By Dava Stewart
October 2, 2017 | Major depressive disorder (MDD) affects more than 16 million adults in the United States, (https://adaa.org/about-adaa/press-room/facts-statistics) yet there is still much that is unknown or not clearly understood about the condition. For instance, men and women experience depression differently, and some treatments work for some patients but not for others. Researchers are investigating the reasons behind the many questions that still linger about how MDD occurs, and a number of recent studies are opening new paths of inquiry that may one day lead to changes in how depression is diagnosed and treated.
Breakthrough or cutting edge research is sometimes years away from being applicable at the clinical level. William Pollack, of Harvard Medical School and Cambridge Hospital, says of this recent research, “We are very close to the beginnings of doing more studies. It doesn’t give us exactly what we need to do in the consulting room.” Post-mortem and animal studies, and many early in vivo studies, suggest more questions but provide few answers.
Gene Expression and Gender in Depression
When it comes to how gender impacts the diagnosis and experience of depression, there is much that experts do not fully understand. For example, although it has been long accepted that more women than men are diagnosed with depression, experts are learning that that could be due to how depression is defined and measured.
According to Pollack, the tools that exist for measuring depression are skewed to measure how women experience the condition, and often don’t pick up depression in men at all. “The work that I and other colleagues have done points out that the classic measures for depression often don’t pick up male depression,” he says.
He notes that if the endpoint of untreated or poorly treated depression is suicide, it doesn’t make sense that men are more likely to complete a suicide than women, if more women are depressed. “Maybe more men are depressed than the tools we are using pick up,” he says.
A study in Nature Medicine entitled Sex-Specific Transcriptome Signatures in Human Depression (DOI:10.1038/nm.4386), co-authored by Benoit Labonté, examined the transcriptional patterns, or patterns of gene expression, in the post-mortem brain tissue of depressed males and females, as well as in a mouse model. Labonté says, “At the beginning we were interested in looking at which genes are involved in depression in males and females and we thought that it would be mostly common alterations.”
What they actually found surprised them. “When we did the direct comparison, we saw minimal overlap. Roughly 5-10% of the alterations were common. In some of the cases, the overlap was small but the effect was different. Genes that were upregulated in males were downregulated in females,” says Labonté. The differences were so marked, Labonté says, “If we were to consider depression from only a transcriptional point of view, it would be two entirely different conditions in men and women.”
Post-mortem and animal studies, though, are basic science, and provide foundational knowledge. Labonté says the next step will be to reproduce these findings. He hopes that this line of inquiry will eventually lead to the identification of a biomarker in what he describes as a “more available tissue.”
“We could identify one of the cell types that represents what is happening in the brain and associate these gene expression profiles in the blood,” says Labonté. Such a leap forward in technology could help solve the problem that Pollack and his colleagues have elucidated. Labonté explains, “Combining molecular profiling with symptomatic profiling could narrow things down and help clinicians and patients know what treatment would work best.”
Predicting Outcomes in the Treatment of Depression
Generally, depression is treated in two ways: psychotherapy or medication. There are many different types of therapy and medications, and some patients benefit from a combination of the two types of treatment. A study conducted at Emory University, called PReDICT (Predictors of Remission in Depression to Individual and Combined Treatments) and published in the American Journal of Psychiatry (DOI:10.1176/appi.ajp.2016.16050517), investigated whether or not patient preferences regarding treatment method impacts treatment outcome.
The researchers write in their conclusion, “Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes.” In other words, the type of treatment patients prefer does not always help them achieve positive outcomes. Boadie Dunlop, director of the Mood and Anxiety Disorders Program at Emory University, says the results were not surprising, because several previous studies had shown that treatment preference had only a small effect on outcome.
Notably, whether or not patients receive the type of treatment they prefer does affect whether or not they continue treatment, which is an important factor. However, Dunlop says, “But even taking that into account, preference didn’t make big differences. Preference is a very weak predictor.”
Another study from Emory titled “Functional Connectivity of the Subcallosal Cingulate Cortex and Differential Outcomes to Treatment with Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder” (DOI:10.1176/appi.ajp.2016.16050518) investigated the possibility of a neuroimaging biomarker that could better inform the first-line treatment choice for depressed patients. Using functional magnetic resonance imaging (fMRI), the researchers examined four regions of the brain, and conducted resting-state connectivity analyses. The same patients who participated in the PReDICT study, all of whom completed 12 weeks of either cognitive behavioral therapy (CBT) or antidepressant medication, were included in this study as well.
Dunlop explains that a “resting state” is when a person isn’t thinking about anything in particular; there’s no task to be performed. “Certain regions of the brain get blood flow in synchrony—they are working at the same time, having a higher metabolic rate at the same time,” says Dunlop. That network of blood flow, prior to starting treatment, he says, “could predict whether they are likely to get better with one treatment or the other.”
According to the results of the study, those patients who had higher levels of blood flow in synchrony in four brain regions before treatment had higher rates of success with CBT, and those who had lower levels of blood flow in synchrony had better outcomes with medication. “There was no obvious effect of gender in the likelihood of treatment outcomes,” says Dunlop, adding that age did not appear to influence treatment outcomes, either.
One of the challenges that the researchers faced was in recruiting participants. “We saw a lot of people who had other disorders that needed to be treated; we saw people who had undiagnosed diabetes or thyroid disease. Others had bipolar disorder, PTSD, or a substance abuse disorder,” says Dunlop, adding that such factors can sometimes be neglected if the focus is on depression alone.
The idea that a patient could undergo an fMRI scan and that the results could tell a clinician which treatment has the highest possibility of success is exciting. But, the findings of this study are preliminary. There is more work yet to be done. The team at Emory is currently working on a second phase of the PReDICT study, and Dunlop says, “It’s not ready for prime time yet.”
Perhaps someday, if a clinician suspects a patient has depression, they can draw blood, conduct a test, examine a particular molecular profile, pair that with a symptomatic profile, order an fMRI for the patient, and have a clear understanding what the best treatment for that individual patient will be. These studies, and many more like them, are leading us steadily toward a future of individualized, personalized care.
“Now things are running faster,” says Labonté. “It’s not taking so long anymore, especially if you know what you are looking for.”