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Attention-deficit/hyperactivity disorder (ADHD) is a common condition and can be quite disabling, bearing important implications on individuals’ executive function. Among women of reproductive age, 3% suffer from ADHD and, especially in moderate to severe cases, the therapeutic benefits of stimulant medications are 

Approximately 1 in 100 women were found to take ADHD medications during pregnancy, doubling the number from the late 

 Among them, a small increased risk of preeclampsia and preterm birth was 

As for teratogenicity, a study examining data from the National Birth Defects Prevention Study aimed to find associations between infants with birth defects and any maternal factors. When maternal ADHD treatment was considered, women who took ADHD medications during pregnancy (compared to those who did not) were found to have associated infants with birth defects including gastroschisis, omphalocele, and transverse limb deficiency. The study was criticized, however, for being based on a retrospective review of a small number of children with birth defects, and hence it added little value to literature related to ADHD safety in pregnancy (

Based on several population-based cohort studies, first trimester exposure to prescription stimulants was not found to be associated with increased risk of 

 A 2018 meta-analysis of 8 cohort studies did not find an association between exposure to ADHD medication throughout pregnancy and any major malformation or 

 But in another study from the United States and Nordic countries, which included 3474 methylphenidate-exposed pregnancies, researchers determined that methylphenidate was associated with an 

 of cardiac malformations (RR = 1.27; 95% CI, 0.99-1.63).

More research is needed to elucidate the safety of ADHD medications in pregnancy, including risks for birth defects. To date, all the data and studies on the pregnancy safety of these medications are restricted to live births, which may underestimate severe teratogenic effects that cause fetal demise or termination of pregnancy. The study discussed in this journal club addresses this limitation by including data from both prenatal and postnatal diagnoses of major malformations.

 What is the association between first trimester exposure to ADHD medications and major malformations?

 Cross-sectional epidemiology study of singleton pregnancies in Denmark using data from several large Danish databases.

The study population included data from 364,012 Danish singleton pregnancies with a live fetus at 12 gestational weeks (determined by ultrasound) and onwards 

between the dates of November 1, 2007 and February 1, 2014

Inclusion criteria for the exposed group in this study included any pregnancy in the first trimester after 11 gestational weeks, in which the mother was prescribed 1 or more ADHD medication (either methylphenidate, atomoxetine, modafinil, dextroamphetamine, lisdexamphetamine) from 28 days prior to conception through 70 days after conception (well into first trimester). Inclusion criteria for the unexposed group in this study were mothers who were not prescribed ADHD medications between 28 days prior to conception and 70 days after conception.

Any pregnancy in which there were fetal chromosomal abnormalities were also excluded from the study.

Information about the patients included in the study was gleaned from the following Danish databases: Danish Fetal Medicine Database, Danish National Patient Registry, Danish Medical Birth Registry, and Danish Health Services Prescription Database.

The study analyzed pregnancy outcomes for patients who were and were not exposed to ADHD medication during the first trimester. The primary endpoint for the study was defined as any major malformation overall (cardiac, central nervous system, eye, respiratory, orofacial clefts, face, digestive system, abdominal wall defect, urinary, genital, and limb). The secondary endpoints of the study were defined as either malformations of the heart or the central nervous system. Cardiac malformations were further classified into severe cardiac malformations (SCM) and non-SCM.

Other pregnancy outcomes were also considered, again comparing ADHD-exposed with unexposed groups: pregnancy terminations at 11 weeks or later, miscarriages at less than 22 weeks, stillborn/singleton at later than 22 weeks, or live born.

The study also carried out a sensitivity analysis, where first-trimester exposure was redefined as someone who has been prescribed 2 or greater ADHD medications.

The authors of the study used log-binomial regression in order to determine prevalence ratios (PR) with a 95% CI between exposed and unexposed groups. Prevalence ratios were presented as either crude, minimally adjusted, or fully adjusted. Minimally adjusted prevalence ratios included the following covariates: age and smoking status. Fully adjusted prevalence ratios included the following covariates: ethnicity, civil status, parity, age, BMI, smoking status, exposure to teratogens, exposure to antihypertensives, exposure to antidiabetics, use of other psychotropic drugs, and a diabetes diagnosis.

