Psychotic disorders such as schizophrenia and mood disorders including bipolar disorder (BD) and major depressive disorder (MDD) have overlapping clinical presentations and share similarities in several underlying endophenotypic abnormalities, such as cognitive and motor deficits [1, 2]. These pathologies further share progressive neurobiological disturbances, including structural brain changes (e.g., prefrontal lobe volume reductions, enlarged lateral ventricles) [3] and abnormal functional connectivity [4, 5]. It is hypothesized that these progressive changes are mediated by neuroinflammatory and oxidative stress (OS) [6] (Fig. 1).

Fig. 1.

A model for immune dysregulation and OS towards psychotic and mood symptoms.

Fig. 1.

A model for immune dysregulation and OS towards psychotic and mood symptoms.

Close modal

Peripheral and central immune abnormalities are present in both mood and psychotic disorders [7-9]. Centrally, immune alterations are evidenced by abnormal microglial activation patterns [10, 11] as well as a disequilibrium in the kynurenine pathway [12]. Activated microglia have been associated with excessive synaptic pruning in schizophrenia [13], thus affecting brain structure and functioning. Moreover, the kynurenine pathway, which is activated by inflammatory cytokines, additionally accounts for altered brain operation in these illnesses. This pathway consists of two branches, with 3-OH-kynurenine and quinolinic acid being produced by microglia on the one hand and kynurenic acid by astrocytes on the other. Interestingly, the microglia-generated metabolites are known to be neurotoxic. Moreover, across psychotic disorders including schizophrenia, BD, and MDD, both quinolinic acid and kynurenic acid were shown to be dysregulated, affecting glutamatergic and cholinergic neurotransmission, which may bridge immune effects and mood- and psychosis-related symptoms. This is in line with the findings of Condray et al. [14] who demonstrated microglial kynurenine metabolites not only to correlate with symptom severity in neuroleptic-naive schizophrenia patients but also to predict clinical change at 4 weeks of treatment. Finally, a proinflammatory state has an impact on growth factor levels (such as brain-derived neurotrophic factor or vascular endothelial growth factor) in mood and psychotic disorders [9], generally influencing synaptic homeostasis and neuronal regeneration. In sum, central nervous immune dysregulation may critically affect symptoms of psychotic disorders.

Besides central immune abnormalities, peripheral proinflammatory cytokine alterations have been found in these three illnesses [15]. Moreover, these cytokine changes are comparably present in these disorders, again suggesting a common underlying pathway for immune dysfunction [15]. Interestingly, proinflammatory activity has been associated with structural brain changes [16] as well as with the cognitive and motor dysfunctions [17, 18] seen in each of these disorders. It should be noted that although peripheral and central immune alterations are present, these may be unrelated [19] and may even be inversely related [20, 21], which could point towards compensatory reverse mechanisms in the brain following systemic proinflammatory immune activity [20, 21]. Nevertheless, methodological shortcomings limit this emerging research field; thus, caution is warranted in interpreting such findings. For example, microglial PET-tracer specificity is unclear, and different mathematical models calculating microglial activation in these PET studies have yielded different results. Nonetheless, results suggest peripheral systemic abnormal immune processes being present in mood and psychotic disorder, which may be independent from those present in the central nervous system.

Chronic inflammation is bidirectionally associated to OS, also present in schizophrenia and mood disorders [22]. OS induces cell damage due to an imbalance in the release of toxic-free radicals (reactive oxygen species, ROS) from redox reactions over protective antioxidants. Of note, central nervous system tissue is particularly vulnerable to oxidative damage [22]. ROS are mostly generated by mitochondria, which play a key role in meeting cellular energy demands [23]. Importantly, decreases in mitochondrial numbers as well as changes in mitochondria morphology and function have been reported in schizophrenia [6] and BD [24]. In addition, mitochondrial DNA polymorphisms have been associated to increase familial risk for schizophrenia [25]. Finally, antioxidant defense systems appear to be compromised in schizophrenia [26]. In this line, aberrant peripheral markers for OS have been demonstrated in schizophrenia, BD [27], and MDD [28]. Multiple risk factors (obstetric complication, infections) and psychological stress are found to be associated with an increase in OS [29]. Oxidative damage to cell membranes, proteins, and DNA will impair cell function, signal transduction, and connectivity, which may account for the neuroprogressive course of these disorders [30]. Together, genetics and environmental factors contribute to OS in psychotic disorders through multiple pathways.

The aforementioned immune system abnormalities as well as markers of OS have been associated with age in schizophrenia [20] and BD [27]. In fact, findings suggest an aggravation of immune-induced and oxidative damage with increasing age, significantly more so than in healthy elderly controls. Reversely, the free-radical theory of aging assumes that aging (partially) occurs as a result of damage to cells and connective tissue caused by free radicals [23]. In this line, several aging-related physiological abnormalities can be seen in younger patients with schizophrenia and mood disorders, including a higher prevalence of metabolic and cardiovascular disease, a reduction in life expectancy of 10–20 years, a reduced telomere length, and brain volume reductions [23, 31]. These findings form the basis of the so-called “aging hypothesis” for schizophrenia and mood disorders [23, 27, 32], also suggesting these disorders to be “whole-body disorders” rather than disorders restricted to the brain [33].

A complex interaction between genetic predisposition [22], lifestyle choices [34, 35], psychological and other stressors [36] trigger immune abnormalities towards a proinflammatory state and induce OS. These changes lead to progressive cellular and structural damage [11, 37], resulting in symptoms related to the underlying disorders. Figure 1 summarizes these complex interactions. This notion opens up many interesting research avenues. Longitudinal studies could investigate how immune and oxidative processes are related to the progressive nature of these illnesses. Their relationship with mood and psychotic symptoms, but also with cognitive symptoms, should be gauged further. Motor symptoms such as catatonia and psychomotor slowing are typical features of psychotic and mood disorders, but to what extent they result from OS and immune changes is far from clear. When we look at catatonia as a case example, interesting findings point towards a role of the immune system: autoimmune encephalitis is often associated with catatonic features; a higher prevalence of catatonia has been demonstrated in winter months; increases in monocytes can be seen in catatonic patients irresponsive to lorazepam; and fever is present in some catatonic patients [38]. A case report describes the onset of catatonia after interferon treatment [39]. Furthermore, a mouse model of catatonia has been linked to mild inflammation of frontal white matter [40]. All these findings suggest a possible role of the immune system in the pathogenesis of catatonia. State and trait characteristics of these neurobiological abnormalities are another venue for research that can be explored. Finally, the use of peripheral markers can lead to diagnostical tools, especially when considering these psychiatric disorders as whole-body disorders, and may even define inflammatory subtypes of psychotic and mood disorders.

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