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Combination medication for ADHD

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Combination medication for ADHD

Contrary to still frequently held assumptions, there are multiple ways to combine medications in ADHD (augmentation).1 The combination of several agents of identical or different pharmacological classes (polypharmacy) is an increasingly widespread strategy in ADHD treatment2, which has found inclusion in various treatment guidelines, particularly in the case of comorbidities and cases resistant to monotreatment. 3456

A medical registry analysis found that a combination of different ADHD medication drug classes was used in 10.3% (for sufferers with health insurance) to 24.3% (for sufferers with Medicaid “insurance”) of all 1,125,119 and 721,986 months of treatment, respectively.7

When combination medication was used, the following drug classes were most commonly involved:7

  • Unretarded stimulants: 70.0%
  • Α2-adrenergic agonists (guanfacine, clonidine): 63.8%
  • Half-day-retarded stimulants: 51.8 %

Another study found that about a quarter of ADHD-affected children and adolescents who received stimulants received supplemental medications alongside them:8

  • Children: approx. 24 %
  • Teenagers: approx. 26.7

The most common additional medications given were:

  • SSRI
    • Children: approx. 7.4
    • Teenagers: approx. 13.8
  • Atypical antipsychotics
    • Children approx. 4.8
    • Teenagers: approx. 5.8
  • Guanfacin
    • Children approx. 6 %
    • Teenagers: approx. 3 %

Barkley reports that the typical ADHD medications each address about 70% of the same brain regions, but also target about 30% of other brain regions. He therefore recommends combination medication to achieve a broader effect with fewer side effects.9

All combinations or intake options described below are based on studies or reports of affected persons, which were made in consultation with the treating physician. It is expressly warned against unauthorized dosage or intake handling by affected persons!

1. Methylphenidate preparations among each other

It is possible to combine different methylphenidate preparations, especially retarded and unretarded, without any problems.
Unretarded MPH has its special significance in balancing the duration of action and adapting to special stress situations. Unretarded MPH can prolong the duration of action in the afternoon or early evening or bridge the time in the morning until the appropriate intensity of action of the sustained-release preparation is reached.
One study found that 40% of adults with ADHD receive such a combination to extend daytime coverage.10Similarly, Mason reports from his own medical practice that most of his adult ADHD patients take sustained-release stimulants, which typically last 8-10 hours, so most of them need additional unretained medications to supplement in order to get through the day.11

Occasionally, (experienced) sufferers report that they cope better with 2 different half-day MPH retard preparations in the morning and early afternoon than with taking the same retard preparation again. These sufferers also often use unretarded MPH to extend the day’s coverage.
It must be mentioned that the fine-tuning of such combinations is mostly done by the patient himself, and requires that the attending physician recognizes the necessary sense of responsibility to accompany him in the adequate adjustment of medication. In the case of children, this may be difficult to achieve, especially if the medication is already difficult to take evenly throughout the day.

2. Amphetamine drugs among themselves

Combining different amphetamine medications is usually done not to improve symptoms or reduce side effects but to provide better daytime coverage.

Some patients report good experiences with a combination of attentin (unretarded D-amphetamine) and retarded amphetamine (Elvanse). While Elvanse releases the amphetamine bound to lysine only very slowly via the intestine and blood, which can take up to 2 hours until the full onset of effect, a noticeable onset of effect is reported for attentin after about 15 minutes, which corresponds to unretarded MPH.

While Elvanse is effective for 10 to 11 hours from ingestion in most sufferers (a few sufferers report metabolization within 6 hours, with isolated cases even much faster), Attentin has an effective time of around 5 hours.

Some people have good experiences with taking a small dose of attentin in the morning and Elvanse at the same time or a few hours later. Others report that taking Attentin in the afternoon or early evening helps them get through a long day. In all cases, the Elvanse dose is reduced somewhat after a previous attentine dose.
In addition, quite a few sufferers report that those who manage best with two smaller doses of Elvanse taken at different times.

