KELLIE NEWSOME: We close our series on adult ADHD with a practical guide to making the diagnosis and ruling out other causes. Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. 

CHRIS AIKEN: I'm Chris Aiken, the editor-in-chief of the Carlat Report.

KELLIE NEWSOME: And I'm Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. Last week we looked at the history behind the “better explained” clause in the DSM. It revealed a secret world where some disorders are more valid than others, and adult ADHD hangs low on that totem pole. But first, a preview of the quiz. You can earn CME credit through the link in the show notes.

1. Which type of depression did pramipexole improve in a new randomized trial?

A. Inflammatory depression

B. Treatment-resistant depression

C. Anhedonic depression

D. Atypical depression

CHRIS AIKEN: I think adult ADHD is one of the most difficult diagnoses to make. It requires us to understand cognitive symptoms of many other disorders. The DSM won’t help here, as non-specific symptoms like cognition and anxiety are largely missing from the manual because they are common to all diagnoses but indicative of none. Take bipolar disorder. Several hypomanic symptoms overlap with ADHD: distractibility, hyperactivity, impulsivity, racing thoughts, rapid speech, and irritability. At first glance, that might seem easy to sort out because ADHD symptoms are constant while bipolar symptoms come and go; they are episodic. But many people with bipolar disorder have affective temperaments like cyclothymic or hyperthymic, where these hypomanic symptoms are nearly constant. And again, at first glance, it looks pretty straightforward to tell these apart. I mean, these affective temperaments ought to come with a lot of mood symptoms we wouldn’t see in ADHD. But no. Affective temperaments are nearly as common in adult ADHD as they are in bipolar disorder, so there’s no easy way out of this morass.

KELLIE NEWSOME: OK, so we’ve covered two ways that bipolar and ADHD symptoms overlap – hypomania, and affective temperaments. A third is cognitive impairment. Around 30 to 50% of people with bipolar disorder have cognitive impairments that persist after the mood episodes lift. Here's one way to sort these out from ADHD: in ADHD, cognitive symptoms start in childhood and improve with age as the frontal lobes mature. In bipolar disorder, they worsen over time. Each new episode acts like a small head injury, and the deficits accumulate.

CHRIS AIKEN: The time course helps, but the specific cognitive problems usually don't. Cognitive testing turns up the same results in ADHD and bipolar disorder: trouble with working memory, verbal fluency, and executive function. In bipolar disorder, the executive impairments tend to be more severe. Compared to adults with ADHD, they have less flexibility with changing rules, more trouble planning a complex task, and more difficulty filtering out irrelevant information. That leaves plenty of people with bipolar disorder struggling with attention and organization even when they are euthymic, and after a few TikTok videos they might start to think they have ADHD.

KELLIE NEWSOME: Before diagnosing adult ADHD, I check a short list of conditions. Finding one of these doesn't rule out ADHD, but it at least means there's more than one cause at play. Besides medical and psychiatric disorders, think about:

1) Anything that could injure the brain: past substance use, vascular disease, inflammation (including obesity), and traumatic brain injury.

2) Anything that disrupts sleep, especially sleep deprivation and sleep apnea.

3) Medications that impair cognition, like anticholinergics, sedatives, opioids, and anticonvulsants.

CHRIS AIKEN: Those are the treatable causes to rule out. Other causes trace back to early childhood: premature birth, drug or infection exposure in the womb, nutritional deficiency, childhood abuse and neglect. ADHD is neurodevelopmental, but both genetic and environmental causes contribute, and it's still ADHD even when the cause is mostly environmental, as long as the symptoms are present from childhood. Artificial food colorings carry a small effect. Other environmental factors linked to ADHD include lead, air pollution, hormone-disrupting chemicals in processed food and cosmetics, pesticides, and screen time.

KELLIE NEWSOME: The more clear-cut a disorder, the easier the diagnosis. Adult ADHD, with so many possible causes for the same cognitive problems, is rarely clear-cut. Here's how we approach it in practice.

CHRIS AIKEN: First, I run a structured interview, one that asks about the DSM criteria in plain English, like the DIVA. For each symptom, ask how it looked in childhood, and ask for specific examples. Then I follow with a structured interview for the twelve valid disorders that need ruling out. The basic versions of the MINI and the SCID screen for these, and I built a free version you can use on my website: psych-partners.com/dsm5interview. That version also covers adult causes of ADHD, including the psychiatric disorders and brain injuries we just reviewed.

KELLIE NEWSOME: Next, take a developmental history: school records, report cards, and reports from anyone who knew the patient as a child. If they had symptoms but no impairment as a child, ADHD is still possible, but this requires some clinical judgment. First, confirm the symptoms were real in childhood, such as through teacher or parent report. Next, look for an explanation as to why they didn’t have impairment – do they have a high IQ? Did they have a highly structured household or attend an undemanding school?

