Diagnosis and Management of Attention Deficit Hyperactivity Disorder (ADHD) – Focus on Adult ADHD

HISTORY OF ADHD

The earliest description of ADHD syndrome was by Weikard in a German textbook.

Hoffman’s characters from Struwwelpeter (book of poems for children) – Fidgety Phil and Johnny Head-in-Air show several symptoms of ADHD.

The DSM-V update in 2013 includes some important changes

• Specific ADHD examples across the life span
• Increase in the age of onset criteria from 7 to 12 years
• Symptom threshold change with the cutoff for ADHD of 5 out of 9  criteria from either domain (inattention or hyperactivity-impulsivity criteria) required for a diagnosis rather than 6 criteria
• Comorbid diagnosis of autism can be made
• Placement of ADHD under the neurodevelopmental disorder section

IMPACT OF ADULT ADHD ACROSS THE LIFESPAN

ADHD can impair psychosocial functioning and impair quality of life significantly. [Faraone et al., 2015]

Patients with ADHD or a history of childhood ADHD have higher mortality rates than those without ADHD. [Dalsgaard et al., 2015]

 

The increased risk of mortality is multifactorial in origin. [Faraone, 2015]

 

The impact of ADHD across the life span is summarised in the following diagram. [Faraone, 2015]

EPIDEMIOLOGY OF ADHD

Gender:

• Male to female ratio 4:1 in clinical studies and 2.4:1 in population studies.
• In adulthood, the sex discrepancy tends to disappear which may be due to referral patterns biases or gender-specific effects on the outcome of ADHD. [Gender differences in ADHD]

Genetic Factors:

• ADHD tends to have a high degree of heritability and twin studies show that ADHD has a heritability of 70% to 80% in both children and adults.
• The inattention and hyperactivity-impulsivity are separate symptoms domain with a genetic correlation of approximately 0.6.

Environmental Factors:

• Maternal smoking and alcohol use during pregnancy.
• Premature birth
• Parental hostility – reverse causality may play a role (e.g. parental hostility due to behavioural issues in the child)
• Low Family Income
• Dose-dependent relationship between the length of maternal deprivation and the risk of developing ADHD symptoms.
• Exposure to environmental toxins such as organophosphate pesticides, polychlorinated biphenyl and zinc and lead.
• Environmental risk factors have shown not to substantially influence aetiology and play the greatest part in a non-shared, familiar environment or may act through the development of epigenetic changes.

Gene-environment interactions:

• Gene-Environment interactions may be the main mechanism by which environmental risk factors increase the risk of ADHD.
• For example, a variant in the 5-HTTLPR – the serotonin transporter encoded by SLC6A4 gene is involved in hyperactivity and impulsivity dimension of ADHD and interaction with stress.

GENETICS OF ADHD

Genome-Wide Association Study (GWAS):

• 40% of the heritability of ADHD can be attributed to common genetic variants.
• There are 4 genome-wide significant loci shared by ADHD, autism spectrum disorder, depression, bipolar disorder and schizophrenia.

Copy Number Variants (CNV’s):

• 16p13.11 – Chromosome 16p13.11 microduplication is a risk factor associated with various neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, intellectual disabilities, developmental delay and autistic spectrum disorder.
• 15q11 – 15q13 region which encodes the nicotinic α-7 acetylcholine receptor subunit.
• Glutamate receptor genes
• Neuropeptide Y gene

Other candidate genes: 

• Sodium-dependent dopamine transporter encoded by SLC6A3
• Variants in genes encoding D4 and D1B dopamine receptors
• SLC6A4 encoding the sodium-dependent serotonin transporter.
• HTR1B encoding the 5-hydroxytryptamine receptor 1B
• SNAP-25 (synaptosomal-associated protein 25)

DIAGNOSIS OF ADULT ADHD

The diagnostic criteria proposed for adult ADHD are as follows:

 

Patients with ADHD show a significant degree of heterogeneity in symptoms and impairments. The DSM-V recognised this heterogeneity and has classified three different presentations of ADHD.

