Adult Attention-deficit/Hyperactivity Disorder (aADHD)

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The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) classifies attention-deficit/hyperactivity disorder (ADHD) as a neurodevelopmental disorder characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development.¹ There is growing evidence that symptoms of ADHD can persist into adulthood and can cause significant impairments in social, academic, and occupational functioning. In addition, there is emerging evidence for the existence of a different variant of adult ADHD (aADHD) where ADHD symptoms emerge for the first time in young adulthood without any symptoms being noted in childhood.² In this article we review various aspects of adult ADHD (aADHD) and suggest possible treatments.

Prevalence

The prevalence of ADHD in childhood is between 4% and 7%.³ Emerging evidence indicates that ADHD symptoms may persist into adulthood in approximately 15% to 65% of children with ADHD.⁴ Additionally, there is new evidence to suggest that adult ADHD (aADHD) is not just a continuation of childhood onset ADHD (cADHD), as many individuals do not have a history of this disorder in childhood.^5,6 It is postulated that there may be 2 distinct subtypes of aADHD: the first with childhood onset and the other with onset exclusively in adulthood. A meta-analysis evaluating the risk markers that predicted the persistence of ADHD from childhood into adulthood found that the severity of ADHD (odds ratio (OR) = 2.33, P < 0.001), treatment for ADHD (OR = 2.09, P = 0.037), comorbid conduct disorder (OR = 1.85, P = 0.030), and comorbid major depressive disorder (OR = 1.8, P = 0.019) emerged as predictors for childhood ADHD persisting into adulthood.⁵ 

A meta-analysis by Simon et al, found the conservative pooled prevalence rate for adult ADHD (aADHD) to be 2.5%.⁷ This study also found that the proportion of individuals with ADHD decreases with age, and the prevalence rates were equal among men and women. This data is in contrast to cADHD, where boys had 3 to 10 times greater prevalence rates when compared to girls. The authors also opined that the true prevalence rate of adult ADHD may be an underestimate, as some children with ADHD do not outgrow the disorder but outgrow the current diagnostic criteria (Table 1).

Prevalence of Childhood and Adult ADHD

Consequences

Adult ADHD results in significant impairments in the individual’s personal, social, and professional life.⁸ Individuals with aADHD tend to have poor self-esteem and reduced quality of interpersonal and professional relationships. These individuals are twice as likely to be divorced, when compared to age-matched controls. They also have significant educational difficulties with lower grades, greater rates of academic suspension and dropout rates, and are less likely to graduate than students without ADHD. Individuals with aADHD have greater rates of traffic violations and motor vehicle accidents, and higher rates of emergency room visits and hospital admissions. They also have lower life expectancies and higher risk for death, including accidental deaths. Individuals with aADHD are more likely to be unemployed and have a greater likelihood of being involved in criminal behaviors. The overall national annual incremental costs of ADHD ranges from $143 to $266 billion.⁹ Most of these costs were incurred by adults ($105 billion to $194 billion) compared to children ($38 to $72 billion), and the largest cost category in this group was productivity and income losses of $87 billion to $138 billion.

Comorbidities

Approximately 80% of aADHD cases present with at least 1 lifetime psychiatric comorbidity.¹⁰ The National Comorbidity Survey found that aADHD was significantly comorbid with mood disorders (OR = 2.7 to 7.5), anxiety disorders (OR = 1.5 to 5.5), substance use disorders (SUDs, OR = 1.5 to 7.9), and intermittent explosive disorder (OR = 3.7).¹¹ aADHD was also associated with greater disability in both basic functioning (self-care, mobility, and cognition) and instrumental functioning (days out of role), productive role functioning and also on social role functioning). Only 10.9% of these individuals with aADHD received treatment for ADHD in the preceding 12 months.

Heritability

Available evidence from family, twin, and adoption studies indicates that ADHD tends to run in families, with a high heritability rate of 74%.¹¹ In addition, a third of ADHD’s heritability is due to a polygenic component, indicating many common variants with each having small effects. The heritability of aADHD and cADHD appear to be very similar, although family studies indicate that there may be an increased familial liability for aADHD when compared with cADHD.¹² Twin studies that are based on self-rated symptoms among a sample of adult population show a moderate heritability rate at 30% to 40%.

Current evidence indicates that some of the same genes that may be involved in cADHD may also be involved in aADHD.¹³ Linkage studies have identified LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In a systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed among individuals with aADHD found an association between aADHD and the gene brain-specific angiogenesis inhibitor 1-associated protein 2.¹⁴ They also found lower serum docosahexaenoic acid (DHA) levels among aADHD individuals.

Neurobiology

There is evidence from neuroimaging studies that among individuals with ADHD there is a dysfunction of dopamine pathways that are involved in attention, executive function, and motivation and reward.¹⁵ Additionally, dysfunctions are also noted in noradrenergic pathways, especially those projecting into the prefrontal cortex, the central region for executive function.

