Trial and Error
I consider ADHD to be one of the most fascinating topics out there—I think that society needs to radically improve education on this topic.
I haven’t been publishing much lately because I’ve been titrating ADHD medication—my process has been tedious but I’m very hopeful that it’ll be successful. The titration reminds me of doing an eye exam in a way—you increase the dose and ask whether the new effect is better.
I’ll use this short piece to talk about ADHD’s costs, how ADHD science challenges DSM—and DSM-5—assumptions, and ADHD-medication effectiveness.
ADHD’s Costs
A 23 October 2020 article says: ADHD “is a common childhood-onset neurobiological disorder that has been demonstrated to affect approximately 6 to 10% of children and 4.4% of adults”; despite “the estimated prevalence of adult ADHD of 4.4% in the USA, only a minority of patients are recognized and engaged in treatment”; a large-scale study found “only 10.9% of adults with ADHD in the USA were obtaining treatment, even though 40% of adults diagnosed with ADHD sought out treatment with a healthcare professional during the prior year”; and Medco Health Solutions performed another study that “evaluated managed healthcare plan subscribers using the plan’s prescription benefit plans from 2000 to 2005 and identified that only 1.2% of young adults (ages 20 to 44) received treatment for ADHD”.
And the article points out: from “the clinical standpoint, there has been increased recognition that adults with ADHD exhibit symptoms that extend beyond the DSM-5 delineated symptoms of inattention and hyperactivity-impulsivity”; deficits including “cognitive domains like response inhibition, non-verbal working memory, verbal working memory, emotional and motivational self-regulation, planning, and problem-solving, are frequently identified in adult patients”; and “adult ADHD patients frequently experience emotional dysregulation characterized by affective disturbances, impulsivity, mood lability, and emotional over-reactivity”.
One can of course contest the facts—maybe Big Pharma is inflating the problem in order to reap profits. But it would be a remarkable situation if only “10.9% of adults with ADHD in the USA were obtaining treatment”. Or if “only 1.2% of young adults (ages 20 to 44)” were receiving ADHD treatment, which is only 27%—about a quarter—of the 4.4% figure that the article gives for the estimated prevalence. That means—whether you’re talking about around 10% or around 25%—that there are a lot of untreated people with ADHD walking around out there.
I can’t speak to what the media coverage is like overall—it certainly seems like there’s a lot of talk about the dangers of medication, but maybe there are also lots of articles about the costs of undertreatment for all I know.
We can all understand—regarding ADHD—that undertreatment destroys lives. It’s unbelievably tragic. And there are different levels of tragedy—it’s a tragedy if you end up moving between unfulfilling jobs instead of having the career that you dreamed of having, but it’s far more tragic if you end up in a car accident that kills you and/or someone else.
It’s striking to consider how undertreatment of ADHD affects crime and incarceration. There’s an interesting chapter—in the 2022 book Clinical Forensic Psychology—that says: “ADHD is highly prevalent in offender populations, yet for many the diagnosis has been missed or misdiagnosed”; identifying “this subgroup of the population, who present with complex mental health needs, is not just a matter of conferring health gain for the individual”; there “are also clear advantages for the custodial system itself and, more broadly, for society associated with increased productivity, decreased resource utilization, and reduced rates of reoffending”; and early “diagnosis may mean that early interventions can be put in place that might interrupt, or even prevent, the antisocial trajectory and pathway to crime that lies in wait for some individuals with ADHD”.
You can imagine how profound the issue might be—it’s a matter of (1) how bad undertreatment is and (2) what happens to society given the level of undertreatment. There are many potential benefits if undertreatment is aggressively tackled—the chapter refers to “increased productivity”, “decreased resource utilization”, “reduced rates of reoffending”, and the potential to “interrupt, or even prevent, the antisocial trajectory and pathway to crime”.
