New Pharmacological Treatments for Attention Deficit Hyperactivity Disorder (ADHD) – Viloxazine | Azstarys | Mazindol | Centanafadine

CURRENT TREATMENTS

Existing pharmacological treatments are classified into stimulants and non-stimulants. However, both drug classes are well known for their side effects and relatively high non-adherence rates. [Ahmed and Aslani 2013]

• Stimulants – Methylphenidate and amphetamine are first-line therapies. Although they have substantial short-term efficacy, they only provide symptom control for approximately 12 hours per dose and come with adverse effects such as decreased appetite, sleep disturbances, and nausea. There is also potential for abuse and misuse. [Posner et al. 2020]
• Non-stimulants – Atomoxetine, clonidine, and guanfacine are often prescribed in children with aggressive behavioural issues or who experience insomnia or tics. Furthermore, they are routinely prescribed alongside other psychotropic medications, particularly when comorbidities are present; however, drug-drug interactions are common. [Wu et al. 2018]

Overall, there is a current and pressing need to develop drugs that have enhanced safety and efficacy. Higher tolerability, fewer side effects, and enhanced long-term efficacy, especially in adults, are a keen focus of the competitive environment in the ADHD field. [Heal et al. 2022]

NEUROBIOLOGICAL TARGETS

MRI findings have suggested that the core features of ADHD are linked to dysregulation in the dopaminergic and noradrenergic systems in specific cortico-striato-thalamo-cortical circuits. [Sobel et al. 2010]

As such, inhibiting dopamine reuptake increases levels in the prefrontal cortex, thus reducing symptoms of inattention and hyperactivity. This is how stimulant medications such as methylphenidate and amphetamine are proposed to act.

Read a detailed review on the neurobiology of ADHD. 

Over the past decade and a half, several treatments have been proposed for ADHD, whether as an add-on therapy to improve efficacy or to mitigate the cognitive impairments observed in patients. Research has shown how:

• Dopamine receptors (e.g., D4) are also linked to the glutamatergic system, although it is unknown what mechanisms underlie how AMPA receptor modulators reduce hyperactivity. [Olsen et al. 2010]
• Melatoninergic agonists can counteract stimulant-induced impairments to the sleep-wake cycle [Molina-Carballo et al. 2013] and reduce the development of ADHD-related phenomena. [Park et al. 2018]
• Phytocannabinoids can enhance dopaminergic neurotransmission and, although controversial, have been suggested to have therapeutic qualities in patients with ADHD [Bossong et al. 2009]; [Bossong et al. 2015]

Some interesting (and promising) results have been seen using drugs that moderate systems outside of the dopaminergic and noradrenergic systems in specific cortico-striato-thalamo-cortical circuits. However, countless drug candidates have failed in the face of these results (e.g., dasotraline, vortioxetine, edivoxetine, and pozanicline). [Heal et al. 2022]

NOVEL PHARMACOLOGICAL TREATMENTS FOR ADHD

Besides the addition of the amphetamine prodrug, lisdexamfetamine [Coghill et al. 2017],  and the extended-release formulations of guanfacine [Huss et al. 2016] and clonidine [Jain et al. 2011], there have been two therapeutics recently added to the currently approved drugs for the management of ADHD:

VILOXAZINE (QUELBREE)

The FDA approved viloxazine extended-release in April 2021 to treat ADHD in paediatric patients aged 6 to 17 years.

Mechanism of Action: 

• Viloxazine increases serotonin levels in the prefrontal cortex, exhibits moderate inhibitory effects on the norepinephrine transporter and elicits moderate activity at noradrenergic and dopaminergic systems [Yu et al., 2020].
• Viloxazine is classified as a serotonin-norepinephrine modulating agent, with its serotonin modulating activity as an important (if not the predominant) component of its mechanism of action.
• It is a once-daily medication with a slow onset of action and moderate efficacy at reducing total functional impairments. (QELBREE Prescribing Information, 2021)

Pharmacokinetics:

• Viloxazine is a potent CYP1A2 inhibitor and weak CYP2D6 and CYP3A4 inhibitor
• The mean half-life is around 7 hrs.

Dosing: 

• The recommended starting dosage for pediatric patients 6 to 11 is 100 mg orally once daily.
• Dosage may be titrated in increments of 100 mg at weekly intervals to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability.
• The recommended starting dosage for pediatric patients 12 to 17 is 200 mg orally once daily. After one week, the dosage may be titrated by an increment of 200 mg to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability.

Side Effects:

• Common: sleepiness, decreased appetite, fatigue, nausea, vomiting, insomnia, and irritability
• However, given the potential to induce suicidal thoughts and behaviours, especially during the initial few months of therapy, a black box warning requires paediatric patients to be closely monitored.

