3. Pills and ADHD

Why, For Whom and How?

Annick Vincent and Michel Sirois | 2014-10-10

You have assessed both Nathan and his father and see them again at a follow-up visit. Since ADHD is affecting their daily functioning, you are considering drug treatment for them. What are the available options? Where to begin? Is the treatment different for children and adults? How can you sort out everything the parents have heard and read in the media?

Why Treat ADHD?

You remind the family that ADHD is a neurobiological disorder that causes chronic self-regulation problems. Prescribing medication is part of a multimodal approach (see Table 1) primarily composed of promoting a healthy lifestyle to maintain good brain function.^1,2 Understanding ADHD helps people use coping strategies to reduce their functional impairments (see the articles “ADHD: Tips and Tricks for Young People” and “ADHD: Tips and Tricks for Adults” in this special edition). When residual symptoms continue to have a negative effect, specific drug therapy must be considered.

Dr. Annick Vincent, psychiatrist, practices at Clinique Focus, affiliated with the Centre médical l’Hêtrière, in Saint-Augustin-de-Desmaures. Dr. Michel Sirois, family physician. practises in the family medicine group GMF-Centre medical l’Hêtrière, and at Clinique Focus.

Expectations must be clearly defined because there is no miracle pill! (“Pills don’t build skills!” recalled Dr. Margaret Weiss at the international French-language conference on ADHD held in Quebec City in 2012.) Just as reading glasses are designed to help people to focus and pick out words, not to teach them to read, a well-adjusted drug does not cure ADHD but relieves symptoms, improves functioning and enables patients to tap into their full potential.³

Who to Treat?

During your last appointment with Nathan and his father, you noticed symptoms, functional impacts and compensatory strategies (see the article “In-Office Assessment of ADHD: Step-by-Step Approach” in this special edition). You opted for drug treatment, knowing that the clinical response will not confirm a diagnosis of ADHD.

There is no maximum age to initiate treatment as long as the patient’s physical condition allows it. The recommended minimum age is 6 years. Given the few existing studies on risks in utero and in infants, it is best for women to cease this medication during pregnancy and breastfeeding.⁴

Before starting, physicians should ensure that patients have no pre-existing problems that could decompensate during treatment. Specialist advice may be indicated in some complex cases (see the chapters in the Canadian ADHD Practice Guidelines on co-morbid disorders, pharmacological treatment and cardiovascular risks).²

Pharmacotherapy for ADHD is part of a multimodal and individualized approach. It is recommended to start with an extended-release psychostimulant.

You explain the available options and mention that the drugs approved for the treatment of ADHD have shown significant clinical efficacy compared with placebo. Their safety profile is also good. You add that each patient’s clinical response is different and that it is not possible to predict which drug will be more effective in relation to the type or severity of the symptoms.

How to Treat?

You inform the family that ADHD medications include methylphenidate-based and amphetamine-based psychostimulants and non-stimulants. These products all promote the neurotransmission of dopamine and-or norepinephrine. They each have different mechanisms of action and release. Methylphenidate and amphetamines mainly act as dopamine reuptake inhibitors, while atomoxetine acts as a norepinephrine reuptake inhibitor. Guanfacine binds to post-synaptic alpha-2a adrenergic receptors. You use Table 2 to illustrate your explanations and to check the dose-adjustment strategies.^2,5

Psychostimulants

h Psychostimulants are approved for the treatment of ADHD in children and adults. In therapeutic doses, their clinical effect is noticeable within hours of administration. There is no dose-response relationship based on body weight.

h It is necessary to start with low doses and to gradually adjust them each week based on clinical response, regardless of patient age. Modes of release and dosages vary from one product to the other (Table 2).^2,5 In the United States, other preparations are offered, including patches and liquid preparations.

Non-Stimulants

h Atomoxetine is approved for the treatment of ADHD in children and adults, while extended-release guanfacine has recently been approved as single-agent therapy and as an adjunct to psychostimulants in the case of a suboptimal response in children aged 6 to 12 years.

h Non-stimulants have a gradual clinical action. At an effective dose, a therapeutic response may be observed within two weeks. A complete response may take several weeks. There may be a dose-response relationship based on body weight.

h It is best to start with low doses and then to gradually increase them at 7- to 14-day intervals based on clinical response, regardless of age. Non-stimulants must be taken regularly and on a daily basis. This class of agents is of particular benefit in situations where a sustained clinical effect is sought or where there is little potential for abuse.

