Lesson 5 - Non-stimulant Medication in ADHD

1. Introduction

Why This Topic Matters

Stimulant medication is often highly effective for ADHD but it is not the right treatment for every patient.

Some people obtain insufficient benefit from stimulants. Others experience adverse effects that prevent an adequate therapeutic dose from being reached. There may be concerns about misuse or diversion or a patient's physical or psychiatric circumstances may make a non-stimulant approach more appropriate. Some patients simply prefer not to take stimulant medication.

Understanding non-stimulant medication is therefore an essential part of competent ADHD prescribing.

The principal non-stimulant medications encountered in UK ADHD practice include:

• Atomoxetine

• Guanfacine

Other medications may occasionally be considered in specialist circumstances but their place in treatment differs and prescribing should follow current guidance and the individual clinical situation.

Non-stimulants should not simply be thought of as:

"what we use when stimulants fail."

They have different pharmacological properties, adverse-effect profiles, monitoring requirements and clinical characteristics. Selecting them requires the same careful formulation and individualisation as stimulant prescribing.

Non-stimulants Behave Differently From Stimulants

One of the most important differences for patients and clinicians to understand is the time course of response.

With stimulant medication, therapeutic effects can often be observed relatively quickly once an effective dose is reached.

Non-stimulants are different.

Atomoxetine, for example, generally requires ongoing regular administration and its therapeutic effects develop more gradually. Patients should therefore not expect to take a dose in the morning and determine by lunchtime whether it has worked.

This has important implications for clinical practice.

If expectations are not explained properly, a patient may take Atomoxetine for a short period and conclude:

"It doesn't do anything."

The problem may not be treatment failure.

The medication may not yet have had an adequate therapeutic trial.

The clinician therefore needs to understand:

how the medication is titrated

how long benefit may take to emerge

what adverse effects should be monitored

and

when it is reasonable to conclude that treatment has been ineffective.

Different Medication, Different Monitoring

Non-stimulant does not mean:

"no monitoring required."

Each medication has its own safety considerations.

With Atomoxetine, clinicians need to consider areas including:

• pulse and blood pressure

• appetite and weight

• gastrointestinal adverse effects

• sleep

• mood and behavioural change

• cardiovascular symptoms

• potential drug interactions

• relevant hepatic symptoms

• suicidality or significant changes in mental state where clinically relevant

Guanfacine has a different clinical profile.

Important considerations include:

• blood pressure

• pulse

• sedation

• fatigue

• dizziness

• orthostatic symptoms

• syncope

• the potential consequences of abrupt discontinuation

The monitoring plan therefore needs to reflect the medication being prescribed, rather than simply using the same checklist for every ADHD treatment.

Understanding Atomoxetine

Atomoxetine is a selective noradrenaline reuptake inhibitor.

It is not a stimulant and it is not used in the same way as immediate symptom-control medication.

Its gradual onset can be both an advantage and a disadvantage.

There is less of a clear:

"medication working → medication wearing off"

pattern across the day than may occur with shorter-acting stimulant treatment.

However, patients need to understand that meaningful benefit may take time to develop.

This makes careful follow-up important.

The clinician needs to distinguish:

treatment has not worked

from

treatment has not had sufficient time or dose exposure to determine whether it works.

Understanding Guanfacine

Guanfacine works through a different mechanism from both stimulants and Atomoxetine. It is an alpha-2A adrenergic receptor agonist.

Its adverse-effect profile is therefore different.

Sedation and fatigue can be clinically important, particularly during initiation and titration.

Its effects on blood pressure and pulse also require appropriate monitoring.

A patient who says:

"I'm exhausted since starting it"

requires a different clinical assessment from a patient taking Methylphenidate who reports appetite suppression.

The drug determines the questions we need to ask.

Non-stimulants Are Not Necessarily "Milder"

Patients sometimes assume:

"I'd rather take the non-stimulant because it must be gentler."

That is not necessarily correct.

Non-stimulants have different risks and adverse effects rather than simply fewer risks.

Similarly, the term non-stimulant should not be interpreted as:

• natural

• side-effect free

• requiring less monitoring

• universally safer

• less clinically significant

Medication choice should be based on the expected balance of benefits, adverse effects, safety and individual circumstances, not on the label attached to the medication class.

Why Might We Consider a Non-stimulant?

There are several clinical situations in which non-stimulant treatment may become relevant.

These can include:

Inadequate stimulant response

A patient may have undergone appropriate stimulant trials without sufficient improvement.

Unacceptable stimulant adverse effects

Stimulants may produce meaningful benefit but adverse effects may prevent continued treatment or adequate optimisation.

Problems with misuse or diversion

The risk profile of stimulant prescribing may influence medication selection in some individuals.

Patient preference

Following an informed discussion of benefits and risks, some patients may prefer a non-stimulant approach.

Individual clinical circumstances

Comorbidity, previous treatment response and other aspects of the clinical formulation may influence the choice of medication.

The decision should follow current clinical guidance rather than simply reflecting whether the prescriber personally prefers stimulant or non-stimulant medication.

Medication Response Is Not a Diagnostic Test

This is worth reinforcing.

If Atomoxetine improves someone's concentration, that does not prove they have ADHD.

If Atomoxetine does not work, that does not prove they do not have ADHD.

The same principle applies to stimulants.

ADHD is diagnosed through appropriate clinical assessment.

Medication response helps us determine whether a particular treatment is useful for a person who has been appropriately assessed.

Treatment Still Needs Functional Targets

As with stimulant prescribing, identify what treatment is intended to improve.

Do not settle for:

"We are trying Atomoxetine for ADHD."

Instead identify functional targets such as:

• completing classroom work

• following instructions

• reducing impulsive behaviour

• managing homework

• improving occupational task completion

• reducing careless errors

• improving everyday organisation

• functioning more consistently at home

This becomes particularly important with non-stimulants because the therapeutic response may emerge gradually.

Without clear baseline targets, gradual improvement can be difficult to recognise.

The Importance of Expectations

Expectation-setting is one of the most important parts of non-stimulant prescribing.

Before treatment begins, patients should understand:

why this medication has been selected

how it differs from stimulant treatment

how it will be titrated

that benefit may develop gradually

which adverse effects should be monitored

when follow-up will occur

what would require earlier clinical review

This improves the quality of subsequent treatment decisions.

It also reduces the risk that medication is abandoned prematurely because the patient expected an immediate effect.

Non-stimulant Does Not Mean Non-pharmacological

Another terminology point is worth clarifying.

A non-stimulant medication is still pharmacological treatment.

It should not be confused with the non-pharmacological interventions covered in the previous lesson such as environmental modification, behavioural interventions, psychological therapy and organisational support.

A patient may therefore receive:

non-stimulant medication

and

non-pharmacological treatment

at the same time.

These are entirely different concepts.

How This Lesson Fits Into the Overall Course

The previous lesson examined stimulant medication and introduced the central principles of ADHD pharmacological management:

appropriate medication selection

↓

baseline assessment

↓

careful initiation

↓

titration

↓

monitoring

↓

assessment of functional benefit

↓

management of adverse effects

↓

long-term review

Those principles continue to apply.

However, non-stimulant medications introduce a different set of clinical considerations.

We now need to understand:

• where non-stimulants fit within the ADHD treatment pathway

• Atomoxetine

• Guanfacine

• relevant mechanisms of action

• medication selection

• initiation and titration

• expected time course of response

• assessment of effectiveness

• physical monitoring

• common adverse effects

• clinically important safety concerns

• drug interactions

• switching from stimulant treatment

• discontinuation

• circumstances requiring specialist judgement

The lesson therefore builds directly on stimulant prescribing while emphasising an important principle:

ADHD medications cannot all be prescribed, monitored and evaluated in the same way.

Each medication has its own pharmacology, expected time course, adverse-effect profile and safety considerations.

The clinician needs to understand those differences and translate them into practical prescribing decisions.

The central question remains the same:

Is this treatment producing sufficient meaningful improvement in the patient's symptoms and everyday functioning to justify its adverse effects and risks?

That principle applies whether the medication is a stimulant or a non-stimulant.

2. Learning Outcomes

By the end of this lesson, learners should be able to:

1. Explain the role of non-stimulant medication in ADHD management, including where Atomoxetine and Guanfacine may fit within the treatment pathway and the clinical circumstances in which non-stimulant treatment may be considered.

2. Describe the key pharmacological and clinical differences between Atomoxetine, Guanfacine and stimulant medications, including their mechanisms of action, expected time course of response and implications for assessing treatment effectiveness.

3. Safely initiate and titrate non-stimulant medication, including completing an appropriate baseline assessment, selecting an appropriate dosing approach and allowing an adequate therapeutic trial before determining whether treatment has been effective.

4. Monitor the effectiveness and safety of non-stimulant treatment, including assessment of ADHD symptoms, functional outcomes, pulse, blood pressure, weight and other medication-specific physical and mental health considerations.

