Stimulant and non-stimulant agents for ADHD

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is diagnosed through analysis of behaviour. It is one of the most common mental health conditions and affects both adults and children^​1​. People with ADHD show a persistent pattern of inattention and/or hyperactivity–impulsivity that interferes with day-to-day functioning and development^​2​.

ADHD is often more obvious in children because adults may have found ways to manage their outward symptoms. There are three core symptoms that define ADHD, although not everyone diagnosed will have all three symptoms^​3​: 

• Inattention — finding it hard to concentrate;
• Hyperactivity — feeling restless and struggling to sit still;
• Impulsivity — saying or doing things without thinking about the consequences first.

There are also differences in presentation between women and men with ADHD (see Figure 1^​4​). Males with ADHD are more likely to have symptoms that are presented externally, such as disruptive hyperactivity (see Figure 2^​5​), and symptoms are often noticeable from a younger age. In females, ADHD can present as anxiety, low mood and a greater likelihood of presenting with inattentive symptoms, such as forgetfulness. More males than females are diagnosed with ADHD; however, this discrepancy may be attributed to the varying manifestations seen, gender bias and misdiagnosis for conditions such as anxiety in girls and women^​3​.

Reproduced with permission from Neurodivergence Insights

ADHD should only be diagnosed by a specialist, such as a psychiatrist, paediatrician or other qualified healthcare professional with expertise in ADHD. The diagnosis is based on a thorough assessment, including the person’s medical and psychiatric history, as well as reports from others about their behaviour. For a diagnosis, symptoms of hyperactivity, impulsivity and/or inattention must^​6​:

• Meet the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) or the International Classification of Diseases, 11th revision (ICD-11)^​7,8​;
• Cause significant issues in daily life;
• Be consistent across different settings. 

For further information regarding ADHD diagnosis, see ‘Attention deficit hyperactivity disorder: characteristics and diagnosis‘^​9​. 

The mainstay treatment for ADHD is pharmacological management, using either stimulant or non-stimulant medications^​6​. The aims of pharmacological treatment of ADHD are to reduce functional impairment, severity of symptoms and improve quality of life^​6​. This is done by modulating important neurotransmitters, such as dopamine and noradrenaline, in the prefrontal cortex, which is the area of the brain that regulates attention, behaviour and emotion^​10​.

Since October 2023, there have been national shortages of all ADHD medications, which has profoundly affected the neurodiverse population in the UK^​11​. Pharmacists play a crucial role in managing these shortages and ensuring treatment is accessible to the most vulnerable patients. 

Pharmacological management 

The first-line pharmacological treatment for ADHD in children aged over five years, adolescents and adults is stimulant medications^​6​. Treatment options and recommendations are outlined in ‘Attention deficit hyperactivity disorder: management and support‘^​12​. 

Table 1 outlines the treatment options for all age groups^​6​. 

Breaking down the differences between stimulants, non-stimulants and their various formulations will help pharmacists understand why one class may be a better fit for certain individuals.

Stimulant and non-stimulant medications

Stimulant medications work by increasing the levels of certain neurotransmitters in the brain: dopamine and norepinephrine^​10​. Stimulants block both noradrenaline and dopamine transporters, therefore increasing their availability in the presynaptic space and their activity in the prefrontal cortex (see Figure 3)^​10​. The prefrontal cortex is the part of the brain that regulates attention, behaviour and emotion. This increased neurotransmitter activity helps improve focus, reduce impulsivity and control hyperactivity. Stimulant medications are either methylphenidate-based or amphetamine-based (lisdexamfetamine and dexamphetamine in the UK)^​6​. 

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Non-stimulant medications for the treatment of ADHD are atomoxetine and guanfacine (unlicensed in adults)^​10​. Atomoxetine is a selective noradrenaline reuptake inhibitor, which acts by increasing the amount of noradrenaline in the synapse, leading to improved function in the prefrontal cortex (see Figure 4)^​13​.

Guanfacine is an alpha₂-adrenoceptor agonist. It is the only ADHD treatment that works post-synoptically, though the mode of action has not been fully established^​14​. Stimulation of alpha_2a receptors inhibits cyclic adenosine monophosphate (cAMP) production, which in turn closes the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, improving the efficiency of synaptic transmission (see Figure 5)^​14​.

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Differences between stimulant and non-stimulant medications

There are fundamental differences between stimulant and non-stimulant medications that determine the way in which these drugs are prescribed and used. Stimulants start working quickly, with patients feeling the effect of the drug within 30–90 minutes. These drugs and their effects also leave the body much quicker, with the maximum duration of action being around 13 hours^​15,16​. Non-stimulants can take two to four weeks to start working and should be taken daily to ensure steady state is maintained^​17​. 

Stimulant medications have a wide variety of release profiles; therefore, they allow pharmacists to cater to the individual needs of the patient. There is no one-size-fits-all approach to ADHD treatment^​18​.

Treatment selection should be based on the patient’s individual circumstances and preferences. For instance, if a patient struggles with treatment adherence, then a non-stimulant may not be the best option because regular medication use over weeks is required to reach a steady state; however, for a patient who experiences a change in appetite and weight loss with stimulants, a non-stimulant may be a better option.

Table 2 presents a summary of ADHD medication types^​18​.

Medication education for patients 

ADHD medications can be life-changing for many patients, and it is crucial that they are provided with all the information and support they need to use these treatments effectively and achieve the best possible outcomes. This section will be split up into the following subsections: ‘Supply‘, ‘Administration‘ and ‘Outcomes‘.

