Schizophrenia: the new etiological synthesis. Markus J. Rantala et al. Neuroscience & Biobehavioral Reviews, September 28 2022, 104894. https://doi.org/10.1016/j.neubiorev.2022.104894
Highlights
• Schizophrenia (SZR) is rare or nonexistent in hunter-gatherer populations
• Several microbial infections can trigger SZR
• SZR is associated with neuroinflammation and gut dysbiosis
• Parasite x genotype x stress interaction forms the new etiological synthesis for SZR
• Evolutionary mismatch explains SZR better than other evolutionary hypotheses
Abstract: Schizophrenia has been an evolutionary paradox: it has high heritability, but it is associated with decreased reproductive success. The causal genetic variants underlying schizophrenia are thought to be under weak negative selection. To unravel this paradox, many evolutionary explanations have been suggested for schizophrenia. We critically discuss the constellation of evolutionary hypotheses for schizophrenia, highlighting the lack of empirical support for most existing evolutionary hypotheses—with the exception of the relatively well supported evolutionary mismatch hypothesis. It posits that evolutionarily novel features of contemporary environments, such as chronic stress, low-grade systemic inflammation, and gut dysbiosis, increase susceptibility to schizophrenia. Environmental factors such as microbial infections (e.g., Toxoplasma gondii) can better predict the onset of schizophrenia than polygenic risk scores. However, researchers have not been able to explain why only a small minority of infected people develop schizophrenia. The new etiological synthesis of schizophrenia indicates that an interaction between host genotype, microbe infection, and chronic stress causes schizophrenia, with neuroinflammation and gut dysbiosis mediating this etiological pathway. Instead of just alleviating symptoms with drugs, the parasite x genotype x stress model emphasizes that schizophrenia treatment should focus on detecting and treating possible underlying microbial infection(s), neuroinflammation, gut dysbiosis, and chronic stress.
6. Critical evaluation of previous evolutionary hypotheses for schizophrenia
Many of these previous evolutionary hypotheses lack proper empirical validation (Fig. 2) and, above and beyond the critical discussion presented in this article, scientific approaches to schizophrenia would benefit from critical appraisals and rigorous research devising crucial experiments that pitch each hypothesis against one other (cf. Platt, 1964). Even though some of the previous evolutionary hypotheses presented above might explain some of the characteristic manifestations of psychosis or delusions and their relations to the genetics of schizophrenia, all of them—with the exception of the mismatch hypothesis—fail to provide a convincing explanation for the negative symptoms of schizophrenia such as blunting of affect, violent behavior, aggression, apathy, anhedonia, loss of motivation, or cognitive deficit. The hypotheses—with the exception of the mismatch hypothesis—also fail to explain impairments in executive functions typically observed in schizophrenic patients. In addition, the hypotheses have not been able to explain why schizophrenia is commonly comorbid with many other mental disorders (Buckley et al., 2009, Tsai and Rosenheck, 2013). Major depressive disorder, for instance, is a common psychiatric comorbidity in patients with schizophrenia. A recent meta-analysis found that 32.6% of patients with schizophrenia would meet the diagnostic criteria of major depressive disorder (Etchecopar-Etchart et al., 2021) and symptoms of major depressive disorder are common prodromal symptoms of psychosis (Hafner and an der Heiden, 2011). In addition, a 12-month follow-up study found that 80% of patients with first-episode psychosis would also fulfill the diagnostic criteria of major depressive disorder (Upthegrove et al., 2010). Psychosis may also occur in patients with major depressive disorder, bipolar disorder, and schizoaffective disorder (Dubovsky et al., 2021), highlighting that these disorders are not completely separate entities. The comorbidity of these disorders is most elegantly explained by the parasite hypothesis of schizophrenia presented in Section 2, as well as their shared genetic basis (Anttila et al., 2018; Hindley, 2021; Legge et al., 2021). These disorders are characterized by sickness behavior that is caused either by the activation of the immune system via low-grade systemic inflammation (Rantala et al., 2018, Rantala et al., 2021) or direct manipulation of host behavior by parasites (Borráz-León et al., 2021).
Schizophrenia is not a discrete disorder and separating it from other disorders is often difficult. This makes all previous evolutionary hypotheses (except the mismatch hypothesis) somewhat problematic. The classification of these disorders is often difficult because of overlapping symptoms, which may result in a patient receiving different diagnoses from different psychiatrists. Hallucinations and delusions occur also in patients with bipolar disorder and Alzheimer’s disease. About half of Alzheimer’s patients have psychosis (Murray et al., 2014) and a study on 1 342 patients with bipolar disorder type I found that 73.8% had a lifetime prevalence of psychotic symptoms (van Bergen et al., 2019). A plausible scientific framework would also explain occurrences of psychosis, delusions, and hallucinations in other disorders, not just in schizophrenia. The parasite hypothesis is able to explain why psychosis may occur in other disorders: differences in the parasite species that individuals are infected with, differences in timing of infection, genetic vulnerability, and microbiota may explain whether a person will have symptoms of schizophrenia or, say, bipolar disorder, or depression with psychotic features (see Section 2.3).