Can you quantify the economic damage that ADHD does? A 6 February 2022 article attempts to do this and says: this “comprehensive societal analysis of the excess economic burden of ADHD among children and adolescents found the total societal costs associated with ADHD in the US in 2018 to be ∼$19.4 billion among children and $13.8 billion among adolescents with ADHD”; these “findings demonstrate the substantial economic burden of ADHD in children and adolescents in the US and highlight the current unmet need in these populations”; and we could “improve various aspects of the patient’s life across life stages and reduce the economic burden from a societal perspective” if we “improved intervention strategies as well as policies and awareness around ADHD”.
The article concludes that we might “reduce the clinical and economic burden of ADHD in children and adolescents” if we develop “more effective, safe, convenient, and accessible intervention strategies”. And that we might “help alleviate the long-term implications of ADHD”—and “ultimately reduce the economic burden across the life course”—if we improve ADHD-symptom management.
As for the total economic impact in the US, an October 2012 review says: this “article comprehensively reviews studies reporting ADHD-related incremental (excess) costs for children/adolescents and adults and presents estimates of annual national incremental costs of ADHD”; overall “national annual incremental costs of ADHD ranged from $143 to $266 billion”; most “of these costs were incurred by adults ($105B–$194B) compared with children/adolescents ($38B–$72B)”; for “adults, the largest cost category was productivity and income losses ($87B–$138B)”; for “children, the largest cost categories were health care ($21B–$44B) and education ($15B–$25B)”; spillover “costs borne by the family members of individuals with ADHD were also substantial ($33B–$43B)”; and despite “a wide range in the magnitude of the cost estimates, this study indicates that ADHD has a substantial economic impact in the United States”.
Challenging DSM Assumptions
There are certain DSM criteria that are used to diagnose ADHD. But an 11 October 2022 review says that the “current review and accompanying perspectives highlight the way in which research data increasingly challenges some core assumptions of the current DSM paradigm”—“scientific progress is challenging some of the core assumptions of the current DSM model of ADHD and the way it is conceptualized with regard to related disorders”.
The review says: a “core assumption in DSM is that ADHD is a category with nonarbitrary boundaries that distinguish cases from noncases”; a “second DSM assumption is that, despite its obvious surface level heterogeneity (i.e., symptom profiles, co-occurring conditions, and impairment), ADHD represents a causally distinctive condition at a deeper level, marked by a common etiology and pathophysiology”; and DSM “also assumes that ADHD is a neurodevelopmental condition unfolding across development from its roots in early childhood”.
The review also says: “cases that manifest clinically in a similar way” show “great heterogeneity in genetic and environmental risk, underlying pathophysiology and associated neuropsychological deficits and differences”; no “particular factor or combination of factors represent a necessary and sufficient basis for the condition”; such “heterogeneity almost certainly contributes to the very small ADHD-related effects reported in recent large-scale neuroimaging and genetic studies”; at “the same time, there also appears to be considerable genetic, environmental, and neuro-psychological/−biological overlap between ADHD and conditions that DSM conceptualizes as distinct from it”; and this “encourages a fundamental remapping of ADHD symptoms to their underlying causes”.
There are—due to “awareness of clinical and neurobiological heterogeneity in ADHD”—“calls for a more a personalized approach to intervention”. It’s “hoped that future research will use a more targeted approach with refined ADHD phenotypes”—the review asks whether medications that “indirectly impact catecholamine function” might “be more suitable for a subpopulation of individuals with ADHD”, which would mean that studying these medications “in the larger ADHD population might yield an overall inadequate response”.
Medication Effectiveness
We understand very little about the brain—the more you read the literature on the brain the more you see just how little we know. A brain scientist once told me that actually working with the organ induces humility.
But you don’t need to understand the brain in order to do a trial-and-error titration process—take a look at this useful information:
There are various molecules to try regarding ADHD treatment—you can even combine different molecules.
I recognize that—given individual variability—there are no algorithms. But some ADHD medications have been in use for decades—I’d therefore love to see a lot more detail in the guidance. I’m surprised at how little the guidance says—how long should you spend at each dose in order to assess it, how should the medication make you feel, does a given undesirable state indicate a too-high or too-low dose, and how can changes in state be interpreted pharmacokinetically?