5. Recognise and manage important adverse effects and safety concerns associated with non-stimulant medication, including gastrointestinal symptoms, appetite changes, sedation, fatigue, cardiovascular effects, mood or behavioural changes and other symptoms requiring further clinical assessment.

6. Apply clinical judgement when reviewing, switching or discontinuing non-stimulant treatment, considering inadequate response, tolerability, adherence, drug interactions, comorbidity, patient preference and the overall balance between meaningful functional benefit and treatment-related risk.

3. The Lecture

Non-stimulants Require a Different Prescribing Mindset

We have just spent a lesson discussing stimulant medication. Many of the general prescribing principles remain the same:

establish the treatment target

↓

complete an appropriate baseline assessment

↓

start treatment appropriately

↓

titrate

↓

monitor benefit and adverse effects

↓

optimise treatment

↓

review whether it remains appropriate

However, there is an important mistake to avoid.

Do not prescribe a non-stimulant as though it were simply a stimulant that happens not to be controlled.

The pharmacology is different.

The time course is different.

The adverse-effect profiles are different.

The way we interpret treatment response is therefore different.

For doctors beginning to prescribe ADHD medication, the two principal non-stimulants to understand are Atomoxetine and Guanfacine.

Where Do Non-stimulants Fit Into ADHD Treatment?

Non-stimulants are important treatments but they do not occupy exactly the same place as stimulants within the UK treatment pathway.

For children and young people, Atomoxetine or Guanfacine may be considered when appropriate stimulant treatment has not been tolerated or when symptoms have not responded sufficiently to adequate stimulant trials in accordance with current guidance.

For adults, Atomoxetine is the principal licensed non-stimulant option within the standard treatment pathway when appropriate stimulant trials have not been tolerated or have produced insufficient response.

Guanfacine has a different licensing and guideline position in adults and specialist advice is required if considering treatment outside standard recommendations.

The practical lesson is:

Know where the medication sits in the current guideline before prescribing it.

Do not assume that because a medication is used for ADHD in one age group it has the same place in another.

The Two Main Non-stimulants

FeatureAtomoxetineGuanfacinePharmacological classSelective noradrenaline reuptake inhibitorAlpha-2A adrenergic receptor agonistStimulant?NoNoControlled drug?NoNoTherapeutic responseGradualGradualImportant monitoringPulse, blood pressure, weight and mental/physical adverse effectsPulse, blood pressure, weight, sedation and cardiovascular effectsImportant practical issueBenefit may take several weeks to emergeSedation and hypotension can be clinically importantAbrupt discontinuationFollow appropriate prescribing guidanceAvoid abrupt withdrawal because of potential blood pressure effects

The table is useful as an orientation.

Clinical prescribing requires more detail.

Atomoxetine

How Does Atomoxetine Work?

Atomoxetine selectively inhibits the presynaptic noradrenaline transporter, increasing noradrenergic signalling.

For patients, you do not need to provide a lengthy pharmacology lecture.

A useful explanation might be:

"Atomoxetine is a non-stimulant ADHD medication. It works through noradrenaline signalling and needs to be taken regularly. Unlike stimulant medication, we usually expect the benefit to build gradually rather than appearing immediately after each dose."

That final sentence is particularly important.

Atomoxetine Is Not an "As Required" Medication

A stimulant can often produce a clinically observable effect on the day it is taken.

Atomoxetine does not work in the same way.

A patient cannot sensibly take Atomoxetine on Monday, skip Tuesday and Wednesday, take it again on Thursday and then decide whether it improves their ADHD.

It requires consistent administration.

This has implications for adherence.

If the patient has taken the medication inconsistently, be cautious about concluding that an adequate treatment trial has failed.

The Time Course of Atomoxetine

This is one of the most important concepts in the lesson.

Patients should understand that improvement can develop gradually over several weeks and may continue to increase with an adequate treatment trial.

Do not ask:

"Did you feel it kick in?"

That question makes sense for some stimulant experiences but is much less useful for Atomoxetine.

Instead ask:

"Looking back over the last few weeks, what has become easier?"

For example:

• Are tasks being completed more reliably?

• Are conversations easier to follow?

• Is impulsivity reduced?

• Is classroom functioning changing?

• Is organisation improving?

• What have parents, partners or teachers noticed?

With gradual-onset medication, comparison over time becomes particularly important.

Clinical Example: "I've Taken It for a Week and Nothing Has Happened"

A 27-year-old starts Atomoxetine.

At the first review he says:

"I've taken it every day for a week and honestly I can't feel anything."

The wrong response is:

"Atomoxetine has failed."

The first questions should include:

• What dose is he taking?

• Has he taken it consistently?

• Has titration progressed as intended?

• Are adverse effects present?

• Have any subtle functional changes emerged?

• Has there been sufficient time at an appropriate dose to judge efficacy?

One week without obvious benefit is very different from an adequate therapeutic trial with no meaningful response.

Atomoxetine Dosing

Atomoxetine dosing differs according to factors including age and body weight and should follow the current product information and clinical guidance.

In children and young people, body weight is particularly relevant to dosing.

In adults and those above relevant weight thresholds, dosing follows a different approach.

The key teaching point for newly prescribing doctors is not to memorise a single universal Atomoxetine dose.

It is:

Check the correct dosing schedule for the individual patient and formulation before prescribing.

Then document:

• starting dose

• intended titration

• target or review point

• tolerability

• adherence

• clinical response

Atomoxetine and CYP2D6

Atomoxetine is metabolised substantially through CYP2D6.

Why does this matter clinically?

Because both genetic variation and interacting medication can affect Atomoxetine exposure.

Some people are CYP2D6 poor metabolisers and may experience higher exposure to Atomoxetine.

In addition, strong CYP2D6 inhibitors can increase Atomoxetine concentrations.

This means that when prescribing Atomoxetine you should review the medication list rather than considering the ADHD prescription in isolation.

If adverse effects appear unexpectedly pronounced or treatment circumstances change following introduction of interacting medication, reconsider the pharmacological picture.

Common Atomoxetine Adverse Effects

Adverse effects vary between individuals but clinically relevant problems can include:

• gastrointestinal symptoms

• nausea

• reduced appetite

• abdominal discomfort

• headache

• sleep disturbance or somnolence

• dizziness

• changes in pulse

• changes in blood pressure

Adults may also experience sexual or genitourinary adverse effects.

Do not simply read the adverse-effect list to the patient.

Prioritise the effects that are common, clinically important or require action.

Managing Gastrointestinal Adverse Effects

Suppose a patient says:

"Every time I take it, I feel sick."

Clarify:

• how severe the nausea is

• when it begins

• how long it lasts

• whether vomiting occurs

• whether oral intake is affected

• whether weight is changing

• whether symptoms are improving with time

• whether administration factors might be relevant

Mild early adverse effects may settle.

Severe or persistent adverse effects may require treatment modification.

Again, avoid binary thinking:

side effect = stop

or

recognised side effect = ignore.

Assess clinical significance.

Appetite and Weight

Atomoxetine can affect appetite and weight.

The same principles discussed with stimulant treatment apply:

measure

monitor the trajectory

assess nutritional impact

intervene when clinically significant

In children and young people, growth monitoring remains important.

Do not assume that appetite monitoring only matters with stimulants.

Cardiovascular Effects of Atomoxetine

Atomoxetine can increase pulse and blood pressure in some patients.

This is another reason why:

non-stimulant does not mean cardiovascularly irrelevant.

Baseline cardiovascular assessment and appropriate ongoing monitoring remain important.

If significant tachycardia, hypertension, palpitations, chest pain or other concerning cardiovascular symptoms occur, assess them appropriately.

Do not reassure simply because the medication is not a stimulant.

Atomoxetine and Mental State

Mental state should remain under review during treatment.

Particular attention should be paid to significant changes in:

• mood

• behaviour

• agitation

• emotional state

• suicidal thinking

• unusual psychiatric symptoms

Children and young people require particular vigilance for suicidal thinking or behavioural change during treatment.

This does not mean that Atomoxetine routinely causes suicidality.

It means that this is a recognised safety issue that clinicians prescribing the medication should understand and monitor appropriately.

If clinically significant deterioration occurs, assess the patient rather than simply continuing the titration schedule.

Rare but Important Hepatic Concerns

Rare hepatic injury has been reported with Atomoxetine.

Routine liver-function testing is not generally required in every patient without a clinical indication.

However, patients should be assessed if symptoms suggest possible hepatic dysfunction.

Examples might include:

• unexplained jaundice

• dark urine

• significant unexplained abdominal symptoms

• other clinical features suggestive of liver injury

The principle is the same as with cardiovascular investigation:

Do not perform investigations mechanically when they are not indicated but recognise the symptoms that should trigger investigation.

Guanfacine

How Does Guanfacine Work?