While quite a number of people affected by Elvanse report improved evening sleepiness and thus improved ability to fall asleep, if the ability to fall asleep worsens and does not subside even after several weeks, consideration should be given to changing the times at which the drug is taken in order to achieve an earlier end to the effective period.

3. Amphetamine drugs and methylphenidate

Many patients report taking amphetamine medication and (especially unretarded) MPH on the same day at different times in consultation with their doctor. No negative experiences are known.
Again, the greatest importance of (unretarded) MPH is in the time-delayed addition of the duration of action of the retarded amphetamine drug (Elvanse) early in the morning or in the evening.

In the (rather rare) cases in which MPH or AMP alone does not have sufficient effect up to the respective usually acceptable daily doses, parallel administration of MPH and AMP is also possible.

In addition, there are quite a few medications that can support the effect of other medications in ADHD.

4. Guanfacine/clonidine in addition to stimulants

A larger randomized double-blind placebo-controlled trial over 9 weeks in children with inadequate ADHD symptom improvement with stimulants showed substantial improvements with guanfacine given in addition without additional side effects. Apparently, several publications treat the same study.121314
Several other studies also found positive results of augmentative administration of guanfacine in ADHD sufferers who were not optimally controlled with stimulants alone, in relation to children15 and in relation to children and adolescents.1617
Another double-blind placebo-controlled study in 50 children 6 to 12 years of age with ADHD found improvement in executive functions with individually optimized guanfacine administration, which was in addition to previous stimulants, without additional side effects.18 A study on effects of combined administration of guanfacine and MPH on EEG in children with ADHD confirms the results.19
A randomized double-blind comparative trial between monotherapy with MPH or guanfacine and combination medication with MPH and guanfacine found a small but consistent benefit of combination therapy in reducing inattentive subscale scores of ADHD-RS-IV and a greater response rate (responding) than monotherapy. Combination therapy showed no serious cardiovascular events. Sedation, somnolence, lethargy, and fatigue were greater with guanfacine monotherapy as with combination therapy. All treatments were well tolerated.20 Another (?) randomized double-blind trial by the same authors from the same year concluded that combined treatment with MPH and guanfacine resulted in greater improvements in working memory than placebo or guanfacine alone, but was not superior to monotherapy with MPH, even in other cognitive domains.21 Combination therapy of MPH and guanfacine showed smaller cardiovascular effects than monotherapy of MPH or guanfacine.22

Guanfacine, which like clonidine is an α₂-adrenoceptor agonist, appears to be approved in some countries for combination medication with stimulants in ADHD,2324 and in children with ADHD who respond poorly to stimulants alone, together with stimulants improves symptoms significantly more than stimulants alone.

A randomized double-blind placebo-controlled study of adults with ADHD who had unsatisfactory improvements in their ADHD symptoms with stimulants and who were also individually augmented with 1 to 6 mg guanfacine showed significant improvement in the guanfacine group and, surprisingly, likewise in the placebo group. Increased side effects were not found.25 Two studies in healthy adults also found no complications with combination medication of guanfacine with lisdexamfetamine (Elvanse) and MPH.2627 In a single case, it was reported that clonidine given augmentatively could eliminate MPH-induced nocturnal teeth grinding.28
It would be interesting to know whether guanfacine/clonidine might also be able to reduce other tension-reducing actions (nail biting, lip biting) that sometimes occur as side effects with stimulants. An individual case report is not yet sufficient evidence for this.

One study came to a positive result of augmenting administration of clonidine to stimulants in ADHD.29 Nevertheless, guanfacine is probably to be preferred today due to its lower side effect profile.

5. Atomoxetine in combination with other ADHD medications

5.1. Atomoxetine and stimulants

Although there is no official approval of a combination medication of atomoxetine and other ADHD-indicated medications, a study7 found the use of such a combination medication in

  • 22.2% of those aged 6-17 with health insurance coverage
  • 9.8 % of those with health insurance aged 18 and over
  • 36.1% of Medicaid ADHS beneficiaries.

