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Issue 53, Sep 2016
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Can ADHD start in adulthood? Study one

Moffitt et al. Is Adult ADHD a Childhood-Onset Neurodevelopmental Disorder? Evidence From a Four-Decade Longitudinal Cohort Study. Am J Psychiatry. 2015 Oct;172(10):967-77. PubMed PMID: 25998281; PubMed Central PMCID: PMC4591104.

Editorial: Castellanos FX. Is Adult-Onset ADHD a Distinct Entity? Am J Psychiatry. 2015 Oct;172(10):929-31. PubMed PMID: 26423474.

Why is this study important?

There is increasing recognition of the importance of adult ADHD. Adult ADHD can be very impairing by itself and, in addition, it worsens the prognosis of various disorders with which it can be comorbid.

Adult ADHD is conceptualized as a continuation of childhood ADHD. The requirement of a childhood onset has always been a key criterion for the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adults. However, in many patients a history of ADHD in early childhood is absent. In recognition of this problem, in DSM-5 the age by which symptoms must be identified was raised to 12 years.

However, clinicians routinely see adults with symptoms of ADHD but without a clear history of ADHD even by the age of 12 years. Therefore, a question of great clinical importance is—can ADHD have new onset in adulthood?  Also a very important question—if ADHD can start in adulthood, is late-onset ADHD a different condition? Three recent studies from 3 different countries, have looked at these questions, have reported surprising findings, and have received a lot of press.

This first study is unique in that it has the longest follow-up ever, from childhood to age 38 years. It assessed both childhood ADHD and adult ADHD in the same cohort of participants. 

Background

Even though adult ADHD is conceptualized as a childhood-onset neurodevelopmental disorder, surprisingly, no prospective longitudinal study has described the childhoods of persons with adult ADHD.

This study provided data on follow up of ADHD cases diagnosed in childhood and follow-back data on ADHD cases diagnosed in adulthood. 

Methods

A representative birth cohort of 1,037 children born in the same town in New Zealand have been followed to the age of 38 years with a remarkable 95% retention.

Detailed data are available: symptoms of ADHD, associated clinical features, comorbid disorders, neuropsychological deficits, genetic data, and measures of functional impairment.

Data were obtained from multiple sources: the participants, parents, teachers, informants, neuropsychological test results, and administrative records.

The diagnoses of adult ADHD were made using DSM-5 criteria except age of onset and corroboration across different settings (home, work, etc.).

Results

The prevalence of childhood ADHD was 6%, with more males than females.

Childhood ADHD was associated with comorbid disorders in childhood, neurocognitive deficits, polygenic risk, and impairment that continued into adulthood.

The prevalence of adult ADHD was 3%, with equal proportions of males and females.

Adult ADHD was associated with substance dependence and functional impairment in adulthood.

Now, here’s the very surprising finding—the childhood ADHD and adult ADHD groups comprised virtually non-overlapping sets. Of the adult ADHD cases, 90% did not have a history of childhood ADHD, neuropsychological deficits on testing in childhood or in adulthood, or polygenic risk for childhood ADHD. Only 5% of the childhood cases met the full diagnostic criteria for ADHD as adults.

Another interesting and surprising finding was that among documented childhood ADHD cases, in only 23% the parents later recalled that their child had core ADHD symptoms or was diagnosed with ADHD. This is important because clinicians rely on parents to report childhood symptoms. 

Conclusions

This study suggests that adults presenting with the symptoms of ADHD may not have a childhood-onset neurodevelopmental disorder. 

Clinical Commentary

For a long time, I have been puzzled by seeing clinical patients with adult ADHD who did not have clear symptoms of ADHD as children.

As clinicians we must distinguish between patients who had subthreshold symptoms of ADHD as children and those who had no symptoms of ADHD as children.

The authors note that the study raises the “intriguing possibility… that adult ADHD is a bonafide disorder that has unfortunately been mistaken for the neurodevelopmental disorder of ADHD because of surface similarities, and given the wrong name.”

The 3 recent studies on adult ADHD discussed in this month’s GME Research Review are likely to have a huge effect on the field. They are important steps towards parsing out subgroups within the patient population currently subsumed under the term ADHD. This will likely have considerable implications for understanding the biology of these conditions and on their treatment. 