A simultaneous electroencephalography and functional magnetic resonance imaging (fMRI) study found that aADHD individuals had increased medial/lateral frontal and parietal activity during the voluntary selection task on fMRI.¹⁶ A meta-analysis found that right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in cADHD.¹⁷ Additionally, these changes and alterations in limbic regions like anterior cingulate cortex and amygdala were more pronounced among non-treated individuals and these appeared to diminish over time from childhood to adulthood.

In a study that sought to delineate the neural correlates of component-specific inhibitory deficits in aADHD using fMRI, brain activation was assessed during 3 stages of behavioral inhibition, ie interference inhibition (Simon task), action withholding (Go/no-go task), and action cancelation (Stop-signal task).¹⁸ Individuals with ADHD were impaired in all tasks. It was noted that impaired interference inhibition was associated with hypoactivation in parietal and medial frontal regions. During action withholding and cancelation, individuals with ADHD displayed hypoactivation in a fronto-striatal network. These findings indicate that at least 2 disturbed neural circuits in aADHD differentially associated with deficits in separate inhibitory subcomponents. Frontal brain responses were reduced among individuals with aADHD when compared to controls during free responses, whereas parietal brain functions seemed to be unaffected. These results appear to indicate that selection processes are related to dysfunctions, predominantly in frontal brain regions among individuals with ADHD.

A study that investigated neural and behavioral correlates of visual encoding during a working memory (WM) task among young adults with aADHD found that there was ineffective allocation of attentional resources involved in encoding of information in WM.¹⁹ It has been noted that individuals with aADHD have significantly lower sensory gating than controls, suggesting an impaired ability to filter incoming information.²⁰ Additionally, increased connectivity between the default mode network and a region within left lateral prefrontal cortex (PFC) has been noted. Furthermore, greater levels of resting state activity within that area of PFC was noted to be associated with reduced performance on attentional tasks.

Diagnosis

Adult ADHD is often underdiagnosed.²¹ A common reason for this under-diagnosis is the nature of the illness, as it shares many clinical characteristics with common psychiatric disorders. These disorders include major depression, bipolar disorder, anxiety disorders, SUDs, and personality disorders. Given this overlap in symptomatology, it is recommended that aADHD should be evaluated using a dimensional rather than a categorical approach.²² Katzman et al recommend asking about long-standing and consistent problems with attention and distractibility. Additionally, inquire about complaints from the last 10 to 20 years, conceptualizing how the individual would have been as a child in a classroom. Early diagnosis and treatment of comorbid disorders appear to improve the outcomes among individuals with aADHD. (Table 2)

Potential Diagnostic Tools for ADHD

It is also recommended that the focus of the evaluation in an adult presenting with symptoms of ADHD should be on the individual’s mental state, as it adds immediate and greater clinical value than the use of cognitive or neuroimaging information.²¹ Additionally, certain symptoms like physically restless, emotional dysregulation, excessive mental wandering, and sleep-onset insomnia may suggest a diagnosis of aADHD. It is also prudent to exercise caution when evaluating individuals with aADHD, as some individuals may feign ADHD symptoms in order to obtain stimulant medications for diversion to non-medical use.¹⁵ 

To meet the DSM-5 diagnostic criteria for ADHD among adults, the individual needs to have 5 or more of the 9 symptoms of inattention and/or of hyperactivity and impulsivity.¹ These symptoms need to also have persisted for at least 6 months. In addition, several inattentive or hyperactive–impulsive symptoms should have been present prior to the age of 12 years. These symptoms should be present in 2 or more settings, including home, school, or work; with friends or relatives; in other activities. Furthermore, there should be clear impairment with/or reduced quality of social, academic, or occupational functioning. These symptoms should not occur due to another psychiatric disorder, especially due to psychotic, mood, or anxiety disorders; or due to substance intoxication or withdrawal. The DSM-5 also defines 3 clinical presentations of ADHD based on symptom profile: predominantly inattentive, predominantly hyperactive/impulsive, and a combined (inattentive and hyperactive and impulsive) presentation. The DSM-5 recommends that collateral information should be obtained, as adult recall of childhood symptoms tend to be unreliable.

Treatments

As there is significant co-occurrence of many common psychiatric disorders with aADHD, these disorders should ideally be diagnosed and treated first.² This will ensure that the best treatment can be chosen for the core aADHD symptoms. If that is not possible, co-treating these disorders may also be beneficial among individuals with aADHD.

Pharmacological agents are considered first line interventions for the treatment of aADHD.^2,23 The medications that are approved for the treatment of adult ADHD include stimulants, such as amphetamines (amphetamine, dextroamphetamine, and lisdexamfetamine) and methylphenidate (methylphenidate and dexmethylphenidate); and non-stimulants (atomoxetine).² Other medications that are used off-label include modafinil, guanfacine, venlafaxine, bupropion, and desipramine.¹⁵

Both amphetamines and methylphenidate are available as immediate release preparations requiring multiple dosing each day and sustained release preparations for once or twice daily dosing.¹⁵ The amphetamines and methylphenidate have been found equally efficacious in the treatment of aADHD, with approximately 70% of individuals reporting immediate improvement in core symptoms within 1 hour after administration of the drug. The common adverse effects of these drugs include insomnia, dry mouth, decreased appetite, weight loss, headaches, depression, and anxiety. They are contraindicated among individuals with hypertension, psychosis, or tics, as the medications may worsen these conditions. These medications need to be used with caution among individuals with serious heart disease. Stimulant medications are classified by the Drug Enforcement Agency as Schedule II substances, as they have a potential for abuse especially among individuals with SUDs.

