More than 264 million people worldwide are affected by depression, according to the World Health Organization. And that number only includes the people who are actually diagnosed. For individuals who are depressed, recognizing that state and asking for help is the first big hurdle. The second hurdle is obtaining a correct diagnosis.

People who are depressed are often not correctly diagnosed which can lead to a host of problems, the biggest being that they could be mistreated. Scott Aaronson, MD, director of clinical research programs at Sheppard Pratt, agrees: “A lot of diagnosis [are] incorrect,” he says.  “Someone diagnosed with depression may actually have bipolar disorder, substance abuse, or post-traumatic stress disorder.”

A recent study that looked at more than 46,000 patients discovered that most adults who screen positive for depression are not treated, while those who were treated did not screen positive. In other words, could clinicians be treating the wrong people and not treating the ones who really need it?

Why Is Depression Tricky To Diagnose?

Researchers often argue that the diagnostic dilemma with depression is mainly because someone having symptoms tends to go to their primary care physician first – this doctor may or not be fluent in psychiatric conditions or know when to refer. Another reason is that people who turn to their PCP are typically not experiencing symptoms that are as severe as someone who may need treatment via a psychiatric center. And of course, we know that sometimes symptoms manifest somatically (eg, fatigue, headaches) or are misinterpreted that way.

Available diagnostic screenings aren’t perfect either. Clinicians assess patients based on diagnostic criteria and through structured interview assessment tools, but these methods – in many cases – were developed to describe patients already known to have depression, not the average person who shows up at their family doctor. The result is milder forms of depression fall under the radar.

Why Is Medication for Depression Often Trial-and-Error Based?

Clinicians know that people who need medication don’t always get it, and people who don’t need it are sometimes getting it, but there’s more to the story. The bottom line is that prescription medication can be ineffective – even when the diagnosis is correct. A 2008 study found that there was virtually no difference in improvement of depression between drug and placebo in patients with moderate depression, and only a small difference in antidepressant efficacy for severely depressed patients.

Here’s the problem: “We’ve got a whole bunch of medications that all do the same thing. The majority of antidepressants we have will basically raise extracellular levels of serotonin. Because we’re looking at many different illnesses, not all versions of depression will necessarily respond to this increase in extracellular serotonin,” Dr. Aaronson says. Think of it in this somewhat exaggerated way, it’s almost like assuming your car keys will start every car in a parking lot.

Dr. Aaronson continues: “Every antidepressant that has been marketed since 1959 until 2019, until two antidepressants that came out this year —all work by changing extracellular amounts of serotonin, norepinephrine or dopamine. The good news is, for two-thirds of the folks we actually do okay with that. It’s that third of the folks, who have difficult to treat depression, that if you don’t respond to the things we’ve got, we’ve got to come up with something new.”

There are times when depression doesn’t get better, even with treatment. Treatment-resistant depression is commonly defined as occurring in cases where someone diagnosed with major depressive disorder (MDD) is unresponsive to at least two antidepressant therapies. And, Dr. Aaronson notes, “the odds of responding to a third antidepressant if you’ve failed two are less than 25%.”

Biomarkers Offer Hope For A Depression Blood Test

In the near future, a particular type of depression could be determined by a blood test and treated with more precision than ever before. A study published in Translational Psychiatry demonstrated that four biomarkers were able to accurately and reliably distinguish among patients with MDD, bipolar depression, and controls. For the first time, having an objective laboratory-based diagnostic test may not seem like the stuff of science fiction.

“Depression is not a single gene disease but rather seems to be related to multiple genes in interaction with environmental factors, which lead to a spectrum of aversive outcomes, ranging from depressive symptoms to full-blown MDD [major depressive disorder],” the study states. In other words, testing for depression won’t be like a strep test where you’ll just have a quick “yes” or “no” answer.

The findings may offer hope for people with treatment-resistant depression if results can help to sub-type depression and predict who might best response to particular interventions – for example, the vagus nerve stimulation (VNS) treatments with which Dr. Aaronson works. This new research could also help to refocus incorrect diagnoses, for example in a case of someone diagnosed with depression who actually has bipolar disorder, or substance abuse or PTSD.

“Patients like [genetic testing] because there is confirmation that there is something wrong with them. There continues to be an awful stigma against people with psychiatric illness, because we don’t really understand what the underpinnings of these illnesses are. When we’ve got someone with an abnormality with their serotonin transporter, they can say, ‘It’s an abnormality in my serotonin transporter that’s causing my depression’. That’s something that’s concrete,” Dr. Aaronson says.

The results of this particular study could potentially serve as an objective marker for either the existence of depression or the severity of illness. However, “these are very complicated illnesses that have lots of different genetic as well as biologic underpinnings,” Dr. Aaronson says. “We’re learning that it’s really hard what these underpinnings are.”

Beyond The Biomarkers

The medical field is still learning what effect the findings on biomarkers will have on screening for and treating depression, and with that comes many questions. Will it work hand in hand with a clinical diagnosis? Will it trickle down to drug development, as there has not yet been an ability to target medications to specific characteristics of the illness that are biologic? How will additional research be funded?

While biomarkers could play a role in screening and treatment, Dr. Aaronson cautions, “We still have to rely on that clinical interview.” He notes: “You’re comparing the [bio]markers to the clinical diagnosis. Are you going to diagnosis somebody because they have an abnormality in one of their biomarkers, or are you going to diagnose somebody based on their clinical interview?”

After all, abnormalities in markers can have tremendous overlap, or someone diagnosed with treatment-resistant depression could show to have normal genetic testing results. “We want to pigeonhole people, but biology doesn’t care about our phenomenological bench holes. A lot of folks don’t fit easily into DSM boxes,” Dr. Aaronson states.

Editor’s Note: This article was originally published on

Last Updated: Oct 16, 2020