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Can ADHD start in adulthood? Study two

Caye et al. Attention-Deficit/Hyperactivity Disorder Trajectories From Childhood to Young Adulthood: Evidence From a Birth Cohort Supporting a Late-Onset Syndrome. JAMA Psychiatry. 2016 Jul 1;73(7):705-12. PubMed PMID: 27192050.

Editorial: Faraone SV, Biederman J. Can Attention-Deficit/Hyperactivity Disorder Onset Occur in Adulthood? JAMA Psychiatry. 2016 Jul 1;73(7):655-6. PubMed PMID: 27191055.)

Why is this study important?

Please see “Can ADHD start in adulthood? Study One”

Background

This study looked at the question of whether young adults with significant, impairing ADHD symptoms always have a childhood-onset of ADHD. 

Methods

This was a population-based longitudinal study.

5249 persons born in a particular town in Brazil were followed from birth to the age of 18 or 19. Of those included at birth, 81% could be followed to the end of the study.

The ADHD diagnosis was first assessed at 11 years of age using a screening instrument (hyperactivity subscale of the Strength and Difficulties Questionnaire) calibrated for a DSM-IV ADHD diagnosis based on clinical interviews with parents.

At 18 to 19 years of age, the diagnosis of ADHD was derived using DSM-5 criteria, except the criterion about age at onset. 

Results

At 11 years of age, childhood ADHD was present in 9% of the children. At 18 to 19 years of age, ignoring the age at onset criterion, 12% of participants fulfilled all the other DSM-5 criteria for ADHD.

Children with the diagnosis of ADHD at age 11 had a male preponderance (64%). However, those with an ADHD diagnosis at age 18 to 19 years had a female preponderance (61%).

Both groups had increased levels of impairment in adulthood, as measured by traffic incidents, criminal behavior, incarceration, suicide attempts, and comorbidities.

Importantly, only 17% of the children with a diagnosis of ADHD continued to have a diagnosis of ADHD as young adults, and only 13% of young adults with ADHD had the disorder in childhood.

Conclusions

The authors concluded that the findings of this study do not support the traditional assumption that adulthood ADHD is necessarily a continuation of childhood ADHD.

Rather, they suggested that there appear to be 2 syndromes that have different developmental trajectories.

Clinical Commentary

Two possible erroneous conclusions could be drawn from this study and we should be warned against them:

1. The Editorial (Faraone and Biederman, 2016) accompanying two of the articles on late-onset ADHD published together appropriately warns that the lower rates of cases meeting full diagnostic criteria in adulthood ignore the much higher rate of perisisting and impairing ADHD symptoms. That is, even if the person does not meet the full diagnostic criteria, clinically significant symptoms persist in 2/3rds of patients.

2. Before concluding that the incidence is “late-onset” ADHD is high, we should note that the fact that many persons met diagnostic criteria for ADHD at age 18 but not earlier does not mean that they didn’t have any symptoms of ADHD in childhood. Meeting the full diagnostic criteria at a later age does not necessarily imply onset of the illness at a later age.

It does seem though, that consistent with clinical experience, some persons (especially females and those with inattentive symptoms) may be less impaired in childhood and may not have the diagnosis of ADHD. However, many of these persons may, nevertheless, be significantly impaired as adults.

These observations have diagnostic implications--presence of significant, impairing symptoms and a full syndrome of ADHD in childhood may not be essential for having a diagnosis of adult ADHD. Clinicians and researchers should look at all the ways in which these two groups of patients may differ including how treatment may be approached differently.

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Can ADHD start in adulthood? Study three

Agnew-Blais et al. Evaluation of the Persistence, Remission, and Emergence of Attention-Deficit/Hyperactivity Disorder in Young Adulthood. JAMA Psychiatry. 2016 Jul 1;73(7):713-20. PubMed PMID: 27192174.

Editorial: Faraone SV, Biederman J. Can Attention-Deficit/Hyperactivity Disorder Onset Occur in Adulthood? JAMA Psychiatry. 2016 Jul 1;73(7):655-6. PubMed PMID: 27191055.)

Why is this study important?

Please see “Can ADHD start in adulthood? Study One”

Background

Limited data are available about the prospective course of ADHD into adulthood, the risk factors for its persistence, and the possibility of its later emerging in young adulthood.

