With the advent of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) in the 1950s, depression treatment was revolutionized. These medicines target the monoamine system, including the neurotransmitters serotonin, norepinephrine and dopamine.

For decades, the dominant hypothesis of depression has been that low levels of monoamines in the brain cause this debilitating disorder.

In the ‘80s, the selective serotonin reuptake inhibitor (SSRI) fluoxetine (brand name: Prozac) heralded a new era of safer drugs which also target the monoamine system. Since then, various SSRIs and serotonin-norepinephrine reuptake inhibitors (or SNRIs) have been developed as new antidepressants. While these drugs aren’t more effective than older antidepressants, they are less toxic.

But SSRIs and SNRIs don’t work for everyone, so MAOIs and TCAs still are prescribed.

Two out of three patients with depression do not fully recover on an antidepressant medication according to findings from STAR*D, the largest clinical trial study of treatments for major depressive disorder, funded by the National Institute of Mental Health. (One-third of patients do have a remission of their depression symptoms.)

These results “are important because previously it was unclear just how effective (or ineffective) antidepressant medications are in patients seeking treatment in real-world settings,” said James Murrough, M.D., board-certified psychiatrist and a research fellow at the Mount Sinai School of Medicine Mood and Anxiety Disorders Program.

As Murrough explained, depression treatment can be thought of in thirds: “for one third of patients, symptoms remit; another third don’t have as good of an outcome, experiencing residual symptoms and waxing and waning course or chronic course and are at risk for relapse whether they’re on or off medication; and then a third don’t get much benefit at all.”

He added that around “10 to 20 percent have persistent clinically significant symptoms that aren’t decreased by current treatment — these are the patients that we are the most worried about.”

So there’s a real need to find treatments that work for these patients. Since the 1950s and 1980s breakthroughs, researchers haven’t discovered drugs that target chemical systems in the brain other than the monoamine system.

“We haven’t been able to find any new systems, because we don’t understand the underlying biology of depression,” Murrough said.

But researchers are studying other mechanisms of depression and various drugs have recently been approved to treat depression. Below, you’ll learn about these drugs along with several chemical systems research is exploring.

Recently Approved Drugs for Depression

Recently approved drugs for depression are generally “me-too” drugs. A “me-too drug is a drug whose mechanism of action (what it does at the molecular level in the brain) is not meaningfully different than its predecessor,” Dr. Murrough said.

Prime examples of me-too drugs are desvenlafaxine (Pristiq), an SNRI, and escitalopram (Lexapro), an SSRI, he said. Pristiq is simply Effexor’s main metabolite. Lexapro is essentially a close relative derivative of citalopram (Celexa). Interestingly, sales still skyrocketed when Lexapro came out.

As Murrough said, there is value in some me-too drugs. Generally, all drugs within the classes SSRIs and SNRIs are me-too drugs. But the side effect profiles for each drug have slight differences, which can help patients.

For instance, Prozac tends to be more activating, so a doctor may prescribe it for patients with low energy, Murrough said. In contrast, paroxetine (Paxil) makes people more tired, so it’s prescribed to patients who have trouble sleeping, he said.

The drug Oleptro was approved this year for depression. It doesn’t target new mechanisms, and it isn’t even a me-too drug, Murrough said. It’s a reformulation of trazodone, an atypical antidepressant that’s been used as a sleeping aid by psychiatrists and other doctors. Because it’s so sedating, its earlier form would just put patients to sleep. “It is unclear if the new formulation will offer any benefit for patients over the original,” Murrough said.

These recently approved medicines “characterize the state of drugs in psychiatry,” Murrough said, and speak to “what’s wrong with antidepressant drug development today.” Novel treatments just aren’t on the market.

Augmentation of Depression Drugs

Recently, the biggest development in depression treatment has been the use of augmenting agents, said David Marks, M.D., assistant professor at the Department of Psychiatry & Behavioral Sciences at the Duke University Medical Center.

Specifically, some research has found that adding atypical antipsychotic drugs, like aripiprazole (Abilify) and quetiapine (Seroquel), to an antidepressant can boost its effectiveness.

Atypical antipsychotics are used to treat schizophrenia and bipolar disorder. “Abilify has three strong studies that show how well it works in patients that have partially responded to antidepressants,” Marks said. According to Murrough, augmentation has become a common strategy in depression treatment.

The Glutamate System and Depression

Researchers have looked at the role of the glutamate system in depression. Glutamate is abundant in the brain and is one of the most common neurotransmitters. It’s involved in memory, learning and cognition.

Some research has implicated the dysfunction of the glutamate system in medical conditions, such as Huntington’s chorea and epilepsy, and psychological disorders, such as schizophrenia and anxiety disorders.

Recent research suggests that drugs targeting a specific type of glutamate receptor in the brain — called the NMDA receptor — may have antidepressant effects.

Studies have explored ketamine, an NMDA antagonist, in treating treatment-resistant depression and acute suicidal ideation. Ketamine has a long history in analgesia and anesthesiology.

Currently, when a person is at imminent risk for attempting suicide or has attempted suicide, they’re admitted to a psychiatric hospital and closely monitored. But, as Murrough explained, medically, there’s nothing doctors can do to help with suicidal ideation or intense depressed mood. Antidepressants typically four to six weeks to work.

Ketamine appears to have fast antidepressant effects — within hours or a day. Thus, it may help protect patients from suicidal thinking or acute dysphoria when they’re in the hospital. Unfortunately, its effects only last seven to 10 days.

This research is “highly experimental, and probably less than 100 patients in the country have participated in controlled depression studies of ketamine,” Murrough said. The patients in these studies typically have treatment-resistant depression: They haven’t responded to several antidepressants and have moderate to severe symptoms of depression.

They’re admitted to the hospital and receive ketamine intravenously from an anesthesiologist, while their vital signs are closely monitored.

Ketamine is a drug of abuse, known by such street names as “Special K.” It induces trance-like or hallucination states. It also produces mild to moderate cognitive side effects, like other anesthetics. People report feeling “out of it,” intoxicated and disconnected in general.

These side effects actually “introduce a potential bias to the study design” because participants know they’re getting the treatment (when saline is given in the placebo condition), Murrough said.

To eliminate this bias, Murrough and his team are conducting the first-ever study to compare ketamine to a different anesthetic — the benzodiazepine midazolam (Versed) — which has similar transient effects as ketamine, he said. The study is currently recruiting participants.

Murrough cautioned that ketamine isn’t meant to be a treatment administrated at your doctor’s office. In a recent article in the journal Nature Medicine, he said ketamine treatment may be “akin to electroconvulsive shock treatment.”

Studying ketamine may reveal mechanisms underlying depression and help to find drugs that can be prescribed as antidepressants to a wider patient population.

Pharmaceutical companies have started exploring other NMDA receptor antagonists for treatment-resistant depression. For instance, in July 2010, the pharmaceutical company Evotec Neurosciences began testing a compound in a Phase II study, which evaluates the safety and efficacy of a drug.

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.

Final Thoughts

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.