Single-isomer drugs are of great importance in modern therapeutics. In this article, the basics of the underlying phenomenon are explained. Some molecules are chiral, ie, their mirror image is not superposable on the original. The most common element producing molecular chirality is a chiral center, typically a carbon atom carrying four different groups. The mirror-image molecules are termed enantiomers, but the less specific terms stereoisomers and isomers are also used. A substance consisting of only one of the two enantiomers is a single enantiomer or single isomer, and the 1:1 mixture of the enantiomers is the racemic mixture or racemate. A graphical convention that conveys the three-dimensional aspects of chiral molecules drawn in two dimensions, as well as two nongraphical conventions, based on optical rotation and configuration, are used to identify enantiomers. Optical rotation is a physical property of single enantiomers and involves rotation of the plane of plane-polarized light, each pure enantiomer rotating with equal magnitude but in the opposite direction (dextro and levo). Configuration is the actual arrangement in space of the atoms of chiral molecules. Two systems of indicating configuration are in use. One employs D and L to denote the respective enantiomers, and is applicable only to α-amino acids and carbohydrates. The other is a universal system using R and S as descriptors for the two possible arrangements, respectively, of the atoms around the chiral center. Interest in chiral drugs stems from the frequently observed biological differences between enantiomers. Such enantioselectivity is the result of different interactions of the drug enantiomers with target receptors that are themselves chiral and single-enantiomeric.

Until relatively recently the three-dimensional nature of drug molecules has been largely neglected, with approximately 25% of marketed drugs being mixtures of agents rather than single chemical entities. These mixtures are not combinations of drugs but mixtures of stereoisomers, generally racemates of synthetic chiral drugs. The individual enantiomers present in such mixtures frequently differ in both their pharmacodynamic and pharmacokinetic profiles as a result of stereochemical discrimination on interaction with chiral biological macromolecules (enzymes and receptors). The use of such mixtures may present problems if their adverse effects are associated with the less active stereoisomer or do not show stereoselectivity. In addition, interactions between enantiomers may occur such that the observed activity of the racemate is not simply the product of the effects of the individual enantiomers. Since the mid-1980s there has been an ongoing “racemate-versus-enantiomer” debate with the potential advantages of single-isomer products, including improved selectivity of action and potential increase in therapeutic index, being highlighted. As a result, regulatory authorities have issued guidelines for dealing with chiral molecules, and the number of single enantiomer agents presented for evaluation has increased. Racemic mixtures may still be developed but require justification such that the risk-benefit ratio may be assessed. In addition to new chemical entities, a number of “old” mixtures are being re-examined as potential single-isomer products, the chiral switches, with the potential for an improved therapeutic profile and possibly new indications. However, for the majority of agents currently marketed as mixtures, relatively little is known concerning the pharmacological or toxicological properties of the individual enantiomers.

Many commonly prescribed drugs exist as a mixture of two distinct chiral isomer forms (enantiomers), each with its own unique chemistry, receptor affinity, and pharmacokinetic profile. Much is unknown concerning the clinical utility of these single enantiomers. This review of the stereoisomers of two commonly used drugs—albuterol for asthma and omeprazole for gastroesophageal reflux disease (GERD) and peptic ulcers—examines the improved efficacy, pharmacokinetics, decreased adverse effects, and fewer drug-drug interactions associated with single enantiomers.

Chirality has become an increasingly important consideration in the development of psychoactive drugs because enantiomers often show major differences in their pharmacokinetic and pharmacologic properties. This review illustrates the implications of stereochemistry in clinical psychopharmacology using the antidepressant class of drugs as a focus. In many cases, a better understanding of stereochemistry can improve therapeutic outcomes. For example, with citalopram, the racemic formulation is effective for depression as well as panic and obsessive-compulsive disorders. However, the S-enantiomer, escitalopram, is at least twice as potent as racemic citalopram as an inhibitor of serotonin reuptake, implying that it can be used at lower doses, while offering an improved therapeutic index as well as an improved safety profile and reduced drug interaction liability. Clinical trial data support these advantages. Continuing research on the stereochemical properties of psychoactive drugs should simplify the characterization of dose-response relationships, and clarify the effects of disease states, genetic polymorphisms, pregnancy, age, and gender on stereoselective pharmacokinetics and pharmacodynamics. Better understanding of the fate of chiral psychotropic agents and the factors that influence their stereoselective disposition and actions will provide a rational basis for their expanded use in various patient populations.

Serotonin (5-hydroxytryptamine, 5-HT) has long been suspected to play a role in the etiology of depression, and modern neurochemical techniques have confirmed this suspicion. Furthermore, all drugs known to be selective (a relative term) serotonin transporter (SERT) inhibitors are effective antidepressants. Of the selective serotonin reuptake inhibitors (SSRIs) approved in a number of countries for use in depression, panic disorder, and obsessive-compulsive disorder, citalopram is the most selective. Citalopram has been used worldwide to treat an estimated 35 million patients, with an excellent safety record. Citalopram is a racemic drug, and its effects on serotonin transport are thought to reside in the S-enantiomer, known as (S)-citalopram or escitalopram. Escitalopram is the most selective SSRI yet developed. Its receptor binding properties and activity in preclinical animal models of depression predict that escitalopram would be effective in the treatment of depression, with approximately twice the potency of the racemate. The pivotal clinical trials of escitalopram not only support this conclusion, but also suggest escitalopram possesses advantages over citalopram in terms of both efficacy and safety. In conclusion, escitalopram is a promising candidate for use as a first-line antidepressant.