The following results are some of the pertinent positive and negative findings from the study. Not all of the results from the study are included below, but instead the ones that are relevant to our discussion.

For the primary endpoint, the crude PR comparing any ADHD medication vs. unexposed was 1.10 with a 95% CI between 0.77 and1.57, and the adjusted PR was 0.98, with a CI between 0.68 and 1.41. For methylphenidate vs unexposed, the crude PR was 1.09 with a CI between 0.74 and 1.61, and the adjusted PR was 1.04 with CI between 0.70 and 1.55. For modafinil vs unexposed, the crude PR was 2.87 with a CI between 1.15 and 7.15, and the fully adjusted PR was not calculated since there were too few cases to perform this type of analysis (the crude PR is also likely falsely elevated due to a small sample size with a small number of skewed results). For atomoxetine vs unexposed, the crude PR was 1.22 with a CI of 0.52 to 2.87, and the fully adjusted PR was 1.15 with a CI of 0.49-2.69.

For any cardiac malformations, crude PR for any ADHD medication vs unexposed was 2.05 (95% CI 1.17-3.59), and the fully adjusted PR was 1.75 (95% CI 1.00-3.06). For methylphenidate specifically vs unexposed, the crude PR was 2.06 (95% CI 1.11-3.80), and the fully adjusted PR was 1.65 (95% CI 0.89-3.05).

For SCM, crude PR for any ADHD medication vs unexposed was 3.63 (95% CI 1.51-8.71), and the fully adjusted PR was 3.23 (95% CI 1.35-7.74). The crude PR for methylphenidate vs unexposed was 3.49 (95% CI 1.31-9.29), and the fully adjusted PR was 2.59 (95% CI 0.98-6.90). Of note, the sample sizes for both the any ADHD medication group (5/569) and the methylphenidate group (< 5/473) were small, potentially skewing the PR as a result.

For ventricular septal defect (VSD), crude PR for any ADHD medication vs unexposed was 2.12 (95% CI 0.80-5.65), and the fully adjusted PR was 2.57 (95% CI 0.96-6.83). The crude PR for methylphenidate vs unexposed was 2.56 (95% CI 0.96-6.79), and the fully adjusted PR was 2.74 (95% CI 1.03-7.28). Of note again, the sample size of the methylphenidate group was small (< 5/473), potentially skewing the PR as a result.

For CNS malformations, crude PR for any ADHD medications vs unexposed was 2.03 (95% CI 0.76-5.39), and the fully adjusted PR was 1.66 (95% CI 0.54-5.13). Crude PR for methylphenidate vs unexposed was 2.44 (95% CI 0.92-6.48), and the fully adjusted PR was 2.03 (95% CI 0.65-6.27).

During the period between 2007 and 2014, the authors of the study also found that there was a 5-fold increase in ADHD medication use among the pregnant population in Denmark, highlighting the importance of understanding the effects of these medications in pregnancy.

Unlike previous studies exploring the association between ADHD medications and impact on pregnancy, this highly powered cross-sectional study is the first not to limit outcomes strictly to live births. Instead, the study also attempted to include data on severe malformations that led to spontaneous or induced pregnancy loss.

When zooming into statistically significant findings, exposure to any ADHD medication (methylphenidate, atomoxetine, modafinil, dextroamphetamine, lisdexamphetamine) had a higher likelihood of being correlated with cardiac malformations in comparison to the unexposed group with a fully adjusted PR of 1.75. Exposure to any of the included ADHD medication was also more likely to be correlated to SCM with a fully adjusted PR of 3.23, though this number should be considered in the context of a small sample size (5/569), and the PR could be skewed above its true value. In the study, SCM included terminations, miscarriage, death, or surgery. The study also found an association between methylphenidate usage and ventral septal defects in comparison to the unexposed group with a fully adjusted PR of 2.74. Again, this number should be evaluated in the context of a small sample size(< 5/473), and the PR could be potentially skewed.

Similar to other studies, the authors did not find any association between ADHD medications and major malformations in general. There was no clinically significant association seen between methylphenidate and malformations overall. However, this study found that there is in fact a clinically significant association between overall ADHD medication use and cardiac malformations and SCM, as well methylphenidate use and VSDs, which can help inform counseling around ADHD medication usage during pregnancy. In fact, the absolute risk and prevalence of cardiac malformations among the exposed group for any ADHD medication was 2% (12/569), which is 

1. Study population is limited to Danish women of reproductive age, hence may not be generalizable to other potentially more diverse populations.

