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Combination medication for ADHD

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Combination medication for ADHD

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In 30 to 50% of adults with ADHD, the use of stimulants alone is not sufficient1
Contrary to widespread assumptions, there are many ways to combine medications for ADHD (augmentation).2 The combination of several active ingredients of identical or different pharmacological classes (polypharmacy) is an increasingly common strategy in the treatment of ADHD3, which has been included in various treatment guidelines, particularly for comorbidities and cases that are resistant to monotherapies.4567
A medical registry analysis found that a combination of different ADHD medication drug classes was used in 10.3% (among health-insured people with ADHD) to 24.3% (among Medicaid-“insured” people with ADHD).8

The following drug classes were most frequently involved in combination medication:8

  • Immediate release stimulants: 70.0 %
  • Α2-adrenergic agonists (guanfacine, clonidine): 63.8 %
  • Stimulants with a half-day delay: 51.8 %

Another study found that around a quarter of children and adolescents with ADHD who received stimulants also received supplementary medication:9

  • Children: approx. 24 %
  • Young people: approx. 26.7 %

The most common additional medications given were

  • SSRI
    • Children: approx. 7.4 %
    • Young people: approx. 13.8 %
  • Atypical antipsychotics
    • Children approx. 4.8 %
    • Young people: approx. 5.8 %
  • Guanfacine
    • Children approx. 6 %
    • Young people: approx. 3 %

Barkley reports that the typical ADHD medications each address around 70% of the same brain regions, but also respond to around 30% of other brain regions. He therefore recommends a combination medication in order to achieve a broader effect with fewer side effects.10

For information on the choice of medication for comorbidities, see Choice of medication for ADHD or ADHD with comorbidity

All combinations or intake options described below are based on examinations or reports from people with ADHD, which were carried out in consultation with the attending physician. People with ADHD are expressly warned against unauthorized dosing or administration!

1. Methylphenidate preparations among themselves

It is possible to combine different methylphenidate preparations, especially sustained release and immediate release, without any problems11
Immediate release MPH is particularly important for balancing the duration of action and adapting to special stress situations. Immediate release MPH can extend 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.12
One study found that 40% of adults with ADHD receive such a combination to extend daytime coverage.13 Likewise, Mason reports from his own medical practice that most of his adult ADHD patients take sustained release stimulants, which typically last 8 to 10 hours, so most of them need additional immediate release medication to supplement to get through the day.14

Occasionally, (experienced) people with ADHD report that they cope better with 2 different half-day MPH extended-release preparations in the morning and early afternoon than with a repeated intake of the same extended-release preparation. These people with ADHD also often use immediate release MPH to extend their daytime coverage.
It must be mentioned that the fine-tuning of such combinations is usually largely carried out by the person with ADHD themselves and requires that the doctor caring for them recognizes the necessary sense of responsibility to accompany them in the adequate adjustment of medication. This is likely to be difficult with children, especially if taking medication evenly throughout the day causes difficulties.

2. Amphetamine drugs among each other

The combination of different amphetamine medications is usually not used to improve symptoms or reduce side effects, but to provide better daily coverage.

Some people with ADHD report good experiences with a combination of Attentin (immediate release D-amphetamine) and sustained release amphetamine (Vyvanse). While Vyvanse only releases the amphetamine bound to lysine very slowly via the intestine and blood, which can take up to 2 hours until the full effect sets in, Attentin is reported to have a noticeable onset of effect after around 15 minutes, which corresponds to immediate release MPH.

While Vyvanse works for 10 to 11 hours after ingestion in most persons with ADHD (a few people with ADHD report metabolization within 6 hours, individual cases even faster), Attentin has an effect time of around 5 hours.

Some people with ADHD have good experiences with taking a small dose of Attentin in the morning and taking Vyvanse at the same time or a few hours later. Others report that taking Attentin in the afternoon or early evening helps them to get through a long day. As a rule, the Vyvanse dose is reduced slightly after a previous Attentin dose.
In addition, many people with ADHD report that they cope best with two smaller doses of Vyvanse taken at different times.

While a number of people with ADHD report improved evening sleepiness and thus improved sleep behavior, if the sleepiness worsens and does not subside even after a few weeks, a change in the intake times should be considered in order to achieve an earlier end of the effective period.

