From the Editor

For my patient, ADHD medications transformed his life, helping him focus at school and at work – and even drive better. Many have had similar experiences. Do ADHD medications also reduce mortality? We know that those with ADHD have higher mortality rates and thus it’s reasonable to ask about the possible benefits of methylphenidate and sister drugs.

Lin Li (of the Karolinska Institutet) and her co-authors try to answer that question in a new JAMA Psychiatry paper. Drawing on Swedish databases, they analyzed data from almost 150 000 people with ADHD and looked at two-year mortality, including for those who die by unintentional injuries, suicide, or poisonings, by doing a target trial emulsion – simulating a randomized trial. “Among individuals diagnosed with ADHD, medication initiation was associated with significantly lower all-cause mortality, particularly for death due to unnatural causes.” We consider the paper, the editorial that accompanies it, and the clinical implications.

ADHD meds: life saver?

And in the other selection, Dr. Rebecca Lawrence writes about support in a blog for Doctor and Patient. She is personal – besides working as psychiatrist, Dr. Lawrence has been treated for depression, including with ECT. She notes the incredible help her husband has given her over the years. “I look at myself in the mirror and am appalled, but he still smiles at me.


Selection 1: “ADHD Pharmacotherapy and Mortality in Individuals With ADHD”

Lin Li, Nanbo Zhu, Le Zhang, et al.

JAMA Psychiatry, 12 March 2024

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental condition, affecting 5.9% of youths and 2.5% of adults worldwide, according to the 2021 World Federation of ADHD International Consensus Statement. In the US, the prevalence of ADHD is estimated to be 9.8% among children and adolescents and 4.4% among adults. The disorder is associated with a broad range of psychiatric and physical comorbidities, as well as adverse functional outcomes. Furthermore, individuals with ADHD have a 2-fold increased risk of premature death compared with those without it, mainly due to unnatural causes. 

Pharmacological treatment, including stimulant and nonstimulant medications, is recommended for both children and adults diagnosed with ADHD, alongside nonpharmacological treatment. Randomized controlled trials have demonstrated that ADHD medications are effective in reducing core ADHD symptoms. Pharmacoepidemiological studies have also shown reduced risks of negative outcomes, including injuries, traffic collisions, and criminality, which would be expected to decrease the mortality rate…

To date, 3 studies have examined the association between ADHD medication and mortality with mixed results. These studies had important limitations, including a small number of deaths, indication bias (eg, starting methylphenidate in patients with depression or other debilitating conditions in their latest phase of life), no consideration of time-varying exposure, and absence of a control group.

So begins a paper by Li et al.

Here’s what they did:

  • They used data from several Swedish registries to identify individuals aged 6 to 64 who were diagnosed with ADHD between 2007 and 2018 to conduct a target trial emulation.
  • They focused on those who didn’t have ADHD medications before diagnosis (that is, it was a new diagnosis) and then looked at “follow-up started from ADHD diagnosis until death, emigration, 2 years after ADHD diagnosis, or December 31, 2020, whichever came first.”
  • ADHD medication initiation was defined as “dispensing of medication within 3 months of diagnosis.” 
  • There were six recognized ADHD medications: methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, atomoxetine, and guanfacine.
  • The main outcomes were (1) all-cause mortality, (2) natural-cause mortality (e.g., physical conditions) and (3) unnatural-cause mortality (e.g., unintentional injuries, suicide, and accidental poisonings) during a 2-year follow-up period.

Here’s what they found:

  • 148 578 individuals met criteria for ADHD.
  • Demographics. The average age was 17.4 years; most patients were male (58.7%) and Swedish (92.2%); common comorbidities included depressive disorders (19.1%) and alcohol use disorder (8.7%).
  • 84 204 (56.7%) initiated ADHD medications within three months of diagnosis.
  • Two-year mortality. “The 2-year mortality risk was lower in the initiation treatment strategy group (39.1 per 10 000 individuals) than in the noninitiation treatment strategy group (48.1 per 10 000 individuals), with a risk difference of −8.9 per 10 000 individuals…”
  • Mortality types. “ADHD medication initiation was associated with significantly lower rate of all-cause mortality (hazard ratio [HR], 0.79…) and unnatural-cause mortality (2-year mortality risk, 25.9 per 10 000 individuals vs 33.3 per 10 000 individuals; risk difference, −7.4 per 10 000 individuals…), but not natural-cause mortality (2-year mortality risk, 13.1 per 10 000 individuals vs 14.7 per 10 000 individuals; risk difference, −1.6 per 10 000 …).”
  • Gender. “Females with ADHD had lower mortality risk for both natural (5.9 per 10 000) and unnatural causes (9.3 per 10 000) than males (8.5 per 10 000 for natural cause and 20.2 per 10 000 for unnatural cause), and ADHD medication initiation was only associated with lower rate of natural-cause mortality in females (2-year mortality risk, 8.5 vs 12.9 per 10 000; risk difference, −4.4 per 10 000…).”

A few thoughts:

1. This is a well-powered and large study, published in a major journal.

2. The main finding in three words: the meds worked.

3. To provide more detail: all-cause mortality was reduced, particularly unnatural-cause mortality (though with a difference between males and females).