[American Psychiatric Association. 2013]

 

Although there is robust evidence that ADHD frequently persists into adulthood and its presentation changes with age, adult ADHD continues to be undertreated.  This may be due to: [Young and Goodman, 2016]

1. Lack of access to services for adult ADHD.
2. The absence of a childhood diagnosis of ADHD, meaning that the adult may not receive the diagnosis of adult ADHD. The absence of childhood ADHD should not disqualify adults with ADHD from being diagnosed.
3. There have been studies that have analysed the trends and trajectories of adult ADHD and shown that ADHD symptoms may not appear until adulthood. [Agnew-Blais J et al., 2016], [Caye A et al., 2016]
4. In some cases the ADHD symptoms may decrease with age or adults may develop effective coping strategies that make their impairment less evident or may choose to work in non-challenging jobs that may further mask the disorder.
5. Also, the DSM did not recognise adult ADHD until 2013, and therefore the absence of standardised protocols has likely meant that some adults may not have been identified during a previous visit to their clinician. [Goodman, 2009]
6. Lack of standardised protocol for adult ADHD.
7. Comorbidity may have masked the diagnosis of ADHD.  Significant comorbidities include autism spectrum disorder, depression, dysthymia, anxiety disorder, personality disorder, bipolar disorder, substance use disorder including nicotine dependence and eating disorders.

Differences in presentation between childhood and adolescent ADHD and Adult ADHD

• Symptoms of hyperactivity-impulsivity tend to dissipate with age
• Symptoms of hyperactivity in adults may be experienced as inner restlessness, emotional dysregulation and executive dysfunction.

DIAGNOSIS OF ADULT ADHD [CADDRA GUIDELINES 4TH EDITION]

Step 1: History Taking:

Clinical assessment should be supplemented with questionnaires for the patient including collateral information and childhood history.  The key elements include the following:

• Confirming the presence of current impairing ADHD symptoms.
• Obtaining school records and speaking with family members to establish a childhood history.
• Evaluating the impairment observed by self and others over a lifespan.
• Complete family history for relevant psychiatric disorders, substance abuse.
• Eliminating psychiatric comorbidity.
• Use a clinical rating scale. e.g., an adult ADHD screen questionnaire should be completed such as the Adult Self-Report Scale (ASRS) which is a subset of the WHO’s 18-question Adult ADHD Self-Report Scale (Adult ASRS-V1.1).

Step 2: Medical Review Including Review of Diet and Lifestyle

After the initial information gathering step, a medical review is required to exclude any other potential causes that have similar ADHD symptoms.

In addition, a review of the nutritional and lifestyle habits of the individual is required including sleep, exercise, and substance abuse to determine the presence of any possible complications and outcomes that are specific to the patient.

Step 3: ADHD Specific Interview

If ADHD is suspected, then an ADHD-specific interview is required.

• Perinatal history
• Developmental milestones
• Impact of symptoms on learning, socialisation and independent functioning
• Symptoms of ADHD before the age of 12.
• Patient observation during the interview(Mental state examination)
• Examples of ADHD specific interviews include the CADDRA ADHD Assessment and the Diva 2.0 Diagnostic Interview.

Step 4: Feedback and Recommendations:

After reviewing the ADHD-specific assessment questionnaire, as well as considering the presence of any other psychiatric comorbidities, the following feedback and treatment recommendations can be made:

• Feedback on the diagnosis to patient and family.
• Provide resources and information to educate the patient and family.
• Evaluate potential treatment options, taking into consideration any previously described contraindications, and any available adaptation measures or strategies.

 

Supplementary assessment modalities

Neuropsychological testing:

• Neuropsychological testing may be indicated in cases of diagnostic uncertainty or for educational purposes (e.g., academic performance, IQ testing, etc.)
• Adults with ADHD may display slow performance in tasks, poor working memory and impairment in sustained attention and set shifting.

Imaging techniques:

• Brain imaging technology lacks the specificity for diagnosis and is currently mainly used for research purposes.
• However, an MRI may be useful in ruling out organic pathology.

MANAGEMENT PRINCIPLES IN ADHD

Management modalities broadly consist of pharmacological and non-pharmacological strategies. [Faraone, 2015].