Guanfacine is an alpha-2A adrenergic receptor agonist.

Its pharmacological profile differs substantially from both stimulants and Atomoxetine.

Clinically, this becomes most apparent through effects such as:

• sedation

• fatigue

• reduced blood pressure

• reduced pulse

• dizziness

• orthostatic symptoms

The monitoring priorities therefore differ.

Guanfacine and Sedation

Sedation is one of the most important practical issues when initiating Guanfacine.

A parent might say:

"His behaviour is much calmer but he is falling asleep after school."

Be careful with the interpretation.

Reduced activity caused by excessive sedation is not necessarily therapeutic improvement in ADHD.

Ask:

Is attention actually better?

Is impulsivity better?

Is functioning better?

Or is the patient simply too tired to be active?

This distinction is essential.

Clinical Example: "He's Much Quieter"

An 11-year-old starts Guanfacine.

At review his father says:

"It's definitely working. He's much quieter."

Further questioning reveals:

• he is sleeping during car journeys

• teachers report he appears tired

• he has stopped participating in football

• concentration has not clearly improved

This is not convincing evidence of successful ADHD treatment.

It may represent clinically significant sedation.

Never confuse:

less movement

with

better ADHD control.

Blood Pressure and Pulse

Because of its alpha-adrenergic effects, Guanfacine can lower blood pressure and pulse.

Monitoring should therefore include appropriate assessment of:

• blood pressure

• pulse

• dizziness

• postural symptoms

• syncope

• fatigue

A patient reporting:

"I feel dizzy every time I stand up"

requires clinical assessment rather than reassurance that tiredness is common with Guanfacine.

Titrating Guanfacine

Guanfacine should be titrated according to current prescribing information and clinical guidance.

Dose changes should take account of:

• clinical response

• sedation

• blood pressure

• pulse

• weight

• other adverse effects

As with stimulant medication, the aim is not to reach the maximum dose.

The objective is to identify a dose that provides meaningful benefit while remaining safe and tolerable.

Do Not Stop Guanfacine Abruptly

This is an important practical safety point.

Abrupt withdrawal can lead to increases in blood pressure and pulse.

Guanfacine should therefore generally be reduced gradually according to current prescribing guidance when treatment is being discontinued.

This is very different from the way patients may sometimes use stimulant medication.

Make sure patients and families understand this.

A patient should not independently decide:

"It's the school holidays, so I'll stop it tomorrow."

without understanding the discontinuation requirements.

Missed Guanfacine Doses

Repeated missed doses matter.

If several doses have been missed, do not automatically advise restarting at the previous dose without considering the relevant prescribing guidance.

Depending on the interruption, re-titration may be necessary.

This is another reason to ask about adherence specifically.

Comparing Atomoxetine and Guanfacine

The question is not:

"Which non-stimulant is better?"

The better question is:

"Which treatment is appropriate for this patient at this point in the pathway?"

Consider:

• age

• licensing and guideline position

• previous stimulant trials

• previous response

• cardiovascular profile

• sedation

• appetite and weight

• adherence

• comorbidities

• interacting medication

• patient and family preference

Medication selection should emerge from the clinical formulation.

Non-stimulants and Tics

ADHD commonly coexists with tic disorders.

Do not automatically assume that the presence of tics requires a non-stimulant.

Stimulants can still be appropriate for many patients with ADHD and tics.

However, the presence and severity of tics may form part of the overall medication decision.

The broader lesson is:

Do not select medication from one comorbidity in isolation.

Consider the whole patient.

Non-stimulants and Anxiety

Similarly, do not automatically assume:

"Anxiety means use Atomoxetine rather than a stimulant."

ADHD and anxiety commonly coexist.

The appropriate medication depends on the individual clinical picture.

Consider:

• severity of ADHD

• severity and nature of anxiety

• previous treatment

• functional impairment

• adverse-effect vulnerability

• patient preference

Avoid medication selection based on simplistic rules.

Non-stimulants and Substance Misuse

The absence of controlled-drug status can make non-stimulants clinically attractive where misuse or diversion is a significant concern.

However, this should not become another automatic rule.

A history of substance misuse does not necessarily mean:

"No stimulant ever."

Nor does it mean:

"Atomoxetine automatically."

Undertake an individualised assessment of:

• current substance use

• severity

• stability

• diversion risk

• treatment setting

• safeguarding

• previous response

• wider psychiatric risk

Medication choice should reflect the whole risk-benefit formulation.

What Does an Adequate Trial Mean?

This is particularly important with non-stimulants.

To decide that a treatment has failed, ask:

Was it actually taken?

Adherence must be sufficient.

Was an appropriate dose reached?

A prolonged period on an inadequate dose may not constitute an adequate therapeutic trial.

Was there enough time?

Gradual-onset medications require adequate exposure before efficacy can be judged.

Were adverse effects preventing optimisation?

If so, the medication may have failed because of tolerability rather than lack of efficacy.

Were meaningful outcomes assessed?

Look beyond whether the patient could "feel" the medication.

Only after considering these questions can you reasonably determine whether the treatment has produced insufficient benefit.

Measuring Gradual Improvement

Because non-stimulants do not necessarily produce an obvious daily on-off effect, structured outcome monitoring can be particularly useful.

Establish baseline difficulties such as:

Before treatment:

• misses three deadlines each week

• requires repeated prompts every morning

• receives daily behavioural sanctions at school

• interrupts most conversations

• completes very little independent study

Then review these same areas.

This allows gradual improvement to become visible.

Without baseline targets, both the patient and clinician may struggle to recognise change.

Switching From a Stimulant to a Non-stimulant

This requires planning.

Do not simply tell every patient:

"Stop the stimulant today and start Atomoxetine tomorrow."

The appropriate strategy depends on:

• why the stimulant is being stopped

• severity of current impairment

• adverse effects

• clinical risk

• the medication being introduced

• whether overlap is clinically appropriate

• relevant product guidance

• individual circumstances

Remember that Atomoxetine takes time to develop therapeutic benefit.

Stopping an effective stimulant before a non-stimulant has begun to work may create a period of substantial untreated impairment.

In some circumstances this may be appropriate or unavoidable.

In others, a carefully planned transition may be preferable.

Follow current guidance and seek specialist advice when necessary.

Combination Treatment

Clinicians will occasionally encounter patients taking stimulant and non-stimulant medication together.

Do not assume that combination prescribing is routine simply because it occurs in specialist practice.

Combination treatment may involve additional complexity around:

• evidence

• licensing

• cardiovascular monitoring

• adverse effects

• drug interactions

• responsibility for prescribing

If considering treatment outside standard guideline pathways, obtain appropriate specialist advice.

For newly qualified doctors, the safest principle is:

Understand standard monotherapy pathways well before becoming comfortable with complex combination prescribing.

When Atomoxetine Appears Ineffective

Suppose an adult has taken Atomoxetine for several weeks and reports no improvement.

Before switching, ask:

• Has the medication been taken every day?

• What dose has actually been taken?

• How long has the patient been at an appropriate therapeutic dose?

• Have there been interruptions?

• Are adverse effects limiting titration?

• What functional outcomes were expected to improve?

• Have family members or colleagues noticed anything?

• Is another condition driving the impairment?

Then decide whether the trial has genuinely been adequate.

When Guanfacine Appears Effective

Suppose a child becomes less impulsive and classroom functioning improves after Guanfacine.

Good.

Now ask:

• Is daytime alertness satisfactory?

• Is blood pressure satisfactory?

• Is pulse satisfactory?

• Is dizziness present?

• Is weight satisfactory?

• Is the child functioning better outside school?

• Is the benefit clinically meaningful?

Never stop evaluating safety simply because treatment is effective.

Adherence Is Particularly Important

Non-stimulant medication generally depends on regular administration.

Ask directly:

"How many doses have been missed this week?"

This is more useful than:

"Are you taking it regularly?"

Explore barriers such as:

• forgetting

• adverse effects

• difficulty swallowing medication

• disagreement about treatment

• disrupted routines

• problems obtaining medication

Poor adherence is clinical information.

It should prompt problem-solving rather than criticism.

Medication Interactions

Always review the full medication list.

This includes:

• prescribed medication

• over-the-counter medication

• relevant supplements

• recent medication changes

Atomoxetine is particularly important in relation to CYP2D6 interactions.

Guanfacine also has clinically relevant interaction considerations and its exposure can be affected by medicines influencing its metabolism.

Do not prescribe ADHD medication as though it exists in a separate pharmacological universe from the patient's other treatment.

Physical Monitoring

A useful conceptual framework is:

Atomoxetine

Think particularly about:

pulse

blood pressure

weight and growth where appropriate

appetite

mental state

cardiovascular symptoms

relevant hepatic symptoms

Guanfacine

Think particularly about:

pulse

blood pressure

weight

sedation

fatigue

dizziness

postural symptoms

syncope

Monitoring should follow current guidance and the individual patient's clinical needs.