4. Some may view the diagnosis as being “softer” than others, with treatments that are less necessary – making the major finding that much more important.

5. The study is built on target trial emulsion – an attempt to emulate a hypothetical randomized trial. The approach is growing in popularity, though clearly is not as strong as randomized trial. A detailed explanation by Miguel A. Hernán (of Harvard University) and his co-authors was published in JAMA:

6. Dr. Frances R. Levin (of Columbia University) and her co-authors write an accompanying editorial, “Treating Attention-Deficit/Hyperactivity Disorder Matters.”

They write enthusiastically about the study but note that there are many unanswered questions. “Although the results from Li et al highlight the potential public health importance of treating ADHD, numerous questions remain. Does the type of stimulant matter? Li et al found that more than 90% of participants in their study received a prescription stimulant but do not report what percentage received an amphetamine vs a methylphenidate formulation. A recent review suggests that amphetamine formulations have greater effect sizes than methylphenidate in adult populations, perhaps resulting in better outcomes.” 

They continue to focus on medications. “Additionally, the present study does not address medication adherence or dosing. For some patients, medication may not have been prescribed at adequate doses or taken with sufficient regularity to reduce the risk of mortality… Another question not addressed in this study is whether severity of baseline ADHD symptoms moderates the observed reduction in mortality in those who initiated ADHD medications.”

Frances R. Levin

They also wonder about how the medications may have resulted in the mortality reduction. “Is ADHD treatment directly reducing impulsive behaviors that increase the risk of premature death? Or is the treatment of ADHD symptoms indirectly reducing accidental poisonings by reducing substance use (through better implementation of protective strategies) or reducing suicides by improving depressive symptoms associated with ADHD? Finally, the study was not designed to address whether the benefit of prescribed ADHD medication is maintained over time. This emulation trial analyzed individual outcomes over a 2- and 5-year follow-up. Given that mortality is a relatively uncommon outcome (less than 1% died during the 2-year assessment), future studies evaluating individuals for a longer period is warranted, including a larger sample of older adults.”

7. Clinically, the study shows the importance of diagnosing and treating ADHD. But a word of caution: overdiagnosis is possible. As Levin et al. observe: “Overdiagnosis may occur when assessments are brief and clinicians do not attend to possible alternative medical or psychiatric conditions that may mimic the symptoms of ADHD.”

8. How to think about diagnosing ADHD in adults? What screening tool could you use? Psychiatry in Primary Care has a practical chapter, which you can find here:

(Useful, even for those of us who aren’t in primary care.)

For the record, Dr. Umesh Jain recommends the Adult ADHD Self-Report Scale for both patients and their family.

The full JAMA Psych paper can be found here:

Selection 2: “Love and relationships”

Rebecca Lawrence

Doctor & Patient, 24 March 2024

As a patient with mental illness, I am very grateful to my partner. He has stayed with me throughout, been there for the difficult times, and still takes me to my regular ECT maintenance sessions. I hate going for these; the treatment is no fun, but I also hate having to go there with him when I look my worst, hair unwashed (what’s the point?) make-up unworn, my face pale and dark in places. I look unwell, and frankly unattractive.

I don’t remember, when we married each other all those years ago, whether we mentioned sickness or health – I simply don’t remember. But I don’t think either of us thought that mental sickness would be an issue.

So begins an essay by Dr. Lawrence.

She talks about the difference between physical and mental illnesses. “It’s not like a lot of physical illnesses – I know that some of them may also be hard to mention, but there is something different about mental illness.”

But their love is strong, she writes. “Yes, we’ve had our ups and downs, but we’ve had a lot of happiness. If it wasn’t for him, I wouldn’t be able to have out-patient ECT, as there would be no-one to take me. Yet, I have friends whom I might ask to take me for treatment for a physical illness, so what would stop me asking them for this? Both shame and self-stigma (something which is not, in my opinion, caused by the self), and also not wanting to be seen at a time when I am mentally (and physically) vulnerable. But I let him see me then…”

She notes his coping strategy. “Maybe he thinks of the person I was – funny, even pretty once – and can separate himself from the greyness and the pain, when it comes back. If you stayed in the moment always, trying to answer nonsensical questions, trying to talk sense into nonsense, then you’d burn out pretty quickly. This doesn’t negate his love in any way, but it may help him to cope. I couldn’t do it.”

“I suppose that I should try to accept his love more readily – it’s not flattering to him if I keep asking him why he loves me, or saying he shouldn’t, and puts doubt on his choice. Casting myself as the mentally ill patient who is hence undeserving of love is in itself profoundly stigmatising. I think I am less confident than him overall, but mental illness has added to this; however, the best return for love is love.”

A few thoughts:

1. Like so much of Dr. Lawrence’s writing, this blog is raw and honest.

2. She seems particularly frank in her worries about the relationship: “But I do still wonder why he stays with me.”

3. Dr. Lawrence’s writing has been selected for past Readings, including one in which she discussed her decision to go into psychiatry. “My career in psychiatry actually started on the other side, as a psychiatric inpatient going through multiple admissions, medications and courses of electroconvulsive therapy (ECT).” That Reading can be found here:

The full Doctor & Patient blog can be found here:

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.