• Out-of-school 0.29, n = 1 study¹⁵⁸ although at the same time an Effect size of 0.85 was attributed to antidepressants, 0.35 to stimulants and 0.28 to multimodal treatment, which raises questions about the robustness of the data.
• School-based 0.50, n = 3 studies¹⁵⁸ although at the same time an Effect size of 0.85 was attributed to antidepressants, 0.35 to stimulants and 0.28 to multimodal treatment, which raises questions regarding the robustness of the data.

1.1.2.9. Food diets: 0.51¶

Effect only during faultless dietary compliance.
High values can be achieved under test conditions if food intolerance is present.
An elimination diet places very high demands on compliance in the elimination phase and, as a form of treatment, is a very serious intervention in lifestyle with a high potential for errors in daily life. It is barely feasible for children and has considerable social consequences.

Studies:

• Oligoantigenic diet:
  • 0,2¹⁵⁹
  • 0,2¹⁶⁰
• Avoidance of known antigens
  • 0,29¹⁶¹
  • 0,6¹⁶²
  • 0,7¹⁶³
  • 1,9¹⁶⁴
• Elimination diet
  • 3,58¹⁶⁵
  • 5,13¹⁶⁶
• Avoidance of food supplements / colorants: 0.2 (0.08 to 0.44)
  • 0.08 to 0.11 (teacher and observer rating)⁸⁶
  • 0.12 to 0.25¹⁶¹
  • 0.21 to 0.283 (with the addition of smaller, less high-quality studies)¹⁶⁷
  • 0.21 to 0.44 in the parent rating⁸⁶
  • 0.42 when only blinded studies were used; of 8 studies, 6 showed no statistically significant results; 0.32 when all studies were included¹³⁹

Meta-analyses of dietary interventions:

• 0.51 to 0.8⁸⁶
• 0.51 (0.2 to 1.9) if only the blinded studies were used; 1.48 (0.2 to 5.13) if all studies were included¹³⁹

There is evidence that an elimination diet only works for certain people with ADHD (“subgroup”).¹⁶⁸
In our opinion, this is in the nature of things, as the elimination of foods can only bring about an improvement if there is a food intolerance. However, these are highly individual.

1.1.2.10. Cognitive training: 0.22 to 0.45¶

0.45 after a meta-analysis of k = 4 studies with n = 159 subjects.¹⁶⁹

A meta-analysis examined the Effect size of cognitive training¹⁷⁰

• Treatment reports (unblinded):
  • 0.37 on ADHD in total
  • 0.47 on symptoms of inattention
  • 0.79 on ADHD overall through interventions targeting multiple neuropsychological deficits
• (presumably) blinded reports:
  • 0.20 on ADHD as a whole
  • 0.32 on symptoms of inattention

Children and young people:

• 0.78 for attention symptoms (meta-analysis of k = 10 studies with n = 446 children compared to placebo)¹⁷¹
  • 1.3 in children under 10 years of age) (meta-analysis of k = 10 studies with n = 446 children compared to placebo)¹⁷¹
  • 0.95 for training duration of more than 30 days (meta-analysis of k = 10 studies with n = 446 children compared to placebo)¹⁷¹
• 0.56 for executive functions (meta-analysis of k = 10 studies with n = 446 children compared to placebo)¹⁷¹
• 0.37 on ADHD symptoms in children and adolescents (meta-analysis, k = 12, n = 655)²⁵

• 0.22 (meta-analysis)¹⁷²

One review found limited to minor symptom improvement with computerized cognitive training (CCT)¹⁷³
* 0.12 on ADHD total symptoms when restricted to the “probably blinded” results (PBLIND; k = 14 studies)
* 0.12 on hyperactivity/impulsivity symptoms when restricted to the “probably blinded” results (PBLIND; k = 14 studies)
* 0.17 on the symptoms of inattention when restricted to the “probably blinded” results (PBLIND; k = 14 studies)
* 0.40 on the symptoms of inattention during assessment immediately after training (indication of rater bias)
* 0.38 on working memory verbal
* 0.49 on working memory visual-spatial
* No improvement in attention, inhibition, reading or arithmetic*

Overall, there were improvements:¹⁷⁴

• 0.52 verbal working memory
• 0.3 Executive functions in the parent rating
• There were no significant effects with regard to
  • Hyperactivity/impulsivity
  • School performance