Aims of treatment

• Improve symptoms
• Optimise functional performance
• Remove behavioural obstacles

Medications are the mainstay of ADHD treatment in adults.

Stimulants are more efficacious than non-stimulants and continue to be a first-line pharmacological treatment for patients of all ages with ADHD. [Faraone, 2015]

Prescribing:

The choice of stimulant is assessed by the severity of the symptoms, the presence of co-morbidities and the period when symptom relief is required.

Evidence suggests that treatment of adult ADHD with stimulants is efficacious in the short term; however, confirmation of long-term efficacy is limited.

A systematic review and meta-analysis examining the long term outcomes of treatment in ADHD concluded that [Shaw et al., 2012]:

The present analysis supports the premise that without treatment, people with ADHD often experience poorer long-term outcomes and that treatment may improve the long-term outcomes of ADHD for some individuals, but not necessarily to the degree of healthy controls.

Non-adherence is a significant issue in treatment and is associated with poor outcomes. The common reasons for non-adherence are ineffectiveness and side effects. Adherence and consistency rates improve in ADHD when using long-acting agents and stimulants.

The persistence and adherence to psychostimulants and psychological well-being were examined in adults with ADHD in a naturalistic follow-up (n=96) for up to 3 years. [Bijlenga D et al., 2017]

Nonadherence was related to worse general functioning, lower mood, and poorer sleep quality. Risk factors for non-adherence are female sex, higher educational level and a combined ADHD subtype.

More studies are needed to examine the rates of non-adherence in adults, predictors of non-adherence and the associated outcomes.

MEDICATION IN ADULT ADHD

Medications are divided into stimulants and non-stimulants.

 

 

The risks of serious side effects associated with stimulants and non-stimulants for treating ADHD are low for healthy adults.

A large study from the US showed that MPH, AMPH and atomoxetine did not increase risk of serious cardiovascular events in children and young adults. [Cooper et al., 2011]

However, caution is to be exercised when prescribing to patients with cardiovascular disease.

In cardiovascular disease, a cardiologist opinion should be sought and if prescribed blood pressure is to be monitored.

Stimulants should be used cautiously or avoided in cases of anxiety, tic disorders, bipolar disorder, substance use and seizures.

MANAGEMENT OF CO-MORBIDITIES IN ADHD

ADHD is a highly comorbid condition and the nature of the co-morbidity will influence management. ADHD and Comorbidities – Management Principles

Management of comorbidity in ADHD

The dictum is to address the most serious disorder first. Once the disorder is addressed, ADHD can then be treated. Therefore, combined treatments are frequently used in the management of comorbid ADHD.

 

STIMULANT MEDICATION IN ADHD

When considering prescribing a stimulant one can choose between a methylphenidate product or an amphetamine product.

The efficacy for both is similar, but there are individual differences in response and tolerability. There are no reliable predictors of patient response to one or the other.

Methylphenidate (DAT and NAT Inhibitor):

Mechanism of action:

Methylphenidate (MPH) non-competitively blocks the reuptake of dopamine and noradrenaline into the terminal by blocking dopamine transporter (DAT) and noradrenaline transporter (NAT), increasing levels of dopamine and noradrenaline in the synaptic cleft.

Metabolism and Half-life:

Methylphenidate is metabolised primarily by de-esterification to α-phenyl-piperidine acetic acid (PPAA) which has little or no pharmacologic activity.

Carboxylesterase-1A1 (CES-1), located in the stomach and liver, is the primary enzyme involved with first-pass MPH metabolism.

Elimination half-life that is independent of the preparation of MPH (2.5 to 3.5 hours after oral administration

Methylphenidate Immediate Release (Ritalin)

• Ritalin is a racemate consisting of a 1:1 mixture of d-threo methylphenidate (d-MPH) and l-threo methylphenidate (l-MPH).
• Available as a tablet
• Onset – 20 to 60 minutes
• Duration of action – 2 to 4 hours.
• Dosing – Dose initially 5 mg to 10 mg titrated up in weekly increments by 5 mg to 10 mg to a maximum of 2.1 mg/kg/day, maximum dose 60 mg daily.
• Recommended monitoring blood pressure, pulse, appetite
• Monitor for insomnia, mood changes and development of tics.

