According to the National Institutes of Mental Health, more than 15 million American adults suffer at least one major depressive episode in a given year – about 6.7 percent of the population, a percentage that makes depression one of the nation’s most common and burdensome mental health disorders.

Among active-duty service members and veterans, this rate is higher: The landmark Army STARRS Study, completed in 2014, found major depression to be five times as high among active-duty soldiers as civilians. In 2008, the Department of Veterans Affairs (VA) estimated that about 1 out of every 3 veterans visiting a primary care facility displayed at least one symptom of depression, while 1 in 5 had serious symptoms suggesting the need for further evaluation. According to the National Alliance on Mental Illness, the diagnosis rate for major depression among veterans, requiring treatment with psychotherapy or antidepressants, is 14 percent.

More than the occasional bout of melancholy or grief, depressive disorder is marked by sustained feelings of sadness or hopelessness that last for two weeks or longer, often accompanied by a loss of interest in activities once enjoyed. It can lead to other emotional and physical problems, and can be disabling, reducing a person’s ability to function at home and at work. Untreated depression is known to increase the risk for suicide, a cause of death that has been on the increase among veterans – particularly younger veterans – in recent years.

Despite its often devastating effects, major depression is a treatable illness; about 8 out of 10 veterans receiving VA care are effectively treated. VA researchers aim to increase this percentage by developing models of intervention and social support to help veterans recover from depression and other mood disorders. Some investigators are exploring which risk factors – including brain chemistry, genetics, personality, and environmental factors such as stress or trauma – increase the likelihood of depression; others are evaluating the effectiveness of medications and other treatments.

Developing a “picture of depression”

Identifying risk factors for depression is more difficult than with most illnesses; depression weaves a tangled etiological web with other mental and physical health problems. It can occur along with literally all other psychiatric and physical diagnoses. Physical illness is known to increase the risk of developing depressive illness, though many of the cause-effect relationships – or whether they involve cause-effect relationships at all – remain unknown.

Many VA investigators explore relationships between depression and factors often associated with the disorder – whether they can be determined to be risk factors or not – and whether these relationships may have implications for further treatment. Dr. Alan Teo, M.S., an investigator at the Center to Improve Veteran Involvement in Care at the VA Portland Health Care System and an associate professor of psychiatry at Oregon Health & Science University, has spent much of his career exploring the role of social contact in depression. In April 2018, Teo and colleagues published a study in the Journal of Affective Disorders, measuring the degree to which several facets of social connectedness – number of confidants, social support, interpersonal conflict, social norms, and loneliness – are correlated with depression.

Teo and his investigators didn’t mean for loneliness to be the dominant theme of the study, he explained, but it became one of the primary takeaways: Among veterans in VA primary care, loneliness – a level of social engagement below what one hopes for – was associated with higher levels of depression and suicidal ideation, as well as lower patient help-seeking intentions and behaviors.

“Loneliness is not a defining symptom for depression,” said Teo, a practicing psychiatrist – but at the same time, he and his colleagues know it’s a common experience among their veteran patients. “It’s there between the lines,” he said, “without patients explicitly bringing it up, this idea of being disconnected from people or lacking social relationships. We don’t use it to diagnose depression, so we often don’t think of it as something to treat. But it impacts their mental well-being, so I think it’s something we need to think about as a health issue. It’s definitely distinct from depression, but it’s a significant part of the picture of depression in veterans.”

Teo isn’t consumed with determining whether loneliness is a cause or consequence of depression; he views it as both, and also as a treatable circumstance. To build on this study, Teo intends to explore the obvious question: Can making people less lonely make them less depressed? “That’s an unanswered question,” he said. “But I think it’s an important one.” Teo has a head start in answering it: In several studies, he’s already explored whether using certain 21st century modes of social connection – email, video chatting, and social media platforms such as Facebook – are linked to reduced risk of developing depression. So far, he’s discovering there is no substitute for face-to-face contact between human beings – including video chatting, which may be a tool to help fend off depression.

“We should think about measuring and asking our primary care patients about loneliness,” Teo said. “And that can open up the opportunity for thinking through strategies to address it. The jury is still out on definitely what is going to work.”

Another condition known to strongly correlate with depression – to the point that it is, actually, one of the diagnostic criteria for the disorder – is insomnia. Fully two-thirds of people with depression also meet the diagnostic criteria for insomnia. The reason for this association isn’t known, but insomnia worsens the course of depression and makes patients more resistant to treatment – and unfortunately, some commonly prescribed antidepressants are known to promote or worsen sleep disturbance.

Elaine Boland, Ph.D., a research psychologist at the Corporal Michael J. Crescenz VA Medical Center and clinical associate at the Perelman School of Medicine of the University of Pennsylvania, is conducting a study aimed at identifying the biopsychosocial processes common to both insomnia and depression – and ultimately, perhaps, developing a treatment targeting patients suffering from both.