Atomoxetine

h Atomoxetine is available as a brand name (Strattera) and as a generic drug.

h The capsule is best taken after meals to minimize adverse digestive effects.

Extended-release guanfacine (Intuniv XR)

h Extended-release guanfacine has recently been approved by Health Canada. Treatment with this agent requires closer, more specialized medical follow-up, given its particular side-effect profile and potential drug interactions.

h The tablet must be swallowed whole. When split or chewed, the tablet loses its extended-release action.

h Clinical experience has seen a reduction in tics and impulsivity, although this indication is not listed in the product monograph.

h Guanfacine may slow heart rate and lower blood pressure, while a sudden cessation of this drug may increase them. A gradual adjustment reduces the tiredness reported at the start of treatment. These parameters must be carefully monitored.

What About Generic Drugs?

Bio-equivalent does not mean clinically equivalent, especially when the release mechanism differs. For a generic drug to be declared bio-equivalent, the total quantity and maximum drug concentration (Cmax) of the active chemical must fall within a confidence interval of 80% to 125% in relation to the original product. The time to reach maximum drug concentration (Tmax) may differ and may increase the side effects, in addition to hindering the start and duration of action.

N.B.: Given that generic drugs have not been tested on clinical populations, their monographs contain information about the original product and the results of pharmacokinetic studies with small groups of healthy volunteers.

Other Agents

Research has shown that other agents such as bupropion and modafinil may be relatively effective in reducing ADHD symptoms. They are sometimes used as off-label drugs after the failure of conventional treatments.

Each patient’s clinical response is different. It is not possible to predict which medication will be most effective by symptom type or severity.

Over-the-Counter Drugs

Supplements formulated from a blend of omega-3 and omega-6 (Equazen Eye Q)

h Equazen Eye Q, a product containing a blend of omega-3 and omega-6 essential fatty acids, has been approved by Health Canada for children older than three years and for adolescents who have ADHD.

h It comes in the form of single-dose or multiple-dose chewable capsules (may be swallowed whole). The initial dosage is six capsules per day for three months, followed by a maintenance dose of two capsules per day.

h Note that clinical research measuring the effects of these products is in its infancy. A few recent studies in children show a clinical effect that is superior to that of placebo.^6-8 For the time being, these supplements are an option to be viewed as a complement to ADHD treatments, not as an equivalent solution.

Synthetic melatonin (may help in restoring circadian rhythm)

* The dose is from 3 mg to 6 mg, taken one or two hours before bedtime. Melatonin is available in the form of tablets and sublingual melts and as a liquid. In cases when melatonin supplementation has a direct hypnotic effect, sleep facilitation can be observed if taken 30 minutes before bedtime.

h It is recommended to avoid using it on a long-term basis and during pregnancy because no studies exist on this topic.

h N.B.: Melatonin loses its effect if exposed to light. That is why melatonin tablets are kept in opaque containers.

How to Choose?

Canadian experts report that all ADHD drugs vary by type of active ingredient and release mode. Clinical symptoms (inattention or hyperactivity-impulsivity) do not allow us to predict which type of treatment will be the most effective. In addition, some people respond better to one product than to another, even within the same category of stimulants (preferential response). It is important to know that there is no relationship between dose, body weight and symptom severity when adjusting the dose of a psychostimulant.

In choosing among the available pharmacological options, clinicians must take into account several factors and points (Table 3).² Table 4² reviews the general principles to reduce adverse effects, while Table 5^2,9 summarizes the points to consider in the presence of co-occurring disorders.

Nathan’s parents thank you for your explanations. You give them an infosheet on ADHD drug treatment (Toolbox Icon I) and on the management of side effects (Toolbox Icon 2), along with the CADDRA Patient ADHD Medication Form in the CADDRA Toolkit. You then schedule another appointment. You plan to provide more intensive follow-up during the drug adjustment period (from one to three months), then every six to twelve months when the patient’s condition has stabilized, taking into account developmental stages (more intensive for children and during transition periods). For school-aged children, it is best to meet with them after the first school semester (November) and before the last semester (April).