2. The majority of exposed pregnancies (473/569, 83%) in the study were exposed to methylphenidate. As a result, conclusions related to the “any ADHD” medication group are heavily skewed towards factors related to methylphenidate usage, making it harder to glean clinical recommendations around ADHD medications more popular in North America, such as lisdexamphetamine and dextroamphetamine/amphetamine.

3. The authors do not know if all study participants actually took ADHD medications (only know it was prescribed), and the dosage of ADHD medications taken were not taken into account.

4. There was no way to account for misuse of prescribed medication and how it factors into the overall outcome.

5. The study did not take into consideration participants’ comorbid SUD history (ie, are they also using other teratogenic substances).

With the prevalence of ADHD treatment longitudinally, a greater number of women will end up on ADHD medications or wanting to continue on them during pregnancy. It is important to further elucidate the risks that these medications may impose on the fetus. From this study and previous ones, there is a signal that cardiac malformations may be associated with in utero exposure, and particularly VSD with methylphenidate products. However, the absolute risks of any major malformation are low at 2%.

When encountering patients who want to become pregnant or who are pregnant, a risk/benefit discussion about the use of ADHD medications during pregnancy should occur. This discussion should include the potential risks to the mother of untreated ADHD during pregnancy, especially during the first trimester, as compared to the potential risks of malformations, especially cardiac malformation, to the developing fetus.

is a 5th year MD, MBA candidate at Dartmouth’s Geisel school of Medicine and Tuck School of Business. 

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for

. The author reports no conflicts of interest concerning the subject matter of this article.

1. Baker AS, Freeman MP. Management of attention deficit hyperactivity disorder during pregnancy. 

2. Anderson KN, Dutton AC, Broussard CS,. ADHD Medication use during pregnancy and risk for selected birth defects: National Birth Defects Prevention Study, 1998-2011. 

3. Cohen JM, Hernández-Díaz S, Bateman BT, et al. Placental complications associated with psychostimulant use in pregnancy. 

4. Källén B, Borg N, Reis M. The use of central nervous system active drugs during pregnancy. 

5. Pottegård A, Hallas J, Andersen JT, et al. First-trimester exposure to methylphenidate: a population-based cohort study. 

6. Jiang HY, Zhang X, Jiang CM, Fu HB. Maternal and neonatal outcomes after exposure to ADHD medication during pregnancy: A systematic review and meta-analysis. 

7. Huybrechts KF, Bröms G, Christensen LB, et al. Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the International Pregnancy Safety Study Consortium. 

8. Kolding L, Ehrenstein V, Pedersen L, et al. Associations between ADHD medication use in pregnancy and severe malformations based on prenatal and postnatal diagnoses: a Danish registry-based study. 

9. Hoffman JI, Kaplan S. The incidence of congenital heart disease. 

10. Reller MD, Strickland MJ, Riehle-Colarusso T, et al. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. 

A new study provides guidance for clinicians discussing the risks of ADHD medications with their pregnant patients. 

What to Expect When Your Patients With ADHD Are Expecting 

How To Switch Stimulants: A Dosing Guide for ADHD

Getting the dose just right can be tough...

How to Switch Stimulants: A Dosing Guide for ADHD

The US Food and Drug Administration (FDA) approved the New Drug Application (NDA) for KemPharm’s AZSTARYS™, previously known as KP415, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years and older.

AZSTARYS, a once-daily product, consists of serdexmethylphenidate (SDX), KemPharm’s prodrug of d-methylphenidate (d-MPH), co-formulated with immediate-release d-MPH. 

“The FDA approval of the AZSTARYS NDA is a transformational event for KemPharm and, we believe, an important advancement in the treatment of ADHD,” Travis C. Mickle, PhD, President and CEO of KemPharm, told the press. “Today’s approval highlights both the value potential of SDX, our prodrug of d-MPH, and the ability of our LAT® platform technology to develop new prodrugs of approved medications that improve one or more of the attributes of the parent drug.”