The 2021 guide above talks about what to do when breakthrough symptoms happen. And says that one should—for end-of-day breakthrough symptoms—consider the following options: (1) increasing the dose, (2) changing to a formulation that lasts longer, (3) adding a nonstimulant, (4) adding an end-of-day short-acting stimulant to a long-acting stimulant, and (5) layering two doses—one in the morning and one at around noon—of long-acting stimulant. So as you can see, optimization can mean more than titrating a single molecule—you might have to layer doses, combine formulations, or combine molecules.
The guide stresses how important optimization is. Studies “around the world have demonstrated the need to gradually adjust the dose and titrate for optimal effect”—many “consumer databases have shown that quite often ADHD medications are being prescribed at doses below what was shown to be the optimal effective dose”. A “recent study with MPH DR/ER dosed in the evening for ADHD children demonstrated that ADHD symptoms could be decreased from 42 to 11 after 6 weeks of dose titration”. This study points—along with others—to “the importance of appropriate titration to optimize outcomes in our patients with ADHD”. These “children were highly symptomatic with ADHD scores that were moderate or severe on all 18 items”, but after “6 weeks their ADHD symptoms were mild or none on average”.
The “rule of thumb is to titrate until there are no breakthrough symptoms or residual functional difficulties or one encounters a dose-limiting side effect or has reached the maximum dose”—one “should then consider trying an alternative molecule” that “may address breakthrough symptoms at the beginning, the middle, or the end of the day”. A patient can be “partially better but not well”—the question is “are they normalized, are they partially better but still symptomatic, are their symptoms still causing functional difficulties at various points throughout the day or in certain areas of their life”.
I wonder how many ADHD sufferers take medication but are far from optimization—I also wonder how clinical trials ensure that everyone in the trial is optimized.
And I’d like to know what the biggest success stories are that you can point to when it comes to ADHD medication—I think that that’s an intriguing starting point for any psychiatric medication even if it’s not representative. I want to see some interviews with patients who had the best possible response to ADHD medication—it would be remarkable to hear these people’s stories, hear their descriptions of what treatment was like, and hear their thoughts looking back on their lives.
You’d have to dive into the data in order to investigate how well ADHD medication works in general when optimized. And it’s important to make sure that Big Pharma’s influence doesn’t taint investigation on this front—they naturally have an incentive to exaggerate things. The guide says: “ADHD medications have some of the highest effect sizes of any medical intervention”; clinicians and patients “may be tempted to be satisfied with 30% improvement, even though the evidence is clear that such minimal improvement almost inevitably means continued functional impairment”; for “most patients, further improvement is possible”; and long-term “trials demonstrate that nearly 75% to 80% of patients can achieve >50% symptom reduction and achieve symptomatic remission”.
What does it mean to experience “no breakthrough symptoms or residual functional difficulties”? And how common is this experience? What does it mean to “achieve >50% symptom reduction and achieve symptomatic remission”? The guide says that “nearly 75% to 80% of patients can” do this. What does it mean to be “normalized”—or “well”—as opposed to “partially better but still symptomatic”?
I would find it very informative to see interviews with—and documentaries about—ADHD patients who illustrate what different levels of symptom reduction might look like. And who illustrate what “symptomatic remission”—and lack of “residual functional difficulties”—might look like. ADHD medications have been in use for a long time—how many people are out there whose stories might help to illustrate these medications’ effectiveness?
The thing about looking at children one thinks are ADHD, often they miss that they might be gifted. I have a piece in my queue that covers this idea. I had teachers at a school tell me that’s what they believed about my kiddo. Turned out he is highly gifted. When you’re looking for ADHD, that’s what they find, especially in children. Rarely do they recommend gifted assessment before hooking a kid up on the ADHD drugs.
Here’s a description from CHADD about how giftedness and ADHD can be confused: https://chadd.org/attention-article/giftedness-adhd-a-strengths-based-perspective-and-approach/
Good luck in your search.
Wonderful and thought-provoking article on ADHD, Andrew! Keep up the good work on this important topic.