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Original Investigation
March 28, 2018

Association of Brain Cortical Changes With Relapse in Patients With Major Depressive Disorder

Author Affiliations
  • 1Department of Psychiatry, University of Münster, Münster, Germany
  • 2Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia
  • 3Department of Psychology, University of Münster, Münster, Germany
  • 4Department of Clinical Radiology, University of Münster, Münster, Germany
JAMA Psychiatry. Published online March 28, 2018. doi:10.1001/jamapsychiatry.2018.0123
Key Points

Question  Is relapse in major depressive disorder associated with morphologic brain changes?

Findings  In this longitudinal, case-control, magnetic resonance imaging study, patients with major depressive disorder showed different trajectories of cortical gray matter changes depending on whether they experienced a relapse during the follow-up interval. These changes were not significantly associated with psychiatric medication or with severity of depression at follow-up.

Meaning  Relapse in major depressive disorder is associated with morphologic changes in brain regions that are crucial for regulation of emotions and cognitive control.


Importance  More than half of all patients with major depressive disorder (MDD) experience a relapse within 2 years after recovery. It is unclear how relapse affects brain morphologic features during the course of MDD.

Objective  To use structural magnetic resonance imaging to identify morphologic brain changes associated with relapse in MDD.

Design, Setting, and Participants  In this longitudinal case-control study, patients with acute MDD at baseline and healthy controls were recruited from the University of Münster Department of Psychiatry from March 21, 2010, to November 14, 2014, and were reassessed from November 11, 2012, to October 28, 2016. Depending on patients’ course of illness during follow-up, they were subdivided into groups of patients with and without relapse. Whole-brain gray matter volume and cortical thickness of the anterior cingulate cortex, orbitofrontal cortex, middle frontal gyrus, and insula were assessed via 3-T magnetic resonance imaging at baseline and 2 years later.

Main Outcomes and Measures  Gray matter was analyzed via group (no relapse, relapse, and healthy controls) by time (baseline and follow-up) analysis of covariance, controlling for age and total intracranial volume. Confounding factors of medication and depression severity were assessed.

Results  This study included 37 patients with MDD and a relapse (19 women and 18 men; mean [SD] age, 37.0 [12.7] years), 23 patients with MDD and without relapse (13 women and 10 men; mean [SD] age, 32.5 [10.5] years), and 54 age- and sex-matched healthy controls (24 women and 30 men; mean [SD] age, 37.5 [8.7] years). A significant group-by-time interaction controlling for age and total intracranial volume revealed that patients with relapse showed a significant decline of insular volume (difference, −0.032; 95% CI, −0.063 to −0.002; P = .04) and dorsolateral prefrontal volume (difference, −0.079; 95% CI, −0.113 to −0.045; P < .001) from baseline to follow-up. In patients without relapse, gray matter volume in these regions did not change significantly (insula: difference, 0.027; 95% CI, −0.012 to 0.066; P = .17; and dorsolateral prefrontal volume: difference, 0.023; 95% CI, −0.020 to 0.066; P = .30). Volume changes were not correlated with psychiatric medication or with severity of depression at follow-up. Additional analysis of cortical thickness showed an increase in the anterior cingulate cortex (difference, 0.073 mm; 95% CI, 0.023-0.123 mm; P = .005) and orbitofrontal cortex (difference, 0.089 mm; 95% CI, 0.032-0.147 mm; P = .003) from baseline to follow-up in patients without relapse.

Conclusion and Relevance  A distinct association of relapse in MDD with brain morphologic features was revealed using a longitudinal design. Relapse is associated with brain structures that are crucial for regulation of emotions and thus needs to be prevented. This study might be a step to guide future prognosis and maintenance treatment in patients with recurrent MDD.