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I’m Optimistic about Depression

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As Lydia* walked into my office, I could see all was not well with her even before she sat down. She moved slowly, much more so than would be expected for a woman in her early 60s. Her face was impassive and didn’t display any of the usual warmth, curiosity, or expectation one normally shows when meeting someone new. She looked around — not really confused but not quite sure of what to do — before sitting in the offered chair. Only when asked did she begin to tell me of her two-year battle with feelings of sadness, hopelessness, and worthlessness, accompanied by a lack of energy and motivation. Her weekly lunches with friends left her feeling isolated rather than embraced, she couldn’t be bothered to care for her home, and she had no appetite for eating much less cooking the meals she and her husband used to enjoy nightly.

Lydia’s story is not an uncommon one. She suffered from what psychiatrists call “major depressive disorder, recurrent,” and what colloquially we and millions of others call “depression.” Although Lydia had felt this way before, in the past she had always responded to a course of antidepressant medication. Something was different this time.

About 7 percent of U.S. adults report experiencing an episode of depression in the past 12 months, according to the 2016 National Survey on Drug Use and Health conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA), a U.S. Government agency. The rate of depression is even higher in women and adolescents. And, while effective treatments exist for depression, many individuals like Lydia suffer for extended periods or relapse after feeling better. Furthermore, many individuals suffer from comorbid medical and other psychiatric conditions and are at risk for suicidal thoughts and behavior. NIMH-supported research aims to reduce this suffering, through a variety of research programs focused on increasing our understanding of major depressive disorder and on developing and implementing effective therapies.

Understanding Depression: Causes and Consequences

Research has shown that depression, like most psychiatric disorders, has at its source a combination of genetic and environmental risk factors. Scientists have made a great deal of progress in understanding both genetic and environmental causes of depression. Among the environmental factors that contribute to depression are trauma and stress. In particular, traumatic events that happen early in life, including deprivation or maltreatment, raise the risk for depression later on in adulthood.

Multiple biological mechanisms have been discovered that may mediate the long-term effects of early childhood traumas. One such mechanism relies on epigenetics, a set of pathways by which long-lasting chemical modifications to the genome change the way genes are regulated — turning them on or off or increasing or decreasing their expression. Epigenetic marks can change important regulatory systems like those that govern the stress hormone cortisol or that control the immune system. Disruptions in stress hormones and immune function have been seen in patients with depression, and treatments that address such disruptions are currently being tested to see if they might help individuals with major depressive disorder. Other relatively common physical health issues, including thyroid imbalances and problems with drug or alcohol use, can also contribute to depression.

Environmental factors in adulthood such as stress, pregnancy, and seasonality also contribute to the risk for depression. Stressful events can trigger episodes of depression in susceptible individuals, though in many people there are no such identifiable precipitating stressors. Pregnancy, and especially the postpartum period, is a time of increased risk, likely because of rapid changes in hormones. And some individuals suffer from depression in the wintertime, likely because of the shorter daylight hours.

Finally, recent studies have begun to clarify the genetic contributors to depression. Like other psychiatric disorders, the genetics of depression are complex. Unlike other genetic disorders, like sickle cell anemia, which results from mutations in a single gene, depression results from the combined effects of multiple interacting genetic changes and interactions with environmental and developmental factors. A recent study funded by NIMH identified dozens of genes that contribute to the risk for depression and suggested that there are hundreds more that are yet to be discovered.

Just as there are multiple factors that can cause depression, there are also multiple ways people can experience depression. Depression can result in decreased sleep or decreased appetite, or increased sleep and increased appetite. Some individuals experience agitation or needing to move constantly, while others are nearly immobile. There are literally thousands of possible combinations of the various symptoms that characterize depression. In addition, the time course and evolution of these symptoms can vary, as can the severity.

Parsing Heterogeneity: Improving Treatments Individual by Individual

Despite this considerable heterogeneity in the causes and consequences of depression, treatments are typically applied more generally. While some people, especially those with milder depression, might respond to psychotherapy alone, people with moderate or severe depression might also need medication. Discussing treatment options enables patients to participate in the decision-making process, which is important because it can take a couple of weeks or longer for patients to feel the therapeutic effects of a medication, and some treatments may cause side effects that occur before therapeutic effects are felt.

There are numerous types of antidepressant medications— some targeting the serotonin system and others affecting other neurotransmitters systems. Selecting a specific treatment for a specific patient is a matter of trial and error — discovering which medication works best and causes the least side effects happens through experience rather than any prior knowledge of what might work for that patient. This can result in a disappointing series of treatment failures until the person finds the medication that is right for them. Strategies to shorten this period of suffering while the right treatment is identified could have a tremendously beneficial impact and could prevent a great amount of suffering. Genetic testing to match patients with the best medication, while still not ready for public use, is one possible approach that is likely to benefit from ongoing research.

