The association between cats and lunacy is a common one in pop culture. Think of James Bond’s villain Ernst Stavro Blofeld (Number 1) and his cat, or Inspector Gadget’s Doctor Claw and M.A.D. Cat; or think of Dr. Eleanor Abernathy, the Crazy Cat Lady from The Simpsons. Is it somehow stored in our collective unconscious that cats go hand in hand with mental illness? Where did this perception come from? Is there a reason? Apparently, yes. It turns out that this association may not be totally random.

The parasite Toxoplasma gondii is mostly known for causing the disease toxoplasmosis. The only known definitive hosts (hosts in which a parasite reproduces sexually) for Toxoplasma are felids, such as domestic cats and their relatives. Its sexual reproduction leads to the formation of oocysts, which are encysted or encapsulated structures in which spores develop and that serve to transfer them to new hosts. These oocysts can then be shed in cats’ feces; they then take 1-5 days to sporulate in the environment and become infective.

Most species of warm blooded animals, including humans, can be intermediate hosts (hosts where its replication is asexual) for Toxoplasma and can become infected by ingestion of contaminated material. Shortly after ingestion, oocysts evolve into a rapidly multiplying stage named tachyzoite until the immune system of the host subdues the parasite. These tachyzoites accumulate in neural and muscle tissue and then transform into a slow replicating stage celled bradyzoite, forming intracellular cysts in muscle, liver, and neuronal cells, there residing in a latent stage most likely for the rest of the host’s life.

Animals destined for human consumption may become infected with tissue cysts after ingestion of sporulated oocysts in the environment. Humans can therefore become infected by eating undercooked meat of infected animals, or by consuming other contaminated food or water; other routes of infection are contact with cat feces or contaminated environmental samples (such as the litter box of a pet cat, for example), blood transfusion or organ transplantation, and transplacental transmission from mother to fetus.

In the human host, the parasites also form tissue cysts, most commonly in skeletal muscle, myocardium, brain, and eyes. In healthy humans, it is mostly inoffensive, causing asymptomatic latent infections and being easily controlled by the immune system. However, it may cause serious health problems to pregnant women and immunocompromised individuals, including brain damage.

Lately, a substantial amount of evidence has been suggesting that latent toxoplasmosis can cause behavioral changes in humans. The existence of this association has actually been suspected since the 1950s, or even earlier, but that hypothesis was revamped in the 1990s by studies highlighting a common risk factor between toxoplasmosis and schizophrenia: contact with cats. Currently, the available evidence for this association is massive.

Research has shown that schizophrenia patients have a significantly higher prevalence of Toxoplasma gondii in their serum; likewise, having anti-Toxoplasma antibodies significantly increases the likelihood of being diagnosed with schizophrenia. Toxoplasma infections preceding the development of schizophrenia are widely described, and this association gets stronger throughout disease progression. Furthermore, a higher severity of schizophrenia-associated symptoms has been reported in patients that have been infected with the parasite.

However, given that up to half of the world’s human population is estimated to carry a Toxoplasma infection, it is safe to assume that the simple presence of Toxoplasma is not the determining factor per se. Indeed, studies evaluating the correlation between the serum intensity of Toxoplasma in schizophrenia patients compared to controls indicate that either a more active infection or a stronger immune response may be a causal factor in the development of schizophrenia.

An association between the immune system and psychoses has been extensively demonstrated, either through glial activation, altered serum levels of cytokines, changes in enzymes of immuno-modulatory pathways, or immuno-genetic markers. Similarly, the type of immune response in patients with schizophrenia to Toxoplasma infection has been linked to several deleterious effects associated with the disease. Interestingly, some antipsychotic drugs seem to have anti-toxoplasmic activity, with this action potentially contributing to their antipsychotic efficacy.

Regarding this neuroinflammation hypothesis, there are many findings that support it in the context of schizophrenia. Glial cell activation, a key mechanism in various inflammatory conditions in the nervous system, has been increasingly recognized as a relevant element in the pathophysiology of schizophrenia, having been experimentally demonstrated in vivo. Glial cells play a role in managing Toxoplasma infections in the brain, most likely through the immuno-modulatory pathways known to be altered in psychotic conditions. Astrocytes and microglial cells seem to be able to inhibit Toxoplasma replication; on the other hand, the production of the cytokine interleukine-6 (IL-6) by macrophages seems to revert this inhibition, and IL-6 has consistently been found to be overproduced in schizophrenia patients.

A considerable amount of schizophrenia susceptibility genes are implicated in the life cycle of pathogens such as Toxoplasma gondii, with these genes having a role not only in immunity, but also in influencing signaling pathways that regulate dopamine-dependent behavior, for example.

Therefore, another hypothesis explaining the link between Toxoplasma infection and schizophrenia establishes a role for dopamine in these mechanisms. An effect of Toxoplasma infection on increasing the dopamine levels has been experimentally demonstrated in vitro and in mice. Accordingly, dopamine-blocking agents have shown some efficacy in the treatment of this pathology.

However, dopamine and immunological disturbances are not unique to schizophrenia, within the realm of psychiatric disorders. Both have been reported in other pathologies, namely in bipolar disorder and obsessive-compulsive disorder (OCD). On the other hand, no link has so far been found with major depression. Although evidence linking Toxoplasma gondii infection with bipolar disorder and OCD is still less striking, there are indeed indications that it may also be a risk factor in the development of these disorders.

References

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Image via Vinogradov Illya / Shutterstock.