When to Pause Titration

Do not continue increasing medication simply because a titration schedule was written several weeks earlier.

Pause and reassess when:

• significant adverse effects emerge

• physical observations become concerning

• cardiovascular symptoms occur

• sedation becomes clinically significant

• mental state deteriorates

• adherence is unclear

• interacting medication has changed

• the clinical picture no longer makes sense

A titration schedule is a plan.

It is not an instruction to ignore new clinical information.

Long-Term Review

Once a patient is stable, do not allow non-stimulant treatment to become an indefinite repeat prescription without review.

Periodically ask:

Is it still helping?

What happens if doses are missed?

Are adverse effects still acceptable?

Are physical observations satisfactory?

Has weight or growth changed?

Has the patient's clinical situation changed?

Are there new medications or interactions?

Does the current treatment still fit the person's needs?

The fact that medication was appropriate two years ago does not automatically mean that the same regimen remains optimal today.

Clinical Case: Atomoxetine

A 14-year-old with ADHD has previously had inadequate benefit or poor tolerability from appropriate stimulant treatment and starts Atomoxetine.

After two weeks:

• medication has been taken consistently

• mild nausea occurred initially but is improving

• appetite is satisfactory

• pulse and blood pressure remain satisfactory

• no significant mental-state concerns have emerged

• parents report no obvious improvement in ADHD symptoms

Should Atomoxetine be declared ineffective?

Not yet.

The first question is whether the patient has received an adequate therapeutic trial.

If treatment remains tolerated, further titration and observation may be appropriate according to the dosing plan and current guidance.

The absence of rapid improvement is not surprising for a gradual-onset medication.

Clinical Case: Guanfacine

An 11-year-old starts Guanfacine.

At review, his mother reports that impulsive behaviour has reduced.

However:

• he is very tired during the day

• he has stopped participating in activities after school

• he reports dizziness on standing

• his blood pressure has fallen substantially from baseline

Do not conclude:

"The medication is working, so continue."

There may be therapeutic benefit but tolerability and cardiovascular effects require review.

The relevant question is:

Does the overall balance of benefit and harm justify the current regimen?

That question should guide every ADHD medication review.

A Practical Non-stimulant Review Framework

At each appointment, work through six areas.

1. Adherence

Has the medication actually been taken consistently?

2. Dose and Duration

What dose is being taken and has there been sufficient time at an appropriate dose?

3. Benefit

Which ADHD symptoms have improved?

4. Function

What is easier in everyday life?

5. Adverse Effects

What has changed since treatment began?

6. Safety

Are physical observations, mental state and medication-specific safety considerations satisfactory?

Then decide whether to:

continue

titrate

reduce

change medication

pause and investigate

or

discontinue appropriately.

Avoiding Common Conceptual Errors

Do not think:

Non-stimulant = weaker stimulant

Think:

different pharmacology and different clinical behaviour.

Do not think:

No improvement after several days = treatment failure

Think:

Has there been an adequate trial?

Do not think:

Non-stimulant = safer

Think:

different risk profile.

Do not think:

A quieter child = successfully treated ADHD

Think:

Has attention, impulsivity and functioning improved without excessive sedation?

Do not think:

Medication worked = continue indefinitely

Think:

Does the benefit continue to justify treatment at each review?

The Central Clinical Comparison

The difference between stimulant and non-stimulant prescribing can be simplified conceptually.

With a stimulant, you may often ask:

"What happened today after the medication was taken?"

With a gradual-onset non-stimulant, you are more likely to ask:

"What has changed over the last several weeks?"

That change in time perspective is fundamental.

Key Learning Points

Non-stimulant medication is an important component of ADHD pharmacological treatment.

The principal medications doctors should understand are Atomoxetine and Guanfacine although their licensing and guideline positions differ according to age and clinical circumstances.

Atomoxetine is a selective noradrenaline reuptake inhibitor and has a gradual therapeutic onset.

Guanfacine is an alpha-2A adrenergic receptor agonist and has clinically important effects including sedation and reductions in pulse and blood pressure.

Non-stimulants should not be considered simply milder or safer versions of stimulant medication.

They have different adverse-effect profiles and different monitoring requirements.

Atomoxetine requires attention to areas including cardiovascular parameters, appetite and weight, mental state, drug interactions and rare but important hepatic concerns.

Guanfacine requires particular attention to sedation, fatigue, blood pressure, pulse, dizziness and syncope.

Guanfacine should not generally be stopped abruptly because of the risk of increases in blood pressure and pulse.

Adherence is especially important because non-stimulant treatments depend on regular administration.

Do not conclude that a non-stimulant has failed until the patient has received an adequate trial at an appropriate dose for an appropriate period, provided treatment remains tolerable and safe.

Use meaningful functional targets to identify gradual improvement.

Medication selection should follow current clinical guidance and consider age, previous treatment, comorbidity, physical health, interactions, adverse effects and patient preference.

At every review ask:

Has it been taken?

Has the trial been adequate?

Is it effective?

Is functioning better?

Is it tolerable?

Is it safe?

The central principle is:

Non-stimulant prescribing requires the same careful clinical reasoning as stimulant prescribing but the pharmacology, time course, adverse effects and monitoring requirements are different.

4. Clinical Perspective

Non-stimulant prescribing often requires more patience than stimulant prescribing. The therapeutic response may be less immediately obvious and adverse effects can emerge before meaningful improvement in ADHD symptoms is apparent.

This creates an important clinical challenge.

With stimulant medication, patients can often describe what happens during a particular day. With Atomoxetine or Guanfacine, clinicians frequently need to assess patterns of change over several weeks.

The quality of the review therefore matters enormously.

Clinical Pearls

Do Not Assess Atomoxetine Like a Stimulant

A common mistake is asking:

"Can you feel the medication working?"

This is often the wrong question.

Instead ask:

"Compared with a month ago, what is easier now?"

Look for gradual changes in:

• attention

• impulsivity

• organisation

• task completion

• emotional regulation

• educational functioning

• occupational functioning

• family life

A patient may not notice a dramatic medication effect but may gradually begin functioning more effectively.

Do Not Declare Treatment Failure Too Early

Atomoxetine requires an adequate therapeutic trial.

Before deciding that it has not worked, establish:

• whether it has been taken consistently

• what dose has actually been reached

• how long the patient has been taking an appropriate dose

• whether adverse effects prevented adequate titration

• whether meaningful functional outcomes have been assessed

Several weeks of inconsistent treatment at a low dose is not the same as an adequate therapeutic trial.

Improvement May Continue Gradually

Patients should understand from the beginning that Atomoxetine may take time to produce its full clinical benefit.

This is particularly important for patients who have previously taken stimulants.

Someone accustomed to noticing a stimulant effect relatively quickly may conclude that Atomoxetine is ineffective because there is no obvious daily onset.

Expectation-setting improves adherence and makes subsequent reviews more meaningful.

Non-stimulant Does Not Mean Side-effect Free

Patients sometimes choose a non-stimulant because they believe it is inherently safer or milder.

Explain that the adverse-effect profile is different, not absent.

Atomoxetine may affect appetite, gastrointestinal function, pulse, blood pressure and mental state.

Guanfacine may cause sedation, fatigue, dizziness, hypotension and bradycardia.

Medication choice should therefore be based on the individual's clinical circumstances rather than assumptions about the word non-stimulant.

A Quieter Child Is Not Necessarily a Better Child

This is particularly important with Guanfacine.

A parent may report:

"It's definitely working. He's much calmer."

Ask what calmer means.

Has impulsivity improved while the child remains alert and engaged?

Or is the child sleepy, lethargic and less active because of sedation?

The therapeutic goal is improved regulation and functioning.

It is not simply reduced activity.

Always Know Why the Previous Medication Was Stopped

Before starting a non-stimulant after stimulant treatment, establish exactly what happened previously.

There is a major difference between:

"Methylphenidate didn't work."

and:

"Methylphenidate substantially improved ADHD symptoms but caused unacceptable appetite suppression despite optimisation."

Similarly:

"Lisdexamfetamine failed."

is less informative than:

"Lisdexamfetamine produced good morning symptom control but clinically significant anxiety emerged following dose escalation."

The previous response helps inform the next treatment decision.

Practical Tips for Everyday Practice

Establish Baseline Treatment Targets

Before starting treatment, identify several specific problems that can be reviewed later.

For example:

Target 1: completing morning routines with fewer prompts.

Target 2: completing more classroom work.

Target 3: interrupting conversations less frequently.

Target 4: completing homework more independently.

At follow-up, return to the same targets.

This is much more informative than asking:

"Do you think the Atomoxetine is helping?"

Ask About Adherence Numerically

Instead of:

"Have you been taking it regularly?"

ask:

"How many doses have you missed in the last seven days?"

The answer is often more informative.

With gradual-onset medication, inconsistent adherence can make assessment particularly difficult.

