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September 13, 2024

Population Study: Stimulants Shown to Reduce Hospitalization and Suicidality

Swedish Population Study Suggests Stimulants Reduce Hospitalization and Suicidality, Have No Significant Effect on Work Disability

A meta-analysis of short-term, placebo-controlled, randomized clinical trials (Cortese et al. 2018), looking at both efficacy and safety, supported prescribing stimulants – methylphenidate use in children and adolescents and amphetamine use in adults – as first-choice medications. 

However, these were short-term studies, and they focused on relieving ADHD symptoms. What about longer-term outcomes, especially looking more broadly at functional impairment and overall quality of life? 

Sweden has a single-payer health insurance system that encompasses virtually every resident and is linked to national registers that enable researchers to conduct nationwide population studies. 

A joint Finnish-Swedish research team used Sweden’s registers to study outcomes for all individuals of working age, 16 to 65 years old, living in Sweden who had received a diagnosis of ADHD from 2006 through 2021. The resulting study cohort encompassed 221,714 persons with ADHD. 

The team adjusted for the following confounding variables: Genetics, baseline severity of symptoms, baseline comorbidities, temporal order of treatments (which medication was used as first, second, third, and so forth, including also nonuse of ADHD medications), time since cohort entry, and time-varying use of psychotropic drugs, including antidepressants, anxiolytics, hypnotics, mood stabilizers (carbamazepine, valproic acid, and lamotrigine), lithium, antipsychotics, and drugs for addictive disorders. 

With these adjustments, they discovered that amphetamine treatment was associated with a roughly 25% reduction in psychiatric hospitalization relative to unmedicated ADHD. Lisdexamphetamine was associated with a roughly 20% reduction, dexamphetamine with a 12% reduction, and methylphenidate with a 7% reduction. All four medications are stimulants

None of the non-stimulant medications – atomoxetine, guanfacine, clonidine – had any significant effect on psychiatric hospitalization. Nor did modafinil a drug that is not FDA approved for ADHD but is sometimes used when other drugs fail. 

Amphetamine was also associated with the greatest reduction in suicide attempts or deaths, with a roughly 40% decline relative to unmedicated ADHD. Dexamphetamine was associated with a roughly 30% decline and lisdexamphetamine with a roughly 25% decline. The stimulant methylphenidate was only associated with an 8% reduction, and modafinil had no significant effect. 

Surprisingly, non-stimulant medications were associated with significant increases in suicide attempts or deaths: 20% for atomoxetine, 65% for guanfacine, and almost double for clonidine

Amphetamine and lisdexamphetamine also reduced the risk of nonpsychiatric hospitalization by more than a third compared to unmedicated ADHD. Dexamphetamine was associated with a risk reduction of more than 25%, methylphenidate with 20% lesser risk.  

The non-stimulant atomoxetine was associated with a roughly 15% reduction in risk of nonpsychiatric hospitalization. But neither guanfacine nor clonidine had any significant effect. 

Turning to work disability, atomoxetine was the only ADHD medication associated with a reduction – a roughly 10% improvement. All other medications had no significant effect

The team concluded, “In this cohort study of adolescents and adults with ADHD, the use of medications for ADHD, especially lisdexamphetamine and other stimulants, was associated with decreased risk of psychiatric hospitalizations, suicidal behavior, and nonpsychiatric hospitalizations during periods when they were used compared with periods when ADHD medication was not used. Non-stimulant atomoxetine use was associated with decreased risk of work disability.” 

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Is there an association between asthma and ADHD?

Is there an association between asthma and ADHD?

An international team of researchers has carefully examined the best current evidence and found strong evidence for an association between asthma and ADHD by combining a meta-analysis of prior data with a new analysis of the Swedish population.

The meta-analysis identified 46 datasets with a total of more than 3.3 million persons.  It computed an unadjusted (odds)'s ratio (OR) of 1.7, which indicates that ADHD patients have about twice the risk of developing asthma compared with people without ADHD. Limiting the meta-analysis to studies that adjusted for confounding factors, 30 datasets with more than a third of a million participants still led to an adjusted (odds)' ratio of 1.5 (95% CI 1.4 - 1.7). The likelihood of obtaining this result by chance in such a large sample would be less than one in ten thousand.

When the team further checked this result against the results for the Swedish population of more than one and a half million persons, the (odds)  ratio was almost identical to 1.6. Adjusting for confounding factors reduced it to 1.5 (95% CI 1.41 - 1.48). That means the findings are very robust: asthma and ADHD are associated, with an (odds)'ratio of 1.5, after adjusting for confounding factors.

