The use of lisdexamfetamine dimesylate for the treatment of ADHD and other psychiatric disorders

Abstract

Lisdexamfetamine dimesylate (LDX) is a long-acting oral prodrug stimulant. It is inactive until enzymatically hydrolyzed in the blood to active d-amphetamine. The pharmacological action of this compound involves blocking norepinephrine (NE) and dopamine reuptake into presynaptic neurons and promoting the release of NE and dopamine into the extraneuronal space. LDX has been approved for treating ADHD, which is the most common psychiatric disorder in children and adolescents. Also, LDX has been proposed for other psychiatric conditions related with dopaminergic and NE CNS. LDX is the first long-acting oral prodrug indicated for the treatment of ADHD in children (6–12 years), adolescents (13–17 years) and in adults in the USA and Canada, whereas, in Europe, LDX is licensed in several countries for the treatment of children and adolescents with ADHD who have had a clinically inadequate response to methylphenidate. This article covers the most important pharmacological aspects of LDX as well as data on the efficacy, tolerability and safety of this long-acting amphetamine prodrug collected from clinical studies recently published in the literature.

Keywords::

• ADHD
• efficacy
• lisdexamfetamine dimesylate
• prodrug
• safety
• tolerability

Financial & competing interests disclosure

The study has been supported by grants from the Instituto de Salud Carlos III, Redes Temáticas de Investigación Cooperativa, Red de Trastornos Adictivos RD06/0001/0020 and RD12/0028/0012 (Spain). C Roncero has received fees to give talks for Janssen-Cilag, Bristol-Mayers Squibb, Ferrer-Brainfarma, Pfizer, Reckitt-Benckiser, Lundbeck, Otsuka, Servier, Lilly, Shire, GSK, Rovi and Adamed. He has received financial compensation for his participation as a member of the Janssen-Cilag, Lilly and Shire board. He has carried out the PROTEUS project, which was funded by a grant from Reckitt-Benckisert.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors thank M Pulido for editing the manuscript and for editorial assistance. The fees of medical writing and editing were paid by Nature Publishing Group Iberoamérica, Madrid, Spain.

Key issues

• Lisdexamfetamine dimesylate (LDX) is a prodrug long-acting stimulant with a novel delivery mechanism. After oral ingestion, LDX is converted to l-lysine and d-amphetamine, the latter being the active drug for therapeutic effect. Conversion takes places by enzyme hydrolysis in the red blood cells.

• LDX is not metabolized by the hepatic cytochrome P450 system, which means a low potential for drug–drug interaction. This is a key feature because comorbidity in patients with ADHD (the main indication of LDX) is very frequent and, therefore, may receive multiple psychopharmacological medications.

• LDX has been shown to be effective up to 13 h (children) and 14 h (adults) post-doses. The initial dose of 30 mg/day can be uptitrated based on clinical response to a maximum of 70 mg/day in weekly increments of 10–20 mg.

• LDX also shows low intrasubject and intersubject pharmacokinetic variability.

• LDX has an attenuated response on measures of abuse liability when compared with immediate-release amphetamine. The risk of misuse is minimal as compared with other drugs and stimulants.

• There is strong evidence of the efficacy of LDX in children (6–12 years), adolescents (13–17 years) and adults in reducing ADHD symptoms according to results of randomized, double-blind, placebo-controlled clinical trials. The inclusion of patients with comorbid mental disorders and/or medical conditions is not well studied in clinical trials.

• Adverse events associated with LDX are consistent with those expected with stimulants. However, treatment with LDX in all age strata (children, adolescents, adults) is generally well tolerated and safe.

• Clinical trials have been recently conducted in possible future indications of LDX (e.g., major depression, binge eating disorders).