CHRIS AIKEN: As you look for impairments, ask specifically about transition points: middle school to high school, high school to college, the first year at a new job. That's where compensations tend to fail.

KELLIE NEWSOME: Finally, consider malingering, including recreational use and diversion of stimulants. This is common. Last year, a survey of 84,000 adults who were prescribed stimulants found that one in four misused their stimulant, taking it differently than prescribed, and one in ten met criteria for stimulant use disorder (Han B et al, JAMA Psychiatry 2025;82(6):572-581). Among college students and people with substance use disorders, the rates are higher. There are real incentives tied to an ADHD diagnosis, stimulant access, testing accommodations, and some adults with no history of the disorder will present convincingly. All this is to say, don’t just rely on a symptom check list. Take it from Keith Conners, who created the Conners rating scale. Toward the end of his life, Dr. Conners came to regret how those scales were used to diagnose ADHD. In a 2013 interview with the New York Times, he called the rise in ADHD diagnoses “a national disaster of dangerous proportions,” and described rating scales as “a concoction to justify the giving out of medication at unprecedented and unjustifiable levels.”

CHRIS AIKEN: Some clinics use computerized cognitive testing, but it has no evidence to improve the diagnosis or rule out malingering. It can help personalize treatment by flagging specific areas of impairment, but it doesn't distinguish ADHD from bipolar disorder, substance use, brain injury, or the other causes we've covered. Even though it doesn’t clarify the diagnosis, some practices require cognitive testing to put some barriers up to the flow of stimulants. I’ve never advocated for measures that slow down access to care, but here I can sympathize. Many practices that are getting inundated with requests for stimulants are requiring one of these steps before finalizing the diagnosis: 1) Cognitive testing, 2) Family input, or 3) School records.

KELLIE NEWSOME: Next week, we look at what happened when a large practice did the opposite, removing barriers and speeding up stimulant access. The business and clinical leaders who created those pathways are now in jail, and the story carries lessons for all of us. Today's research update looks at a new option for anhedonia, the loss of pleasure and drive that shows up in up to 70% of patients with depression. The study comes from Fredrik Ventorp and colleagues in Nature Medicine.

CHRIS AIKEN: SSRIs don't do much for anhedonia, and can make it worse by causing apathy, dampening emotional reactions to both positive and negative events. Pramipexole acts directly on the pathway thought to drive anhedonia: dopamine D3 receptors in the nucleus accumbens and ventral striatum. We’ve had uncontrolled data on pramipexole and anhedonia for years, but this is the first trial to test it against placebo in anhedonic depression.

KELLIE NEWSOME: Researchers randomized 82 adults with depression, dysthymia, or bipolar depression, all with significant anhedonia, to pramipexole or placebo. The medication was added to their current antidepressant for nine weeks. Then everyone continued on open-label pramipexole for six months.

CHRIS AIKEN: Pramipexole worked. On the anhedonia scale, it dropped scores by 6.5 points versus 2.4 on placebo, a moderate effect that showed up by week 3. The patients on pramipexole were also less apathetic, and they moved about more – measured by accelerometer. The symptomatic change was backed up by brain imaging. Pramipexole preserved reward activity in the ventral striatum, while that activity declined on placebo. The average dose was 3.5 mg, which is higher than most trials use, and higher than I'd recommend. That dose can cause more hallucinations, though none were seen here. Instead, pramipexole caused sleep problems, nausea, dizziness, and anxiety. I've used pramipexole for over 20 years, and usually dosed it to 1.5 mg, but I now push higher based on studies showing better results at 2.5 mg for highly refractory depression. But 3.5 mg is higher than I’ve gone with it. The main limitation: blinding was imperfect; placebo patients guessed their assignment two-thirds of the time. Also small size.

KELLIE NEWSOME: The bottom line. If your patient has significant anhedonia or treatment-resistant depression, consider pramipexole, either as monotherapy or augmentation. I'll often explain it this way: “It looks like you've tried a lot of medications, but most of them work on the same neurotransmitters: serotonin and norepinephrine. Have you heard of dopamine? It's involved in motivation and drive, that feeling that tasks are rewarding and life is meaningful.” Patients usually respond positively, and I'll add, “You've never tried a medication that targets dopamine directly. This one does. It never gained FDA approval because its antidepressant effects were discovered just as it was going generic.” That opens the door to the main risk: “If pramipexole pushes your drive too high, you do too much, like overspending or other pleasurable activities, but there are no reports of excess substance use on it.” Learn how to use pramipexole in Dr. Aiken's book, Difficult to Treat Depression, available in print or audio. The book ranks medication augmentation strategies by their evidence, starting with lithium, antipsychotics, and pramipexole, followed by thyroid and celecoxib, then amantadine, d-cycloserine, and minocycline, with ketamine reserved for antidepressant acceleration. Each chapter explains when to use it, how to dose it, and how to manage the side effects.