In his Aphorisms, Hippocrates defined melancholia, an early understanding of depression, as a state of “fears and despondencies, if they last a long time.” It was caused, he believed, by an excess of bile in the body (the word “melancholia” is ancient Greek for “black bile”).

Ever since then, doctors have struggled to create a more precise and accurate definition of the illness that still isn’t well understood. In the 1920s, the German psychiatrist Kurt Schneider argued that depression could be divided into two separate conditions, each requiring a different form of treatment: depression that resulted from changes in mood, which he called “endogenous depression,” and depression resulting from reactions to outside events, or “reactive depression.” His theory was challenged in 1926, when the British psychologist Edward Mapother argued in the British Medical Journal that there was no evidence for two distinct types of depression, and that the apparent differences between depression patients were just differences in the severity of the condition.

Today, Schneider’s subtypes have largely fallen out of favor—but over the years, many more definitions were offered in their place. In 1969, the American existential psychologist Rollo May wrote in his book Love and Will that “depression is the inability to construct a future,” while the cognitive psychologist Albert Ellis argued in 1987 that depression, unlike “appropriate sadness,” stemmed from “irrational beliefs”—“absolutistic, dogmatic shoulds, oughts, and musts,” he wrote—that left sufferers ill-equipped to deal with even mild setbacks.

In 1952, the American Psychiatric Association tried to standardize the definitions of mental illnesses, including depression, by creating a taxonomy of mental illnesses. In the first edition of the Diagnostic and Statistical Manual, depression was listed under the broad category of “disorders without clearly defined physical cause,” which also included schizophrenia, paranoia, and mania. The DSM-III, published in 1980, was the APA’s first attempt to clarify the definitions of specific disorders by listing their symptoms; the new edition included guidelines for differentiating depression from other disorders like schizophrenia, dementia, and uncomplicated bereavement, and outlined eight symptoms of depression, included “poor appetite or significant weight loss” and “complaints or evidence of diminished ability to think or concentrate.” If an adult met four of the eight symptoms, the manual counseled, he or she would meet the criteria for clinical depression. In the DSM-V, published in 2013, depressive disorders were finally allocated their own chapter. The diagnostic criteria were mostly unchanged, with the exception of one additional symptom: “Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).”

Some scientists believe that the DSM-V definition is still too vague. As the psychiatrist Daniel Goldberg noted in the journal World Psychiatry in 2011, many of the DSM symptoms are opposites, which can make it difficult for researchers working to develop a more precise understanding of the condition. “A patient who has psychomotor retardation, hypersomnia, and gaining weight is scored as having identical symptoms as another who is agitated, sleeping badly, and has weight loss,” Goldberg wrote.

Many recent studies have corroborated Goldberg’s concerns. In 2000, for example, a group of researchers at Johns Hopkins University attempted to identify subtypes of depression by studying the symptoms of nearly 2,000 patients. However, the researchers were unable to find much of a pattern connecting gender, family history, symptoms, and the degree of the condition (mild to severe). “Depression is heterogeneous,” they concluded, adding that “the severity of an episode appears to be more informative than the pattern of symptoms.” And in 2010, researchers in Germany testing the validity of the DSM-IV definition found that the criteria captured a huge population of patients with “widely varying associations with the pattern of co-morbidity, personality traits, features of the depressive episode and demographic characteristics.” The results, they argued, “challenge our understanding of major depression as a homogeneous categorical entity.”

Part of the problem, said Scott Monroe, a professor of psychology at the University of Notre Dame, is that in medical parlance, depression is considered a syndrome rather than a disease. (While a disease is a specific condition characterized by a common underlying cause and consistent physical traits, a syndrome is a collection of signs and symptoms known to frequently appear together, but without a single known cause.) In a paper published in June in the journal Current Directions in Psychological Science, Monroe called for scientists to begin defining depression with more precision. “It is in this vague and imprecise realm that problems can arise,” he wrote, “and vague insights based on imperfect similarities and differences eventually may prove to be clear oversights.”

Part of the reason that scientists are still working in the “vague and imprecise realm,” as Monroe put it, is because they still don’t have a clear answer for what causes depression. In the 1960s, the dominant hypothesis was that it stemmed from a chemical imbalance in the brain, specifically from lower levels of the neurotransmitter serotonin. As a result, drug companies poured resources into developing “selective serotonin reuptake inhibitors” (SSRIs), drugs that increased the amount of serotonin in the brain. SSRIs (a group that includes Paxil, Zoloft, and Prozac, among others) are still the most commonly prescribed type of antidepressant—despite the fact that research has shown that lower levels of serotonin do not necessarily cause depression for all individuals. And in 2010, a review of three decades’ worth of studies on antidepressants found that while SSRIs can be helpful for severely depressed people, their effectiveness “may be minimal or nonexistent” in those with mild or moderate depression.

Bruce Cuthbert, the director of adult translational research and treatment development at the National Institute of Mental Health (NIMH), thinks that part of the problem is that researchers have largely focused their attention on finding a one-size-fits-all treatment that doesn’t exist. “When you do a clinical trial, you’re getting a bunch of people who are ‘depressed,’ but they’re actually very different,” he said. “It’s like comparing apples, pears, and tangerines. You’re not going to see a significant effect. You’re not going to be able to say, ‘This treatment works for fruits.’” Trying to create a singular treatment for depression, Cuthbert said, is like trying to create one for cancer: too unspecific to actually be helpful.

“While DSM has been described as a ‘Bible’ for the field, it is, at best, a dictionary, creating a set of labels and defining each,” the NIMH director Tom Insel wrote in 2013. “Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.”

In 2010, Insel invited Cuthbert, who was then working as a psychology professor at the University of Minnesota, to help the NIMH develop a new framework for defining mental illness. The result, unveiled in 2013, was the Research Domain Criteria (RDoC), a system created to flip the way researchers think about mental disorders. Unlike the DSM, RDoC isn’t organized by disorder; instead, it’s organized around specific symptoms, like fear, anhedonia (the inability to feel pleasure), and willingness or unwillingness to work. The system also lists the genes, neural circuits, physical response, and self-reported behavior associated with each symptom.

The theory behind this RDoC system is that treating a specific symptom will produce better results than treating a broad category of illness. Many depression patients exhibit anhedonia, for example, but many others don’t. But if researchers took a group of patients who all displayed anhedonia, regardless of their diagnosis (it’s also a common symptom of schizophrenia) and tested treatments for that very specific symptom, they would get better results for treating anhedonia.

The current definition of depression, Cuthbert explains, has largely stemmed from scientists observing patients and then developing lists of symptoms based on what they saw. “The belief was that if you described the disorder well enough, you would be able to define it,” he said. But it’s becoming increasingly clear, he said, that by relying on describing the disorder, scientists are only skimming the surface in terms of understanding it. Cuthbert hopes that the RDoC system will challenge researchers to look at the mechanics of each symptom more closely, and in the process, come up with more well-informed ideas around how to diagnose mental illness. “We’re starting over with how we think about mental disorders,” Cuthbert said. “Our current diagnostic system is running out of steam for research.”

“Our current concept of depression is left over from times when we didn’t really understand it very much,” he added. “We know so much more about it now—physically, genetically, neurochemically—and we should be using that.”