What does this small but statistically very reliable association between asthma and ADHD mean? For researchers, it suggests that the two disorders may have common risk factors and that the search for these shared risk factors might lead to improved treatments.  These risk factors might also be shared with two other somatic conditions for which ADHD patients are at increased risk: obesity and eczema.  Common inflammatory processes may account for this overlap among disorders.  Clinicians should be aware that children with asthma have an increased risk for ADHD, although, given the small association, systematic screening may not be warranted.  But given that ADHD might interfere with asthma medication compliance, the disorder should be considered among noncompliant youth, especially among those who show other evidence of inattention, poor memory, or disorganization.

June 12, 2021
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ADHD Affects the Efficacy of Treatment for Eating Disorders in Adult Women

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 Center for Eating Disorders over two years and nine months. Out of 1,517 women who came to the clinic, 1,143remained 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 to age, body mass index, and scores on tests for depression, anxiety, compulsively, 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 the 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 scoring18 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, thy were about three times less likely to recover from the 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

June 10, 2021
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Mindfulness-Based Cognitive Therapy for Adults with ADHD

Mindfulness-Based Cognitive Therapy for Adults with ADHD

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 meditation exercises (body scan, sitting meditation, mindful movement), psychoeducation about ADHD, and group exercises. TAU consisted of usual treatment in the Netherlands, including medications and other psychological treatments. 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 3.4points on the Conner's 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, about 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.

June 8, 2021
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Is Cognitive Behavior Therapy Effective for Older Adults with ADHD?

Is Cognitive Behavior Therapy Effective for Older Adults with ADHD?

Though there have been numerous studies on 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 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 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, were 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 and0.9 and were not statistically significant.

Given the non-significant 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 non-significant. 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.

June 6, 2021
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Digital Media Use and ADHD

Digital Media Use and ADHD

A two-year study examined the effect of digital media use on ADHD symptoms in over 2500 adolescents. An earlier meta-analysis found that traditional media use (TV and video console games) was modestly associated with ADHD-like behaviors (Nikkelen et al 2014). The current study extends the examination to a large sample, with modern digital media delivery of high-intensity stimuli, including mobile platforms.

The authors used the Current Symptom Self-Report Scale (Barkley R 1998) to establish ADHD symptoms at baseline and six-month assessments over 24 months. None of the subjects reported having ADHD, study entry. Subjects were considered to be ADHD symptom-positive (the primary binary outcome) if they had greater than or equal to six inattentive and/or hyperactive-impulsive symptoms rated on this frequency-based scale (0-3). Modern digital media use was surveyed on a frequency basis for 14 media activities(including checking social media sites, texting, browsing, downloading or streaming music, posting pictures, online chatting, playing games, online shopping, and video chatting). The most common media activity was the high-frequency checking of social media. Of note, high-frequency engagement in each of the digital media activities was significantly, but moderately, associated with having ADHD symptoms at each six-month follow-up (OR 1.10), even after adjusting for covariates. High-frequency media use at baseline seemed to be associated with the development of ADHD symptoms.

Among the 495 students who reported no high-frequency media use at baseline, 4.6% met ADHD symptom criteria at follow-up. Among 114 students scoring 7 for high-frequency media use at baseline, 9.5% met the symptoms criteria. For the 51 students with a score of 14 for high-frequency media use at baseline, the rate was 10.5% (both comparisons were statistically significant).

This study is important in that it notes that an association between high-frequency digital media use (in current platforms and modalities) may be associated with the development of ADHD-like symptoms. A significant limitation of the study, as noted by the authors, is that ADHD-like symptoms do not establish a diagnosis of ADHD and do not assess impairment; therefore, these results must be interpreted with some caution. It does highlight that even with the current level of understanding, it might be prudent for clinicians to recommend limiting high-frequency media use for adolescent patients.

October 9, 2023
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The State of the Art on Identifying and Treating Persons with Comorbid ADHD and Substance Use Disorders

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

An international group of twelve experts recently published a consensus report examining the state of the evidence and offering recommendations to guide the 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:

Diagnosis

  •  The strongest recommendation, the only one based on a 2+ level of evidence (well-conducted case-control or cohort studies with allowing 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.

Treatmen

  •  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;

June 2, 2021
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Assessing Undertreatment and Misuse of ADHD Medications on Four Continents

Assessing undertreatment and misuse of ADHD medications on four continents

To what extent are ADHD medications insufficiently used to address properly diagnosed ADHD? To what extent are they misused by persons who are either undiagnosed or improperly diagnosed?
In search of answers, an international team of researchers from Brazil, the United Kingdom, and the United States conducted a systematic review of the peer-reviewed literature and a meta-analysis of studies from four continents - South America, North America, Europe, and Australia.