Another study reported 824 sufferers who received combination therapy of atomoxetine and methylphenidate.30
Ryffel-Rawak cites a personal communication from J. Krause that atomoxetine is effective primarily in combination with stimulants.31
Brown reports 4 cases in which only combination therapy of atomoxetine with stimulants produced adequate improvement in ADHD symptoms.32
Mason11
reports that in 2003, when atomoxetine came on the market, he switched 35 children with ADHD from stimulants to atomoxetine. To make the switch as smooth as possible, the previous stimulant dose was initially halved in a first step and supplemented with half the target dose of atomoxetine. after 14 days, the complete switch to the atomoxetine target dose was made in a second step. Surprisingly, about half of the subjects asked to continue the combination of reduced stimulants and half the atomoxetine dose. This combination therapy proved to be very successful. Most sufferers significantly reduced their previous stimulant dose. Side effects were less than in patients receiving stimulants alone. In particular, those on the combination therapy reported that family life had improved because the meltdowns, which many families already considered normal outside the stimulant period, had decreased. This seems to us a plausible consequence of the fact that atomoxetine, as a level medication, remains effective throughout the day, whereas stimulants have only a limited time during the day.

Mason11 reports on a study by Wilens in 2006 at Harvard in which atomoxetine and sustained-release MPH (Concerta) were each combined in high doses to test the maximum possible symptom reduction. In the process, patients who completed the study would have shown symptom reductions of more than 90%. Their ADHD symptoms had disappeared and attention was normal.
However, it was problematic that the high drug dosage used here triggered intolerable side effects in many patients, which was due to the study design, which had aimed solely at maximum symptom improvement.

A study (albeit funded by atomoxetine manufacturer Lilly) found no benefit in symptom improvement with combination therapy of atomoxetine with other ADHD medications compared with monotherapy (possibly because prescribing was based on the individual needs of the affected persons by the treating physicians and was not the same for all subjects in a group), but also no higher side effects than with monotherapy with atomoxetine (the figures, however, show reduced side effects with combination therapy).33 It should be noted that atomoxetine alone generally has significantly higher side effects than stimulants alone.

A review article of 16 studies showed that combination medication of atomoxetine and stimulants was mostly due to an unsatisfactory response to monomedication. Most of these were male children and adolescents with ADHD-C. Combination of atomoxetine with methylphenidate was most commonly reported. In some, but not all, affected individuals, the combination medication improved symptoms. No serious adverse events were reported.34
Another review reported that administration of atomoxetine alongside stimulants was problem-free, at least during a meictation change.35
Another study reported symptom improvement by additional administration of sustained-release MPH in ADHD-affected children who did not show sufficient symptom improvement on atomoxetine.36 That increased side effects occurred within the first 4 weeks of combination therapy (i.e., during the dosing phase of the additionally given MPH),37 is not particularly surprising. More relevant is the side effect profile after the dosing phase.
Another study also reported significant symptom improvements with combination therapy of atomoxetine and methylphenidate compared with monotherapy.30

Mason11 reports from his own medical practice that most of his adult ADHD patients take retarded stimulants that typically last for 8-10 hours, so most of them need additional unretarded medications to supplement to get through the day.
In contrast, those patients in his practice who take a combination of atomoxetine with stimulants use low to moderate doses of stimulants and report a duration of action greater than 12 hours.
Mason reports isolated cases:

  • In one case, the previous administration of 72 mg MPH per day (with an unsatisfactory symptom reduction of 25%) was changed to 27 mg MPH and 60 mg atomoxetine per day. This resulted in an 80% symptom reduction, which persisted for many years without adjustment effects.
  • In another single case, a reduction in amphetamine medication (Adderall) from 50 to 30 mg/day with concomitant administration of 40 mg atomoxetine/day resulted in an improvement in symptom reduction to 67%.
    Further improvement to now 74% symptom reduction resulted from switching from 50 mg Adderall to 50 mg Vyvanse (in EU: Elvanse), equivalent to 20 mg Adderall, while continuing 40 mg atomoxetine.