To measure both the positive and negative effects of the treatment, you suggest that they complete some clinical checklists and a drug therapy follow-up questionnaire (see the tools suggested in the article “In-Office Assessment of ADHD: Step-by-Step Approach” in this special edition).

Treatment for ADHD may include medication in the form of methylphenidate-based or amphetamine-based psychostimulants and non-stimulants.

Unsatisfactory Treatment Response?

In the event of an unsatisfactory response to treatment, you must review the diagnosis, ensure treatment compliance, make sure that no new factors have emerged to complicate the clinical presentation, and then consider switching to another drug.

Possible Solutions

h When patients describe peak-and-trough clinical effects or a rebound effect after the final dose of the day, you can change the mode of release to provide a longer therapeutic effect or you can add a dose of the immediate-release form of the same psychostimulant for the period where the rebound is observed.

hIf there is only a partial clinical effect after the dose has been optimized, switch to another release mode or active ingredient. Combining a psychostimulant and a non- stimulant is sometimes an option. Only the combination of a psychostimulant with extended-release guanfacine has been approved by Health Canada for treating ADHD in children aged 6-12 years who have a sub-optimal response to a psychostimulant.

h In the event of adverse effects limiting dose optimization, switch to another release mode or active ingredient.

h When considering a switch to another psychostimulant, plan to do so during an appropriate transition period, such as school holidays or weekends. Some basic principles must be followed when you switch to another active ingredient:

h When patients switch from a methylphenidate-based psychostimulant to a drug with a different release mode, they must stop the first and must start taking an equivalent dose of the second, calculated according to the release mode (N.B.: % immediate/delayed release: Biphentin = 40/60 and Concerta = 22/78).

h There is no direct equivalence in the case of switching from an amphetamine-based psychostimulant to a drug with a different release mode or to a new class (e.g. methylphenidate → amphetamine). The first must be stopped and the initial dose of the second must be started.

You follow up Nathan’s family on a regular basis. The son and father are doing better after a few pharmacological adjustments and the gradual introduction of winning strategies (see the articles “ADHD: Tips and Tricks for Young People” and “ADHD: Tips and Tricks for Adults” in this special edition). The family thanks you for all the help you have given them. It warms your heart to see the progress both have made. //

French Version: Received: January 27, 2013 Accepted: April 11, 2013
Translated in English: September, 2014

Dr. Annick Vincent is a speaker and advisory committee member for Biovail, Lundbeck, Bristol Myers Squibb, Lilly, Purdue, Janssen and Shire. She received grants from Purdue, Shire and Janssen from 2011 to 2013. Dr. Michel Sirois was a speaker for Janssen Pharmaceuticals in 2012–2013 and an advisory committee member for Shire and Janssen Pharmaceuticals in 2012.

references

1. Collège des médecins du Québec. Le trouble déficit de l’attention avec ou sans hyperactivité. Traitement pharmacologique (mise à jour); June 2006.
2. CADDRA. Lignes directrices canadiennes sur le TDAH. 3^rd ed. Toronto: CADDRA; 2011. Website: www.caddra.ca/cms4/pdfs/fr_caddraGuidelines2011.pdf (Accessed: February 15, 2013).
3. Molina BSG, Hinshaw SP, Swanson JM et al. The MTA at 8 years: prospective follow-up of children treated for combined type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009; 48: 484-500.
4. Malo J, St-André M. TDAH, grossesse et allaitement : comment conseiller nos patientes ? Québec Pharmacie 2011; 58(2): 11-6.
5. Université Laval, CADDRA. Traitements pharmacologiques du TDAH. Septembre 2013. Website: www.attentiondeficit-info.com/pdf/quick-guide-adhd-medication-quebec.pdf (Accessed: February 28, 2013).
6. Sinn N, Bryan J. Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J Dev Behav Pediatr 2007; 28(2): 82-91.
7. Richardson AJ, Montgomery P. The Oxford-Durham Study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics 2005; 115(5): 1360-6.
8. Johnson M, Ostlund S, Fransson G et al. Omega-3/omega-6 fatty acids for attention deficit hyperactivity disorder: a randomized placebo-controlled trial in children and adolescents J Atten Disord 2009; 12(5): 394-401.
9. Biederman J. Pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) decreases the risk for substance abuse: findings from a longitudinal follow-up of youths with and without ADHD. J Clin Psychiatry 2003; 64 (suppl. 11): 3-8.