1.1.2.11. Total psychological behavioral interventions: 0.35 for children and adolescents¶

A meta-analysis found an Effect size on ADHD symptoms of 0.35 (k = 14, n = 1,686) for the entirety of psychosocial behavioral interventions aimed at children and adolescents.²⁵ When limited to RCTs, the value remained at 0.36. 8 of the 6 studies found no statistically significant effect.
The psychological behavioral interventions included comprised

• Skills training (e.g. executive function training, homework training or organizational skills training)
• Social skills training
• Executive function therapy for preschool children
• Driving program for young drivers
• sleep-focused intervention
• dialectical behavioral therapy
• cognitive behavioral therapy
• Attention training
• complex behavior modification intervention
• Behavioral counseling with school and home components
• Parent-child psychotherapy for mothers and their children with ADHD
• Mindfulness training
• Music therapy
• playful intervention
• dog-assisted therapy

With an Effect size of 0.007 (k = 3, n = 459), there was no improvement in school performance.²⁵

1.1.2.12. Social skills training: 0.26 to 0.31¶

A Cochrane meta-analysis found a therapeutically unhelpful Effect size of social skills training for children and adolescents aged 5 to 17 in the teacher evaluation:¹⁷⁵

• ADHD total symptoms: 0.26 (k = 14 RCT with n = 1379)

• 0.11 Social competence (k = 11 RTC, n = 1,271)
• 0.02 Emotional competence (k = 2, n = 129)
• 0.06 General behavior (k = 8, n = 1,002)

Social skills training was included in this meta-analysis:

• Social skills training
• cognitive behavioral therapy
• multimodal behavioral/psychosocial therapy
• Treatment of children’s life and attention skills
• Life skills training
• the “Program for challenging horizons”
• verbal self-instruction
• metacognitive training (a variant of cognitive behavioral therapy)
• Behavioral therapy
• Treatment of behavior and social skills
• psychosocial treatment.

Skills training also includes leadership training, homework or organizational skills training.²⁵

• METASTUDY of k = 3 studies¹⁵⁸
  • 0.31; however, 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 and suggests inflated Effect size results

1.1.2.13. Transcranial direct current stimulation (tDCS): 0.23¶

For tDCS in ADHD, a review study of k = 102 studies found an Effect size of 0.23.¹⁷⁶

1.1.2.14. Teacher training¶

A meta-analysis of k = 22 studies found for teacher training:¹⁷⁷

• 0.71 to 0.78 Behavioral improvement of the children with ADHD as a consequence of the adapted teacher behavior

In addition, there was a strong improvement in the trained teachers’ knowledge about ADHD immediately after the training (1.96), which, however, decreased again by 1.21 within 3 months.

1.1.2.15. Virtual reality interventions¶

A meta-analysis of k = 4 studies with n = 125 people with ADHD found an Effect size for virtual reality-based interventions of¹⁷⁸

• 1.38 on omission error (omission error)
• 1.50 for correct answers
• 1.07 on perceptual sensitivity
• 0.62 on commission error
• 0.67 on reaction time
• No effect on impulsivity

1.1.2.16. Online interventions¶

A meta-analysis of k = 6 RCTs with n = 261 subjects found an Effect size of online interventions in improving attention deficit and social functioning of adults and children with ADHD compared to the waiting list of 0.59.¹⁷⁹

1.1.2.17. Working memory training¶

A meta-analysis of k = 12 studies found working memory training to be effective in children and adults with and without ADHD:¹⁸⁰¹⁸¹

• 0.37 on inattention in everyday life
• 0.62 on visual-spatial working memory tasks
• 0.41 on verbal working memory tasks

1.1.2.18. Digital interventions¶

A meta-analysis (k = 25 RCT, n = 1,780) found an Effect size of¹⁸²

• 0.33 on ADHD symptoms overall
• 0.31 on inattention
• 0.15 on hyperactivity/impulsivity

1.1.2.19. Digital therapy games¶

A meta-analysis of k = 20 studies found an Effect size of digital therapy games for ADHD:¹⁸³

• Inattention
  • 0.21 in the teacher rating
  • 0.28 in the parent rating
• Hyperactivity/impulsivity
  • minus 0.01 in the teacher rating
  • 0.16 in the parent rating

Most of the study results were not statistically significant.

