Ketamine research focuses on mechanisms of action and biomarker development

The most notable limitations of current pharmacological treatments for depressive disorders are low response rates and a long treatment-response time. The anesthetic drug ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist, has generated considerable interest because it seems to overcome these limitations. Investigational studies suggest that subanesthesia doses of ketamine can improve mood and suicidal thinking in treatment-resistant patients in a matter of hours.

But Susannah J. Tye, Ph.D., a neurobiologist at Mayo Clinic's campus in Rochester, Minnesota, says enthusiasm for the drug and its ready availability mean it can be administered without sufficient evidence to guide its use. "We want to make sure treatment is evidence-based, so we are focusing our preclinical and clinical research on understanding ketamine's mechanism of action, identifying who is going to respond to it — because not everyone does — and learning how to optimize treatment," she says.

Mechanisms of action

Dr. Tye's research focuses on understanding the factors contributing to treatment resistance in depression and the neurobiological mechanisms underlying the antidepressant actions of drugs such as ketamine. She notes that alterations in glutamatergic signaling may play an important role in the pathophysiology of depressive disorders and that ketamine might have antidepressant actions by restoring function to this system through two key mechanisms of action.

One is activation of the protein mammalian target of rapamycin (mTOR), which controls protein synthesis critical to cell survival and growth. The other is inhibition of glycogen synthase kinase 3 (GSK3), which has long been implicated in mood regulation and plays an important role in neurogenesis and synaptic plasticity — the regulation of synaptic connections between neurons.

These mechanisms correlate strongly with an antidepressant response in animal models of treatment-resistant depression, and it is hoped this understanding will lead to the development of biomarkers that accurately predict response to treatment in humans. "Not all treatment-resistant animals respond to ketamine, and we see this clinically, too — some patients respond well and some don't, and this is a real struggle in the treatment of depression," Dr. Tye notes.

In a small Mayo Clinic study published in the May 2013 issue of the Journal of Psychopharmacology, 8 of 10 patients demonstrated at least a 50 percent improvement in symptoms, with 5 of the 8 achieving remission after serial ketamine infusions. Response rates tend to vary from study to study, however.

"One of the ways we may be able to distinguish patients who are likely to receive therapeutic benefit from those who are not is by measuring blood-based biomarkers — some preclinical evidence suggests this is feasible," Dr. Tye says. "We're in the process of starting the next ketamine trial in which we will be collecting blood samples to confirm these biomarkers correlate with clinical response."

In the rapidly expanding field of ketamine research, some investigators are analyzing metabolomic patterns in blood samples to identify those patients most likely to respond to the drug. "That's something we will also look at," Dr. Tye says, "but based on the work we've done preclinically, we believe we can identify not only which patients will respond best to ketamine treatment but how best to treat them with augmentation and maintenance therapies. This is where our biomarker approach has great promise."

Dr. Tye says Mayo investigators are also interested in addressing the lack of research on ketamine as a treatment for bipolar depression. "We have fewer options in patients with bipolar disorder because they don't respond as well to pharmaceutical interventions and can have an adverse response to some of them. The majority of research with ketamine, as for most antidepressant treatments, has been directed toward patients with unipolar depression, so we don't know if it will help or harm patients with comorbid psychiatric illnesses or bipolar depression. It is critical that research address these issues so we can provide safe and effective treatments for our patients."

Ultimately, she says, the integration of preclinical and clinical research and the development of biomarkers is "really where the field needs to go."

For more information

Rasmussen KG, et al. Serial infusions of low-dose ketamine for major depression. Journal of Psychopharmacology. 2013;27:444.