Schizophrenia as parasitic behavior manipulation: can we put together the pieces of an evolutionary puzzle?
Authors: Martin Brüne
Journal: World Psychiatry (2020)

It is a disturbing fact that a diagnosis of schizophrenia is still associated with a poor prognosis concerning quality of life and community functioning, and that life expectancy of people with this diagnosis is reduced by about 14.5 years compared to the general population1. Over the last decades, this has changed very little, despite intensive research into drug development and psychological therapy. This calls for fresh ideas concerning the etiology of the disorder to pave the way for novel treatment approaches. Even though it is undisputed that schizophrenia is highly heritable, decades of research have failed to find a conclusive answer concerning its genetic biology. One of the few replicated findings is that genes pertaining to immunological competency play a significant role, particularly those involved in the major histocompatibility complex2. It is also unclear why predisposing genes have remained in the genepool, despite their detrimental effect on reproduction, thus rendering schizophrenia an "evolutionary enigma"3. Accumulating evidence suggests that some cases of schizophrenia are associated with a latent infection with Toxoplasma gondii, a protozoic agent known to affect warm-blooded animals4. In essence, individuals with T. gondii antibodies have a 2.7-fold elevated risk for schizophrenia compared to unaffected subjects, and the risk for schizophrenia associated with the infection by far exceeds the risk conveyed by any single gene putatively involved in the etiology of the disorder4. In light of figures suggesting that about two billion people worldwide are infected with T. gondii, and observations that the risk of infection with this agent relies on the genetic make-up of one's major histocompatibility complex2, there is a clear need for studying these associations in greater detail. The reproductive cycle of T. gondii is complex, with felines being the definitive host for sexual reproduction. The felines' feces contain oocysts, which can infect intermediate hosts by oral pathways. There, asexually produced bradyzoites travel to the brain, the heart and other organs, where they build cysts and remain for the host's lifetime. The reproductive cycle of T. gondii closes when felines feed on infected animals through predation. T. gondii has the potential to actively manipulate the intermediate host's behavior for its own reproductive benefit. Rodents infected with T. gondii, for example, display decreased vigilance for predators. Strikingly, infected rats lose their innate avoidance of cat urine odor. Instead, they seem to approach locations expressing cat (urine) odor in a "suicidal" manner, thus increasing their risk of predation. Experimental evidence from rodent studies suggests that the parasite manipulates the host's dopamine turnover and impacts on glutamatergic neural pathways, which is entirely consistent with the prevailing neurotransmitter models of schizophrenia5. But what about the behavioral manifestations of T. gondii infection in human hosts? Might schizophrenia be seen as a possible phenotypic expression of the parasite's manipulation? In fact, most researchers believe that human infection is an "accident" of T. gondii exposure4. From an evolutionary viewpoint, however, it is possible to argue that genetically vulnerable early humans (and their ancestors) were as logic a target to become an intermediate host as rodents now are. The manipulatory action of T. gondii in humans could have aimed at their exclusion from the social community, because in gregarious species like Homo sapiens individuals bare the greatest risk of predation when isolated from the social group6. Following this line of reasoning, many "core" symptoms associated with schizophrenia support the idea that the disorder may be the phenotypic correlate of manipulation by T. gondii ultimately promoting social exclusion. For example, social cognitive impairments lead patients to believe that others have malevolent intentions, thus giving way to paranoid ideation causing social withdrawal or aggression against the perceived perpetrator, which ultimately promotes marginalization of the individual. Negative symptoms such as affective flattening, apathy or abulia cause rejection from others, and many patients fail to experience social interaction as rewarding7. Together, it is possible to hypothesize that the typical signs and symptoms associated with schizophrenia may have served in the past the parasite's biological interests, i.e. to increase the risk of predation for its host by forcing the individual to leave or be expelled from his/her social community. Current therapeutic approaches to schizophrenia mainly depend on the anti-dopaminergic action of antipsychotic drugs. Interestingly, some antipsychotics possess anti-parasitic properties, due to chemical similarities to naturally occurring plant deterrents of parasites4. This invites speculations that drug efficacy in the treatment of schizophrenia might be related, in part, to the anti-parasitic effect of the medications. However, currently available drugs against T. gondii infection do not have the potential to ameliorate the symptoms of schizophrenia. Parasitic behavior manipulation is widespread in nature, yet under-researched as a causative factor of disease in humans. This is so because knowledge about parasite-host interaction and other evolutionary aspects germane to medicine still linger to be implemented in curricula at medical schools8. Thus, both clinicians and pharmaceutical companies are oblivious to putative mechanisms of parasitic action. However, if action were taken to follow up on the above evolutionary insights, one could see schizophrenia as an ancestral "vestige" from a time when early humans fell prey to large feline predators. Future research into schizophrenia may be advised to study the link between T. gondii infection, clinical symptomatology contributing to social exclusion, and genetic factors involving the major histocompatibility complex and other immunologically relevant genes such as DISC19, some of which have been positively selected during human evolution. It might eventually turn out that there is a chance of causal treatment for schizophrenia realized by the development of new antibiotics against latent toxoplasmosis, rather than (or in addition to) reiterating attempts to ameliorate epiphenomena of the condition.