Methylphenidate is also available in the extended-release version.

Ritalin LA (Long-acting)

• Ritalin LA is available in capsule form.
• One Ritalin LA capsule contains 10 mg, 20mg, 30mg,40mg or 60 mg of methylphenidate hydrochloride.
• Each modified-release, the hard-gelatin capsule contains half the dose as immediate-release beads and the remaining half of the dose as enteric-coated, delayed-release beads. This provides an immediate release of methylphenidate followed by a delayed release of methylphenidate.
• Duration of action – 6-8 hours
• These beaded preparations are useful for children who cannot take or who dislike taking pills, as parents can open the capsules and sprinkle the medicine on their child’s food.

Concerta:

• Methylphenidate XR (Concerta) uses an osmotic release oral system (OROS) which has an osmotic pump mechanism that creates an ascending profile of MPH in the blood, providing effective treatment for up to 10 to 12 hours.
• Approximately 25% of the methylphenidate is delivered immediately, with the remaining 75% released gradually for sustained symptomatic relief.
• Available in doses of 18 mg, 27 mg, 36 mg, and 54 mg.

Amphetamine (AMPH):

Amphetamine has a d-isomer and an l-isomer.

The d-isomer is the active isomer.

Mechanism of action

Amphetamine has the following mechanisms:

1. Competitive inhibitor at DAT competing with dopamine and noradrenaline at NAT.
2. Competitive inhibitor of VMAT

3. High levels amphetamine will lead to the displacement of dopamine from the vesicle into the terminal

4. Reversal of DAT.

Metabolism:

All types of AMPH are metabolised in the liver by side-chain oxidative deamination and by ring hydroxylation since acidification of the urine increases the urinary output of AMPH.

Therefore, taking medicine with ascorbic acid or fruit juice may decrease its absorption, while the use of alkalinising agents (e.g., sodium bicarbonate) may increase AMPH absorption.

Dexamphetamine (d-amphetamine) and lisdexamfetamine:

D-amphetamine is a competitive inhibitor of DAT, NAT, and VMAT.

Lisdexamfetamine is a prodrug of d-amphetamine which is linked to the amino acid lysine.  It is cleaved to compounds d-amphetamine and inactive L-lysine.

Lisdexamfetamine is converted to dexamphetamine and L-lysine, not by cytochrome P450 enzymes metabolism, but by metabolism in blood primarily due to the hydrolytic activity of red blood cells. [PI]

 

Dexamphetamine (d-amphetamine)

• Onset of action – 20 to 60 minutes.
• Duration – 3 to 6 hours.
• Dosing: Starting 2.5 mg to 10 mg daily titrated at weekly increments of 2.5 mg to 5 mg daily.  Recommended doses are 0.3–1.5 mg/kg with a maximum of 60 mg a day for adults.

Lisdexamfetamine

• Onset – approx 90 minutes.
• Duration – 13 plus hours
• Doses: 30 mg, 50 mg, 70 mg.

Following administration, conversion of lisdexamfetamine to d-amphetamine occurs in approximately 1.5 hours, with duration from 1.5 to 13 hours in children and 2 to 14 hours in adults.

Food prolongs time to peak plasma concentration by approximately 1 hour.

The prodrug nature of Lisdexamfetamine, its rapid uptake from the gut, and its rate-limiting hydrolysis in the blood to produce active d-amphetamine have several important clinical implications.[Sharman and Pennick, 2014]

• The profile of d-amphetamine delivery by Lisdexamfetamine underlies its long daily duration of action in relieving ADHD symptoms.
• Oral administration of Lisdexamfetamine results in systemic exposure to d-amphetamine that is proportional to the Lisdexamfetamine dose and that exhibits low intraindividual and interindividual variability.
• Low potential for pharmacokinetic interactions
• Less ‘drug-liking’ effects

Other Extended-release dexamphetamine formulations:

An extended-release mixed amphetamine salt formulation is a dual-pulse capsule preparation that includes both immediate- and extended-release beads. This formulation is not available in Australia.

