The State of the Art on Identifying and Treating Persons with Comorbid ADHD and Substance Use Disorders

Stephen V. Faraone, PhD on June 7, 2018

An international group of twelve experts recently published a consensus report examining the state of the evidence and offering recommendations to guide screening, diagnosis, and treatment of individuals with ADHD-SUD comorbidity.

In a clear sign that we are still in the early stages of understanding this relationship, five of the thirteen recommendations received the lowest recommendation grade (D), eight received the next-lowest (C), and none received the highest (A and B). The lower grades reflected the absence of the highest level of evidence, obtained from meta-analyses or systematic reviews of relevant randomized controlled trials (RCTs).

Nevertheless, with these limitations in mind, the experts agreed on the following points:

Diagnosis

  • The strongest recommendation, the only one based on a 2+ level of evidence (well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal) is that the “Short Version of the Adult ADHD Self-Report Scale (ASRS-SV) screener is currently the most widely used and investigated screening tool in individuals with ADHD and comorbid SUD, with good sensitivity and specificity across studies.”
  • Two other recommendations were graded C: The diagnostic process should include current and past substance abuse and seek to involve partners and relatives in evaluating symptoms and functional impairments.
  • Four recommendations got the lowest grade, D. The experts suggested starting the diagnostic process as soon as possible and focusing on drug- and alcohol-free periods in the patient’s life during history taking. They also recommended that physicians and clinical psychologists should only make diagnoses if they have extensive training in diagnosing ADHD, as well as experience with adults with ADHD and with addiction care, and that they should consider treating adults with sufficiently severe ADHD symptoms.

Treatment

  • In general, evidence was stronger in this area, and only one of the six recommendations was graded D. The other five recommendations were graded C, with the highest level of evidence being 2 (cohort or case and control studies with undetermined risk of bias), although in three cases it was level 3 (non-analytical studies, such as case reports and case series).
  • The grade D recommendation was to always consider a combination of psychotherapy and pharmacotherapy.

The grade C recommendations included considering adequate medical treatment of both ADHD and SUD; integrating ADHD treatment with SUD treatment as soon as possible;
considering psychotherapy targeting both; use of long-acting methylphenidate, extended-release amphetamines, and atomoxetine because of their low potential for abuse; and careful clinical management to avoid abuse and diversion of prescribed stimulants.

Cleo L. Crunelle at al., “International Consensus Statement on Screening, Diagnosis and Treatment of Substance Use Disorder Patients with Comorbid Attention Deficit/Hyperactivity Disorder,” European Addiction Research, published online March 6, 2018, DOI: 10.1159/000487767.

To What Extent Does ADHD Affect Sleep in Adults, and In What Ways?

Stephen V. Faraone, PhD on June 6, 2018

We are only beginning to explore how ADHD affects sleep in adults. A team of European researchers recently published the first meta-analysis on the subject, drawing on thirteen studies with 1,439 participants. They examined both subjective evaluations from sleep questionnaires and objective measurements from actigraphy and polysomnography. However, due to differences among the studies, only two to seven could be combined for any single topic, generally with considerably fewer participants (88 to 873).

Several patterns emerged. Looking at results from sleep questionnaires, they found that adults with ADHD were far more likely to report general sleep problems (very large SMD effect size 1.55). Getting more specific, they were also more likely to report frequent night awakenings (medium effect size 0.56), taking longer to get to sleep (medium-to-large effect size 0.67), lower sleep quality (medium-to-large effect size 0.69), lower sleep efficiency (medium effect size 0.55), and feeling sleepy during the daytime (large effect size 0.75). There was little to no sign of publication bias, though considerable heterogeneity on all but night awakenings and sleep quality.

Actigraphy readings confirmed some of the subjective reports. On average, adults with ADHD took longer to get to sleep (large effect size 0.80) and had lower sleep efficiency (medium-to-large effect size 0.68). They also spent more time awake (small-to-medium effect size 0.40). There was little to no sign of publication bias and there was little heterogeneity among studies.

None of the polysomnographic measurements, however, found any significant differences between adults with and without ADHD. All effect sizes were small (under 0.20), and none came close to being statistically significant.