This study aimed to assess childhood risk factors and young adult functioning of individuals with a persistent diagnosis of ADHD, with a diagnosis of ADHD in childhood only, and with a diagnosis of ADHD at age 18 or 19 years only. 

Methods

This study was based on a large sample of same gender twins.

The twins were evaluated for ADHD at ages 5, 7, 10, 12, and 18 years. 

Results

A total of 2040 individuals were included. Of these, 247 persons met the diagnostic criteria for childhood ADHD.

At the age of 18 years, only 22% of those with childhood ADHD continued to meet full diagnostic criteria for ADHD.

Persistence of the diagnosis of ADHD was associated with having had more symptoms as children and with lower IQ.

When those who had a persistent diagnosis of ADHD at age 18 years were compared to those who no longer had a diagnosis of ADHD as adults, individuals with a persistent diagnosis of ADHD were much more likely to have functional impairment at school/work and at home/with friends. They were also more likely to have generalized anxiety disorder, conduct disorder, and cannabis dependence.  

Now here’s an interesting finding: Among those who met diagnostic criteria for ADHD at age 18, 68% did not meet criteria for the diagnosis at any point in childhood.

How did these individuals with apparent “late-onset” ADHD differ from those in whom the diagnosis of ADHD had persisted from childhood?  Those who appeared to have “late-onset” had higher IQs and fewer externalizing problems in childhood.

Does that mean that “late-onset” ADHD was a milder form? No, at age 18 years, those with “late-onset” ADHD had similar ADHD symptoms, similar levels of impairment, and similarly elevated rates of other mental health disorders.

Conclusions

Young adults with ADHD consisted of a large group with “late-onset” ADHD and a smaller group with ADHD that had persisted from childhood.

The differences between childhood-onset and “late-onset” adult ADHD may be relevant for understanding the biology of ADHD and perhaps for its treatment.

Clinical Commentary

Two possible erroneous conclusions could be drawn from this study and we should be warned against them:

1. The Editorial (Faraone and Biederman, 2016) accompanying the two articles on late-onset ADHD published together appropriately warns that the lower rates of cases meeting full diagnostic criteria (22% at age 18 in this study) ignore the much higher persistence rate of impairing ADHD symptoms. That is, even if the person does not meet the full diagnostic criteria, clinically significant symptoms persist in 2/3rds of patients.

2. Before concluding that the incidence is “late-onset” ADHD is high, we should note that the fact that many persons met diagnostic criteria for ADHD at age 18 but not earlier does not mean that they didn’t have any symptoms of ADHD in childhood. Meeting the full diagnostic criteria at a later age does not necessarily imply onset of the illness at a later age.

It does seem though, that consistent with clinical experience, some persons (especially females and those with inattentive symptoms) may be less impaired in childhood and may not have the diagnosis of ADHD. However, many of these persons may, nevertheless, be significantly impaired as adults.

These observations have diagnostic implications--presence of significant, impairing symptoms and a full syndrome of ADHD in childhood does not appear to be essential for having a diagnosis of ADHD. Clinicians and researchers should look at all the ways in which these two groups of patients may differ including how treatment may be approached differently.

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Are buprenorphine implants better than sublingual buprenorphine for opioid dependence?

Rosenthal et al; PRO-814 Study Group. Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine: A Randomized Clinical Trial. JAMA. 2016 Jul 19;316(3):282-90. PubMed PMID: 27434441.

Why is this study important?

We are in the midst of an epidemic of opioid dependence and the number of deaths due to opioid overdose has increased.

However, our current treatments have limited efficacy. For the problem of non-adherence to opioid agonist treatment, one potential solution, attractive on the face of it, is to use medication implants that can be placed every few months. Implants may also be better because pills can be abused or given to others, while implants cannot. 

Background

This study aimed to determine whether buprenorphine implants (administered once and expected to last for the next 6 months) are non-inferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients who have been stable in their abstinence.

Methods

This was an outpatient, randomized, active-controlled, 24-week, double-blind, clinical trial.

Patients were included if they:

1. Had been taking daily sublingual buprenorphine for 6 months or more

2. Were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer

3. Were clinically stable.

177 participants (mean age, 39 years; 41% female) were enrolled.

