Biomarkers May Predict Treatment Response in Depression

Deborah Brauser

May 30, 2013

SAN FRANCISCO — Metabolic biomarkers may help identify differences in response to adjunctive L-methylfolate in patients with major depressive disorder (MDD), new research analysis suggests.

In the original study, which was published last December in the American Journal of Psychiatry, 75 adult outpatients with MDD who had an inadequate response to a selective serotonin reuptake inhibitor (SSRI) were randomly assigned to receive either L-methylfolate plus an SSRI for 60 days, placebo plus an SSRI for 60 days, or 30 days of the latter combination followed by the 30 days of the former.

Results showed that the group that started with adjunctive L-methylfolate had significantly higher response rates compared with the groups that started with adjunctive placebo.

In further analysis of the study's secondary endpoints, investigators examined these responses on the basis of specific patient biomarkers. They found that those who had a high body mass index (BMI) and/or elevated baseline high sensitivity C-reactive protein (hs-CRP) showed significantly greater improvements in depression symptoms when receiving L-methylfolate than when receiving placebo.

"I think biomarkers are potentially very valuable down the road to clinicians," coinvestigator David Mischoulon, MD, PhD, director of research at the Depression Clinical Research Program at Massachusetts General Hospital and associate professor of psychiatry at Harvard Medical School in Boston, told Medscape Medical News.

"One of the challenges in psychopharmacology of depression, as well as in most other psychiatric conditions, is that it's largely a process of trial and error. If these biomarkers were to allow us to identify a priori patients more likely to respond to a particular treatment, that could save us weeks, months, or even years of failed trials of antidepressants," he added.

Dr. David Mischoulon

Dr. Mischoulon, who presented these findings here at the American Psychiatric Association's 2013 Annual Meeting, noted that the public health implications could be tremendous.

"We're not there yet. But I suspect in the next decade or so, biomarkers are going to become more important as far as guiding our clinical decision-making in psychiatry."

Crosses Blood-Brain Barrier

During his presentation, Dr. Mischoulon noted that L-methylfolate is the only form of folate that crosses the blood-brain barrier.

"Though some clinical trials support use of adjunctive folate for MDD in partial responders to standard antidepressants, high-dose synthetic folic acid may result in an increase in depression," he said.

Because it does not contain synthetic folic acid, L-methylfolate "passes more readily into the central nervous system to increase neurotransmitter synthesis in depressed individuals."

In the original study, 75 outpatients between the ages of 18 and 65 years with SSRI-resistant MDD were enrolled at 6 clinical sites and randomly assigned to receive daily either L-methylfolate 15 mg plus their previous SSRI dosage for 60 days, placebo plus SSRI for 60 days, or placebo plus SSRI for 30 days followed by L-methylfolate 15 mg plus SSRI for 30 days.

The SSRIs that were used were fluoxetine, citalopram, paroxetine, escitalopram, or sertraline.

The trial's primary outcome measure was difference in response rate and degree of improvement score as shown on the Hamilton Depression Rating Scale (HDRS).

For this analysis, the investigators pooled together the subgroups that received L-methylfolate during the first and second phases and pooled together the subgroups that received placebo.

They assessed the effect of treatment, as shown in mean change from baseline to endpoint on the Maier subscale of the HDRS (items 1, 2, 7-10, and 13), and possible correlations with inflammatory biomarkers.

BMI and hs-CRP data were also collected and examined. An elevated baseline hs-CRP was considered to be equal to or greater than the median level of 2.25 mg/L.

Biomarkers Predict Response

Results showed that mean change on the Maier subscale was significantly greater for the group receiving L-methylfolate compared with those receiving placebo (-3.3 ± 3.7 vs -1.5 ± 3.2, respectively; 95% confidence interval [CI], -2.936; P = .016).

In addition, symptom improvement was significantly greater with L-methylfolate vs placebo among the participants with a BMI ≥ 30 kg/m2 (-7.4 ± 7.9 vs -2.4 ± 5.3; 95% CI, -7.449; P = .001) and in those with elevated baseline hs-CRP (-7.7 ± 7.4 vs -3.7 ± 7.5; 95% CI, -7.227; P = .05).

Symptom improvement was also significantly better after receiving L-methylfolate for the outpatients with methylation levels that were below the median at baseline and those with high baseline oxidative stress levels, as measured by hydroxynonenal-histidine (HNE-his).

"These findings represent a consistent signal, suggesting that something is going on with respect to the metabolic, inflammatory, and oxidative profile of some patients that renders them particularly susceptible to the therapeutic effects of L-methylfolate as adjunctive therapy above and beyond placebo," said coprincipal investigator Dr. Papakostas, MD, from Massachusetts General Hospital, in a release.

"These baseline biomarkers may be good predictors of response and, consequently, useful in determining which patients may be good candidates for treatment. For those who are obese or have other metabolic disturbances, the addition of L-methylfolate to the standard antidepressant regime may be an especially desirable strategy," added Dr. Mischoulon.

He noted that this was "1 small study," so confirmatory trials are now needed.

"But the findings are encouraging, particularly because they were pretty consistent across the board for these various biomarkers. Once this work is replicated, I think it'll allow clinicians to make prescribing decisions with greater confidence," he said.

"Interesting Proposition"

"I think this appears to be an interesting proposition," session moderator Nitin Gupta, MD, associate professor of psychiatry at Government Medical College and Hospital in Chandigarh, India, told Medscape Medical News.

Dr. Nitin Gupta

"It was interesting to see L-methylfolate used as an augmenting strategy, and it appears to be safe."

Dr. Gupta, who was not involved with this research, noted that the investigators were "very cautious in their interpretation and reasonably realistic and balanced in how they presented it."

He added that a lot of research has been going for quite a while in trying to find depression biomarkers.

"And if one is able to make some consistent headway, that would be a real bonus for us. So if [the investigators] are able to replicate their findings in a large sample size, then that would be really helpful," said Dr. Gupta.

The original study was funded by Pamlab, L.L.C. The study authors have disclosed several possible conflicts, which are listed in the original article. Dr. Gupta did not disclose any relevant financial relationships.

The American Psychiatric Association's 2013 Annual Meeting. Abstract SCR27-2. Presented May 22, 2013.

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