Adverse effects:

Common: Insomnia, decreased appetite, dysphoria, irritability

Rare: anxiety, depression, psychosis, mania

 

EFFECT OF STIMULANTS ON THE PREFRONTAL CORTEX NORADRENALINE AND DOPAMINE

The prefrontal cortex (PFC) is implicated in the neurobiology of ADHD. Optimal prefrontal cortex functioning is dependent on an optimal balance of NA and DA in the PFC.

 

Advantages of Immediate-release vs extended-release stimulants

Immediate release stimulants result in pulsatile dopamine release which can mimic actions of DA in substance use which could result in compulsive use and dependence.

Pulsatile dopamine release can also lead to high dopamine levels which can induce a stress like state.

Extended-release stimulants  provide a slow rising constant steady state level which reduces risk of dependence.

ATOMOXETINE AND BUPROPION IN ADHD

Mechanism of atomoxetine:

Atomoxetine is a selective norepinephrine reuptake inhibitor or NARI, resulting in increased noradrenaline or dopamine levels in the prefrontal cortex.

Metabolism:

Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway.

Duration of action: 24 hrs

Dosing: Total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening.

After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response

Indications for Atomoxetine:

• Need 24 h symptom coverage
• Have tics or comorbid anxiety symptoms that are worsened with stimulants
• Experience resistance and side effects to stimulant medications, including problems with worsening sleep
• Have concurrent Substance use disorder
• Have comorbid enuresis

Side effects: dry mouth, insomnia, nausea and vomiting, decreased appetite and irritability.

Although suicidal ideation and behaviour is a precaution for the prescription of atomoxetine, treatment of individuals aged 5 to 18 with atomoxetine compared with stimulants was not significantly associated with an increased risk of suicidal events.

Bupropion

Mechanism of action:

Bupropion is a norepinephrine and dopamine reuptake inhibitor resulting in increased levels of norepinephrine and dopamine in the synaptic cleft.

 

ALPHA 2 - ADRENERGIC AGONISTS

 

Both clonidine and guanfacine stimulate Alpha-2 adrenergic receptors pre and post-synaptically.

Clonidine

Mechanism action of clonidine:

• Alpha-2 adrenergic receptors are present at high levels in the prefrontal cortex.
• The alpha 2 agonists clonidine and guanfacine mimic norepinephrine (NE) actions in the PFC through the stimulation of postsynaptic alpha 2A receptors on PFC neurons
• Presynaptic stimulation of alpha-2 receptors reduces the firing of presynaptic neurons releasing norepinephrine into the prefrontal cortex which improves the impulsive and hyperactive behaviour seen in attention-deficit/hyperactivity disorder
• Adjunctive effects on serotonin and γ-aminobutyric acid receptors make α-2 agonists the most widely used medications to treat insomnia in children with attention-deficit/hyperactivity disorder
• Clonidine stimulates α-2 adrenergic postsynaptic receptors and increases noradrenaline signalling to normal levels.
• Clonidine also binds the imidazoline receptors contributing to the hypotensive effect.
• Dose – The extended-release version was approved by the FDA for monotherapy or adjunctive treatment at doses of 100 mcg – 400mcg /day. (Children aged 6-17)
• Duration of action – 3-5 hours
• Half-life – 6-23 hours

Guanfacine

Mechanism  of action:

• Guanfacine is selective for alpha 2A receptors and exhibits therapeutic efficacy with a reduced side effect profile compared to clonidine, enhancing prefrontal cortical functioning leading to behavioural improvement.
• The recommended starting dose for guanfacine is 1 mg once a day.
• Maximum dose 4 mg/day (6-12 years); 7 mg/day (13-17 years)
• For adjunctive treatment with stimulants maximum recommended dose is 4 mg/day.
• Duration of action: 24 hours
• Half-life – 17 hours
• Discontinuation should be gradual to avoid rebound hypertension.