The only non-stimulant medication that is approved for the treatment of aADHD is atomoxetine.²⁴ It appears to have lower potential for abuse than stimulant medications. It is also preferred for use among individuals with ADHD and comorbid substance use disorders, tics, anxiety, or psychosis. However, atomoxetine appears to be less effective than stimulant drugs in reducing core ADHD symptoms and requires 1 to 2 weeks of treatment to achieve full benefit.

Additionally, there is no convincing evidence that atomoxetineis safer than stimulants, and it needs to be used cautiously among individuals with cardiovascular and cerebrovascular disease. The common side effects of atomoxetine include dry mouth, insomnia, nausea, decreased appetite, constipation, decreased libido, dizziness, and sweating.¹⁵ Other non-stimulant medications that can be used off-label among individuals with aADHD include modafinil, guanfacine, venlafaxine, bupropion, and desipramine, but the evidence for their use is limited to a few small controlled studies of short duration.

In a meta-analysis that included data from 19 trials and studied 13 different drugs, the investigators found that although both stimulant and non-stimulant medications are effective treatments for aADHD, stimulant medications show greater efficacy for the short durations of treatment when compared to placebo.²⁵ However, there were no significant differences noted between short- and long-acting stimulant medications.

A systematic review of 18 published studies found that that cognitive behavioral therapy (CBT) was the most effective psychological treatment for aADHD and the comorbid symptoms of anxiety and depression.²⁶

The National Institute for Health and Care Excellence recommends prescribing medications to adults with ADHD if their ADHD symptoms are causing a significant impairment in at least 1 domain, after environmental modifications have been implemented.²³ The guideline recommends using lisdexamfetamine or methylphenidate as first-line pharmacological agents for the management of aADHD.

Another recommendation is switching between the 2 medications for adults who have had a 6‑week trial of 1 medication at an adequate dose without significant benefit. Atomoxetine was recommended if the individual cannot tolerate lisdexamfetamine or methylphenidate or their symptoms have not responded to separate 6‑week trials with either medication. The guideline recommends using non-pharmacological treatments among individuals with aADHD who have made a choice not to use medications, had difficulty adhering to medications, or found medications to be ineffective or intolerable. The guideline also recommended considering non-pharmacological treatment in combination with medication for individuals with aADHD who have benefited from medications, but whose symptoms are still causing a significant impairment in at least 1 domain. The recommendation involves elements of or a full course of CBT.

In a meta-analysis that evaluated psychostimulants (methylphenidate, dexamphetamine, mixed amphetamine salts, and lisdexamfetamine) and non-psychostimulants (such as atomoxetine) for the treatment of aADHD, the investigators found that pharmacological treatments were significantly more efficacious than placebo (standardized mean difference = 0.45) but less well accepted (odds ratio (OR) = 1.18) and tolerated (OR = 2.29).²⁷ The effects of pharmacological treatments for individuals with co-occurring ADHD and substance use disorder remains uncertain. The evidence for the effectiveness of non-pharmacological treatments for aADHD as well as the combination of pharmacological and non-pharmacological strategies was found to be preliminary.

Concluding Thoughts

Emerging evidence indicates that there may be 2 distinct subtypes of aADHD: the first that arises in childhood and persists into adulthood and the other that occurs only in adulthood. Individuals with aADHD have significant educational, social, and occupational impairments in addition to greater rates of morbidity and mortality. There also appears to be a genetic preponderance for aADHD with moderate heritability. Available evidence indicates both neurochemical and neurofunctional impairments among individuals with aADHD involving the dopaminergic and noradrenergic systems and the frontal and parietal cortices. Unfortunately, aADHD is often underdiagnosed as this condition shares many clinical characteristics with common psychiatric illnesses including mood and anxiety disorders. Stimulant medications are the treatment of choice among individuals with aADHD with similar efficacy noted for the amphetamine and methylphenidate group of drugs. Atomoxetine is the only non-stimulant medication that is approved for the treatment of aADHD. CBT has the best evidence among non-pharmacological treatments and is beneficial for those individuals who decline pharmacotherapy, are intolerant to medications, or have residual symptoms despite adequate pharmacotherapeutic trials.

Dr Tampi is chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Cleveland, OH; and professor of medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH. Ms Tampi is co-founder and managing principal, Behavioral Health Advisory Group, Princeton, NJ. Dr Elahi is program director, Psychiatry Residency Program, Cleveland Clinic Akron General, Akron, OH; clinical professor of psychiatry at Northeast Ohio Medical University, Rootstown, OH.

Disclosures

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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