AZSTARYS (SERDEXMETHYLPHENIDATE AND DEXMETHYLPHENIDATE)

• A fixed-dose combination of serdexmethylphenidate (SDX) and dexmethylphenidate was approved by the FDA in March 2021 to treat ADHD in patients at least six years old. [AZSTARYS Prescribing Information, 2021]
• SDX is a prodrug that is enzymatically converted to d-methylphenidate; however, because of the lag before therapeutic concentrations are achieved, it is unsuitable for monotherapy, thus why there is a requirement for it to be combined with dexmethylphenidate.
• Dexmethylphenidate is the more pharmacologically active d-enantiomer of racemic d, l methylphenidate.
• Each capsule contains a fixed molar ratio of 30% dexmethylphenidate and 70% SDX.
• The combined molar dose of SDX and dexmethylphenidate in each dosage strength of AZSTARYS is equivalent to 20, 30, or 40 mg dexmethylphenidate hydrochloride, respectively (equivalent to 17.3, 25.9 or 34.6 mg dexmethylphenidate free base, respectively).

Pharmacokinetics: 

• The median time to reach Cmax of SDX and dexmethylphenidate (Tmax) is about 2 hours following a single dose administration of AZSTARYS under fasted conditions.
• The mean plasma terminal elimination half-life of SDX and dexmethylphenidate in healthy adult subjects was about 5.7 hours and 11.7 hours, respectively, following a single dose of 52.3 mg/10.4 mg AZSTARYS.
• SDX is a prodrug of dexmethylphenidate and is likely converted to dexmethylphenidate mainly in the lower gastrointestinal tract. Enzymes involved in the conversion process are not identified. Dexmethylphenidate is metabolised primarily via de-esterification to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid).

Dosing: 

Pediatric Patients 6 to 12 years of age: 

• The recommended starting dosage of AZSTARYS is 39.2 mg SDX/ 7.8 mg dexmethylphenidate once daily in the morning.
• The dosage may be increased after one week to 52.3 mg SDX/10.4 mg dexmethylphenidate per day or decreased after one week to 26.1 mg SDX /5.2 mg dexmethylphenidate per day, depending on response and tolerability.
• The maximum recommended dosage is 52.3 mg SDX /10.4 mg dexmethylphenidate once daily.

Adults and Pediatric Patients 13 to 17 years of age:

• The recommended starting dosage of AZSTARYS is 39.2 mg SDX/7.8 mg dexmethylphenidate once daily in the morning.
• Increase the dosage after one week to 52.3 mg SDX /10.4 mg dexmethylphenidate per day.
• The maximum recommended dosage is 52.3 mg SDX/10.4 mg dexmethylphenidate once daily.

The side effects are similar to methylphenidate.

Methylphenidate – Mechanism of Action, Side Effects and Dosing

MAZINDOL AND CENTANAFADINE

Ongoing and emerging treatments include two noradrenaline and dopamine reuptake inhibitors, mazindol [Wigal et al. 2018] and centanafadine. [Wigal et al. 2020]

Mazindol: 

• Mazindol is considered a multimodal stimulant that inhibits monoamine transporters and modulates serotonin, muscarinic, histamine H1, μ-opioid, and orexin-2 receptors.
• Mazindol is a reuptake inhibitor of noradrenaline (highly potent) and dopamine (moderately potent) with a weak dopamine-releasing effect with a lower abuse potential than stimulants. It was initially developed as an appetite suppressant for patients with obesity. However, it is no longer marketed in the USA and was banned by the EMA in 2003. It has been trialled in children [Konofal et al. 2014] and adults [Wigal et al. 2018], with significant reductions in symptom severity reported.

Centanafadine: 

• Centanafadine is a triple reuptake inhibitor (noradrenaline > dopamine > serotonin).
• Centanafadine is a potent monoamine reuptake inhibitor that increases noradrenaline and dopamine levels by 300-400%. [Bymaster et al. 2012] Phase 2 and phase 3 trials in ADHD patients have reported positive efficacy and safety results with significant improvements in the Adult ADHD Investigator Symptom Rating Scale (AISRS) and Clinical Global Impressions Scale (CGI-S). At present, trials in paediatric patients are ongoing.
• In the phase 2b study, the centanafadine-SR treatment showed a statistically significant improvement in ADHD-RS-IV from baseline to week three compared with placebo, with significant efficacy demonstrated as early as week 1. The medication was well tolerated at doses ≤400 mg. [Wigal & Sharon, 2020] 

SUMMARY

In children and adults, stimulants effectively reduce ADHD symptom severity and show good tolerability.

Overall, there is a current and pressing need to develop drugs that have enhanced safety and efficacy.