Most of us have confessed, at one time or another, to feeling depressed. But often what we really mean is: I’m sad. Or maybe, I’m tired. Or bored. Actual depression, also known as major depressive disorder, is more than sad feelings. People living with this disorder may experience, among other symptoms, changes in appetite, suicidal thoughts, difficulty sleeping or oversleeping and a feeling of hopelessness.

PARTICIPANTS IN A WASHINGTON UNIVERSITY STUDY LED BY ERIC LENZE, MD, AND HANADI AJAM OUGHLI, MD, ARE WEARING NEUROSTIMULATION CAPS WHILE LEARNING HOW TO PRACTICE MINDFULNESS AND MEDITATION.

According to the National Institute of Mental Health, when such symptoms “last most of the day, nearly every day, for at least two weeks,” the cause may be depression. A definitive cause for depression remains elusive. In some, a propensity for the disease may be inherited; in others, it may be tied to the presence of specific genes. Environment, too, can play a role. The disease’s prevalence, however, is easier to pin down. The National Alliance on Mental Illness estimates that 16 million American adults (7% of the population) have had at least one major depressive episode in the past year. The significance of those numbers has helped drive new treatments for depression, a field of research and medicine that has burgeoned over the last three decades. That’s important because, with early detection, diagnosis and treatment, many people with major depressive disorder can and do get better. Without treatment, depressive episodes can last from months to years.

Despite the range of new treatments available, none of them have achieved a one-size-fits-all status. Charles Zorumski, MD, a Washington University psychiatrist at Barnes-Jewish Hospital and the head of psychiatry at the university, says that is due in part to the fact that “depression is not a single disorder.” Instead, he notes, “it is multiple illnesses with a lot more complexity than one might think.”

To effectively care for a person with depression, a psychiatrist must first identify what illness, or illnesses, are present. The course of treatment prescribed is then tailored to the individual, a process, Zorumski says, that often involves trial and error.

Untreated or poorly treated depression can inhibit a person’s ability to work or otherwise be productive. It is also a key driver of suicide; according to the American Foundation for Suicide Prevention, more than 50% of all people who die by suicide suffer from major depression. If alcoholics with depression are included in this group, the foundation says, this figure increases to more than 75%. Standard treatment options Selective serotonin reuptake inhibitors, or SSRIs—Prozac, for example, and Zoloft—are the mainstays of today’s treatment options and have been available to patients since the late 1980s. And, Zorumski notes, evidence-based forms of psychotherapy, including cognitive or interpersonal therapy, can be effective for mild to moderately severe depression, especially when paired with medication. Certain techniques known as neurostimulation—modulating the body’s nervous system either invasively or noninvasively—can also effectively treat depression in some people. For nearly a century, electroconvulsive therapy (ECT) has been the most effective and fastest-working treatment for severe and refractory, or treatment-resistant, depression, and it remains so today. Though its mechanism of action is not fully understood, it appears to work by altering how the brain communicates with itself, changing the brain’s blood-flow patterns and metabolism. Most often, ECT is prescribed after a person has seen no improvement with drug therapy. Repetitive transcranial magnetic stimulation, or rTMS, is another effective outpatient treatment for severe depression. It involves the use of a high-powered magnet to stimulate nerve cells on the surface of the brain.

Though not new treatments, ECT and rTMS continue to be prescribed because they are often effective. Though each requires a time commitment—rTMS is administered daily over a period of weeks and, at least initially, ECT is administered every other day for eight to 12 treatments—many patients like them because they deliver rapid and positive results. But they don’t work for everyone, and ECT has significant side effects.

In truth, none of these standard therapies work for all people all of the time. Consequently, researchers continue to study alternatives, focusing on new drug strategies and neurostimulation techniques. Zorumski notes that advances in neuroimaging, a process that maps the brain’s networks and functions, may help “unravel the mysteries of depression.”

Treatment-resistant depression

Psychiatrist Charles Conway, MD, leads the Washington University Treatment-Resistant Depression and Neurostimulation Clinic, and the Washington University Resistant Mood Disorders Center. For the past 10 years, the clinic and center have helped people with depression that has not responded to standard treatment. “Resistant depression is a very challenging disorder,” says Conway. “If an individual has tried three different drugs and gets no relief, it’s time to think about something mechanistically different.”

To get at what “different” might be, Conway and clinic staff perform a comprehensive review of a patient’s medication and treatment history. They then make recommendations to the patient and his or her referring psychiatrist for further treatments to try. These usually include novel pharmacologic therapies or neurostimulation, or a combination of both. “It can be frustrating; a patient may have to try multiple treatments over time to get the right combination that helps,” says Conway.

To date, the clinic has treated about 175 people who, on average, had each received eight previous treatments for depression that did not relieve symptoms. Conway notes that informal analysis shows that about 35% of those individuals are doing much better after trying different approaches.

Some patients seen at the clinic and center benefit by becoming participants in Washington University research initiatives looking at new forms of treatment. One such study involves intravenous infusion of ketamine. With a reputation as a party drug, ketamine has long been understood to enhance mood. In a current Washington University study of ketamine, participants receive a 40-minute infusion of the drug that has resulted in rapid improvement in symptoms over a few hours; benefits typically last a week or two. Efforts are underway to find dosing schemes that produce more prolonged benefits.

Though study results to date are positive, Zorumski says the treatment is not yet ready for use in routine clinical practice. Researchers first need to better understand how ketamine use can best achieve and then sustain its benefits. The key advantage to ketamine treatment is that patients experience a near-immediate positive effect in mood once infused. Downsides include the time commitment for treatment and, because it is a narcotic, ketamine’s potential for addiction.