Similarly, while therapists seek to select the form of therapy matched to the patients’ needs, they cannot know in advance whether their selection is the one the patient is most likely to respond to. Such treatments are reasonably helpful — findings from the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study indicate that about a third of patients will do well on the first treatment they try, and about two thirds will do well by the time they’ve tried their third treatment.

Nonetheless, many people do not respond to psychotherapy or any of the commonly prescribed medications. For these people — suffering from what we call “treatment-resistant depression” — there are several more options. These include electroconvulsive therapy (ECT), which is tremendously effective but underutilized despite recent NIMH-supported advances in improving its safety and prolonging its efficacy; transcranial magnetic stimulation (TMS), which was approved by the Food and Drug Administration (FDA) in 2008 and grew out of early work in the National Institutes of Health (NIH) Intramural Research Program and was further refined through NIMH-supported studies seeking to improve its efficacy; and, most recently, esketamine, which grew out of NIMH research and is the first and only medication approved by the FDA for treatment-resistant depression.

Still, we need to do better for the many people who are not helped by current therapies. NIMH-supported research seeks to develop and test novel treatment approaches. For example, most antidepressant treatments take weeks to work. Esketamine and other drugs like it currently being studied improve depression in hours to days, potentially saving patients weeks to months, and in some cases years, of distress.

NIMH scientists are hard at work trying to understand how these fast-acting antidepressants work on a biological level. Carlos Zarate, M.D., of the NIMH Intramural Research Program, showed that ketamine increases activity in the dorsal anterior cingulate cortex, a part of the brain important for regulating emotion and evaluating threats and rewards. Studies by Ronald Duman, Ph.D., of Yale University, Conor Liston, M.D., Ph.D., of the Weill Cornell School of Medicine, and others have shown that ketamine repairs the fine structure of neurons in this region that were previously damaged by stress. Working with Todd Gould, M.D., of the University of Maryland School of Medicine, Dr. Zarate and others showed that a metabolite of ketamine (hydroxynorketamine) also has antidepressant properties and fewer side effects in laboratory animals. With the help of the two other NIH institutes, National Center for Advancing Translational Sciences and the National Institute on Aging, NIMH is planning first-in-human trials of this metabolite in the near future.

Another active focus of NIMH-supported research builds on our emerging understanding of the heterogeneity of depression. As I’ve written about before, researchers have begun to use large datasets and advanced neuroscience technologies to develop tests that might help us determine which individuals with depression are likely to respond best to which treatments.

Finally, the heterogeneity of depression can also be utilized to develop preventative measures. Focusing in on women who are at risk for postpartum depression, researchers have developed psychotherapies that can be administered during pregnancy, which reduce the risk of women developing depression after delivery. These therapies work well — so well, that the United States Preventative Services Task Force (USPSTF) recommended their use to prevent postpartum depression in high-risk women. This recommendation is exciting news because many care providers, including Medicare and many health insurers, use USPSTF recommendations to decide whether to reimburse for preventative care. The USPSTF recommendation could, therefore, enable access to evidence-based care for many women at risk, reducing suffering, and saving lives.

Depression Care—Transformed

When I think about what NIMH research has shown and what we’re studying now, I can’t help but think back to Lydia and her treatment trajectory. When she first came to me, we tried several different antidepressant medications, in addition to psychotherapy, but she continued to suffer. A year into the treatment, Lydia tried ECT, and although she got better, some of the side effects made it impossible for her to continue with it. Finally, after trials of several more medications, we found a combination that worked for her. Two years after her first visit with me, after four years of suffering, she finally blossomed. The zest and energy she displayed surprised me with its vigor. Imagine if I could have saved Lydia years of torment by having access to the right combination of tests to predict which treatment would work for her. Or if esketamine were available then, might it have worked for her? Imagine the impact of these research efforts on Lydia, and on millions like her. I do — and that’s what keeps me optimistic about depression, and more generally, the future for psychiatry.

*Name changed to protect the patient’s privacy.

References:

Lally, N., Nugent, A. C., Luckenbaugh, D. A., Niciu, M. J., Roiser, J. P., & Zarate, C. A., Jr. (2015). Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. Journal of Psychopharmacology, 29, 596-607.

Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. H., … & Liston, C. (2019). Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science, 364(6436).

Li, N., Lee, B., Liu, R. J., Banasr, M., Dwyer, J. M., Iwata, M., ... & Duman, R. S. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 329, 959-964.

Zanos, P., Moaddel, R., Morris, P.J., Georgiou, P., Fischell, J., Elmer, G.I., … & Gould, T.D. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533, 481-6.