Review the Actual Dose

Do not assume that the patient followed the intended titration schedule.

Ask:

"What strength are you taking now?"

"How many capsules or tablets?"

"When did you increase?"

"Have there been any days when you reduced or stopped it?"

The prescribed dose and the dose actually taken are not always the same.

Ask About Timing of Adverse Effects

The timing can help enormously.

For nausea:

"How long after Atomoxetine do you feel sick?"

For Guanfacine:

"When during the day are you most tired?"

For dizziness:

"Does it happen when you stand up?"

For sleep:

"Is the problem falling asleep, staying asleep or feeling excessively sleepy during the day?"

Do not document simply:

"Side effects present."

Characterise them.

Monitor Trends Rather Than Isolated Numbers

This applies particularly to:

• weight

• blood pressure

• pulse

• growth in children and young people

A single measurement provides limited information.

Ask:

What was the baseline?

What is the trajectory?

Is the change clinically significant?

Monitoring becomes clinically useful when measurements are interpreted over time.

Review the Whole Medication List

This is especially important with Atomoxetine because of CYP2D6 metabolism and potential interactions.

Ask about:

• prescribed medication

• recently started medication

• over-the-counter preparations

• relevant supplements

If a previously stable patient suddenly develops substantial adverse effects following another medication change, consider whether an interaction may be contributing.

Common Pitfalls and Misconceptions

"Atomoxetine Hasn't Worked After One Week"

This is generally far too early to determine therapeutic failure.

First establish adherence, dose, tolerability and duration of treatment.

"Non-stimulants Work Immediately Once the Correct Dose Is Reached"

Not necessarily.

The clinical effect of Atomoxetine develops gradually and continued improvement may occur over time.

The assessment period therefore differs from that used with many stimulants.

"Guanfacine Is Working Because the Child Is Sleepier and Quieter"

Sedation is not equivalent to therapeutic response.

Ask whether ADHD symptoms and functioning have actually improved.

"Non-stimulants Do Not Affect the Cardiovascular System"

Incorrect.

Atomoxetine can increase pulse and blood pressure.

Guanfacine can reduce pulse and blood pressure.

The direction of the cardiovascular effect may differ but both require appropriate monitoring.

"Guanfacine Can Be Stopped Whenever the Patient Wants"

This is an important safety misconception.

Guanfacine should generally be tapered rather than abruptly discontinued because blood pressure and pulse may increase following sudden withdrawal.

Patients and families should understand this when treatment begins.

"Atomoxetine Does Not Require Mental-State Monitoring"

Incorrect.

Changes in mood, behaviour and suicidal thinking are important considerations, particularly in children and young people.

Significant mental-state deterioration requires clinical assessment rather than routine continuation of titration.

"If Two Stimulants Have Failed, Atomoxetine Will Definitely Work"

No medication can be guaranteed to work.

Non-stimulants provide additional treatment options but response remains individual.

Explain uncertainty appropriately.

"Medication Response Confirms the Diagnosis"

It does not.

Improvement with Atomoxetine does not prove ADHD.

Failure to respond does not disprove ADHD.

Diagnosis and treatment response are separate clinical questions.

Advice for Newly Qualified Doctors

Learn One Medication Properly Before Memorising Every Dose

Understand the medication you are prescribing.

For Atomoxetine, know:

• where it sits in the treatment pathway

• how dosing is determined

• how it is titrated

• expected time course

• important adverse effects

• cardiovascular monitoring

• relevant interactions

• important mental-state considerations

For Guanfacine, know:

• where it sits in the treatment pathway

• dosing and titration principles

• sedation risk

• blood pressure and pulse effects

• missed-dose considerations

• discontinuation requirements

It is safer to check an authoritative prescribing reference than to prescribe from memory when uncertain.

Do Not Follow a Titration Schedule Blindly

A titration schedule is a proposed plan.

It is not an instruction to continue increasing medication regardless of what happens clinically.

Before each increase ask:

Is the medication tolerated?

Are physical observations satisfactory?

Has anything clinically significant changed?

Is the planned increase still appropriate?

If not, pause.

Document Why You Are Changing the Dose

Your clinical record should make the reasoning clear.

For example:

"Atomoxetine has been well tolerated with no significant adverse effects. ADHD symptoms remain impairing and there has not yet been an adequate therapeutic trial at the planned treatment dose. Titration will therefore continue."

This is much more useful than:

"Increase Atomoxetine."

Do Not Be Afraid to Pause Treatment

If something does not make clinical sense, stop and reassess.

Examples include:

• unexpected cardiovascular findings

• significant dizziness or syncope

• severe sedation

• substantial mental-state deterioration

• significant weight loss

• possible medication interaction

• unclear adherence

• uncertainty about what medication the patient is actually taking

Completing the titration is never more important than patient safety.

Check Current Guidance When Uncertain

ADHD prescribing involves age-specific licensing, medication-specific titration and potentially important interactions.

Check current:

• NICE guidance

• BNF or BNF for Children

• Summary of Product Characteristics

• local prescribing guidance

Do not guess.

Situations Requiring Particular Clinical Judgement

Atomoxetine With Significant Mood Deterioration

Suppose a young person develops substantial low mood or suicidal thinking after Atomoxetine is started.

Do not simply assume:

"This is their ADHD."

Equally, do not automatically conclude that Atomoxetine caused it.

Undertake an appropriate risk and mental-state assessment.

Consider:

• temporal relationship

• baseline mental health

• previous self-harm or suicidal thinking

• psychosocial circumstances

• other medication

• recent stressors

• severity and immediacy of risk

The immediate priority is appropriate assessment and management of risk.

Significant Cardiovascular Symptoms

Palpitations, chest pain, syncope or clinically important abnormalities in pulse or blood pressure require appropriate assessment.

The fact that Atomoxetine is a non-stimulant should not provide false reassurance.

Similarly, significant dizziness, hypotension, bradycardia or syncope during Guanfacine treatment requires review.

Excessive Sedation With Guanfacine

Mild tiredness may sometimes occur during titration.

However, if a child:

• repeatedly falls asleep during the day

• cannot participate in school

• stops engaging in activities

• appears cognitively slowed

• experiences associated dizziness

the treatment requires review.

The clinical question is not merely:

"Can the patient tolerate this?"

It is:

"Is the treatment allowing the patient to function better overall?"

Poor Response to Atomoxetine

Before declaring treatment failure, systematically review:

Adherence

Was it taken consistently?

Dose

Was an appropriate therapeutic dose reached?

Duration

Was sufficient time allowed?

Tolerability

Did adverse effects prevent optimisation?

Outcomes

Were meaningful functional targets measured?

Formulation

Is ADHD still the principal explanation for the remaining impairment?

Only then decide whether another treatment strategy is required.

Switching From an Effective Stimulant

Suppose a stimulant is producing good ADHD symptom control but unacceptable adverse effects.

Remember that switching to Atomoxetine may involve a period before the new treatment provides meaningful benefit.

Consider how the transition will affect:

• education

• employment

• driving

• family functioning

• behavioural risk

• examinations

• other important responsibilities

Medication transitions should be planned rather than treated as purely pharmacological substitutions.

Guanfacine and Low Blood Pressure

A low blood pressure reading does not automatically require treatment discontinuation.

Interpret the result alongside:

• baseline blood pressure

• symptoms

• pulse

• postural symptoms

• dose

• recent titration

• hydration

• other medication

An asymptomatic patient with a modest change requires different management from someone experiencing recurrent presyncope.

Treat the patient and the clinical pattern rather than an isolated number.

Repeated Missed Guanfacine Doses

If several doses have been missed, do not simply advise the patient to restart their previous dose without checking current prescribing guidance.

Depending on the duration of interruption, re-titration may be appropriate.

This is an easy issue to overlook in routine practice.

Complex Comorbidity

Seek senior or specialist advice where there is uncertainty involving:

• significant cardiovascular disease

• complex psychopharmacology

• bipolar disorder

• psychosis

• substantial substance misuse

• significant eating difficulties

• severe behavioural disturbance

• complex medication interactions

• treatment outside standard licensing or guideline recommendations

The existence of ADHD does not make the rest of the psychiatric or medical formulation disappear.

A Practical Review Structure

When reviewing a patient taking a non-stimulant, work through the following sequence.

1. What are they actually taking?

Confirm medication, dose, timing and adherence.

2. How long have they been taking it?

Establish how long they have been at the current dose.

3. What has changed?

Review the original treatment targets.

4. What has improved functionally?

Ask for concrete examples.

5. What adverse effects are present?

Characterise severity and timing.

6. What do the physical observations show?

Interpret them against baseline and previous measurements.

7. Has mental state changed?

Particularly consider clinically significant mood or behavioural change.

8. Is the trial adequate?

Do not judge efficacy prematurely.