1.1.2.20. School interventions¶

• 0.50 on ADHD symptoms; not statistically significant; meta-analysis of k = 5 studies with n = 822 children and adolescents²⁵
• 0.36 (not statistically significant) Meta-analysis of k = 39 studies on school interventions in low- and middle-income countries¹⁸⁴

1.1.2.21. Acupuncture¶

A Chinese meta-analysis of k = 13 studies with n = 1,304 participants reported an Effect size of for acupuncture:¹⁸⁵

• 0.94 in terms of overall efficacy rate and Conners Index reduction rate for hyperactivity compared to other treatment groups
• 1.14 in improving Chinese medicine syndrome (liver-kidney-yin hypoactivity) in children with ADHD (and thus comparable to methylphenidate)
• fewer serious adverse effects than with pharmacotherapy (loss of appetite, dry mouth, nausea and constipation)

We take the liberty of noting that no reproducible treatment successes of acupuncture are reported in the German ADHD forum of ADxS, although the readers there have a strong interest in a successful non-drug form of treatment.

1.1.2.22. Age difference within school classes¶

A population study with n = 14,643 participants in the UK found an impact on overall mental health in the parenting advice of:¹⁸⁶

• 0.22 for 1-year difference at 11 years
• 0.02 for 1-year difference at 25 years
• 0.02 for 1-year difference before starting school

1.1.2.23. Weighted blankets in relation to anxiety symptoms¶

0.47 compared to placebo (meta-analysis of k = 6 studies)¹⁸⁷

1.2. Comparison after risk reduction¶

In a comparison after risk reduction, a lower hazard risk represents an improvement.

1.2.1. Reducing the risk of psychiatric hospitalization¶

Influence on the risk of psychiatric hospitalization¹⁸⁸

• Amphetamine (adjusted hazard ratio, aHR: 0.74 = reduction of 26%)
• Lisdexamfetamine (aHR: 0.80 = reduction by 20 %)
• ADHD medication polytherapy (aHR: 0.85 = reduction by 15 %)
• Dexamphetamine (aHR:0.88 = reduction by 12 %)
• Methylphenidate (aHR: 0.93 = reduction by 7 %)
• Modafinil: unchanged
• Atomoxetine: unchanged
• Clonidine: unchanged
• Guanfacine: unchanged

1.2.2. Risk reduction of non-psychiatric hospitalization¶

Influence on the risk of non-psychiatric hospitalization¹⁸⁸
Amphetamine, lisdexamfetamine, polytherapy (combination medication), dexamphetamine, methylphenidate and atomoxetine reduced the risk of non-psychiatric hospitalization.

1.2.3. Risk reduction of suicidal behavior¶

Influence on the risk of suicidal behavior¹⁸⁸

• Dexamphetamine (aHR: 0.69)
• Lisdexamfetamine (aHR: 0.76)
• Methylphenidate (aHR: 0.92)

1.2.4. Risk reduction of incapacity for work¶

Influence on the risk of incapacity for work¹⁸⁸

• Atomoxetine (aHR: 0.89)
  • particularly among adolescents and young adults aged 16 to 29 (aHR: 0.82)
    All other ADHD medications investigated: not significant.

1.3. Comparison according to odds ratio (OR)¶

Overview according to Catalá-López et al (2017).¹³ The data compare the probability of treatment success compared to placebo. OR = 1 would be equivalent to placebo, an OR higher than 1 favors the treatment method.

Placebo: 1 (comparative value)

1.3.1. Drug interventions¶

Comparison according to odds ratio (OR)

• Total stimulants: 6.21

  • Amphetamine drugs: 7.45
  • Methylphenidate: 5.26

• Total non-stimulants: 3.95

  • Modafinil: 5.51
  • Atomoxetine: 3.63
  • Guanfacine: 3.29
  • Clonidine: 3.96
  • Bupropion: 2.41
  • Venlafaxine: 4.07
  • Reboxetine: 3.58
  • Antipsychotics: 1.36
  • Thioridazine: 1.04
  • Carbamazepine: 0.18

1.3.2. Minerals / vitamins / amino acids / herbal remedies¶

Comparison according to odds ratio (OR)

• Zinc: 2.42
• Polyunsaturated fatty acids (or PUFAs): 2.14
• Omega-3 and -3/6 fatty acids: 1.99
• L-carnitine: 1.20
• Amino acids: 1.19
• St. John’s wort (Hypericum perforatum): 1.00 (0.23-4.26)
• Ginkgo biloba: 0.21

