PET imaging suggests major depression is a neurodegenerative disease

Major depressive disorder has always been a persistent, all-consuming disease, but imaging research out of Canada suggests the illness could also be neurodegenerative, worsening steadily as patients get older, according to a study published in The Lancet Psychiatry this week.

While diagnosed depressive patients often have access to antidepressants, psychotherapy and a host of other treatment tools, the untreated demographic tends to suffer from increasingly frequent, raw depressive episodes as they age, corresponding author Jeffrey H. Meyer, MD, PhD, and colleagues wrote.

“Major depressive disorder is the leading cause of death and disability in moderate-income to high-income nations, and a substantial proportion of this burden is attributable to the clinical progression of this disorder,” Meyer et al. said. “There is a paucity of empirical data to show greater magnitude of pathophysiologies with greater duration of illness in patients with major depressive disorder, which is a fundamentally important limitation in the literature supporting a neuroprogression model.”

Though linking depression with neuroprogression makes a lot of sense, the authors wrote, clinical evidence of such a phenomenon is scarce. Still, patients continue to claim their depressive episodes are getting longer—and more aggressive—with time.

To expand the body of research on the subject, Meyer and his colleagues at the University of Toronto recruited 81 patients who either had major depressive episodes in addition to major depressive disorder or were healthy. To enroll in the study, patients had to score a minimum of 17 on the 17-item Hamilton Depression Rating Scale, had to be medication-free or taking meds steadily for at least a month, couldn’t smoke tobacco and had no history of substance dependence, the authors wrote.

Each patient underwent PET imaging, which consisted of scanning three primary gray-matter regions in the brain, including the prefrontal cortex, anterior cingulate cortex and insula, in addition to 12 subregions. The researchers focused on microglial activation as a marker of neuroprogression—microglial activation is implicated in neuroprogression, they said, and can be measured by translocator protein total distribution volume (TSPO V).

Results were clear: longer duration of major depressive disorder translated to greater levels of TSPO V throughout all three major brain regions, suggesting microglial activation was greatest in patients with chronologically advanced major depressive disorder and long periods of no antidepressant treatment. In those with untreated major depression for a decade or longer, TSPO V was up to 33 percent greater in the prefrontal cortex, anterior cingulate cortex and insula than those who’d been untreated for nine years or less.

“These findings show that a known marker of advanced neurodegeneration increases with greater duration of untreated major depressive disorder, suggesting that progressive neurodegeneration itself occurs in major depressive disorder,” Meyer and co-authors wrote. “Major depressive disorder, when untreated for a long time, probably requires the development of distinctly different therapeutics to address the increased microglial activation and implicated neurodegeneration.”