Boland’s study is designed to build on the knowledge that people with depression tend to devalue rewards that require significant effort to obtain – a phenomenon known as “effort discounting.” Some preliminary evidence suggests sleep disturbance may lead to effort discounting, but it’s never been evaluated among adults with clinically significant insomnia. Boland’s volunteer subjects will take a computerized battery of behavioral tests – “Designed,” Boland said, “to assess how much effort individuals will put forth for monetary rewards.” The subject sample includes individuals who have sleep disturbance, and also individuals who don’t, with individuals who may have some degree of depression in the mix.

“The question I was really interested in answering,” Boland said, “is when sleep disturbance is severe enough, does it actually exert kind of an additional effect on the reward system that makes it even harder for these depressed patients to recover?” If improving sleep can reduce effort discounting, such a finding would encourage further studies into how insomnia and depression are treated together.

“I think it might help us get closer to developing more targeted treatment for veterans that have both depression and insomnia,” said Boland. “They clearly aren’t responding as well to traditional depression treatments. I think we need to do a better job, through either the development of psychotherapies that target sleep and depression together, or maybe rehabilitating the desired reward response.”

New and improved treatments

VA investigators are working to develop and refine treatments for the 20 percent of patients with depression who don’t respond well to established treatments – who have what’s known as “treatment-resistant” depression. Antidepressant medications, for example, work well for the majority of patients with major depression, but a 2015 study by investigators at the Institute of Psychopathology in Rome, Italy, suggested these drugs don’t improve symptoms for 10 to 15 percent of patients with depression. Thirty to 40 percent of patients who take them notice only a partial improvement in their symptoms.

In 2017, VA began recruiting for an ambitious clinical trial aimed at evaluating the link between patient genomics and the effectiveness of these antidepressants: the PRIME Care (PRecision Medicine in MEntal Health Care) initiative, led by Dr. David Oslin, director of the regional (VISN4) Mental Illness Research, Education and Clinical Center (MIRECC) at the Crescenz VA Medical Center in Philadelphia.

As Oslin pointed out, variations in the human genome account for differences in the way some antidepressants are metabolized in the liver or processed by the brain – but without knowledge of an individual patient’s genes, it’s impossible for clinicians to tailor medications and dosages appropriately. The standard dosage of sertraline (Zoloft®), for example, is 100 milligrams, but some patients do fine on a dose of 50 milligrams, while others may need a dose of 200.

It’s still unknown whether genes explain these different dosage requirements, but investigators in the PRIME Care initiative aim to find out – and to discover, as well, whether genes may make patients more receptive to some medications than others. The study, scheduled to be completed in 2022, seeks to enroll 2,000 veterans who have not responded well to previous treatments for depression. From each of these patients, 12 genes associated with the brain’s and body’s ability to metabolize and process 55 commonly prescribed drugs will be gathered by means of a simple cheek swab and analyzed with an algorithm designed by a private company, Myriad Genetics, Inc.

In addition to analyzing these outcomes, the study is designed to examine the best ways to provide these test results to veterans and their health care providers – and perhaps to guide similar pharmacogenomic studies of other illnesses.

It’s sometimes the case even when patients with major depression are responsive to antidepressants, these drugs sometimes take several weeks or even months to achieve their maximal effect. VA researchers including Dr. Sanjay Mathew, a psychiatrist with the Michael E. DeBakey VAMC in Houston, and a professor of psychiatry at the Baylor College of Medicine, have been exploring the effectiveness of ketamine – traditionally an anesthetic – as a rapid-acting antidepressant. In early 2019, the U.S. Food and Drug Agency (FDA) approved the use of esketamine (a patented derivative of ketamine) as a nasal spray, in conjunction with an oral antidepressant, for adults with treatment-resistant depression.

Dr. Paul Holtzheimer, M.S., deputy director of research at the National Center for PTSD (post-traumatic stress disorder) in White River Junction, Vermont, and an associate professor of psychiatry and surgery at Dartmouth Geisel School of Medicine, said that VA researchers are continuing to explore the implications of ketamine’s faster-acting antidepressant effect. The VA has recognized ketamine’s potential for treating patients with severe depression, including those at risk for suicide.

“Ketamine,” said Holtzheimer, “has been shown to have very rapid antidepressant effects that unfortunately tend to wear off in a few days or a few weeks. So, we’re looking at different ways of extending the efficacy of that.” Investigators in the National Center for PTSD’s Clinical Neurosciences Division have also been looking into ketamine’s potential for the treatment of PTSD. “Early findings are suggesting there may actually be some efficacy there as well,” Holzheimer said.

