Meta-analysis finds no association between sugar consumption and ADHD, but a possible link with sugar-sweetened beverages

The Background on ADHD Treatments, rTMS and tDCS:

Methylphenidate is known as the gold-standard treatment for ADHD, increasing dopamine concentrations and helping to focus. However, these psychostimulants may be less well-tolerated in adults. Adverse effects include decreased appetite, nausea, racing heartbeat, restlessness, nervousness, and insomnia. 

Neurofeedback is a non-pharmaceutical treatment that combines cognitive behavioral therapy techniques like conditioning and positive reinforcement with electroencephalography (EEG) feedback. Electrodes are placed on specific brain areas, guiding patients to regulate their brainwave activity. 

Repetitive transcranial magnetic stimulation (rTMS) uses electromagnetism to induce an electric field by passing a magnetic field through the scalp. Transcranial direct current stimulation (tDCS), on the other hand, directly applies an electric current through the scalp. Both repetitive transcranial magnetic stimulation (rTMS) and tDCS primarily target the outermost layers of neurons, as they are non-invasive methods. Nevertheless, both techniques are believed to affect deeper layers through interconnected neuronal networks.  

The Study:

A French research team conducted a systematic search of the peer-reviewed medical literature to perform a meta-analysis to explore the efficacy of these experimental treatment techniques. 

Eight studies – four using rTMS and another four using tDCS – met the inclusion criteria. Studies had to be randomized controlled trials (RCTs), and had to involve multiple sessions of treatment. Participants had to be adults previously diagnosed with ADHD.  

Outcomes were measured through self-rated scales, neuropsychological tests, and electrophysiological pre-post evaluations. 

Separate meta-analyses of the four tDCS RCTs combining 154 participants and of the four rTMS RCTs encompassing 149 participants likewise reported no significant improvements. In all cases variation in outcomes between studies was moderate, and there were no signs of publication bias. 

The Conclusion on Neuromechanistic Treatments for ADHD:

Meta-analysis of all eight studies with a combined total of 421 participants reported no significant improvements over controls. Narrowing down to studies that used sham controls likewise produced no significant improvements. So, despite the title of this study, these neuromechanistic treatments do not appear to be the future of treatment for adult ADHD.

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According to the World Health Organization, suicide is the second leading cause of death among individuals aged 15 to 29 years. 

A European study team recently released findings of the first meta-analysis to explore the association between clinically diagnosed ADHD in children and adolescents and subsequent suicidality.  

The criteria for study inclusion were: 

• Most participants had to be under 18 at baseline. 

• Longitudinal design, meaning that participants were followed over time. 

• Having an ADHD sample diagnosed in childhood that was followed up for suicidal behavior. 

• Having a control group without ADHD that was followed up for suicidal behavior. 

• That ADHD was clinically diagnosed based on DSM-5 criteria. 

• The total number of participants and of those with suicidal behavior in both the ADHD group and the control group during follow-up were reported. 

All selected studies scored at least eight out of 11 points after quality assessment. The most frequent defect was that it was unclear whether suicidal behavior had occurred before study initiation. 

Meta-analysis of all nine included studies, encompassing more than 4.4 million participants, reported more than threefold greater odds of overall suicidal behavior among children and adolescents previously diagnosed with ADHD, as opposed to children and adolescents not previously diagnosed with ADHD. Study outcomes varied significantly (high heterogeneity) but showed no publication bias. 

Breaking this down into subcategories of risk: 

• Two studies combining 521 participants reported roughly fourfold greater odds of suicidal ideation among those previously diagnosed with ADHD, with negligible heterogeneity. 

• Six studies encompassing a total of more than 87,000 children and adolescents reported more than threefold greater odds of suicide attempt among those previously diagnosed with ADHD, with high heterogeneity. 

• Two studies combining more than 2.6 million participants reported a near-quadrupling of the odds of suicide death among those previously diagnosed with ADHD, with negligible heterogeneity. 

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The team concluded, “the current systematic review and meta-analysis has confirmed previous findings that there is an elevated risk for suicidal behavior in ADHD patients.” They also note, however, that “this relationship is heterogeneous and complex, with significant differences across ADHD subtypes, age groups, sexes, comorbidities, and social issues, all of which play important roles in the development of suicidal behavior.”

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The Newest Non-stimulant Medication for ADHD

Centanafadine, which is currently under investigation as a treatment for ADHD, will be the first triple reuptake inhibitor for the disorder if it is approved by the FDA. It improves norepinephrine, dopamine and serotonin levels. This new medication is not a stimulant, but due to the dopamine component, it has a stimulant-like effect in patients. In adults, two phase 3 trials and a year-long extension have shown sustained benefits and a tolerable safety profile, laying the groundwork for pediatric research.

Based on this study, improvement was already noticeable after the first week and held steady through week 6. The lower dose (164.4 mg) didn’t separate from placebo, reminding us that getting the dose right will be critical. The effect size was smaller than what is seen for stimulants but 50% of patients had excellent outcomes as indicated by reductions in the ADHD-RS of 50% or more.

Side effect patterns look familiar to anyone who prescribes ADHD medications; loss of appetite, nausea and headaches topped the list. About half of teens on the higher dose reported at least one treatment-emergent adverse event, compared with a quarter of those on placebo. Severe reactions were rare but did include isolated liver enzyme spikes, rash, and a few reports of aggression or somnolence. For everyday practice, that translates to routine growth checks, a look at baseline liver function, and clear guidance to families about reporting rashes or mood changes promptly.

The researchers noted that the study had certain limitations, including limited generalizability to adolescents beyond North America, the exclusion of teacher ratings on the ADHD-RS-5 scale and the study’s short duration. They added that future studies should explore long-term treatment outcomes and efficacy compared with other ADHD treatments, as well as its effect on treating ADHD with comorbid conditions.

Why should this matter to clinicians already juggling multiple non-stimulant options for ADHD?

First, speed. Centanafadine separated from placebo within a week. In this regard, it might be closer to stimulants than to the multi-week ramp-up we expect from current non-stimulants. Second, it offers another option when stimulants are contraindicated or poorly tolerated, or when they raise diversion concerns. Its mechanism also makes it intriguing for patients who need both norepinephrine and dopamine coverage but prefer to avoid schedule II drugs. Because it also improves serotonergic transmission, it may be useful for some of ADHD’s comorbidities (see our new article for evidence about serotonin’s role in these disorders).

Keep in mind that centanafadine for ADHD is still investigational, so participation in clinical trials remains the only access route.

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