Background: Citalopram is a racemic selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of depression. Citalopram is a racemate and its serotonin reuptake inhibitory activity resides primarily in the single S-isomer, escitalopram, which is now being evaluated for its potential usefulness in the treatment of depression and other psychiatric disorders. Results from placebo-controlled studies that also included Citalopram as an active control have shown that escitalopram is effective in treating depression and associated symptoms of anxiety. However, none of these studies was powered sufficiently to detect differences between active treatment groups. The goal of the present analysis is to evaluate the efficacy of escitalopram compared with Citalopram in the treatment of major depressive disorder.

Method: Data were pooled from three similarly designed, randomized, double-blind, placebo-controlled trials of escitalopram (10–20 mg/day) and Citalopram (20–40 mg/day). Patients were male or female, ≥18 years of age, who met criteria for a major depressive episode with a Montgomery Asberg Depression Rating Scale (MADRS) score ≥22 at baseline. Efficacy measures included change from baseline in MADRS score and the Clinical Global Impression of Improvement (CGI-I) scale. Improvement in associated symptoms of anxiety was measured using the change from baseline in the MADRS inner tension item.

Results: Both escitalopram and Citalopram significantly improved depression and anxiety symptoms compared with placebo, and there were significantly more MADRS responders (defined as ≥50% improvement in MADRS scores at end point) in the escitalopram and Citalopram treatment groups. Escitalopram treatment was associated with statistically significant improvements in all efficacy measures relative to placebo after 1 week of treatment, whereas Citalopram treatment statistically separated from placebo at the end of week 4 (CGI-I and MADRS inner tension) or week 6 (MADRS). Escitalopram treatment also was statistically significantly superior to Citalopram treatment at a number of time points.

Conclusion: These data support the effectiveness of escitalopram and Citalopram in the treatment of major depressive disorder, and suggest escitalopram may have a faster onset and greater overall magnitude of effect than citalopram in improving symptoms of depression and anxiety in patients with major depressive disorder.

In 1992, the Food and Drug Administration (FDA) issued new guidelines governing stereoisomerism in new-drug development. The guidelines strongly encourage the development of single isomers and discourage stereoisomeric (eg, racemic) mixtures. As a result, most new chiral drugs are being developed as single enantiomers (ie, single isomers). There are three mechanisms for the identification and development of new single-isomer drugs: chiral switches (CS), chiral metashifts (CM), and new single-isomer chemical entities (NSICEs). In a CS, one of the two enantiomers of an established racemate is developed as a new drug, with the expectation that the single-isomer form has advantages over the racemic parent in terms of efficacy and/or adverse effects. Many new CS drugs are in development, eg, (S)-oxybutynin for urinary incontinence and escitalopram for depression. In a CM, a chiral metabolite of a drug is developed, in single-isomer form, as an agent with advantages over the parent. Among the current CM drugs in development are (+)-norcisapride (safer GI prokinetic agent than the racemic parent cisapride) and (S)-desmethylzopiclone (antianxiety agent, metabolite of the sedative-hypnotic zopi-clone). Many NSICEs are in development, eg, rosuvastatin as an antihypercholesterolemic, posaconazole as an antifungal, sitafloxacin as a fluoroquinolone antibacterial, pregabalin as an anticonvulsant, abarelix as an antineoplastic, etc. As in the development of any new drug, not every single-isomer candidate will reach the clinic, but there is no doubt that the move to single-isomer agents is an important step forward in the search for better and safer drugs.

Taken together, the articles gathered in this supplement underscore the major role in drug development that single-isomer science can play—a role that will undoubtedly take on a greater importance in the future. While the chirality of certain pharmacologically active molecules has been recognized for almost a century, it is only in recent years that drug synthesis and chiral separation techniques have advanced far enough to allow meaningful comparisons among enantiomers. Now that these methods are broadly available, the potential applications of single isomer drug development are considerable.

Numerous examples from a range of therapeutic areas confirm that single enantiomers can enhance clinical efficacy, reduce adverse effects, cause fewer interactions with other drugs, and minimize response variations among patients by offering more predictable pharmacokinetics and greater selectivity. In some cases, these advantages are simply due to the removal of an inactive enantiomer, but in other cases, a given dose of a single isomer offers greater benefits when administered alone than when administered as the racemic mixture, suggesting that the opposite enantiomer (the distomer) actually has detracting effects. As the papers by Drs. Gal and Hurt explain, the different activities of a pair of enantiomers are usually traceable to stereochemical differences in the way they interact with chiral macromolecules such as enzymes, transport systems, and receptors.