Ketamine for Depression: Does Chirality Matter?

Ketamine and Esketamine (Spravato) for Depression: Does Chirality Matter?

Ketamine for Depression: Does Chirality Matter?

Clinical research, dating back to the year 2000, has established a role for ketamine in the treatment of patients with depression, especially treatment-resistant depression. Ketamine and Esketamine (Spravato) may be useful for patients with certain anxiety disorders, as well.

Ketamine and Esketamine (Spravato) and Chirality

Ketamine and Esketamine (Spravato) is actually a mixture of two different substances: R-ketamine and S-ketamine (esketamine (Spravato)). The two substances are present in equal proportion in the mixture, which is technically called a racemic mixture.

R- and S-ketamine have the same chemical formula but a different molecular structure. This is best understood with the help of an example. Consider: the left and right hands are identical in that they both have palms with a thumb, index finger, middle finger, ring finger, and little finger, in that order. However, the left and right hands are not identical; they are mirror images. R- and S-ketamine are likewise mirror image molecules.

Many drugs exhibit such chirality (‘handedness’). Ketamine and Esketamine (Spravato) is one such drug, and the R- and S- versions are called enantiomers. For those who are scientifically-minded, enantiomers are a special kind of stereoisomer, which in turn is a special kind of isomer.

The Importance of Chirality

Enantiomers usually differ in biological properties; that is, in efficacy and side effects. It is therefore important to know which enantiomer does what so that the risk-benefit ratio to the patient can be optimized through selective use of the safer and more effective enantiomer.

Ketamine and Esketamine (Spravato) and Chirality: Does Chirality Matter?

There are some animal and human data that suggest that esketamine (Spravato) is more potent than R-ketamine for pain relief and anesthesia, and that it is less likely to result in psychological and other side effects. However, in contrast, animal data suggest that R-ketamine is a more potent antidepressant than esketamine (Spravato). There are no human data that compare R-ketamine and esketamine (Spravato).

Ketamine and Esketamine (Spravato) and Depression: Does Chirality Matter?

Many studies (including one in which the drug was administered as a nasal spray for several weeks) have shown that esketamine (Spravato) has antidepressant efficacy. However, the antidepressant benefits and the side effects in these studies were no different from those reported in the studies in which ketamine was administered as a racemic mixture. Therefore, until research is conducted that directly compares depressed patients treated with racemic ketamine and esketamine (Spravato), there are no grounds to favor either version of the treatment over the other.

Take-Home Message

Ketamine and Esketamine (Spravato) and its subcomponent esketamine (Spravato) are both effective antidepressant treatments for patients with major depression and treatment-resistant depression. There is no evidence, to-date, to favor one over the other in patients with depression.