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Abnormal neuropathology observed with longer duration of untreated depression

Patients with longer duration of untreated major depressive disorder showed greater microglial activation — evidenced by translocator protein total distribution volume — compared with those with shorter periods of untreated MDD, according to data published in The Lancet Psychiatry.

“Results from prospective studies indicate that with greater length of illness, major depressive disorder often transitions ... towards increasingly persistent disease, with greater proportions of time spent in the midst of a major depressive episode, a phenomenon that is strongly suggestive of neuropathological progression,” Elaine Setiawan, PhD, from the Centre for Addiction and Mental Health, Toronto, and colleagues wrote. “Neuroprogression ... is not well established in major depressive disorder, with few investigations showing greater levels of pathology with longer duration of illness.”

Researchers analyzed the link between translocator protein total distribution volume (TSPO V_T), a marker of microglial activation that’s implicated in neuroprogression, and duration of untreated major depression, total illness duration and exposure to antidepressants in a cross-sectional study. Specifically, the investigators examined whether these factors could be predictive of TSPO V_T.

They recruited both healthy adults and adults with depression from the Toronto area and the Centre for Addiction and Mental Health; participants with MDD were antidepressant-free or taking a stable dose of medication for at least 4 weeks before positron emission tomography scanning. To measure TSPO V_T, researchers scanned the prefrontal cortex, anterior cingulate cortex and insula, along with 12 other gray-matter regions and subregions.

In total, 30 healthy patients and 51 patients with MDD were included in the study. Analysis revealed that duration of untreated major depression (P < .0001), total illness duration (P = .0021) and antidepressant exposure duration (P = .037) were all strong predictors of TSPO V_T.

After separating the MDD group into participants with 10 or more years of no antidepressant treatment (long-term) and those with no treatment for 9 years or less (short-term), researchers observed that participants with longer durations of untreated depression had greater microglial activation in all sampled grey-matter regions, according to the TSPO V_T, than those with shorter durations. In those with long-term untreated depression, TSPO V_T was 29% to 33% greater in the prefrontal cortex, anterior cingulate cortex and insula. Furthermore, in these participants with longer duration of untreated depression, the TSPO V_T was 31% to 39% greater in grey-matter regions when compared with healthy participants (P = .00047).

“This finding of progressively abnormal neuropathology with more advanced illness has major implications for conceptualizing neuroprogression in major depressive disorder, and the relationship of TSPO V_T with antidepressant exposure is important to understand the effect of antidepressants on microglial activation in the clinical setting,” Setiawan and colleagues wrote. “Given that microglial activation is a marker of advancing disease and is implicated in depressive symptoms, it might be advantageous to clinically investigate and categorize chronologically advanced major depressive disorder differently.” – by Savannah Demko

Disclosure: Setiawan reports no relevant financial disclosures. Please see the full study for all other authors’ relevant disclosures.