Reframing ADHD: New Science, New Treatments, New Perspectives

 

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Clinical Education for NP Students & New Graduates

Reframing ADHD: New Science, New Treatments, New Perspectives

Psychiatry  |  Board Prep  |  Chronic Disease Management

ADHD has a reputation problem in primary care: it's often treated as a straightforward diagnosis with a straightforward fix — confirm inattention or hyperactivity, start a stimulant, done. A recent Pri-Med Institute CE session led by Charles Vega, MD, FAAFP (UC Irvine) and Ajay Shah, MD (Texas Children's Hospital / Baylor College of Medicine) makes the case that this picture is incomplete in ways that matter for real patients. This post distills the session's key clinical content, organized around the case of “Hannah,” a 32-year-old woman whose presentation illustrates most of the diagnostic blind spots the talk addresses.

CASE FROM PRACTICE Hannah, 32, presents with persistent anxiety, excessive worry, and difficulty “shutting off” her mind. She reports trouble sleeping, is easily irritated and frustrated, and is experiencing occupational impairment — missed deadlines, job instability, being passed over for promotion. On the surface, this reads as a generalized anxiety presentation. It's also a textbook example of how adult ADHD frequently presents: not as obvious hyperactivity, but as chronic underperformance, irritability, and what looks like an anxiety or mood disorder.

ADHD Across the Lifespan: How Common, and How Missed

ADHD remains one of the most common neurodevelopmental conditions, and it does not stop at childhood. As of the most recent surveillance data cited in the session:

•     Approximately 15.5 million US adults (6.0%) had a current ADHD diagnosis in 2023 based on self-report — and roughly half of them received that diagnosis at age 18 or older.

•     Approximately 6.5 million US children and adolescents (10.5%) had ADHD in 2022, and 1 in 9 (11.4%) US children have ever received an ADHD diagnosis.

•     An estimated 60% of children with ADHD experience persistence of symptoms into adulthood, and 57% of people with ADHD are diagnosed before age 14.

The gap between those two statistics — 60% of childhood ADHD persisting into adulthood, but only about half of adult diagnoses tracing back to childhood — points to a real problem: a large share of adults living with ADHD were never identified as children, and many still aren't being identified now.

Why Underdiagnosis Happens, and Who It Happens To

NUANCE TO FLAG An estimated 14% of the adult population may meet criteria for undiagnosed ADHD, with women disproportionately affected. Delayed diagnosis is especially common in girls, who typically present with primarily inattentive symptoms and fewer of the disruptive behaviors that tend to trigger evaluation in childhood. Groups at elevated risk for underrecognition also include people who are incarcerated, patients in addiction and mental health treatment settings, and ethnic and racial minorities, including African American and Latino individuals. Many adults with undiagnosed ADHD have simply built coping mechanisms that mask symptoms at work and at home — which is part of why the condition can go unrecognized well into adulthood, often until a life transition (new job, new relationship, parenthood) removes the scaffolding those coping strategies depended on.

Beyond Inattention and Hyperactivity: What Gets Missed

The session emphasized that the formal DSM-5-TR criteria capture only part of the clinical picture. Emotional dysregulation and executive dysfunction — often the most functionally impairing features for adult patients — are not part of the core diagnostic criteria and are not assessed by most standard screening tools, meaning they can go entirely unassessed even in a thorough workup.

•     Emotional dysregulation (low frustration tolerance, irritability, mood lability, disproportionate emotional responses) affects 25–45% of children and 30–70% of adults with ADHD.

•     In a study of 1,500 children, emotional problems had a greater impact on well-being and self-esteem than hyperactivity and inattention did.

•     Executive dysfunction — deficits in working memory, cognitive set-shifting, planning, organization, and time management — was present in at least one domain in 50% of children with ADHD.

•     Notably, stronger working memory skills predict better emotional regulation independent of ADHD symptom severity, suggesting the two domains are mechanistically linked rather than coincidental.

The Disease Burden Goes Well Beyond the Core Symptoms

Untreated or poorly managed ADHD carries measurable downstream consequences across multiple life domains, which is part of why accurate, timely diagnosis matters beyond symptom control alone:

•     Academic: poorer school performance and increased risk of academic failure compared with unaffected peers.