There were four instances where measurement criteria overlapped those from actigraphy and self-reporting, with varying degrees of agreement and divergence. There was no significant difference in total sleep time, matching findings from both the questionnaires and actigraphy. On percent time spent awake, polysomnography found little to no effect size with no statistical significance, whereas actigraphy found a small-to-medium effect size that did not quite reach significance, and self-reporting came up with a medium effect size that was statistically significant. On sleep onset latency and sleep efficiency, for which questionnaires and actigraphy found medium-to-large effects, the polysomnographic measurements found little to none, with no statistical significance.

Polysomnography found no significant differences in stage 1 sleep, stage 2 sleep, slow wave sleep, and REM sleep. With the exception of slow wave sleep, there was no sign of publication bias. Heterogeneity was generally minimal.

One problem with the extant literature is that many studies did not take medication status into account. In fact, the authors concluded, “future studies should be conducted in medication naïve samples of adults with and without ADHD matched for comorbid psychiatric disorders and other relevant demographic variables.”

In summary, these findings provide robust evidence that ADHD adults report a variety of sleep problems. In contrast, objective demonstrations of sleep abnormalities have not been consistently demonstrated. More work in medication naïve samples is needed to confirm these conclusions.

REFERENCES
Amparo Díaz-Román, Raziya Mitchell, Samuele Cortese, “Sleep in adults with ADHD: Systematic review and meta-analysis of subjective and objective studies,” Neuroscience and Biobehavioral Reviews, vol. 89, p. 61-71 (2018).

Is Prenatal Exposure to Bisphenol A (BPA) Associatd with Childhood ADHD?

Stephen V. Faraone, PhD on May 31, 2018

A team of U.S. endocrinologists recently published the results of a meta-analysis examining a possible association between bisphenol A (BPA) and childhood ADHD. BPA is used in a variety of consumer products, including plastic bottles for food and drink, epoxy resins used to line cans of food, dental sealants, and the thermal receipts issued by stores.

A review of the literature found 29 rodent studies but only three with humans. The human studies were too different from each other to be suitable for meta-analysis. One found no association between prenatal exposure and ADHD. A second found prenatal BPA exposure to be associated with teacher-reported hyperactivity in 4-year-old boys, but not girls. The third found it to be associated with hyperactivity scores in 3-year-old girls.

As the authors note, “Often, there is little human data available, particularly in the environmental toxicology/health fields, due to the time and expense of conducting epidemiological studies and the ethical barriers for human controlled trials that involve human exposure to potentially hazardous chemicals. Thus, it is important to have methods for using animal data to inform human health hazard conclusions; indeed, animal models are traditionally used to study human health.”

Twelve of the mice and rat studies, with a total of 709 rodents, were suitable for meta-analysis.

Overall these pointed to a tiny SMD effect size of 0.09, but it was not significant, with the odds of such a result being obtained by chance being almost one in four (p = 0.237). But when results from the 356 males and 353 females were looked at separately, a significant sex difference emerged. There was essentially no effect on female rodents, with an effect size of -0.07 and a 95% confidence interval of -0.27 to 0.14, widely spanning the zero mark, rendering the result statistically nonsignificant. Among male rodents, however, there was a small but statistically significant effect size (0.24), with a 95% confidence interval from 0.04 to 0.45. The odds of obtaining this outcome by chance were only one in 50 (p = .02).

This result must be viewed with caution, as rodent physiology often differs substantially from that of humans. The authors therefore conclude, “early BPA exposure is associated with a presumed hazard of hyperactivity in humans. Our conclusion is based on ‘moderate’ levels of evidence for the human and ‘high’ levels of evidence for animal literature.”

REFERENCES
Johanna R. Rochester, Ashley L. Bolden, Carol F. Kwiatkowski, “Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis,” Environment International, vol. 114, p. 343-356 (2018).