The benchmarks set for proper ADHD diagnosis were any of the following:
·        Criteria established in the Diagnostic and Statistical Manual of Mental Disorders (DSM)or the International Statistical Classification of Diseases and Related Health Problems (ICD), confirmed by validated diagnostic instruments or clinical interviews.
·        Use of validated ADHD symptom scales with pre-specified thresholds.
·        Participants or caregivers affirming ADHD diagnosis by a physician.

Medications reviewed were those recommended by the majority of the international guidelines-both stimulant(methylphenidate, dexmethylphenidate, amphetamines), and non-stimulant (atomoxetine).
The team excluded studies relying on the insurance health system and third-party reimbursement datasets because the focus was on rates of ADHD medication use in the entire population rather than among individuals searching for treatment.
A meta-analysis of18 studies with a total of 3,311 children and adolescents properly diagnosed with ADHD in seven countries on four continents (Canada, United States, Australia, Brazil, Netherlands, England, Venezuela) found an overall pharmacological treatment rate of only 19%. There was considerable variation, with the highest treatment rates in the United States (frequently over 40%) and the lowest treatment rates in Brazil, Venezuela, and Canada (under 10%). There was no sign of publication bias.
A second meta-analysis pooled 14 studies with a total of 29,559 children and adolescents without a proper diagnosis of ADHD in five countries on four continents (United States, Canada, Venezuela, Australia, Netherlands). Roughly 1% were using ADHD medications. Again, there was considerable variation, with the highest rates of medication misuse being reported in the United States and Venezuela (3-7%). Again, there was no sign of publication bias.
The authors cautioned, "it is important to note that even though the data collected constitute the most comprehensive evidence available in the literature and response/completion rates observed are acceptable, it does not constitute a world representative sample." Also, the predominance of samples from prosperous countries "most certainly inflates the treatment rates due to the exclusion of a large proportion of the world population with significant financial, cultural, and health access barriers to ADHD treatment."
They concluded, "Despite these limitations, our meta-analysis provides evidence for substantial undertreatment of children and adolescents affected by ADHD in different countries. This is a relevant public health issue worldwide since ADHD under treatment is associated with known negative outcomes in education, healthcare, and productivity systems. At the same time, we found evidence of overtreatment/misuse in individuals without a formal ADHD diagnosis. This practice might expose individuals to undesirable side effects of medications, increased risk of medication misuse, and unmeasured costs for the health care system."

May 31, 2021
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Can ADHD be Treated with Fish Oil?

Can ADHD be Treated with Fish Oil?

If you've been reading my blogs about ADHD, you know that I play by the rules of evidence-based medicine. My view is that the only way to be sure that a treatment 'works' is to see what researchers have published in scientific journals. The highest level of evidence is a meta-analysis of randomized controlled clinical trials.  For my lay readers, that means that many rigorous studies have been conducted and summarized with a sophisticated mathematical method. If you are interested in fish oil as a treatment for ADHD, there is some good news.  Many good studies have been published and these have been subjected to meta-analysis. To be more exact, we're discussing omega-3 polyunsaturated fatty acids (PUF As), which are found in many fish oils. Omega-3 PUF As reduces inflammation and oxidative stress, which is why they had been tested as treatments for ADHD. When these studies were meta-analyzed, it became clear that omega-3 PUFAs high in eicosapentaenoic acid (EPA) helped to reduce ADHD symptoms. For details see: Bloch, M. H. and J. Mulqueen (2014). "Nutritional supplements for the treatment of ADHD." Child Addles Psychiatry Clin N Am23(4): 883-897. So, if omega-3 PUF helps reduce ADHD symptoms, why are doctors still prescribing ADHD drugs? The reason is simple. Omega-3supplements work, but not very well. On a scale of one to 10 where 10 is the best effect, drug therapy scores 9 to 10but omega-3 therapy scores only 2.  Some patients or parents of patients might want to try omega-3 therapy first, in the hopes that it will work well for them. That is a possibility, but if that is your choice, you should not delay the more effective drug treatments for too long in the likely event that omega-3 therapy is not sufficient.  What about combining ADHD drugs with omega-3 supplements? We don't know. I hope that future research will see if combined therapy might reduce the number of drugs required for each patient. Keep in mind that the treatment guidelines from professional organizations point to ADHD drugs as the first-line treatment for ADHD. The only exception is for preschool children where medication is only the first-line treatment for severe ADHD; the guidelines recommend that other preschoolers with ADHD be treated with non-pharmacologic treatments, when available. You can learn more about non-pharmacologic treatments for ADHD from a book I recently edited: Faraone, S. V. & Antshel, K. M. (2014). ADHD: Non-Pharmacologic Interventions. Child Addles psychiatry Clin N Am 23, xiii-xiv.

