Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii 's ability to alter host behaviour

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Abstract

With increasing pressure to understand transmissible agents, renewed recognition of infectious causation of both acute and chronic diseases is occurring. Epidemiological and neuropathological studies indicate that some cases of schizophrenia may be associated with environmental factors, such as exposure to the ubiquitous protozoan Toxoplasma gondii. Reasons for this include T. gondii's ability to establish persistent infection within the central nervous system, its ability to manipulate intermediate host behaviour, the occurrence of neurological and psychiatric symptoms in some infected individuals, and an association between infection with increased incidence of schizophrenia. Moreover, several of the medications used to treat schizophrenia and other psychiatric disease have recently been demonstrated in vitro to possess anti-parasitic, and in particular anti-T. gondii, properties. Our aim here was thus to test the hypothesis that the anti-psychotic and mood stabilizing activity of some medications may be achieved, or at least augmented, through their in vivo inhibition of T. gondii replication and invasion in infected individuals. In particular we predicted, using the epidemiologically and clinically applicable rat-T. gondii model system, and following a previously described and neurologically characterized 'feline attraction' protocol that haloperidol (an anti-psychotic used in the treatment of mental illnesses including schizophrenia) and/or valproic acid (a mood stabilizer used in the treatment of mental illnesses including schizophrenia), would be, at least, as effective in preventing the development of T. gondii-associated behavioural and cognitive alterations as the standard anti-T. gondii chemotherapeutics pyrimethamine with Dapsone. We demonstrate that, while T. gondii appears to alter the rats' perception of predation risk turning their innate aversion into a 'suicidal' feline attraction, anti-psychotic drugs prove as efficient as anti-T. gondii drugs in preventing such behavioural alterations. Our results have important implications regarding the aetiology and treatment of such disorders.

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Severe acquired toxoplasmosis in immunocompetent adult patients in French Guiana.

C Aznar, R Bouyne, M Bourbigot … (2002)

The most common presentation of symptomatic postnatally acquired toxoplasmosis in immunocompetent patients is painless cervical adenopathy. Acute visceral manifestations are associated in rare cases. We report 16 cases of severe primary toxoplasmosis diagnosed in French Guiana during a 6.5-year period. All of the subjects were immunocompetent adults hospitalized with clinical presentations consisting of a marked, nonspecific infectious syndrome accompanied by an altered general status with at least one visceral localization, mainly pulmonary involvement (14 cases). Acute toxoplasmosis was diagnosed according to the results of serological tests suggestive of recent primary infection and the absence of an alternative etiology. Recovery was rapid following specific antitoxoplasmosis treatment. Thirteen of the 16 patients had consumed game in the 2 weeks before the onset of the symptoms, and in eight cases the game was considered to have been undercooked. Toxoplasma strains, which were virulent in mice, were isolated from three patients. Microsatellite analysis showed that all of these isolates exhibited an atypical multilocus genotype, with one allele found only for isolates of this region.

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Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy.

José Nobrega, Shitij Kapur, Johanna C. vanderSpek … (2003)

What is the appropriate dose of an antipsychotic in an animal model? The literature reveals no standard rationale across studies. This study was designed to use in vivo dopamine D(2) receptor occupancy as a cross-species principle for deriving clinically comparable doses for animal models. The relationship between dose, plasma levels, and in vivo dopamine D(2) receptor occupancy was established in rats for a range of doses administered as a single dose or multiple doses (daily injections or osmotic minipump infusions) for five of the most commonly used antipsychotics. As a single dose, haloperidol (0.04-0.08 mg/kg), clozapine (5-15 mg/kg), olanzapine (1-2 mg/kg), risperidone (0.5-1 mg/kg), and quetiapine (10-25 mg/kg) reached clinically comparable occupancies. However, when these "optimal" single doses were administered as multiple doses, either by injection or by a mini-pump, it led to no or inappropriately low trough (24-h) occupancies. This discrepancy arises because the half-life of antipsychotics in rodents is 4 to 6 times faster than in humans. Only when doses 5 times higher than the optimal single dose were administered by pump were clinically comparable occupancies obtained (e.g., haloperidol, 0.25 mg/kg/day; olanzapine, 7.5 mg/kg/day). This could not be achieved for clozapine or quetiapine due to solubility and administration constraints. The study provides a rationale as well as clinically comparable dosing regimens for animal studies and raises questions about the inferences drawn from previous studies that have used doses unrepresentative of the clinical situation.