Mason himself points out that not every sufferer experienced (such) improvements by switching to combination therapy of atomoxetine and stimulants.

Finally, Mason points to the experience of other physicians who achieved comparable positive effects by supplementing stimulants with guanfacine, bupropion, or antidepressants.

One study reported reduced drug discontinuation with a combination of stimulants and atomoxetine compared with each taken alone.38 This is likely to indicate a reduced rate of side effects.

Barkley, in a presentation, reports benefits of combining stimulants and atomoxetine to counter stimulant-induced dampening of the limbic system and the accompanying diminished emotion perception.39

A German neurologist we know often works with a combination of stimulants and bupropion (mostly for ADHD-I, not ADHD-HI or ADHD-C, due to the activating effect of bupropion).

5.2. Atomoxetine and hopantenic acid

A Russian article describes benefits of augmenting administration of hopantenic acid (Phenibut, Pantogam) in children with ADHD.40 A single case report by the same lead author suggests similar results.41

Hopantenic acid decreased the D2 receptor in mice even slightly more than atomoxetine and additionally increased the GABAB receptor.42

Hopantenic acid (N-pantoyl-GABA) is more commonly used in Russia to treat ADHD. It is not approved in the USA and the EU.

The evidence on hopantenic acid is too imprecise to recommend treatment with it.

6. MAO inhibitors and stimulants

A study of comedicamentation of stimulants and MAO inhibitors in depression found no problems arising.43 One study reported successful comedication of selegiline and lisdexamfetamine (Vyvanse) in ADHD and comorbid depression44

7. MPH and tipepidine

Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) is a synthetic, non-opioid cough blocker (antitussive). Tipepidine increases dopamine levels in the nucleus accumbens via inhibition of GIRK channels, but without increasing motor activity or producing methamphetamine-like behavioral sensitization.
It has been used in Japan since 1959 and could be an interesting alternative to MPH and AMP due to its lack of stimulant properties.45

Tipepidine alone shows significant improvements in ADHD symptomatology.46
A placebo-based double-blind study found a beneficial effect of tipepidine given in addition to MPH.47

8. Desipramine and stimulants

One study found no adverse interactions of combination therapy with desipramine and stimulants.48

Desipramine is the active metabolite of imipramine. Desipramine drugs are now largely out of circulation. Mutual reinforcement is known to occur between imipramine and MPH as an interaction.

9. Combination medication with other substances

The active ingredients listed below are not prescription drugs. They can, like the additional administration of vitamins, minerals or polyunsaturated fatty acids, support the treatment of ADHD,

In the following, studies are presented that were explicitly prepared for combination therapy with stimulants. However, the administration of vitamins, minerals or polyunsaturated fatty acids in addition to stimulants is not subject to any particular concerns.

Vitamins, minerals, dietary supplements for ADHD

9.1. Resveratrol next to MPH

Resveratrol is an antioxidant.
A double-blind placebo-controlled study found positive effects with 500 mg resveratrol in addition to the MPH given anyway in children with ADHD in parent ratings but not in teacher ratings.49

9.2. L-Carnosine next to MPH

L-carnosine is a bioactive dipeptide consisting of the amino acids ß-alanine and histidine.
A double-blind placebo-controlled study found positive effects with 800 mg L-carnosine in addition to MPH given anyway in children with ADHD in parent ratings but not in teacher ratings.50

9.3. Zinc sulfate next to MPH

A double-blind placebo-controlled study in children with ADHD found positive effects of zinc sulfate medicated in addition to the MPH given anyway.51

