Riluzole — an FDA-approved drug that treats amyotrophic lateral sclerosis, known as ALS or Lou Gehrig’s disease — also may be promising. It acts on a different part of the glutamate system.
In one study, 10 participants with treatment-resistant depression took Riluzole along with their regular antidepressant. After six to 12 weeks, they experienced almost a 10-point drop on the Hamilton Depression Rating Scale. According to Murrough, the National Institute of Health just funded a large study to attempt to replicate these findings.
Triple Reuptake Inhibitors for Depression
“The triple reuptake inhibitors [TRIs] are the newest and latest drugs in the line of monoamine antidepressants,” Murrough said. These compounds work by blocking the reuptake of serotonin, norepinephrine and dopamine simultaneously.
“The thought is that if you can effectively enhance the neurotransmitters for these pathways at the same time that you might have a better antidepressant, higher response rates or more rapid mode of onset and more rapid resolution of depressive symptoms,” David Marks said.
“What’s new here is these drugs increase availability of dopamine in addition to the other monoamines (e.g., serotonin and norepinephrine),” Murrough noted. There’s evidence that dopamine is underactive in depression.
Dopamine has been linked to lack of motivation and anhedonia, or lack of interest in previously pleasurable activities. Drugs that deplete dopamine, such as reserpine (used to treat high blood pressure), seem to trigger depression symptoms in people.
Currently, there are no TRIs on the market, and research is preliminary. Research has “moved from pre-clinical stage in animals to small studies in humans focusing on safety,” Murrough said.
Euthymics, a privately held drug development company in Boston, along with researchers at Massachusetts General Hospital, will begin testing the TRI compound EB-1010 in 2011. They believe it can be used as a second line of treatment when patients with depression don’t respond to SSRIs. According to the company, the compound seems to have no sexual side effects.
In 2009, the drug agomelatine, under the brand name Valdoxan, was approved in Europe to treat major depression. It has a unique mechanism of action by targeting the melatonin system in the brain. It is the first melatonergic antidepressant.
Related to serotonin, melatonin seems to be important in regulating circadian rhythms, or sleep, according to Murrough. Sleep is greatly disturbed in depression. Clinical trials in the U.S. are ongoing.
Brain-Derived Neurotrophic Factor
Another hypothesis of depression states that there’s a loss of brain-derived neurotrophic factor, or BDNF, in the disorder. BDNF is a member of the nerve growth factor family, which helps with the survival and growth of neurons. Stress, however, seems to decrease levels of BDNF.
Increasing BDNF may be a new strategy to develop antidepressants, said Murrough.
As of right now, truly revolutionary treatments for depression are all in the research phase. Still, while it’s helpful “to have new tools at our disposal, we don’t want to abandon some of our tried and true medications that have been effective,” Marks cautioned.
He also noted that psychotherapy is underutilized, and we need to work more on “making sure that our patients have access to non-pharmacological treatment.”
References & Further Reading
De Bodinat, C., Guardiola-Lemaitre, B., Mocaër, E., Renard, P., Muñoz, C., & Millian, M.J. (2010). Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nature Reviews Drug Discovery, 9(8), 628-42.
Liang, Y., & Richelson, E. (2008). Triple Reuptake Inhibitors: Next-Generation Antidepressants. Primary Psychiatry, 15(4), 50-56. (See full-text here.)
Marks, D.M., Pae, C., & Patkar, A.A. (2008). Triple reuptake inhibitors: A premise and a promise. Psychiatry Investigation, 5(3), 142–147. (Full-text.)
Murrough J.W., & Charney, D.S. (2010). Lifting the mood with ketamine. Nature Medicine, 16(12), 1384-1385.
Sanacora, G., Kendell, S.F., Levin, Y., Simen, A.A., Fenton, L.R., Coric, V., & Krystal, J.H. (2007). Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biological Psychiatry, 61(6), 822-825.
Sanacora, G., Zarate, C.A., Krystal, J.H., & Manji, H.K. (2008). Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Reviews Drug Discovery 7, 426-437.
Photo by Pink Sherbet Photography, available under a Creative Commons attribution license.