3. Amphetamine medication and methylphenidate

Many people with ADHD report taking amphetamine medication and (especially immediate release) MPH on the same day in consultation with their doctor. No negative experiences are known.
Here, too, the greatest significance of (immediate release) MPH lies in the time-delayed supplementation of the duration of action of the sustained release amphetamine drug (Vyvanse) early in the morning or in the evening.

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

There are also a number of medications that can support the effect of other medications for ADHD.

4. Guanfacine/clonidine in addition to stimulants

Guanfacine, which like clonidine is an α₂-adrenoceptor agonist, appears to be approved in some countries for combination medication with stimulants in ADHD,1516 and in children with ADHD who respond poorly to stimulants alone, together with stimulants improve symptoms significantly more than stimulants alone.

METASTUDIES

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 symptoms17

  • 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).

A meta-analysis of k = 16 studies consistently found a greater improvement in ADHD symptoms with a combination of alpha-2 agonists with stimulants compared to monotherapy with alpha-2 agonists, but no greater improvement than with monotherapy with stimulants18

Studies

A larger randomized double-blind placebo-controlled study over 9 weeks in children with inadequate ADHD symptom improvement with stimulants showed significant improvements with additional guanfacine given without additional side effects. Apparently, several publications cover the same study.192021
Several other studies also came to positive results of augmentative administration of guanfacine in persons with ADHD who were not optimally controlled with stimulants alone, in relation to children22 as well as in relation to children and adolescents.2324
Another double-blind placebo-controlled study on 50 children aged 6 to 12 years with ADHD found an improvement in executive functions with individually optimized guanfacine administration in addition to the previous stimulants, without any additional side effects.25 A study on the effects of combined administration of guanfacine and MPH on the EEG in children with ADHD confirms the results.26
A randomized double-blind comparative study 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 responding rate than monotherapy. The combination therapy showed no serious cardiovascular events. Sedation, somnolence, lethargy and fatigue were greater with guanfacine monotherapy than with combination therapy. All treatments were well tolerated27

  • Guanfacine alone (symptom reduction 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)

Combined treatment with MPH and guanfacine showed greater improvements in working memory than placebo or guanfacine alone, but was not superior to monotherapy with MPH, even in other cognitive domains28
A combination therapy of MPH and guanfacine showed lower cardiovascular effects than a monotherapy of MPH or guanfacine.29

A randomized double-blind placebo-controlled study of adults with ADHD who had unsatisfactory improvements in their ADHD symptoms with stimulants and who were additionally augmented individually with 1 to 6 mg guanfacine showed a significant improvement in the guanfacine group and, surprisingly, also in the placebo group. There were no increased side effects.30 Two studies in healthy adults also found no complications with the combination medication of guanfacine with lisdexamfetamine (Vyvanse) and MPH.3132 In one individual case, it was reported that augmenting clonidine was able to eliminate nocturnal teeth grinding induced by MPH.33
It would be interesting to see 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 sufficient evidence for this.

One study came to a positive result of augmenting administration of clonidine to stimulants in ADHD.34 Nevertheless, guanfacine should 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-induced medications, a study8 found the use of such a combination medication in

  • 22.2 % of people with ADHD with health insurance between the ages of 6 and 17
  • 9.8 % of people with ADHD aged 18 and over who have health insurance
  • 36.1% of people with ADHD on Medicaid

Reviews and more recent studies report that the combined administration of atomoxetine and stimulants is safe and effective,3536 even during a medication change phase.37 One study reported on 824 persons with ADHD who received a combination therapy of atomoxetine and methylphenidate.38 A meta-analysis found mixed results18

Ryffel-Rawak quotes a personal communication from J. Krause, according to which atomoxetine is particularly effective in combination with stimulants.39 Brown reports 4 cases in which only a combination therapy of atomoxetine with stimulants brought about an adequate improvement in ADHD symptoms.40 Mason14 reports that in 2003, when atomoxetine came on the market, he switched 35 children with ADHD from stimulants to atomoxetine. In order 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 took place in a second step. Surprisingly, about half of the persons with ADHD asked to continue the combination of reduced stimulants and half the atomoxetine dose. This combination therapy proved to be very successful. Most of the people with ADHD significantly reduced their previous stimulant dose. Side effects were lower than in the patients who received stimulants alone. In particular, the people with ADHD reported that family life had improved because the breakdowns, which many families already considered normal outside the stimulant period, had decreased. This seems to us to be a plausible consequence of the fact that atomoxetine, as a level medication, remains effective for most of the day, whereas stimulants only have a limited time during the day.
Mason14 reports on a study conducted by Wilens at Harvard in 2006, in which atomoxetine and sustained release MPH (Concerta) were combined in high doses to test the maximum possible symptom reduction. The patients who completed the study showed symptom reductions of more than 90 %. Their ADHD symptoms had disappeared and their 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 was aimed solely at maximizing symptom improvement.