1.3.3. Non-drug interventions¶

Comparison according to odds ratio (OR)

• Behavioral therapy: 2.97
• Neurofeedback: 1.96
• Parent training: 1.19
• Child, parent and/or teacher training: 2.73
• Cognitive training: 0.70
• Working memory training: 0.34

1.4. Multimodal therapy¶

Individual studies
In the “Multimodal Treatment Study of Children with ADHD” (MTA study) in the late 1990s, 579 children aged 7 to 10 were treated with medication, behavioral interventions or both for 14 months.¹⁸⁹ The MTA study only included group interventions (parent group training, child summer camp and school support) and no individual behavioral therapy.
Teachers and parents rated the reduction in symptoms with regard to the core symptoms of ADHD better in the children treated with medication only than in the children treated with parent and behavioral training only. The children who received medication and parent and behavioral training performed even slightly better than the children treated with medication alone, albeit with reduced medication requirements. When not only the core symptoms but all symptoms were considered, the children treated with medication and parent and behavioral training clearly performed best. In contrast, the effect of parent and behavioral training alone was lower than treatment with medication alone.¹¹

METASTUDIES

• A comprehensive meta-analysis on the multimodal treatment of children and adolescents with ADHD found an Effect size for additional psychological treatment of
  • 0.36 on ADHD symptoms compared to medication alone (k = 7, n = 841, statistically marginally non-significant, low risk of bias)²⁵
    • The greatest Effect size was shown by a behavioral and social skills course for children and their parents and cognitive behavioral therapy for adolescents
  • 0.42 on broadband symptoms compared to medication alone (k = 3, n = 171, not statistically significant, high risk of bias)²⁵
    • Multimodal psychosocial treatment plus MPH versus MPH alone, group cognitive-behavioral therapy plus MPH versus MPH, and individual cognitive-behavioral therapy plus FDA-approved medications versus these medications alone were assessed.
• Another meta-analysis found that
  • 0.1 for parent and behavioral training alone versus no treatment
  • minus 0.4 if only the blinded raters were used, i.e. a deterioration compared to no parent and behavioral training.¹³⁹

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. Psychotherapy¶

• Behavioral therapy:
  • Cognitive VT:
    Self-esteem, social behavior, stress reduction
    To a certain extent, changes in stress processing, including hormonal and immunological physical changes¹⁹⁰
  • 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 immediate 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.¹⁹¹
  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 better ability to regulate through greater understanding of the person with ADHD
  Increased self-esteem through the feeling of coming home, meeting and exchanging ideas with other people with ADHD

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 curative effect), while methylphenidate administration in somewhat older animals (“after puberty”) no longer had this effect.¹⁹² These results have not yet been reproduced.

No permanent reduction in DAT in the striatum is known in the treatment of humans with MPH, even in children before puberty.

Despite the immense importance of this question, no further studies are known to confirm the results. A dosage of twice 5 mg / kg / day in rats from the 7th day to the 35th day after birth resulted in short-term reductions in the DAT count, but these were no longer found on the 135th day of life.¹⁹³
There were no structural changes in the brain structures either immediately after the end of treatment on day 35 or on day 135.¹⁹³ 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 treatment¹⁴¹⁹⁴ 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 post-maturation of those brain structures that are affected by a developmental delay in ADHD.

In ADHD, dysfunctional executive functions are associated with a reduced amount of brain matter in the cortex.¹⁹⁵ In children with ADHD, the growth of brain matter in the cortex is significantly reduced, with the greatest delays in the PFC and ACC.¹⁹⁵
Adult people with ADHD who are treated with stimulants have a significantly larger brain mass in the relevant brain regions than adult people with ADHD who are not treated with stimulants.¹⁹⁶ This could indicate that treatment with stimulants can make up for or compensate for the developmental delay.¹⁹⁵
In people with ADHD 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.¹⁹⁷

4.4. Multimodal treatment: non-drug therapy and medication¶

There is evidence that dopaminergic ADHD medications - in the 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.¹⁹⁸

We are convinced that psychotherapeutic measures are significantly less effective for people with ADHD who are not medicated, as the ability to learn and absorb is massively reduced by ADHD itself. Since ADHD medication improves the impaired neuroplasticity in ADHD and thus often enough creates the ability to learn in the first place, we believe that prior medication is clearly recommended for successful psychotherapy.
Apart from that, in our opinion, 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 person with ADHD after a longer period (1 year or more) of properly adjusted medication.
This is particularly true for people with ADHD, as motivation in ADHD is altered in the direction of significantly increased intrinsic control. ADHD means that following extrinsic prompts is massively more difficult.