9.4. L-Methylfolate next to MPH

A study of augmentation of optimally adjusted MPH with 15 mg L-methylfolate in 44 adults with ADHD showed no improvement but rather increased MPH requirements.52

9.5. Viloxazine next to MPH

Combination of viloxazine with methylphenidate is possible.53

9.5. Antipsychotics alongside stimulants

Contrary to basic research, studies showed that comedication of stimulants and antipsychotics may be more effective than stimulants alone in the treatment of ADHD. Nevertheless, this comedication is uncommon in clinical practice.54 However, the improvement with a combination of thioridazine and MPH over MPH alone lasted only a few weeks and then remained at the level of MPH alone. While MPH was often associated with appetite deficiency, thioridazine showed an increase in appetite as a side effect.55 Atypical antipsychotics were reported to show an even stronger effect toward weight gain and metabolic syndrome.56 An improvement in ADHD symptoms was already found with a low-dose neuroleptic augmentation of MPH.57
A registry study found that 3.9% of ADHD-affected children and adolescents who received stimulants were comedicated with atypical antipsychotics.58

Combination treatment with antipsychotics and psychostimulants is becoming increasingly common. The notion that stimulants significantly reduce the metabolic effects of antipsychotics has been refuted. However, a consistent improvement over stimulant monotherapy has not been demonstrated to date. Comedication may be particularly helpful for comorbid aggression when monotherapy with stimulants and combination of stimulants with behavioral interventions have been insufficient to treat aggression.59 One study reported that comedication of MPH and risperidone was particularly promising for comorbid conduct disorder (CD).60

While stimulants increase the dopamine level / the dopamine effect, i.e. have an agonistic effect, antipsychotics act as dopamine antagonists. This makes comedication seem contradictory and illogical at first. However, they act on different receptor subtypes and brain regions. The main effect of antipsychotics is blockade of mesolimbic D2 receptors, whereas stimulants increase synaptic DA in the mesocortical system. Presumably, the synergistic interaction between antipsychotics and stimulants is even more complicated, as both agents also exert effects outside the mentioned brain regions.56

10. Combination therapy with ADHD medications for comorbid disorders

10.1. Depression or anxiety and ADHD

In ADHD with mild comorbid depression, monotherapy with stimulants should be given first.
In about one-third of all treatment-resistant depression, previously undiagnosed ADHD is found.
Given the rapid effectiveness of stimulants, it should be observed whether the elimination of the ADHD problem eliminates the stressor driving the depression. This is quite often the case.

10.1.1. Fluoxetine and MPH for comorbid depression and ADHD

A study of ADHD patients with comorbid depression, who did not show sufficient improvement in ADHD symptoms with MPH alone, found significant improvements in ADHD symptoms with augmentative fluoxetine in almost all subjects. In 40% of the subjects, an additional administration of less than 20 mg of fluoxetine was sufficient. There were no increased side effects.61

Fluoxetine is said to be the only SSRI with a drive-enhancing effect. As monotherapy, it does not appear to be suitable for the treatment of ADHD. Fluoxetine in ADHD

Co-administration of MH and fluoxetine to juvenile rats produced increased sensitivity to reward stimuli (which should be positive in ADHD) and increased anxiety and stress sensitivity (which would be detrimental in ADHD) in adult animals.62 However, healthy animals and not ADHD model animals were tested.

