Introduction

The CNS stimulants amphetamine and methylphenidate were first synthesized in 1887 in Germany and 1944 in Switzerland, respectively, and approved for use in ADHD (Attention Deficit Hyperactivity Disorder) in 1960 and 1955. It is quite amazing that these molecules – and their pharmacologic classes – still serve as the mainstay of ADHD therapy. Although their duration of action is relatively short, development of various modified release formulations has resulted in improved concentration vs. time profiles of these drugs. Other developments have involved the introduction of the dextro enantiomers of these compounds, and more recently, the introduction of a prodrug of the dextro enantiomer of amphetamine.

Drug Approvals

There have been a total of 7 new molecule approvals for this therapeutic class, in 5 pharmacologic classes. The mainstay of therapy, the CNS stimulants amphetamine or methylphenidate, are both racemates, with the dextro enantiomers being the more active enantiomers. The original approvals of amphetamine (Adderall, 1960) and methylphenidate (Ritalin, 1955) involved the racemates. Subsequently, there have been numerous introductions of different formulations of both molecular entities, including modified release formulations of the racemates, the dextro enantiomers of both drugs, and a prodrug of the dextro amphetamine. In keeping with our convention of focusing on new molecules and not listing new formulations or new routes of administration of previously approved compounds, only the original approvals of new molecules are counted. Similarly, prodrugs of previously approved small molecules are not counted, since the active molecular moiety is still the same. However, the first approvals of the dextro enantiomers of both amphetamine and methylphenidate and of the prodrug of the dextro amphetamine are shown for reference on the accompanying chart (click for a larger chart). Also, in keeping with our convention, included are newly approved drugs for this indication, although they may have been previously approved for another indication, i.e., the two alpha-2 adrenergic receptor agonists. The new molecule approvals are listed below:

• Amphetamine (CNS Stimulant): 2 new molecules; Desoxyn (methamphetamine, 1943) and Adderall (mixed amphetamine, 1960). The first dextro amphetamine, Dexedrine (dextroamphetamine, 1976) and the first prodrug of dextro amphetamine, a lysine adduct, Vyvanse (lisdextroamphetamine, 2007), are also shown on the graph for reference.
• Methylphenidate (CNS Stimulant): 1 new molecule; Ritalin (methylphenidate, 1955). The first dextro enantiomer, Focalin (dextromethylphenidate, 2001) is also shown on the graph for reference.
• Oxazolidine: 1 new molecule; Cylert (pemoline, 1975); withdrawn due to hepatotoxicity.
• Selective Norepinephrine Reuptake Inhibitor: 1 new molecule; Strattera (atomoxetine, 2002).
• Alpha-2 Adrenergic Receptor Agonist: 2 new molecules; Intuniv (guanfacine, 2009) and Kapvay (clonidine, 2009).

Comments

It is noteworthy that there have been a total of approximately three times as many introductions in this therapeutic class as there have been new molecule approvals. This is principally due to the approvals of numerous new formulations of both amphetamine and methylphenidate, and their dextro enantiomers, to improve their concentration vs. time profiles. A few specific comments follow:

• As mentioned above only new molecule approvals are counted. Other approvals are not listed, except for reference. For descriptions of the characteristics of the different new formulations of amphetamine and methylphenidate, and their dextro enantiomers, please refer to a textbook chapter (1). It’s noteworthy in this context that few, in any, therapeutic classes have as many approved new formulations of more than half a century old molecules.
• It is remarkable that after the initial approvals of the CNS stimulants amphetamine and methylphenidate for ADHD in 1960 and 1955, respectively, that these two compounds still represent the mainstay of therapy, and that there have not been introductions of new active molecules in these pharmacologic classes.
• Note that the two centrally-acting alpha-2 adrenergic receptor agonists, Intuniv (guanfacine, 2009) and Kapvay (clonidine, 2009), were previously approved for use in Hypertension in the late 1980’s and early 1970’s, as Tenex and Catapres, respectively.

Conclusions

Two old CNS stimulants, amphetamine and methylphenidate, still continue as the active ingredients of the mainstay of ADHD therapy. This suggests there is a need for a renewed research focus on the etiology and pathophysiology of this disease, including genomics, with the goal of identifying improved therapeutic options. Over one year ago, on this website (2), the slow progress in two other psychopharmacologic therapeutics classes, Schizophrenia and Depression, was discussed, although in contrast to ADHD, there has been a number of new molecule approvals for these indications, but these have been confined to a few pharmacologic classes, half of which have their origins in the late 1950’s. Again, these observations strongly suggest a need for more basic research to identify new therapeutic options in the psychopharmacologic therapeutics category.

References

1. Mrazek DA, Schak KM: Attention-Deficit/Hyperactivity Disorder, in: Waldman SA, Terzic A, Pharmacology and Therapeutics, Saunders Elsevier, Philadelphia, 2009, pp.759-768
2. TRI-institute.org: Slow Progress in Psychopharmacologic Therapeutics, Sep 2014, https://tri-institute.org/?p=184.

Refer to page 22 of Progression of Modern Therapeutics (2014 Report) available under Reports on this website; this report also includes the methodology used.