A review of 16 studies showed that a combination medication of atomoxetine and stimulants was usually given due to an unsatisfactory response to monomedication. In most cases, these were male children and adolescents with ADHD-C. A combination of atomoxetine with methylphenidate was reported most frequently. In some, but not all, persons with ADHD, the combination medication improved symptoms. No serious adverse events were reported.41
Another study reports an improvement in symptoms through the additional administration of sustained release MPH in children with ADHD who did not show sufficient symptom improvement on atomoxetine.42 The fact that increased side effects occurred within the first 4 weeks of combination therapy (i.e. in the dosing phase of the additionally administered MPH),43 is not particularly surprising. More relevant is the side effect profile after the single-dose phase.
Another study also reported significant symptom improvements with a combination therapy of atomoxetine and methylphenidate compared to monotherapy.38

Mason14 reports from his own medical practice that most of his adult ADHD patients take sustained release stimulants that typically last 8 to 10 hours, so most of them need additional immediate release 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 effect of more than 12 hours.
Mason reports on individual 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% reduction in symptoms, which persisted for many years without adaptation effects.
  • In another individual case, a reduction in amphetamine medication (Adderall) from 50 to 30 mg / day with simultaneous administration of 40 mg atomoxetine / day led to an improvement in symptom reduction to 67 %.
    A further improvement to 74% symptom reduction was achieved by switching from 50 mg Adderall to 50 mg Vyvanse (in the EU: Vyvanse), which corresponds to 20 mg Adderall, while continuing the 40 mg atomoxetine.

Mason himself points out that not every person with ADHD experienced (such) improvements by switching to a combination therapy of atomoxetine and stimulants. Mason also refers to the experiences of other doctors who achieved comparable positive effects by supplementing stimulants with guanfacine, bupropion or antidepressants.14 A neurologist known to us often worked with a combination of stimulants and bupropion (due to the activating effect of bupropion mostly in ADHD-I, not in ADHD-HI or ADHD-C).

One study reports reduced discontinuation of medication when taking a combination of stimulants and atomoxetine compared to taking each alone.44 This may indicate a reduced rate of side effects.

Barkley reports in a lecture on the advantages of a combination of stimulants and atomoxetine to counteract the dampening of the limbic system caused by stimulants and the associated reduced perception of emotions.45

A study (albeit funded by the atomoxetine manufacturer Lilly) found no advantage in symptom improvement with a combination therapy of atomoxetine with other ADHD drugs compared to monotherapy (possibly because the prescription was based on the individual needs of the person with ADHD 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 show reduced side effects with combination therapy, however).46 It should be noted that atomoxetine alone generally has significantly higher side effects than stimulants alone.

Methylphenidate and atomoxetine increase the efficiency of the prefrontal pyramidal neurons, albeit via different mechanisms:47

  • Methylphenidate reduced non-specific signals, i.e. neuronal noise, via D1 receptors
  • Atomoxetine increased the strength of specific signals via the activation of alpha-2 receptors.
    This explains why a combination of these active ingredients can be useful for patients with ADHD who do not respond optimally to monotherapy.

According to our observations, a combination of atomoxetine and stimulants is a suitable method for the treatment of ADHD. It combines the advantages of atomoxetine (all-day effect, especially on the symptoms of emotional dysregulation) and stimulants (increased drive during the day). When combining ATX and amphetamine medications, it should be noted that both are metabolized via CYP2D6, which requires correspondingly lower doses. However, as the combination is aimed at the same symptoms, barely any problems are to be expected here due to the mutual influence on metabolization

5.2. Atomoxetine and hopantenic acid

A Russian article describes benefits of augmentative administration of hopantenic acid (Phenibut, Pantogam) in children with ADHD.48 A single case report by the same lead author suggests similar results.49

Hopanteninic acid reduced the D2 receptor in mice slightly more than atomoxetine and also increased the GABAB receptor.50

Hopanteninic acid (N-pantoyl-GABA) is more commonly used in Russia for the treatment of ADHD. It is not approved in the USA and the EU.

The findings on hopantenic acid are too imprecise to recommend treatment with it.