5. Compatibility¶

A higher odds ratio (OR) means poorer tolerability than placebo.

• Amphetamine drugs
  • In children (OR: 2.30)³⁸
  • In adults (OR: 3.26)³⁸
• Atomoxetine (OR: 2.33)³⁸
• Methylphenidate (OR: 2.39)³⁸
• Guanfacine in children and adults (OR: 2.64)³⁸
• Modafinil (OR: 4.01)³⁸

6. Comparative values: Effect size for other disorders¶

6.1. Effect size of medication for depression¶

6.1.1. Classic antidepressants: 0.30¶

Effect size of classic antidepressants (SMD):⁵
Amitriptyline: 0.48
Duloxetine: 0.37
Mirtazapine: 0.37
Venlafaxine: 0.33
Clomipramine: 0.33
Paroxetine: 0.32
Milnacipran: 0.30
Escitalopram: 0.29
Sertraline: 0.27
Vortioxetine: 0.28
Agomelatine: 0.26
Bupropion: 0.25
Citalopram: 0.24
Fluoxetine: 0.23

The average of the classic antidepressants mentioned is therefore 0.30.

6.1.2. Psilocybin treatment embedded in psychotherapy (PAP): 0.78 to 1.5¶

Treatment of major depression by psilocybin treatment embedded in psychotherapy (PAP) showed a high Effect size on depression.

METASTUDY:

• Meta-analysis (k = 10, n = 208)¹⁹⁹
  • 0.75 on day 1
  • 1.74 after 1 week
  • 1.35 after 1 month
  • 0.91 after 3 months
  • 1.12 after 6 months.
• Meta-analysis (k = 8) for psychedelic depression treatment²⁰⁰
  • 1.5 on day 1 (k = 5)
  • 1.07 after 6 months (k = 5)
  • No serious undesirable effect.
  • Temporary increase in heart rate and systolic and diastolic blood pressure.
    -0.78 (meta-analysis, k = 9, n = 596, p<0.001)²⁰¹

Studies:

• n = 15, Cohen’s d²⁰²
  • 4.08 3 weeks after treatment, 24 points improvement in MADRS
  • 3.39 12 weeks after treatment
• n = 24, Cohen’s d²⁰³
  • 2.6 on day 1 after treatment
  • 2.5 5 weeks after treatment
  • 2.6 8 weeks after treatment
• n = 24, Cohen’s d²⁰⁴
  • 2.3 1 month after treatment
  • 2.0 3 months after treatment
  • 2.6 6 months after treatment
  • 2.4 12 months after treatment
• n = 20, Cohen’s d, open label without controls²⁰⁵
  • 2.2 after 1 week
  • 2.3 after 5 weeks
  • 1.5 after 3 months
  • 1.3 after 6 months.
• n = 29, Cohen’s d, Depression in cancer patients²⁰⁶
  • 1.23 after 1 day
  • 1.12 after 2 weeks
  • 1.32 after 6 weeks
  • 0.98 after 7 weeks
• n = 29, Hedges g
  • 1,07²⁰⁷

A meta-analysis found 9 studies on psilocybin, ayahuasca and LSD. The Effect size of the three psychedelics was approximately the same:²⁰⁸

• 1.36 on depression
• 1.26 on fear

The Effect size of ketamine on depression is significantly lower (0.4 to 0.65).²⁰⁹

6.1.3. Electroconvulsive therapy¶

Electroconvulsive therapy showed an Effect size on depression of 0.69 compared to ketamine.²¹⁰

6.2. Effect size of psychotherapy for depression 0.34¶

Effect size in SMD.
NNT: Number needed to treat. For 100 % treatment success, NNT = 1. The higher the NNT, the worse the efficacy.

