Attention deficit hyperactivity disorder

Could we have an ADHD stimulant medication with once-daily administration and whole-day efficacy?

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by inattention, distractability, poor impulse control, fidgeting, and hyperactivity. Children with ADHD may have trouble performing well at school, whereas adults with ADHD often experience trouble being productive in the workplace.

Biopharmaceutical company Cingulate recently initiated the first phase 3 clinical trial of CTx-1301, which is an extended-release tablet of dexmethylphenidate. This formulation promises a faster onset of action (∼30 minutes) and an efficacy lasting up to 16 hours, according to Cingulate. In contrast, the extended-release capsules, available in the market, exhibit a first peak effect at 1.5 hours and an overall duration of about 12 hours [1].

[ADHD is associated with functional impairments in neurotransmitter systems and dysregulated dopaminergic functioning - editor's comment] Medicinal treatments for ADHD are typically divided into two categories: stimulants and non-stimulants. These categories differ in terms of mechanisms of action, efficacy rates, and side effects, but they’re similar in that they act to favour monoamine (mainly dopamine and noradrenaline) neurotransmission in the brain.

Stimulants are the first-line medication prescribed for ADHD. Amphetamine, amphetamine analogs (e.g. methamphetamine), and phenidates (e.g. methylphenidate) all belong in this category of medications. In therapeutic doses, they increase focus, improve attention, enhance performance, and elevate mood. Although stimulants exert similar effects, different stimulants (amphetamines, phenidates) exhibit different specific mechanisms of action [2]. Whereas methylphenidate and amphetamines block presynaptic dopamine and noradrenaline transporters, amphetamines additionally favour presynaptic release of dopamine into the synaptic cleft [2]. These mechanisms of action are broadly summarised under Figure 1.

Figure 1

Stimulants are thought to promote vesicle deacidification [3] and the efflux of neurotransmitters from vesicles into the cytoplasm of the presynaptic cell via the vesicular monoamine transporter VMAT2 [3, 4]. Stimulants can block MATs. They may also promote phosphorylation-dependent MAT removal and/or MAT function reversal, via the sequential activation of TAAR1 and protein kinases [5]. Amphetamines can inhibit mitochondrial monoamine oxidases (MAO) [6], which metabolize and inactivate monoamine neurotransmitters.

Non-stimulants are second-line medications prescribed to patients with contraindications, adverse reactions, or pharmacoresistance to stimulants. Their main difference from stimulants is in the mechanisms of action that they exhibit. Guanfacine activates postsynaptic α2A noradrenaline receptors in the prefrontal cortex [7], a key brain region for executive functions like attention. Atomoxetine is a selective noradrenaline reuptake inhibitor. Non-stimulants are less efficacious compared to stimulants [8]. Considering atomoxetine, it’s maximum efficacy may not be reached until several weeks have passed [8].

Stimulants are an effective treatment against symptoms of ADHD in about 70% of adults and 70-80% of children [9]. However, they are imperfect therapeutic strategies. Stimulants are associated with side effects, such as insomnia, weight loss, and addiction, and with high discontinuation rates [10]. Another complication is the frequency with which they need to be taken per day, along with likely rebound effects occurring when they wear off. Due to the disorder, people with ADHD may also be forgetful and omit taking their medication at times. These complications could best be addressed by eliminating the need for extra doses per day.

“No currently available ADHD medications offer a single oral dose that provides whole-day efficacy,” writes Leah Kuntz for Psychiatric Times.

A whole-day efficacy and once-daily administration are, thus, Cingulate’s aims for its stimulant, CTx-1301, according to their Press Release. Results from their phase 3 study are expected in the first half of 2023.

Reference list - see at the bottom of this page

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13.02.2023

Text by George Louloudis, illustration by Alisa Lapkovskaya

reviewed by Nikita Mikhailov and Irina Belaia

Reference list

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Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review. Quintero J et al. Neurol Ther. 2022; 11(4): 1489-1517.
Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Freyberg Z et al. Nat Commun. 2016; 7: 10652.
VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Eiden LE & Weihe E. Ann N Y Acad Sci. 2011; 1216(1): 86-98.
The Emerging Role of Trace Amine Associated Receptor 1 in the Functional Regulation of Monoamine Transporters and Dopaminergic Activity. Miller GM. J Neurochem. 2011; 116(2): 164-76.
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α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting Camp-HCN Channel Signaling in Prefrontal Cortex. Wang M et al. Cell 2007; 129(2): 397-410.
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Attention-deficit hyperactivity disorder (ADHD) stimulant medications as cognitive enhancers. Advokat C & Scheithauer M. Front Neurosci. 2013; 7: 82.
Genetic, clinical, and sociodemographic factors associated with stimulant treatment outcomes in ADHD. Brikell I et al. Am J Psychiatry 2021; 178(9): 854-64.

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