•     Occupational: higher rates of unemployment, lower occupational attainment, more frequent job changes, and reduced earnings.

•     Medical comorbidity: increased rates of obesity, type 2 diabetes, cardiovascular disease, and anxiety/mood disorders.

•     Mortality: higher risk of premature death from accidental injury, motor vehicle accidents, and suicide.

Psychiatric comorbidity specifically is the norm, not the exception. In a nationally representative sample of adults with ADHD: 38% had mood disorders, 47% had anxiety disorders, and 15% had substance use disorders. Roughly 89% of one studied population had clinical depression in adulthood and 50% had anxiety disorders — figures that vary somewhat across studies but consistently point to very high comorbidity burden.

CLINICAL BOTTOM LINE — RECOGNITION Adult ADHD frequently hides behind an anxiety, mood, or substance use presentation — particularly in women, who are more likely to have been missed in childhood. When a patient's history includes long-standing (not new-onset) difficulty with attention and distractibility, ask directly: how long has this been a problem — years or decades, not weeks or months? What would this patient have looked like in a childhood classroom? Emotional dysregulation and executive dysfunction are common, functionally significant, and not captured by most screening tools — they have to be asked about directly.

Diagnosis: A Three-Part Process, Not a Checklist

The DSM-5-TR requires 6 or more symptoms of inattention or hyperactivity/impulsivity (5 or more if age 17+) present for at least 6 months, with several symptoms present before age 12, in two or more settings, causing functional impairment not better explained by another mental disorder.

Inattention	Hyperactivity/Impulsivity
Lack of attention to detail; difficulty sustaining attention	Fidgeting or squirming in seat
Doesn't listen when spoken to directly	Leaves seat when not supposed to; restless/overactive
Trouble completing tasks; poor organization	Difficulty engaging in leisure activities quietly
Avoids sustained mental effort; easily distracted	Always “on the go”; talks excessively
Loses/misplaces things; forgetful in daily activities	Blurts out answers; interrupts others; difficulty waiting turn

 

The American Academy of Family Physicians recommends a 3-part diagnostic approach: clinical history, validated self-report/observer screening tools (e.g., the Adult ADHD Self-Report Scale), and formal assessment against DSM-5-TR criteria. Notably, a survey of 178 clinicians who regularly perform adult ADHD assessments found real gaps in practice: only 31% used a structured or semi-structured interview, and “difficulties concentrating” was the only core feature endorsed as such by a majority of respondents — suggesting many clinicians' working concept of ADHD is narrower than the diagnostic reality.

Screening Tools: Useful, Not Sufficient Alone

Population	Example Validated Tools
Adults	ADHD Rating Scale-IV (with Adult Prompts); Adult ADHD Clinical Diagnostic Scale (ACDS); Adult ADHD Self-Report Scale (ASRS)
Children	ADHD Rating Scale (ADHD-RS); Child Behavior Checklist (CBCL); Vanderbilt scales; Conners' Rating Scale

 

A 2022 meta-analysis found these tools have high diagnostic accuracy overall (pooled AUC 0.82) but insufficient sensitivity and specificity individually (both below 0.8) — the explicit reason screening tools should never be used alone to establish a diagnosis.

CASE FROM PRACTICE Returning to Hannah: she has 5 symptoms from the inattention domain and a childhood history of academic underachievement despite high intelligence — a classic pattern in patients (especially women) who compensated well enough to avoid earlier detection. Beyond the core criteria, DSM-5-TR associated features that support the diagnosis include mild language/motor/social developmental delays, low frustration tolerance, irritability, mood lability, impaired work/academic performance, deficits on memory and executive function testing, and increased risk of suicide attempt in early adulthood — several of which show up directly in Hannah's presentation.