9. What is the next clinical decision?

This may be:

continue unchanged

continue to allow further therapeutic response

increase cautiously

reduce

pause

investigate

switch treatment

or

discontinue appropriately.

The Three Questions That Prevent Many Prescribing Errors

When non-stimulant treatment does not appear successful, ask:

Has the patient actually taken it?

Adherence.

Have they taken enough for long enough?

Dose and duration.

What exactly are we expecting it to improve?

Treatment targets.

These three questions resolve a surprising number of apparently complicated medication reviews.

Final Clinical Message

The central skill in non-stimulant prescribing is patient, structured assessment.

Do not expect Atomoxetine to behave like Methylphenidate.

Do not interpret sedation from Guanfacine as successful treatment.

Do not assume that non-stimulant means low risk.

Do not continue titration automatically when clinically important adverse effects emerge.

Do not declare treatment failure before establishing that the patient has received an adequate therapeutic trial.

At every review ask:

Has it been taken consistently?

Has the dose and duration been adequate?

Are ADHD symptoms improving?

Is everyday functioning improving?

Are adverse effects acceptable?

Are physical observations satisfactory?

Is the patient's mental state satisfactory?

Does the overall benefit still justify treatment?

Non-stimulant prescribing is not necessarily more difficult than stimulant prescribing.

It simply requires clinicians to understand that different medications demand different expectations, different monitoring and different clinical decisions.

5. Summary

Non-stimulant medication is an important part of ADHD treatment and requires a different clinical approach from stimulant prescribing. The principal non-stimulant medications encountered in UK ADHD practice are Atomoxetine and Guanfacine, although their licensing and guideline positions differ according to age and clinical circumstances.

Non-stimulants should not be thought of as weaker or inherently safer versions of stimulant medication. They have different mechanisms of action, different adverse-effect profiles, different monitoring requirements and a different expected time course of therapeutic response.

Atomoxetine is a selective noradrenaline reuptake inhibitor. Its effects generally develop gradually and treatment needs to be taken consistently. A lack of noticeable benefit after a short period does not necessarily represent treatment failure.

Before concluding that Atomoxetine has been ineffective, clinicians should consider:

Was it taken consistently?

Was an appropriate dose reached?

Was sufficient time allowed?

Were adverse effects limiting titration?

Were meaningful functional outcomes assessed?

Adherence is therefore particularly important when evaluating non-stimulant treatment.

Atomoxetine requires appropriate monitoring of pulse, blood pressure, appetite, weight and mental state. Clinicians should also be aware of potential drug interactions, particularly those involving CYP2D6 metabolism, and rare but important hepatic adverse effects.

Guanfacine is an alpha-2A adrenergic receptor agonist and has a different clinical profile. Sedation, fatigue, dizziness, hypotension and reductions in pulse can be clinically important during treatment.

A reduction in activity should not automatically be interpreted as improvement. A child who appears quieter because they are excessively sedated has not necessarily experienced meaningful improvement in ADHD.

The key question remains:

Has attention, impulsivity and everyday functioning improved while the medication remains acceptably tolerated?

Guanfacine should not generally be stopped abruptly because of the potential for increases in blood pressure and pulse. Missed doses may also affect how treatment should be restarted and current prescribing guidance should be checked when clinically relevant.

Monitoring should always reflect the medication being prescribed.

For Atomoxetine, particular attention should be given to:

• pulse

• blood pressure

• appetite

• weight and growth where appropriate

• mental state

• cardiovascular symptoms

• relevant hepatic symptoms

• medication interactions

For Guanfacine, particular attention should be given to:

• pulse

• blood pressure

• weight

• sedation

• fatigue

• dizziness

• postural symptoms

• syncope

Medication choice should follow the overall clinical formulation rather than a simplistic rule. Age, previous stimulant response, adverse effects, physical health, comorbidities, medication interactions, misuse or diversion risk and patient preference may all influence treatment selection.

Non-stimulants may be particularly relevant when appropriate stimulant treatment has produced insufficient benefit, unacceptable adverse effects or when other clinical circumstances make a non-stimulant approach more appropriate.

However, medication selection should continue to follow current clinical guidelines and licensing considerations. A treatment used in one age group should not automatically be assumed to have the same place in another.

As with stimulant medication, treatment effectiveness should be assessed through functional improvement as well as symptom change.

Examples might include:

• improved classroom engagement

• greater independence with routines

• fewer impulsive behaviours

• improved task completion

• better occupational functioning

• improved organisation

• reduced need for repeated prompting

Because non-stimulant improvement may develop gradually, clearly defined baseline treatment targets are particularly useful.

When treatment appears ineffective, clinicians should avoid changing medication prematurely. First review adherence, dose, treatment duration, tolerability and whether the correct functional outcomes have been measured.

When adverse effects emerge, they should be interpreted according to severity, timing and clinical significance. A recognised adverse effect should neither be automatically ignored nor automatically lead to treatment discontinuation.

Titration plans should remain flexible. If significant sedation, cardiovascular symptoms, concerning physical observations, mental-state deterioration or another clinically important problem develops, titration should pause while the situation is assessed.

Switching from stimulant to non-stimulant medication may also require careful planning because the therapeutic effect of the new treatment may not develop immediately. The potential impact on education, employment, driving, family life and other areas of functioning should be considered.

Long-term prescribing should involve periodic review. Non-stimulant medication should not become an indefinite repeat prescription without reassessing ongoing benefit, tolerability, adherence, physical monitoring and whether the treatment still meets the patient's needs.

A useful framework for every non-stimulant review is:

Has the medication been taken consistently?

Has the trial been adequate in dose and duration?

Are ADHD symptoms improving?

Is everyday functioning improving?

Are adverse effects acceptable?

Are physical observations satisfactory?

Is mental state satisfactory?

Does the overall balance of benefit and harm justify continuing treatment?

The central lesson is that non-stimulant prescribing requires patience, structured monitoring and medication-specific clinical reasoning.

The clinician should understand not only what the medication is but how it behaves over time, what needs to be monitored and when the evidence is sufficient to decide whether treatment is working.

6. Further Reading

The following resources provide a useful evidence base for understanding non-stimulant medication in ADHD. Clinicians should use these alongside current prescribing information, the BNF or BNF for Children and relevant local prescribing arrangements.

NICE Guidance

National Institute for Health and Care Excellence (NICE)

Attention Deficit Hyperactivity Disorder: Diagnosis and Management (NG87)

NICE NG87 is the principal UK guideline for the diagnosis and management of ADHD.

For children aged 5 years and over and young people, NICE recommends offering Atomoxetine or Guanfacine when Methylphenidate or Lisdexamfetamine cannot be tolerated or when symptoms have not responded to separate adequate trials of these stimulants.

For adults, NICE recommends Atomoxetine when Lisdexamfetamine or Methylphenidate cannot be tolerated or when symptoms have not responded to appropriate trials. Guanfacine does not occupy the same routine position in the adult pathway.

Particularly useful sections include:

• medication choice

• baseline assessment

• dose titration

• monitoring effectiveness

• cardiovascular monitoring

• height and weight monitoring

• adverse effects

• adherence

• medication review

• discontinuation

NICE NG87: ADHD – diagnosis and management

BNF and BNF for Children

The British National Formulary and BNF for Children should be consulted when prescribing Atomoxetine or Guanfacine.

These are particularly important for checking:

• current licensed indications

• age-specific dosing

• weight-based dosing where relevant

• titration schedules

• contraindications

• cautions

• drug interactions

• adverse effects

• monitoring requirements

• advice relating to missed doses

• discontinuation

Guidelines tell us when a medication should be considered.

The BNF and Summary of Product Characteristics help establish how the particular medicine should be prescribed safely.

Summary of Product Characteristics

Clinicians should also become comfortable using the current Summary of Product Characteristics (SmPC) for the individual preparation being prescribed.

This is particularly valuable when a clinical question involves:

• an unusual adverse effect

• drug interactions

• dose adjustment

• hepatic impairment

• missed doses

• treatment discontinuation

• administration instructions

• use outside straightforward routine prescribing

For Guanfacine, the prescribing information is particularly important when considering dose titration, cardiovascular monitoring and gradual discontinuation.

For Atomoxetine, it provides detailed information regarding dosing, CYP2D6 interactions and clinically important safety considerations.

International Clinical Guidelines

Australian Evidence-Based Clinical Practice Guideline for ADHD

The Australian Evidence-Based Clinical Practice Guideline for Attention Deficit Hyperactivity Disorder provides a detailed evidence-based discussion of pharmacological treatment.

The guideline considers Atomoxetine and Guanfacine as non-stimulant alternatives when stimulant treatment is ineffective or cannot be used. It also emphasises individual medication optimisation and ongoing assessment of effectiveness and unwanted effects.

This guideline is particularly useful for exploring:

• comparative medication effectiveness

• treatment sequencing

• medication selection

• comorbidity

• monitoring

• treatment optimisation

Australian Evidence-Based Clinical Practice Guideline for ADHD

Landmark Atomoxetine Research

Michelson et al. – Once-Daily Atomoxetine

Michelson D, Allen AJ, Busner J, et al.

Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. American Journal of Psychiatry. 2002;159(11):1896–1901.

This double-blind randomised controlled trial included 171 children and adolescents aged 6–16 years who received Atomoxetine or placebo for six weeks. It represents an important part of the early evidence establishing Atomoxetine as an effective non-stimulant treatment for ADHD.

It is useful for understanding the development of Atomoxetine as a treatment option and the evidence underlying its use in children and adolescents.

Michelson et al. – Atomoxetine randomised controlled trial

Landmark Guanfacine Research

Biederman et al. – Extended-Release Guanfacine

Biederman J, Melmed RD, Patel A, et al.

A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008;121(1):e73–e84.

This multicentre trial randomised 345 children and adolescents to extended-release Guanfacine at different doses or placebo.

Guanfacine produced significantly greater reductions in ADHD symptom scores than placebo.

This is useful foundational reading for understanding the evidence supporting Guanfacine monotherapy in paediatric ADHD.

Biederman et al. – Guanfacine extended-release trial

Sallee et al. – Guanfacine in Children and Adolescents

Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial.

This nine-week randomised trial examined Guanfacine extended release in young people aged 6–17 years.

Guanfacine produced statistically significant reductions in ADHD symptoms compared with placebo. The study also demonstrated the cardiovascular effects clinicians need to understand when prescribing Guanfacine, with reductions in heart rate and blood pressure observed during treatment.

This paper is particularly helpful because it connects therapeutic efficacy with the physical monitoring required in clinical practice.

Guanfacine placebo-controlled trial

Guanfacine Compared With Atomoxetine

Hervas et al.

Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, phase III trial.

This European study compared dose-optimised Guanfacine and placebo with an Atomoxetine reference arm in children and adolescents aged 6–17 years.

Both active treatments demonstrated improvement in ADHD symptoms compared with placebo. The study also assessed functional outcomes and adverse effects. Somnolence, headache and fatigue were among the commonly reported adverse effects with Guanfacine.

This is particularly useful reading because it allows clinicians to consider symptom improvement alongside function and tolerability rather than looking solely at ADHD rating-scale scores.

Hervas et al. – Guanfacine and Atomoxetine trial

Guanfacine and Oppositional Symptoms

Connor et al.

Effects of guanfacine extended release on oppositional symptoms in children aged 6–12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial.

This study is useful for clinicians working with children who have ADHD accompanied by significant oppositional behaviour.

Children receiving Guanfacine demonstrated improvement in both oppositional symptoms and ADHD symptoms compared with placebo. Sedation-related adverse effects were common including somnolence and fatigue.

An important clinical lesson from this literature is that improvement in disruptive behaviour needs to be distinguished from simple medication-related sedation.

Connor et al. – Guanfacine and oppositional symptoms

Guanfacine as Adjunctive Treatment

Wilens et al.

A controlled trial of extended-release guanfacine and psychostimulants for attention-deficit/hyperactivity disorder.

This trial studied children and adolescents who had obtained a partial but insufficient response to a long-acting stimulant.

Adding extended-release Guanfacine produced greater improvement in ADHD symptom scores than adding placebo.

This study is useful for understanding why combination treatment may sometimes be encountered in specialist practice.

However, it should not be interpreted as meaning that stimulant plus Guanfacine should routinely be used before standard monotherapy approaches have been appropriately optimised.

Wilens et al. – Guanfacine adjunctive to stimulant treatment

Recommended Reading Priorities

For doctors with limited time, I would suggest the following order:

1. NICE NG87

Start here. Understand where Atomoxetine and Guanfacine sit within the UK treatment pathway and review the recommendations concerning baseline assessment, titration, monitoring and medication review.

2. BNF or BNF for Children

Use this alongside NICE whenever prescribing. Pay particular attention to dosing, interactions, cautions and monitoring.

3. Current Summary of Product Characteristics

Use this when initiating or adjusting the specific preparation, particularly where there are questions about missed doses, interactions, adverse effects or discontinuation.

4. Australian ADHD Clinical Practice Guideline

Useful for a broader evidence-based discussion of medication choice and comparative treatment evidence.

5. Michelson et al.

Useful foundational reading for Atomoxetine.

6. Biederman et al. and the subsequent Guanfacine trials

Useful for understanding the evidence for Guanfacine and its characteristic adverse-effect profile.

What Clinicians Should Take From the Literature

The evidence supports both Atomoxetine and Guanfacine as effective non-stimulant treatments for ADHD in appropriate populations. Their place within treatment pathways differs according to age, licensing and previous treatment.

The literature also reinforces several practical principles.

Non-stimulants generally have a slower therapeutic onset than stimulants. They should therefore not be judged using the same immediate-response expectations.

Medication effectiveness should be considered alongside functional improvement. Symptom scores are useful but treatment ultimately needs to make a meaningful difference to everyday life. Trials of Guanfacine have specifically examined functional as well as symptomatic outcomes.

Adverse effects are medication-specific. Guanfacine's effects on sedation, pulse and blood pressure are clinically important and should form part of routine treatment assessment.

Medication choice remains individualised. Guidelines provide a treatment pathway but the clinician still needs to consider previous response, tolerability, physical health, comorbidity, interactions and patient preference.

The central reading message is therefore:

Use NICE to understand where the medication fits.

Use the BNF and SmPC to understand how to prescribe it safely.

Use the research literature to understand the evidence behind the treatment.

Then apply all three to the individual patient in front of you.

7. Knowledge Check

The following questions are designed to reinforce the practical principles of prescribing and monitoring non-stimulant medication for ADHD. Select the single best answer for each question.

Question 1

A 14-year-old starts Atomoxetine following inadequate response to appropriate stimulant treatment. After one week, his parents report that they have noticed no improvement in his ADHD symptoms. He is taking the medication consistently and has no significant adverse effects.

What is the most appropriate interpretation?

A. Atomoxetine has failed and should immediately be stopped.
B. The ADHD diagnosis is probably incorrect.
C. It is too early to determine whether Atomoxetine will be effective and treatment should continue according to the appropriate titration and monitoring plan.
D. Atomoxetine should only be taken on days when symptoms are particularly severe.

Correct Answer: C

Explanation

A. Incorrect. Atomoxetine has a gradual therapeutic onset. One week without obvious improvement does not constitute an adequate therapeutic trial.

B. Incorrect. Medication response is not a diagnostic test for ADHD. Failure to respond to a particular medication would not in itself invalidate the diagnosis.

C. Correct. Provided treatment remains safe and tolerable, Atomoxetine requires sufficient time at an appropriate dose before effectiveness can reasonably be assessed.

D. Incorrect. Atomoxetine requires regular administration. It is not an "as required" treatment for individual periods of ADHD symptoms.

The key principle is:

Do not assess Atomoxetine using stimulant expectations.

Question 2

A 10-year-old starts Guanfacine. At review, his father reports that he is "much calmer". Further questioning reveals that he frequently falls asleep after school, appears tired during lessons and has stopped participating in football. His attention has not clearly improved.

What is the best interpretation?

A. The medication is clearly effective because his activity level has reduced.
B. The dose should be increased because some hyperactivity remains.
C. The apparent improvement may primarily reflect clinically significant sedation rather than adequate ADHD symptom control.
D. Sedation is irrelevant when assessing Guanfacine.

Correct Answer: C

Explanation

A. Incorrect. Reduced activity does not necessarily represent therapeutic improvement.

B. Incorrect. Increasing the dose in the presence of substantial sedation could worsen the problem.

C. Correct. Guanfacine can cause sedation and fatigue. The clinician should establish whether attention, impulsivity and functioning have genuinely improved rather than assuming that a quieter child has better-controlled ADHD.

D. Incorrect. Sedation is an important adverse effect and should form part of routine assessment.

Remember:

A sedated child is not necessarily a successfully treated child.

Question 3

Which statement about cardiovascular effects is most accurate?

A. Non-stimulant ADHD medications do not affect the cardiovascular system.
B. Atomoxetine may increase pulse and blood pressure while Guanfacine may reduce pulse and blood pressure.
C. Guanfacine usually produces substantial hypertension during treatment.
D. Cardiovascular monitoring is only necessary for stimulant medication.

Correct Answer: B

Explanation

A. Incorrect. The term non-stimulant does not mean cardiovascularly inactive.

B. Correct. Atomoxetine can increase heart rate and blood pressure in some patients while Guanfacine can produce reductions in heart rate and blood pressure.

C. Incorrect. Guanfacine is more commonly associated with reductions in blood pressure during treatment. Increases in blood pressure are particularly relevant to inappropriate abrupt withdrawal.

D. Incorrect. Appropriate cardiovascular assessment and monitoring are also required with non-stimulant medication.

The monitoring plan should reflect the specific medication, not simply whether it is labelled a stimulant.