6. Viloxazine next to MPH

A combination of viloxazine with methylphenidate is possible.51

7. Bupropion and stimulants

One neurologist we know often worked with a combination of stimulants and bupropion (due to the activating effect of bupropion mostly in ADHD-I, not in ADHD-HI or ADHD-C).
When combining bupropion with amphetamine medications, it should be noted that both are metabolized via CYP2D6, which requires correspondingly lower doses. However, as the combination is aimed at the same symptoms, barely any problems are to be expected here due to the mutual influence on metabolization.
Several people with ADHD reported a positive effect of co-medication with bupropion in order to slow down a previously too rapid metabolism of amphetamine drugs to a suitable level.

8. MAO inhibitors and stimulants

A review on the co-medication of stimulants and MAO inhibitors in depression found no problems arising from this.52 One study reports successful co-medication of selegiline and lisdexamfetamine (Vyvanse) for ADHD and comorbid depression53

With MAO inhibitors, possible metebolization cross-effects must always be taken into account.

9. 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 by inhibiting GIRK channels, but without increasing motor activity or producing methamphetamine-like behavioural 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.54

Tipepidine alone shows significant improvements in ADHD symptoms.55
A placebo-based double-blind study found a positive effect of tipepidine given in addition to MPH.56

10. Desipramine and stimulants

One study found no negative interactions of combination therapy with desipramine and stimulants.57

Desipramine is the active metabolite of imipramine. Desipramine medications are largely no longer available. Imipramine and MPH are known to interact with each other.

11. Antipsychotics alongside stimulants

A meta-analysis found evidence for a benefit of augmentative administration of risperidone or divalproex in comorbid aggression18

Contrary to basic research, studies have shown that co-medication with stimulants and antipsychotics can be more effective in the treatment of ADHD than taking stimulants alone. Nevertheless, this co-medication is uncommon in clinical practice.58 However, the improvement with a combination of thioridazine and MPH compared to MPH alone only lasted a few weeks and then remained at the level of MPH alone. While MPH was often associated with a lack of appetite, thioridazine showed an increase in appetite as a side effect.59 Atypical antipsychotics are said to have an even stronger effect in terms of weight gain and metabolic syndrome.60 An improvement in ADHD symptoms was already found with low-dose neuroleptic augmentation of MPH.61
According to a registry study, 3.9% of children and adolescents with ADHD who received stimulants are augmented with atypical antipsychotics.62

The idea that stimulants significantly reduce the metabolic effect of antipsychotics has been refuted. However, there is no evidence to date of a consistent improvement through combination treatment with antipsychotics and stimulants compared to stimulant monotherapy. Comedication can be particularly helpful in cases of comorbid aggression when monotherapy with stimulants and a combination of stimulants with behavioral interventions have not been sufficient to treat aggression.63 One study reports that comedication of MPH and risperidone is particularly promising for comorbid conduct disorder (CD).64

While stimulants increase the dopamine level / the dopamine effect, i.e. have an agonistic effect, antipsychotics act as dopamine antagonists. This initially makes comedication seem contradictory and illogical. However, they act on different receptor subtypes and brain regions. The main effect of antipsychotics is a blockade of the mesolimbic D2 receptors, while stimulants increase synaptic DA in the mesocortical system. Presumably, the synergistic interaction between antipsychotics and stimulants is even more complicated, as both drugs also exert effects outside the brain regions mentioned.60

12. Combination medication with other substances

The active ingredients listed below are not prescription drugs. Like the additional administration of vitamins, minerals or polyunsaturated fatty acids, they can 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, but should only be carried out after prior testing of blood values, as an overdose of vitamins or minerals can have considerable harmful effects.

⇒ Vitamins, minerals, dietary supplements for ADHD

12.1. Resveratrol next to MPH

Resveratrol is an antioxidant.
A double-blind placebo-controlled study found positive effects of 500 mg resveratrol in addition to the MPH already given to children with ADHD in the parent evaluation, but not in the teacher evaluation.65

12.2. 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 of 800 mg L-carnosine in addition to the MPH already given to children with ADHD in the parent evaluation, but not in the teacher evaluation.66

12.3. Zinc sulphate next to MPH

A double-blind placebo-controlled study on children with ADHD found positive effects of zinc sulphate, which was administered in addition to the MPH already given.67

12.4. 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 the MPH requirement.68

13. Combination therapy with ADHD medication for comorbid disorders

To avoid duplicate presentation, see Choice of medication for ADHD or ADHD with comorbidity

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