Because ADHD symptoms overlap substantially with depression, anxiety, bipolar disorder, substance use disorders, and personality disorders (poor concentration, distractibility, mood swings, irritability, restlessness are common to several of these), guidelines recommend treating the most impairing condition first when ADHD coexists with other psychopathology. Three practical questions can help surface ADHD in a complicated presentation: Have these attention/distractibility problems been long-standing and consistent? Have current complaints been present for 10–20 years, not just recently? What would this patient have looked like in a childhood classroom?

The Neurobiology, in Plain Terms

ADHD involves dysregulation across three interacting neurotransmitter systems, and understanding this framework has direct treatment implications.

System	Primary Roles
Dopaminergic	Movement regulation, mood, attention, learning/memory, novelty and reward processing
Noradrenergic	Attention and arousal, signal-to-noise processing, mood regulation, stress response
Serotonergic	Modulates both dopamine and norepinephrine pathways; implicated in impulsivity, emotional dysregulation, and cognitive inflexibility

 

The relative contribution of each pathway varies by individual and across the lifespan — part of why ADHD is increasingly understood as a highly heterogeneous disorder requiring a multifactorial, dimensional view rather than a single unifying mechanism. Current pharmacotherapy targets dopaminergic and noradrenergic pathways almost exclusively. That matters clinically: while these medications often improve core inattention and hyperactivity-impulsivity symptoms, many patients continue to struggle with organization, emotion regulation, motivation, or functional performance despite adequate adherence — domains more closely tied to serotonergic and executive-network function than to dopamine/norepinephrine alone.

CLINICAL BOTTOM LINE — NEUROBIOLOGY If a patient on an adequately dosed, adherently taken stimulant or nonstimulant still reports significant executive dysfunction, emotional dysregulation, or functional impairment, that is not necessarily a sign of inadequate dosing — it may reflect that current medications primarily target dopamine/norepinephrine pathways and leave serotonergic and broader executive-network contributions to the disorder comparatively unaddressed.

Current Medications: Strengths and Real Limitations

Class	Examples	Key Advantages	Key Limitations
Stimulants	Methylphenidate, amphetamines (lisdexamfetamine, dextroamphetamine)	Large effect size; rapid onset; helps comorbid ODD/conduct issues	Appetite/sleep/CV effects; limited daily duration; rebound; Schedule II
NRIs	Atomoxetine, viloxazine ER	Around-the-clock effect; not controlled; option in comorbid SUD	Smaller effect size; 6–12 wks to effect; black box suicidality warning
Alpha-2 agonists	Clonidine ER, guanfacine ER	Around-the-clock; option in comorbid tics/anxiety/CV disease	Sedation; smaller effect size; 2–4 wks to effect
Bupropion (off-label)	Bupropion XL	Once-daily; may help comorbid depression/anxiety/SUD	Seizure risk; smaller effect size; suicidality warning under age 25

 

Clinical factors that specifically favor a nonstimulant: concern for stimulant misuse or diversion, comorbid anxiety that stimulants might worsen (favoring atomoxetine/viloxazine), cardiovascular contraindications, or comorbid tics/Tourette syndrome — which occurs in 8–10% of patients with ADHD (favoring alpha-2 agonists).

Pediatric guidance from the AAP/AAFP: behavioral therapy first-line for ages 4–5, with methylphenidate reserved for cases with continued moderate-to-severe functional disability; FDA-approved medication and/or behavioral therapy for ages 6–11; medication with patient assent (plus optional behavioral therapy) for ages 12–18. None of the nonstimulants currently carry FDA approval for preschool-age children. Notably, no formal adult ADHD management guidelines currently exist in the US, though the American Professional Society of ADHD and Related Disorders (APSARD) is working to develop them.

The Real-World Gap

NUANCE TO FLAG Real-world outcomes data cited in the session are sobering: an estimated 95% of adults and roughly 60% of children experience at least one treatment-related adverse event, and two-thirds of individuals change their ADHD medication within the first 12 months. A 2025 component network meta-analysis (N=14,887) found that while stimulants and atomoxetine show consistent short-term efficacy for core symptoms in adults, ADHD medications were not shown to be efficacious for quality-of-life outcomes, with little long-term evidence either way. Non-pharmacologic strategies (CBT, cognitive remediation, mindfulness, psychoeducation, tDCS) showed inconsistent results, and — notably — neither medications nor cognitive training were effective at improving executive dysfunction in adults in this analysis. This is a meaningful treatment gap, not a reason to withhold first-line therapy, but a reason to set realistic expectations with patients about what medication will and won't fix.

