A new study published in Neuropsychopharmacology Provides preliminary evidence that amlodipine, a drug widely used for high blood pressure, can help manage the symptoms of attention / hyperactivity deficit disorder (ADHD). In a series of experiences using animal models and human genetic data, researchers have found that amlodipine reduced hyperactivity and impulsiveness – key characteristics of ADHD – while also demonstrating potential advantages compared to current stimulating drugs. The results suggest that this well tolerated medication could serve as a basis for a new type of treatment that is not stimulating for the disease.
ADHD is a common neurodevelopmental condition which generally emerges in childhood and can persist in adulthood. It is characterized by persistent symptoms of inattention, hyperactivity and impulsiveness that interfere with daily life, academic success, work performance and social relationships. ADHD affects approximately 2 to 5% of the world’s population and is associated with a higher risk of mental health problems, including mood and anxiety disorders, consumption of substances and even suicide.
Current ADHD treatments generally involve stimulating drugs such as methylphenidate or amphetamines. These drugs can be effective for many people, but they are also associated with several drawbacks. Side effects such as insomnia, loss of appetite, headache and the increase in blood pressure are common. There is also an abusive potential for use, especially in adolescents and young adults. Above all, around 25% of people with ADHD do not have adequate relief of the symptoms of any available medication. These limitations have prompted researchers to explore new therapeutic options which are both effective and better tolerated.
Researchers of 3z pharmaceuticals in Iceland have sought to identify an unstimping drug that could offer an alternative to people who do not respond well to existing treatments. They focused on amlodipine, a drug widely used to treat high blood pressure, as it targets calcium l – proteins in the brain which helps regulate electrical activity in neurons and are increasingly recognized as playing a role in neuropsychiatric disorders.
Researchers have hypothesized that modulation of these calcium channels could help to mitigate the symptoms of ADHD. Their objective was to determine if the amlodipine, which already has a solid security file, could be reused as a new treatment for disorder. Their strategy was to integrate results into several experimental systems, including behavioral tests in rats and zebra fish, pharmacological and cerebral imaging and human genetic analyzes.
“At 3z, we have developed a high-speed behavioral screening platform for the discovery of drugs, using genetically modified zebra models,” explained the corresponding author Karl ægir Karlsson, CEO of 3z and professor of neuroscience at the University of Reykjavik. “The platform is designed to detect therapeutic effects through a wide range of neuropsychiatric disorders with a behavioral phenotype. ADHD was a natural adjustment: it is very widespread, current drugs have significant limits – including negative effects and a large non -response group – and there is a clear need for new therapies. “
“Above all, we have also designed a robust ADHD zebra fish model which has basic behavioral symptoms such as hyperactivity and impulsivity.
In the first part of the study, the researchers tested five candidates drugs in high rats to present ADHD hyperactivity. Among the options, only amlodipine has systematically reduced hyperactive behavior, especially in female rats. These effects were observed after 30 days of treatment and were confirmed by objective measures such as the distance traveled and the time spent. Other compounds tested have not shown significant effects.
To extend their results to another species, Karlsson and his colleagues examined how amlodipine affected behavior in zebra fish with a genetic mutation linked to impulsivity and hyperactivity. Zebra fish is a useful model for studying brain function, as they share a large part of their genes with humans. In this experience, researchers used a behavioral task designed to measure impulsive actions. They found that amlodipine significantly reduced premature responses in zebra fish, indicating better control of pulses. The results were comparable to those produced by methylphenidate.
The researchers then explored if the amlodipine could enter the brain and influence neural activity. They confirmed that the drug crosses the blood-brain barrier in zebra fish and rats. In zebra fish, exposure to amlodipine has reduced the activation of a brain region involved in the regulation of attention and behavior, as indicated by a drop in the expression of a protein called C-FOS. These results suggest that the behavioral effects of amlodipine are probably due to its direct action on the brain, not just its effects on blood pressure.
“The extent and consistency of the behavioral effects of amlodipine in our TDH model were unexpected, given the widespread hypothesis that the drug does not significantly cross the blood-brain barrier (BBB),” Karlsson told Psychost. “This posed a challenge in the interpretation of our data: the effects were too robust to result in plausibly peripheral mechanisms alone.”
