Somatic Comorbidity in Schizophrenia: Some Possible Biological Mechanisms Across the Life Span

Abstract

Schizophrenia is associated with decreased life expectancy (15–25 y) compared to the general population, with comorbid somatic diseases and in particular cardiovascular diseases being a major cause. Life style and medication probably account for much of the increased mortality risk due to somatic diseases in schizophrenia, but the evidence implicating biological pathways potentially affecting both body and brain is increasing. This includes overlapping genes between schizophrenia and somatic diseases, prenatal risk factors such as hypoxia and infections, and increased cardiovascular disease risk in drug-naïve patients at illness onset. Although environmental bias increases throughout the disease course, there are also some studies on chronic schizophrenia and postmortem brain samples that warrant further attention. In the following, we will attempt to move beyond environmental impact and explore some of the shared pathophysiological mechanisms potentially underlying both schizophrenia and somatic diseases.

Introduction

One of the major challenges in psychiatric health care is addressing the high mortality rate in patients with psychotic disorders. Schizophrenia is associated with substantially decreased life expectancy (15–25 y) compared to the general population, with somatic diseases being a major cause for all these years of lost life.¹ There is little doubt that some second generation antipsychotics and poor life style habits are associated with dyslipidemia, hyperglycemia, and overweight contributing to the overall risk of developing somatic diseases, including the metabolic syndrome and cardiovascular disease. The causal link between these second generation antipsychotics and poor cardiovascular health has, however, been difficult to identify. Firstly, taking antipsychotic medication is associated with lower mortality due to somatic diseases in patients with psychotic disorders.² Secondly, clinical studies have indicated increased risk for metabolic syndrome in drug-naïve patients and in first-degree relatives of schizophrenia patients.³ Third, evidence from recent genetic studies implicates shared genetic risk (pleiotropy) for cardiovascular risk factors and psychotic disorders.⁴ In addition schizophrenia patients face increased risk for autoimmune disease, infections, chronic obstructive pulmonary disease (COPD) and cancers.¹ The latter 2 are presumably caused by life style factors such as smoking and poor health care. Spanning from studies exploring risk genes and altered expression in vivo or postmortem to physiological changes in real-life patients, we will here move beyond environmental risk factors and explore a few selected biological mechanisms potentially underlying the increased somatic comorbidity in schizophrenia across the life span.

The Genetic Link

One hypothetical link is shared genetic makeup between somatic disorders and schizophrenia. In addition to the aforementioned study indicating pleiotropy between schizophrenia and dyslipidemia,⁴ a genetic link between schizophrenia and autoimmune diseases, cardiovascular disorders and type 2 diabetes have been suggested. Novel schizophrenia risk genes⁵ involved in ion channel signaling pathways are also linked to cardiovascular disease and have been suggested as a promising pharmacological target for hypertension and heart failure.^5–9 In the same vein, several novel schizophrenia risk loci⁵ are located within immune-related genes and in addition these risk variants were found to be strongly expressed in immune cells providing further support for a link between the immune system and schizophrenia.

Prenatal Life and Neurodevelopment

Prenatal adversities have been linked to adult mental disease through mechanisms including maternal hypothalamic-pituitary-adrenal (HPA) axis dysregulation, excessive glucocorticoids, and inflammation.¹⁰ The neurodevelopmental hypothesis for schizophrenia is a conceptual framework, in which early insults such as prenatal infections, maternal starvation, intrauterine growth restriction, Caesarean section and pre- and or perinatal hypoxia are hypothesized to lead to altered neurodevelopment and an increased risk for developing schizophrenia later in life, as shown in epidemiological, clinical, brain imaging, and animal studies.^11,12 The fetal origin of adult health hypothesis (Barker hypothesis) states that in utero undernutrition may permanently change the body’s metabolism and lead to adult cardiovascular and metabolic diseases. The hypothesis is based on large observational studies showing increased cardiovascular death rates among persons with low birth weight.¹³ Animal studies point toward the biological mechanisms underpinning this association, including disturbed prenatal renin–angiotensin system function, disturbed placental function (materno-fetal endocrine exchanges), or prenatal undernutrition-related epigenetic regulation of gene expression.¹⁴

The exact biological mechanisms are not clear, but with regard to later cardiovascular risk it is known that several of the schizophrenia susceptibility genes that are involved in prenatal neurodevelopment are regulated by hypoxia and/or expressed in the vasculature.¹⁵ Moreover, the cytokine-associated inflammatory response to prenatal infection may lead to abnormal brain development, later development of psychosis, and have been shown to cause altered glycemic regulation and adult excess fat deposition in mice.¹⁶ The prenatal origin of adult health-hypothesis suggests an important biological link between abnormal prenatal development, schizophrenia risk, and somatic disorders that precede lifestyle related factors and medication use later in life.