May 29, 2021
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Can Computers Train the Brain to Cure ADHD?

Can Computers Train the Brain to Cure ADHD?

It sounds like science fiction, but scientists have been testing computerized methods to train the brains of ADHD people to reduce both ADHD symptoms and cognitive deficits such as difficulties with memory or attention.  

Two main approaches have been used: cognitive training and neurofeedback. Cognitive training methods ask patients to practice tasks aimed at teaching specific skills, such as retaining information in memory or inhibiting impulsive responses.

Currently, results from ADHD brain studies suggest that the ADHD brain is not very different from the non-ADHD brain, but that ADHD leads to small differences in the structure, organization, and functioning of the brain. The idea behind cognitive training is that the brain can be reorganized to accomplish tasks through a structured learning process. Cognitive retraining helps people who have suffered brain damage, so it was logical to think it might help the types of brain differences seen in ADHD people. Several software packages have been created to deliver cognitive training sessions to ADHD people.

Neurofeedback was applied to ADHD after it had been observed, in many studies, that people with ADHD have unusual brain waves as measured by the electroencephalogram (EEG). We believe that these unusual brain waves are caused by the different ways that the ADHD brain processes information. Because these differences lead to problems with memory, attention, inhibiting responses, and other areas of cognition and behavior, it was believed that normalizing the brain waves might reduce ADHD symptoms.

In a neurofeedback session, patients sit with a computer that reads their brain waves via wires connected to their heads. The patient is asked to do a task on the computer that is known to produce a specific type of brain wave.  The computer gives feedback via sound or a visual on the computer screen that tells the patient how 'normal' their brainwaves are. By modifying their behavior, patients learn to change their brain waves. The method is called neurofeedback because it gives patients direct feedback about how their brains are processing information.

Both cognitive training and neurofeedback have been extensively studied. If you've been reading my blogs about ADHD, you know that I play by the rules of evidence-based medicine. My view is that the only way to be sure that a treatment works is to see what researchers have published in scientific journals. The highest level of evidence is a meta-analysis of randomized controlled clinical trials. This ensures that many rigorous studies have been conducted and summarized with a sophisticated mathematical method.  

Although both cognitive training and neurofeedback are rational methods based on good science, meta-analyses suggest that they do not help reduce ADHD symptoms. They may be helpful for specific problems, such as problems with memory, but more work is needed to be certain if that is true. The future may bring better news about these methods if they are modified and become more effective. You can learn more about non-pharmacologic treatment for ADHD from a book I recently edited: Faraone, S. V. &Antshel, K. M. (2014). ADHD: Non-Pharmacologic Interventions. Child Adolesc Psychiatr Clin N Am 23, xiii-xiv.

October 5, 2023
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ADHD Increases Risky Decision Making: Evidence from a Meta-Analysis

ADHD Increases Risky Decision Making: Evidence from a Meta-Analysis

Adults with ADHD are more likely to have accidents, drive unsafely, have unsafe sex, and abuse substances. These 'real world' impairments suggest that people with ADHD may be predisposed to making risky decisions. Many studies have attempted to address this, but it is only recently that their results have been aggregated into a systematic review and meta-analysis.  This paper by Dekkers and colleagues reports 37 laboratory studies of risky decision-making that studied a total of 1175 ADHD patients and 1222 controls. In these laboratory tasks, research participants are given a task to complete which requires that they make choices that have varying degrees of risk and reward. Using the results of such experiments, researchers can score the degree to which participants make risky decisions. When Dekkers and colleagues analyzed the 37 studies together, they found substantial evidence that ADHD people are more likely to make risky decisions than people without ADHD. The tendency to make risky decisions was greatest for those who, in addition to having ADHD, also had conduct or oppositional disorders, which both have features that indicate antisocial behavior and aggressiveness. We can not tell from these studies why ADHD patients make risky decisions. One explanation is that it is simply the impulsivity of ADHD people that leads to rash, unwise decisions. Another theory postulates that risky decisions reflect deficits in one's sensitivity to rewards and punishments. If we are very motivated by reward and not aware of or affected by the possibility of punishment, then risky decisions will be common. The studies analyzed in the meta-analysis were not designed to demonstrate a link between risky decision-making in the lab and the real world, risky decisions that lead to accidents, and other outcomes. It is reasonable to hypothesize such a link, which is why clinicians should consider risky decision-making when planning treatments.  If you suspect deficits in this area, it will not change your approach to pharmacologic treatment but, given the potential adverse consequences of risky decisions, you should consider referring such patients to cognitive behavior therapy for adult ADHD as this talk therapy may be able to teach ADHD adults how to cope with their decision-making deficits.

May 25, 2021
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