Self vs Clinician Rating Scales

Lenard A. Adler, on May 24, 2018

Silverstein et al. (2017) recently published a study which reported a validation of two expanded adult ADHD scales, self-report (Adult ADHD Self Report Rating Scale (ASRS) v1.1 Symptom Checklist) and clinician/investigator (Adult ADHD Investigator Symptom Rating Scale – AISRS); both scale were expanded beyond the classic 18 DSM symptoms of inattention (IA) and hyperactivity-impulsivity (HI) to include 13 additional commonly co-traveling items of executive function deficits (EFDs) (eg. difficulty with organization, planning, task execution and procrastination) and emotional control deficits (EC) (eg. moodiness, over-reactivity of mood), creating 31 item scales.

Data was examined on 297 individuals (either referred adults with ADHD or individuals in a primary care practice, who were mostly controls) at the NYU School of Medicine. The psychometric properties of both scales were examined in terms of internal consistency (Cronbach’s alpha) and cut-off’s from normative data to predict a diagnosis. The internal consistency was high on both scales for measuring not only DSM IA and HI symptoms but also symptoms of EFD and EC (subscales ranging from 0.84 to 0.96); however, the internal consistency for EC was less for EFD, indicating that EC symptoms are less homogeneous than those of EFD, as had been suggested in a factor analysis by Adler et al (2017). Cut-off scores predictive of adult ADHD on the AISRS for dsm IA and HI 18 symptoms were between 23 and 26; this validates the empirical choice utilized in many clinical trials in adult ADHD of a cut-off score of 24.

This study highlights the importance to clinicians of assessing not only DSM symptoms of IA and HI, but also the co-traveling symptoms of EFD and EC and that clinician or self-report scales can be utilized in clinical practice. Also, the assessment of EFD and EC is especially important for clinicians as these symptom sets are less robustly responsive to pharmacotherapy than classic symptoms of IA and HI and may be more amenable to the addition of psycho-social interventions, such as cognitive behavioral therapy.

REFERENCES
Adler LA, Faraone SV, Spencer TJ, Berglund P, Alperin S, Kessler RC. The structure of adult ADHD. Int J Methods Psychiatr Res. 2017 Mar;26(1). doi: 10.1002/mpr.1555. Epub 2017 Feb 17

Silverstein MJ, Faraone SV, Alperin S, Leon TL, Biederman J, Spencer TJ, Adler LA. Validation of the Expanded Versions of the Adult ADHD Self-Report Scale v1.1 Symptom Checklist and the Adult ADHD Investigator Symptom Rating Scale. J Atten Disord. 2018 Feb 1:1087054718756198. doi: 10.1177/1087054718756198.

ADHD Screener

Lenard A. Adler, on May 17, 2018

Ustun et al. (2017) recently published an updated version of the adult ADHD screener which is validated for DSM-5: the ASRS v1.1 Screener: DSM-5. The prior DSM-IV version of the screener was established using two populations: a community-based sample from the National Co-Morbidity Survey (NCS-R) and a sample of individuals from a health care plan.

The first step was to recalibrate the new screener using these same two samples, but applying updated DSM-5 criteria; symptoms included not only core symptoms of inattention (IA) and hyperactivity-impulsivity (HI) as defined in DSM, but additional co-traveling symptoms of executive dysfunction (eg: deficits in organization, planning, working memory) or emotional dysregulation (eg: over emotionality, changeable mood).

The symptoms of executive dysfunction have been shown to carry a high symptom burden and in many ways drive the symptom presentation when present in a recent factor analysis (Adler et al. 2017). The selection and weighting of the symptoms was selected by SLIM artificial intelligence – six items were selected: four were from DSM classic symptoms of IA and HI, but two were symptoms of executive dysfunction beyond those defined in the DSM. The process was again repeated and validated in a new sample of referred individuals for ADHD evaluations and controls from primary care practices from the NYU School of Medicine as second validation. The screener is again self-report and rated on a frequency basis of 0-4 (never to very often), with a cut-off score of > = 14 indicating a positive screen. The weighting of items in the screener is not evenly distributed and the scoring algorithm will shortly be available through an educational program on this website.