Effect size of psychotherapy for depression:²¹²¹¹

• Behavioral activation: 0.82 (NNT = 2; 11 studies)
• Mindfulness-based cognitive behavioral therapy (MBCT): 0.73 (NNT = 3; 6 studies)
• Cognitive behavioral therapy: 0.71 (NNT = 3; 159 studies) to 0.79 (409 studies)²¹²
• Interpersonal psychotherapy: 0.67 (NNT = 3; 22 studies)
• Problem-solving therapy: 0.48 (NNT = 4; 21 studies)
• Supportive therapy: 0.52 (NNT = 4; 17 studies)
• Psychodynamic therapy: 0.44 (NNT = 4; 8 studies)

The studies are subject to a strong bias. The example of cognitive behavioral therapy:
When only the higher-quality studies were taken into account, the Effect size decreased by 0.2.²¹³
When all studies that compared with waiting lists were excluded, the Effect size decreased by 0.17.²¹
When all studies with a high risk of bias were excluded, the Effect size decreased by 0.32 to 0.39 (NNT = 5; 34 studies)²¹
If publication bias was also taken into account, the Effect size dropped to 0.34 (NNT = 5; 38 studies)²¹

If only the studies that fulfill all basic quality criteria are considered, an effect size of only 0.22 (instead of 0.74) remains.²¹¹²¹⁴

6.3. Effect size of medication for ASA¶

According to a meta-analysis, ASA as a whole improved by

• Methylphenidate: 0.53 in the teacher rating (k = 2, n = 36)²¹⁵

A meta-analysis examined k = 125 RCTs with n = 7,450 children/adolescents and k = 18 RCTs with n = 1,104 adults in comparison to placebo:²¹⁶

Social communication problems:

• Children and young people
  • 0.27 Aripiprazole (k = 6)
  • 0.51 Methylphenidate (k = 3, n = 63)²¹⁵

Repetitive behavior:

• Children and young people
  • 0.60 Risperidone (k = 6)
  • 0.49 Atomoxetone (k = 3)
  • 0.35 Bumetanide (k = 4)
  • 0.34 Methylphenidate (k = 3, n = 69)²¹⁵
• Adults
  • 1.2 Fluoxetine (k = 1)
  • 1.0 Fluvoxamine (k = 1)
  • 0.97 Risperidone (k = 1)
  • 0.41 Oxytocin (k = 6)

Irritability:

• 0.90 Atypical antipsychotics compared to placebo; k = 12, n = 973²¹⁷
• 0.18 Neurohormones compared to placebo; k = 8, n = 466²¹⁷
• 0.20 ADHD medication compared to placebo; k = 10, n = 400²¹⁷
• 0.06 Antidepressants compared to placebo; k = 3, n = 267²¹⁷

Aggression:

• 0.44 Atypical antipsychotics compared to placebo; k = 1, n = 77²¹⁷

Reduce self-harm:

• 1.43 Atypical antipsychotics compared to placebo; k = 1, n = 30²¹⁷
• 0.62 ADHD medication compared to placebo; k = 1, n = 16²¹⁷

ADHD symptoms in children and adolescents with ASD:

• Methylphenidate
  • Hyperactivity
    • 0.81 (teacher rating) to 0.63 (parent rating)²¹⁸
    • 0.78 (teacher evaluation)²¹⁹
  • Inattention 0.36 (parent rating) to 0.30 (teacher rating)²¹⁸
• Atomoxetine
  • Hyperactivity
    • 0.49 (parent rating) to 0.43 (teacher rating)²¹⁸
    • 0.73 (parental rating, CI = -1.15 to -0.34; meta-analysis,k = 3, n = 241)²²⁰
  • Inattention
    • 0.54 (parent rating) to 0.38 (teacher rating)²¹⁸
    • 0.53 (parental rating, CI = -1.15 to -0.34; meta-analysis,k = 3, n = 241)²²⁰

Intranasal immunotherapy with M2 macrophage secretome improved speech disorders and autism-like behavior in children. Unfortunately, no SMD was reported.²²¹

6.4. NNT for other disorders¶

Number needed to treat for various disorders:²¹

• Schizophrenia Response
  • Antipsychotics: NNT = 7
• Schizophrenia relapse prevention
  • Antipsychotics: NNT =N 3
• Depression - Response
  • SSRI: NNT = 7
• Depression - Relapse prevention
  • SSRI: NNT = 5
• Depression - Remission
  • Cognitive behavioral therapy vs. medication: NNT = 34
• Alcohol - Relapse
  • Acamprosate: NNT = 10
  • Naltrexone: NNT = 50