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Study takes a novel approach to treatment-resistant major depressive disorder


Communications Coordinator, Department of Psychiatry

Major depressive disorder impacts the lives of many people and their families. It can become an almost insurmountable challenge when those with this diagnosis begin to experience resistance to conventional medications currently available. 

“You just don’t snap out of it,” said Becky Hamm, a 59-year-old who has struggled with depression for almost 30 years. “It’s very frustrating to think that I may have to live like this the rest of my life.”

Hamm has tried over 10 different medications, along with electroconvulsive therapy, but none of them have gotten her to a normal mood and kept her there. Instead, she feels lethargic on a daily basis, which causes her to ignore others and exclude herself from social gatherings and events. She tries not to get her hopes up when trying new medications because her feelings of sadness and isolation have persisted.

About 15% of people will develop major depressive disorder in their lifetime. While about 70% of them do well with the roughly 25 medications that are available to treat the illness, that still leaves a large group of people who do not, and who suffer immensely as a result. That leaves a lot of people who are desperate for a treatment that can bring relief.

One of the exciting new experimental treatments for depression is a medication called ketamine. It has been shown to get people better very quickly, but the big question is whether it keeps them better. Does the effect last for just a few hours or days, or does it last? William Coryell, MD, Professor of Psychiatry, is spearheading the Iowa portion of a larger national study that will examine this question. Dr. Coryell, who has been at Iowa since 1977, is one of the nation’s leading experts on depression. He has authored more than 400 papers on the illness, and he was part of the national task group that wrote the guidelines for it in the Diagnostic and Statistical Manual (DSM)-5.

In a study funded by Janssen Pharmaceuticals, Coryell will measure the impact of a version of ketamine, called esketamine, on people with major depressive disorder. The newer version of the drug is simpler to use, as it can be delivered through the nose rather than having to be given through an intravenous line. For the purposes of this study, participants will have tried two existing antidepressant drugs during their current depressive episode with less-than-successful outcomes – meaning their depression persisted despite these treatments. Also, participants will not be those with substance abuse, bipolar disorder, psychosis or recently prominent suicidal urges as part of their overall narrative.

Antidepressants currently on the market typically target serotonin, dopamine, or norepinephrine neurotransmitters. Dr. Coryell’s new study is looking at treating MDD by targeting a new and different system in the brain, the glutamate system, with esketamine. Under supervision, study participants will be given a dose of esketamine twice a week, which will be administered via a nasal mist, a delivery system not unlike the flu vaccine people get every Fall. Once this dosing is underway, participants will be asked how they have been feeling through a standard set of questions to assess their depression.

The rapid effect from esketamine is dramatically different from that seen with standard antidepressants, which can take weeks to have an impact. Coryell says that faster relief from distressing symptoms is certainly desirable. The rapid response helps underscore the difference in mechanisms from other available antidepressant drugs. This ability to operate through a different mechanism may be a reason that esketamine might work where traditional antidepressants have failed. The rapid response may also lead to a higher likelihood that patients will continue taking this medication, as compared to traditional antidepressants.

This study is the first of its kind. While the studies that have shown that ketamine helps in the short term have been around for more than 15 years, this will be the first study to examine the long term effects of the medication on depression. Coryell’s study is slated for a full year of follow-up. Coryell noted that some participants may only need to receive doses of esketamine for a short period of time before their depressive episode concludes. He says it is possible that there will be participants who do not need to continue for the entire year. A brief treatment period with esketamine could prove to have lasting positive outcomes for years after the final doses are administered.

“Esketamine and ketamine definitely work in the short term,” says Coryell. “This is a long-term study to see whether participants will both get well and stay well.”

The University of Iowa Department of Psychiatry is a national leader in research into the causes and mechanisms of mental illnesses, and also in the study of new treatments for them. The department has experts studying the genetic basis of mood disorders—depression and bipolar disorder—including Professor and Chair James Potash and Associate Professor Virginia Willour. Experts in brain imaging of mood disorders include Professor John Wemmie and Associate Professor Jess Fiedorowicz. Professor Andrew Pieper works on developing new medications to treat depression. Professor Scott Stuart focuses on the treatment of women who experience depression during and after pregnancy. Clinical Associate Professor James Beeghly treats patients with severe depression with electroconvulsive therapy (ECT) as do Clinical Assistant Professors Ki Won Nam and Erin Crocker.

Dr. Beeghly notes that it is important to understand that those with treatment-resistant depression arrive at that stage in their treatment in many different ways. Some people begin mental health treatment with a simple visit to the family doctor, while others’ first encounter with treatment could be just after a suicide attempt. Those with major depressive disorder of the treatment-resistant variety face many challenges, including sometimes having other serious mental conditions such as such as anxiety disorders, substance use disorders or personality disorders.

“Treatment-resistant depression is potentially among the most disabling of psychiatric illnesses,” says Beeghly, adding that there are those with treatment-resistant depression who maintain jobs and family lives, while others are unable to function well enough to continue in these areas of life.

Ultimately, Coryell hopes this study will show that esketamine is a safe and effective drug that can be used for a sustained benefit to those with treatment-resistant major depressive disorder.

When Hamm participated in the first esketamine trial from May 2015 through July 2015, she reported feeling euphoric after receiving a dose of the drug, describing it as being “back in the 70’s.”

Even after the initial burst of excitement and happiness subsided, she said her depression was gone for two days following the dosage.

“My husband thinks it was a wonder drug,” she said. “It’s the best he’s ever seen me.”

Although Hamm still struggles with depression today, she said she hopes to participate in future esketamine trials and to use the medication again.


Tuesday, December 20, 2016