The ASRS v1.1 Sceener: DSM-5 has a high degree of sensitivity and specificity (first sample: 91.4%; 96.0%, respectively; second NYU sample: 91.9%, 74.0%, respectively). Given the high sensitivity and specificity, the new screener can be a highly effective tool for clinicians to identify individuals at risk for adult ADHD who merit further evaluation and a full diagnostic evaluation.

REFERENCES
Adler LA, Faraone SV, Spencer TJ, Berglund P, Alperin S, Kessler RC. The structure of adult ADHD. Int J Methods Psychiatr Res. 2017 Mar;26(1). doi: 10.1002/mpr.1555. Epub 2017 Feb 17.

Ustun B, Adler LA, Rudin C, Faraone SV, Spencer TJ, Berglund P, Gruber MJ, Kessler RC. The World Health Organization Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale for DSM-5. JAMA Psychiatry. 2017 May 1;74(5):520-526. doi: 10.1001/jamapsychiatry.2017.0298.

ADHD and Eating Disorders

Stephen V. Faraone, PhD on May 8, 2018

ADHD Affects the Efficacy of Treatment for Eating Disorders in Adult Women

Swedish researchers examined outcomes for adult women who sought treatment at the Stockholm Centre for Eating Disorders over a period of two years and nine months. Out of 1,517 women who came to the clinic 1,143 remained eligible for the study, after excluding women whose symptoms did not fulfill the DSM-IV criteria for eating disorders or had incomplete records.

Of these, seven hundred patients could not be reached or declined to participate, leaving 443 for follow-up. To guard against the possibility that the follow-up group might not be representative of the overall treatment group, researchers compared age, body mass index, and scores on tests for depression, anxiety, compulsivity, inattention, and hyperactivity. The only statistically significant differences were small ones. The median age of the group lost to follow-up was one year younger, they were less likely to be living alone, and on average scored a single point higher on the depression test. Otherwise they were broadly similar.

The one-year follow-up on the study group found a substantial difference in rate of recovery from eating disorders between those with and without comorbid ADHD. Almost three out of four patients (72%) who scored lower (between 0-17) on the World Health Organization adult ADHD self-report scale had recovered from their eating disorder. Among those scoring 18 and higher, on the other hand, it was less than half (47%). This difference was extraordinarily unlikely (one chance in one thousand) to be due to chance (p=.001).

Another way of expressing this is through odds ratios. Those scoring 18 and up on the ADHD self-report scale were about two and a half times less likely to recover from their eating disorders following treatment. More specifically, they were about three times less likely to recover from loss of control and binging, and almost three and a half times less likely to recover from purging.

To improve outcomes, the researchers suggest “identifying concomitant ADHD symptoms and customizing treatment interventions based on this.” They specifically propose controlled clinical trials to explore the effect of combining stimulant medications with standard treatment for eating disorders.

REFERENCES
Nils Erik Svedlund, Claes Norring, Ylva Ginsberg, Yvonne von Hausswolff‐Juhlin, “Are treatment results for eating disorders affected by ADHD symptoms? A one‐year follow‐up of adult females,” European Eating Disorders Review (2018).

Identifying and Treating Persons with Comorbid ADHD and Substance Use Disorders

Stephen V. Faraone, PhD on May 6, 2018

An international group of twelve experts recently published a consensus report examining the state of the evidence and offering recommendations to guide screening, diagnosis, and treatment of individuals with ADHD-SUD comorbidity.1

In a clear sign that we are still in the early stages of understanding this relationship, five of the thirteen recommendations received the lowest recommendation grade (D), eight received the next-lowest (C), and none received the highest (A and B).

The lower grades reflected the absence of the highest level of evidence, obtained from meta-analyses or systematic reviews of relevant randomized controlled trials (RCTs).