10.1.2. Atomoxetine and antidepressants for comorbid anxiety or depression and ADHD

10.1.2.1. Atomoxetine and fluoxetine

A double-blind placebo-controlled study examined combination treatment with atomoxetine and fluoxetine (an SSRI) compared with monotherapy with atomoxetine in children and adolescents with ADHD and comorbid symptoms of depression or anxiety. The study found no relevant improvements in ADHD symptoms with combination treatment. Small improvements were found in the symptomatology of comorbid depression with combination therapy compared with monotherapy with atomoxetine, with the latter already improving symptoms of depression and anxiety in addition to ADHD symptoms. Combination treatment did not show increased side effects. Blood pressure with combination therapy was slightly more elevated than with monotherapy.63

10.1.2.2. Atomoxetine and SSRI / SNRI

One study examined combination treatment of atomoxetine with SNRI and SSRI in adults with ADHD and comorbid generalized anxiety disorder. In all subjects, SNRI or SRI alone failed to improve anxiety symptoms. Combination treatment of SNRI or SSRI with atomoxetine showed significant improvements in anxiety symptoms compared with prior monotherapy with SNRI/SSRI.64

10.1.3. Vortioxetine and methylphenidate for comorbid ODD, anxiety, and ADHD

A single case report noted a good long-term effect of a combination medication of vortioxetine (10 mg/day) and MPH on stimulant-induced anxiety and ADHD symptomatology in a 15-year-old ADHD sufferer who did not respond to atomoxetine, reacted to MPH with dysphoria, and did not tolerate augmenting clonidine. This was achieved with high tolerability.65

10.1.4. Duloxetine alleviates comorbid enuresis and stimulant-induced dysphoria in ADHD

A single case report noted relief of comorbid enuresis (wetting), stimulant-induced dysphoria, and improvement in cognitive abilities in an adolescent with ADHD.66

10.1.5. Selegiline and stimulants for comorbid depression

One study reported successful comedication of selegiline and lisdexamfetamine (Vyvanse) in ADHD and comorbid depression.44 Another study of comedicamentation of stimulants and MAO inhibitors in depression found no problems arising in the process43
Thus, combination medication of selegiline with stimulants may also be considered for ADHD.

10.2. Disruptive Mood Dysregulation Disorder (DMDD) and ADHD

DMDD is characterized by persistent severe irritability and high impulsivity. ADHD often occurs comorbidly.

10.2.1. Aripiprazole and methylphenidate in DMDD and ADHD

One study found a positive effect of combination therapy of aripiprazole and methylphenidate children with comorbid DMDD and ADHD. Increased side effects were not found.67

10.3. Behavioral disorders or tics and ADHD

Conduct disorder or tics are often treated with antipsychotics.

One study found among children and adolescents who began medication with methylphenidate from 2005 to 2013, 67,595 children received combination therapy of MPH and antipsychotics. Among them was a combination with

  • Risperidone (72%)
  • Pipamperone (15 %)
  • Tiapride (8%)

A quarter of users of combination therapy of MPH and antipsychotics were prescribed it only once.
Use of the combinations of MPH with risperidone and tiapride was frequently appropriate (>72%), whereas use of the MPH-pipamperone combination was rarely appropriate (<15%).68

For comorbid ODD and ADHD, combination treatment with risperidone and MPH proved helpful69, as well as for comorbid conduct disorder (CD).60

Barkley, in a presentation, reported benefits of combining stimulants and guanfacine (which was helpful in comorbid tics) to counter the stimulant-induced dampening of the limbic system and the accompanying decreased emotion perception.70

One study found good improvement in ADHD symptomatology with selegiline in children with ADHD and comorbid tic disorder over a test period of more than 6 months. Only 2 of the 29 subjects reported worsening of tics. Side effects were mild.71 Another study of 24 children with ADHD and comorbid Tourette’s disorder found only modest improvements in ADHD symptomatology with a concomitant high dropout rate among participants72

10.4. Obsessive Compulsive Disorder and ADHD

10.4.1. Sertraline and guanfacine and behavioral therapy

A report of 2 children with compulsivity and AD(H)D (ages 9 and 10) suggested a positive effect of a combination of behavior therapy, sertraline, and guanfacine.73

10.5. Sleep problems and ADHD

10.5.1. Melatonin and stimulants

A Swedish cohort study found that two-thirds of boys and half of girls who received melatonin also received ADHD medications.74


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