While the majority of these studies tested people already diagnosed with schizophrenia for T. gondii antibodies, associations between T. gondii and schizophrenia have been found prior to the onset of schizophrenia symptoms. Sex differences in the age of schizophrenia onset may be explained in part by a second peak of T. gondii infection incidence during ages 25–30 in females only. Although a mechanism supporting the association between schizophrenia and T. gondii infection is unclear, studies have investigated a molecular basis of this correlation. Antipsychotic drugs used in schizophrenia appear to inhibit the replication of T. gondii tachyzoites in cell culture. Supposing a causal link exists between T. gondii and schizophrenia, studies have yet to determine why only some individuals with latent toxoplasmosis develop schizophrenia; some plausible explanations include differing genetic susceptibility, parasite strain differences, and differences in the route of the acquired T. gondii infection.Correlations have also been found between antibody titers to T. gondii and OCD, as well as suicide among people with mood disorders including bipolar disorder. Positive antibody titers to T. gondii appear to be uncorrelated with major depression or dysthymia. Although there is a correlation between T. gondii and many psychological disorders, the underlying mechanism is unclear. A 2016 study of 236 persons with high levels of toxoplasmosis antibodies found that "there was little evidence that T. gondii was related to increased risk of psychiatric disorder, poor impulse control, personality aberrations or neurocognitive impairment".
Interactions
When combined with intravenous agalsidase alfa or beta, which are recombinant versions of the enzyme α-GalA, migalastat increases tissue concentrations of functional α-GalA compared to agalsidase given alone up to fivefold.Migalastat is not intended to be combined with agalsidase.Migalastat does not inhibit or induce cytochrome P450 liver enzymes or transporter proteins and is therefore expected to have a low potential for interactions with other drugs. Pharmacology
Mechanism of action
Fabry disease is a genetic disorder caused by various mutations of the enzyme α-GalA, which is responsible for breaking down the sphingolipid globotriaosylceramide (Gb3), among other glycolipids and glycoproteins. Some of these mutations result in misfolding of α-GalA, which subsequently fails protein quality control in the endoplasmic reticulum and is decomposed. Lack of functional α-GalA leads to accumulation of Gb3 in blood vessels and other tissues, with a wide range of symptoms including kidney, heart, and skin problems.Migalastat is a potent, orally available inhibitor of α-GalA (IC50: 4 μM). When binding to faulty α-GalA, it shifts the folding behaviour towards the proper conformation, resulting in a functional enzyme provided the mutation is amenable. Molecules with this type of mechanism are called pharmacological chaperones.When the enzyme reaches its destination, the lysosome, migalastat dissociates because of the low pH and the relative abundance of Gb3 and other substrates, leaving α-GalA free to fulfill its function. Depending on the mutation, the EC50 is between 0.8 μM and over 1 mM in cellular models.