Nevertheless, with these limitations in mind, the experts agreed on the following points:

ADHD Diagnosis

  • The strongest recommendation, the only one based on a 2+ level of evidence (well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal) is that the “Short Version of the Adult ADHD Self-Report Scale (ASRS-SV) screener is currently the most widely used and investigated screening tool in individuals with ADHD and comorbid SUD, with good sensitivity and specificity across studies.”
  • Two other recommendations were graded C: The diagnostic process should include current and past substance abuse and seek to involve partners and relatives in evaluating symptoms and functional impairments.
  • Four recommendations got the lowest grade, D. The experts suggested starting the diagnostic process as soon as possible and focusing on drug- and alcohol-free periods in the patient’s life during history taking. They also recommended that physicians and clinical psychologists should only make diagnoses if they have extensive training in diagnosing ADHD, as well as experience with adults with ADHD and with addiction care, and that they should consider treating adults with sufficiently severe ADHD symptoms.

ADHD Treatment

  • In general, evidence was stronger in this area, and only one of the six recommendations was graded D. The other five recommendations were graded C, with the highest level of evidence being 2 (cohort or case and control studies with undetermined risk of bias), although in three cases it was level 3 (non-analytical studies, such as case reports and case series).
  • The grade D recommendation was to always consider a combination of psychotherapy and pharmacotherapy.
  • The grade C recommendations included considering adequate medical treatment of both ADHD and SUD; integrating ADHD treatment with SUD treatment as soon as possible; considering psychotherapy targeting both; use of long-acting methylphenidate, extended-release amphetamines, and atomoxetine because of their low potential for abuse; and careful clinical management to avoid abuse and diversion of prescribed stimulants.

Note: Andrew Reding is a co-author on this post.

REFERENCES
1Cleo L. Crunelle at al., “International Consensus Statement on Screening, Diagnosis and Treatment of Substance Use Disorder Patients with Comorbid Attention Deficit/Hyperactivity Disorder,” European Addiction Research, published online March 6, 2018, DOI: 10.1159/000487767.

Mindfulness-Based Cognitive Therapy for Adults with ADHD

Stephen V. Faraone, PhD on April 6, 2018

A Dutch study compared the efficacy of mindfulness-based cognitive therapy (MBCT) combined with treatment as usual (TAU), with TAU-only as the control group. MBCT consisted of an eight-week group therapy consisting of mindfulness exercises (bodyscan, sitting meditation, mindful movement), psychoeducation about ADHD, and group exercises. TAU consisted of usual treatment in the Netherlands, including medications and other psychological treatment. Sixty individuals were randomly assigned to each group. MBCT was taught in subgroups of 8 to 12 individuals. Patients assigned to TAU were not brought together in small groups. Baseline demographic and clinical characteristics were closely matched for both groups.

Outcomes were evaluated at the start, immediately following treatment, and again after 3 and 6 months using well-validated rating scales. Following treatment, the MBCT + TAU group outperformed the TAU group by an average of 3.4 points on the Conners’ Adult Rating Scale, corresponding to a standardized mean difference of .41. Thirty-one percent of the MBCT + TAU group made significant gains, versus 5% of the TAU group. 27% of MBCT +TAU patients scored a symptom reduction of at least 30 percent, as opposed to only 4% of TAU patients. Three and six-month follow-up effects were stable, with an effect size of .43.

The authors concluded “that MBCT has significant benefits to adults with ADHD up to 6 months after post-treatment, with regard to both ADHD symptoms and positive outcomes.” Yet in their section on limitations, they overlook a potentially important one. There was no active placebo control. Those who were undergoing TAU-only were aware that they were not doing anything different from what they had been doing before the study. Hence no substantial placebo response would be expected from this group during the intervention period (post-treatment they were offered an opportunity to undergo MBCT). Moreover, MBCT + TAU participants were gathered into small groups, whereas TAU participants were not. We therefore have no way of knowing what effect group interaction had on the outcomes, because it was not controlled for. So, although these results are intriguing and suggest that further research is worthwhile, the work is not sufficiently rigorous to definitively conclude that MBCT should be prescribed for adults with ADHD.

Note: This post was co-authored by Andrew Reding.

REFERENCES
Janssen L, Kan CC, Carpentier PJ, Sizoo B, Hepark S, Schellekens MPJ, Donders ART, Buitelaar JK, Speckens AEM. “Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial,” Psychological Medicine (2018), https:// doi.org/10.1017/S0033291718000429

Is Cognitive Behavioral Therapy Effective for Older Adults with ADHD?

