VIII. Treatment Approaches to Toxoplasmosis and Schizophrenia
§ Background: Protozoa
Antipsychotic medications have been shown to have antiprotozoal activity. As early as 1891, it was reported that the phenothiazine dye methylene blue killed Plasmodium vivax, one causative agent of malaria (Guttman P, Ehrlich P, Über die wirkung des Methylenglau bei Malaria, Berl Klin Wochenschr 1891;39:953–956). In more recent years, in vitro studies have shown that phenothiazines such as chlorpromazine inhibit the growth of Tetrahymena pyriformis (Forrest IS, Quesada F, Deitchman GL, Unicellular organisms as model systems for the mode of action of phenothiazine and related drugs, Proc West Pharmacol Soc 1963;6:42–44); Paramecium spp. (Saitow F, Nakaoka Y, The photodynamic action of methylene blue on the ion channels of Paramecium causes cell damage, Photochem Photobiol 1997;65:902–907); Leishmania donovani (Pearson RD, Manian AA, Hall D et al., Antileishmanial activity of chlorpromazine, Antimicrob Agents Chemother 1984;25:571–574); Trypanosoma brucei and Trypanosoma cruzi (Benson TJ, McKie JH, Garforth J et al., Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures, Biochem J 1992;286:9–11; Gutierrez-Correa J, Fairlamb AH, Stoppani AO, Trypanosoma cruzi trypanothione reductase is inactivated by peroxidase-generated phenothiazine cationic radicals, Free Radic Res 2001;34:363–378; Seebeck T, Gehr P, Trypanocidal action of neuroleptic phenothiazines in Trypanosoma brucei, Mol Biochem Parasitol 1983;9:197–208); Plasmodium falciparum (Kristiansen JE, Jepsen S, The susceptibility of Plasmodium falciparum in vitro to chlorpromazine and the stereo-isometric compounds cis(Z)- and trans(E)-clopenthixol, Acta Pathol Microbiol Immunol Scand B 1985;93:249–251); and Entamoeba histolytica (Ondarza RN, Hernandez E, Itrube A et al., Inhibitory and lytic effects of phenothiazine derivatives and related tricyclic neuroleptic compounds on Entamoeba histolytica HK9 and HM1 trophozoites, Biotechnol Appl Biochem 2000;32:61–67). In addition, an in vivo study reported that chlorpromazine ointment was effective in treating cutaneous leishmaniasis (Henriksen T-H, Lende S, Treatment of diffuse cutaneous leishmaniasis with chlorpromazine ointment (letter), Lancet 1983;i:26).
The first report of antipsychotic inhibition of Toxoplasma gondii was an in vitro study using the phenothiazine trifluoperazine (Stelazine), which was said to have “membrane-active detergent-like effects” on T. gondii (Pezzella N, Bouchot A, Bonhomme A et al., Involvement of calcium and calmodulin in Toxoplasma gondii tachyzoite invasion, Eur J Cell Biol 1997;74:92–101). An extensive in vitro study of eight antipsychotics and metabolites and four mood stabilizers compared their effectiveness in inhibiting T. gondii against the effectiveness of trimethroprim, a standard treatment for toxoplasmosis. Haloperidol was more effective than trimethoprim. Valproic acid and sodium valproate were equally effective to trimethoprim. Chlorpromazine, fluphenazine, risperidone, clozapine, quetiapine, and carbamazapine all showed some activity but less than trimethoprim. Lithium showed no inhibition of T. gondii (Jones-Brando L, Torrey EF, Yolken R, Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii, Schizophr Res 2003;62:237–244).
§ Trials of drugs known to be effective against T. gondii on patients with schizophrenia
§ azithromycin (Zithromax) 600 mg: 56 outpatients with schizophrenia;
double-blind, placebo trial; 16 weeks; add-on to regular antipsychotic;
negative study (Dickerson et al., Sheppard Pratt Hospital, Baltimore).
§ trimethoprim 200 mg: 91 male outpatients with mostly chronic schizophrenia;
double-blind, placebo trial; 6 months; add-on to chlorpromazine or haloperidol.
Both groups improved markedly, perhaps reflecting being on a regular
antipsychotic with monitoring and follow-up. The trimethoprim group improved
more on the negative symptom subscale, but the difference did not achieve
statistical significance (Shibre et al., Butajira, Ethiopia, being submitted for publication).
§ trimethoprim 160 mg–sulfamethoxazole 800 mg (Bactrim DS): 80 inpatients
with chronic schizophrenia; open-label; 16 weeks; add-on to regular medication.
Bactrim group showed more improvement at 8 weeks but not at 16 weeks
(Desta et al., Addis Ababa, Ethiopia).
§ trimethoprim 480 mg–sufamethoxazole 2400 mg (Bactrim): 82 schizophrenia
and 61 bipolar patients; double-blind, placebo trial; 6 weeks; add-on to
flexible-dose risperidone 1–6 mg; Bactrim improved psychotic symptoms but
just short of statistical significance (p=0.059); patients on Bactrim needed
significantly lower doses of risperidone (Quiying et al., Wuhan, China).
§ pyrmethamine 75 mg–sufadiazine 2 g (Fansidar): 14 patients with acute schizophrenia; double-blind, placebo trial; 14 days; add-on to regular antipsychotic; both groups improved; numbers too small to do meaningful analysis (Hinze-Selch et al., Germany)