Exploring New Therapeutic Areas in the Treatment of Depression and Bipolar Disorder

August 7, 2013

Dr Gerard Sanacora discusses novel antidepressant agents with potential clinical relevance for the treatment of major depressive disorder and bipolar disorder.

Dr Gerard Sanacora discusses novel antidepressant agents with potential clinical relevance for the treatment of major depressive disorder and bipolar disorder. Dr Sanacora is Professor of Psychiatry and Director of Yale Depression Research Program at Yale School of Medicine. He is a scheduled speaker at this year's US Psychiatric and Mental Health Congress in Las Vegas in a presentation titled "New Developments in the Treatment of Major Depressive Disorder."

We have recently become aware of the limitations of existing antidepressant medication. Studies such as the Star*D and the StepBD have hightlighted [this fact], first in the onset of action requiring a lag time of several weeks.1,2 There is a limited efficacy, and although large percentage of treated patients feel better, about one third of patients that achieve little benefit from current medications. Lastly, we realize that there are limitations in complete remission and of those that do achieve remission, a large percentage will have a relapse in following years.

Based on the acknowledgement of some of these limitations, there has been a large push to develop novel antidepressant treatments. The hope is that the next generation of antidepressant medications will come from a greater understanding of the pathophysiology of these disorders.

One of the things my laboratory has been has been interested in looking at is the effect of chronic stress on the brain and how that could generate pathophysiologic changes similar to what is seen in the brains of depressed patients. Evidence has been accumulating over the years that chronic, unpredictable stress has an impact on several aspects of the glutamatergic neurotransmitter system. Identifying these changes induced by stress now allows us to identify targets that can be used to develop novel antidepressant treatment strategies.

Based on these models, we have identified several sites that are potential targets for pharmaceutical development. The one that has probably gained the greatest amount of attention at this point is targeting the NMDA receptor, specifically using NMDA receptor antagonist drugs to induce antidepressant effects.

Ketamine is the model that has been used most frequently. The original studies with ketamine were published in 2000. Studies by Berman et al3 at Yale showed that ketamine had a very rapid antidepressant effect, having effects within hours but lasting for days if not weeks in some patients. These findings were replicated later by the NIMH group by Dr Zarate4 and others were able to show that these effects were in fact replicable with over 70% of the patients having a response within one day and further went on to show that the same magnitude of effect could be seen in patients with bipolar disorder.

Since then, there have been several studies replicating these findings of a rapid robust antidepressant effect of ketamine that lasts for several days with some evidence lasting for in some individual patients.

There are also some studies coming out suggesting that ketamine may be beneficial in specific cases, such as acute suicidal ideation, having a rapid effect on these symptoms. This might have potential clinical relevance or clinical usefulness.

There are several limitations with the use of ketamine. Ketamine is an anesthetic agent, so it has to be used with caution. It has significant effects on physiologic measures, such as blood pressure and heart rate, requiring monitoring during the administration. It also has significant psychological effects, such as effects on cognition and perception that limit its potential usefulness in the general clinical setting.

With these limitations, there has been a strong drive to develop novel agents affecting the NMDA receptor, but not having the same adverse event profile that can be associated with ketamine. Two such NMDA receptor antagonist agents, such as AZD6765 and GLYX-13, have recently completed moderate sized Phase II trials.5,6 This information was presented at the 2012 ACMP annual meeting and should be published in the near future.

Targets of interest and final thoughts
Using this model, there are also other targets that can be identified within the glutamatergic system. One is the glutamate transporters. These are the transporters similar to the serotonergic transporter that is responsible for clearing glutamate from the extracellular space. There is evidence that some drugs such as ceftriaxone and riluzole might have effects by increasing the clearance of glutamate from the extracellular space.

There have been several studies suggesting that riluzole, a drug currently approved for amyotrophic lateral sclerosis, may have antidepressant and anxiolytic effects in patients with bipolar, unipolar, and anxiety disorders.7-9 However, it is important to know that all of these studies to date have been open label, looking specifically at the effects of riluzole in the treatment of these disorders. Until now there has not been a large randomized placebo controlled evaluating the efficacy or safety of this drug in this population.

Other targets of interest are the metabotropic glutamate receptors, such as the mGlu5 receptor and the mGlu2/3 receptors. Trials using pharmaceutical agents targeting these receptors are currently also in progress and can be found on www.clinicaltrials.gov.


1. National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. http://www.nimh.nih.gov/trials/practical/stard/index.shtml. Accessed April 27, 2012.
2. National Institute of Mental Health. Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). http://www.nimh.nih.gov/trials/practical/step-bd/index.shtml. Accessed April 27, 2012. 1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
3. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.
4. http://clinicaltrials.gov/ct2/show/NCT00986479.
5. http://clinicaltrials.gov/ct2/show/NCT01234558.
6. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57:430-432.
7.Brennan BP, Hudson JI, Jensen JE, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010;35:834-846.
8. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61:822-825.