Leading the commercialization of AZSTARYS is Corium, a portfolio company of Gurnet Point Capital (GPC), as per the definitive collaboration and license agreement between KemPharm and an affiliate of GPC. AZSTARYS could be commercially available in the US as soon as late 2021.

“Today’s approval by the FDA is met with great excitement for this innovative new ADHD therapy and the potential it holds to meet the unmet needs of children, adolescents and adults,” said Perry Sternberg, CEO of Corium. “Our team is mobilized to put our commercial plans into action as the approval of the AZSTARYS NDA now enables us to finalize our preparations for commercial launch as early as the second half of this year.”

“We look forward to continuing our support of Corium as they forge ahead with the commercial launch of AZSTARYS,” Mickle said further.

Ann Childress, MD, an investigator in the AZSTARYS clinical trial and President of the Center for Psychiatry and Behavioral Medicine, is excited about this new development. She had this to say on the NDA approval: “The ADHD industry, and specifically the MPH space, has seen little innovation in recent years, leaving prescribers and patients desiring new treatment options. In my research and practice, 3 properties are repeatedly cited by patients and their caregivers as being underserved by current ADHD medications: onset of action, duration of effect, and consistency of therapy. Having investigated AZSTARYS and directly observed its clinical impact on patients, I believe this product will be an important new tool for physicians to use in providing effective care for patients with ADHD.”

1. KenPharm. KemPharm announces FDA approval of AZSTARYS™ (serdexmethylphenidate and dexmethylphenidate capsules, for oral use, CII), a new once-daily treatment for ADHD. News release. March 2, 2021. 

https://www.globenewswire.com/news-release/2021/03/03/2185820/0/en/KemPharm-Announces-FDA-Approval-of-AZSTARYS-serdexmethylphenidate-and-dexmethylphenidate-capsules-for-oral-use-CII-A-New-Once-Daily-Treatment-for-ADHD.html

The FDA has approved the New Drug Application for a once-daily ADHD treatment. 

ADHD Treatment Gets the Green Light

Timothy Wilens, MD, talks about the presentation of the APSARD 2021 conference on ADAIR Pharmacokinetics and Pharmacodynamic Data. More on the presentation can be found 

is chief of the Division of Child and Adolescent Psychiatry and is co-director of the Center for Addiction Medicine at Massachusetts General Hospital.

What observations are being noted in the field with new agents for the treatment of ADHD?

New Deterrent Stimulants for ADHD

Previous systematic reviews estimate the 

 of attention-deficit/hyperactivity disorder (ADHD) worldwide as 5.6% to 7.2%.

 that some ethnocultural groups, such as Black individuals, are underrepresented in studies.

 found a higher prevalence of ADHD in Black than white youth, with evidence for a wide range in individual estimates for Black youth.

 Many factors may contribute to this variability.

 conducted a systematic review and meta-analysis to determine the pooled prevalence estimate of ADHD and associated individual, familial, and social factors among Black individuals, toward evidence-based and culturally adapted programs. The authors search PsychInfo, MEDLINE, Embase, Cochrane CENTRAL, CINAHL, ERIC, and Education Source from inception through October 2019. The search was designed by considering previous systematic review search strategies focused on Black participants. The authors included journal articles published in English or French with empirical data on the prevalence of ADHD samples in Black individuals in countries where they are considered a minority population (eg, United States and Canada).

The authors screened 3833 articles by title/abstract, from which they assessed 99 full-text articles for eligibility. Twenty articles met the inclusion criteria, and an additional article was found by manually searching the reference lists of these articles (

). Thus, 21 studies (24 independent samples), including 2 samples of adults, were included in the meta-analysis, all of which came from the United States.Each study was subjected to a quality assessment. Random effects meta-analysis on the proportion of 

The included studies had a combined sample size of 154,818. The pooled prevalence of ADHD was 14.5% (95% CI 10.6%-19.6%), with significant between-study heterogeneity. There was no evidence of publication bias based on a funnel plot and Kendall τ rank-order correlation. A similar pooled prevalence of 13.9% was found after excluding the 2 adult samples. Although some individual studies found sociodemographic (eg, age, sex, socioeconomic status), familial, and environmental risk factors, and risk behaviors, there were inadequate data to perform a moderation analysis, so a narrative review was performed. Some replicated risk factors (reported in 3 or more studies) include male sex, Black (versus other) race, low socioeconomic status, and 

or childhood exposure to toxic substances. The authors conducted the first meta-analysis of the prevalence and risk factors associated with ADHD in Black individuals in the United States. The 14.5% prevalence of ADHD in this population is greater than estimates from previous systematic reviews, suggesting a higher prevalence of ADHD in Black individuals.