Schizophrenia has traditionally been classified into different subtypes that differ in symptomatology. The prevalence of these subtypes varies geographically and by time (Jablensky et al., 1992). Schizophrenia is not a single disorder. Instead, it seems that schizophrenia is only an umbrella term for a group of separate disorders with some overlapping symptoms. None of the previous evolutionary explanations for schizophrenia have explained the heterogeneous subtypes of schizophrenia and their persistence in modern human populations—although the mismatch hypothesis and the balanced polymorphism hypothesis could conceivably account for these findings. The parasite hypothesis, in contrast, provides an explanation for the heterogeneity by suggesting that it results from different parasite/pathogen species causing schizophrenia and/or individual differences in responses to microbial infections (see Section 2).
With the exception of the mismatch hypothesis, all previous evolutionary hypotheses also fail to provide a rationale for why and how neuroinflammation plays a role in schizophrenia (see Section 2.1.) and why there are inflammatory marker subtypes in schizophrenia (see e.g., Lizano et al., 2021). The parasite hypothesis, in combination with the mismatch hypothesis, explains why neuroinflammation occurs in schizophrenia and why there are different inflammatory marker subtypes. The parasite x genotype x stress model also explains why schizophrenia is more common in cities than in rural areas (see Section 3). Since chronic stress—which is often a triggering factor in psychosis—is rare among people with hunter-gatherer lifestyle(s) (Brenner et al., 2015), the parasite x genotype x stress model, coupled with the mismatch hypothesis, explains why schizophrenia is rare among them (cf. (Abed and Abbas, 2011b). Except for the mismatch hypothesis, previous evolutionary hypotheses for schizophrenia have not been able to explain why schizophrenia is more common in people with modern western lifestyles and why exposure to natural environments in neighborhoods or around residential areas is associated with lower schizophrenia rates (Engemann et al., 2019, Engemann et al., 2020, Kristine et al., 2018).
None of the previous evolutionary hypotheses have been able to explain why adverse life events play an important role in the onset of schizophrenia and psychosis. For example, exposure to childhood trauma is associated with a 2- to 3-fold increase in risk of psychotic outcomes (Croft et al., 2019, Rokita et al., 2021, Trotta et al., 2015). Likewise, cumulative stress pathophysiology is often a triggering factor in psychosis (Nugent et al., 2015), and cortical stress regulation is disrupted in patients with schizophrenia (Schifani et al., 2018). There are also differences in gut microbiota between healthy people and those with schizophrenia (Section 4). These observations do not fit well with previous evolutionary hypotheses for schizophrenia, with the exception of the mismatch hypothesis. Thus, most existing evolutionary hypotheses do not explain empirical findings about schizophrenia and have acquired limited empirical support of their own. The parasite x genotype x stress model, in contrast, suggests that stress negatively impacts immune function and thereby facilitates parasitic/pathogenic effects on the brain (see Section 2).
Many of the previous evolutionary explanations of schizophrenia are examples of evolutionary storytelling: they provide adaptive explanations for a phenomenon which is neither adaptive nor an adaptation, but rather a pathological side effect of microbial infection and chronic stress. Although the parasite x genotype x stress model can explain the occurrence of schizophrenia at one level of analysis, the sexual selection hypothesis (Nettle, 2001), the reformulated social brain hypothesis (Abed and Abbas, 2011b), and the life history hypothesis of schizophrenia (Del Giudice, 2010, 2017; Del Giudice et al., 2014) may partly explain why genetic variants that interact with pathogen infection and chronic stress (Fig. 1) may exist in the human gene pool in the first place. Furthermore, the mismatch hypothesis is an integral component of the parasite x genotype x stress model; environmental mismatch, after all, leads to the chronic stress that makes individuals with contemporary western lifestyles more susceptible to schizophrenia than those with traditional lifestyles (Fig. 1). Despite the abundant evidence supporting the parasite x genotype x stress model coupled with the environmental mismatch hypothesis of schizophrenia, it is also possible that future research will discover other hypotheses at proximate and ultimate levels of analysis that more accurately carve the biopsychosocial nature of schizophrenia at its joints.
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