CASE FROM PRACTICE After a full discussion of stimulant, nonstimulant, and nonpharmacologic options, Hannah chooses a stimulant. After 3 months of treatment, her core symptoms have overall improved — but she is still having significant frustration and irritability. This is exactly the residual-symptom pattern the neurobiology framework predicts: dopaminergic/noradrenergic-targeted treatment often does not fully resolve emotional dysregulation, which may have a stronger serotonergic component.

Emerging Treatments: Targeting a Third Pathway

Two investigational agents highlighted in the session take a different mechanistic approach by adding serotonergic activity to the more traditional dopamine/norepinephrine targets.

Centanafadine — Triple Reuptake Inhibitor

Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin simultaneously. Across 4 completed phase 3 trials (N=2,477) in children, adolescents, and adults, centanafadine showed statistically significant improvement in ADHD symptom scores versus placebo, with open-label extension data suggesting sustained efficacy. Preliminary analyses suggest possible additional benefit in executive functioning, mood/anxiety symptoms, and emotional dysregulation — domains current medications often leave unaddressed. A phase 3b trial (N=315) specifically in adults with ADHD and comorbid generalized or social anxiety disorder found a statistically significant 18.5-point reduction in ADHD symptom scores (vs. 12.6 for placebo) and a significant reduction on the Hamilton Anxiety Rating Scale as well, with effects seen as early as week 1. Common adverse events were insomnia, decreased appetite, nausea, headache, and rash, most mild-to-moderate.

Solriamfetol — Dopamine-Norepinephrine Reuptake Inhibitor

Solriamfetol is already FDA-approved for narcolepsy and obstructive sleep apnea, and is being studied for ADHD via its dopamine/norepinephrine reuptake inhibition plus additional TAAR1 and 5-HT1A receptor activity. In the phase 3 FOCUS trial (N=516), once-daily solriamfetol produced a statistically significant 17.7-point reduction in ADHD symptom scores (vs. 14.3 for placebo) over 6 months, with a 53.5% clinical response rate versus 41.3% for placebo. Onset of effect was observed as early as week 1, with no serious adverse events reported; pediatric trials are planned.

NUANCE TO FLAG Both centanafadine and solriamfetol are investigational for ADHD and not yet FDA-approved for this indication — they are not currently prescribable for ADHD. This CE activity was supported by an educational grant from Otsuka America Pharmaceutical, which has a commercial interest in centanafadine; Axsome Therapeutics, developer of solriamfetol, was also cited via company and industry-conference sources for some of the data presented. None of this invalidates the underlying trial data, but it's worth reading efficacy figures from company press releases and conference posters with the same scrutiny you'd apply to any pharma-sourced data — awaiting independent peer-reviewed publication and, eventually, FDA review, before treating these as established options.

Key Takeaways

•     ADHD is a highly prevalent, heterogeneous, chronic neurodevelopmental disorder; roughly 60% of children have symptoms that persist into adulthood, and adult presentations — especially in women — are frequently missed for years.

•     Psychiatric comorbidity is the norm: roughly half of adults with ADHD have a mood disorder and nearly half have an anxiety disorder.

•     Executive dysfunction and emotional dysregulation are common, functionally significant, and not reliably captured by core DSM-5-TR criteria or standard screening tools — ask about them directly.

•     The neurobiology involves dopamine, norepinephrine, and serotonin pathways; current first-line medications target only the first two, which may explain persistent residual symptoms in appropriately treated patients.

•     Emerging triple- and dual-reuptake inhibitors (centanafadine, solriamfetol) aim to address that gap, but remain investigational for this indication as of this writing.

 

Reference

Vega, C., & Shah, A. (2026). Reframing ADHD: New science, new treatments, new perspectives. Pri-Med Institute CE activity, supported by an educational grant from Otsuka America Pharmaceutical, Inc.