Stephen V. Faraone, PhD on March 6, 2018

Though there have been numerous studies of the efficacy of cognitive behavioral therapy (CBT) for ADHD symptoms in children, adolescents, and adults, few have examined efficacy among adults over 50. A new study begins to fill that void.

Psychiatric researchers from the New York University School of Medicine, Massachusetts General Hospital, and Pfizer randomly assigned 88 adults diagnosed with elevated levels of ADHD to one of two groups. The first group received 12 weeks of CBT targeting executive dysfunction – a deficiency in the ability to properly analyze, plan, organize, schedule, and complete tasks. The second group was assigned to a support group, intended to serve as a control for any effects arising from participating in a group therapy. Each group was split into subgroups of six to eight participants. One of the CBT subgroups was run concurrently with one of the support-only subgroups and matched on the percent receiving ADHD medications.

Outcomes were obtained for different ADHD demographics, 26 adults aged 50 or older (12 in CBT and 14 in support) and compared with 55 younger adults (29 in CBT and 26 in support). The mean age of the younger group was 35 and of the older group 56. Roughly half of the older group, and 3/5ths of the younger group, was on medication. Independent (“blinded”) clinicians rated symptoms of ADHD before and after treatment.

In the blind structured interview, both inattentive scores and executive function scores improved significantly and almost identically for both older and younger adults following CBT. When compared with the controls (support groups), however, there was a marked divergence. In younger adults, CBT groups significantly outperformed support groups, with mean relative score improvements of 3.7 for inattentive symptoms and 2.9 for executive functioning. In older adults, however, the relative score improvements were only 1.1 and 0.9, and were not statistically significant.

Given the nonsignificant improvements over placebo, the authors’ conclusion that “The results provide preliminary evidence that CBT is an effective intervention for older adults with ADHD” is premature. As they note, a similar large placebo effect was seen in adults over 50 in a meta-analysis of CBT for depression, rendering the outcomes nonsignificant. Perhaps structured human contact is the key ingredient in this age group. It may also be, as suggested by the positive relative gains on six of seven measures, that CBT has a small net benefit over placebo, which cannot be validated with such a small sample size. Awaiting results from studies with larger sample sizes, it is for now impossible to reach any definitive conclusions about the efficacy of CBT for treating adults over 50.

Note: Andrew Reding is co-author on this post.

REFERENCES
Mary V. Solanto, Craig B. Surman, Jose Ma. J. Alvir, “The efficacy of cognitive–behavioral therapy for older adults with ADHD: a randomized controlled trial,” ADHD Attention Deficit and Hyperactivity Disorders (2018)

ADHD and Acetaminophen Use During Pregnancy

Stephen V. Faraone, PhD on October 31, 2017

A recent CNN report, http://tinyurl.com/yannlfd6, highlighted a paper published in Pediatrics, which reported that pregnant women who use acetaminophen during pregnancy put their unborn child at two-fold increased risk for attention deficit hyperactivity disorder (ADHD).   In that study, acetaminophen use during pregnancy was common; nearly half of women surveyed used the painkiller during a pregnancy.   Other studies have reported similar associations of acetaminophen, also known as paracetamol with ADHD or with other problems in childhood (e.g., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300094/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177119/, https://www.ncbi.nlm.nih.gov/pubmed/24566677, https://www.ncbi.nlm.nih.gov/pubmed/24163279).

Given these prior findings, it seems unlikely that the new report is a chance finding. But does it make any biological sense?   One answer to that question came from an epigenetic study. Such studies figure out if assaults from the environment change the genetic code. One epigenetic study found that prenatal exposure, changes the fetal genome via a process called methylation. Such genomic changes could increase risk for ADHD (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540511/)/ .

Because all of these studies are observational studies, one cannot assert with certainty that there is a causal link between acetaminophen use during pregnancy. The observed association could be due to some unmeasured third factor. Although the researchers did a respectable job ruling out some third factors, we must acknowledge some uncertainty in the finding. That said, what should pregnant women do if they need a acetaminophen.   I suggest you bring this information to your physician and ask if there is a suitable alternative.