Depression, PTSD, and neural circuitry

It’s unsurprising, Holtzheimer said, that some treatments may be effective in treating both depression and PTSD. “In patients with PTSD,” he said, “there’s an extremely high comorbidity with depression. Fifty percent or more of patients with PTSD have clinically significant depression. There are also a lot of PTSD symptoms that really overlap with symptoms of depression as well, and that indicates possible overlap of neurobiology.”

Holtzheimer’s own research into depression and other mood disorders has focused on interventions involving the brain’s neural circuitry – direct stimulation of brain neurons – which show promise for treating both treatment-resistant depression and PTSD. One of the most effective treatments for severe or treatment-resistant depression is electroconvulsive therapy (ECT), a procedure done under general anesthesia in which electrical currents are passed through the brain and trigger a brief seizure.

ECT appears to cause changes in brain chemistry that can quickly reverse symptoms of depression, and is much safer today than in its early years, when higher voltages of electricity were administered without anesthesia. But several side effects and drawbacks remain: It’s still an indiscriminate application of electricity that may produce confusion, memory loss, or other side effects.

VA investigators are exploring more targeted neuro-stimulation techniques, interventions aimed at areas of the brain known to be involved in mood and emotion. The less invasive of these options, transcranial magnetic stimulation, or TMS, involves the application of magnetic currents from a coil placed on the patient’s head. More than 30 studies of TMS have been done over the past two decades, and most have suggested the procedure is effective for at least some patients suffering from depression. A 2012 study at 42 TMS clinics in the United States evaluated outcomes among more than 300 patients who were non-responsive to antidepressants, and found that 58 percent “responded positively” to TMS, while 37 percent had their symptoms go into remission.

A handful of recent studies, including a 2017 investigation by Chinese researchers, have suggested that TMS may also be helpful in treating PTSD. But

researchers still have much to learn about TMS: how and why it works, and how many treatments are necessary for the most effective outcome. A VA study of 81 veteran patients with treatment-resistant depression, published in June 2018, demonstrated a similar rate of remission, 40 percent, among patients who received active stimulation – but 37 percent of those who received a “sham” treatment, or procedural placebo, also reported remission. “In most of the prior TMS studies, the sham remission rate is down around 5 to maybe 10 percent,” said Holtzheimer. “To have a study with such a high [sham] remission rate suggests something about the study, or something about the patients being enrolled, is very different from all of the probably close to a thousand patients enrolled in studies prior to that.”

Holtzheimer has collaborated with Dr. Helen Mayberg, a neurologist at Emory University, in analyzing a brain stimulation technique Mayberg pioneered to target the subcallosal cingulate region of the brain. Often known simply as Area 25, this region is rich in serotonin transporters and is known to be metabolically overactive in patients with treatment-resistant depression. Mayberg’s intervention, deep brain stimulation (DBS), involves the surgical insertion of a battery-powered electrode directly into this region of the brain. The amount and frequency of pulses delivered by the device are fine tuned after the surgery.

According to Mayberg, many of the patients who received the first DBS implants have lived depression-free since the first operations were performed more than a dozen years ago, while other patients with depression appear not to be helped by DBS. So far nobody, including Mayberg nor Holtzheimer, understands why, and the FDA hasn’t yet approved it for the treatment of depression. Holtzheimer’s most recent study of the procedure, published in Lancet Psychiatry in 2017, demonstrated that it was a safe and feasible procedure – and that while it was only slightly more effective than sham treatments after a period of six months, patients who were treated over a period of two years did well compared to subjects of earlier studies. “There’s still the possibility that longer-term stimulation could be effective in highly resistant patients,” Holtzheimer said, “and the patients who get better didn’t seem to relapse. They tended to stay better over time.” More studies are needed, he concluded, to investigate factors such as electrode placement and other clinical features.

“We’re hoping we can do another study, designed somewhat differently,” he said, “to better show that active stimulation works and evaluate longer-term effects of the treatment. The flipside of this is that in patients where DBS seems to work – and we did this in our first study at Emory – when you turn off the stimulation, almost 100 percent of the patients get depressed again … and then if you turn it back on, they get less depressed.”

More data are coming out from patients studied at both Emory and Dartmouth, Holtzheimer said, and more studies of the procedure are being planned. In the last few years, early studies of DBS in the regions of the brain associated with fear and anxiety – including a 2015 study of veterans at the VA Greater Los Angeles Healthcare System – have shown the procedure to be safe and effective in treating PTSD. Activation of the brain’s neural circuits represents a new frontier in treating depression and other psychiatric conditions, and Holtzheimer and other VA investigators are at the vanguard of explorers hoping to unlock their secrets and put them to work for American veterans.