Connecting REM Sleep and Substance Use Vulnerability

Colleen McClung, PhD, discussed disorder-specific patterns of circadian gene expression in the brain across schizophrenia, major depressive disorder (MDD), and bipolar disorder, and described the reciprocal relationship between sleep disruption and substance use vulnerability.

McClung described her group's work in the dorsolateral prefrontal cortex in schizophrenia, an area critical for cognitive control. She reported a shift in the timing of rhythmic gene expression, particularly among mitochondrial regulatory genes. In healthy individuals, these genes typically peak near the beginning and end of the day to prepare the body and brain for wakefulness and sleep; in subjects with schizophrenia, peak expression instead shifted to static, specific times.¹ McClung noted that this finding has been independently replicated and extended by her group's subsequent work identifying altered 12-hour ultradian rhythms in the same brain region in schizophrenia.²

In MDD, McClung described a markedly different pattern, characterized by substantial sex differences in rhythmic gene expression between men and women and prominent alterations in neuroimmune and inflammatory pathway genes. In bipolar disorder, her group observed pronounced seasonal effects, including a marked summertime spike in expression of mitochondrial function-related genes coinciding with periods of increased manic risk.

McClung also turned to the bidirectional relationship between sleep and substance use, noting that sleep deficits increase vulnerability to impulsive and reward-seeking behavior, including substance use, while substance use itself further disrupts the sleep-wake cycle—creating what she described as "a vicious cycle." She cited the work of a Pittsburgh colleague studying how drugs of abuse affect rapid eye movement (REM) sleep in rodent models, noting that experimentally restoring REM sleep during the rodents' inactive period reduced subsequent drug-seeking behavior, a finding with potential implications for addiction intervention design.

McClung concluded with practical recommendations for patients with psychiatric disorders, emphasizing that the timing and consistency of sleep—not merely total sleep duration—are critical. She recommended consolidated nighttime sleep rather than daytime napping, and consistent daily timing of sleep, meals, exercise, and social interaction to stabilize circadian rhythms, particularly for patients with mood disorders.

Dr McClung is professor of psychiatry and clinical and translational science at the University of Pittsburgh School of Medicine.

References

1. Seney ML, Cahill K, Enwright JF 3rd, et al. Diurnal rhythms in gene expression in the prefrontal cortex in schizophrenia. Nat Commun. 2019;10(1):3355.

2. Scott MR, Zong W, Ketchesin KD, et al. Twelve-hour rhythms in transcript expression within the human dorsolateral prefrontal cortex are altered in schizophrenia. PLoS Biol. 2023;21(1):e3001688.