Illness Onset and the Early Years

Cardiovascular disease risk factors such as metabolic syndrome was long considered to be a comorbid outcome of schizophrenia after years of medication, excess smoking, unhealthy diets and a sedate life. However, recent clinical studies have shown that even young drug-naïve schizophrenia patients face increased cardiovascular disease risk, with higher levels of cholesterol and increased insulin resistance compared to their healthy peers.¹⁷

There are several possible explanations for this, implicating inflammatory, hormonal and endothelial mechanisms and interactions within these pathways. First, studies carried out on drug-naïve schizophrenia patients have suggested that increased insulin levels and/or insulin insensitivity play a role in schizophrenia disease mechanisms¹⁸ which might either directly or through the HPA-axis affect the brain.¹⁹ Secondly, studies in first-episode psychosis patients show increased levels of inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), interleukin 1-receptor antagonist (IL-1Ra), and tumor necrosis factor (TNF)²⁰ all of which have been implicated in metabolic syndrome, type 2 diabetes and vascular plaque disease. As with all naturalistic study designs, the direction of effects is unclear and there is no definite answer to the crucial question as to what comes first. In light of the recent findings identifying a functional lymphatic system in the brain,²¹ one might speculate that astrocytes and microglia brain cells in genetically predisposed individuals produce an abundance of pro-inflammatory cytokines²² which are drained from the central nervous system to the peripheral circulation subsequently increasing cardiovascular disease risk in schizophrenia. On the other hand, there might be a cross-talk between body and brain through the passage of cytokines, leukocytes and lymphocytes induced by peripheral metabolic and vascular dysfunctional activity across the blood brain barrier affecting and interacting with central neurotransmitter systems. Another interesting study implicating neurotransmitters such as glutamate and dopamine pathways have suggested that deficits within the reward system in the striatum might represent a link between obesity and schizophrenia,²³ which further supports that shared molecular mechanisms might to some extent underlie the abundance of somatic comorbidity associated with schizophrenia.

Chronic Illness and Accelerated Aging

Speculating on potential shared mechanisms between schizophrenia and somatic comorbidity based on results from studies carried out on patients with chronic schizophrenia, has its obvious limitations in terms of bias from medication and life style factors, such as smoking, poor diet habits, and a sedate life style. Age represents an independent risk factor for all somatic diseases across all ethnicities, gender, and other diagnoses. It is therefore interesting that recent studies have indicated that schizophrenia is associated with accelerated aging possibly due to shortened telomeres (repeated nucleotide sequences protecting the chromosome from damage).²⁴

Accelerated aging in schizophrenia on a brain macroscopic level has been reported using magnetic resonance imaging (MRI) and support vector machine classification of the neuroanatomy from illness onset and across the adult life span.²⁵ We have recently shown an association between increased levels of an endothelial marker and increased basal ganglia volume in patients with psychotic disorders indicating a potential link between endothelial related inflammation and brain morphology.²⁶ This is supported by recent in vivo studies of the microvasulature in schizophrenia by the use of retinal imaging show wider retinal venules in schizophrenia than in healthy controls, a finding that has also been associated with an increased risk for stroke, dementia, and other cerebrovascular disorders.²⁷

Postmortem Analyses of the Brain

Schizophrenia is characterized by macroscopic brain changes including cortical thinning, ventricular enlargement, and hippocampal volume reduction.²⁸ The microscopic underpinnings (from “postmortem” studies) of these changes include smaller pyramidal neuron cell bodies, reduced dendritic spine density, and reduced interneuron density and number.²⁹ With regard to cardiovascular disease pathology, a postmortem study of the brain cortex in schizophrenia showed abnormalities of the capillaries including thickening, deformation of basal lamina, vacuolation of cytoplasm of endothelial cells, basal lamina and astrocytic end-feet.³⁰ The findings support that blood-brain barrier dysfunction may be of importance on a microscopic level in schizophrenia. Another postmortem study showed differences in gene expression in the cerebral microvasculature between schizophrenia patients and controls primarily in genes relating to inflammatory processes.³¹ A recent meta-analysis of postmortem brain tissue studies in schizophrenia found up- and down-regulation of genes spanning several molecular mechanisms including cell adhesion, neurotransmitter secretion, genes involved in oxidative phosphorylation and ubiquitination, cell organization/maintenance factors and stress response genes as well as genes without known function.³² Although the results from small postmortem studies must be interpreted with caution due to small number of subjects, pH- and batch differences and environmental influence such as medication and substance abuse, they do provide some evidence of microvascular pathology in schizophrenia.

Summary and Conclusion

Schizophrenia is a complex disorder, with a high heritability, yet little is known about the underlying mechanisms. The etiology involves multiple genes, interacting biological pathways, and a variety of environmental risk factors. Schizophrenia is, however, increasingly recognized as a systemic disorder and these patients face an additional burden in terms of somatic comorbidity implying overlapping and interacting disease mechanisms that involve neurotransmitter, inflammatory, endothelial and hormonal pathways among others.

Funding

The authors received no funding for this article.