A Wake Up Call

Sleep disturbances and increased inflammation linked to persons with schizophrenia

Persons with schizophrenia, and women in particular, are at high risk for sleep disturbances and inflammatory activation. “Both sleep and inflammation are potentially modifiable – and our group is very interested in finding modifiable factors that influence aging and health in schizophrenia,” said Ellen Lee, MD, Assistant Professor of Psychiatry at the University of California, San Diego (UCSD) and Staff Psychiatrist at the San Diego VA Healthcare System.

That’s the short story behind Dr. Lee’s presentation as part of a longer APA 2021 virtual Annual Meeting session titled The Impact of Sleep on Geriatric Mental Health: Research Findings in Schizophrenia, Affective Disorders, and Cognitive Disorders.

Backtracking a bit, Dr. Lee’s “group” includes researchers investigating the sleep-inflammation link in persons with schizophrenia and its relationship with demographic, clinical, and cognitive variables. The project, based on the USCD campus, is ongoing and specific to inflammatory mechanisms underlying sleep and cognition in middle-aged and older adults (41-70 years old) with schizophrenia (SZ).

The study’s ultimate goal is to help inform future development of targeted interventions that can improve functioning in this vulnerable population.

It’s About Time

It’s a study that’s long overdue, Dr. Lee suggests. “Persons with schizophrenia have a 2 to 12 times higher mortality rate and a 16 to 20 year shorter lifespan than the general population. The increased physical comorbidity and premature mortality is not driven by suicides and accidents but rather by age-related chronic diseases, like heart disease, cancer, stroke, and diabetes. “That makes schizophrenia not only a serious mental illness but also a serious physical illness,” Dr. Lee said.

Dr. Lee noted that risk factors for poor health – and subsequent chronic diseases –  among those with schizophrenia are complex. This group tends to have higher rates of smoking, substance use, poor diet, and sedentary lifestyle. There are also environmental risk factors at play, such as poverty, stigma, and chronic exposure to psychotics. In addition, there can be a higher risk for poor access to healthcare.

“We reviewed longitudinal mortality studies in schizophrenia and found that since the 1970s the average lifespan of the general population in western countries has increased by about 10 years. At the same time, the longevity gap between people with schizophrenia and the general population has increased by 37%,” Dr. Lee said. “So it appears that individuals with schizophrenia are really being left out of the healthy longevity revolution, and they’re not benefiting from the same medical and lifestyle improvements that have increased longevity for the general population.”

Schizophrenia and Sleep

Dr. Lee explained that 30 to 80% of adults with schizophrenia have sleep abnormalities, which can include shorter or longer sleep duration, decreased sleep efficiency with more frequent overnight awakenings, difficulties with sleep initiation or longer sleep latency, slow wave sleep deficits, and disturbed circadian activity rhythms. “These sleep issues have clear implications for quality of life, cognition, frontal lobe functioning, brain health, and aging. However, the neurobiological mechanisms that connect sleep and psychopathology are not fully understood,” Dr. Lee said. “Because both sleep and inflammation are potentially modifiable, understanding this connection may help us improve the overall health for those with schizophrenia.”

To examine the sleep-inflammation link in persons with schizophrenia, this cross-sectional case-control study includes a cohort of individuals with schizophrenia (N=144, 46% women) and non-psychiatric comparison (NC) participants (N=134, 52% women), age 26 to 65 years.

Since the study’s start, assessments include reported sleep disturbances (sleep quality and duration) as well as mental and physical health. Cognitive assessments include executive functioning (Delis-Kaplan Executive Function System) and global cognitive functioning (Telephone Interview for Cognitive Status – modified.) Inflammatory biomarkers include pro-inflammatory cytokines (high sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, Tumor Necrosis Factor-α (TNF-α)) and an anti-inflammatory cytokine (IL-10).

Results report that the schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of hs-CRP, IL-6, and TNF-α compared to NCs. Women with schizophrenia were less likely to have good sleep quality and had elevated levels of hs-CRP and IL-6 compared to men with schizophrenia. In the schizophrenia group, worse sleep quality and global cognitive functioning were associated with higher hs-CRP and IL-6 levels. Female sex and younger age were also associated with higher hs-CRP levels.

More Data

The study determined that improvements in sleep quality were associated with improvements in physical and mental wellbeing. “However, to really understand these individual patterns and changes over time, we needed more granular and objective assessments of sleep,” Dr. Lee said.

To this end, a small, ongoing, longitudinal study began to assess 43 individuals, all equipped with an actigraphy and other wrist-worn activity tracker. Initial data, which includes roughly 427 nights, shows that individuals with schizophrenia and individuals in the nonpsychiatric comparison group had similar total sleep time and similar sleep efficiency, although those with schizophrenia had greater intra-individual night-to-night variability of all objective sleep parameters, including total sleep time as well as sleep efficiency, wake after sleep onset, bedtimes, and wake times.

In addition, an examination of how objective sleep measures related to metabolic function showed that those with shorter sleep times had higher hemoglobin A1C levels. However, only in the schizophrenia group was the increased total sleep time variability associated with higher hemoglobin A1C levels.

Moving Forward

Next steps, said Dr. Lee, include a deeper look at obstructive sleep apnea in those with schizophrenia. “We found in the published literature that people with schizophrenia are have an increased prevalence or incidence of obstructive sleep apnea,” Dr. Lee said. “In our own data set, we found that 48% of individuals with schizophrenia had a higher risk for obstructive sleep apnea but only 6% of that same sample reported actually having a formal diagnosis of obstructive sleep apnea.”

In addition, the increased risk for obstructive sleep apnea among those with SZ remains even after adjusting for sex, age, comorbidities, and antipsychotic use.

“We’re interested in getting deeper into how sleep apnea and insomnia may have different impacts on cognitive functioning in this group,” Dr. Lee said.