 is a risk factor for ADHD in Black individuals, high socioeconomic status is not a protective factor. The authors noted that findings highlight the need for studies on associations between race and race-associated experiences and the diagnosis, prevalence, and risk factors associated with ADHD. Research on ADHD in other non-US Western countries should take ethnicity into account, and the absence of data from these countries is a limitation of the present study.Another limitation was the absence of inadequate data to quantitatively investigate potential moderating factors (eg, age, sex).

Findings from this meta-analysis challenge the notion that Black individuals have a lower prevalence of ADHD than other races. More research is needed to establish accurate diagnoses and culturally appropriate care for Black youth with ADHD.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Polanczyk G, de Lima MS, Horta BL, et al. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. 

Prevalence of attention-deficit/ hyperactivity disorder

Attention deficit hyperactivity disorder in African American children: what can be concluded from the past ten years?

From under-diagnoses to over-representation: black children, ADHD, and the school-to-prison pipeline

5. Cenat JM, Blais-Rochette C, Morse C, et al. 

Prevalence and risk factors associated with a ttention-deficity/hyperactivity disorder among US black individuals: a systematic review and meta-analysis

Diagnostic and Statistical Manual of Mental Disorders, 5th edition

 Arlington, VA; American Psychiatric Association: 2013.

Research on the prevalence of ADHD in Black individuals in the United States highlights the need for future research in this underrepresented group.









Busting Myths About Black Individuals With ADHD

Recent study results revealed that children with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) had a 

 in the incidence of later development of bipolar disorder (BD) compared with matched children without ADHD.

 is common, has a more severe course than either diagnosis alone, and is associated with greater risk of suicide attempts.

 Clinicians will have trouble determining which diagnosis best fits the patient, and it could be that the patient has both diagnoses. Often the patient (and/or prescriber) prefers the ADHD diagnosis and the stimulant medications used to treat it. They hope to avoid the BD diagnosis and medications used to treat it, because of the perceived stigma and complexity of treatment. The differential diagnosis is made by recognizing that bipolar (hypo)manias occur in discrete episodes of at least 4 to 7 days, whereas the hyperactivity and associated symptoms of ADHD are more or less constantly present as features of the individual’s temperament.

The comorbidity of ADHD and BD may involve overlapping genetics. In Sweden, 13,532 twin pairs (aged 9 to 12 years) were 

 using parent-rated instruments for ADHD and hypomanic episodes.

 Overlapping symptoms were removed to aid in the analysis. The twin pairs were reassessed when aged 15 years and again when aged 18 years (N = 3013 pairs). They found that genetic factors associated with hypomania explained 25% to 42% of the likelihood of ADHD’s hyperactive/impulsive symptoms. There was less effect on the inattentive symptoms of ADHD. Monozygotic twins had a stronger association of the 2 conditions than dizygotic twins. The rest of the variance was presumed to be associated with causes of ADHD that do not contribute to causing hypomania.

The bottom line of these data is that it is important to take the time to diagnose bipolar disorder accurately in patients with a history of ADHD or who are presenting with current ADHD. Mood-stabilizing medications such as lithium will usually be indicated for the bipolar condition.

Stimulant treatment of ADHD when there is comorbid BD has been controversial. However, an important 2016 study by 

 that may influence practice. This large observational study found that if patients are treated with methylphenidate for ADHD and their BD is not being treated with a mood stabilizer, the likelihood of manic switch over 3 to 6 months is multiplied by nearly 7-fold, compared with 

 not treated with methylphenidate. However, if patients are on a bipolar mood stabilizer, the addition of methylphenidate was associated with reduced odds of becoming manic, compared with the control patients with BD who were not given a stimulant, with a hazard ratio of 0.6 (ie, a 40% reduction). Thus, it seemed that methylphenidate can be safe and effective for ADHD symptoms if the patient is on a mood stabilizer to manage the BD. Note that amphetamine products were not evaluated in this Scandinavian study; many European countries have not approved these agents.

