Pretreatment brain activity predicts better outcomes in depression

Higher rostral anterior cingulate cortex (rACC) theta activity at baseline predicts better prognosis in depressed patients, according to a novel study published in JAMA Psychiatry.

“Nonspecific markers of depressive symptom improvement (prognostic markers) could be used to allocate individuals at risk of poor outcome to a more intensive intervention from the outset and suggest more careful monitoring,” wrote the authors, led by Diego A. Pizzagalli, PhD, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA. “Identification of such variables could inform our understanding of treatment mechanisms and hasten the development of novel interventions.”

In 1997, researchers first discovered that heightened pretreatment activity of rACC was significantly linked to better treatment outcomes in depressed patients taking antidepressants. A later meta-analysis showed that in 19 of 23 studies, increased pretreatment rACC activity predicted better treatment outcomes in a variety of patients, including those taking multiple antidepressants, those who are sleep deprived, those receiving transcranial magnetic stimulation, and those administered placebo. Nevertheless, other researchers have found it challenging to replicate these findings.

Overall, it appears that higher pretreatment rACC theta activity serves as a generalized prognostic biomarker of improvement in depressive symptoms. In the current study, the authors endeavored to understand this relationship using higher statistical power, a placebo arm, and statistical adjustment for clinical and demographic covariates.

The current trial is part of the multisite Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) Study, which aims to ascertain biology-based, objective strategies to treat mood disorders.

In turn, the EMBARC Study is a response to the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study, which showed that as many as two-thirds of patients are refractory to initial antidepressant treatment.

“Given the relative ease associated with collecting clinical and demographic variables, imaging measures must show incremental predictive validity to justify the costs and technical complexities associated with their use in the context of treatment outcome prediction,” the investigators wrote.

In the current double-blind study, the team screened 634 patients with psychosis and chronic/recurrent major depressive disorder (MDD) from Harvard University, Columbia University, the University of Michigan, and the University of Texas Southwestern Medical Center.

In total, the researchers randomized 296 patients (9 patients dropped out) to 8 weeks of treatment with either sertraline hydrochloride (≤ 200mg daily) or placebo. Of the 287 remaining patients, 266 had electroencephalographic (EEG) readings and 248 had EEG data that was usable. Medication doses could be adjusted at weeks 1, 2, 3, 4, and 6, as needed.

The team documented resting EEG data at baseline and one week after the trial commenced. They also performed source localization analyses utilizing low-resolution electromagnetic tomography.

The primary outcome for the study was scores on the 17-Hamilton Rating Scale for Depression (HRSD), which was administered at baseline and weeks 1, 2, 3, 4, 6, and 8.

Dr. Pizzagalli and co-authors found that increased rACC theta activity at baseline and at week 1 was positively correlated with improvements in depressive symptoms. These results held even after adjustment for demographic and clinical factors that were also tied to treatment outcomes, and were not moderated by the treatment arm.

The rACC theta marker contributed to 8.5% of the variance in symptom change, and when combined with clinical and demographic variables, it accounted for 39.6% of this variance.

The researchers note that the exact mechanisms underlying the relationship between higher pretreatment rACC theta activity and improved treatment outcomes with antidepressants has yet to be elucidated. Nonetheless, they suggest that this relationship may have something to do with a decrease in maladaptive forms of rumination, such as critical self-introspection, difficulty with mitigating negative emotions, and problems with attention.

“The current multicenter study shows that higher baseline rACC theta activity predicted greater improvement in depressive symptoms, even when controlling for clinical and demographic variables previously linked to treatment response,” the researchers concluded. “This prognostic marker of treatment outcome warrants further scrutiny for possible implementation in clinical care.”

More specifically, the researchers suggest that electrical activity in the brain can indicate whether a patient can benefit from an SSRI before starting treatment.

Madhukar H. Trivedi, MD, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, who oversees EMBARC, shed light on how results of this first study combined with an anticipated four additional studies in coming months will change the field of psychiatry.

“When the results from these tests are combined, we hope to have up to 80% accuracy in predicting whether common antidepressants will work for a patient,” he says. “This research is very likely to alter the mindset of how depression should be diagnosed and treated.”

This study was funded by the NIMH and NIH.

To read more about this study, click here.