However, even for those with treatment access, current pharmaceutical therapies are hardly ideal. It is against this backdrop that the potential for a novel therapy lies in an infamous drug of abuse – ketamine. Ketamine and its derivatives, such as GLYX-13, represent recent advances in alternative treatments for depression, and could provide much-needed respite especially for intractable depression.

In general, the success rate for any given antidepressant is approximately 50%, and efficacy varies greatly from individual to individual. Finding an effective drug for any patient is thus largely based on trial and error, which can be both frustrating and dangerous for a seriously depressed individual. Antidepressants also require weeks of treatment before the beneficial effects are realized and often come with a myriad of side effects. Finally, there is a subset of approximately 20% of patients who seem resistant to existing medications, and these patients are in dire need for new treatments that will provide relief.

Ketamine is an approved anesthetic drug that has gained notoriety as a club drug. Recent studies, however, have shown that ketamine can provide rapid relief of depression symptoms in a matter of hours, which is markedly different from the mainstay antidepressants. Although depression is traditionally thought to be the result of low neurotransmitter levels in key brain regions, a different theory suggests that depression is actually caused by damage to cells in brain regions that control mood. This damage can be a direct result of chronic stress, since high levels of stress hormones can cause excessive release of the neurotransmitter glutamate, leading to toxicity and cell damage.

A recent review article in the journal Science suggests that ketamine may exert its antidepressant effects by causing the rapid growth of new connections between brain cells, and in so doing, may reverse some of the atrophy associated with chronic stress. Due to its hallucinogenic effects, and potential for abuse, there are limitations to the administration of ketamine, and it can only be used in a hospital setting under the guidance of a doctor. However, there are companies such as Naurex that are actively developing derivatives of ketamine (GLYX-13), which retain the efficacy of ketamine while reducing the side effects. GLYX-13, like ketamine, is an NMDA receptor modulator; however, results from a Phase I trial of GLYX-13 showed that adverse events for the groups receiving GLYX-13 and placebo were all rated as mild, and there were no signs of the schizophrenia-like side effects associated with ketamine. The drug is currently in Phase II clinical trials to assess the efficacy and safety of intravenous GLYX-13 in treatment-resistant depression, with results of these trials set to be released later in 2012.

The treatment of depression saw a paradigm shift in the 1980s with the introduction of the blockbuster drug Prozac, a Selective Serotonin Reuptake Inhibitor (SSRI). Since then the pharmaceutical industry has responded to Prozac’s commercial success by introducing and eventually flooding the market with numerous other SSRIs. While the newer neurotransmitter reuptake inhibitors have been successful in the market and offer fewer side effects, there haven’t been any advances that offer faster relief of depression symptoms, or adequately treat refractory patients. The only significant shift in drug development for depression since the ‘80s has been the adjunctive use of antipsychotics such as Abilify to further alleviate depression symptoms.

GLYX-13 represents a novel approach to treatment of depression that addresses the unmet needs for faster-acting drugs and treatments that work in refractory patients. Because the drug is currently only administered intravenously, it is unlikely to be a first-line treatment for depression unless oral formulations can be developed. However, given the large size of the market and the unmet needs it addresses, if eventually approved, GLYX-13 would be revolutionary and a significant advance in depression treatment.