Voided REM Sleep (V-REM): A Candidate Biomarker Linking Treatment-Resistant PTSD and Major Depressive Disorder

A substantial proportion of patients with posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) do not respond to first-line treatment. Approximately 40% of PTSD patients do not respond to first-line psychotherapy, and 30.9% of MDD patients meet criteria for treatment-resistant depression. Yet standard polysomnography in these patients frequently shows REM sleep that appears architecturally normal. I propose that this apparent normality may be masking a functional anomaly in which the ventromedial prefrontal cortex (vmPFC) node of the default mode network and the amygdala show abnormal connectivity during REM epochs, occurring despite intact brainstem-generated REM markers (muscle atonia, rapid eye movements, characteristic EEG activity). I term this pattern Voided REM sleep (V-REM), REM sleep that completes its brainstem-generated form without completing its forebrain-mediated emotional-processing function. I outline the anatomical and physiological rationale for distinguishing REM’s form from its function, review evidence consistent with the hypothesis in both PTSD and MDD, specify a falsifiability criterion, and propose a functional MRI protocol using four matched comparison groups to test the hypothesis directly. Establishing V-REM as a biomarker would not require resolving, at this stage, whether the anomaly is a cause or a consequence of treatment resistance. As history has shown with other biomarkers whose clinical value was established well before their causal role was understood, this would not diminish the potentially pivotal role such a discovery could play in identifying and treating this subgroup of patients.