Participants were randomized to receive either:

1. Sublingual buprenorphine plus placebo implants, OR

2. Sublingual placebo plus implants containing 80-mg of buprenorphine.

The implants were placed at the time of randomization and were expected to last for 6 months. 

Results

“Responder” was defined as being free of opioids (by self-report and urine drug testing) for 4 or more of the 6 months of the study. Of patients receiving buprenorphine implants 96% and of patients receiving sublingual buprenorphine 88% were “responders” indicating that the implants were at least not inferior to sublingual buprenorphine.

Over the 6 months, 86% of those receiving buprenorphine implants and 72% of those receiving sublingual buprenorphine were fully abstinent from opioids, a statistically significant difference in favor of the implants. 

Conclusions

In this population (adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine), changing to buprenorphine implants was not inferior to continuing sublingual buprenorphine.

In this study, the control group (sublingual buprenorphine) did unexpectedly well. In other populations where adherence to daily sublingual buprenorphine is lower, it is possible that the implants may show even greater benefits. 

Clinical Commentary

A buprenorphine implant that releases buprenorphine over 6 months was approved the United States FDA in May, 2016, and is available under the brand name Probuphine.

Use of the implant may help reduce the problems of non-adherence, misuse, or diversion to of the medication others. 

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A “milestone” in medication treatment for cocaine-dependence

Nuijten et al. Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 May 28;387(10034):2226-34. PubMed PMID: 27015909.

Editorial: Dürsteler KM, Vogel M. Effective drug therapy for cocaine dependence: a milestone. Lancet. 2016 May 28;387(10034):2171-3. PubMed PMID: 27015910.

 

Why is this study important?

Cocaine dependence is a devastating problem and success rates of available treatments are discouragingly low.

While agonist treatment can be quite successful for opioid or nicotine dependence, this has not been the case for cocaine-dependence.

The field desperately needs progress in medication treatment for cocaine dependent persons. 

Background

This study was done is a specific subset of patients. In Netherlands, where this study was conducted, heroin-assisted treatment is used and found to be effective for patients with heroin dependence. However, many of these patients being treated for their opioid dependence at heroin-assisted treatment centers continue to use cocaine.

This study aimed to evaluate the use of sustained-release dexamfetamine (in Europe they spell amphetamine as amfetamine) for the treatment of cocaine dependence in this subgroup of patients. 

Methods

This was a multicentre, randomized, double-blind, placebo-controlled trial.

The patients were treatment-refractory, defined as having had at least two earlier failed treatments aimed at reducing or abstaining from cocaine use. They were currently using crack-cocaine regularly, defined as 8 or more days per month.

Patients were randomly assigned to receive 12 weeks of daily, supervised administration of either oral sustained-release dexamfetamine (60 mg/day) or placebo. They also continued on opioid agonist treatment, either methadone or diacetylmorphine (heroin). 

Results

73 patients were randomized.

Patients who received sustained-release dexamfetamine had statistically significantly fewer days of cocaine use than those who received placebo (45 days vs. 61 days). The effect size for this difference (Cohen's d) was 0.6 indicating a moderately large effect.

Conclusions

Sustained-release dexamfetamine was a partially effective agonist medication treatment for patients with comorbid treatment-refractory cocaine dependence in heroin-dependent patients in heroin-assisted treatment. 

Clinical Commentary

Patients in this study were in a highly controlled setting. This is not a flaw in the study; it just means that the results apply only to such settings. Settings in which patients have to come daily and get supervised medication may be essential to benefiting from agonist treatment for cocaine dependence.

An accompanying editorial in the Lancet (Dürsteler and Vogel, 2016) is titled, “Effective Drug Therapy for Cocaine Dependence: A Milestone.” The editorial points out the strengths of this study: adequate power (yes, even with only 73 patients), a high enough dose of dexamfetamine, use of a longer-acting preparation, and reduced attrition due to the requirement to come to the center daily to receive the opioid.

The editorial concludes that, “Although this might not be the ‘holy grail’ of cocaine-dependence treatment, it could be an important step in the quest for an effective pharmacotherapy of this severe disorder.”

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Rajnish Mago, MD
Medical Editor, GME Research Review

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is author of "The Latest Antidepressants" and "Side Effects of Psychiatric Medications: Prevention, Assessment, and Management." Dr. Mago selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Mago the citation at [email protected].

To contact GME, email us at [email protected]


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