Supply

ADHD medications should be initiated by a specialist. This could be a consultant or other qualified healthcare professional, such as a nurse or pharmacist prescriber with a scope of practice in ADHD. Medications are carefully titrated to the optimum dose and monitored for adverse effects. For the monitoring requirements for ADHD medications, see Table 3 of ‘Attention deficit hyperactivity disorder: management and support‘^​12​. 

Stimulant medications (lisdexamfetamine and methylphenidate) are Schedule 2 controlled drugs and should therefore be prescribed in line with the Misuse of Drug Regulations^​19​. Electronic or handwritten prescriptions should follow the legal requirements. They must:

• Be indelible;
• Be signed by the prescriber;
• Include the date on which they were signed;
• Specify the prescriber’s address (must be within the UK). 

A computer-generated prescription is acceptable, but it must include a handwritten signature from the prescriber. For Schedule 2 and 3 controlled drugs, advanced electronic signatures are also permitted when using the electronic prescribing service.

Non-stimulant medications are not subject to controlled drug requirements; however, they should also be also initiated and titrated by the qualified specialists. Prescriptions are valid for six months from the date of prescription. 

Once the patient is titrated onto a stable dose of ADHD treatment and is finding benefit from the medication, the supply may be continued via ‘shared care’ arrangements. Shared care arrangements vary across the country, and local guidelines should be referred to. 

Prescribers should ensure that a thorough risk assessment is conducted before prescribing to ensure that the prescribed quantities are safe and appropriate for the patient. The recommended limit on Schedule 2 controlled drug prescriptions is 30 days, and the clinical rationale should be explained if more is supplied under certain circumstances, such as long travels. Prescribers should also consider explaining the safe storage requirements for these medications, as other children and family members may have access to them at the patient’s home. 

Administration 

ADHD medication is typically administered in the morning, before or after breakfast. This is to allow for control of ADHD symptoms during the day, while ensuring the effects of the medication wear off by the evening, so sleep is not affected. If a patient requires alternate timings, such as attending work later in the day, the timings may be adjusted. Non-stimulant medications take longer to work and, therefore, the timing of when they are taken should be maintained.

The variety of formulations available allow for flexibility with administration requirements to suit the patient. If a patient requires ADHD symptom control periodically, for a few hours in the day, immediate-release stimulant preparations can be used to provide instant effect with a short duration of action.

Methylphenidate modified-release capsules can be opened and mixed with a small amount of soft food to ease administration. They should not be chewed or crushed. Lisdexamphetamine capsules can be opened and the contents mixed with water for administration. 

The formulations available for non-stimulant medications are more limited. Atomoxetine is currently available as a capsule. It was previously available as Strattera 4mg/1 mL oral solution (atomoxetine hydrochloride; Eli Lilly), but it has recently been discontinued by the manufacturer and stocks are expected to be exhausted by September 2025^​20​. Guanfacine is a prolonged-release tablet that is unavailable in another form. If a non-stimulant is to be trialled in a patient with swallowing difficulties, they should be encouraged to use techniques that may aid the administration. The Medicines for Children website lists and explains several methods of helping children to swallow medications, such as the bottle method or the ‘big gulp’ method.

Outcomes

ADHD medication outcomes are carefully monitored by the prescriber, patient, carers and, sometimes, teachers (where applicable). Useful tools include the Swanson, Nolan and Pelham (SNAP) assessments for children and young people and the Adult ADHD Self-Report Scale (ASRS) for adults. These checklists help to monitor response and therefore help ensure the patient is getting the maximum benefit from medication at the lowest possible dose to mitigate side effects.

All outcomes and adverse effects are monitored. Individual NHS trusts may have their own variation of monitoring checklists to be complete during reviews with the prescriber. 

Switching or stopping ADHD treatment

Drug holidays and stopping

Under certain circumstances, patients may wish to take a ‘drug holiday’. This refers to temporarily stopping ADHD medication, typically during weekends, holidays or school breaks. This is particularly useful for patients who suffer from side effects, such as loss of appetite or sleep disturbances. This can only be done with stimulant medication because of its fast clearance from the body. The patient is unlikely to experience any withdrawal symptoms and can safely skip a day of medication. If stimulant medication needs to be stopped entirely, it can be tapered off slowly over time (depending on the dose) or it can be stopped abruptly^{​6,15,16​}. 

Non-stimulant medications are not suitable for drug holidays, as their effectiveness depends on them being taken regularly. Atomoxetine may be stopped abruptly if needed or can be tapered off over a suitable period. Guanfacine should not be stopped abruptly, as there is a risk of rebound hypertension. Guanfacine should be reduced by 1mg every three to seven days^​15​. If abrupt withdrawal is required, blood pressure should be monitored.

Drug holidays are not suitable for everyone and should only be done under the supervision of a healthcare provider.

Switching

Patients are often switched from one ADHD agent to another, either owing to lack of response or adverse effects. There are various ways to safely switch ADHD medications; clinicians should discuss the options with the patient and choose the safest method. The table below shows examples of switching ADHD medication^​21​. Care should be taken when deciding whether to cross taper or stop and start medication.

Methylphenidate: differences in release profiles and when to switch

The national ADHD drug shortages have highlighted gaps in knowledge about the differences in methylphenidate preparations and when it is acceptable to switch between them. Table 4 highlights the main points that can be used as an aid to pharmacy staff, focusing on the modified-release preparations^​22​.

The main difference between the release profiles is that capsules are 6–8-hour preparations and tablets are 12-hour preparations. A prescription for modified-release capsules should always specify the brand, as the varying release profiles can influence the response if the patient receives the incorrect brand.