Micro-Factors May Explain the Connection Between COVID-19, Schizophrenia

A study suggests energy metabolism dysregulation, immune system disruption, and abnormalities in the central nervous system are linked to high COVID-19 infection and mortality rates among individuals with schizophrenia.1

During the COVID-19 pandemic, people with schizophrenia had substantially greater rates of SARS-CoV-2 infection and COVID-19 mortality rates compared with patients with other mental disorders. One study published in 2021 even found schizophrenia was the second-highest risk factor for COVID-19, the first being age.2 Investigators wanted to explore why this may be—what micro-factors were linked to greater COVID-19 infection rates among individuals with schizophrenia.1

Dysregulated cerebral glucose metabolism serves as a fundamental factor in the pathogenesis of schizophrenia and, evidently, the subacute stage of COVID-19 and long COVID. Disorders of carbon and energy metabolism, often present in both schizophrenia and COVID-19, involve many processes: lycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, and oxidative phosphorylation.

Abnormalities in energy metabolism and the change of signaling pathways influence synaptic plasticity, neuronal survival, mood regulation, and immune responses.

“This raises the question of whether these disturbances are connected to the increased mortality rates observed in patients with [schizophrenia] who are affected by COVID-19,” wrote investigators, led by Zhen-Ying Li, Yu-Qian Li, and Jing-Ru Zhou, all from Hainan Medical University in China.

Furthermore, disruptions in energy metabolism can disrupt amino acids, such as alanine, aspartate, and glutamate, and these disruptions have been identified in both schizophrenia and COVID-19. The amino acid glutamate, a key neurotransmitter, functions through glutamatergic synapses and its receptors: AMPA, kainate, and NMDA. In COVID-19, NMDA receptor subunits 1 and 2A are downregulated, and reduced NMDA receptor activity is seen in schizophrenia's pathophysiology.

Glutamate metabolism disorders can also lead to a GABAergic system disorder. GABA, an inhibitory neurotransmitter, is synthesized from glutamate by the enzymes GAD1 and GAD2. In schizophrenia, various brain regions demonstrate reduced GAD1 expression (mRNA and protein), GAD1 gene mutations, and lower GABA levels.

Patients with schizophrenia and COVID-19 also have dysregulation of retrograde endocannabinoid signaling.

Additionally, immune system disruptions have been observed in individuals with COVID-19 and schizophrenia. Patients with COVID-19 and schizophrenia both experience the depletion of lymphocyte subsets, such as natural killer cells, that lead to a greater viral load and compromise the immune response.

Patients with COVID-19 tend to have greater levels of interleukin-6 in peripheral tissues than people without COVID-19—and these levels were greater in those who died than survived. Patients with COVID-19 were observed with monocytic encephalitis in brain tissue, a virus characterized by monocyte infiltration, activation of microglia and astrocytes, and the release of IL-4, IL-6, and IL-12.

As for patients with schizophrenia, immune dysfunction and inflammation were detected through elevated levels of proinflammatory cytokines, such as IFN-γ, IL-1, and tumor necrosis factor α, in the plasma. Patients with schizophrenia also had increased IL-6 levels in the cerebrospinal fluid, and reduced IL-3 activity was linked to more severe illness, greater viral loads, and increased likelihood of death among those infected with SARS-CoV-2.

Increased rates of early psychiatric discharge during the pandemic, resulting in disrupted face-to-face psychiatric care, contributed to the increased risk of COVID-19 among patients with schizophrenia.

Investigators suggested several strategies to address the micro-factors contributing to the high infection of COVID-19 among patients with schizophrenia: using a collaborative-care model and including family members and caregivers, improving vaccine accessibility, developing novel drugs or interventions for COVID-19, and improving diagnostic and intervention measures.

“The development of targeted vaccination programs for this population is urgently needed,” investigators wrote. “It is also essential to prioritize COVID-19 vaccination for individuals with serious mental illnesses, such as schizophrenia, due to their higher risk of infection and greater need for medical resources.”

References

1. Li ZY, Li YQ, Zhou JR, Wang J, Liu KZ, Wang P, Gong CM, Wang H, Zhang YJ, Cao Y, Gu Y, Zhang HB, Lu H, Lu LF, Feng RJ. Causes and countermeasures for the increased infection and COVID-19 mortality rates in patients with schizophrenia. IBRO Neurosci Rep. 2024 Nov 15;17:456-462. doi: 10.1016/j.ibneur.2024.11.009. PMID: 39634030; PMCID: PMC11616062.
2. Mohan M, Perry BI, Saravanan P, Singh SP. COVID-19 in People With Schizophrenia: Potential Mechanisms Linking Schizophrenia to Poor Prognosis. Front Psychiatry. 2021 May 17;12:666067. doi: 10.3389/fpsyt.2021.666067. PMID: 34079487; PMCID: PMC8166317.