“By applying Occam’s razor, the simplest explanation was that amlodipine actually reaches the brain. We have confirmed that this directly using tests of brain and plasma partition coefficient unrelated through several species, including zebra fish, mice and rats.
To understand how these results can apply to humans, researchers have carried out genetic analyzes using large data sets. An analysis used a technique called Mendelian randomization to explore if the genetic variations that affect calcium channels are linked to ADHD. The results showed a significant association between ADHD and several subunits of calcium channels type L – the same targeted by amlodipine. This supports the idea that these channels can play a role in the symptoms of ADHD and could be a significant treatment target.
A second genetic analysis examined British biobank data, a large -scale health database with genetic and health information of more than 500,000 participants. People with higher genetic risk of ADHD were more likely to report mood swings and risk -taking behavior. However, among those who take amlodipine, these trends were less common, which suggests that the drug can help manage certain basic Characteristics of ADHD even outside a clinical diagnosis.
“We have identified the amlodipine, a blocker of calcium channels commonly prescribed for hypertension, as a candidate for the reuse of ADHD,” said Karlsson. “Our results suggest that it targets a mechanism previously underestimated in the brain relevant to the attention and control of pulses. This is important because it shows how existing drugs, already well characterized in terms of safety and pharmacology, can be redirected to meet the needs not followed in psychiatric disorders – potentially reducing the time and cost of the drug. “
Researchers point out that if these results are promising, amlodipine is not yet approved for the treatment of ADHD and other tests in clinical trials are necessary. However, the long -standing safety file of the drug and the widespread availability make it an attractive candidate for reuse. Amlodipine is already approved by the Food and Drug Administration, is inexpensive and has a low risk of drug interactions.
A strength of the study was his several -component approach, which combined laboratory experiences with large -scale human genetic data. By showing coherent effects between species and methods, the researchers were able to build a convincing case for a more in -depth investigation. The study has also introduced a new way to use genetic tools to assess the effects of drugs on several organic targets, an approach that could help accelerate the discovery of drugs for other brain disorders.
However, research is not without limits. Animal studies, although informative, do not fully capture the complexity of human ADHD, which involves a wide range of behavioral and cognitive symptoms. In addition, genetic analyzes were based on self -declared symptoms and indirect measurements of ADHD lines rather than formal diagnoses. Future clinical studies will be necessary to determine whether the advantages of amlodipine extend to diagnosed individuals and how the drug is compared to existing treatments in real contexts.
“Although amlodipine is promising in preclinical models, it is not currently suitable for use in ADHD in its marketed form,” noted Karlsson. “An optimization more in -depth by chemical modification is necessary to improve the selectivity of the SNC and ensure a favorable therapeutic index in the context of ADHD.”
Researchers are now preparing to launch a phase II clinical trial to officially assess the safety and efficiency of amlodipine for ADHD in humans. In the event of success, this effort could open the way to a new class of non -stimulating treatments, offering hope to people who do not respond or cannot tolerate current drugs.
“Although the spotlights are on amlodipine and ADHD, this work also represents proof of concept for a wider drug reuse pipeline for SNC disorders,” Karlsson said. “Our approach combines the impartial screening of relevant zebra fish models with the disease with human genetic validation to prioritize and deactivate candidates before clinical development. This double strategy can accelerate the discovery of new SNC therapies by taking advantage of the molecules known to new ways – a particularly attractive proposal in a field where the traditional development of the drug has often fought. “
The study, “validation of the amlodipine of blocking channel blockers type L as a new ADHD treatment with inter-species analysis, Mendelian randomization of the drug and clinical evidence of medical records”, was written by Haraldur þorsteinsson, Hannes A. Baukmann, Hildur S. Sveinsdóttir, Dagmar Ir. Halldórsdóttir, Bartosz Grzymala, Courtney Hillman, Jude Rolfe-Tarrant, Matthew O. Parker, Justin L. Cope, Charles Nj Ravrani, Marco F. Schmidt and Karl Karlsson.