Alpha 2 adrenergic agonists can be administered once or twice daily combined with therapeutic stimulants, atomoxetine or long-acting in patients who are unresponsive to monotherapy.

REFRACTORY ADHD

Strategies in refractory ADHD include: [Young and Goodman, 2016]

• Increasing dose of current medication
• Switching to another stimulant
• Lisdexamfetamine can be an alternative for ADHD patients with an unsatisfactory response to MPH or AMPH
• Combining stimulants with a non-stimulant medication such as atomoxetine, guanfacine or clonidine
• Bupropion, Desipramine and Nortriptyline

NON-PHARMACOLOGICAL INTERVENTIONS

Nonpharmacological treatments: [CADDRA Guidelines 4th Edition], [Faraone, 2015]

Dietary interventions: 

• The best evidence of supplementation is for omega-3 with small clinical effects.
• There is insufficient evidence to recommend other vitamins as a supplement
• Phosphatidylserine (PS) monotherapy, a fat-soluble amino acid derivative found at high levels in the brain found an improvement of ADHD symptoms and short-term auditory memory in children
• Exclusion diets have also demonstrated positive effects but again small effects.

Behavioural interventions:

• These are based on the principles of positive and negative reinforcement, social learning and parent-child relationships.
• CBT  (e.g. self-control training, problem-solving, use of compensatory strategies, diaries or time schedules). CBT is beneficial in combination with medication for adolescents and adults.
• CBT helps reduce impairments resulting from executive dysfunction that is not optimally addressed with medication.

Life management coaching skills

• Highly individualised intervention in which a coach guides the patient in achieving tasks and goals.

Neurofeedback (NF):

• NF consists of measuring the brain wave activity of participants in real time and using adaptive reward-based techniques when EEG readings show brain activity that is correlated with focus, attention and problem-solving.
• Theta and beta brain waves in the right prefrontal cortex are measured. Beta waves are associated with thinking, focusing and sustaining attention whereas theta waves are linked to distractibility.
• ADHD is believed to be caused by dysfunction in the right
  prefrontal cortex. Therefore, it is hypothesised that lowering the theta-beta ratio in the right prefrontal cortex is a means of increasing focus.
• Slow cortical potential protocol (SCP) and theta-beta ratio (TBR) are the most common treatment protocols.
• A recent meta-analysis in 2018 showed sustained clinical benefits in both inattention and hyperactivity-impulsivity domains after NF over an average 6–12 month follow-up period, compared to control groups. [Van Doren et al., 2019]

The authors conclude:

As such, NF can be considered a non-pharmacological treatment option for ADHD with evidence of treatment effects that are sustained when treatment is completed and withdrawn.

• Guidelines, however, have not yet explicitly recommended NF as routine treatment in ADHD.

Read Evidence Based Summary of the ADHD International Consensus Statement

FUTURE DEVELOPMENTS IN ADHD

Future developments can be conceptualised based on the pathogenesis of ADHD at different levels. [Tripp and Wickens,2009]

Genetic advances

• GWAS and use of exome sequencing or whole-genome sequencing technologies
• Neuroimaging genetic studies via large multicentre collaborations such as the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium.

Clinical Advances

• Refining current diagnostic criteria to better suit diagnosis with the best symptom thresholds across the life span

Biomarkers

• Future biomarkers may be obtained via machine learning for better predictive accuracy

Pharmacological advances 

Newer agents acting via

• Nicotinic acetylcholine receptors
• Glutamate
• GABA
• Serotonin
• Neurite outgrowth or endosomal systems

Developments in non-pharmacological approaches

• Diet
• Mindfulness
• Neurofeedback
• Cognitive training
• Computer gaming

Increased real-world research using pragmatic RCT’s

 

CONCLUSION

ADHD is a treatable condition that begins in childhood and adolescence which in many cases can persist during adulthood.

Cases of Adult ADHD are and undertreated which can have a significant impact on the individual and societal level.

Clinicians are advised to have a high index of suspicion for Adult ADHD as part of routine assessment of patients presenting with psychological distress.

Read the ADHD International consensus statement by the World Federation of ADHD.