In summary, it is critically important to carefully evaluate whether patients with ADHD also have BD. If you miss the bipolar diagnosis and treat the ADHD with a stimulant, the potential for harm (ie, induction of mania) is considerable. However, if the bipolar disorder is under control with a mood stabilizer, the use of a stimulant (at least methylphenidate) need not be avoided. Indeed, it may be quite helpful.

is associate professor of psychiatry, Harvard Medical School, and co-lead psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA. He is a member of the 

 Editorial Board. The author reports no conflicts of interest concerning the subject matter of this article.

This article was originally posted ahead of print on October 30, 2020 under the title ADHD in Bipolar Patients: Genetics, Diagnosis, and Treatment, and has since been updated. -Ed

1. Meier SM, Pavlova B, Dalsgaard S, et al. 

Attention-deficit hyperactivity disorder and anxiety disorders as precursors of bipolar disorder onset in adulthood

Comorbidity of ADHD and suicide attempts among adolescents and young adults with bipolar disorder: a nationwide longitudinal study

3. Hosang GM, Lichtenstein P, Ronald A, Lundström, Taylor MJ. 

Association of genetic and environmental risks for attention-deficit/hyperactivity disorder with hypomanic symptoms in youths

4. Viktorin A, Rydén E, Thase ME, et al. 

The risk of treatment-emergent mania with methylphenidate in bipolar disorder

Although clinicians and patients may wish otherwise, the comorbidity of ADHD and bipolar disorder needs to be considered.  

ADHD in Patients With Bipolar Disorder: Genetics, Diagnosis, and Treatment

A recent finding that ADHD can begin in adulthood has surprised researchers. Here are reasons why it may be wrong.

Discovery of Adult-Onset ADHD Raises Questions

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.

 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 

 In this article we review various aspects of adult ADHD (aADHD) and suggest possible treatments.

The prevalence of ADHD in childhood is between 

 Emerging evidence indicates that ADHD symptoms may persist into adulthood in approximately 

 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 

 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, 

 < 0.001), treatment for ADHD (OR = 2.09, 

 = 0.037), comorbid conduct disorder (OR = 1.85, 

 = 0.030), and comorbid major depressive disorder (OR = 1.8, 

 = 0.019) emerged as predictors for childhood ADHD persisting into adulthood.

A meta-analysis by Simon et al, found the conservative pooled prevalence rate for adult ADHD (aADHD) to be 

 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 (

Adult ADHD results in significant impairments in the individual’s personal, social, and professional life.

 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.

 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. 

Approximately 80% of aADHD cases present with at least 1 lifetime psychiatric comorbidity.

 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).

 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.

Available evidence from family, twin, and adoption studies indicates that ADHD tends to run in families, with a high heritability rate of 74%.

 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.

 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.

 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.

 They also found lower serum docosahexaenoic acid (DHA) levels among aADHD individuals.

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.

 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.

 A meta-analysis found that right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in cADHD.

 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).

 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.

 It has been noted that individuals with aADHD have significantly lower sensory gating than controls, suggesting an impaired ability to filter incoming information.

 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.

 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.

 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. 

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.

 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.

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.

 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.

As there is significant co-occurrence of many common psychiatric disorders with aADHD, these disorders should ideally be diagnosed and treated first.

 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.

 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).

 Other medications that are used off-label include modafinil, guanfacine, venlafaxine, bupropion, and desipramine.

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.

 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.

 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.

 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.

 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.

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 

, after environmental modifications have been implemented.

 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).

 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.

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.

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. 

co-founder and managing principal, Behavioral Health Advisory Group, Princeton, NJ

is program director, Psychiatry Residency Program, Cleveland Clinic Akron General, Akron, OH; clinical professor of psychiatry at Northeast Ohio Medical University, Rootstown, OH.

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.

Desk Reference To The Diagnostic Criteria From Diagnostic and Statistical Manual of Mental Disorders

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Although normally associated with children, attention-deficit/hyperactivity disorder can also persist in adulthood, presenting challenges to both patients and clinicians. 

ADHD