Abstract
Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trials together with those that have not have also been considered. What emerges confirms and consolidates the hypothesis that clinically effective ADHD drugs indirectly or directly increase catecholaminergic neurotransmission in the prefrontal cortex (PFC). Attempts to enhance catecholaminergic signalling through modulatory neurotransmitter systems or cognitive-enhancing drugs have all failed. New drugs approved for ADHD are catecholaminergic reuptake inhibitors and releasing agents, or selective noradrenaline reuptake inhibitors. Triple reuptake inhibitors with preferential effects on dopamine have not been successful. The substantial number of failures probably accounts for a continued focus on developing novel catecholaminergic and noradrenergic drugs, and a dearth of drug-candidates with novel mechanisms entering clinical development. However, substantial improvements in ADHD pharmacotherapy have been achieved by the almost exclusive use of once-daily medications and prodrugs, e.g. lisdexamfetamine and Azstarys®, which improve compliance, deliver greater efficacy and reduce risks for diversion and abuse.
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Abbreviations
- ADHD:
-
Attention-deficit hyperactivity disorder
- ADHD RS :
-
ADHD Research Scale
- AE:
-
Adverse event
- AISRS:
-
Adult ADHD Investigator Symptom Rating Scale
- BED:
-
Binge-eating disorder
- BIS-11:
-
Barratt Impulsiveness Scale, Version 11
- BRIEF:
-
Behaviour Rating Inventory of Executive Function
- C-II; CIV:
-
Schedule 2; Schedule 4 controlled drug
- CGI-S:
-
Clinical Global Impressions Scale
- CNS:
-
Central nervous system
- DA:
-
Dopamine
- DAT:
-
Dopamine reuptake transporter
- DBRCT:
-
Double-blind, randomized clinical trials
- EDE-Q7:
-
Eating Disorder Examination Questionnaire Brief Version
- ER:
-
Extended release
- FDA:
-
Food and Drug Administration
- IR:
-
Immediate release
- LDX:
-
Lisdexamfetamine
- MTA:
-
Multimodal treatment of ADHD
- NA:
-
Noradrenaline (norepinephrine)
- NET:
-
Norepinephrine reuptake transporter
- NICE:
-
National Institute for Health and Care Excellence
- NSDUH:
-
National Survey on Drug Use and Health
- PERMP :
-
Permanent Product Measure of Performance
- PFC/FC:
-
Prefrontal cortex/Frontal cortex
- SDX:
-
Serdexmethylphenidate
- SERT:
-
Serotonin reuptake transporter
- SKAMP:
-
Swanson, Kotkin, Agler, M-Flynn and Pelham scale
- YBOCS-BE:
-
Yale-Brown Obsessive Compulsive Scale adapted for Binge Eating
- XR:
-
Extended release
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D.J. Heal, J. Gosden and S. Smith are shareholders and employees of DevelRx Ltd. DevelRx provides consultancy to a wide range of pharmaceutical companies conducting R&D in ADHD. The authors received no financial support for writing this review and no commercial organization had any input on its content.
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Heal, D.J., Gosden, J., Smith, S.L. (2022). New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development. In: Stanford, S.C., Sciberras, E. (eds) New Discoveries in the Behavioral Neuroscience of Attention-Deficit Hyperactivity Disorder. Current Topics in Behavioral Neurosciences, vol 57. Springer, Cham. https://doi.org/10.1007/7854_2022_332
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