A second area of research at Washington University involves drugs that affect neurosteroids: molecules in the brain that are related to mood. Delivered intravenously, one such drug shows promise for treating severe postpartum depression. The drug, called brexanolone, was on the fast track for approval by the Food and Drug Administration (FDA), with final approval publicized in March of this year. Early data indicate that other neurosteroids also may work as general antidepressants in both women and men.

Vagus nerve stimulation (VNS), a procedure initially developed to treat refractory seizure disorders such as epilepsy, has shown promising results in individuals with severe treatment-resistant depression. It was approved for that use by the FDA in 2005, and studies of VNS in treatment-resistant depression have demonstrated a one-year response rate of 40 to 55%. Most critically, studies looking at VNS’s effects in treatment-resistant depression suggest that those patients who do respond to treatment may stay well over many months, even years.

In the VNS implantation procedure, a specialist places an electrical generator under the patient’s collarbone and attaches it to the vagus nerve, one of the cranial nerves in the neck region that connects the brain to the body. Once activated, the device delivers an electric current every five minutes for 30 seconds, around the clock. The majority of the electrical current travels toward the brain and has been demonstrated to activate regions responsible for mood. After the device has been in place for several months, delivering ongoing stimulation to the vagus nerve, changes occur in brain activity. The patient begins to feel well, with minimal side effects.

For most people, the relief associated with VNS may take five to seven months to occur. However, once it does, the results can be life-changing. One of the clinic’s patients who received VNS has been depression-free for more than 17 years, several others for more than a decade. Conway notes that those who benefit from VNS will likely need to stay with it for the rest of their lives. “Depression has returned in some patients when the device’s battery runs out,” he says. Batteries last about 10 years; when they expire, a surgeon removes the device and replaces it with a new one. To date, the clinic has treated 90 individuals with VNS implantation, with 65 to 70% of those patients reporting relief from symptoms.

In 2007, Medicare decided not to cover VNS treatment for depression, deeming it experimental. As a result, only those people participating in a clinical trial or who could pay for the procedure out of pocket could receive treatment. In late 2018, however, Medicare announced funding of a large, multicenter trial to examine the effectiveness of VNS in treating depression. Washington University has been tapped as one of the lead sites for the study, which is scheduled to begin in late 2019.

Anesthesiologists Peter Nagele, MD, and Ben Palanca, MD, PhD, are working with Conway in Washington University studies using nitrous oxide, or laughing gas, to treat severe depression. Conway says most patients tolerate the procedure well and, unlike ketamine treatment, the potential for addiction is less of a concern. The study has treated 70 participants with nitrous oxide, with good results, and a second wave of studies using the gas is currently underway.

Digital intervention

Eric Lenze, MD, a Washington University psychiatrist at Barnes-Jewish Hospital, is interested in another trend in research: development of treatments for depression that allow patients to take a more active role in their therapy. He notes that teletherapy, a form of internet-based talk therapy, has become accepted by physicians and patients. And he expects that digital therapeutics, including cellphone apps and other internet-based interventions, will become more common and accepted because they are convenient and patient-centered.

Lenze notes that these therapies may help address the irony that exists in treating depression: A person who is enervated by the disease must somehow summon the motivation to seek help and stick with it. Imagine this scenario as an alternative, Lenze says. “What if an app on your cellphone asked you about symptoms and then, after a few weeks, could discover your pattern and tell you what to do about it.” Such an app might send a message that says: “Hey, you’re sad, take a walk right now.” And if that intervention helps you feel better over time, the app would learn from that to help circumvent behavior that can contribute to depression.

Use of outpatient devices to treat depression is on the rise, Lenze says, whether consumers use biofeedback sensors to measure stress levels (similar to Fitbit’s measure of physical activity) or are able to control their own vagus nerve through a noninvasive stimulator. Using such a device, a person could test their individual parameters and change the settings as they learned what works best for them. Rather than being a passive recipient of care, someone using such a device would have greater autonomy and more choices.

Tailoring the treatment to the individual

As a geriatric psychiatrist at Washington University, Lenze is also interested in the effects of chronic depression in older adults. He says research shows that depression tends to accelerate the aging process, putting these individuals at greater risk for other age-related conditions, such as Alzheimer’s disease. He also says that older adults with depression get prescribed the same medications as younger adults, based on the assumption that they work the same in both groups of people. Much of Lenze’s research is aimed at determining which medications work best for older adults and work safely in combination with medications they may be taking for other conditions.

In another study, Lenze and colleagues examined ways the practice of mindfulness can help to improve depression, as well as anxiety, in older adults. They are now studying whether individuals show improvement in both areas using a combination of meditation and transcranial direct current stimulation (TDCS), which appears to improve cognitive functioning.

Working at the other end of the age spectrum, Joan Luby, MD, a Washington University child psychiatrist at St. Louis Children’s Hospital, is studying brain neuroplasticity, specifically whether early psychosocial intervention can be an effective treatment for depression in preschool-aged children. This research evolved from her earlier studies showing that, in addition to environmental factors, abnormalities in brain function and structure play a key role in depression’s progression.

Although depression symptoms manifest in developmentally adjusted ways in children, the core symptoms of the disease, such as sadness, anhedonia (the inability to feel pleasure), and sleep and appetite disturbances, are fundamentally the same as in adults. By disrupting depression’s progression early in life, Luby and colleagues hope to protect these children from a disease that would almost certainly worsen as they reach adolescence and then adulthood.

Lenze sums up the current and future state of depression treatment this way: “Physicians have a wide range of options for treating people with major depressive disorder today. Going forward, taking each person’s physiological makeup into account will make individualized treatment the norm.”