Question 4

An adult taking Atomoxetine has been prescribed a new medication that is a strong CYP2D6 inhibitor.

Why might this be clinically important?

A. CYP2D6 inhibition may increase exposure to Atomoxetine and potentially increase adverse effects.
B. CYP2D6 inhibition causes Atomoxetine to become a stimulant.
C. CYP2D6 has no clinically relevant relationship with Atomoxetine.
D. The interaction means Atomoxetine will always become completely ineffective.

Correct Answer: A

Explanation

A. Correct. Atomoxetine is substantially metabolised through CYP2D6. Strong inhibition of this pathway can increase Atomoxetine exposure and may affect tolerability and dosing considerations.

B. Incorrect. A metabolic interaction does not change Atomoxetine into a stimulant.

C. Incorrect. CYP2D6 metabolism is clinically relevant to Atomoxetine prescribing.

D. Incorrect. CYP2D6 inhibition would not be expected to make Atomoxetine universally ineffective. The concern is altered exposure and potentially increased adverse effects.

This illustrates why ADHD medication should never be prescribed without considering the patient's full medication list.

Question 5

A 13-year-old has been taking Atomoxetine for several weeks. She develops significant deterioration in mood and reports new suicidal thoughts.

What is the most appropriate response?

A. Continue the planned titration because Atomoxetine takes time to work.
B. Reassure her that this is an expected adverse effect.
C. Undertake an appropriate mental-state and risk assessment and review the medication in the context of the clinical presentation.
D. Ignore the symptoms unless ADHD symptoms have also deteriorated.

Correct Answer: C

Explanation

A. Incorrect. A titration schedule should never take priority over clinically significant deterioration in mental state.

B. Incorrect. Suicidal thinking requires appropriate clinical assessment and should not simply be normalised as an expected treatment effect.

C. Correct. Significant mood or behavioural change and suicidal thinking require appropriate assessment. Consider severity, immediacy of risk, baseline mental health, temporal relationship with treatment, psychosocial factors and other potential contributors.

D. Incorrect. Risk assessment is required regardless of whether ADHD symptoms have improved or deteriorated.

The principle is:

New clinical information overrides the titration schedule.

Question 6

A child has been taking Guanfacine successfully for several months. His parents decide that he no longer needs treatment and ask whether they can simply stop it tomorrow.

What is the best advice?

A. Yes. All ADHD medications can be stopped abruptly.
B. Yes. Guanfacine has no clinically important withdrawal considerations.
C. Guanfacine should generally be reduced gradually according to current prescribing guidance because abrupt discontinuation can cause increases in blood pressure and pulse.
D. Guanfacine can never be discontinued once started.

Correct Answer: C

Explanation

A. Incorrect. Different ADHD medications have different discontinuation requirements.

B. Incorrect. Abrupt discontinuation of Guanfacine can have clinically important cardiovascular consequences.

C. Correct. Guanfacine should generally be tapered in accordance with current prescribing information with appropriate monitoring because blood pressure and pulse may increase following abrupt withdrawal.

D. Incorrect. Guanfacine can be discontinued when clinically appropriate but this should be done safely.

This is an important distinction between Guanfacine and many stimulant treatment arrangements.

Question 7

An adult has taken Atomoxetine intermittently for six weeks. He frequently forgets doses and estimates that he takes the medication approximately three days each week. He reports no benefit.

What is the most appropriate conclusion?

A. Atomoxetine has definitely failed.
B. The patient has not yet received an adequate therapeutic trial because adherence has been insufficient.
C. Atomoxetine should be changed to an "as required" prescription.
D. The lack of response proves that the ADHD diagnosis is incorrect.

Correct Answer: B

Explanation

A. Incorrect. A medication cannot reasonably be declared ineffective when it has not been taken sufficiently consistently.

B. Correct. Atomoxetine depends on regular administration. Before assessing efficacy, the clinician should address adherence and establish whether an adequate trial can be completed.

C. Incorrect. Atomoxetine is not an "as required" medication.

D. Incorrect. Medication response does not establish or disprove the diagnosis.

When reviewing apparent treatment failure, ask first:

Has the patient actually taken the treatment?

Question 8

A child taking Guanfacine reports dizziness when standing. His blood pressure has fallen from baseline and his pulse is lower than previously.

What is the most appropriate response?

A. Ignore the findings because Guanfacine is a non-stimulant.
B. Increase the dose because lower blood pressure demonstrates therapeutic response.
C. Assess the symptoms and cardiovascular findings and review whether the current treatment remains appropriate.
D. Diagnose anxiety without further assessment.

Correct Answer: C

Explanation

A. Incorrect. Guanfacine can have clinically important cardiovascular effects.

B. Incorrect. Reduced blood pressure is not a treatment target for ADHD and symptomatic hypotension should not be interpreted as evidence of successful treatment.

C. Correct. Dizziness, particularly when associated with changes in blood pressure or pulse, requires clinical assessment. Consider severity, postural symptoms, hydration, dose, recent titration, concurrent medication and other relevant factors.

D. Incorrect. Anxiety may cause dizziness but should not be assumed when there is a plausible medication-related cardiovascular explanation.

Treat the clinical pattern, not simply the number.

Question 9

A 15-year-old has taken Atomoxetine consistently and has completed an adequate trial at an appropriate dose. ADHD symptoms and functional impairment remain substantially unchanged.

Which statement is most accurate?

A. The dose should continue increasing indefinitely until improvement occurs.
B. The lack of response automatically means the patient does not have ADHD.
C. The clinician should review the adequacy of the trial and wider formulation then consider an alternative treatment strategy if Atomoxetine has provided insufficient benefit.
D. Atomoxetine must be continued because non-stimulants require several years to work.

Correct Answer: C

Explanation

A. Incorrect. Dose escalation should remain within appropriate prescribing guidance and should have a clinical rationale. There is no justification for indefinite escalation.

B. Incorrect. Medication response is not a diagnostic test.

C. Correct. Once adherence, dose, duration and treatment targets confirm that an adequate trial has occurred, persistent lack of meaningful benefit should prompt reconsideration of treatment. The broader formulation should also be reviewed.

D. Incorrect. Although Atomoxetine has a gradual onset, this does not mean that ineffective treatment should be continued indefinitely.

The important distinction is between:

prematurely declaring failure

and

continuing an adequately failed treatment for too long.

Question 10

Which approach best describes a high-quality review of non-stimulant ADHD medication?

A. Ask whether the patient feels different and continue medication if they say yes.
B. Review ADHD symptoms only because physical monitoring is unnecessary with non-stimulants.
C. Review adherence, dose and duration, functional benefit, adverse effects, physical observations, mental state and whether the overall benefits continue to justify treatment.
D. Continue treatment unchanged provided the medication has previously been helpful.

Correct Answer: C

Explanation

A. Incorrect. Subjective experience is useful but is only one part of treatment assessment. Gradual-onset medications may produce meaningful functional improvement without a dramatic subjective effect.

B. Incorrect. Both Atomoxetine and Guanfacine have important physical monitoring requirements.

C. Correct. A comprehensive review considers whether treatment has actually been taken, whether the trial has been adequate, what has improved, what adverse effects have emerged and whether treatment remains safe and appropriate.

D. Incorrect. Previous benefit does not remove the need for ongoing review. Physical health, mental health, circumstances and treatment requirements can change over time.

Knowledge Check Summary

The central difference between stimulant and non-stimulant prescribing is not simply the medication class. It is the clinical behaviour of the medication over time.

Atomoxetine generally requires consistent administration and an adequate period at an appropriate dose before its effectiveness can reasonably be assessed.

Therefore:

No immediate effect does not equal treatment failure.

When Atomoxetine appears ineffective, check:

adherence

dose

duration

tolerability

functional outcomes

before changing treatment.

Atomoxetine also requires appropriate physical and mental-state monitoring. Clinicians should understand its cardiovascular effects, potential CYP2D6 interactions and important safety considerations including significant changes in mood or suicidal thinking.

Guanfacine has a different clinical profile.

Particular attention should be given to:

sedation

fatigue

blood pressure

pulse

dizziness

postural symptoms

and

syncope.

Do not confuse sedation with successful ADHD treatment.

Guanfacine also has important discontinuation considerations and should generally be tapered according to current prescribing guidance rather than stopped abruptly.

Above all, non-stimulant prescribing should remain clinically purposeful.

At each review ask:

Has the medication actually been taken?

Has there been an adequate therapeutic trial?

Are ADHD symptoms improving?

Is everyday functioning improving?

Are adverse effects acceptable?

Are physical observations satisfactory?

Is mental state satisfactory?

Does the overall balance of benefit and harm justify continuing treatment?

The key lesson is:

Non-stimulant medication requires patience when assessing therapeutic benefit but prompt clinical action when significant safety concerns emerge.