People with major depressive disorder frequently exhibit increasing persistence of major depressive episodes. However, evidence for neuroprogression (ie, increasing brain pathology with longer duration of illness) is scarce. Microglial activation, which is an important component of neuroinflammation, is implicated in neuroprogression. We examined the relationship of translocator protein (TSPO) total distribution volume (V_T), a marker of microglial activation, with duration of untreated major depressive disorder, and with total illness duration and antidepressant exposure.

In this cross-sectional study, we recruited participants aged 18–75 years from the Toronto area and the Centre for Addiction and Mental Health (Toronto, ON, Canada). Participants either had major depressive episodes secondary to major depressive disorder or were healthy, as confirmed with a structured clinical interview and consultation with a study psychiatrist. To be enrolled, participants with major depressive episodes had to score a minimum of 17 on the 17-item Hamilton Depression Rating Scale, and had to be medication free or taking a stable dose of medication for at least 4 weeks before PET scanning. Eligible participants were non-smokers; had no history of or concurrent alcohol or substance dependence, neurological illness, autoimmune disorder, or severe medical problems; and were free from acute medical illnesses for the previous 2 weeks before PET scanning. Participants were excluded if they had used brain stimulation treatments within the 6 months before scanning, had used anti-inflammatory drugs lasting at least 1 week within the past month, were taking hormone replacement therapy, had psychotic symptoms, had bipolar disorder (type I or II) or borderline antisocial personality disorder, or were pregnant or breastfeeding. We scanned three primary grey-matter regions of interest (prefrontal cortex, anterior cingulate cortex, and insula) and 12 additional regions and subregions using ¹⁸F-FEPPA PET to measure TSPO V_T. We investigated the duration of untreated major depressive disorder, and the combination of total duration of disease and duration of antidepressant treatment, as predictor variables of TSPO V_T, assessing their significance.

Between Sept 1, 2009, and July 6, 2017, we screened 134 participants for eligibility, of whom 81 were included in the study (current major depressive episode n=51, healthy n=30). We excluded one participant with a major depressive episode from the analysis because of unreliable information about previous medication use. Duration of untreated major depressive disorder was a strong predictor of TSPO V_T (p<0·0001), as were total illness duration (p=0·0021) and duration of antidepressant exposure (p=0·037). The combination of these predictors accounted for about 50% of variance in TSPO V_T in the prefrontal cortex, anterior cingulate cortex, and insula. In participants who had untreated major depressive disorder for 10 years or longer, TSPO V_T was 29–33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO V_T was also 31–39% greater in the three primary grey-matter regions of participants with long duration of untreated major depressive disorder compared with healthy participants (p=0·00047).

Microglial activation, as shown by TSPO V_T, is greater in patients with chronologically advanced major depressive disorder with long periods of no antidepressant treatment than in patients with major depressive disorder with short periods of no antidepressant treatment, which is strongly suggestive of a …